Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Mar 30, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley from the VCU Health Pauley Heart Center in Richmond, Virginia. Well, Carolyn, we've got a great feature article this week, evaluating do we wait or do we do now ablation of ventricular tachycardia in patients with ischemic cardiomyopathy and implantable defibrillators? But before we get to that, how about if we grab our coffee or whatever it may be and jump into the other articles?

Dr Carolyn Lam:               Sure. Well, Greg, have you ever wondered what the outcomes are of transcatheter aortic valve replacement, or TAVR, in patients with bicuspid aortic valve stenosis? Now, remember, patients with bicuspid aortic valve stenosis were excluded from the pivotal evaluations of TAVR.

Dr Greg Hundley: I wondered that yesterday, Carolyn.

Dr Carolyn Lam: Well, guess what, Greg, it's your lucky day because we're going to get answers now from corresponding author Dr Brennan from DCRI and coauthors who use data from the Society of Thoracic Surgeons, American College of Cardiology, TAVR registry from 2011 to 2018 to determine the device success procedural outcomes, post-TAVR valve performance and in-hospital clinical outcomes in almost 171,000 eligible procedures, of which 5,412 TAVR procedures were performed in bicuspid aortic valve patients, including 3,705 with current generation devices.

Dr Greg Hundley: Wow. Carolyn, this sounds to me like probably one of the largest collections of patients that have had TAVR and bicuspid valves. What did they find?

Dr Carolyn Lam: Well, compared to patients with tricuspid aortic valves, bicuspid aortic valve patients were younger and had a lower STS predicted risk of operative mortality score, so you have to bear that in mind first. With the current generation TAVR devices, the incidence of device success was only slightly lower for bicuspid versus tricuspid aortic valve patients and residual two-plus aortic insufficiency remains slightly higher, though, for bicuspid versus tricuspid aortic valve patients.

There was no difference in adjusted one-year hazard of stroke in patients with bicuspid versus tricuspid valves, but the adjusted one-year hazard of mortality was lower among bicuspid aortic valve patients. Thus, using current generation technology, TAVR appears both safe and effective for the treatment of bicuspid aortic valve stenosis, although there remains a low incidence of moderate or greater aortic insufficiency among both bicuspid and tricuspid aortic valve patients.

Dr Greg Hundley: Very nice. Well, Carolyn, do you ever wonder how white cells are recruited into areas of the heart that have sustained a myocardial infarction?

Dr Carolyn Lam: Every day, Greg. Every day I think about that.

Dr Greg Hundley: You know, we've got so much wondering on your side of the world and on my side of the world, but if we connect that we will solve a lot of things. Well, this paper is from Dr Prabhakara Nagareddy from Ohio State University. This group of investigators used a mouse model involving ligation of the LAD and flow cytometry to characterize the temporal and spatial effects of myocardial infarction on different myeloid cell types, a process termed myelopoiesis, that results in heightened production of neutrophils.

The investigators sought to understand the mechanisms that sustain white blood cell production in recruitment to the injured heart using global transcriptome analysis of different cardiac cell types within the infarct. In addition, just as these clever circulation papers do, also a human subject study was performed utilizing a combination of genetic and pharmacologic strategies. The authors identified the sequela of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography and the association of early indices of neutrophilia with major cardiac events, or MACE, was studied in those patients sustaining an MI.

Dr Carolyn Lam: Wow, that's a huge amount of work. What was the bottom line results?

Dr Greg Hundley: So, first, in the patients with acute coronary syndromes, a higher neutrophil count on admission and post-revascularization correlated positively with major adverse cardiovascular disease outcomes. And then, second, from the basic science component, the study identified novel evidence for the primary role of neutrophil-derived alarmins and, in particular in this study, S100A8-A9 in dictating the nature of the ensuing inflammatory response following myocardial injury.

Therapeutic strategies aimed at disruption of this S100A8-A9 signaling, or its downstream mediators in neutrophils, were shown to suppress granulopoiesis and therefore, perhaps in the future, could improve cardiac function in those patients sustaining an acute coronary syndrome. Really elegant work. That combination of the basic science in the animal model and then the translational work in the human subject model.

Dr Carolyn Lam: Exactly what I was going to say. Translational work. Well, hold onto your seat because this next one is super cool, too. It is the first time a pre-clinical development and first in human proof-of-concept of peritoneal direct sodium removal using a zero-sodium solution as a candidate therapy for volume overload. So, as a background, remember that loop diuretics have been well described to have toxicities and that loss of response to these agents are common when we try to treat volume overload. So alternative strategies are clearly needed for the maintenance of euvolemia in heart failure.

These authors, led by Dr Testani from Yale University hypothesized that non-renal removal of sodium directly across the peritoneal membrane, that is called direct sodium removal, using a sodium-free osmotic solution should result in extraction of large quantities of sodium with limited off-target solute removal. So what they did is they performed porcine experiments followed by a human study in which participants with end-stage renal failure on peritoneal dialysis underwent randomization and crossover to either a two-hour dwell with one liter of this direct sodium removal solution or a standard peritoneal dialysis solution. Sodium-free 10% dextrose, by the way, was utilized as the direct sodium removal solution.

Dr Greg Hundley: Boy, Carolyn, this is really another one of these elegant translational studies. So we have the animal model, we have the human subjects and then we have different concentrations of these peritoneal fluid that are injected and then extracted for dialysis. I can't wait to hear. So what did they find?

Dr Carolyn Lam: First, cycling a sodium-free osmotic solution that's a 10% dextrose across the peritoneal cavity of swine resulted in substantial sodium removal. So, proof of principle there. The sodium removal increased proportionately as the volume of 10% dextrose cycled across the peritoneum increased. Experimental elevation of right-sided cardiac filling pressures also resulted in substantial increased sodium removal with this technique. Now, in the humans, a single dose of sodium-free 10% dextrose was well tolerated in human subjects and resulted in over four-fold greater sodium removal than the strongest commercially available peritoneal dialysis solution.

So, direct sodium removal with a sodium-free osmotic peritoneum solution represents a new potential therapy for non-renal sodium and fluid removal in edematous disorders such as heart failure. However, there is a long way to go in deploying such a procedure in the heart failure population. And this is really highlighted and discussed in an accompanying editorial by Dr Robert Toto from UT Southwestern.

Dr Greg Hundley: Fantastic. Carolyn. Bob Toto always puts things really in perspective. That'll be a great read. Well, let me tell you about a couple other articles in this issue. Dr Bina Ahmed from Santa Barbara Cardiovascular Group has a very nice on-my-mind piece getting at this issue of how we should, as physicians, be reacting to the healthcare issues. Also, particularly in cardiovascular disease, as they occur in the face of climate crisis. A great read. Then there's a beautiful adult learning excerpt put together by Dr Daniel Kramer from the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center.

It involves a patient that presents with some symptomatology associated with their thoracic spine. They have to undergo an MRI. They've got an implanted device. How do you work through that? What do we need to do with anticoagulation? It turns out the patient also may need a Watchman device. Who is a candidate for that? Boy, it's just a great educational read.

Carolyn, there is a lot in the mailbag this week. Professor John Madias from the Icahn School of Medicine at Mount Sinai and Dr Adaya Weissler-Snir from the Hartford Hospital and University of Connecticut exchanged some letters regarding the article previously published on hypertrophic cardiomyopathy-related sudden cardiac death in young people in Ontario.

Robin Woods from Monash University has a research letter involving no modulation of aspirins effect by body weight in healthy older men and women. And then Myra Lipes from the Joslin Diabetes Center Harvard Medical School has a research letter entitled the Cardiac Autoimmunity is Associated with Subclinical Myocardial Dysfunction in Patients with Type 1 Diabetes.

Dr Carolyn Lam: And I'll add one more research letter by Dr Dempsey on prospective associations of accelerometer-measured physical activity and sedentary time with incident cardiovascular disease, cancer and all-cause mortality. So something that's really a hot topic now. Man, that has been a great issue. But let's move on to our feature discussion, shall we?

Dr Greg Hundley: You bet. Well, listeners, welcome to this feature discussion where we're going to understand a little bit more about ICDs and ventricular tachycardia and we have Dr Karl-Heinz Kuck from the University Hospital of Lübeck. We have Francis Marchlinski from the University of Pennsylvania and we have Dr Sammy Viskin, our own associate editor from the Tel Aviv Medical Center. What a great study. So, Karl, I'd like to start with you. Can you give us a little bit of background about why you wanted to perform the study and what was your hypothesis?

Dr Karl-Heinz Kuck: There is an ongoing debate in clinical electrophysiology, what would be the optimal timing of catheter ablation in patients with ventricular tachycardia and ventricular fibrillation. Now, until today, most patients come to catheter ablation at a very late stage of the disease, mostly after multiple ICD shocks. So the patients are in a very bad condition and our strong feeling is the patients should undergo, much early, a successful catheter ablation.

The study was initiated with the background that we, and others, have shown that a very catheter ablation, which is before any ICTD shock, a so-called preventative ablation, is superior with respect to clinical endpoints as compared to optimal medical treatment. That's number one. And number two is that we know from retrospective analysis of multiple ICD studies that ICD shocks increase mortality as compared to patients with ICDs that have no shocks.

So, on one side we have the benefit of a preventive ablation which has been shown in three randomized trials, and on the other side we know that ICD shocks increase mortality. So somewhere in between multiple ICD shocks and no shock should be the benefit of catheter ablation and this, exactly, was the background of the BERLIN-VT Trial to investigate whether a very only catheter ablation study, which is after the first episode of VT/VF, before any ICD shock, would be superior as compared to having an ICD implanted and follow the patients and then ablate the patients after an arbitrary taken number that we set to three ICD shocks. We were looking then for a combined clinical endpoint to see whether there is any benefit of prophylactic, or preventative, ablation versus what we call deferred catheter ablation.

Dr Greg Hundley: Can you tell us about the BERLIN-VT? What was your study population? A little bit about the design.

Dr Karl-Heinz Kuck: Yeah. The patients that we investigated were patients only with ischemic cardiomyopathy who would had a previous myocardial infarct, to reduce the number of interventions that would require an epicardial access in that patient population. That's number one. And number two, the patients should have an ejection fraction above 35 because a previous study that we have done, the VTACH Study showed that there was no benefit of catheter ablation in patients with a very low ejection fraction, so this was the patient population that we were looking. And then patients had to have had at least one episode of VT/VF before they were randomized either into preventive ablation or into deferred ablation.

Dr Greg Hundley: How many participants were in your study? And then tell us a little bit about the study results.

Dr Karl-Heinz Kuck: We randomized the 76 patients to preventive ablation, and 83 patients do differed ablation. The number, we originally thought to be higher, but we had redesigned interim analysis and after the second interim analysis at the DSMV, we commanded to terminate the trial for futility. And at that point in time when the study was terminated, these numbers were included, which was almost two thirds of the patients which were originally included in to the front.

Dr Greg Hundley: What were your results?

Dr Karl-Heinz Kuck: Now, which respect to the endpoint of the trial, which was the primary endpoint, which was a composite endpoint of all-cause mortality and unplanned re-hospitalizations for worsening of heart failure or ventricular arrhythmias, we did not find any significant difference between the preventive and the deferred ablation group. Actually, after 12 months, there were 21% of patients in the differed, and 27% in the preventive ablation group, and these numbers almost doubled over two years but didn't show any difference.

So with respect to the components of the combined endpoint, we also didn't see any significant difference with respect to overall mortality, hospitalization for worsening of heart failure and hospitalization for worsening of ventricular tachycardia or ventricular fibrillation, despite the fact that there was a strong trend to a reduction of hospitalization for VT/VF in the preventive group as compared to the deferred group.

But this was fully compensated for the primary endpoint by an increase of hospitalizations, early hospitalizations after ablation for worsening of heart failure and a somewhat higher mortality rate in the preventive group as compared to the deferred group, which I believe was really bad luck because almost none of the six [inaudible 00:17:12] in the preventive group died due to cardiovascular reasons. Whereas most patients in the deferred group died because of ventricular tachycardia, ventricular fibrillation.

Now, what is interesting to mention is that with respect to the secondary endpoint, which is sustained VT and VF and appropriate ICD therapy, there was a significant benefit of preventive catheter ablation as compared to deferred catheter ablation but, as I mentioned before, this could not be translated into a benefit with respect to clinical outcome in the trial.

Dr Greg Hundley: Thank you, Dr Kuck. Dr Marchlinski, could you help us put this in perspective as we're thinking about patients with ischemic heart disease that we are considering implantation of an ICD?

Dr Frank Marchlinski: Yes, definitely. First, I like to congratulate the investigators. This is a real tour de force, a lot of effort, multiple centers involved. Dr Willems, Dr Kuck, congratulations because this is an important effort. I think that one needs to realize, of course, that it is our goal to try to eliminate VT with the hope that we're going to improve mortality outcome in addition to improving quality of life. It's a worthwhile goal. I hope someday we will achieve it and that we'll be able to use ablative therapy very early in the course, even in advance of ICD implantation and potentially even to prevent ICDs. That's a worthwhile goal and something that we all need to target as investigators in this area.

But Dr Kuck's study demonstrated that we're not there yet to use it as very early in the course of a disease before patients manifest a lot of arrhythmia recurrences. One thing is for certain, though. This study, although important in suggesting that we need to take our time in terms of planning to do the ablation procedure, we don't want to delay. There's enough evidence to say that repeated shocks can increase mortality, as Dr Kuck pointed out, and enhance a bad outcome.

It certainly provides a very poor quality of life for the patient to experience these shocks, so we need to consider the timing of when it's appropriate, when patients begin to experience ICD shocks after receiving a defibrillator and not wait for repeated shocks, not wait for excessive dosing with Amiodarone, but rather to intervene in a timely fashion after a patient begins to get the shock therapy. It was clear that even the BERLIN-VT investigators didn't wait for multiple additional shocks. As soon as patients received one or two shocks, they got enrolled in this study, this is the deferred limb, and took advantage of the effectiveness of ablation to reduce the number of VT episodes.

Dr Greg Hundley: Sammy, now back to you. What study do we need to perform next in this field? How do you think the results here guide us moving forward with research in this area?

Sammy Viskin: As Frank said, in [inaudible 00:20:25], it is very important that patients are not referred too late for ablation when they arrive after many shocks and they're already, sometimes even encouraged to getting shocks. The present study shows that perhaps they should not be referred for ablation too early at this point, at least not until we get better with our ablation techniques. So we need studies on how to improve our ablation techniques. They keep getting better, but they still have a long way to go. And then we should be able to define the optimal time when it's not too early and when it's not too late to perform the ablation procedure.

Dr Karl-Heinz Kuck: I agree with all of what had been said. I just would like to mention that the study, the BERLIN-VT Study compared, actually, very early catheter ablation versus early catheter ablation. We just wanted to know whether very early ablation is better than early because I think that all the three physicians here, the three electrophysiologists, would agree that we would be happy if most of the patients would even be sent after the second or third shock. Many patients having multiple more shocks before they are sent for catheter ablation.

So, in this sense, the BERLIN-VT Study was an aggressive study because they did not allow patients to be sent after the 10th shock, after the 15th shock, after an electrical storm. So we are comparing very early versus early ablation and I'm not giving up, like Frank Marchlinski was saying. I'm not giving up on the idea.

Sammy is saying we are not yet there, but we should continue to prove that an early ablation is superior to a late ablation. But BERLIN-VT did not look at the very late ablation component of the strategy here. I think what this study shows and what all the other studies also show how difficult it is, in the field of VT/VF and severely diseased patients, to do such a randomized trial. We have a lot of problems to enroll these patients and therefore, I was glad that we could at least get some information out of the trial.

I'm still supporting the idea that the international community should work closer together in the field of catheter ablation of ventricular tachycardia and ventricular fibrillation so that we could increase the number of patients within a rather short period of time that should be included in these VT ablation trials. That's, I think, another learning that I've done from this trial but also from some of the other trials that we and others have done in the field.

Dr Greg Hundley: Well, listeners, we want to thank Dr Karl Kuck from University of Lübeck in Germany, Dr Frank Marchlinski from University of Pennsylvania, and Dr Sammy Viskin from Tel Aviv Medical Center. We've really heard some insightful results related to ICD placement and those with ischemic heart disease from the BERLIN-VT Study. It really emphasizes the importance of, as we move forward, international collaborations when we're trying to study this patient population.

Well, on behalf of Carolyn and myself, we wish you a great week and look forward to chatting with you and grabbing a cup of coffee next week. Take care. Of this program is copyright of the American Heart Association 2020.


Mar 23, 2020

Dr Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast soiree and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor for the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:            And I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week we're going to talk about carotid stenosis, and you remember how we measure those a lot with ultrasound, and what that thickness is, and IMT? Well, we're going to talk about getting some thresholds and an update in that with our feature discussion today. But before we get there, how about grab a cup of coffee and we get started with other papers.

Dr Carolyn Lam:               All right. Well, I've got my coffee and I'm ready to tell you about two papers. They're both on left ventricular hypertrophy. One is basic and one is clinical. I will start with the basic paper because it is a super cool one that uncovers a novel mechanism underlying myocardial hypertrophy. And this involves S-nitrosylation, a prototypic, redux-based post-translational modification, S-nitrosylation.

So this is from co-corresponding authors, Drs Xie, Han, and Ji from Nanjing Medical University, who performed a series of elegant experiments using myocardial samples from patients and animal models exhibiting myocardial hypertrophy, and they demonstrated that S-nitrosylation of muscle limb protein plays a crucial role in myocardial hypertrophy.

This muscle limb protein modification enhanced binding to toll-like receptor 3 and receptor interacting protein kinase 3, which stimulated NOD-like receptor pyrin domain containing 3 or NLRP3 inflammasome activation and consequent caspace-1 and interleukin 1 beta activation, ultimately promoting myocardial hypertrophy. They further showed that the deficiency of S-nitrosylated muscle limb protein governed toll-like receptor 3 really alleviates pathological myocardial hypertrophy.

Okay Greg, I can see the look on your face. You're like what? That was a lot. What are the clinical implications, right?

Dr Greg Hundley:            Yeah, Carolyn, you are taking me back to molecular biology course 410, that I would take as a senior in college. Wow. So tell me what are the clinical implications?

Dr Carolyn Lam:               All right, here's a take-home. The data really identify that S-nitrosylated muscle limb protein is a key regulator, which together with toll-like receptor 3 made therefore serve as putative therapeutic targets in treating pathological myocardial hypertrophy in heart failure. That's the take-home. Before any further comments, let's go to the clinical study.

Now, this one focuses on a malignant subphenotype of left ventricular hypertrophy in which minimal elevations of cardiac biomarkers identify individuals with left ventricular hypertrophy at high risk for developing heart failure. And this is from corresponding author Dr James de Lemos from UT Southwestern. He and his colleagues tested the hypothesis that a higher prevalence of the malignant left ventricular hypertrophy phenotype among blacks may contribute to racial disparities in heart failure risk. So they pooled data from three large multi-ethnic cohorts, that is Eric, Dallas Heart Study, and MESA, totaling more than 15,700 participants. These participants were then classified into three groups: One, those without ECG left ventricular hypertrophy; two, those with ECG left ventricular hypertrophy but normal biomarkers; and three, those with ECG left ventricular hypertrophy and at normal levels of two biomarkers, high sensitivity troponin T above six nanogram per liters, or NT-proBNP above 100 picograms per milliliter. And that last group were the malignant left ventricular hypertrophy group.

They found that the prevalence of malignant left ventricular hypertrophy was threefold higher among black men and women versus white men and women. Compared to participants without left ventricular hypertrophy, the adjusted hazard ratio for heart failure was 2.8 in those with malignant ventricular hypertrophy and only 0.9 in those with left ventricular hypertrophy and normal biomarkers. And these were similar findings in each race and sex subgroups.

Mediation analysis indicated that 33% of the access hazard of heart failure among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant left ventricular hypertrophy in blacks.

Dr Greg Hundley:            So Carolyn, race could be a really important issue in left ventricular hypertrophy. What did the authors conclude? I mean, how should this help us perhaps manage these patients? What was the take-home?

Dr Carolyn Lam:               So this really shows that a higher prevalence of the malignant hypertrophy phenotype may in part, explain the higher risk of heart failure among blacks compared to whites. And what it means too is that when left ventricle hypertrophy is detected by ECG or cardiac imaging, perhaps we should consider measuring high sensitive troponin T or NT-proBNP, which will help distinguish those in whom risk for heart failure is favorable from those at a much higher risk.

Dr Greg Hundley:            Very, very interesting. Well Carolyn, I'm going to switch. I've got a basic paper and it's going to focus on dysfunctional adipocytes and how they might talk to cardiomyocytes in the situation of ischemia reperfusion injury. And the corresponding author is Xin-Liang Ma, from Thomas Jefferson University in Pennsylvania.

So Carolyn, do you have any thoughts regarding how patients with diabetes might experience a greater degree of myocardial ischemia reperfusion injury in the setting of an MI?

Dr Carolyn Lam:               Oh my goodness, you're really putting me on this spot here. Well, I know things that come to mind would be oxidative stress, microvascular disease.

Dr Greg Hundley:            Very good. Open-ended questions for Carolyn's quiz. I'm going to give you a 90. That was very good. So Carolyn, this current study attempted to clarify whether and how small extracellular vesicles may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating myocardial ischemia reperfusion injury. And to do this, adult male mice were fed a normal or high fat diet for 12 weeks.

The small extracellular vesicles from diabetic serum, diabetic adipocytes, high glucose, high lipid-challenged, non-diabetic adipocytes were injected then, intramyocardially, distal of the site of a coronary ligation.

Dr Carolyn Lam:               Okay. So Greg, I would not have guessed it was about extracellular vesicles, but very interesting. What did they find?

Dr Greg Hundley:            Intramyocardial injection of diabetic serum small extracellular vesicles or these SEVs, in the nondiabetic heart, significantly exacerbated myocardial ischemia reperfusion injury, as evidenced by poor cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. And administration of small extracellular vesicles, biogenesis inhibitors, significantly mitigated the myocardial ischemia reperfusion injury in diabetic mice. And mechanistic investigations in these studies identified that MIR 130B3P is a common molecule, significantly increased in diabetic serum of small extracellular vesicles and mediated the pathological communication between the dysfunctional adipocytes and the cardiomyocytes. Therefore, if in the future, we could interfere with this molecule, that could perhaps be a novel strategy for attenuating diabetic exacerbation of myocardial ischemia reperfusion injury. Really, a clever study, I think. What else did you find in this issue of the journal?

Dr Carolyn Lam:               Yeah, Greg, this week's issue is packed with other papers too. For example, there's the research priorities for HFpEF by NHLBI working group summary by Dr Shah, et al. There's a research letter by Dr Kaltman on the disparities in congenital heart disease mortality based on proximity to a specialized pediatric cardiac center. There's also another research letter by Dr Irisawa, on the impact of low-flow duration on favorable neurological outcomes of extracorporeal CPR, after out-of-hospital cardiac arrest, and this is a multicenter prospective study.

Dr Greg Hundley:            It sounds like a lot's in the mailbag. In the couple of things that I wanted to talk about, Dr Giulia Rivasi from the University of Florence, and William White from University of Connecticut, exchange a series of letters back and forth regarding a previous publication on the effects of intensive versus standard ambulatory blood pressure control on cerebrovascular outcomes in older individuals.

I have another research letter entitled, The Cardiac Cell Therapy Rejuvenates the Infarcted Rodent Heart via Direct Injection, but not by Vascular Infusions. And that is from Dr Jeffrey Molkentin from Cincinnati Children's Hospital Medical Center.

Finally, though Carolyn, there's a very interesting piece from Dr Carl Bakker at the Ann and Robert H. Lurie Children's Hospital of Chicago, discussing are we now in a time, in the United States, where congenital heart surgery should be coalesced or regionalized? And that really comes on the back of a discussion of there have been several high-profile articles in the national media, reporting on US congenital heart surgery programs. And that's led to, the author describes, some closure of several centers and at least in five programs. So a great discussion on, should this be regionalized? But we've got a great feature article coming ahead and how about if we head to that.

Dr Carolyn Lam:               Let's go, Greg.

Dr Greg Hundley:            Welcome everyone, to this feature discussion where we are going to discuss the use of diagnostic ultrasound in the carotid arteries and how that pertains to selection of patients for vascular surgery. And with us today, we have Dr Jesse Columbo from the Geisel School of Medicine at Dartmouth University in Hanover, New Hampshire. We also have Dr Bob Zwolak, from the Manchester VA at the Dartmouth School of Medicine and we have our own Josh Beckman from Vanderbilt University, one of our associate editors at Circulation. And Bob, let's get started with you. Could you tell us a little bit, what was the background of this study and what hypothesis were you looking to test?

Dr Robert Zwolak:           It goes without saying that stroke is still a huge health problem in the United States. If there is any good news, it's that stroke incidence is falling slightly, but there are still over 100,000 deaths from stroke each year in United States and as many as 700,000 new strokes each year, and a significant proportion of those derive from atherosclerotic plaque in the carotid bifurcations.

Carotid duplex ultrasound is a fantastic way to assess the presence of plaque in the carotid bifurcations because it does not use any ionizing radiation, does not require any contrast. Ultrasound is a relatively less expensive technology than CT or MR, and the study can be repeated so we can follow people over time, who are found to have significant atherosclerotic plaque in their bifurcations.

The hypothesis of our study though, was that there is variation in the diagnostic thresholds used by various carotid ultrasound testing laboratories, such that it may impact the healthcare and the treatment plans of people who undergo the studies. Jesse will tell you the details, but specifically, we hypothesized that people who undergo this carotid ultrasound test may or may not be inducted into a surveillance program and intensive therapy based on the diagnostic criteria that were used by the individuals conducting their ultrasound study. And even more substantially, we hypothesized that individuals who undergo carotid endarterectomy or potentially carotid stenting, could also have their procedure influenced, whether or not they undergo surgery or stenting based on the carotid ultrasound results. It might vary from one facility to another. So it potentially could be that an individual would be inducted into ultrasound surveillance or even undergo carotid surgery, depending on the vascular laboratory in which they were tested.

Dr Greg Hundley:            Jesse, could you tell us a little bit, what was your study population and how did you design this to address the hypothesis that Bob just stated?

Dr Jesse Columbo:          Sure. A review of the published literature really shows a variability in that ultrasound criteria that's used for diagnosing carotid stenosis. And so our first objective was to see if we could obtain as many in-use criteria as possible. Our first step was to partner with the Intersocietal Accreditation Commission, the commission that accredits vascular labs. We partnered with them and obtained a 25% random sample of ultrasound criteria in use across the US. And so that kind of gave us the starting point for the criteria upon which to look at.

We then wanted to apply those to a couple of different groups. As Dr Zwolak mentioned, there's really two primary breakpoints here. One, you either have mild stenosis, where you get medical therapy, but no further surveillance, or moderate stenosis, at which point you then are dedicated to long-term surveillance per the AAJ recommendations, or then, the break point between moderate and severe stenosis where surgery is considered.

What we wanted to do is examine the impact of moderate and severe stenosis thresholds. For the severe stenosis thresholds, we use the Vascular Quality Initiative Registry, which collects information on patients who underwent carotid endarterectomy. When we studied patients specifically that we thought the percent stenosis would be the major deciding factor in who got surgery, those are the asymptomatic stenosis and we applied the range of severe stenosis criteria from the IAC to those patients. We then wanted to study other individuals who might be committed to long-term surveillance based on the criteria used. And so for that, we used participants in the Cardiovascular Health Study, which had their induction into the study, had baseline data on carotid stenosis collected. And so that kind of formed our basis of the study, applying the criteria to those two different groups of individuals.

Dr Greg Hundley:            And so how many subjects did you have in the two cohorts? And then tell us what were your study results?

Dr Jesse Columbo:          Sure. Once we narrowed down that patients in the vascular quality initiative to those who underwent surgery for asymptomatic carotid stenosis, we had about 28,000 patients. And then when we examined the Cardiovascular Health Study, we had about 4,800 or 5,000 patients in that group. What we found was pretty interesting.

If you look at individuals who underwent surgery, and you take the carotid threshold criteria and apply it to them, and if you say, "Well, we're going to take criteria in the fifth percentile versus criteria in the 95th percentile," what you'll find is that 10% of patients who got surgery, fall between that range. And what that means is that there are patients, approximately 10% of patients, who are undergoing surgery that may not have been offered surgery if they had gone to a different institution, which we thought a pretty important finding.

The second part was studying patients who maybe committed to long-term surveillance. And if we took centers that were in the fifth percentile versus those in the 95th percentile for their carotid stenosis thresholds, we found a twofold difference in the number of patients that would be committed to long-term surveillance. And remember, this is the difference between getting aspirin and a statin and medical therapy, but no longer surveillance and getting carotid ultrasound every six months to a year for a long period of time. That twofold difference really could have a meaningful impact on patients.

Dr Greg Hundley:            It sounds like we've got a variance issue here and that could really impact clinical care. So while ultrasound's very portable and advantageous, how do we use these results to more effectively select how we're going to implement ultrasound to monitor these patients?

Dr Joshua Beckman:       I have to say the results of this study, when I read them the first time were eye opening. One point that doesn't come out clearly to those folks who aren't necessarily in the field, is that these are the labs that have been accredited and they are the top labs in the United States. This doesn't include at least half of the rest of the labs in the United States and suggest that if there's variation in the very best of labs, you know that there's even more variation that's being practiced routinely around the United States. So when I read this, I thought that there was a huge problem that they were uncovering. There are many, many millions of patients with atherosclerosis.

And so what we have to figure out now is how to standardize the measurement and reading of these studies so that ultrasound can be deployed routinely, without a fear of your treatment varying based on which doctor you decide to see and where you decided to go. And I think the fact that these guys highlighted that in such a nice and clear way, really raises the alarm and raises the flag that attention needs to be paid here quite soon because it's quite important.

Dr Greg Hundley:            So what study could we perform next? And maybe I'll ask, Bob, you just start off. What study could we perform next to help clarify and guide us to the better use of ultrasound in this situation?

Dr Robert Zwolak:           Well, I think there are two issues. The first issue that this manuscript points out is the one of variation and it's real and the results speak for themselves. The second issue is the one of accuracy, and the question of what are the best thresholds? And there are several ways that this can be standardized. I'm pleased to say that the Intersocietal Accreditation Commission, the IAC, that Jesse mentioned, is actually tackling this problem.

Dr Robert Zwolak:           But what's the gold standard? 40 years ago when ultrasound was developed, these thresholds that people are discussing, were related to measurements on contrast arteriograms. And the catheter-based contrast arteriogram, a relatively invasive study, was the source and we compared ultrasound velocities to the measurements on the contrast arteriograms to determine these thresholds that Jesse has investigated. That resulted in substantial variation depending on the individual authors. The question is, over time, have the machines changed? Is there really a central focus that we can look at? Most of these studies were very small and so it accounts for the variation in recommendations.

Dr Robert Zwolak:           The IAC now, is going back and collecting contemporary contrast arteriograms, not so many of which are done anymore and so, it's taken a very substantial multicenter effort. But trying to look again, to see if there are more accurate results that could be published, studied in a way such that they would be universally accepted and potentially promulgated by professional societies within guidelines. And standardized such that various specialties, whether it's vascular surgeons who run the labs, or a cardiologist, or radiologist, would agree on a set of both accurate and reproducible and constant velocity thresholds to standardize this technology, which is otherwise a very, very good technology and eliminate this variation that we've seen.

Dr Greg Hundley:            Well, this has been a phenomenal discussion in a very interesting piece of research. Jesse, can you give us sort of a point forward from here, how do we move forward with some of these results and what you anticipate seeing going forward?

Dr Jesse Columbo:          Well, a duplex ultrasound for carotid stenosis is really important. There are lots of studies done. It's a great way to follow patients over time, in a noninvasive manner. And I might hope that this paper would open the eyes of some of the listeners as to what the carotid ultrasound really means. Instead of just looking at the percent stenosis on the report, to perhaps look at the raw velocities and interpret them in the context of the patient, because I think that has really important impact on how we might manage some of these individuals, for each person that you see.

Dr Greg Hundley:            Well, listeners, we want to thank Dr Jesse Columbo, Dr Bob Zwolak, also Dr Josh Beckman, for discussing this very informative research related to the use of ultrasound for assessing carotid stenosis.

Dr Greg Hundley:            On behalf of both Carolyn and myself, we wish you a great week and see you next week. This program is copyright, the American Heart Association 2020.


Mar 16, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Dr Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, this issue features a very important, but rather somber subject and it talks about suicide attempts among LVAD recipients and the real-life data from the Assist-ICD study. Now we have to get to that and it's a very interesting discussion, but first, let's discuss a couple of papers and I'll start.

Now, we know that extracorporeal cardiopulmonary resuscitation using extracorporeal membrane oxygenation or ECMO, for hemodynamic support has been shown to enhance survival for patients with refractory VF or VT out of hospital cardiac arrest. However, what are the effects of prolonged CPR on development of metabolic derangements and neurologically favorable survival in these patients?

Well, this was examined by Dr Bartos from University of Minnesota School of Medicine and colleagues who retrospectively evaluated survival in 160 consecutive adults with refractory VF/VT out of hospital cardiac arrest, treated with extracorporeal cardiopulmonary resuscitation, and compared these with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial.

They found that extracorporeal CPR was associated with improved neurologically favorable survival compared to standard CPR at all CPR durations less than 60 minutes. However, CPR duration remained a critical determinant of survival with a 25% increase in mortality with every 10 minutes of CPR beyond 30 minutes. The progressive metabolic derangement which developed during prolonged CPR was associated with reduced neurologically favorable survival.

Dr Greg Hundley: This mirrors an article that we had maybe about a month ago. What are the clinical implications of this particular study?

Dr Carolyn Lam: Well, healthcare systems utilizing extracorporeal CPR for out of hospital cardiac arrest should optimize pre-hospital and in-hospital processes to minimize time to CPR. Further research is needed to identify strategies to increase CPR efficiency, improve profusion, and decrease the metabolic demands such that the progressive metabolic derangement associated with prolonged CPR can be delayed. This is discussed in an editorial by Dr Sonneville and Schmidt.


Dr Greg Hundley: Very nice, Carolyn. Well, my next article is from Roxana Mehran from the Icahn School of Medicine at Mount Sinai. It's really getting at the issue of high-risk implantation of inter-coronary stents and balancing where is that risk. Is it from bleeding or a complication from the procedure? In this study, they had a total of 10,502 patients and they were included from four registries. 3,507 were identified as having high bleeding risk. The authors aimed to evaluate the long-term adverse events in the high bleeding risk patients undergoing PCI with cobalt chromium, everolimus-eluting stent implantation.

Dr Carolyn Lam: Ah, Greg. Awesome. I'm a fan of Dr Mehran and looks like I'm going to be a fan of this study. What did they find?

Dr Greg Hundley: Well, Carolyn, I love just thinking about coated stents. How about that? Interestingly, those at high bleeding risk had more comorbidities. They had higher lesion complexity and a higher risk of four-year mortality. In fact, four times that of those without those risk factors. The risk of mortality was increased after coronary thrombotic events and after major bleeding. Thus, rather than just being evaluated as a subset of patients in whom the risk of bleeding takes precedence, high bleeding risk patients must be considered a vulnerable population in whom both ischemic as well as bleeding events have a significant impact on their mortality.

Dr Carolyn Lam: Nice, Greg, and you said all of that without repeating everolimus.

Dr Greg Hundley: Coated, remember, coated stents.

Dr Carolyn Lam: These tongue twisters, but hey, my next paper provides novel insights into mechanisms underlying diastolic stiffness in cardiomyocytes and the myocardium. This is from Dr Prosser from Perelman School of Medicine in Philadelphia and colleagues, who interrogated the role of the microtubule network in the diastolic mechanics of human cardiomyocytes and myocardium. They found that stable detyrosinated microtubules contributed viscous forces during diastolic stretch that increased cardiomyocyte stiffness, particularly in patients with heart failure. Depolymerizing microtubules reduced myocardial stiffness over the range of strains and strain rates associated with early rapid filling in tissue from patients with diastolic dysfunction.

Dr Greg Hundley: Now, how are we going to take this to patients? Are there any translational insights?

Dr Carolyn Lam: Microtubule deep polymerization using colchicine. Colchicine, the stuff we use for gout, this reduced myocardial viscoelasticity with an effect that decreased with increasing strain. Post-hoc subgroup analysis revealed that myocardium from patients with heart failure reduced ejection fraction were more fibrotic and elastic than myocardium from patients with heart failure preserved ejection fraction, which were relatively more viscous. Now, colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium, but may confer greater benefit in conditions with limited myocardial fibrosis including HFpEF. How's that for translational?

Dr Greg Hundley: Oh, very nice, Carolyn. My next paper comes from Dr Lior Zangi from Mount Sinai School of Medicine. Carolyn, in this study, the authors performed transcriptomics sphingolipid and protein analyses to evaluate sphingolipid metabolism and signaling after myocardial infarction. They investigated the effect of altering sphingolipid metabolism through a loss of chemical inhibitors or gain modified MRNA and modified RNA of acid ceramidase function post hypoxia or MI.

Dr Carolyn Lam: Whoa, so what did they find?

Dr Greg Hundley: Well, Carolyn, translationally, the authors found that transiently altering sphingolipid metabolism through acid ceramidase over expression is sufficient and necessary to induce cardio-protection after myocardial infarction. Carolyn, these results highlight a new therapeutic potential of acid ceramidase modified messenger RNA in ischemic heart disease. The basic science is just phenomenal in our journal.

Dr Carolyn Lam: It is, and I loved the way you explained that one, Greg, thanks. Now, there's lots of stuff also in the journal. There's an On My Mind by Dr Ray entitled "LDL Cholesterol Lowering Strategies and Population Health: Time to move to accumulative exposure model." We also have a research letter by Dr Chen describing a novel mouse knock-in strategy utilizing a biotin ligase-based system called biotin identification 2, to identify the cardiac diet proteome in vivo. Well, very interesting stuff, especially in terms of this particular novel strategy.

Dr Greg Hundley: You know, Carolyn, this week the mailbox is just full, so I've got a research letter emphasizing trends in anti-arrhythmic drug use among US patients between 2004 and 2016 and it's from Dr David Frankel from the Hospital of the University of Pennsylvania.

I've also got a letter to the editor regarding the association between the use of primary prevention implantable cardio defibrillators in mortality in patients with heart failure, a prospective propensity matched analysis from the Swedish Heart Failure Registry, and the corresponding author is Professor Laszlo Littman from atrium health at the Carolinas Medical Center in Charlotte, North Carolina. There is also a response to this letter from Dr Gianluigi Savarese from Karolinska Institute.

Then finally I have a new another EKG challenge, Carolyn, from Dr Miguel Arias. It's a case of new onset, recurrent syncope triggered by fever. Can you get it right from just looking at the EKG?

Well, Carolyn, should we head on to our feature discussion, which this week has a very somber tone?

Dr Carolyn Lam: Let's go.

Left ventricular assist devices or LVADs are really becoming established therapy for end stage heart failure. Now, we who manage such patients realize there are numerous complications and have seen patients who suffer things like anxiety and depression. Interestingly, until today, there was very little data regarding the suicide risk in this population.

I am so pleased to welcome the authors of a very unique and important research letter and they are Vincent Galand as well as Erwan Flécher, both from Ren University Hospital in France, and of course Mark Drazner, our associate editor from UT Southwestern. Vincent, could you start us off by telling us what made you do this important study and what did you find?

Dr Vincent Galand: As you know, in the entire population where a lot of tests have thromboses or infection or ventricular arrhythmias, but there is a lack of data about the clarity of life for the secret distress or suicide in this population. I think it's very important to have information about the population.

At the beginning is the Assist-ICD study is a study focused on arrhythmias in this population, but we recorded data about suicide in this population. What the objective of this study was to analyze the incidents of suicide in this population and to see if there is some predictor of suicides in this population.

Dr Carolyn Lam: What did you find?

Dr Vincent Galand: We find that in centers without LVAD nurse coordinator, the incidents of suicide, was higher. It was not significant, but it was a very big trend. Additionally, we found that patient implanted in destination therapy was a bigger risk of suicide compared to patient granted bridge transportation or bridge to recovery. I think there is two factors of suicide. The first one is a lack of LVAD nurse coordinator and the second one is the implementation and destination therapy.

Dr Carolyn Lam: Yeah, and the really cool thing is that that first factor is something that I suppose can be addressed in future efforts. Mark, could I just ask you to put these findings and this research that are into context for circulation to publish quite a specialty, if you may, topic, why is this so important?


Dr Mark Drazner: DT vans are really a rapidly emerging therapy for patients with advanced heart failure, with almost exponential growth. As these profound technologies are emerging on the scene, it's important, first, to consider all the ramifications for our patients. I think anyone could imagine having an LVAD implant and how that might have profound influence on your life in totality and the impact on the psychological aspects.

While there's been previous studies, there seems to be much avoidance in us really fully understanding the total impact. There have been previous case reports of suicide, but not anything to this magnitude where a systematic series with an estimate of the frequency of as high as 2%, which may not sound high, but, compared to the general population, is increased. We view this as an important look at a critical topic. It's the beginning, there needs to be, as you said, it's a research writer on a case series, but it's a cautionary tale and really is pointing the way for us to proceed with further investigation as potentially important complication related to that. That's essentially why the editorial board found this interesting.

Dr Carolyn Lam: Indeed. Could you just remind us how big this study was? Because this is really big for an LVAD study.

Dr Erwan Flécher: We collected data from 19 university centers in France over 10 years period and we collected a lot of that especially in the fields of arrhythmia. As Vincent said, we thought it was interesting to take the entire picture, so we collected data about quality of life and how do they live and if they had a lot of risk of suicide, if not, and that's how we succeeded to lead this study.

In France, what is important also for you to know is that we do implant a different population of patients than in the US. We do implants in bad patients, in very, very sick patients. Most of them are currently in cardiogenic shock or already under temporary support, ECMO support, IMPELLA support, so it may impact also our results.

That's an interesting point to say and the overall thing is that our paper demonstrated, I think, that we need to take care of these patients not only about the device, not only about the anticoagulation, but also, I mean again, the entire picture. The social part, the quality of life, the way they do live is very important. Probably they should be proposed for psychological follow-up also, or any kind of support for the family. This is important in order to decrease the risk of suicide, in my opinion.

Dr Carolyn Lam: I liked those take-home messages that are very practical, and you kind of read my mind about that question of generalizability. Mark, did you have any reflection on that? The generalizability to the US population?


Dr Mark Drazner: Yeah, that's an important point. I was struck in the paper that 80% of the patients who committed suicide were followed at centers without LVAD coordinators. That number seems high compared to what we're used to seeing. It would be intriguing how widespread that is, where patients who are getting implanted don't have access to a VAD coordinator in your country.

Dr Erwan Flécher: Well, that's an important point also. It is different in France. I mean, we just created...That coordinator did not exist a few years ago in France and I know you are used to work with VAD coordinator in the US, in the UK, even in Netherlands and Germany, but in France it was not like that and all patients were only followed by cardiologist or cardiac surgeons and a few centers started few years ago, five, eight years ago to have a VAD coordinator nurse program. We do believe it is very, very important. That's also plea for a better organization of care in our country.

Dr Mark Drazner: Yeah, that's a thinking point. I didn't realize that that was not widespread practice and relatively new implementation. It'll be interesting to see if the rates subsequently fall with that change in practice. Can I ask, let me follow up in terms of your previous comment. It sounds like a lot of these patients were acute presentations and I wonder also whether they may not have had the full time to grasp exactly what they were getting into, for example. I think we've all been there.

Someone went into cardiogenic shock, ends up crashing and burning and has to go for a durable VAD. A very different complex in someone who has consolidation has been followed in the center for a while, has a chance to come to understand what all that really is. You think that is a major factor in this experience?

Dr Vincent Galand: We think that patients who are granted in case of emergency; it's a bigger risk of surgical distress afterwards the implantation. In fact, that they cannot many information before the implantation, information about the worth life after the LVAD implantation. Of course if they don't the information, they can't be prepared for life after surgery. I think it's a bigger risk, yeah.

Dr Erwan Flécher: That's why maybe in your country or maybe elsewhere, I don't know, maybe the findings would have been different. That's, that's an option we should consider, also. In France, as we told you, we do implants. Most of our patients are implanted in emergency. They're already in ICU. Most of them are already under mechanical ventilation, so they just wake up and they learned that they have been implanted. Not all of them, but most of them, the vast majority of them, so of course they are not so well prepared and that may have an impact on the follow-up. We try to talk to the family; we try to talk to the general practitioner.

Dr Mark Drazner: Of the 10 patients, it's very interesting that patients are being implanted and not knowing they're being implanted in and say waking up with an LVAD. I don't know if you have the granular detail, but do you know, of these 10 patients, how many of them were in that situation?

Dr Vincent Galand: The patients were implanted in cardiogenic shock, so I think it's four patients, but six patients were implanted without cardiogenic shock. They received this kind of information before the LVAD implantation, so it's not a big part of the population, but it's some patients.

Dr Mark Drazner: Could you, just for our readers, it's a little goory, I will admit, but in terms of how these patients attempted or actually committed suicide, just to explain in terms of, it was oftentimes related to a mechanism through the LVAD. If you could just summarize that and how they tried to commit suicide or commit suicide.

Dr Vincent Galand: That was the case. The suicide was with drive line disconnection or drive line section. In two patients, it was drug suicides, but in most of the patients the drive line is the main way for suicide.

Dr Mark Drazner: It's interesting that the mechanism that these patients tried to commit suicide was directly through the LVAD.

Dr Erwan Flécher: Of course it's the easiest way to terminate their life and they just cut off it. Just don't plug the battery and they are alone and that was the main way to practice their suicide.

Dr Mark Drazner: I know we don't have the initial report, we probably don't have all those, but in terms of you postulating in the paper why patients might get to the state where they would try or commit suicide with the LVAD. If you just want to throw out some of your hypotheses so that our listeners can hear those as well.

Dr Erwan Flécher: I've got in mind two or three points in order to improve our results. First of all, we should implant maybe earlier patients in France in order to have a better way to prepare and to invest the VAD implantation.

The second point would be to have a better organization of care and I think we should develop that VAD nurse coordinators program like in many countries. We still have some but not in all the hospitals implanting that.

The third point would be also to get the better LVADs. I mean, probably the drive line in sections, batteries, the controller, this of course it's much better than it was 10 years ago. There is no noise. It's less big than it was, but still, I think if we can improve the device itself, I think we may observe maybe the decrease in the risk of a system in society, especially the drive line, if there is no drive line, the quality of life should be better. We may suggest that the risk of suicide would decrease.

Dr Carolyn Lam: A very somber topic, but those last take home messages, leaving hope for improvement, were really important. Thank you everyone for sharing with us today, and thank you, audience, for joining us today.


Dr Greg Hundley: This program is copyright, the American Heart Association 2020.


Mar 9, 2020

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, the feature article today is really interesting. It's evaluating the evolution of cardiovascular disease associated adverse events in developing countries and It's really fascinating looking at differences between Russia, China, India, and Brazil, but more to come. Don't want to spoil all that. How about we get started with a cup of coffee and discussing some of the articles in the Journal.

Dr Carolyn Lam: You bet, Greg. Well, I want to start off with this paper that provides really novel insights into the pathogenesis of hypertrophic cardiomyopathy.

Dr Greg Hundley: Carolyn, you're one of the cardiomyopathy experts. Can you give us a little background before we get started?

Dr Carolyn Lam: Not sure about expert, but I can sure give you a background. So. Hypertrophic cardiomyopathy remember, is caused by pathogenic variants in the sarcomere protein genes, and that evokes hypercontractility, poor relaxation, and increased energy consumption by the heart and increases the patient's risk for arrhythmias and heart failure. Recent studies show that the pathogenic missense variants in myosin are clustered in residues that participate in dynamic confirmational states of the sarcomere proteins.

In today's paper from co-corresponding authors Dr Seidman and Toepfer from Harvard Medical School, authors hypothesized that these confirmations were essential to adapt contractile output for energy conservation and that pathophysiology of hypertrophic cardiomyopathy resulted from destabilization of these confirmations.

So they assayed myosin ATP binding to define the proportions of myosin in two confirmational states called SRX or DRX. This was done in healthy rodent and human hearts at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic hypertrophic cardiomyopathy variants.

They found that hypertrophic cardiomyopathy mutations that disrupted the physiologic balance of SRX and DRX altered cardiomyocyte contraction, relaxation and metabolism, and conveyed increased risk for heart failure and atrial fibrillation. In fact, a small molecule could restore the physiologic balance of SRX and DRX and improve functional energetic and cellular abnormalities that occurred in hypertrophic cardiomyopathy.

Dr Greg Hundley: Very interesting, Carolyn. Well, let me tell you about my paper. It's called The OUTSMART Heart Failure. It's a randomized controlled trial of routine versus selective use of cardiovascular magnetic resonance for patients with non-ischemic heart failure. And it's from Dr David Ian Paterson at the University of Alberta.

This is a study from Canada randomizing 500 patients with suspected non-ischemic heart failure to either having a cardiac MRI as the first imaging study or have an echo, and then based on the echo, order an MRI if the physician so indicates. It was an older version of MRIs, so it's a SUNY assessment of function, including the EF, and then delayed enhancement, a technique that again has been available for the past 20 years and incorporates gadolinium contrast.

Dr Carolyn Lam: Greg, this is so unfair. I'm an echo person, you're an MRI person, but you get to tell us the results and inject your thoughts.

Dr Greg Hundley: No bias. So, Clinical outcomes, Carolyn, you'll be very appreciative, were similar for the two groups of subjects, although the heart failure etiology was more frequently derived in those that received an MRI, whether you're randomized to an MRI first or if you had an echo and they said, "Oh, go get an MRI." The patients with specific heart failure etiologies from imaging had worse outcomes, whereas the heart failure etiologies defined clinically did not.

So, if you didn't take the imaging into account, it didn't discriminate. Importantly, the authors note that more modern techniques, involving mapping with or without contrast, were not employed. It's an older form of the MRI imaging, but the results would suggest that physician decisions regarding the potential use of MRI are important. Bringing us in to decide when to get it is a good idea based on these results.

Dr Carolyn Lam: That was very balanced. Thank you, Greg. But I've got a question for you now. What do you think of coconut oil? Do you take it?

Dr Greg Hundley: Well, I love coconut cake. Does that count?

Dr Carolyn Lam: Well, I have to tell you, I cannot even begin to name the number of people, it's friends and relatives and patients, who take coconut oil because they believe it's good for them. They literally spoon it into their mouths. The truth is coconut oil has been accorded much attention in the popular media as a potential beneficial food product. In fact, a survey in 2016 found that 72% of Americans viewed coconut oil as a healthy food. This represents a remarkable success in marketing by coconut oil and related industries calling coconut oil a natural healthful product despite its known action to increase LDL cholesterol. Of course, we know that, that's an established cause of atherosclerosis and cardiovascular events.

This paper in our journal really deserves attention. It's from corresponding author Dr Rob van Dam from Saw Swee Hock School of Public Health and the National University of Singapore. He and his colleagues conducted a systematic review of the effect of coconut oil consumption on blood lipids and other cardiovascular risk factors compared with other cooking oils using data from clinical trials. In a meta-analysis of 16 trials, they found that coconut oil consumption significantly increased LDL cholesterol concentrations as compared with non-vegetable oils. Although coconut oil consumption also increased HDL cholesterol concentrations, we need to remember that efforts to reduce cardiovascular risk by increasing HDL, have not really been successful in the past.

Anyway, there was no evidence of benefits of coconut oil over non-tropical vegetable oils for adiposity or glycemic or inflammatory markers. Now, this is discussed in an editorial by Dr Frank Sacks at Harvard T.H. Chan School of Public Health and it's entitled: “Coconut Oil and Heart Health. Fact or Fiction?”

Dr Greg Hundley: Very nice, Carolyn. Well, I guess I can't use my coconut cake to lower my LDL. How about we get on to what else is in the journal? You want to go first?

Dr Carolyn Lam: Yeah. We have an important white paper by Dr Sharma on the impact of regulatory guidance on evaluating cardiovascular risk of new glucose lowering therapies, to treat type two diabetes. It talks about lessons learned and future directions. All of this was occurring in February 2018 when a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of findings of the completed CV outcome trials. Very, very important read. We also have a research letter from Dr Wanken entitled, “Characterization of Endovascular Abdominal Aortic Aneurysm Repair Surveillance in the Vascular Quality Initiative.” You got to read about that.

Dr Greg Hundley: Well, Paul Ridker writes a very nice perspective piece. Will all atherosclerosis patients soon be treated with combination lipid lowering and inflammatory inhibitors? Very interesting read. In a separate article, there's a nice ECG challenge from Dr Andrei Margulescu, An Irregular Tachycardia that's not Responsive to Medical Treatment: What is the Diagnosis? A great read for those in training.

Got a couple letters to tell you about. One is the research letter on filamin-C and it's essential for heart function from Professor Ju Chen University of California, San Diego. Then, there's a letter to the editor regarding the article, Stroke Risk as a Function of Atrial Fibrillation Duration in CHA2DS2-VASc Scores from Dr Ming-Wu Xia from Hefei Affiliated Hospital and Anhui Medical University. Then there's a response letter from Rod Passman from the Feinberg School of Medicine at Northwestern University. Well, Carolyn, how about we go to learn about the evolution of cardiovascular events and how they're evolving in Russia, China, India, and Brazil.

Dr Carolyn Lam: Super excited about this one. Let's go, Greg. Our feature paper today focuses on cardiovascular disease burden in the BRICS, and that stands for Brazil, Russia, India, China, and South Africa, B. R. I. C. S. Which is a grouping of upper and lower middle-income countries constituting almost half the world's population and contributing almost a third of the world's GDP. A really, really important paper here. I'm so pleased to have with us the corresponding author of this paper, Dr Zhiyong Zou from Peking University School of Public Health.

Dr Jo, can you please start by telling us a little bit about how you did this study? I thought the methods were amazing.

Dr Zhiyong Zou: There was little study on cardiovascular disease in breaks. So most of the studies have focused just fatality across year, and then reported change in different age groups. However, this fails to distinguish cohort from period effects. So our study aims to examine the time change and also the relative contribution of period and cohort facts.

Dr Carolyn Lam: Wow. So that's big and an acute area. So could you tell us a little bit more about how you did this? Like the databases and then some of the very interesting methodology such as net drift, age curves, period, relative effects. Could you maybe describe those?

Dr Zhiyong Zou: The data was derived from global burden disease 2017 which was as estimate by the university of Washington. This data was estimate for the whole population in each country from many original data sources. Our study used a new method, age period, cohort model.

We can use this model to estimate first cohort from period effects so we can compare different post cohort population and the different period population. They have different effects. And also, we can estimate the net drift, net drift is the overall annual percentage change. It is different from other study. Just to calculate the average percentage change. It is different. It was adjusted for period effects.

Dr Carolyn Lam: Audience, I really have to refer you to the figures of this paper. They're beautiful and that really... Pictures say a thousand words, but Dr Zou, could you now tell us what were the key findings?

Dr Zhiyong Zou: First, although there have been reductions in the breaks of the CVD mortality, they have lagged behind North American by over 15%. Yes, it is very decreased slowly but there is a notable exception of Brazil and the second, there was striking difference between countries. Russia consistently has the highest CVD mortality and Brazil have the lowest. Brazil and China have had continuing vitality improvements since 1992 but there has been little decry in India for middle age Indian males. CVD mortality has increased.

The last one is China has a high rate of out of hospital ischemia heart disease test reflecting poor pre-hospital care. Only 11% of the out of hospital desks received a basic cardiopulmonary citation. And the yes in China, this situation is very serious.

Dr Carolyn Lam: So really fascinating results. And maybe I could just add that you observed over a 25-year period from 1992 to 2016 the general picture is at least there's a decline in these areas, but definitely not as much as that observed during the same time in North America. But I absolutely agree that the striking country differences, so you know, maybe we should start with something positive. Dr Zou, what lessons do you think we could learn from Brazil's strikingly exceptional example?

Dr Zhiyong Zou: Brazil stands out for successful epidemiological transition. Yes, they with a rapid reduction. There are two important factors: The first one is Brazil investment in health with a decrease in smoking from 13.5% in 1999 to 17% in 2009 it decreased by 15%. Another factor is Brazil reform of primary health care focus on the family health program and the prevention and the care for the management of SADs.

Dr Carolyn Lam: I like that. From this paper we could get very, very important public health messages that may inform countries on how this burden can be tackled better like that. Good example of Brazil, but now maybe the tougher topic of in China, what do you think is the reason for the continuing problem with ischemic heart disease

Dr Zhiyong Zou: In China? The real mortality of ischemia heart disease increased very quickly, around 13.5% Increase. Compare that with other countries or declined. So in China with that, there were about 300 million more smokers in China. It was the biggest number in the world? Yes. So it's a big challenge for the government to control the smoking rate. And also, we mentioned that only 11% of the outside hospital Does received a cardiopulmonary citation.

Dr Carolyn Lam: Yeah. And so the point about the low CPR rates may point to more systematic issues in a primary care and public setting, isn't it? And it must be so difficult in a place as huge as China with such diversity in rural communities versus urban and so on. So very important points. I mean, do you have any insights for the issues that are seen in, for example, South Africa, Russia and India?

Dr Zhiyong Zou: We don't have data from the other countries.

Dr Carolyn Lam: Sure. One postulation I suppose thinking about things could be just very rapid transition from the era of infectious disease, communicable diseases to noncommunicable diseases. But you know, the diversity even among those is really, really astounding.

And I think everyone really just has to pick up your paper and have a good read. So could I ask, what are some of the take home messages and next steps that you may have in further research?

Dr Zhiyong Zou: The take home message is, Brazil's success suggest that the prevention policies can both reduce the risk for younger both cohorts and also, the greater risk for all age groups indicating greater progress in achieving CVD health is possible in rapid three in merging economics, which provide example for China and for India. And also a failure to investigate CVD prevention in countries undergoing rapid economic change will exert huge human and economic costs. So that's the take home message.

Dr Carolyn Lam: And those are great, great summaries. And do you have personal plans for further research in this area?

Dr Zhiyong Zou: Yes. In future, we will forecast on the risk factors because in this paper we find many priority age groups in different countries like example, in China those aged over 15 years old, is the prime priority age groups. But in India, 35-60 years old is the most priority age group because in these people, they are most of the productive age, but the mortality increased very quickly.

Dr Carolyn Lam: Yeah, a very good point. And investigating those risk factors would be so informative. Well, thank you so much, Dr Zou for sharing your incredible work with us. We're so proud to be publishing this important work.

Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Please tune in again next week.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.


Mar 2, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. You know that problem we have with the development of calcification of the aortic valve, the aorta, etcetera with hemodialysis? Well, our feature is going to talk about the results of a randomized phase 2B study to address this. But first, how about if you get us started with a couple of your papers?

Dr Carolyn Lam: In fact, it is a couple of papers and they're both related to hypertension. So in the first one, we know that exercise is associated with a lower incidence of hypertension, but what's the association of excessive levels of exercise in the incidence of hypertension? This question was examined by Dr Andersen from Uppsala University Hospital and colleagues, who compared the incidence of hypertension among almost 207,000 participants in a long-distance cross-country skiing event and more than 505,500 persons randomly sampled from the general population who are matched to the skiers on age, sex, and place of residence.

Dr Greg Hundley: I love skiing! I want to be in the match group. Tell me, now, how long was this distance that they had to cover?

Dr Carolyn Lam: Ah ha. Now the long distance event was really long. It was the Vasaloppet. I hope I pronounced that right, but it's a 45 to 90 kilometer skiing race. So participation, I'm sure you want to hear this, participation was associated with a 41% lower incidence of hypertension over the next eight years, compared to non-participation. And the better the performance in terms of percent of winning time, the lower the incidence of hypertension. If the observed associations are causal, it really adds to the list of beneficial effects of high, or even very high physical fitness. I can see you smiling, Greg.

Dr Greg Hundley: This is your confirmation that the AHA wants to send us to Norway to do one of these recordings.

Dr Carolyn Lam: Well, this next paper asked the question, what is the association of cumulated blood pressure exposure from young adulthood to midlife with gait and cognitive function in midlife. This is from Dr Mahinrad from Northwestern University Feinberg School of Medicine and colleagues who included 191 participants from the coronary artery risk development in young adults’ study, which is a community-based cohort of young individuals followed over 30 years. Cumulated blood pressure was calculated as the area under the curve for baseline up to year 30 exam and gait and cognition were assessed at the year 30 exam. Cerebral white matter hyperintensity was available at year 30 in a subset of participants who underwent MRI.

Dr Greg Hundley: I heard that MRI word. So what did they find Carolyn?

Dr Carolyn Lam: They found cumulative exposure to higher blood pressures from young adulthood to midlife, even at levels below the clinical definition of hypertension, was associated with worse gait and worse cognitive function in midlife. The impact of cumulative levels of blood pressure exposure was independent of other vascular risk factors during a follow-up period of over 30 years, and the higher burden of midlife cerebral white matter hyperintensity on MRI, Greg, moderated the association of cumulated blood pressure exposure with gait but not with cognitive function.

Dr Greg Hundley: You've got me convinced we now have to go to Norway. But what did the authors think were the clinical implications of their study?

Dr Carolyn Lam: Well, here it is. The deleterious effect of elevated blood pressure on brain structure and function may begin during early adulthood and this really emphasizes the need for all primordial, if you may, prevention of high blood pressure. But also reconsidering individual levels of blood pressure for the diagnosis of hypertension. Furthermore, gait may be an earlier measure of hypertensive brain injury than cognition. Now these issues are discussed an editorial by Angela Jefferson from Vanderbilt University Medical Center.

Dr Greg Hundley: Very nice, Carolyn. Well, I'm going to take another sort of twist on hypertension. My paper is from Dr Thomas Thum from the Hanover Medical School and is really looking at the relationship between cardiac fibrosis and diastolic dysfunction. So the study sought to identify anti-fibrotic drug candidates by functional screening of 480 chemically diverse natural compounds found in human cardiac fibroblasts.

Dr Carolyn Lam: Ooh, interesting. And what did they find?

Dr Greg Hundley: What they found is using multiple in vitro fibrosis assays and stringent selection algorithms, the authors identified the steroid bufalin, also seen in Chinese toad venom, and the alkaloid lycorine, from the Amaryllidaceae species, to be effective anti-fibrotic molecules, both in vitro and in vivo, leading to improvement in diastolic function in two hypertension dependent rodent models of cardiac fibrosis. In addition, administration of these agents at effective doses did not change plasma damage markers, nor the morphology of the kidney and liver. And therefore, it's kind of an early first toxicological safety study.

Dr Carolyn Lam: Fascinating. Not just in the findings and the methods, and who knew we'd be talking about Chinese toad venom on this podcast, Greg? Okay. But let me tell you about what's more in this issue. So, there is a research letter by Dr Djoussé, and it is entitled Supplementation with Vitamin D and/or Omega-3 Fatty Acids and the Incidence of Heart Failure Hospitalization. And this one is a letter from the VITAL-Heart Failure ancillary study of the parent VITAL trial. I'm sure I've got everyone's attention. (You) Got to read that letter.

The next is an On My Mind, by Dr Joe Hill, and is entitled, very intriguingly, Can HFpEF and HFrEF Co-exist? Basically accumulating evidence has revealed that the pathophysiologic mechanisms driving HFrEF and HFpEF are distinct, but this On My Mind paper asks can they coexist? Is it possible to identify subjects who harbor pathophysiological elements of both syndromes simultaneously, and if so, we may find that targeting specific pathways is beneficial and in depth characterization of specific subsets of patients might help overcome the limitations of an ejection fraction driven approach.

Dr Greg Hundley: Very interesting, Carolyn. I've got some letters from the mailbox, and the first letter is regarding SGLT2 inhibitors in cardiac hypertrophy and the corresponding author is Professor Kazushi Tsuda from Kansai University of Health Sciences. Another letter, from the corresponding author Dr Renato Lopes from Duke University Medical Center in Durham, evaluates stent thrombosis in patients with atrial fibrillation undergoing coronary stenting from the AUGUSTUS trial. And our own Tracy Hampton provides an update on cardiology news features. And John Warner, from UT Southwestern, the prior American Heart Association president, discusses his journey through healthcare reform. And then finally, our own Sarah O'Brian provides highlights from other journals in the Circulation family related to high points in cardiovascular disease. Well, Carolyn, how about on to dialysis and calcification?

Dr Carolyn Lam: Can't wait. Let's go.

Our feature discussion today, we will be focusing on patients with end-stage kidney disease. And we know that in these patients, the high cardiovascular morbidity and mortality could partially be due to extensive cardiovascular calcification. Well, our feature paper today is the first double blind placebo-controlled phase 2B trial that tests intravenous myo-inositol hexaphosphate, a novel strategy to inhibit the formation and growth of hydroxyapatite and therefore reduce calcification in these patients. I won't tell you more. I'll leave that to the corresponding author, Professor Paolo Raggi, from University of Alberta, and I'm also so pleased to have with us our editor for digital strategies and associate editor Dr Amit Khera from UT Southwestern. So Paolo, please tell us about SNF472 and your very novel trial.

Prof Paolo Raggi: As you correctly stated, patients with end stage renal disease have phenomenally high morbidity and mortality, particularly cardiovascular, and they also manifest extreme calcification on the cardiovascular system. Both the valves and the vessels are very heavily calcified. There's a very clear impression throughout the literature that calcification contributes, no doubt, to the high morbidity mortality with these patients. SNF472 is a derivative of a natural product that is only present in nature in sub molecular quantities and essentially is administered intravenously and the mechanism of action is quite simple. It keeps calcium and phosphorous molecules separate. In other words, it doesn't allow crystallization of calcium and phosphate into what we call hydroxyapatite, or amorphous calcium crystals. This, hopefully, was developed, this product was developed, to inhibit the final step of calcification. Everything comes down, no matter what the promoting event is, to crystallization of calcium and phosphorus. Therefore, if we were able to stop the final event, hopefully you will be able to inhibit further calcification, and that's what we tested in this particular article, in this particular study.

Dr Carolyn Lam: Oh Paolo, I just love the way you described that. Very, very crystal clear, if you don't mind the pun. But could you please let us know, so a phase 2B trial, does that mean a surrogate outcome, duration of treatment, number of patients? How about telling us a little bit about the trial?

Prof Paolo Raggi: So, the trial involved recruiting three different groups of patients. One would be treated with placebo and two other cohorts would be treated with either 300 milligrams of SNF472 three times a week or 600 milligrams of SNF472 three times a week. The product is injected intravenously into the dialysis line. Therefore, the patients do not have to remember to take a pill or inject themselves. Actually, it's perfect, if you will, compliance because all they have to do is come to their dialysis session and they receive it during dialysis.

The study therefore, it was a relatively small study, but enough to prove our point. Three groups were recruited, about 90 patients each, and the two treatment arms at 300 milligrams and the 600 milligrams, were combined as a single group for the purpose of reporting the primary results. The follow up was at one year, so these patients were submitted to CT scanning of the chest without contrast for measurement of calcification only at baseline and then again at 52 weeks. In the intention to treat group, patients were included if they had a baseline scan and at least one follow-up scan at some point during the study. These are very sick patients and sometimes are referred for transplant. Sometimes they withdraw from studies. So, we asked everybody to have a second scan if they needed or wanted to withdraw before the 12 month mark was reached. That's for the intention to treat analysis. And then we need some confirmatory analysis on patients who actually did have the baseline in an actual 12 months scan and received the entire year treatment with these two drugs, with a drug or placebo.

Dr Carolyn Lam: That's great and please tell us the results.

Prof Paolo Raggi: The results were, in our minds, very exciting. And let me first say, that in all the literature that looked at what is the average progression of calcification in the general population, it's anywhere between 10 to 15% per year. For the person with calcium in the coronary arteries, there's an expected progression about 10 to 15%. All the publications in patients with renal failure and undergoing dialysis, show the progression of anywhere between 25 and 35%, so these people are not only more calcified, these patients also progressing very fast. In the particular trial that we reported in Circulation, we demonstrated on average, a progression of 20% in the group receiving placebo and about 11% in the group receiving SNF472. So, there was about a 45% slowing of progression in the treated group compared to the placebo group.


Interestingly enough, we saw a slower progression unusual in the placebo group. As of today, many more treatments are available to patients with end stage renal disease that were not available when the original studies that I mentioned earlier were conducted. So, the 25 to 35% progression that we saw 15 years ago, it's now slowed, you notice, to a 20% progression in these patients, but SNF472 was even more effective at further slowing that progression.

Dr Carolyn Lam: Well, congratulations first and foremost on a very successful and really striking and novel results. Well, Amit there's so much to discuss I don't even know where to start. But first, maybe can I bring you in by saying, so what, is Circulation now publishing renal papers?

Dr Amit Khera: The answer is absolutely yes. So first I want to congratulate Dr Raggi on a fantastic paper. This was a concomitant late breaking science at the American Heart Association Sessions; so, we always try to think of timely and exciting topics and appreciate working so closely with this group to bring this across the finish line. At Circulation, one thing we've been working on is something called Bridging Disciplines, where purposefully we appreciate the heart is not in isolation and not in a box by itself, but within a larger system, a body system. So, we really enjoy these types of papers that cross disciplines and there's an outstanding editorial by Susan Hedayati, from UT Southwestern who's a nephrologist, who weighed in here as well. So we certainly really value these types of papers in Circulation.

Prof Paolo Raggi: I have to say, working with Circulation was amazing. You know, you get a great job and so fast. It was an incredible, actually.

Dr Amit Khera: Obviously, the results speak for themselves that the study was positive, and we certainly see this diminishing the vascular classification and certainly you've been, for decades now, an expert in vascular calcification and coronary imaging. And you know, the question that always comes up is, what are the implications here? Now, on one side, especially with the coronaries, you think this would be favorable, you get less obstructive disease, perhaps less ischemic heart disease. But there's always been this debate if calcium's a good or bad thing in terms of plaque stabilization, so what are your thoughts on what ends up being the clinical ramifications of this down the road?

Prof Paolo Raggi: Well of course, as we clearly stated in the paper, this has to be followed by some sort of clinical outcome study. So, it is only speculating at this point as to what the benefit might be. But more specifically about your question, I think that there is a misinterpretation of what calcification means in general. And honestly, I would prefer not to have calcification in my cardiovascular system if I had the choice. Many believe, and it's possibly true to a degree, that calcification comes in to repair the plaque and there's some sort of repair mechanism, but we have shown very clearly that the greater the calcification burden, the higher the probability of cardiovascular morbidity mortality. And therefore, it is not benign to have cardiovascular calcification in general.


In the case of the patients with end stage renal disease, calcification is not limited to the atherosclerotic plaque. It extends to the thickness of the entire vessel wall and it's well known that patients with end stage renal disease have severe calcification of the media as well as the intima. This obviously causes a series of other problems, such as stiffening of the vessels and therefore reduce compliance and in the long run, many profusion issues to multiple organs, even in the absence of luminal stenosis. A stiff vessel does not comply with what it's supposed to be doing. It is not allowing proper profusion of an end organ and many have demonstrated that also increases the work of the heart, pumping against very rigid plumbing, if you want to put it that way and simply, and therefore may induce left ventricular dysfunction in the long run, arrhythmias if a patient develops left ventricular hypertrophy and fibrosis. So, I think that there's a cascade of events that goes beyond and above just the single plaque, atherosclerosis, calcification. I think that calcification in general, and especially in patients with end stage renal disease, is a whole marker, very high risk of complications.

Dr Amit Khera: Thanks for that clarification. I think first and foremost, it's so helpful to think beyond just isolated luminal stenosis and sort of all the maladaptive aspects of vascular calcification in patients with end stage renal disease. And that leads to the next thing in your paper, which I thought was also really interesting, which was the aortic valve calcification. We certainly appreciate that focus on aortic stenosis as of late with the new therapies, but you know particularly in patients with end stage renal disease, it becomes a very complex issue. And you saw some abating of this vascular calcification in the aorta as well. Tell us a little bit about what you think the implications of that would be.

Prof Paolo Raggi: So first, a word of caution that the trial was not powered to demonstrate specifically an effect on aortic valve. However, we did demonstrate a beautiful effect on the slowing of the aortic valve calcification as well. It's exciting! I think that it's something that needs to be pursued further and I hope future studies, and definitely is the first time that anything has demonstrated an effect on aortic valve calcification. I'm very well aware of other studies that have attempted, for example, use of statins to slow the progression of valvular calcification and in essence, were completely negative. Patients with end stage renal disease, very severe valvular abnormalities, very, very severe, very important valvular dysfunction as a consequence of massive calcification on the annulus and the leaflets more so of the aortic valve, but also the mitral valve. So this could definitely be a signal for an excellent potential and unexpected if you will, a secondary outcome of this treatment. I believe that in affecting valvular calcification in patients with end stage renal disease would be, could have potentially a massive effect from the point of view of lowering the cardiovascular event rate.

Dr Carolyn Lam: May I chime in with a quick question? What were adverse effects like?

Prof Paolo Raggi: This particular drug actually was associated with the same exact rate of adverse effect as placebo. In other words, we didn't see anything at all that was alarming. There was one patient that had been reported by the investigator as potential side effect of the drug. They reported something, I think it was like acute hepatic failure, but when the case was clearly analyzed by the DMV, we actually assessed dictation as being a case of cholecystitis had been incorrectly labeled, we believe. And except for that one case, there essentially were no side effects, no adverse effects from treatment. In fact, although it was not powered for those outcomes, there was a lower morbidity and mortality with the SNF472 and then with placebo.

Dr Carolyn Lam: I really like that and was really struck by your pointing out a little bit earlier, the ease of administration as part of hemodialysis. That was very nice. Amit, I'm going to give you the final words and questions if I may.

Dr Amit Khera: As expected, this has been an exciting podcast and as much as I've read this paper and looked at it in detail, I learned a lot more as I had anticipated. My question for you, Paolo, now, is what's the next step? This is a phase 2B study. What's the next step in the development or evaluation of this compound and where are you going with this?

Prof Paolo Raggi: There are a few sub analysis that we haven't yet looked at in this particular study that we just reported. One of the things that we are definitely interested in is to evaluate the effect on bone. As you can imagine, it is true that this particular drug has a wonderful effect on vascular calcification, but the next question is, did it do anything adverse to the bone? It's a logical question but I feel that most likely the answer is going to be a resounding no.

But, besides that, the further development of this drug is obvious in my mind. It will have to be addressed in a proper, randomized clinical trial to address some of the clinical questions that we all have. Is this reducing the cardiovascular events? Be it when we need, we will decide together what those cardiovascular events would look like. But obviously myocardial infarction, congestive heart failure, admission for unstable angina, cardiovascular deaths in general, those are going to be very important questions to be answered in a further step. Before we get there, there are a few other questions that we have for the drug itself from this particular 2B study that we can still look at.

Dr Amit Khera: Excellent. Looking forward to those subsequent analyses.

Dr Carolyn Lam: Thank you and we look forward to the next publication on Circulation.

Dr Amit Khera: Absolutely.

Dr Carolyn Lam: I'm sure the audience is actually looking forward to more such discussions as these. Remember, you've been listening to Circulation on the Run.


Dr Greg Hundley: This program is Copyright The American Heart Association 2020.


Feb 24, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center at BCU Health in                                                     Richmond, Virginia.

Dr Carolyn Lam: So Greg, guess what? We are going to be discussing predicting the benefit of evolocumab therapy in patients with atherosclerotic disease using a genetic risk score. That's our featured paper this week coming from the results of the FOURIER trial. I bet you can't wait to discuss it, but I'm not going to let us until we talk about some of the papers in today's issue. Do you have one?

Dr Greg Hundley: Yes, Carolyn, but first I'm going to get a cup of coffee because there's a lot of data in this one. This study is from the ODYSSEY trial and it involves alirocumab and it's from Dr Charles Paulding. Remember Carolyn, the ODYSSEY trial was a randomized double-blind placebo-controlled trial comparing alirocumab, a PCSK9 inhibitor or placebo in 18,924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. And the primary endpoint of this trial comprise death from coronary artery disease, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization. Now Carolyn, this is a sub-study and it was performed an A genome wide polygenic risk score for coronary artery disease comprising 6,579,025 genetic variants. And they were evaluated in 11,953 patients with available DNA samples. Analysis of the MACE risks, all those outcomes together, was performed in placebo treated patients while treatment benefit analysis was performed across all the patients.

Dr Carolyn Lam: Ooh, so what did they find?

Dr Greg Hundley: Well, Carolyn, both the absolute and relative reduction of MACE by alirocumab compared to placebo was greater in high versus low PRS patients. Those genetic, polygenetic risk scores combined in the patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6% and 1.5% respectively, and relative risk reduction in the alirocumab of 37% in the high PRS group versus 13% in the low PRS group. And so Carolyn, these results suggest the possibility of an independent tool for risk stratification using sort of precision medicine by selecting those using these genetic constructs, who may be more likely to benefit from this form of therapy.

Dr Carolyn Lam: Wow Greg, that is really interesting. I genuinely think that our world is moving towards precision medicine and this really, really speaks to remember that feature paper also talking about genetic risk scores, but from the FOURIER trial. But before we get to that, I've got a basic science paper. Now this one provides insights into the mechanisms underlying age related hypertension. And it's from Dr Ying Yu and colleagues from Tianjin Medical University who hypothesize that since proinflammatory cytokines increase in T lymphocytes with aging and prostaglandin D2 suppresses T helper 1 cytokines through the D-prostanoid receptor 1, that this axis in T cells may play a role in age related hypertension.

Dr Greg Hundley: Ah, Carolyn. What did they find in this study?

Dr Carolyn Lam: Prostaglandin D2 biosynthesis and D-prostanoid receptor 1 expression, were both markedly decline in CD4 positive T cells from older humans and aged mice. D-prostanoid receptor 1 depletion in these CD4 positive T cells, exaggerated age dependent blood pressure elevation in mice by increasing tumor necrosis factor alpha and interferon gamma secretion. Whereas its over expression showed the opposite effect and its activation suppressed TH1 cytokines. These results really indicate that D-prostanoid receptor 1 and its downstream pathway may serve as an attractive immuno-therapeutic target for age dependent hypertension.

Dr Greg Hundley: Oh wow. Very insightful Carolyn. Well, I've got a basic science paper to go over and it's from professor Kinya Otsu from Kings College London. This study addresses the mechanism of ongoing inflammation within the hearts of patients with cardiomyopathy. The study involves the assessment of Regnase-1 and RNAs involved in the degradation of a set of pro inflammatory cytokine messenger RNAs in immune cells. And the study involves the role of Regnase-1 in non-immune cells such as cardiomyocytes.

Dr Carolyn Lam: Wow.

Dr Greg Hundley: The degradation of cytokine messenger RNA by Regnase-1 and cardiomyocytes plays an important role in restraining sterile information in failing heart. Once the inflammatory cascade gets going, this is that constant inflammation that's ongoing. In addition, the Regnase-1 mediated pathway might be a therapeutic target to treat patients with heart failure as adeno-associated virus 9 mediated cardiomyocyte targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody, attenuated the development cardiomyopathy induced by severe pressure overload in wild type mice.

Dr Carolyn Lam: Wow, that's really interesting. I find this whole field of inflammation in heart failure of course, of key interest, but I'm going to next tell you about the results of the FUEL trial, which is the Fontan Udenafil Exercise Longitudinal trial.

Dr Greg Hundley: Tell us about the Fontan operation.

Dr Carolyn Lam: Aha, I thought you may ask, Greg. Well, the Fontan operation to remind us all, really creates a total cavopulmonary connection and a circulation in which the importance of pulmonary vascular resistance is therefore magnified. Over time, the circulation needs to deterioration of cardiovascular efficiency associated with a decline in exercise performance. This FUEL trial and reported this time by David Goldberg and colleagues from the Children's Hospital of Philadelphia was a phase 3 clinical trial, which randomized 400 patients with Fontan physiology from 30 sites in North America and the Republic of Korea. The participants were randomly assigned to Udenafil at 87.5 milligrams twice daily or placebo. And the primary outcome was the between group difference in change in oxygen consumption with peak exercise.

Dr Greg Hundley: Hmmm, very large important trial it seems like Carolyn. What did they find?

Dr Carolyn Lam: Treatment with Udenafil did not result in a significant increase in peak oxygen consumption, which was the primary outcome, but did result in improvements in measures of exercise performance at the anaerobic threshold, which was a secondary outcome. Udenafil was well tolerated with side effects limited to those previously known to be associated with phosphodiesterase type 5 inhibitors.

These results and future perspectives are discussed an editorial called FUELing the Search for Medical Therapies in Late Fontan Failure, by Doctors Gewillig and De Bruaene.

Dr Greg Hundley: Very nice, Carolyn. Now how about the rest of the journal?

Dr Carolyn Lam: Oh well I want to tell you about this in-depth review by Dr Rosenkranz and it's entitled, Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure. Very intriguingly, talking about non-cardiac features, as well as cardiac, of right heart failure, a real, real must read with beautiful figures.

In the cardiovascular case series we discuss a case of left ventricular non-compaction and cardiogenic shock by Dr Shenoy. There are also two research letters I want to tell you about one by Dr Gillinov on the accuracy of the Apple watch for detection of atrial fibrillation. And this time looking at the Apple watch series 4, which interestingly employs electrodes to generate a single lead ECG and provides two mechanisms for rhythm assessment. Won't tell you more. You got to pick up this beautiful letter.

The next is by Dr Mazer on the effect of empagliflozin on erythropoietin levels IN stores and red blood cell morphology in patients with type II diabetes and coronary artery disease. And this really provides evidence to suggest that SGLT 2 inhibition with empagliflozin may stimulate erythropoiesis via an early increase in erythropoietin production in people with diabetes.

Dr Greg Hundley: You know Carolyn, we just keep hearing more about EMPA and DAPA and they are just going to really pave the way I think for a whole new class of agents that we're going to be using frequently.

I've got a couple letters in the mailbox and one is by Sugimoto and Taniguchi regarding the article, Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients with Implantable Cardio Defibrillators, a randomized clinical trial. And then also there's another research letter by Dr Hiroshi Sugimoto from Kobe Red Cross Hospital with a response by Jakob Lüker from University of Cologne.

What a great issue. How about we proceed to that feature article?

Dr Carolyn Lam: You bet.

Can a genetic risk score identify individuals who will derive greater benefit from PC SK9 inhibition? Well guess what? We're going to find out now in our feature discussion. So pleased to have with us the first and the corresponding authors of our feature paper, Dr Nicholas Marston and Dr Christian Ruff, both from the TIMI study group in Brigham and Women's Hospital and Harvard Medical School and also to have our lovely associate editor, Dr Svati Shah from Duke University in Durham, North Carolina. Welcome everyone.

Nick, could I get you started with telling us about this exciting analysis that you did from the FOURIER trial?

Dr Nicholas Marston: The FOURIER trial was a 27,000 patient cardiovascular outcomes trial that studied the PC SK9 inhibitor, evolocumab and it demonstrated a significant reduction in major adverse cardiovascular events in patients who had established atherosclerotic disease. And in the study, there was a 15% relative risk reduction and a 2% absolute risk reduction, which earned it a class 2 recommendation for very high-risk patients with atherosclerosis in the recent cholesterol management guidelines. And what we've done in previous lipid trials is we studied the interactions between genetic risk and treatment benefit. For example, in 2015 we showed that patients with high genetic risk, those in the top 20% of genetic risk, had the greatest benefit from statin therapy in terms of both absolute and relative risk reductions. And so now we have the opportunity with evolocumab and data from the FOURIER trial to ask the same question of PC SK9 inhibitor. That is, could a genetic risk score identify patients who will drive a greater treatment benefit and we hypothesize that like statins, there would in fact be a significant interaction between genetic risk and therapeutic benefit.

Dr Carolyn Lam: That's so cool Nick. But could I ask, the question always comes, is it nature versus nurture? And so I really love the way that you dealt with the clinical risk factors as well. Could you maybe walk us through that and then tell us the results?

Dr Nicholas Marston: Yes, absolutely. We for this study, kind of had two objectives. One was to look at risk prediction and then the other look at treatment benefit and using a genetic risk score for both. However, we wanted to go further than just use the genetic risk score. We wanted to incorporate clinical risk factors since that's how we would do it as physicians in the clinic. We would have not just genetic risk data in front of us but also clinical data. And so when we were grading a patient's risk using genetic risk, we also factored in if they had multiple clinical risk factors. And what we found by combining both genetic and clinical risk was that there was a significant gradient of risk across these risk categories.

That is patients who were without high genetic risk and without multiple clinical risk factors actually had no benefit from evolocumab over the 2.2-year follow-up period. However, those without high genetic risk, but who did have multiple clinical risk factors, derived an intermediate benefit. About a 13% relative risk reduction and 1.4% absolute risk reduction. And then it was the high genetic risk group, independent of whether or not they had multiple clinical risk factors that had the largest benefit from evolocumab with a relative risk reduction of 31%, absolute risk reduction of 4% and the number needed to treat of 25. And that's actually a twofold greater benefit than was seen in the overall FOURIER trial population.

Dr Carolyn Lam: That's really stunning results. Now I know Svati's going to have questions for us, so maybe I should invite you Svati, just put these results into context and let the audience know what we were thinking as editors when we saw this brilliant paper.

Dr Svati Shah: Yeah, thanks Carolyn. And I think Nick has done a fantastic job of describing the exciting results from this paper and just kind of taking a step back to help the audience understand what we're talking about when we're talking about genetics. For decades, we've been trying to figure out the genetics of heart disease and we're not talking about the genetics of things that are really rare like long QT syndrome, but the genetics of just common complex heart diseases. And amongst the scientific community, we've tried all different ways of sort of analyzing these data and so I want to make sure that everybody who's listening understands the novelty of really looking at these polygenic risk scores. Where we have now come to understand that it's not a single gene, it's not even two genes, that it's multiple variants and multiple genes and when they're combined, that's when you really have the power to understand how it might be useful in terms of how we take care of patients.

Really important with how Nick and Christian have laid out this really nice paper as well as their prior work in statins, is that not only did they show that these polygenic risk scores are associated with cardiovascular outcomes or even different amongst whether you get treated with the drug or whether you don't, but really importantly they're getting it clinical utility, not only with regards to showing that they compare it to a clinical risk score, but really showing that if you use these polygenic risk scores, you can identify patients who may derive the greatest benefit from PC SK9 inhibitors. And importantly in their paper, they show that if you have low polygenic risk score and low clinical risk score, you may not derive benefit from PC SK9 inhibitors. With all the caveats that this is a secondary prevention population, so I really applaud Christian and Nick and his team for the nice work that was done.

Dr Carolyn Lam: Oh, couldn't agree more, Svati. You know what I was very struck with too, because some people go, I may have a genetic risk. Maybe I could undo it or somehow overcome it with my clinical risk factors. And that's why I really appreciated that they showed that it was additive, and genetics still matter even if you have risk factors and vice versa. That was really cool. Christian, could I ask you to maybe describe a bit, what kind of genetic risk score this was and maybe perhaps point out some of the limitations therefore of what you studied.

Dr Christian Ruff: As Svati mentioned, this is really a quickly evolving field. We now have the ability to either genotype or sequence all of the variation that makes us different from one another. Our susceptibility to disease as well as our potential benefit for treatment. We had for this study, looked at several different risk scores. The one we focused on was a coronary artery disease genetic risk score that had 27 different variants that had been shown to predict having a cardiac event, both in primary and secondary populations. And we have previously identified patients who may have been at a higher risk who received greater benefit from statin therapy. And in this study, we actually compared this 27 variant genetic risk score with actually a much larger score of over six million variants. And interestingly, the two scores performed fairly similar with respect for risk prediction. One of the big questions going forward is, we have lots of ways to develop genetic risk scores, how many different variants do we need? What more information do we have with more complicated scores?

And I think Svati really hit on a really critical point is that really this study is really layering in genetic risk on top of clinical risk factors, which we can easily assess at the bedside. And I think what's reassuring to patients is that not only is genetic risk able to give us much more information for prognosis, but that this risk is modifiable. People think that their genetic risk, they're sort of born with it and there's nothing that they can do about it. But in this study, as Nick pointed out, even over a very short period of time with powerful lipid lowering therapy with a PC SK9 inhibitor, we essentially reduced these patients at high genetic risk to the risk of the very low risk patients on placebo. I think this is a reassuring message that genetics plays an important role for risk prediction and it identifies patients who we might target for more intensive therapy and that we can potentially reduce that risk even though that risk is based on the DNA that they're born with.

Dr Carolyn Lam: Indeed. That's a great point. And Svati, I'm sure you were thinking along those lines when you invited that beautiful editorial by Doctors Daniel Raider and Michael Levin. But Svati, would you like to comment on your thoughts on, is this ready for prime time?

Dr Svati Shah: I think that's the key question. What Christian and Nick and his team have done is take us a big step forward in how we use these polygenic risk scores. I think there still are many skeptics amongst the genetic scientific community about, well great, you can look at 27 variants and some of these polygenic risk scores, you're looking at a million things. How do we actually use that to take care of patients?

I actually want to turn this back, that question back around Carolyn, and I'd like to ask Christian next, what are the next steps? There are a lot of cardiologists who if you're listening to this podcast, should we all run out and get our patient's genotype to order this genetic chip so that we can figure out what their polygenic risk score is?

Dr Christian Ruff: Yeah, that's a great question and I could start off and then hand off to Nick, but I think one of the key questions is obviously there are a lot of genetic risk scores and I don't think as a field that we've come up with which one we really should implement in clinical practice. There's still a lot of fine tuning and figuring out which score gives us the most amount of useful information.

And then I think as something that you had mentioned that these scores are generated in both a healthy cohort population and now, we're looking at it in clinical trials and there's no sort of reference. Like when we have a blood test and we say, "If your hemoglobin A1C is above or below this number that means that you have diabetes." And we haven't figured out, what are the actual thresholds that you use for these genetic risk scores that you can implement broadly across different patient populations. There's still a lot of work that needs to be done to make these scores ready for prime time. This is really setting the stage. Is this something that we should be doing? And I think these studies and others say that the data looks great that we should be doing this, but we haven't yet figured out the logistics of which score and how do we actually reference to population.

Dr Nicholas Marston: Yeah, I agree with Christian definitely that we need to figure out what's the optimal genetic risk tool and for which population and what the cut points are. And then I think another piece that's going to be very important moving forward is doing a lot of this work and studying in non-European ancestry and cohorts and populations. Because most of the work done so far in discovery has been in databases such as the UK Biobank. And that limits us in our analyses to European ancestry patients. And so, I think for this to go to prime time, we want to be able to offer it to all of our patients. And so that means making sure we have scores that fit all populations, not just primary and secondary, but also all different types of ancestry.

Dr Carolyn Lam: Oh, I'm so glad you mentioned that, Nick. That was exactly on my mind coming from Asia. And the other thing of course, would be cost effectiveness of these approaches. Oh my goodness. I wish we had all the time in the world to talk about this more. The implications are enormous, but just let me thank you on behalf of all of us for publishing this remarkable paper in Circulation.

Audience, you've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.


Feb 17, 2020

Dr Biykem Bozkurt: I am Biykem Bozkurt, Professor of Medicine from Baylor College of Medicine, Senior Associate Editor for Circulation and today, I'm joined with Sana Al-Khatib, Professor of Medicine from Duke University, Senior Associate Editor of Circulation, for the podcast for the fourth annual Go Red for Women issue for Circulation. As all our listeners are aware, cardiovascular disease is a leading cause of death among women, but we have significant gaps in our awareness and treatments, and with a recognition of these disparities for cardiovascular care in women, AHA has launched a Go Red for Women campaign back in 2004. We have made great strides, and despite the improvement in awareness, significant gaps persist and adverse trends are emerging for cardiovascular disease in women.

With such recognition, in 2017, Circulation launched the annual Go Red for Women issue, dedicated to cover transformative science, exciting new treatment strategies, recent epidemiological trends, and with an intent to close the gaps and eliminate the disparities for cardiovascular care in women. This is the fourth Go Red for Women issue and we have an exciting portfolio that we'd like to share with our readers and listeners. In this issue, we have quite a few important papers. The first two that we would like to start with are going over the epidemiologic trends. Sana, do you want to walk us through the two papers that we have on myocardial infarction and sudden cardiac death?

Dr Sana Al-Khatib: I would love to start with the paper on sudden cardiac death, which is very fitting. That's what I focus most of my work on. This particular paper actually looked at sudden cardiac death as the first manifestation of heart disease in women, and it was focused on the Oregon sudden unexpected death study, the timeframe for which was between 2004 and 2016 and what they really wanted to do is to assess sex specific trends in sudden cardiac death incidence. And so they focused on out of hospital, sudden cardiac death cases among adults during that time period.

And they divided that 12-year period from February 2004 to January 2016 into three four-year intervals, 2004 to 2007, 2008 to 2011 and 2012 to 2015. And they really looked at these trends among women and men and they found that there were 2,938 sudden cardiac deaths, 37% of who were women. And they found an interesting U-shaped pattern of risk of sudden cardiac death with Anader in 2011. An increase in the years that followed 2011 so regarding that rebound, the rates really increased in 2013 and 2015. And when they specifically looked at women, they found that the rates of sudden cardiac death declined by 30% between the first and second four year time period and increased by 27% between the second and third period.

Interestingly, the subsets with sudden cardiac death as the first manifestation of heart disease, accounted for 58% of the total rebound in sudden cardiac death incidence from period two to three but there was no change in the incidence over time for sudden cardiac death occurring among people with preexisting heart disease. For men actually sudden cardiac death also declined from the first to the second period, but not as much as in women and also increased between the second and third periods. Again, not as much as we saw in women. Subsets of sudden cardiac death occurring in the setting of identifiable heart disease was responsible for 55% of the rebound in overall sudden cardiac deaths incidence. Certainly some significant differences between men and women. Very exciting findings.

Then if we actually turn our attention to the second study looking at sex specific trends in acute myocardial infarction, this particular analysis, Biykem, was done within an integrated healthcare network between 2000 and 2014 and they picked the Kaiser Permanente Southern California network. They were able to identify 45,000 plus acute MI hospitalizations between 2000 and 2014 and they found that age and sex standardized incident rates of AMI declined from 2000 to 2014. And they found that a decline for women was actually more so than in men. And in fact for men it was pretty much stable. And they found that the incidence of hospitalized MI had declined, however, declines are slowing among women compared with men in recent years.

That's actually identified some unmet care needs among women that hopefully can meet people and investigators to tailor their approaches to try to close those gaps and disparities in care. With that, let me actually turn it back to you to potentially talk about to cardiovascular risk assessments in women.

Dr Biykem Bozkurt: With the recognition of the disparities and the recent emerging trends of adverse outcomes, especially in younger women, there has been a focused attention in how to assess risk, cardiovascular risk in women. There is a very comprehensive review by Salim Virani and colleagues who's addressing the cardiovascular risk assessment for women. As our listeners will recall in 2018, ACC/AHA cholesterol professional guidelines specified risk enhancing factors such as premature menopause or preeclampsia for women. And if present, in borderline or intermediate risk patients, would elevate the 10 year risk to a higher category. But now with a recognition of many more risk factors, Virani and colleagues are proposing a more comprehensive cardiovascular risk assessment for women. And these include the risk factors that are not only identified in the 2018 ACC/AHA cholesterol guidelines, but additional such as gestational hypertension and diabetes or adverse pregnancy outcomes such as preterm delivery, small birth for gestational age or placental abruption or infarct or premature menarche or premature menopause, primary ovarian failure or pregnancy loss and additionally inflammatory disorders such as lupus, rheumatoid arthritis, psoriasis and history of cancer and cancer related therapies.

And they formulate this in a nice and well tabulated fashion. And all these risk factors are summarized table one which I think most of our listeners and readers will refer to. And they also come up with a nice approach. What shall we do? And how shall we detect that risk? First recommendation they have is that we should obtain a comprehensive obstetric and gynecological history from all women. And if these risk factors are present, then we should then screen for other traditional risk factors early and frequently and then treat for modifiable risk factors such as hypertension, hyperlipidemia, diabetes, metabolic syndrome, and also implement aggressive lifestyle modification with strategies such as management of blood pressure control, reduction of blood sugars, remaining active eating, healthy, losing weight, and not smoking. Which is summarized as life's simple seven which is an AHA initiative that summarizes healthy lifestyle as life's simple seven.

And very complimentary to Virani’s review paper, we had another wonderful paper that is titled Life's Simple Seven and health by Jacqueline Kulinski who reminds us that not only these seven factors but breastfeeding for postpartum mothers is an important approach to reduce cardiovascular risk. Breastfeeding is not only beneficial for the newborn infants but for the mother as it's been associated with reduction in risk of myocardial infarction, stroke, cardiovascular disease hospitalization rates, future development of diabetes, hypertension, and even mortality. And this paper elaborates on potential mechanisms such as increases in metabolic expenditure, enhancement of insulin sensitivity, reduction in cholesterol, greater mobilization of fat stores and reversal of elevated triglycerides and cholesterol that's seen during pregnancy.

It also emphasizes the importance of recognition and education of women because currently only about 25% of women are exclusively breastfeeding at six months and US has one of the lowest breastfeeding rates among industrialized countries. And we do have disparities according to race and income and black infants and infants living in rural areas in Southeast USA are less likely to be breastfed. And there is definitely increased recognition for importance and but it's also important to be able to accommodate and facilitate breastfeeding for mothers. Currently the paper emphasize that all 50 states now have laws allowing women to be able to breastfeed in public or private locations. But again, there definitely is a necessity for increased awareness and education.

On that end, there is also a great paper covering the news release announcing the partnership between American Heart Association and American College of Gynecology and Obstetricians in promoting risk identification and reduction of cardiovascular disease in women through collaboration between obstetricians and gynecologists. In 2018, AHA and American College of Gynecology issued a call for action for both specialists to team up and increase screening for cardiovascular disease by obstetricians and provide education and appropriate referrals. And I think this initiative is going to increase the opportunities for young women whose primary care provider solely could be an obstetrician, who potentially will get screened for cardiovascular disease and if they have these risk factors, will potentially be able to be offered lifestyle modification, message and intervention strategies.

These, I think, three very complimentary papers are enhancing our recognition for the new risk profile that needs to entail getting a comprehensive obstetric and gynecological history in all women. And in the event we recognize either of these risk factors including the traditional risk factors or obstetric and gynecological risk factors such as pregnancy related complications or preeclampsia or other additional special risk factors such as autoimmune disorders and cancer, then we will need to heighten our awareness for lifestyle modification, risk management, and earlier treatment and closer monitoring.

That brings us to another important risk profile, which is cancer for women. And Sana, I know we do have two great papers related to cancer topic. If you could elaborate on those.

Dr Sana Al-Khatib: I'm really excited about these papers. As you pointed out, Biykem, that cardio oncology is a field that is really expanding and so it was really very gratifying to get these two papers. The first paper had to do with a comparison between aromatase inhibitors and Tamoxifen in women with breast cancer in terms of their association with the risk of cardiovascular outcome. And this particular study was done in the United Kingdom and they studied women though with newly diagnosed breast cancer initiating hormonal therapy, either with everyone at aromatase inhibitors or Tamoxifen between 1998 and 2016. And the study outcomes that they were interested in included myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality.

And they actually had a sizable patient population with 23,000 plus patients included in this analysis of whom close to 18,000 initiated treatment with either an aromatase inhibitor or Tamoxifen. And they found that the use of aromatase inhibitors was associated with a significantly increased risk of heart failure and cardiovascular mortality compared with Tamoxifen and that aromatase inhibitors seemed to have a trend towards increased risk of myocardial infarction, ischemic stroke. Although those differences were not statistically significant. They actually concluded that aromatase inhibitors were associated with an increased risk of heart failure and cardiovascular mortality compared with Tamoxifen and that there were trends toward increased risks also of MI and ischemic stroke. And so they really want clinicians and patients to be aware of these findings when they are trying to make decisions about treatment for breast cancer.

We have another really interesting study, Biykem, that was actually a randomized control trial that studied the effect of exercise therapy dosing schedule on impaired cardiorespiratory fitness in patients with primary breast cancer. And so this randomized trial enrolled 174 post-menopausal patients who were randomly allocated to one of two supervised exercise training interventions, delivered either using a standard linear test or nonlinear test. And they had a control group of just stretching. They did some stretching. And they did the trial over at periods of 16 consecutive weeks and the primary endpoint was change in the VO2 level, PCO2 level from baseline to post intervention.

They had a couple of other secondary endpoints and their results were interesting. They found no serious adverse events during the trial, but they actually found that 40% of patients in both exercise dosing regimens were classified as responders. And they concluded that short term exercise training independent of dosing schedule was associated with modest improvements in cardiorespiratory fitness in patients previously treated for early stage breast cancer. Really interesting, a smaller study, not really looking at hard endpoints yet. It's still important because I believe that it is going to form the basis for more studies and more research in this important field, Biykem.

With this, I'd like to turn it over to you to talk about elevated body mass index in young women.

Dr Biykem Bozkurt: And this is another fascinating study, a large study from Sweden. It involved more than 1.3 million young women. Average age was 27. It was a national prospective cohort. The recruitment was between 1982 and 2014. What they did was they measured the baseline of weight of women in early pregnancy in the first trimester, actually the first antenatal visit before they could gain any weight related to the pregnancy. With their BMI measurement at baseline, then they followed these patients for approximately 30 years and associated this baseline BMI with future developments or dilated cardiomyopathy or any cardiomyopathy. They looked at that dilated cardiomyopathies, hypertrophic cardiomyopathies, these other cardiomyopathies such as alcoholic cardiomyopathy and others.

Interestingly, elevated body mass was associated with future development of dilated cardiomyopathy. A very similar finding was reported in former studies for adolescent men, but we didn't have this finding for young women. This study provides evidence that elevated BMI, even if it is only in the overweight range, is associated with future development of dilated cardiomyopathy. In the past we had numerous studies demonstrating overweight or obesity status being associated with future development of clinical heart failure, clinical symptoms of heart failure, but this is one of the largest scale population based cohorts demonstrating the association with dilated cardiomyopathy.

And interestingly, these women at baseline did not have the usual other confounders or comorbidities associated with future development of cardiomyopathy. The risk of diabetes and hypertension was less than 1% at baseline. Very interestingly, BMI by itself, independent of all these other variables was associated with future risk. And of course the higher the BMI was, the higher the risk was. The highest risk was for those with morbid obesity or BMI over 35 and in those patients the risk was increased by about five fold.

Sana, we talked about the disparities for women. Where are we with women participation in cardiovascular trials? And how do we looked globally overall regarding the disparity of cardiovascular diseases in woman?

Dr Sana Al-Khatib: These are really important questions, Biykem. Let me first start with a study that will be in the Go Red for Women issue on women's participation in cardiovascular clinical trials. They looked at that. Between 2010 and 2017, which is a very important topic as you know, Biykem. And so what they did here is they actually assessed the participation of women in completed cardiovascular trials that were registered in clinical trials between 2010 and 2017. And they parked calculated the female to male ratio for each trial to determine the prevalence adjusted estimates for participation of women. And so they kind of defined it as participation prevalence ratio. And so they said that they were able to identify 740 completed cardiovascular trials including more than 860,000 adults of whom 38% were women. And they talked about how the median female to male ratio of each trial was 0.501 overall and varied by age group and type of intervention and region and trial size and funding sponsors.

Actually, these are really interesting findings. In the interest of time, I'm not going to delve into all those details, but I think it would be really interesting for people to read that and look at this more carefully. But they found that relative to their presence in the disease population, the participation prevalence ratio of women versus men actually was a higher than 0.8 for hypertension, pulmonary arterial hypertension and lower for arrhythmia, coronary artery disease, acute coronary syndromes and heart failure trials. And they found that in the most recent time period, that they defined between 2013 and 2017, they saw a significant increase in the participation and prevalence ratios for stroke and heart failure trials compared to other periods. They concluded, not surprisingly, that among cardiovascular trials in the current decade, men still predominate overall, but that the representation of women actually is improving, especially when it comes to studies related to stroke and heart failure. That's what's really interesting, Biykem.

The other point that you were very nicely raised had to do with sex differences in primary and secondary prevention of cardiovascular disease. And the one study that we have in our issue, Biykem, was actually done in China. I really like this global reach of our issue. I presented a study that was done in the UK. You presented a study done in Sweden. This particular one was done in China and they conducted a community based survey of adults in seven geographic regions of China between 2014 and 2016. They really wanted to determine sex differences in the primary and secondary prevention of cardiovascular disease. And they looked at different factors in terms of age, education level, area of residence. And they had more than 47,000 participants of whom 61% were women. And they found that 5,454 had established cardiovascular disease, 57% of whom were women and 9,532 had a high estimated 10 year cardiovascular disease risk. And of those, 71% were women. And they found that only about 49% of women versus 39%, 60% of men were on any kind of blood pressure lowering medications, lipid lowering medications, antiplatelet therapy for primary and secondary prevention.

And they found that women with established cardiovascular disease were significantly less likely than men to receive blood pressure lowering medications, lipid lowering medications, antiplatelet therapy, so on, so forth. And that woman with established cardiovascular disease had better blood pressure control but less well controlled NVM cholesterol, were less likely to smoke and achieve physical activity targets. Conversely, women at high risk of cardiovascular disease were less likely than men to have their blood pressure LDL cholesterol, body weight controlled, despite the higher use of blood pressure lowering medication. Really interesting gaps in care that this study highlights that hopefully can form the basis for interventions to try to address those disparities.

And then as you know, we actually have a couple of research letters on the representation of women in editorial boards of major general and subspecialty cardiology journals, publishing clinical research. In this particular study, they actually found significant disparities where women were less represented among deputy associate editors and more so in European journals compared with US journals, general cardiology journals. Although editorial board membership was actually similar between Europe and the US, and they found that over 20 years, women deputy associate editors representation increased significantly for our journal, Biykem, Circulation. That was really very encouraging to see. And women editorial board membership increased for Circulation and for JACC without a significant change for the American Journal of Cardiology. That was really nice to see.

The one thing that was notable was in terms of women serving as editors-in-chief, we're still lagging behind in a big way, but I'm hoping that this particular study and several other studies that may get published in the future, will highlight these gaps and hopefully will lead to increased representation of women on editorial boards.

And finally we have an interesting study looking at the representation of women and men among training programs where they looked at the AAMC data and they were interested in looking at training in general cardiovascular disease medicine as well as for adult cardiology sub-specialties. And they also looked at pediatric cardiology by the way. And they found that in 2017 to 2018, among all adult cardiology trainees, only 21% were women. 79% were men. And among trainees in the different adult cardiology subspecialties, the representation was actually pretty poor in interventional cardiology, where only 10% of the trainees were women. And for electrophysiology, my own sub specialty, were only 11.6% of the trainees were women. Really interesting findings, the representation for advanced heart failure and transplant like your specialty, Biykem, women constituted 31% of the trainees and women did better when it came to adult congenital heart disease representing 47% of the training.

Really interesting trends and they concluded that in this review of ACG and the accredited training program, they found that cardiology ranked second for the most under representation of women, preceded as only by orthopedic surgery. And the sub specialty trends that I shared with you were really interesting. Hopefully as we see more of these publications, we'll be able to as a community come together and think about what are the barriers to more representation of women in these training programs? And how can we overcome these failures to encourage more women to go into this wonderful specialty of cardiology and the different sub-specialties, including procedural sub-specialties? Back to you, Biykem.

Dr Biykem Bozkurt: Thank you Sana. Very interesting findings indeed. Another fascinating study that we have in our issue is a study that provides us some insights on peripartive cardiomyopathy and potentially the role of natriuretic peptides during pregnancy.

This is an experimental study that involved natriuretic peptide receptor knockout in mice in which natriuretic peptides would not work. And the investigators demonstrated that these mice, during the postpartum lactation period, had elevated aldosterone levels, evidence of expression of pro inflammatory mediators such as IL-6, cardiac hypertrophy, fibrosis, left ventricular dysfunction, and even increased mortality. And interestingly, they were able to abrogate the effects of the lactation by use of mineralocorticoid receptor antagonists. With MRA use, there was evidence of reduction in LVH and reduction in inflammatory mediators.

There is a great editorial by Denise Hilfiker-Kleiner, who addresses the potential hypothesis of the role of unbalanced oxidative stress with prolactin in peripartum cardiomyopathy. And that the natriuretic peptides can be protected. And raises the question whether there could be a role for augmenting the natriuretic peptides further by use of sacubitril/valsartan. Or as was demonstrated in this study by you as a mineralocorticoid receptor antagonists in the postpartum period. And she also questions why in this experimental model, the detrimental effects were not seen during pregnancy but only in the postpartum lactation period.

Overall, very interesting papers. And finally we have an inspiring piece in our past or discovery section. It's an interview with Barbara Casadei, the President of European Society of Cardiology. She goes in a very detailed fashion over her career path, what she considers as the critical reasons for her success and how she envisions to shape the future of women in cardiology.

Dr Sana Al-Khatib: We would like to thank everyone who submitted their research and their work for this issue and congratulate the authors and investigators who were successful in getting their work published. Thank you very much.

Dr Biykem Bozkurt: We thank you for tuning in to our podcast. We hope that you'll enjoy our fourth issue for the Go Red for Women as we continue to highlight some of the best science for cardiovascular disease in women. Thank you.

This program is copyright, the American Heart Association 2020.


Feb 10, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week relates to an international multi-center evidence-based reappraisal of genes reported to cause congenital long QT syndrome. But, before we get to that, how about if we grab a cup of coffee and start on our other papers? Do you have one you'd like to discuss?

Dr Carolyn Lam: Yes. My favorite part of the week. So this first paper really asks the question, "What's the association between HDL functional characteristics, as opposed to HDL cholesterol levels, and acute coronary syndrome?" The paper comes from Dr Hernáez from IDIBAPS in Barcelona, Spain and colleagues who conducted a case control study nested within the PREDIMED cohort.

Originally a randomized trial where participants followed a Mediterranean or low-fat diet. Cases of incident acute coronary syndrome were individually matched one is to two to controls by sex, age, intervention group, body mass index, and follow-up time. The authors measure it the following functional characteristics, which were HDL cholesterol concentration, cholesterol efflux capacity, antioxidant ability, phospholipase A2 activity and sphingosine-1-phosphate, apolipoproteins A1 and A4, serum amyloid A and complement 3 protein.

Dr Greg Hundley: Wow Carolyn, a detailed analysis. What did they find?

Dr Carolyn Lam: They found that low values of cholesterol efflux capacity, and levels of sphingosine-1-phosphate and apolipoprotein A1 in HDL or all associated with a higher risk of acute coronary syndrome in high cardiovascular risk individuals, irrespective of HDL cholesterol levels and other cardiovascular risk factors. Low cholesterol efflux capacity values and sphingo-1-phosphate levels were particularly associated with an increased risk of myocardial infarction, whereas HDL antioxidant or anti-inflammatory capacity was inversely related to unstable angina.

Now this is significant because it's the first longitudinal study to comprehensively examine the association of several HDL function related biomarkers with incident acute coronary syndrome beyond HDL cholesterol levels in a high-risk cardiovascular risk population.

Greg Hundley: Very nice. Carolyn. It sounds like function over just the levels is important.

Dr Carolyn Lam: Exactly, you summarized it well. Well Greg, I've got another paper and I want to pick your brain first. Is it your impression that type 2 myocardial infarction, the type that occurs due to acute imbalance in myocardial oxygen supply versus demand in the absence of atherothrombosis, do you think that this type of MI is on the rise? It seems more and more common in my country.

Dr Greg Hundley: Do we want to say it's on the rise? Certainly by measuring all these high sensitivity troponins, et cetera, we're finding, I think, more evidence of type 2 MI. So, all in all, yeah it probably is on the rise, but likely related to some of our measurement techniques.

Dr Carolyn Lam: Oh, you are so smart, Greg. Because this paper that I'm about to tell you about really addresses some of these issues and it's from corresponding author Dr Gulati from Mayo Clinic in Rochester, Minnesota. And they really start by acknowledging that despite being frequently encountered in clinical practice, the population base incidents and trends of type 2 myocardial infarction is unknown and long-term outcomes are incompletely characterized. So they prospectively recruited 5,640 residents of Olmsted County, Minnesota who experienced an event associated with cardiac troponin T greater than 99th percentile of a normal reference population, which is greater than or equal to 0.01 nanograms per milliliter. And this was between 2003 and 2012, so very careful to talk about which Troponin T assay exactly to the point you discussed earlier, Greg. The events were retrospectively classified into type 1 versus type 2 MI using the universal definition.

Dr Greg Hundley: So Carolyn, what did they find?

Dr Carolyn Lam: They found that there was an evolution in the types of MI occurring in the community over a decade with the incidence of type 2 MI now being similar to type 1 MI. Adjusted long-term mortality following type 2 MI is markedly higher than after type 1 MI and that's driven by early and non-cardiovascular deaths. Mortality of type 2 MI is associated with a provoking factor and is more favorable when the principle provoking mechanism was an arrhythmia compared with postoperative status, hypotension, anemia or hypoxia. And these findings really underscore the healthcare burden of type 2 MI and provide benchmarks for clinical trial design.

Dr Greg Hundley: Very nice, Carolyn. Well, my paper comes from type 5 long QT syndromes and an analysis. And it's from Dr Jason Roberts from Western University. Through an international, multi-center collaboration, improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in long QT 5 was sought across 22 genetic arrhythmia clinics and four registries from nine countries that included 229 subjects with autosomal dominant long QT five. So there were 229 of those subjects. And then 19 individuals with the recessive type 2 Jervell and Lang-Nielsen syndrome. The authors compared the effects of clinical and genetic predictors on a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter defibrillators shocks, aborted cardiac arrest, and sudden cardiac death.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Well, several things, Carolyn. First, rare loss of function KCNE1 variants are weakly penetrant and do not manifest with a long QT syndrome phenotype in a majority of individuals. That's a little bit of a surprise. Second, QT prolongation and arrhythmic risk associated with type 2 Jervell and Lang-Nielsen syndrome is mild in comparison with the more malignant phenotype observed for type 1 Jervell and Lang-Nielsen syndrome. And then number three, all individuals possessing a rare loss of function KCNE1 variant should be counseled to avoid QT prolonging medications and should undergo a meticulous clinical evaluation to screen for long QTS phenotype.

And then finally, Carolyn, the last finding, in the absence of a long QTS phenotype, more intensive measures, such as beta blockade and exercise restriction, may not be merited.

Dr Carolyn Lam: Oh, very interesting. Well, I've got one more original paper and in this, authors describe a new cellular mechanism linking ischemia-reperfusion injury to the development of donor specific antibody, a pathologic feature of chronic antibody-mediated rejection, which mediates late graph loss. This paper is from corresponding author Dr Jane Witt from Yale University School of Medicine and colleagues who use humanized models and patient specimens to show that ischemia-reperfusion injury promoted elaboration of interleukin 18 from endothelial cells to selectively expand alloreactive interleukin 18 receptor 1 positive T peripheral helper cells in allograph tissues and this promoted donor specific antibody formation.

Dr Greg Hundley: Carolyn, here's the famous question. What does that mean clinically for us?

Dr Carolyn Lam: Aha, I'm prepared. Therapies targeted against endothelial cell derived factors like interleukin 18 may therefore block late complications of ischemia-reperfusion injury.

Dr Greg Hundley: Very nice. Sounds like more research to come. Well, how about other articles in the issue?

Dr Carolyn Lam: Well, I'd love to talk about a white paper from Dr Al-Khatib, and it's about the research needs and priorities for catheter ablation of atrial fibrillation and this is a report from the National Heart, Lung, and Blood Institute Virtual Workshop.

Dr Greg Hundley: Well, I've got another arrhythmia paper, so this is from Professor Michael Ackerman at the Mayo Clinic and its minor long QT gene disease associations by coupling the genome aggregation database. It's a harmonized database of 140,000 or more exomes and genome derived in part from population-based sequencing projects, with phenotypic insights gleaned from a large long QT syndrome registry to reassess the strength of these minor long QT syndrome gene disease associations. Next, Carolyn, in an on my mind piece, Professor Gerd Heusch from University of Essen Medical School discusses, how can the many positive preclinical and clinical proof of concept studies on reduced infarct size by ischemic conditioning interventions and cardioprotective drugs be reconciled with the mostly neutral results in regard to clinical outcomes.

The author discusses the important differences between animal models that have been used a lot in this ischemia reperfusion and infarct size reduction science, and then the clinical scenarios of STEMI in humans as well as the many aspects of coronary reperfusion. How is that affecting the myocytes? How is that affecting the microcirculation, et cetera, that must be addressed? And then finally Carolyn, there is a series of letters, one from Professor Oliver Weingärtner from Universitätsklinikum Jena and another from Professor Yasuyoshi Ouchi from Toranomon Hospital. They're exchanging letters debating the utility of lipid lowering with Ezetimibe in individuals over the age of 75 years.

Dr Carolyn Lam: Very nice, Greg. Thanks so much. Shall we now move to our future discussion.

Dr Greg Hundley: You bet.

Well, welcome everyone. This is our feature discussion and today we're going to hear more about long QT syndrome. We have Dr Michael Gollob from University of Toronto and our own associate editor, Dr Sami Viskin from Tel Aviv Medical Center. Good morning. Good afternoon, gentlemen. Before we get started with a discussion of some of the study findings and results, Michael, could you tell us a little bit about why you performed the study and what were some of the hypotheses you wanted to test?

Dr Michael Gollob: As you know, long QT syndrome is probably the most recognized channelopathy associated with sudden cardiac death in young individuals and adults. And at the present time, there are 17 genes available for clinical genetic testing in cases of suspected long QT syndrome. We simply ask the question, "Is there sufficient scientific evidence to support that each of these genes are single gene causes of long QT syndrome based on our contemporary knowledge of genetics and the human genome?

Dr Greg Hundley: Great, Michael. So, can you tell us a little bit about your study population? How did you go about this and what was your study design?

Dr Michael Gollob: We designed a methods approach that would assure that any conclusions that were made from our working group were not based on the opinions of one or two individuals. We wanted to ensure that this was a consensus conclusion with multiple experts in the field including genomic scientists, genetic counselors, inherited arrhythmia experts, and researchers in the field. We created three independent teams of genetic experts to curate the genetic evidence reported in the medical literature for each of these 17 reported causes of long QT syndrome. This was essentially an evidence-based approach using a pre-specified evidence-based matrix or scoring system depending on the level of evidence, genetic primarily, in the reported literature for each gene.

Each of these curation teams worked independently of each other and they were blinded to each other's work and they were tasked with concluding whether a gene, based on the medical literature and the resource methodologies, had sufficient evidence for disease causation. Their classifications would be one of disputed evidence, limited evidence, moderate evidence, strong or definitive evidence for claims towards disease causation. Remarkably, independently, all of these teams reached the same conclusion. In the end, their summary data was reviewed by a clinical domain expert panel with individuals with expertise, particularly in long QT syndrome and other channelopathies. So in total 19 individuals reviewed all of the literature and the data presented and came to unanimous conclusions for each gene.

Dr Greg Hundley: Out of the 17, were there some that were more important than others or was it uniformly all 17 were relevant?

Dr Michael Gollob: Well, I think the most relevant conclusions of our study are that nine of these genes, more than half of these genes, were felt not to have sufficient evidence to support their causation as a single gene cause for typical long QT syndrome. So nine genes that are currently tested by clinical genetic testing providers do not have enough evidence to support their testing in patients with suspected long QT. And to us, that is the most relevant observation because testing genes that do not have sufficient evidence for disease causation poses a significant risk to patient harm and family harm. We concluded that only three genes had very definitive evidence for causation of long QT syndrome. Those three genes were KCNQ1, KCNH2, and SCN5A. There were another four genes that were concluded to have strong or definitive evidence for unusual presentations of long QT syndrome. And by that, I mean presentations that typically occur in the neonatal period and are associated with heart block seizures or developmental delay or in the case of one of these genes, Triadin, an autosomal recessive form of the disease.

Dr Greg Hundley: So helping us perhaps what types of genes to screen for when we have someone with this condition or suspected. So Sami, can you help us put this into perspective? How does this study help us in management of this clinical situation.

Dr Sami Viskin: In Circulation, we immediately recognize the importance of the manuscript, the importance of the study because unfortunately, there are too many physicians all over who will accept the results of genetic testing essentially like gospel. Now it's in the DNA, it's in the genes, so whatever you find must be true. And too often, clinical decisions on treatment including ICD implantation have been undertaken based on results of genetic testing’s; thus are wrongly interpreted. So we recognize immediately the importance of this paper. We already had a different study by Dr Gollob and his associates. Again, reassessing the role of genes in Brugada syndrome. So we were familiar with this type of analysis.

We recognize the importance and we moved ahead to accept this paper, it went fairly easily, I think only one revision. At the same time, we were getting additional paper by other groups. So in the same issue, we have two more papers, one from Jason Roberts with the International Long QT Registry of long QT 5, reaching similar conclusions that this is a gene with very limited penetrants and another study by the Mayo clinic also showing that many of the genes who are not the major genes are overrepresented in the healthy population. So we put all these three papers together with a very nice editorial by Chris Semsarian in the same issue. So everything is put in the right perspective of how we should be looking at all the genes of these disease in a different way.

Dr Greg Hundley: So as a clinician quickly, how can I use this information in the issue, perhaps this paper and all three, in management of patients with either suspected or long QT syndrome?

Dr Michael Gollob: First off, I would emphasize that the diagnosis of long QT syndrome or any genetic base disease for that matter, should be based on clinical phenotype and not the observation of a genetic change, particularly if genes are being tested that do not have strong evidence for disease causation, as is the case for the nine genes that we've pointed out in this manuscript.

So I think clinicians need to be wary of the genetic testing panels that they are requesting be screened or used in the assessment of their patients and be knowledgeable that at this point in time, we really only have three genes with very strong evidence to support disease causation of the typical form of long QT syndrome. And that for the most part, these other genes should not be tested or should only remain in the realm of research.

I think that responsibility extends further than just the clinician taking care of the patient, but also clinical genetic testing providers, companies that offer these genetic testing services. I think they should assume a responsibility to ensure that they are only offering services for genes that have strong evidence for disease causation because when they report results in genes that are not valid for the disease, that only confuses the care of the patient and that creates a risk of harm to them if that information is misinterpreted by a physician.

As Dr Viskin or Sami pointed out, we do see patients who are inappropriately diagnosed. We remove the diagnosis of roughly 10 to 20% of cases in our own clinic. And unfortunately, many of these patients and their families have suffered undue anxiety. Some of them have ICDs in place that should not have been there. So I think overall, the field needs to be aware of what genes are relevant and what genes still are within the realm of research.

Dr Greg Hundley: Can you tell us just quickly Michael and then also Sami, what do you see as the next study in this field?

Dr Michael Gollob: We're taking a step back now. The first decade of this century saw an exponential growth in reported gene disease associations. And now in the last five or six years, we've learned a lot about human genetic variation, which has provided us an opportunity to reflect back on some of these previous and reported genes as causes for long QT and other diseases.

So I think many individuals in our field may say, "Well, you know, this is disappointing. We believed in these genes. We really thought these genes were causes of long QT." And to that point I would say, we need more research. If you believe in some of these genes that have now been considered to have limited or disputed evidence, research should continue if these remain plausible candidates for the disease.

So I think future research has to continue. There are probably still a few other genes that have not yet been discovered. I think we've got the vast majority. I think in most cases, at least in our experience, 90 to 95% of cases are explained by the top three genes. But there are probably other genes out there and it's always fascinating to learn or discover new genes, but those sorts of studies have to be done with the correct methodologies and rigid protocols. Lastly, I think in the future us clinicians and geneticists and genetic counselors need to work closely with genetic testing providers to ensure that they are offering responsible genetic testing services.

Dr Greg Hundley: Sami, do you have anything to add?

Dr Sami Viskin: Just congratulate the authors. I think they did a very great service to the medical community by pointing out the limitations of the genetic testing and the way we interpret the results, and they deserve to be applauded for reminding us that we have to be careful when we read papers about genetic results or when we get genetic testing results ourselves.

Dr Greg Hundley: I want to thank Michael from University of Toronto and Sami from Tel Aviv Medical Center for participating. And on behalf of both Carolyn and myself, wish you all a great week and look forward to chatting with you next week.

This program is copyright, the American Heart Association 2020.


Feb 3, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, Your Weekly Podcast Summary and Backstage Pass to The Journal and its Editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, this issue is full of super interesting papers, many of which were presented as late-breaking presentations at the American Heart Association, like the feature paper that sacubitril/valsartan across the spectrum of ejection fraction in heart failure, where this was really analyzed across the landmark PARADIGM and PARAGON trials. I'm sure everyone's looking forward to hearing about it, but before we talk about that, I want to share some more very interesting results from a very important trial, the REDUCE-IT trial.

So, as some background, some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. And this was the reason that there was a pre-specified subgroup analysis of the REDUCE-IT trial, which really is the reduction of cardiovascular events with icosapent ethyl-intervention trial, and this analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States.

So, Greg, do you remember what the REDUCE-IT trial was about?

Dr Greg Hundley: Well, Carolyn, I think REDUCE-IT randomized 8,179 statin-treated patients with triglycerides between 135 and 500 milligrams per deciliter and LDL cholesterol levels between 40 and 100 milligrams per deciliter and a history of atherosclerosis or diabetes to Icosapent Ethyl, four grams per day or placebo. And the primary endpoint, I believe, was cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Hah!

Dr Carolyn Lam: Wow, Greg, you pass that quiz, like maybe you had a cheat sheet answer.

Dr Greg Hundley: All right, Carolyn, tell us now what did REDUCE-IT USA find?

Dr Carolyn Lam: This was from a corresponding author, Dr Deepak Bhatt, from Brigham and Women's Hospital Heart and Vascular Center, and his colleagues and they found that in the United States Icosapent Ethyl at four grams a day produced large and significant reductions in multiple ischemic endpoints including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina. Furthermore, REDUCE-IT US demonstrated that Icosapent Ethyl provided a statistically significant 30% relative risk reduction and a 2.6% absolute risk reduction in all-cause mortality. The risk benefit profile of Icosapent Ethyl was highly favorable with an overall safety and tolerability profile virtually identical to placebo.

Dr Greg Hundley: Wow, Carolyn. So, this does have important implications for us in the US, very nice. Thank you for that lovely quiz. So, Carolyn, I'm going to switch now and talk about a paper from Roddy Walsh from Amsterdam in the Netherlands. In this study, the investigators defined the frequency of rare variation in 2,538 patients with dilated cardiomyopathy across protein-coding regions of 56 commonly tested genes and compared this to both 912 confirmed healthy controls and a reference population of 60,706 individuals to identify clinically interpretable genes robustly associated with dominant monogenetic dilated cardiomyopathy.

Dr Carolyn Lam: Wow, wow. That's a huge study. So what did they find?

Dr Greg Hundley: Okay, Carolyn. So overall rare variants in 12 genes potentially explain 17% of cases in the outpatient clinical cohort representing a broad range of adult patients with dilated cardiomyopathy and 26% of cases in the diagnostic referral cohort enriched in familial and early onset dilated cardiomyopathy. And so, practically speaking, by analyzing two dilated cardiomyopathy cohorts with distinctive patient profiles, the authors were able to comprehensively evaluate the genetic basis of dilated cardiomyopathy and identify variant classes that were particularly associated with early-onset disease. By restricting analyses to validated and interpretable genes and variant classes, the authors hoped in this study to increase the accuracy and reduce the uncertainty associated with genetic testing in dilated cardiomyopathy.

Dr Carolyn Lam: Very nice, very practical information. Well, my next paper is, I have to admit a super favorite topic of mine, and that is sex differences in heart failure. Now as a reminder to everybody, women represent over half of patients with heart failure with heart failure preserved ejection fraction, and there are multiple effective drug and device therapies for HFrEF, or heart failure reduced ejection fraction, but none approved for HFpEF. Thus, there is a greater so-called failure therapeutic deficit in women compared to men. So, does the recently presented PARAGON trial provide answers?

Dr Greg Hundley: Ah, Carolyn, you were involved in the PARAGON trial. Maybe tell us a little bit about that first to help us get oriented.

Dr Carolyn Lam: I would love to. So PARAGON compared sacubitril/valsartan with valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes, and the trial overall narrowly missed this primary outcome. However, an intriguing result in PARAGON was a significant sex-by-treatment interaction. And this was explored further in the current pre-specified subgroup analysis of outcomes by sex, which was reported by John McMurray from University of Glasgow and his colleagues.

Dr Greg Hundley: Ah, so I'm interested. What was this interaction?

Dr Carolyn Lam: Ah, so here is how the interaction work. Now, remember this was multi-variably adjusted significant in a pre-specified large subgroup of PARAGON. And what we found was that as compared with valsartan, sacubitril/valsartan seem to reduce the risk of heart failure hospitalization more in women than in men. Now, while the possible sex-related modification of this effect of treatment has potential explanations, the current study really cannot provide a definitive mechanistic basis for this finding.

Dr Greg Hundley: Very interesting. So, perhaps then, in heart failure preserved ejection fraction, sacubitril/valsartan could be very helpful in women.

Dr Carolyn Lam: Yes, and perhaps especially those with each ejection fraction in the lower ejection fraction range. And that is coming up in our future discussions, so let's not preempt it. You got another paper, Greg?

Dr Greg Hundley: Absolutely, Carolyn. My next paper is from Professor Irene Lang at the Medical University of Vienna, and it's related to microvascular disease and chronic thromboembolic pulmonary hypertension and hemodynamic phenotyping and histomorphometric assessments. So, Carolyn, pulmonary endarterectomy is the gold standard for treatment of patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension after PEA or endarterectomy remains a major determinant of poor prognosis.

Dr Carolyn Lam: Ah, so are there any possible solutions to this?

Dr Greg Hundley: Well, Carolyn, today it is thought that a concomitant small vessel arteriography in addition to major pulmonary artery obstruction may play an important role in the development of persistent pulmonary hypertension and survival after pulmonary endarterectomy. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence severity of small vessel arteriopathy.

Dr Carolyn Lam: Huh, that makes a lot of sense. So what did the authors do? What they find?

Dr Greg Hundley: Okay. Well, Carolyn, they had 90 patients with 49 of them receiving lung wedge biopsies for validation. So, in analyses incorporating receiver operating characteristic curves, pulmonary vascular resistance measures and larger arterial upstream resistance beds predicted persistent pulmonary hypertension after pulmonary endarterectomy, and certain values identified patients with poor prognosis after endarterectomy. Therefore, perhaps this form of analysis could be helpful in establishing prognosis in these patients and perhaps suitability for future interventions.

Dr Carolyn Lam: Wow, very interesting. Well, we were saying this issue's full of very important papers, and that also includes research letters. There's a research letter by Dr Cannon talking about evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with an HbA1c less than 7%. And these are very interesting results from the CREDENCE trial that was also presented at the American Heart Association.

There's a research letter by Dr Jackevicius on the population impact of generic valsartan recall in Ontario, Canada, that really highlights the potential burden and risks associated with recalls of chronic oral medications used by large populations. And in Cardiology News, Bridget Kuehn talked about cardiovascular risk biomarkers, high-sensitivity cardiac troponin T and NT-proBNP and talked about how these two biomarkers may help clinicians stratify which patients may benefit the most from therapies for hypertension or diabetes. And this was according to a pair of studies presented, again, at the American Heart Association.

Dr Greg Hundley: Well, Carolyn, that's quite a nice review. I've got just a couple more papers to discuss. There's a perspective piece from Dr Ben Levine and colleagues from UT Southwestern that discusses whether a simple physical exam and maneuvers could actually supplant tilt-table testing. He provides arguments as to whether we should continue with tilt-table testing given the high rate of false positives. And then lastly, from the Mailbag, Dr Shuyang Zhang from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences provides a letter to the editors regarding a prior publication on the clinical applicability of the awareness of androgen-deprivation therapy's effects on ventricular repolarization. And Dr Joe-Eli Salem from Vanderbilt University provides his response.

Well, Carolyn, how about onto that feature?

Dr Carolyn Lam: Let's go. Our feature discussion today is all about left ventricular ejection fraction. Ah, that measure we both love and hate in the world of heart failure, I think. And this paper is truly remarkable, in my opinion. It is the look at the effect of sacubitril/valsartan across the spectrum of left ventricular ejection fraction in the PARADIGM and PARAGON trials. And I'm just so pleased to have none other than the first and corresponding author, Dr Scott Solomon, from Brigham and Women's Hospital and Harvard Medical School, as well as our Senior Associate Editor, Dr Biykem Bozkurt, from Baylor College of Medicine as well.

Scott, could you start by telling us about this analysis and why the opportunity to do such a special analysis in this paper?

Dr Scott Solomon: This was a really fantastic opportunity because, as you know, we did these two trials, PARADIGM and PARAGON, not at the same time but essentially in series. PARADIGM was a trial of patients with heart failure reduced ejection fraction, so ejection fraction of 40%, and PARAGON was a study of patients with heart failure with preserved ejection fraction. And the interesting thing is that, with the exception of ejection fraction, the criteria for enrolling patients in these trial was virtually the same.

In other words, we enrolled patients with signs and symptoms of heart failure, some elevation in natriuretic peptides, and we followed them. So it's really an extraordinary dataset of 13,195 patients in whom we can look at heart failure across that full spectrum of ejection fraction. We haven't been able to do this really since the CHARM study, which enrolled about 8,000 patients across the spectrum of ejection fraction. And it gave us an opportunity to look at a number of things including the effect of sacubitril/valsartan across that full spectrum of ejection fraction.

Dr Carolyn Lam: Great. And, Scott, you want to tell us what you found?

Dr Scott Solomon: When we pooled 13,195 patients, and by the way, this was a pre-specified analysis that we had decided to do prior to unblinding PARAGON. We see that if we put them all together, all these patients together, and just treat them as one group, we see that for every endpoint that we looked at, whether heart failure, hospitalization and cardiovascular death, cardiovascular death, all-cause mortality, whether we look at the time to first event endpoints or the total number of heart failure hospitalizations, we see a significant benefit in patients receiving sacubitril/valsartan compared to patients receiving either enalapril in the PARADIGM study or valsartan in the PARAGON study.

Now, what we also saw though, and this is probably most important, is that there appears to be an attenuation of the treatment effect as ejection fraction rises. Now we know that patients with higher ejection fractions tend to have a lower frequency of these events such as heart failure, hospitalization and cardiovascular death. But we also see here that as ejection fraction goes up that the benefit of sacubitril/valsartan appears to wane, especially when you get over about 60, an ejection fraction of about 60%. We've looked at this in categorical ways and also looking at a continuous spline analysis throughout the entire spectrum.

Dr Carolyn Lam: Yeah, I love that, and I just need to point every listener right now to figures 3 and 4 of your paper. I have a feeling we're going to be seeing these figures in a lot of talks and cited everywhere. Biykem, could I bring you in on this? What are the implications of something like this?

Dr Biykem Bozkurt: The interesting findings from the pooled data are, first, support of what we had seen in PARADIGM, meaning the lower the EF, the more the benefit or the higher the benefits. And as we had seen in PARAGON, which did not show an improvement in the combined endpoint with treatment with sacubitril/valsartan in patients with heart failure with preserved ejection fraction. In the pooled analysis as the EF got higher, there didn't seem to be any benefit, but the interesting, perhaps group of patients that the pooled analysis allowed us to have a deeper dive into was heart failure with mid-range EF. And we can crudely perhaps define this as ejection fraction between 40 and 50%. And by certain analyses, which again this is in the post-hoc and also in a continuous analysis and a specific analysis and a cubic spline analysis, it appeared that the benefit extended into those individuals with mid-range ejection fraction.

Again, we need to keep several points in consideration. One is ejection fraction can vary over time and is not a very precise measurement. There's definitely inter-reader as well as intra-reader variability and is not a good mayor of contractile performance. And we tend to actually have a significant amount of a specific infiltrative cardiomyopathies in that EF range, which tend to be excluded from usual clinical trials. And with that caveat, having kept this in mind, it's also important to recognize from cohorts and population-based studies, about 10 to 20% of our patients currently reside in that have HeFmrEF or heart failure with mid-range EF status. And thus the findings are intriguing, hypothesis generating and also encouraging that we may see perhaps benefits with RAS antagonism in individuals that do have LV systolic dysfunction.

And probably, if this is persistent and a clear reflection of a phenotype that reflects itself as reduced ejection fraction, probably the patient may benefit. Again, these results may need to be supported by future studies, and also we need to keep in mind that infiltrative cardiomyopathies, such as amyloidosis or sarcoidosis or others, were not included in these studies.

Dr Carolyn Lam: Thank you, Biykem. Go ahead, Scott.

Dr Scott Solomon: Carolyn, I agree with many of Biykem's points. I think that this middle range, and you and I kind of coined that term, heart failure with mid-range injection fraction, a number of years ago. The problem, of course, is knowing where that range exactly is, and I think that some people believe it's 40 to 50%, but we know that these are very arbitrary cutoffs. The data from the pooled analysis in PARAGON, in particular, do suggest that the patients who have evidence of some degree of left ventricular dysfunction seem to benefit from sacubitril/valsartan. Now, this is not a completely novel finding because we saw that in patients who received candesartan in the CHARM study and in patients who received spironolactone in the TOPCAT trial that the greatest benefit was observed in the patients in that middle range of ejection fraction, again, below what we would normally consider the normal range. Normal might be 55% or 55% in men and women.

And that gets me to the other thing that I think is really worth mentioning here, which is that we found that the range of benefits does vary by sex, so that women seem to derive greater benefit to a higher ejection fraction than men. We can see that here in figure 4, looking at these two curves that there really does appear to be a difference between men and women. Women overall derive greater benefit in the PARAGON study, it appeared than in men. So I think that the fact that there's biologic plausibility here that patients with cardiac function that is not normal seem to benefit from therapies that we know benefit patients with heart failure with reduced ejection fraction, that patients with ejection fraction that was in this middle range also do appear to benefit from sacubitril/valsartan as we think they did in other studies of other agents that we know work in patients with lower ejection fraction.

Dr Carolyn Lam: Indeed, Scott. You've just pointed out my favorite figure of all, that figure 4. You know how I feel about sex differences and pointing them out. I would love to ask for Biykem's thoughts on it.

But in the meantime, just to emphasize how important findings like these are because it makes us question the cutoffs that we use to define heart failure groups, makes us question is midrange more mildly reduced ejection fraction like we're also writing about. And I think really makes us question, for example, the 2016 ESC Guidelines that say that mid-range ejection fraction should be treated like preserved ejection fraction. Well, maybe this could be really game changing here in that we actually think now this group should be treated more like reduced ejection fraction. So, really, congrats on this incredible paper.

Biykem, what do you think of those sex differences? I have to point out, I love your editorial, which everyone should read.

Dr Biykem Bozkurt: It's very intriguing, very interesting point. The benefits from sacubitril/valsartan was interestingly similar for both sexes at lower EF levels. Women's benefit compared to men's benefit for low EF was comparable; they were not different. But women seem to confer a benefit at higher EF ranges and by this continuous analysis all the way up to the 50 to 60% range, which is very, very interesting. And as to what were the phenotypes of the women compared to men at that range, women were older, had more obesity, less CAD, and of course, at all ranges they usually tend to have a higher baseline EF.

And, interestingly, even though we may state that maybe women may have more systolic dysfunction at higher EF quantification ranges or may have a different phenotype than men for HFpEF, maybe a more clear or pure heart failure phenotype, heart failure with preserved EF phenotype than men. The interesting things were the NT-proBNP levels were lower for women, though the symptoms were a little bit higher, and the benefit seemed to be higher even though the KCCQ scores were not different. So, even though we did have lesser sort of filling pressures for women and perhaps other surrogates for improvement did not seem to differ, and also biological metabolites, such as urinary cyclic GMP to creatine ratios, were not different in women.

So, if we were to think of whether there were biological differences, whether there were differences in NT-proBNP levels or delta changes over time or the urinary cyclic GMP levels, they were not different in women versus men. So, we still have many other substrates for neprilysin. I mean there could be other substrates, such as adrenomedullin or bradykinin or substance P that may be differentially metabolized for women compared to men, and we don't have the data on those. But again, it's very interesting to see this upper scale of EF benefit being higher in women compared to men. So, we don't have any other either biological or other surrogate markers for benefit for women, either for the HFpEF or HFrEF being than different than men.

Dr Carolyn Lam: Biykem, I just love the way you so carefully dissected that, and it's so reflected in that editorial that you and Justin Ezekowitz wrote entitled Substance and Substrate. So I'm going to make sure all readers look for it. We could go on forever. I mean I just was struck, that figure 4, also is really similar if we look at what normally ejection fraction is for women versus men with increasing age. We also see that women are supposed to have higher ejection fractions as they age compared to men at any age. So it's just intriguing to me, but you're right. I think hypothesis generating.

Scott, I'm going to give you the last word.

Dr Scott Solomon: I'm pretty confident that there are biologic differences between men and women. I just don't necessarily know what they are with respect to heart failure, preserved ejection fraction, but I think we're going to be spending a lot of time and effort trying to sort this out. We're pretty confident that the finding of a weighing of benefit with ejection fraction is a real one and that the benefit in this middle range is an important one to pay attention to because I agree with what you said, Carolyn. If we had been thinking about heart failure with reduced ejection fraction as something that went up to a higher level 25 years ago, we would probably have treated a lot more patients with therapies that we now know to benefit patients with heart failure with reduced ejection fraction. So, I think this data helps us rethink how we parse up heart failure and hopefully, ultimately will lead to changes how we treat patients.

Dr Carolyn Lam: Well, listeners, you heard it right here on Circulation on the Run. Thank you so much, Scott and Biykem, for joining us, and don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright The American Heart Association 2020.


Jan 27, 2020

Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Dr Greg Hundley, also Associate Editor, the Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Say, Greg, you know the feature paper this week talks about the perennially hot topic now and that is transcatheter aortic valve replacement or TAVR or TAVI. It's actually data from the France TAVI Registry comparing balloon expandable versus self-expanding transcatheter aortic valve replacement.

I'm sure you want to hear more about it, but first I'm going to tell you about another paper in the same issue, this time also comparing a balloon expandable versus a self-expanding transcatheter aortic valve implantation, but data from a nationwide analysis and from corresponding author Dr Fauchier from Centre Hospitalier Universitaire Trousseau. He and his colleagues basically did a head to head comparison of the two competing transcatheter aortic valve replacement technologies that have been published but have not really been followed for long-term clinical outcomes. This was comparing balloon expandable versus self-expanding technology.

They collected information from more than 31,000 consecutive patients treated with Tavern in France between 2014 and 2018 and based this on the French administrative hospital discharge database. They did propensity score matching, which was used for the analysis of outcomes according to the Sapien 3 balloon expandable versus the Evolut R self-expanding TAVR technology and studied this as nationwide level in France.

Dr Greg Hundley: Wow. Carolyn, 31,000 patients. That's a really large study. What did they find?

Dr Carolyn Lam: They basically found that balloon expandable TAVR was associated with lower mortality rehospitalization heart failure and pacemaker implantation compared with the self-expanding TAVR. Now, that's of course a pretty big finding and this is discussed along with the feature paper that we're going to hear about in an editorial by Drs. Abdel-Wahab and Thiele from Heart Center Leipzig.

I want to tell you about another paper before I let you tell you about yours, okay?

Dr Greg Hundley: Sounds great, Carolyn.

Dr Carolyn Lam: Greg, what is your clinical impression of Impella use in the United States among patients undergoing PCI? Do you think it's increasing or decreasing over time? As a reminder, Impella was approved for mechanical circulatory support in 2008, so from then, what do you think?

Dr Greg Hundley: You know, Carolyn, I really think it's increasing, especially used more frequently rather than an intra-aortic balloon pump. How about you? What's going on in your area of the world?

Dr Carolyn Lam: My impression too, but you know, you're lucky because we now have data looking at the trends in Impella use, but in the United States, and this comes from the corresponding author, Dr Amit Amin from Washington University School of Medicine and colleagues who describe clinical outcomes and costs across U.S. hospitals in PCI patients treated with mechanical circulatory support, which is either the Impella or the intra-aortic balloon pump.

They found that among more than 48,300 real world patients undergoing PCI with mechanical circulatory support at 432 hospitals between 2004 and 2016 in the Premier Healthcare Database, Impella use was indeed found to be rapidly increasing with marked variability across hospitals and not only its use, but also in its associated adverse outcomes. When analyzed by time periods or at the level of the hospitals or at the level of the patients, Impella use was associated with higher rates of adverse events and higher hospital costs.

Dr Greg Hundley: You know, I wasn't thinking about the higher rate of adverse events. You wonder sometimes, are we using a technology in a sicker group of patients? Did this study shine any light on that?

Dr Carolyn Lam: Those are great, great thoughts. The authors concluded that the variability in Impella use, the variability in its associated outcomes, and the association of Impella use with higher adverse events and costs really, really underscore the need for better defining of the appropriate use of mechanical circulatory devices and that was what you indicated as well, Greg, and what we need there is adequately powered randomized clinical trials and prospective real world evidence, which we don't quite have yet. Until then, perhaps a more measured approach is needed in clinical practice that balances risks versus benefits in complex patients undergoing PCI who require mechanical circulatory support.

Dr Greg Hundley: That's going to be really needed, I think in this era, especially with the results from this study. Well, Carolyn, I'm going to switch over to the world of basic science and the first study I'm going to talk about is from Dr Richard Lee from Harvard University and it's a very interesting study. Just as some background, current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells are capable of generating highly pure cardiomyocyte populations, but these cardiomyocytes remain immature and they really more closely resemble the fetal state.

As a result, they have a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared to adult cardiomyocytes. Also, they're prone to ventricular arrhythmias. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of Rapamycin mTOR signaling pathway plays a key role in nutrient sensing and growth, and Dr Lee and colleagues hypothesized that transient inhibition of the mTOR signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation.

Dr Carolyn Lam: Wow Greg, I really love the way you explained that. That's so interesting. What did they find?

Dr Greg Hundley: Among human induced pluripotent stem cell lines, transient treatment with Torin 1, an inhibitor of the mTOR pathway, shifted cells to a quiescent state and enhanced their cardiomyocyte maturity. Also, the investigative team suggests that further testing will be necessary to evaluate whether delivery of Torin 1 treated cardiomyocytes could reduce the risk of ventricular arrhythmias in newly differentiated myocytes derived from pluripotent stem cells. Really an important advance in this whole area of developing mature cardiomyocytes from our own pluripotent stem cells.

Well, Carolyn, my second basic science paper comes from Dr Calum MacRae from Brigham And Women's Hospital, also at the Harvard Medical School. Carolyn, this study used both highly purified human pluripotent stem cell derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells with human MYL4 mutations in a zebrafish MYL4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations associated with definitive genetic causes of atrial fibrillation.

Dr Carolyn Lam: Oh, that's really interesting. Is this new genetic predispositions that they discovered?

Dr Greg Hundley: I think the answer's yes. They found there was evidence of increased retinoic acid signaling in both human pluripotent stem cell derived cardiomyocytes and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins and loss of intracellular NAD and NADH, and thereby established a mechanistic link between the transcriptional, metabolic, and electrical pathways previously implicated in the atrial fibrillation substrate of MYL4. In the future, these data could lead to novel therapies for some patients with atrial fibrillation.

Dr Carolyn Lam: Wow. That really is fascinating, Greg. Well, let me round up by telling you about some of the other things in the issue. There is a research letter by Dr Parish on the effects of Omega-3 fatty acid supplements on arrhythmias and here, these authors reported more comprehensively on atrial fibrillation and other arrhythmias using additional data extracted from linked electronic health records in the ASCEND trial, remember, which was 1 gram of Omega-3 fatty acid supplementation daily in people with diabetes but without known atherosclerotic cardiovascular disease.

Dr Greg Hundley: Oh wow. That's fantastic, Carolyn. I've got a couple other really interesting articles in the issue. First there's an In Depth review from Dr Yvan Devaux from Luxembourg Institute of Health, and he discusses regulatory RNAs in heart failure. In a perspective piece, Dr Alejandro Lucia from Universidad European de Madrid discusses the role of aerobic and resistance training as a therapy in addition to prescribed medications in patients with resistant hypertension. Really interesting.

Then finally, Dr Ify Mordi from University of Dundee examines metformin use and clinical outcomes among patients with diabetes, with or without heart failure, kidney dysfunction observations from the SAVOR-TIMI 53 trial in which Dr Bergmark and colleagues found that metformin use was associated with a reduction in all-cause mortality and cardiovascular death, but not due to myocardial infarction or stroke, particularly in patients without a prior history of heart failure.

What could the mechanism be, if not related to presumed atherosclerosis? Dr Mordi and colleagues proposed possibilities, and Dr Brian Bergmark from the TIMI study group and the cardiovascular division of Brigham and Women's hospital at Harvard Medical School and colleagues, they write a very nice response. It's really interesting listening to how could metformin reduce events but not related to atherosclerosis? How about onto our feature article?

Dr Carolyn Lam: You bet.

Dr Amit Khera: This is Amit Khera, digital strategies editor for Circulation from UT Southwestern Medical Center joined by my colleague, Dr Dharam Kumbhani who's also an associated editor at Circulation and we're pleased to have Dr Eric Van Belle, Professor Van Belle, from Lille University Hospital to discuss the featured article today, "Transcatheter Aortic Valve Replacement Propensity Match Comparison From the France TAVI Registry." Welcome to you both.

Dr Van Belle, I'm going to start with you and we always like to hear a little bit. Perhaps you can tell us some of the background, what led up to this investigation, what led to your group pursuing this manuscript?

Dr Eric Van Belle: Nowadays, the TAVI procedure, the TAVR procedure, is becoming very prominent kind of way of treating patients without stenosis, and basically we have two different type of devices that are available to treat the patients. Once series is based on the balloon expandable concept and the other one on the self-expandable concept. These two type of devices are considered to be used primarily in every kind of patient. Theoretically, we can use any of these two devices, any kind of patient, if we follow the recommendation of the manufacturer and I'll just say that that'd been done.

These two devices are being validated against surgery, so basically, we could potentially use any kind of them. In today, there is no direct and there was no direct comparison between the two different kinds of concept, although they are very different. Again, the device is different. The way we implant the device is different. The major question that we had behind was to say, okay, what is the outcome? If it's a mean patient get one of the devices or can we expect or should we expect a different outcome? That was the main question behind it.

Dr Amit Khera: Okay, so essentially there's two valves, they're both being used fairly regularly and without any kind of direct comparisons. Tell us a little bit about the study design and what you found in this project.

Dr Eric Van Belle: For methodology, we used what is called a French study registry, basically nationwide registry with almost all patients treated in France included, and we used it as a database of patients between 2013 and 2015 with an overall group of 12,000 patients treated with either of these two kinds of devices. This is one of the aspect of this registry. The other very important aspect of this registry, and that's the mortality data survival that was obtained in all the patients in 2008 through 2016, so we have a set of 12,000 patients. It was a cool kind of device with complete mortality data by April 2016 so basically, this is the main methodological aspect. On top of this, we did the best to do some matching on the older clinical variables and all the matching valuables that we had to create pairs of patients that could be matched to one to one. We had, at the end, a group of almost 4,000 patients.

Dr Amit Khera: Okay and tell us a little bit about some of your main findings of this study.

Dr Eric Van Belle: The two main findings were those differences between the two groups of patients, that is a patient treated with self-expandable devices at a higher risk of valvular regurgitation. This was mainly a confirmation because this finding was already reported previously in previous studies trying to compare the two devices, but what was more striking was the difference in mortality. It was a difference mostly in hospital mortality but also in mortality after two years. That was significant with an absolute difference in mortality around 3% by two years.

Dr Amit Khera: Well, obviously important, as you mentioned that paravalvular leak had been seen before and this now a long-term mortality difference. Certainly an important finding and one of the main findings of your study. One of the concerns about comparative effectiveness research, essentially you're using observational data such as this is that there still could be residual confounding. There still may be patient characteristics or decisions made by interventionalists that aren't fully accounted for. How did you all really try to account for some of these components, this residual confounding to try to get the best answer that you could?

Dr Eric Van Belle: That's going to be a major comment, and everything you can do, every best way to try to control for this, there is no better answer than to do a randomized study, and probably we'll discuss on this. Let's see, indeed, we try to do our best to minimize as much as we could, all these potential confounders, so we did it in a different way, indeed.

The first way to do it was to adjust all the potential differences among group but what was very also interesting to remind is that, when you look at the 25 clinical and imaging variables and creating the aortic annulus diameter that was incorporated in the matching, that actually 21 of the 25 variables were already there. We were balanced between the two groups, existing that indeed most of the case, the operators, we are not so much directing or at least if there was selecting it was not captured but all of these valuables because again, out of 25, the correction needed to do the matching was only affecting 4 variables, mainly. Those variables were already pretty well-matched between the two populations.

The other way we did it was to look at what is called falsification endpoint, that it is endpoints that are supposed to be unrelated to the devices to verify that indeed, we have not selected a population that will have issues that are not related to the device itself. We look at, let's say, mortality by infection, mortality by cancer, to verify that, indeed, this kind of event where it did well balanced between the two groups suggesting that the mortality effects that we observed was not related to this kind of unbalance related to something else that was not captured by analysis.

Dr Amit Khera: Yeah, I think that was quite an important observation you mentioned. The first that these two groups are generally well-balanced to begin with, even before with all the matching parameters and then certainly the falsification endpoint helped to add validity to the findings.

Dharam, I'm going to turn it over to you. Maybe you can show this from an associate editor's perspective. What are some of the observations you found interesting about this study and what are some of the considerations we had in some of the discussions about it?

Dr Dharam Kumbhani: I'll just remind our listeners that this was also a late breaker at AHA last year in 2019, so this is really a very important finding. As Eric briefly pointed out, there haven't really been head to head comparisons between, the two dominant valves in the market even though TAVR has pretty much become the dominant strategy for treatment of aortic stenosis.

At the end of the day, it's an observational analysis. We have to take the findings with that in mind. At a minimum, it's first a lot of debate and discussion about the need to have randomized trials and our belief that, perhaps, TAVR is a class effect may not always be true. I think that hypothesis would certainly need to be tested and that's what this paper really sparks as far as discussion going forward.

Dr Amit Khera: Maybe I'll ask both of you. One of the challenges of any type of observational research is time period. First there was a hint towards even maybe a greater effect in the more recent time period than the distant time period. Also, there's always commonly changes in technology, especially interventional field where a study comes out and it's already obsolete because there's some new technology. There are some newer generations of valves that have come out. Do you think that it would affect these findings in any way? Maybe we'll start with you, Eric.

Dr Eric Van Belle: That's always an issue. Again, because it's a very rapidly evolving field and if you want to have strong data, you need to have really long-term follow-up. You need to have mortality data. There is some kind of contradiction between both that the field is evolving very quickly but then to have solid data, you need to have some time.

What we could say, indeed, as a study period was 2013 and 2015, but the device that we are using at that time were already really well matured and also the devices that were used at that time was usually the ones that were used for the comparison with the surgical techniques. Again, these devices are not so much obsolete since they were accepted and used again, when you need this one device study to compare with surgery.

Of course these devices have still had some evolution and change, and it is for the good of the patient, but again, as mentioned there, I'm seeing what is very, very important is that this finding is, in my view, intriguing enough to say, okay, even if it's difficult to conduct this kind of randomized study, it has to be done now because we need to really know. Let's say 80% of the patients could indeed be treated with any of the two device in this large margin of patients. Do we have to choose one or the other one to start with? This has already been well answered in a larger randomized trial.

Dr Amit Khera: Dharam, maybe I'll ask you, do you think this large randomized trial, are you optimistic that that would happen? Certainly it sounds like it's something that would be very helpful for the field. What are your thoughts on whether that's actually going to occur?

Dr Dharam Kumbhani: I know that there are some head to head trials ongoing. I don't know if they will have the sample size to really drill down, as far as hard endpoints, mortality, for example. I think the field clearly needs it. The question is, who's going to sponsor a trial like that? There's probably not much incentive for industry to sponsor something like that. Really it would fall down to whether there's a way for government agencies to partner with industry or other ways to run this. I do agree with Eric that that's really very important and hopefully we'll see that in the field going forward.

I did want to comment on the next iteration of devices as far as what we may see now. The mortality signal, I know we've talked about it. It's an observation study. It's hard to know if there's confounding, and even with all the sophisticated statistical analyses that the team did, there's always a possibility that somehow there was sicker patients that received self-expanding valves.

The signal for paravalvular regurgitation is not just in this study. We've observed it in many other studies and for other self-expanding platforms as well. Both the SCOPE trial and the St. Jude trial last year, both came around the same time. They were self-expanding platforms and both of them showed a higher paravalvular regurgitation rate compared to the balloon expandable rate. That may be a real thing, and I don't know if that is an inherent design flaw in the self-expanding platform or if there are ways that that could be mitigated going forward. Again, I think the trials, for it to be meaningful, it would be obviously important to collect and have short term and imaging markers. Really, what the field needs is long-term evaluation of these two strategies.

Dr Amit Khera: I want to take both Dharam Kumbhani and Dr Eric Van Belle l from Lille University Hospital. Thank you both for joining today.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.


Jan 20, 2020

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Carolyn Lam, Associate Editor from National Heart Center at Duke National University of Singapore.

Dr. Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center in Richmond, Virginia.

Dr. Carolyn Lam: Greg, it is so good to be back. I just love doing these podcasts with you and what more when we get to feature a paper like the one that we have this week. It's all about high sensitivity, cardiac troponin and the universal definition of myocardial infarction, one of these evergreen topics that we truly need to understand better. But before we go onto that, I want to share my first paper. It's a preclinical paper and it provides an important breakthrough discovery that could protect the heart against progressive left ventricular systolic dysfunction following injury. Want to hear about it?

Dr. Greg Hundley: Absolutely.

Dr. Carolyn Lam: Okay. It's from course wanting authors, Drs Sabourin and Benitah from INSERM University, Paris, as well as Doctors Foster and Beech from University of Leeds.

Dr. Carolyn Lam: Now, whereas store operated calcium entry has recently gained attention in cardiac pathophysiology, the role of the prototypic store operated channel known as Orai1 remains elusive. So these authors used a novel genetically modified mouse that specifically disrupts the Orai1 channel in cardiomyocytes and showed that functional inhibition of Orai1 preserved alterations of calcium homeostasis, fibrosis and systolic function without affecting hypertrophy. A novel in vivo small molecule Orai1 channel inhibitor, in fact, markedly improve left ventricular systolic function and calcium handling after pressure overload without causing adverse effects.

Dr. Greg Hundley: Tell me, how does this help me as a clinician?

Dr. Carolyn Lam: All right, you always ask the tough questions. Well, these results really suggest that Orai1 inhibition has the potential for favorable hemodynamic value in the protection of the heart from maladaptive hypotrophy, and therefore might represent a new way to provide inotropic support to help relieve systolic dysfunction.

Dr. Greg Hundley: Very good. Well Carolyn, my first paper is from Dr Peter Kudenchuk from University of Washington Medical Center and this study evaluates the overall survivor after out of hospital cardiac arrest from shock refractory ventricular fibrillation or pulseless ventricular tachycardia related to the route of accessory drug administration. So to accomplish this, the investigators had 2,358 individuals that had received Amiodarone, lidocaine or placebo study drugs and randomized to an IV route.

Dr. Greg Hundley: And then they also included 661 patients that received the same medications, but they were randomized to an intraosseous route.

Dr. Carolyn Lam: So what were the results, Greg?

Dr. Greg Hundley: Well, Carolyn, while no significant effect modification by drug administration route was observed point estimates for the effects of both drugs, both the lidocaine and the Amiodarone, compared to placebo were greater for the IV, as opposed to the intraosseous route and that was across all outcomes. And they had significant increases in survival to hospital admission and discharge and favored improved neurological outcomes with the IV administration.

Dr. Greg Hundley: Unfortunately, however, the study was underpowered to examine for an interaction between the route of vascular access and drug effectiveness and thus additional studies are needed to determine whether Amiodarone in lidocaine may be lifesaving drugs in patients with shock refractory out of hospital cardiac arrest when given IV, but not necessarily intraosseous.

Dr. Carolyn Lam: Very interesting. Well, my next paper is really focused on HIV infection and asks the question, is HIV infection associated with abnormal cardiac repolarization that may contribute to a greater risk for sudden arrhythmic death? Well, corresponding author Wendy Post, our very own from Johns Hopkins University School of Medicine and her colleagues studied 1,123 men, 589 of whom were HIV positive and they were from the multicenter AIDS cohort study and they were studied using the ZioXT ambulatory ECG patch.

Dr. Greg Hundley: Wow. Carolyn, this study sounds like it's the largest study of QT variability in HIV today.

Dr. Greg Hundley: Is that right? And what did the authors find?

Dr. Carolyn Lam: Yeah, it's right. It's huge. And basically they found that HIV positive men had greater beat to beat variability in the QT interval compared to HIV negative men, especially in the setting of HIV viremia and heightened inflammation.

Dr. Carolyn Lam: Among HIV positive men, a higher QT interval variability suggests ventricular repolarization lability which could increase susceptibility to arrhythmias. However, lower heart rate variability also may signal a component of autonomic dysfunction.

Dr. Greg Hundley: Ah, Carolyn. My next paper goes back to the world of basic science and it's from Dr. Chen Yan from University of Rochester. And in this study, Dr. Yon and colleagues examine the role of cyclic nucleotide phosphodiesterase in isolated adult mouse cardiomyocytes and fibroblasts as well as in preclinical mouse models of hypertrophy and/or heart failure. And they found that phosphodiesterase 10A expression is significantly induced in mouse and human failing hearts.

Dr. Greg Hundley: It directly promotes cardiomyocyte hypertrophic growth as well as cardio fiber-blast activation, proliferation, migration and extracellular matrix production. In addition, phosphodiesterase 10A deficiency, so not as much of it, ameliorates cardiac hypertrophy fibrosis and/or dysfunction in different preclinical mouse cardiac disease models. And finally inhibiting phosphodiesterase 10A activity with a compound labeled T P 10 effectively antagonizes the pathological cardiac remodeling in LVH.

Dr. Carolyn Lam: Huh, that's interesting Greg. And now I'll ask you, so what are the clinical implications?

Dr. Greg Hundley: Well, phosphodiesterase 10A inhibitors have been evaluated in phase two clinical trials for treatment of schizophrenia, suggesting that these agents are safe, druggable, if you will, targets. And therefore the results with TP 10 suggests a potential therapeutic effect of targeting phosphodiesterase 10A on antagonizing the development of pathological cardiac remodeling. Perhaps as suggested by Dr. Ezekowitz last week, this could represent another new agent in the treatment of the adverse effects of heart failure syndromes, more pharmacological agents coming to treat heart failure.

Dr. Carolyn Lam: Wow. That is interesting. But okay, let's talk about what else is in this issue. So let me tell you about an online mine by Dr. Kalra and it's called the Cardiovascular Science India Tour. And what this talks about is a multi-pronged initiative bringing together professionals and diverse expertise to allow better understanding of the issues driving the ever-rising cardiovascular disease burden in South Asia.

Dr. Greg Hundley: Oh, very good. And from the mailbag, I've got a research letter, Carolyn from Dr. Julian Luetkens from the University of Bond, who investigates a surrogate of frailty by examining the fat fraction within skeletal muscle at the L three L four level. So it's from an axial CT that's acquired at the time of CT scanning for TAVR pre-evaluation and uses the fat muscle fraction to forecast TAVR outcomes. Well. Carolyn, that's a great wrap up. How about we get onto our feature article?

Dr. Carolyn Lam: You bet.

Dr. Amit Khera: Hi, this is Amit Khera. I am digital strategies editor for circulation and today with our featured podcast we have Dr. Andrew Chapman from the university of Edinburgh, UK who is the first author of a study entitled high sensitivity cardiac proponent and the universal definition of myocardial infarction. Welcome Dr. Chapman. Thanks for joining us.

Dr. Andrew Chapman: Good morning. It's a pleasure. Thank you.

Dr. Amit Khera: This is obviously a very interesting study and timely and on the backs of the prior work that your group has published. Maybe we can start by you telling us a little bit about the impetus, the background which led to this work.

Dr. Andrew Chapman: We've been using high sensitivity cardiac troponin in Europe now for some years, and the way that we diagnose myocardial infarction has, of course changed. We now recognize that myocardial infarction can occur in the context of an occluded coronary artery, be that a STEMI or an NSTEMI, also known as a type one myocardial infarction.

Dr. Andrew Chapman: But increasingly with the use of more sensitive cardiac troponin, we're recognizing myocardial infarction can occur in other conditions. So for example, after arrhythmia or after severe infection with hypoxia. So the real rationale and background for this study is trying to understand better the different subtypes of myocardial infarction. As proposed in the universal definition.

Dr. Andrew Chapman: And we were in quite a unique position to evaluate this as, when we implemented high sensitivity cardiac troponin testing in Scotland as part of a randomized controlled trial. We did so across different hospitals and two of our major cities, Edinburgh and Glasgow, and the trial which formed the basis for this study was called the high States trial and we enrolled 48,000 patients of who we initially used a contemporary sensitive cardiac troponin on an IRC and we then implemented a high sensitivity cardiac troponin IRC.

Dr. Andrew Chapman: And that allowed us to evaluate what impact implementing this high sensitivity test hard firstly on the prevalence of different subtypes in myocardial infarction, but also on the investigations and the treatments received. And finally of course the clinical outcomes of these patients.

Dr. Amit Khera: So obviously at a really sizable study and good forethought on your group to implement this as this step wedge type study design. As you pointed out, the goal here was to understand the different subgroups of myocardial infarction, the prevalence and implications. Tell us a little bit about what you found in this study.

Dr. Andrew Chapman: As I mentioned, we had over 48,000 consecutive patients and that was the real benefit of this step wedge design is that rather than recruiting patients between say nine and five where we had research nurses available, we enrolled all consecutive patients. So we think this is quite a representative population for our area. So of those patients, we found around 10,000 had elevation in the high sensitivity cardiac troponin concentration, and we adjudicated these diagnoses in parallel. So two independent clinicians look through every case, all the clinical information. And we had a consensus from a third when there was disagreement. So in short we found that around half of all elevations in cardiac troponin in this study were to take one myocardial infarction, that is that the blocked artery phenotype and the type two myocardial infarctions or an acute or chronic myocardial injury and myocardial injury being elevation and cardiac troponin, either acute with a rise or fall or chronic with a stable concentration with no evidence of myocardial ischemia and occurred in the other 50% of patients.

Dr. Andrew Chapman: So looking between the phases of the study, we found introducing high sensitivity troponin disproportionately increased the diagnosis of Type II MI or acute or chronic myocardial injury. So there's just an 11% increase in the diagnosis of Type I MI, and I think again that's highlighting that these more sensitive tests are finding myocardial damage in areas that previously it might not have been recognized.

Dr. Andrew Chapman: So moving forward from that, we evaluated the primary outcome of the trial, which was future myocardial infarction or cardiovascular death by subgroup. And we also evaluated unimportant non-cardiovascular death. If I may for just 30 seconds, I'll just discuss why this is important.

Dr. Andrew Chapman: So evaluating future cardiovascular events is very important and in different subgroups of myocardial infarction. However, we know patients with Type II MI and acute or chronic myocardial injury are different. So they tend to be older, they're more commonly female, they have more comorbidities, they're on more medications to start with.

Dr. Andrew Chapman: And these patients are ar increased risk of a competing events to cardiovascular death or a myocardial infarction. And that is that these patients can go on and die, will primarily from their primary illness, be an infection or a pulmonary embolism or what have you. But also they are at increased risk of death from other non-cardiovascular causes.

Dr. Andrew Chapman: So in this study we were able to evaluate future cardiovascular risks using quite advanced competing risks modeling. And I was very grateful for the input of a number of experts and we managed to find that actually, Type I myocardial infarction patients with occlusion or partial occlusion of the coronary artery were at the highest risk of cardiovascular events going forward.

Dr. Andrew Chapman: But interestingly, even despite the vast excess in non-cardiovascular death, patients with Type II MI, and acute or chronic injury also had quite a high cardiovascular risk over three folds out of patients without myocardial injury. And we noticed that these patients did not stand to receive increases in investigations or treatments for coronary heart disease and we speculate and we hypothesize that actually in a proportion of these patients there is some clinical coronary artery disease which has manifested itself during this physiological stress test of an alternative illness. We wonder and we hope that moving forward this might be an opportunity for better targeting it in an investigation and perhaps even improving clinical outcomes.

Dr. Amit Khera: Well, you just shared a ton of important findings there and I'm going to unpackage a few of them. I guess the first is this sort of type I versus type II MI, and I think one of the fears with implementing these high sensitivity troponin would be perhaps an explosion in these type II MIs. And I think, if you look, although you mentioned proportionally, the absolute numbers of increase in type I and type II MI was relatively small so it didn't seem we had this explosion that I think people had feared was implementation.

Dr. Andrew Chapman: Yes, that's a fair point. And also need to bear in mind this is a population of patients from Scotland and our high sensitivity troponin testing is quite selective. You would find differences in the impact of high sensitivity if you're testing practices were different and I know there's prior work from the United States showing that less selective testing or to put it in a different way, testing troponin in more patients. Perhaps some of them may not have symptoms of chest pain or symptoms suggestive of myocardial infarction, is likely to change the prevalence of these different groups and you are likely to pick up more secondary injury or type II MI, but I think we don't need to panic. There's no need for alarm. I don't think there is going to be an explosion in recognition of these patients. If you check a temperature, you'll find a fever, but provided we're sensible and who we're testing, then I don't think practice needs to change dramatically.

Dr. Amit Khera: That was a great way to say it. Unfortunately, we're always looking for fevers in the U.S. So as you pointed out, the prevalence increase may increase a bit, but definitely reassuring from what you're finding in your population was more judicious testing.

Dr. Amit Khera: The second point that you brought up was the event rates, type I versus type II MI. I guess this does remind us again that patients with type II have almost comparable cardiovascular deaths and MI rates as type I, so certainly a higher risk group. As you pointed out, there's many comorbidities there and this gets to your point about treatments. I guess the question is now the event rates are higher, these are higher risk group or what to do about it I think is one of the vexing problems. As you pointed out, there's, there's not a lot of secondary prevention treatments, but what should those treatments be and where do we go from here in terms of these type II MI?

Dr. Andrew Chapman: That's the million dollar question I suppose and something that we've explored in another recent circulation review under the [00:17:07] lead author is what we do for these patients. When we've looked at different strategies, it seems the most reasonable initial approach is determining, does my patient with type II MI or myocardial injury actually have a cardiac problem?

Dr. Andrew Chapman: Now I don't think we have the evidence to support routine and baited testing in this population yet and indeed that might expose patients to harm and that's one of the tensions with this diagnosis.

Dr. Andrew Chapman: For example, consider the patient with gastrointestinal hemorrhage and could it have gone forward for an angiogram. Giving them heparin might not be the best thing to do in their acute illness. However, whether or not these patients would benefit from noninvasive tests such as a CT scan to delineate the coronary anatomy and identify those that might benefit from an iron platelet agent or a statin or indeed an echocardiogram to determine which patients have left ventricular impairment and could benefit from the many number of treatments we have now for LV impairment and that would be my initial thinking is that we need to firstly risk profile these patients.

Dr. Andrew Chapman: What is their pretest probability or likelihood of coronary artery disease? It's not intermediate or high. Let's have a think about investigating their coronary arteries. In the first instance, I think a noninvasive test is going to be most appropriate for the majority of people, but we need a personalized approach. It may be that someone's just had a very brief run of an arrhythmia and that's resulted in a disproportionate level of ischemia and a very high cardiac troponin.

Dr. Andrew Chapman: Your index of suspicion for that patient having coronary disease is going to be significantly higher. So a personalized approach, I think, is where we're heading. And there are trials which are coming in this area. So yeah, two trial is being led by Derek Chu of Melbourne in Australia and they're evaluating the use of CT or invasive angiography to identify coronary disease and target treatment to see if that can improve outcomes.

Dr. Andrew Chapman: And certainly here in Scotland, we're hoping to evaluate the use of a personalized approach to target treatment in patients with type II MI and again, try and improve cardiovascular outcomes. So things are coming.

Dr. Amit Khera: Well, I appreciate that and I think as you pointed out, as we wait for these additional data and additional studies, sort of a thoughtful. algorithmic approach would be helpful and we certainly will make sure the readers and listeners look out for that paper that you mentioned in circulation.

Dr. Amit Khera: I should also point out that your paper here is an excellent editorial by David Morrow, which has a nice figure and illustration of your central findings. So we appreciate that. As we wrap up here, maybe you can tell us what are the main take homes? What should they take away from this study?

Dr. Andrew Chapman: What we've shown is that high sensitivity troponin are useful and we've shown that they increase recognition of patients who have myocardial jury or type II myocardial infarction, where in the past this may not have been found and we've shown quite clearly that these are prognostic. Not only predicting non-cardiovascular disease, but also going on to identify patients at increased risk of myocardial infarction, cardiovascular death.

Dr. Andrew Chapman: So I think moving forward, clinicians using these tests and identifying these patients should be considering investigations to identify coronary or structural heart disease. And until we have that high quality randomized controlled trial data, we need to be pragmatic and we need to evaluate secondary prevention on an individual patient basis, be that an antiplatelet agent or be that a statin as the primary ones. This may even go on to include an ACE inhibitor or a beta blocker if there's LV impairment, but our aim ultimately has to be to try and reduce the cardiovascular event rates in this population who, to date, have been under investigated and undertreated.

Dr. Amit Khera: That summarizes it quite well. And I want to thank Dr. Andrew Chapman for his excellent discussion today and that's why we do these backstage passes to get an inside look as to what the authors were thinking and some behind the scenes on their papers.

Dr. Amit Khera: Again, I'm Omnicare digital strategies editor for circulation, and thank you for joining us on this circulation on the run podcast.

Dr. Greg Hundley: This program is copyright, the American heart association 2020.

Jan 13, 2020

Dr Greg Hundley: Welcome listeners. This is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond, who is in the second of his two-week stint without his dear friend, Dr Carolyn Lam who will be returning in a week or two. Our feature article this week is from Dr Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and the Georgia Institute for Global Health, and University of New South Wales. And we'll review the effects of dapagliflozin on quality of life and other metrics in patients with heart failure and reduced ejection fraction. But first, let's have a look at the other articles in this issue and just like last week we've got four other original manuscripts. The first two are sort of clinically related and that very first article comes from Dr Ben Levine from University of Texas Southwestern and he serves as the corresponding author and he's examining future predictors of the development of heart failure and preserved ejection fraction or HFpEF.

His team tested the hypothesis as to whether patients with LVH and elevated cardiac biomarkers would demonstrate elevated LV myocardial stiffness when compared to healthy controls as a key marker for future HFpEF. The team recruited 46 patients with LVH. The LV septum was greater than 11 millimeters and elevated cardiac biomarkers, so the NTproBNP was greater than 40 or the cardiac troponin T was greater than 0.6. And they were recruited along with 61 age and sex-matched cohort of healthy controls. To define LV pressure volume relationships, right heart catheterization and 3D echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. They found that the left ventricle was less distensible in the LVH patients relative to the controls, that is they had a smaller volume for the same filling pressure. When preload was expressed as transmural filling pressure or wedge pressure minus right atrial pressure left ventricular myocardial stiffness was nearly 30% greater in the LVH group compared to the controls.

The author's note that although LV myocardial stiffness of LVH patients was greater than that of the healthy controls at this relatively early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals.

Well, the second paper comes from Professor John McMurry of the British Heart Foundation Cardiovascular Research Center at the University of Glasgow in the United Kingdom. And the paper is somewhat similar to our feature article because it emanates from the DAPA Heart Failure dataset that we will hear about later. So in this paper, the authors examined the effects of Dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly in the prior trial. A clinical trial that as we know, demonstrated that a reduced risk of mortality and heart failure hospitalizations occurred in patients with HFrEF.

So in this current study, a total of 4,744 patients that were 22 to 94 years of age were randomized. 636 were less than 55 years of age, 1,242 we're 55 to 64 years of age 1,717 were 65 to 74, and finally 1,149 were greater than 75 years of age. Consistent benefits were observed for the components of the primary outcome of all-cause mortality and symptoms across all the age groups. Although the adverse events and the study drug discontinuation increased with age, neither was significantly more common with Dapagliflozin across any of the age groups. There was no significant imbalance and tolerability or safety events between Dapagliflozin and placebo, even in the very old population group. So we'll have more to discuss later in the feature discussion with a second paper that really looks also at the DAPA-HF study.

The next original article comes from our world of Basic Science and it reports that the deficiency of circulating monocytes ameliorates the progression of myxomatous valve degeneration in the Marfan syndrome. And this paper comes from Dr Katherine Yutzey from Cincinnati Children's Medical Center. Well, first is some background, leukocytes comprised primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in myxomatous mitral valve degeneration is not known. So the authors found in this study that Marfan syndrome mice recapitulated the histopathologic features of myxomatous valve disease by two months of age, including mitral valve thickening, increased leaflet cellularity and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation.

Concurrently, disease mitral valves of the Marfan syndrome mice exhibited a marked increase of infiltrating and resident macrophages along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited Marfan syndrome pigs as well as human subjects exhibited increased monocytes and macrophages detected by immunofluorescence. So remarkably deficiency of monocytes was protected against mitral valve disease progression resulting in a significant reduction of macrophages, had minimal leaflet thickening and preserved mitral valve integrity. So the authors identify for the first time in this interesting study from the world of basic science that monocytes are a viable candidate for targeted therapy in myxomatous valve degeneration.

The second basic science original article in this issue is entitled "Genetic IL-6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis" and the corresponding there is Pradeep Natarajan from the Mass. General is background clonal hematopoiesis of indeterminate potential or CHIP is a term that refers to clonal expansion of hematopoietic STEM cells due to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice CHIP accelerates atherosclerosis and increases IL-6 and IL-1 beta expression raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease risk.

So in this study, the authors observed some really exciting results. They analyzed over 34,000 samples from the UK Biobank and identified 1,079 individuals with CHIP, including 432 with large clones an LV fraction greater than 10%. During a 6.9-year median follow-up CHIP presence was associated with increased incidents, cardiovascular disease event risk with greater risk from large CHIP clones. IL6R attenuated cardiovascular event risk among participants with large CHIP clones but not in individuals without CHIP. This really exciting research results suggest that CHIP is associated with increased risk of incident cardiovascular disease. And among carriers of large CHIP clones, genetically reduced IL-6 signaling abdicated this risk. Really exciting results in an emerging area of science.

So what else is in the issue? Well, in our in depth review feature, Professor Stephan Rosencrantz from the University of Cologne Heart Center reviews the systemic consequences of pulmonary hypertension with right side heart failure. And then an On My Mind piece, our own associate editor, Dr Vlad Zaha coupled with doctors Walter Myers and Javid Moslehi from Vanderbilt discuss the impact of evolving immunotherapies for cancer and their impact on the cardiovascular system. In our mailbag, Dr Xiayan Shen from the Medical Classification Center of the Singapore Armed Forces discusses in a research letter the prevalence of Brugada Syndrome in a large Singaporean young male population. In letters to the editor, Dr Muddassir Mehmood from University of Tennessee Medical Center in one letter and Dr Goodarz Danaei from Boston in a response letter discuss the importance of diet relative to the development of HFpEF and how heart failure may be coded in by the World Health Organization when assessing global cardiovascular outcomes.

Bridget Kuhn in our cardiology news feature reports on preliminary results from the International Childhood Cardiovascular Cohort or i3C Consortium that was presented at the 2019 European Society of cardiology Congress. The i3C Consortium used data on 40,000 patients who participated in seven major longitudinal cohort studies that evaluated childhood cardiovascular risk factors from repeated measures during childhood and adolescence. And finally, our own Molly Klemarczyk at Circulation gathered and combined a very nice serial update that highlights important articles from our circulation family of journals, including electrophysiology, imaging, heart failure, and others.

Well, listeners, that's a summary of what's in the journal. But let's now proceed to our feature discussion to learn more about the rapidly emerging field of SGLT2 inhibition.

Well listeners, we are very excited for this feature discussion we have today, Dr Mikhail Kosiborod from Saint Luke's Mid America heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada. And we're going to be discussing the paper related to the effects of Dapagliflozin on symptoms, function and quality of life in patients with heart failure and reduced ejection fraction. They're going to be presenting results from the DAPA Heart Failure trial. Well Mikhail, I was wondering could you orient us a little bit to the DAPA heart failure trial. And then what was the hypothesis that you were trying to address in the current study?

Dr Mikhail Kosiborod: DAPA-HF was the first heart failure outcome trial trying to answer two critical questions about the effects of SGLT2 inhibitors in patients with heart failure and reduced ejection fraction. We knew from prior trials, outcome trials in patients with diabetes SGLT2 agents can effectively prevent heart failure inpatients, overwhelming majority of which did not have heart failure and baseline. But what we didn't know was whether these agents can also be used as therapies for patients with established heart failure, and specifically heart failure with reduced ejection fraction. And they reduce death or worsening heart failure in the patient population. And the second question was whether that effect, if in fact this medications can significantly improve outcomes in patients with heart failure reduced ejection fraction. Can they do that even in patients who do not have type 2 diabetes? Because, in a diabetes trial it appears that that heart failure protective effect may be completely independent on the hemoglobin AONC.

And so DAPA-HF was specifically designed to test those two hypotheses. It enrolled about 4,800 patients with heart failure and reduced ejection fraction about 45% of which had types 2 diabetes. And there's a majority of us, 55% did not. And the main trial results that were published prior to risk analysis showed that in fact dapagliflozin significantly reduced the risk of the composite endpoint of cardiovascular death and worsening heart failure. It was a 26% relative risk reduction and the effects were identical in patients with or without type two diabetes. So both of those hypothesis were proven to be correct. It was effective therapies for established heart failure and reduced ejection fraction, and it was equally effective regardless of diabetes status. Now what we did in this study is really trying to understand the effects not just on cardiovascular deaths and hospitalization for heart failure, but on health status, which is symptoms, physical limitations, and quality of life.

He knows that heart failure is a debilitating disease, causes high burden of symptoms, and physical limitations, has adverse impact on quality of lives. We know that two key goals of managing heart failure are to; one, reduce deaths and hospitalizations for heart failure and two to reduce the burden of symptoms and physical limitations and improve the quality of life. So, that was really the focus of this specific analysis that we're talking about today.

Dr Greg Hundley: Excellent. So I understand you use the KCCQ-12, maybe help us understand what that test is and then tell us a little bit about your methods and your study population. Did you use the whole study population?

Dr Mikhail Kosiborod: KCCQ stands for Kansas City Cardiomyopathy Questionnaire and we actually in the study we use KCCQ-23 which is the full Kansas City Cardiomyopathy Questionnaire, consists of 23 items. And it a disease-specific tools for evaluating health status and heart failure.

So it essentially assesses four key domains, which are the symptom burden, physical implementations, quality of life, and social limitations. In this particular study is a primary endpoint as a primary part of the KCCQ as KCCQ total symptom score, which is a domain that focuses on symptoms. And the idea behind KCCQ is that you have a debilitating disease, which is heart failure. That disease has impact on the patient by causing symptoms, the symptoms then translate to physical limitations. And the combination of the symptom burden physical limitations has an impact on quality of life and social limitation. So that's why are this four different domains assessing these four components of the adverse effects of the heart failure compared to health status. And just very briefly, to mention that KCCQ has been proven to be responsive to clinical change. It's highly for data predictive of death and hospitalizations from heart failure. It has been extensively validated both of them hearts failure was reduced enters and the ejection fraction.

And so we essentially focused, or the primary focus of the paper was really to evaluate the effect of dapagliflozin versus placebo on a Kansas City Cardiomyopathy Questionnaire or KCCQ level symptom score. But we also looked at other domains as well. We looked at the clinical summary score, which includes both symptoms and physical limitations and we looked at the overall summary score, which includes all of the four domains that I mentioned before.

Dr Greg Hundley: What did you find?

Dr Mikhail Kosiborod: The patients treated with dapagliflozin had a greater improvement in health status as assessed by a KCCQ total symptom score or for that matter KCCQ clinical summary overall summary score as compared to patients treated with placebo. So if you look at the mean effect, there is some improvement in the patients taking placebo. That's what we call a placebo effect. And it's very commonly seen in clinical trials. We assessed health status, but there was a greater improvement with dapagliflozin as compared with the placebo, it was statistically significant even in four months. But as the effects were further amplified to eight months and this differences were, I would say favorable when you kind of compare the effect of Dapagliflozin versus other established heart failure therapies when you look at the effects on health status.

What I think was even more important than analysis from a clinician standpoint, and then they think it's actually much more meaningful clinically is what we call a responder analysis. And that's where we look as the proportion of patients that have a clinically meaningful improvement with one type of therapy versus other in this case Dapagliflozin versus placebo.

So it's been previously established that at five-point difference or a five-point change rising KCCQ is what's considered to be clinically meaningful or minimal clinically meaningful difference. So a 5.2 grade deterioration KCCQ means it's a clinically important deterioration. And a five-point or greater improvement is a clinically important improvement. And then we also looked at the proportion of patients with moderate and large improvements in health status as well defined as STEM point of grade of two, or two point a great improvement. And essentially what we found was that significantly fewer patients treated with dapagliflozin and as compared with placebo had a clinical importance deterioration. And significantly greater proportion of patients treated with dapagliflozin has small, moderate, large improvements in health status. And the numbers needed to treat to see those differences, as the small moderate large improvements was very favorable ranging typically between 12 and 18 and over eight-months-treatment period.

Dr Greg Hundley: Outstanding. So both clinically relevant as well as statistically significant findings. Now we're going to bring in Justin, our associate editor. Justin, help us put these results into the just our perspective in looking at SGLT2 inhibitors, particularly for treatment for heart failure.

Dr Justin Ezekowitz: This is an exciting class of medications and we're eagerly awaiting these results because we saw the DAPA-HF Overall results. The majority of us treat patients with a pretty symptomatic disease and as such this quality of life is quite an important change. There's ongoing trials we're eagerly awaiting which are also going to be using other medications in the same class, but I think one question that remained was, are these simply improving symptoms by one meaning, so the total symptom score? Or the overall quality of life? And I think you nicely, elegantly portrayed that in the figures and you have. The one other part maybe Mikhail, you could expand upon, which is when you think about DAPA-HF, and the quality of life gains and across all the three different ways of looking at quality of life, where do you see this in terms of its relationship to other things that we know improve quality of life? Where we send patients, for example, CRT or put them on an RNE. Where does this fit on top of those types of changes?

Dr Mikhail Kosiborod: Thanks Justin. I think it's a really important question because it says think critical from a clinical standpoint to put it in the context of other therapies that had been previously shown to improve health status, which means again, reduced symptoms, improve physical and patient quality of life. And there are a number of perhaps the types of therapies on heart failure and LVCF that have been evaluated particularly on side this one there also have been studies with exercise training in heart failure or and the ones that you brought up, which is cardiac resynchronization therapy in patients with heart failure reduced ejection fraction and left bundle branch block. And as that perhaps, if you kind of think about it. What are some of the most effective treatments to improve the health status? That is ones that we typically would consider as such, which is CRT in patients with half RAF and a left bundle branch block.

And in fact, if you look at the mean effects dapagliflozin compares very favorably even with highly effective therapies such as TRT. Relatively few studies have previously reported to this responder in analysis. But if you look at Digoxin comparing those to dapagliflozin, one of the recent ones that I can think of is [inaudible 00:20:23], again dapagliflozin compares very favorably when you look at this types of responder analysis where again you look at proportion of patients, it was a clinically meaningful change.

So I think the beautiful thing about putting the study in the context of further studies looking at health status and also in the original main results that were published from a DAPA-HF early this year is that it's really kind of a full house if you will. So as the agent reduced deaths, reduced hospitalizations and made patients feel better and all of that, with very favorable safety profile. So, if you kind of think about risk benefit analysis and you look at numbers need to treat both for clinical outcomes such as CVS and hospitalizations for heart failure for example, where health status, it looks really impactful from a clinical standpoint.

Dr Greg Hundley: So relevance to other therapeutic interventions for heart failure is what this whole class of agents seems to be showing? So briefly, what do you see is the next important study in the field?

Dr Mikhail Kosiborod: I will waffle on this question a little bit and say there was more than one, but my views are there kind of two key components to this. One is that there are additional trials going on and heart failure with reduced ejection fraction with other agents. And so seeing what happens with those other agents in the class in a similar patient population and whether is this a class effect or not? Now the diabetes trials would suggest that these may well be class effects but I think it's nice to have validation of that. I would say that is one real important questions that hopefully we will have additional answers to in the coming year or so.

And the second and perhaps I would argue even more important question is whether these agents can also be effective in improving outcomes in patients with heart failure and preserved ejection fraction. That's a patient population that has also very high debilitating burden of symptoms that has poor prognosis and for which unlike them, half rubs, there are very few, if any medications that have been proven to be disease-modifying and actually have shown outcomes and benefit. So I would say those in my mind, are the two critical developments that we'll be seeing. And the good news is, there are the trials going on with more than one agent in a class and half to half as well. Great.

Dr Greg Hundley: And Justin?

Dr Justin Ezekowitz: Yeah, I think that there's been an explosion of therapies and Mikhail is bang on with this is the one class where we're excited about. I think the other groups of medications include Omecamtiv Mecarbil we'll know in a year or two. We'll hear more details in the spring and then there's a few other medications that Mikhail mentioned. I think this is a real good message though, that both HFrEF and HFpEF, it's the rise of medications again. Because we were on a device track for a while, but I think the medications have such more potent effect on the underlying structure and function that it's great to see that there's been such a development and explosion of medications that may obviate the need for implanted devices or advanced therapies, so we're very excited about that.

Dr Greg Hundley: Outstanding. Well, listeners, we've had the opportunity to hear from Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada, and learn more about SGLT2 inhibition and its importance in improving clinically symptomatology both in those with diabetes and heart failure, but also those with heart failure alone.

On behalf of Carolyn and myself, we wish you a great week and we look forward to running and having a coffee chat next week. Take care of. This program is copyright the American Heart Association, 2020


Dec 30, 2019

Dr Greg Hundley: Well listeners, this is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond this week, who is sadly missing his dear friend, Dr Carolyn Lam, who is away for just a week or two. I hope you've experienced a wonderful holiday season and are able to embrace the new year with joy and hope.

In our feature article this week, Dr Marcelo Di Carli and colleagues are going to discuss the role of coronary microvascular dysfunction assessed with cardiac stress during PET, as well as left ventricular remodeling assessed with echocardiography and how both of those relate to clinical outcomes in patients with chronic kidney impairment. But first, let's have a coffee and chat about other articles in this issue.

We have four original manuscripts, two or more clinical papers, and two from the world of basic science. So let's go to the clinical papers first. And the first emanates from our own associate editor, Dr Sana Al-Khatib from Duke University. Her paper comes from the ARISTOTLE trial, a randomized study of 18,201 participants that compared apixaban with warfarin in patients with atrial fibrillation at increased risk of stroke. And so this sub study included 17,423 patients in ARISTOTLE without severe renal or liver disease. And the authors evaluated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking either NSAIDs with therapixaban or warfarin. The authors found that those with NSAID use at baseline, so before starting into the study or incident NSAID use, that is they began an NSAID after initiating this study were more likely, both groups were more likely to have a history of bleeding, nearly a quarter of the patients to a fifth of the patients versus only 15% that had never used NSAIDs either before or after entering the study.

In addition, the safety and efficacy of apixaban versus warfarin appeared not to significantly be altered by NSAID use. That is whether you were taking apixaban or whether you're taking warfarin, the impact of NSAID use was not different between either of those anticoagulants.

The second original clinical article comes from Dr Audrey Blewer, also from Duke University, and evaluates the variation in bystander cardiopulmonary resuscitation delivery and subsequent survival from out of hospital cardiac arrest based on neighborhood level ethnic characteristics.

As background for this research, bystander cardiopulmonary resuscitation delivery and survival from out of hospital cardiac arrest varies at the neighborhood level, was generally lower survival seen in neighborhoods predominantly with individuals from black race. Despite Hispanics being the fastest growing minority population in the United States, few studies have assessed whether the proportion of Hispanics in a neighborhood is also associated with delivery of bystander CPR or subsequent survival for an out of hospital cardiac arrest. Accordingly, the authors in this study assessed whether bystander CPR rates and survival buried by neighborhood level ethnicity. And they hypothesized that neighborhoods with a higher proportion of Hispanics would have lower bystander CPR rates and overall lower survival.

This study was a retrospective cohort and use data from the Resuscitations Outcome Consortium, or ROC Epistry across the United States. So in this study, the authors identified 18,900 cardiac arrests. And they excluded pediatric arrests, EMS witnessed arrests, or arrest occurring in a healthcare or an institutional facility. And they found overall that bystander CPR was administered in 37% of these out-of-hospital arrests. Among neighborhoods with less than 25% Hispanic residents, bystander CPR was administered in 39% of the events, while it was administered in only 27% of the events in those neighborhoods with greater than 75% Hispanic residents. Also, lower rates of survival occurred in neighborhoods with greater than 75% Hispanic residents. And so the authors conclude that these findings suggest there's an important need to understand the underlying disparities in CPR delivery and an unmet CPR training need among Hispanic communities.

Well now let's shift to our two original articles that come from the world of basic science. And the first is from Dr Ying Shen from Baylor College of Medicine and reports on the critical role of cytosolic DNA and its sensing adapters sting in aortic degeneration, dissection and rupture. So as some background for this study, recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing it after sting, a stimulator of interferon genes, plays a critical role in vascular inflammation and destruction. And so in this paper, the authors examine the involvement of this mechanism in aortic degeneration and sporadic aortic aneurysm and dissections. Just like with our other basic science papers, the authors perform both studies in a small animal model, mice, and also in human subjects. So what did they find?

The authors found that in human sporadic aortic dissection tissues, they observe the presence of cytosolic DNA in smooth muscle cells and macrophages. And they had significant activation of this sting pathway. In a mouse model, sting deficient mice showed significant reduction in challenged induced aortic enlargement, dissection and rupture in both the thoracic and abdominal aortic regions. Additional single cell transcriptome analyses were performed and provided some mechanistic understanding for the author's findings.

So in summary, for this very interesting paper from the world of basic science, the author's findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing it after, or sting signaling, is a key mechanism in aortic degeneration. And therefore future studies, perhaps targeting sting, may be performed to see if they could prevent sporadic aortic aneurysm dissection development.

The second basic original article in this issue is entitled In Vivo CRISPR CAS9-mediated gene editing and how that ameliorates atherosclerosis in familial hypercholesterolemia. It comes to us from Dr Bin Zhou from the Chinese Academy of Sciences.

So as background for this study, mutations in the low-density lipoprotein receptor are one of the main causes of familial hypercholesterolemia. The clustered regularly interspace short palindromic repeats of CRISPR and caspase-9 system is an effective tool for gene editing to correct gene mutations and thus ameliorate the disease.

So these authors tested whether in vivo sematic cell gene editing through the CRISPR CAS based nine system delivered by adeno associated virus could treat familial hypercholesterolemia caused by the LDLr mutant in a mouse model. Well, the authors ... As Carolyn would ask, so what did they find, Greg? Well, the authors observed some really exciting results. They found that the LDLr mutation was corrected in a subset of hepatocytes after the CRISPR CAS based nine treatment with LDLr protein expression partially restored. Compared with control animals, the CRISPR CAS based nine targeted SGRNA group had significant reductions in total cholesterol, total triglyceride, and LDL cholesterol in the serum while the aorta had smaller atherosclerotic plaques and a lower degree of macrophage infiltration. So this study really implicates perhaps not only a mechanism of disease, but a potential treatment. But with the relatively small numbers in this study, more research is needed to confirm and substantiate the findings from this group.

So great original articles in this issue. What else is in the issue? And let's move to those. We have a global rounds feature. Remember, global rounds are investigating how cardiovascular disease is assessed and managed in countries from all over the world. Well, in this global rounds feature Professor Ali Oto from Memorial and Cairo Hospital provides a quick reference to the control and management of cardiovascular disease in Turkey. And the next article, an on my mind piece, Dr Milton Packer explorers whether the conditions of atrial fibrillation and heart failure with preserved ejection fraction are two separate diseases that occur frequently together in patients or alternatively, whether these two adverse clinical syndromes may be parallel manifestations of the same underlying myocardial disease with atrial fibrillation affecting the left atrium and heart failure preserved ejection fraction afflicting the left ventricle.

In our what's in the mailbag series, Professor Nicholas Mills from the University of Edinburgh shares in a research letter the relationship between exercise intensity and duration on cardiac troponin release in 10 physically active healthy volunteers averaging 34 years in age. A great read for our readership that is actively exercising. And it looks like in this letter, intensity of exercise matters when evaluating post-exercise serum troponin values. I really encourage everyone to take a look at that letter.

And then finally, there's a letter to the editors from Dr Abdallah Fayssoil from the Raymond Poincare Hospital in Garches, France regarding a prior publication related to nutrition and functional tricuspid regurgitation.

Well, listeners, that sums up our summary. And I hope you had a great coffee or if you're running on your treadmill, a great run. And let's now move on to our feature discussion with Dr Di Carli. Welcome everyone to our feature discussion and we have Dr Marcelo Di Carli from Brigham and Women's Hospital who's going to be discussing with us a manuscript relating to the measurements of coronary micro circulatory function and how they may impact patients with chronic kidney disease. Also discussing today, we have our own associate editor, Dr Victoria Delgado from Leiden in the Netherlands. Well, welcome Marcelo and Victoria. We're so glad to have the opportunity to speak with you. And Marcelo, could you tell us a little bit about what was the hypothesis and some of the background of why you wanted to perform this study?

Dr Marcelo Di Carli: Chronic kidney disease represents a relatively large segment of the population. In the US alone, it's estimated that around 50 million people have the diagnosis of chronic kidney disease. And it's a disease that we all know is associated with a high risk of cardiovascular events. Even in the absence of obstructive coronary disease, it's been shown that the incidents of cardiomyopathy and the absence of obstructive disease, of coronary disease, is pretty high and that associates with a high risk of heart failure and death.

The mechanisms related to cardiomyopathy in patients with chronic kidney disease have been debated for a long time. This has been associated with LVH incidents of non-transmittal or non-ST-elevation MIs, also with microvascular disease as a measure of ischemic heart disease, but there's no clear association with how do these features of chronic kidney disease link to each other. And so our objective was to look at the associations between LV remodeling, coronary microvascular disease and adverse events. And we hypothesized that coronary microvascular dysfunction as a more integrative marker of myocardial ischemia and injury would associate with changes in cardiac structure and function and with increased risk of adverse cardiovascular events.

Dr Greg Hundley: Very nice. So tell us a little bit, Marcelo, about your study population and your study design.

Dr Marcelo Di Carli: Well, this is a cross sectional analysis of a cohort that is well-characterized in our registries. And so it consisted of a consecutive group of patients who underwent both PET scanning for measuring coronary vascular function and echocardiography within 90 days of each other. Could it not have evidence of overt obstructive coronary disease as defined by a history of prior revascularization, prior AMI or an abnormal PET scan indicating presence of obstructive disease.

We also excluded patients with severe valvular disease, cancer, severe LV disfunction to try to avoid confounding elements in the associations where we're trying to study. We used echocardiography to assess quantitatively the changes in LV geometry, diastolic function and subclinical systolic dysfunction. Most of our patients have relatively preserved LV function, LV ejection fraction. And so we looked at peak longitudinal strain, global radial strain and circumferential strain as indicators of systolic dysfunction. And of course we also looked at changes in LV mass. Patients were followed a little over four years for the occurrence of death, hospitalization for heart failure or myocardial infarction. And all of these myocardial infarctions were non-ST-elevation MIs, or people might call it type two MIs.

Dr Greg Hundley: Tell us a little bit about the results. But before you get to that, how old were these patients and what was their breakdown in terms of race and gender?

Dr Marcelo Di Carli: Yeah, so we had a population of 352 patients. The mean age was mid-sixties. not surprisingly, 60% of the patients were female. And this is because we obviously excluded obstructive coronary disease that would be more prevalent in male. They have about a 40% incidence of diabetes, a high percentage of them had hypertension. These are all the features that would typically be associated with chronic kidney disease. The rate of obesity was actually lower in patients with CKD. And we call CKD here as a GFR less than 60. That's the population we're targeting here. And so that's essentially the cohort.

Dr Greg Hundley: And what did you find?

Dr Marcelo Di Carli: Well, there were essentially three or four main findings. Number one and not very surprisingly, patients with CKD had worse myocardial mechanics that is worse diastolic function and worse systolic strain. In multi-variable models, fully adjusted for a number of clinical covariates as well as ejection fraction, we found that these abnormalities in myocardial mechanics were relatively strongly associated with abnormal coronary microvascular function as defined by PET. So this sort of suggests that the variability that we see in diastolic and systolic function are explained largely by microvascular disease, but not necessarily directly linked to GFR as a mediator.

The second finding was that patients with CKD, again, not surprisingly, it showed a higher incidence of MACE, including especially death and heart failure, more than triple the rate of death and doubled the rate of heart failure compared to those without CKD. And in multi-variable analysis, again, MACE was associated with coronary flow reserve as a measure of microvascular dysfunction but not glomerular filtration rate. And there was no interaction between coronary flow reserve and GFR. Interestingly, when we looked at the adverse events subgroup by measures of LV remodeling and we picked three measures. One is changes in LV geometry, diastolic dysfunction, and impaired global longitudinal strain, we found that the incidence of both mace as well as heart failure and myocardial infarction were significantly higher when both abnormal LV mechanics or remodeling were present and the patients also had microvascular disease. So in the absence of either one, the rate of mace was relatively low, indicating that there is a clear interaction between abnormalities in cardiac structure and function and microvascular disease.

And then lastly, we looked at mediation analysis to try to investigate a plausible pathway between impaired renal function and events and we hypothesized that coronary microvascular dysfunction might actually mediate at least part of that relationship. And indeed we found that about a third of the relationship was explained by the presence of microvascular disease. Very nice,

Dr Greg Hundley: Very nice. Very important work. So now we'll turn to our own associate editor, Victoria Delgado. Victoria, help us put this into perspective for what we know about patients with chronic kidney disease. How does the results of this study really move the field forward?

Dr Victoria Delgado: I think that this article brings new evidence on phenotyping of these patients and the factors that influence the cardiac abnormalities that we may see. There are not many studies including patients with chronic kidney disease. These patients are usually underrepresented in randomized control trials. And we know that these patients are associated with an increased mortality and morbidity and mainly heart failure hospitalizations. And I think that this study is showing another piece in the person that can help us understand why these patients are associated with much higher cardiovascular morbidity and mortality. I think that relating the coronary microvascular dysfunction is an important piece and important knowledge because then we may think how to improve the microvascular dysfunction on these patients and see if by improving these microvascular dysfunction, these abnormalities that have been described in terms of a structure and function can be reversed and see how these impacts on the outcome of these patients.

Dr Greg Hundley: So Marcelo, just briefly, what do you think is the next study that needs to be performed in this area of science?

Dr Marcelo Di Carli: I think that obviously our study has some limitations and the causation. Cause and effect cannot be inferred from our study. So I think the next steps will be to try to demonstrate whether indeed modifying microvascular dysfunction leads to improved outcomes. And I think this will be best done by intervention studies that can be targeted towards improving microvascular dysfunction. We can think of novel therapies as well that have been initially associated with improved renal outcomes. I'm talking about for example, SGLT2 inhibitors that can be potentially of benefit not only on renal outcomes but potentially on cardiovascular outcomes as has been shown in populations largely without CKD.

Dr Greg Hundley: Victoria, anything to add in terms of how noninvasive imaging could play a role in some of those next future studies?

Dr Victoria Delgado: I think that the point that Marcelo raise on the use of SGLT2 inhibitors is very timely and very appealing because we know that for patients with diabetes who have renal dysfunction and you have EGFR below 35, they may not be eligible for these therapies. But as you can see in this study, the mean EGFR of the patients with renal dysfunction was 41. So there is a wide range of patients that could be eligible for these therapies. How imaging can help to see or to detect the patients that may benefit from these therapies and see how these therapies may improve the structure and the function of the heart.

Dr Greg Hundley: Well, listeners, we've had a great discussion today with Dr Marcelo Di Carli from Brigham and Women's Hospital and Dr Victoria Delgado from Leiden. And really trying to understand some noninvasive markers of both micro circulatory dysfunction as well as abnormal echocardiographic assessments of both diastolic function as well as systolic dysfunction and how they forecast adverse events in patients with chronic kidney disease.

I want to wish you all a great week and on behalf of Carolyn and myself, I hope to see you next week. Take care now.

This program is copyright the American Heart Association 2020.


Dec 23, 2019

Dr Amit Khera: I'm Amit Khera, I'm digital strategies editor for Circulation and I'm standing in this week for Carolyn Lam and Greg Hunley. And I'm also doing the Circulation on the Run podcast, as well as Discover CircRes podcast with our two editors in chief.
This is Jane Freedman, who recently took over as editor-in-chief of Circulation Research, and Joseph Hill, who is the editor-in-chief of Circulation. So, welcome you both. We're excited to do this.
Dr Joseph Hill: Thank you.
Dr Jane Freedman: Thank you.
Dr Amit Khera: The idea behind this, there's this session here at sessions where we're learning a little bit about Circulation Research and Circulation, pulling back the cover, if you will, and seeing behind the cloak, as what happens in the Journal. So, Dr Freedman, I'll start with you. Tell me a little bit about, as the incoming editor of Circulation Research, some of your vision for the Journal, which you're excited about.
Dr Jane Freedman: Mm-hmm (affirmative). Well, I'm thrilled to be the new editor of Circulation Research. And I've assembled a fabulous team of associate editors, deputy editors and other staff and support, that are going to continue to grow what's already a wonderful journal, to be the preeminent and primary journal for basic and translational cardiovascular sciences. And also support and interact with the other HA family of Journals.
Dr Amit Khera: So obviously that starts with a great team. And it sounds like you've assembled that. Anything new that you're thinking about, and sort of the redesign of Circ Research in your term?
Dr Jane Freedman: Sure. So, we're hoping to expand the original scientific content, so we can have a larger number of articles in original science. And we can have the pages to be able to handle other areas of basic cardiovascular science to include new areas, emerging areas, things like that. We're also increasing some of our early career initiatives, so that's very important to us as well.
Dr Amit Khera: Fantastic. Fantastic. Can you talk about expanding for science? And Joe, that leads to you. I'm going to, in this session tomorrow, one of the goals is when people submit their science, it really goes into a black box and people don't know what happens on the editorial level. Can you maybe enlighten us a little, what happened?
Dr Joseph Hill: Jane and I have been friends for 20 or more years and we now have established a bi-directional, mutually synergistic collaboration where we send papers each way. We have distinct missions, but yet with significant overlap. And I think it's an incredibly exciting time for the entire portfolio of AHA Journals. So as you
say, most people that you hit send and you wait four to six weeks, and you
either get a happy note or an unhappy note.
And, what happens at both our Journals is we have a strategy of multiple
touches on every paper. The paper that first comes in, is first touched by a
senior editor, either myself or James de Lemos, and two or three others. And we
will reject without review, about 50% of the papers at that point. We publish six
papers a week, but we get 110 a week. So we don't need to review 50 of them
to pick the top six.
Out of respect to our authors to save them time, out of respect to our reviewers
who devote tremendous effort to reviewing papers, we don't send them papers
that we don't think have a shot. That said, if a paper makes it past that first
stage, there's about a 50% chance it'll get published either in our Journal, or in
one of the subspecialty journals. Probably a 50-50 chance it'll be published
somewhere in an AHA family Journal.
So if it makes it past that stage, we send it to an associate editor, of which you
are one. And we have about 50 of them. A third are in Dallas, another third are
in the U.S. outside of Dallas, and another third are in countries around the
world, 17 different countries. And that person will probably reject without
review, another five or 10% maybe. But he or she will dig into that paper, and in
parallel send it out to two or sometimes three reviewers, who are trusted and
valued advisors.
They help that associate editor make a strong recommendation. He or she
makes a decision to bring to the larger group, that is informed by those
reviewers. So already that paper has been touched by five different
investigators. Typically, that associate editor will reach out electronically within
his or her affinity group. We have an affinity group in epidemiology, heart
failure, intervention, basic science.
Asking other AEs, "Could you take a look at this paper? One reviewer said this,
one said that, I'm sort of thinking this." And then we'll have a conversation on
our weekly video conference, and then a decision goes out to the authors. So
every paper is touched by at least five, and sometimes 10 different editors and
reviewers, which we have found has been a powerful way to really dig into and
identify things that one or two people might have missed.
Dr Amit Khera: One thing I note here is, if you realize how many people touch these articles, yet
how efficient and how fast this process is, then that's a testament to sort of, the
goals of the Journal, to be really responsive and rapid for our authors. One big
part of that, and come back to Dr Freedman is peer review, right? So, associate
editors have a lot of work, and were affinity groups and so forth, but really
critical are these peer reviewers. And in the modern era, we're all so busy. Tell
us a little bit about the value of peer review, and how we enhance the value to
the peer reviewers themselves.
Dr Jane Freedman: Mm-hmm (affirmative). Well, just as you said, the peer reviewers are absolutely
central, valued and vital parts of making the Journal run correctly. And we, like
Circulation, our associate editors send them out to three different peer
reviewers, and they have a very fixed amount of time to review the articles, and
they provide these wonderful comments.
We also very heavily rely on our editorial board. They know the drill, that it
needs to be back within a fixed amount of time. And for the most part, they do
it. It's an interesting question, "What's the value to them?" I've been a reviewer
too. It's part of your pay back. It's part of educating yourself about what's new
and interesting. There's a lot of reasons for doing it. People enjoy being on the
editorial board and interacting with the Journal. But fundamentally, as an
editor, you're incredibly grateful to your reviewers. They are the unsung heroes
of making a Journal work.
Dr Amit Khera: You mentioned sending out to three, when you have sort of disparate reviews.
It's amazing when some people love it and some people hate it.
Dr Jane Freedman: Yeah.
Dr Amit Khera: How do you handle that?
Dr Jane Freedman: Yeah, well, sometimes it's apparent from the reviews why that happened.
Someone may have focused on something, that the editorial group thinks is less
important. Or they have focused on something that's addressable. The other
thing we do, similar to Joe, is we have a video conference call every single week
on Wednesdays, and that's a period where people can vet any concerns or
questions. And then my editors, my associate and deputy editors know we have
an open communication at all times. So I very frequently, when they have
questions about reviews and how to reconcile disparate reviews, we'll have an
ongoing conversation about that.
Dr Amit Khera: It sounds like, of course you're actively engaged in how this is a dynamic
process. I'll mention one thing, is digital strategies editor and I know both at Circ
Research and Circulation. We're always thinking, "How do we bring these
articles to life? How do we have the most people read them or engage with
them?" And one is traditional social media. So Twitter and Facebook, which is
incredibly important. Podcast, you have a monthly podcast.
Dr Jane Freedman: Mm-hmm (affirmative).
Dr Amit Khera: We have a weekly podcast and really hope that people listen to them because
they're really full of important information. And finally, I think what people
don't appreciate is the media. So we work with the AHA media. Some of our top
stories get over a million media impressions, go all around the world and there's
Professional Heart Daily. So, there's so many ways that we're bringing articles to
life. Joe, I'm going to finish with you. This is a Circ family. The value of having a
family of Journals and how we keep cohesion, and for authors when they're
submitting to sort of a family of Journals, what's the value and how does that
Dr Joseph Hill: Well, there has been complete turnover of all the editors in chief in the entire
family of Journals, of which there are 12. And we are all quite similar in our
personalities, and in our perspectives on the importance, the ultimate
importance of validity. The first question we ask, "Is this true?" If it's not, it's
gone. It doesn't get referred. We reject it. Even if it's going to be on the front
page of the New York Times and cited 10,000 times. And all of us hold ourselves
to that same standard. So our vectors are all pointed in the same direction. We
also care about impact, not impact factor. But does it change the way you think?
Does it matter? Is it incremental, or does it really move the needle?
So we are now in a situation, I think a wonderful situation where we all sink or
swim together. We send papers all around, as you know very well. We send
papers to the subspecialty journals. We send 20 or 30 a week, on an
extraordinarily regular basis. And we send papers horizontally to Circ Research,
or Hypertension, or Stroke and so forth. So, it is a syncytium now I would say, of
a family of journals where we are all looking out for each other. Jane cares
about our Journal and we care about her Journal. And that's really a wonderful
situation to be in.
Dr Amit Khera: Well thanks. That family and how this fluidity of articles and thought and
exchanges, is really part of the value. And ultimately the goal is for a great paper
to find a great home. And I think in this Circ family we do that.
Thank you very much. It's been a wonderful podcast. Again, I'm Amit Khera,
digital strategies editor sitting in for Carolyn Lam and Greg Hundley for
Circulation on the Run, as well as for Discover CircRes. Thank you.
Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Dec 16, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart center and Duke National University of Singapore.

Dr Greg Hundley: And I'm associate editor, Dr Greg Hundley, from VCU Health, the Pauley Heart Center, in Richmond, Virginia.

Well Carolyn, our feature discussion, are results from the Odyssey study and they're presented by Professor Wouter Jukema from Leiden University Medical Center, regarding the relationship between ultra-low LDL levels in both ischemic and hemorrhagic stroke. The study really seeks to answer the question related to concerns that ultra-low LDL levels, less than 15 milligrams per deciliter, in patients treated for ischemic heart disease could increase the risk of hemorrhagic stroke, but more to come on that intriguing question. Carolyn, how about your first paper?

Dr Carolyn Lam: It's from doctors Condorelli and Kallikourdis from Humanitas Clinical and Research Center and Institute of Genetic and Biomedical Research respectively in Rozzano Milan in Italy. Now, these authors used single cell RNA sequencing to map the cardiac immune composition in the standard Murine non ischemic pressure overload heart failure model. They then integrated their findings using multi parameter flow cytometry, immunohistochemistry and tissue clarification immunofluorescence in both the mouse and the human. And they found that despite the absence of infectious agents or an autoimmune trigger, induction of disease led to immune activation that involved far more cell types than previously thought. And that included neutrophils, B cells, natural killer cells, and mast cells. And this really opens up the field of cardio immunology to further investigation using toolkits that have already been developed to study these immune subsets.

Dr Greg Hundley: Ah, so Carolyn, do they have any specific examples?

Dr Carolyn Lam: Hmm, indeed they did. They found that activation lead to up regulation of key subset specific molecules such as pro inflammatory cytokine onco statin M in pro-inflammatory macrophages, and PD1 in T regulatory cells. Now these are significant because they may help to explain clinical findings such as the refractivity of heart failure patients to anti TNF therapy and cardio toxicity during anti PD1 cancer immunotherapy respectively, for the more these subset specific molecules may become useful targets for the diagnosis or therapy of heart failure.

Dr Greg Hundley: Oh, beautiful. Well Carolyn, my next article is from Ambarish Pandey from University of Texas Southwestern Medical Center and it's entitled Incorporation of Biomarkers into Risk Assessment for Allocation of any Hypertensive Medication, According to the 2017 ACC, AHA High Blood Pressure Guidelines, a Pooled Cohort Analysis.

Dr Carolyn Lam: So I suppose asking does consideration of troponin or BNP inform cardiovascular risk in those with hypertension?

Dr Greg Hundley: Great question Carolyn. So in this study, the authors included participant level data from 12,987 participants across three cohort studies, ERIC, the Dallas Heart Study and MESA. And they were pooled excluding individuals with prevalent cardiovascular disease and those taking antihypertension medications at baseline. Participants were analyzed according to blood pressure treatment group from the 2017 ACC AHA Blood Pressure Guideline and those with high blood pressure, 120 to 159 millimeters of mercury, were further stratified by biomarker status.

Dr Carolyn Lam: Okay. So what did they find Greg?

Dr Greg Hundley: Participants with elevated blood pressure or hypertension, not recommended for any hypertensive medication with versus without either elevated high sensitivity, cardiac troponin T or N terminal pro BNP, had a 10-year cardiovascular incidence rate of 11% and 4.6%, with a 10-year number needed to treat to prevent one event for intensive blood pressure lowering of 36 and 85 individuals respectively.

In addition, among participants with stage one or stage two hypertension recommended for antihypertensive medication with a blood pressure less than 160 over a hundred millimeters of mercury, those with versus without an elevated biomarker had a 10-year cardiovascular incidence rate of 15.1% and 7.9% with a 10-year number needed to treat, to prevent one event of 26 individuals and 49 individuals respectively.

Dr Carolyn Lam: Wow, Greg, those are impressive numbers. So does this mean we should be checking biomarkers in everyone?

Dr Greg Hundley: Great question again Carolyn. These results suggest that a biomarker based approach to cardiovascular risk assessment may help identify high risk individuals with elevated blood pressure or stage one hypertension who are currently not recommended for any hypertensive medication, according to the 2017 ACC AHA Blood Pressure Guideline, but who may benefit from blood pressure lowering therapy. And it seems the more we research blood pressure measures, the more we learn regarding individualizing targets for blood pressure lowering.

Dr Carolyn Lam: Very interesting Greg. Thanks. So my next paper sought to understand to what extent do drug costs, which are potentially actionable factors, contribute to medication non-adherence? A very interesting and relevant question, and this is from Dr Nasir from Yale New Haven Health System and colleagues who identified more than 14,000 US adults with a reported history of atherosclerotic cardiovascular disease in the national health interview survey from 2013 to 2017. Now participants were considered to have experienced cost related non-adherence if in the preceding 12 months they reported either skipping doses to save money or taking less medication to save money or delaying filling a prescription to save money. And they used survey analysis to obtain national estimates.

Dr Greg Hundley: Okay, Carolyn. So what did they find?

Dr Carolyn Lam: Listen to this. So they found that one in eight patients with atherosclerotic cardiovascular disease reported non-adherence with medications due to cost, representing nearly 1.5 million estimated patients missing doses, 1.6 million taking lower than prescribed doses and 1.9 million intentionally delaying a medication fill to save costs, all in the United States. Patients less than 65 years of age, had a three fold higher rate of medication noncompliance due to cost, with significantly higher rates in women and among patients from low income families and those without health insurance. Now the take home message I think is that the removal of financial barriers to accessing medications, particularly among vulnerable patient groups, may help improve adherence to essential therapies to reduce atherosclerotic cardiovascular disease, morbidity and mortality.

Dr Greg Hundley: Great paper, Carolyn. We've got a couple other articles in this issue. Let's just run through so our listeners get a synopsis. So Dr Javed Butler from University of Mississippi Medical Center has a nice white paper regarding heart failure endpoints in cardiovascular outcome trials of SGLT2 inhibitors in patients with type two diabetes. Dr Brahmajee Nallamothu in a perspective piece, discusses issues related to the legal prosecution of stent cases and the 70/30 rule. Remember Carolyn, the 70/30 rule, the operator may say a stenosis is 70% of an intracoronary luminal narrowing, but in review, others seem to think it's less than 30% and often these cases are prosecuted for performing coronary artery interventions on these lesions, but what Dr Nallamothu argues is perhaps, these definitions are really related to how that stenosis was measured. Are you taking approximately dilated segment or a distantly dilating segment as your reference point? Really interesting perspective piece.

The next article is from Dr Prateeti Khazanie at the University of Colorado in Denver and provides an on my mind piece with Dr Mark Drazner regarding ethical issues that arise during cardiac transplant allocation process. They review some of the pitfalls associated with current physician subjective assessments used for heart transplants in the United States. Dr Neil Kay presents another EKG challenge related to T, a new wave alternans and consumption of alcohol in association with combinations of antiarrhythmic drugs. Dr Dipan Shah from Houston Methodist provides new data in a letter, a research letter, regarding the association of extracellular volume fraction and MRI measure of interstitial fibrosis in the setting of chronic mitral regurgitation.

And finally, Carolyn, Dr Nirvik Pal and colleagues write a letter referring to an earlier publication related to LVAD adverse outcomes and cardiac transplantation. Well, shall we move on to that feature discussion?

Dr Carolyn Lam: Yeah, let's do that, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion and we're very excited today to have Dr Wouter Jukema from Leiden University Medical Center who's going to tell us about the utility of PCSK9 inhibitors on the impact of both ischemic and hemorrhagic stroke. A large study that comes from the Odyssey study. Welter, we are so glad that you're with us this morning, afternoon, evening, wherever you may be in the world. Could you tell us, what were the thoughts behind putting this study together?

Dr Wouter Jukema: As we all know that patients with acute coronary syndromes, ACS, are at an increased risk for a subsequent stroke. And we also do know that lowering of atherogenic lipoproteins, including LDL cholesterol of course, reduces the risk of ischemic stroke in chronic atherosclerotic cardiovascular disease or recent ACS.

However, concerns have been raised about very low LDL cholesterol levels and the potential risk and increased risk of hemorrhagic stroke.

So the effect of lipid lowering by PCSK9 inhibition, both ischemic and hemorrhagic stroke is actually not fully determined. So what we therefore did to better investigate this is that in the obviously outcomes trial, the main publication was of course in New England Journal of Medicine already, we did a pre-specified analysis. We was designed to assess the effect of LRO come up on the ischemic as well as on the hemorrhagic stroke in patients with a recent ACS in obviously outcomes, all patients had a recent ACS and we have hypothesized that for patients treated with LRO come up that would be one, A, a reduction in risk of ischemic stroke, B, without an increase in hemorrhagic stroke. And we also hypothesize that the results would be irrespective of baseline LDL cholesterol and the history of cerebral vascular disease.

So that was our background and objectives and we investigated this in urology outcomes trial a huge, huge trial. If you may all recall post ACS patients one to 12 months post ACS, they all had a run in period two to 16 weeks of high intensity or maximum tolerated dose of atorvastatin or rosuvastatin, and then you had to meet certain lipids criteria and then you were randomized to LRO come up circuitously every two weeks or placebo. And of course all the patients and investigators were blinded to lipid levels and treatment location. So this was a design.

Dr Greg Hundley: Wouter that was a fantastic description of why we're studying this particular series of issues as both ischemic and hemorrhagic strokes.

Tell us a little bit about your study results?

Dr Wouter Jukema: We looked at the entire population of the Odyssey outcomes trial. This is almost 19000 patients and then we looked if they had a history of prior cerebral vascular disease or we have no history of cerebral vascular disease. The majority, almost 18000 did not have a history of cerebral vascular disease and over 900 did have a history of cerebral vascular disease. And we've also looked at our baseline LDL cholesterol levels. Well, if you can of course, be sure we appreciate people with history of cerebral vascular disease or way out, there are a different study population. So that's of course what you may expect anyway. And that's what we saw.

But regardless if you have the history of a vascular disease or you didn't have that, we saw a reduction of any stroke and actually it was 28% reduction of any stroke, which is quite impressive, in my opinion, as highly significant with a P value of point 0.05 and then afterwards of course, we tried to split it in ischemic stroke and hemorrhagic strokes.

So as I told you, any stroke was reduced with 28% and if you then look at ischemic stroke, it was 27%. Also significant at the P value of 0.01. And then of course, the big question, what would happen with hemorrhagic stroke. And actually this was numerically less also in the LRO come up group. So there was not only a reduction in any stroke, but also in ischemic stroke. But also in hemorrhagic stroke, but this was 17% and then of course you are in the low numbers. So the ischemic ratio for hemorrhagic stroke was 0.83 in favor of LRO come up. And of course that by itself is not significant to the low numbers, but numerically there were less hemorrhagic strokes on top of that, there were less ischemic strokes and that was, I think a very reassuring finding. And the interesting part is that these results were more or less independent.

If you have a history of cerebral vascular disease are not, so people without a price were benefiting and with a price were benefiting. And it was also statistically independent of your baseline LDL cholesterol level. So the results were basically the same. If you had a baseline LDL starting below 80 between 80 and 100 and over 100 the results were the same. LRO come up was always better than placebo. If you look at the data, you could see that it was perhaps doing slightly even better if you had a slightly higher cholesterol from the start, which is conceivable. But the formal test returned 80 did not say show any difference. So you could say the beneficial effect of other LRO come up on stroke in post ACA patients is independent of your history of cerebral vascular disease, is independent of your baseline LDL. LRO come up is just better for ischemic strokes as well as for hemorrhagic strokes at least there was no sign.

Never mind add to that, we did even go one step further and we looked at the risk of hemorrhagic stroke in relation to the HG LDL cholesterol level. So not your baseline LDL cholesterol level, but the achieved LDL cholesterol level in the LRO come up group because there you find the, of course very low numbers and we divided them and below 25 milligrams per deciliter, which we could continue really low between 25 to 15, 15 to 17 over 17 and the numbers of hemorrhagic strokes were exactly the same, always 0.1, 0.2, 0.3%. So very low. And it was certainly not the case that they do very low numbers. We saw more hemorrhagic strokes. So this is again very reassuring data. So even at very low levels of LDL during the trial. Of course we should realize that this trial is of course only a medium duration of two per date, but we didn't see more erratic strokes.

So in my opinion, this is very reassuring data.

Dr Greg Hundley: Very good. I loved all that analysis of subgroups. I want to ask you one quick subgroup question. Was there any difference in outcomes related to gender or age?

Dr Wouter Jukema: As far as we could see there was no differential effect in gender nor in age. Of course you should realize that in very advanced age, of course the numbers get small and if you then start dividing them again in the history of stroke or not, then of course the numbers will get low. But in general there is no age or gender difference.

Dr Greg Hundley: Fantastic. So where do you think, does this field progress from here and what do you think will be the next study that we need related to PCSK9 inhibitors and adverse effects?

Dr Wouter Jukema: I think we have shown now that patients with a recent ACS and dyslipidemia, despite incentive therapy, they do benefit from the PCSK9 LRO Come up, which is reflected by a decrease in the risk of stroke. You should of course realize that this is a post ACS population, so it was not targeted in a post stroke population. This is a atherosclerotic disease population, so the results are applying for an atherosclerotic population of course, many people that have a stroke in the past may have and also from embolic processes from a FIP or whatsoever, and those results may be the same but may of course they may also be different. So that situation was not tested here. This is a atherosclerotic post ACS population. Of course you may be interested in what would happen with strokes in an embolic population with a FIP and that would of course be a very nice trial to do as well. But then you have to do an entirely new trial. And some of these trials are of course underway, but I cannot, with my publication circulation, I cannot provide you with the answer.

Dr Greg Hundley: Well listeners, we've had a great discussion on our feature article today from Dr Wouter Jukema from Leiden university medical center and really some important insights related to PCSK9 inhibitors and the fact in this study, a large study, a sub study from Odyssey that indicates really no increase incidents of both hemorrhagic or ischemic stroke in patients that receive these agents and had previously sustained acute coronary syndromes.

I want to wish you all a great week and on the half of Carolyn and myself. Hope to see you next week. Take care now.

This program is copyright American heart association 2019.


Dec 9, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And this is Dr Greg Hundley from VCU health, the Poly Heart Center in Richmond, Virginia. Well, Carolyn, this week's feature analyzed a pool cohort of all patients in partner one and partner two, both the trials and registries. Patients had severe aortic stenosis and were treated with TAVR or SAVR and then were analyzed with respect to the development of prosthetic valve endocarditis. But more to come on that later.

Dr Carolyn Lam: Let me start by telling you about my picks from this week's journal. So the first one is a really interesting natural experiment. First, do you think that a short term visit to a location with severe air pollution increases the risk of cardiovascular disease?

Dr Greg Hundley: Well, Carolyn, I would say yes.

Dr Carolyn Lam: Greg, you're too smart. But let me tell you what these investigators did. So their co-corresponding authors, Dr Araujo from David Geffen School of Medicine and UCLA, Dr Zhu from UCLA Fielding School of Public Health, and Dr Qiu from College of Environmental Sciences and Engineering in Peking University. These co-corresponding authors and their colleagues did a natural experiment by collecting urine and blood samples from 26 healthy adult residents of Los Angeles before, during, and after they spent 10 weeks in Beijing during the summer of 2014 and 2015.

Dr Greg Hundley: I am really excited to hear this. Carolyn, what did they find?

Dr Carolyn Lam: So traveling from less polluted Los Angeles to more polluted Beijing induced pro oxidative and pro inflammatory effects, which reversed after returning to Los Angeles. This is also the first human study associating exposures to polycyclic aromatic hydrocarbons with changes in paraoxonase 1, enzymatic activity, and circulating levels of hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids. Cool, huh?

Dr Greg Hundley: Absolutely. Carolyn, you did an awesome job. Very nice. Well, my article comes from the world of basic science and it's from Dr Philip Shaul at the University of Texas Southwestern medical Center. So Carolyn, in recent studies of obesity induced insulin resistance in mice with corroborating findings in human type 2 diabetics, this group, Shaul’s group, previously made the surprising discovery that the insulin resistance is driven by an altered post-translational modification in IgG that leads to enhanced activation of FCYR2B in endothelial cells. And as a result, there is an attenuation of insulin transcytosis across endothelial cells and delivery to skeletal muscle myocytes where up to 80% of glucose disposal usually occurs.

Dr Carolyn Lam: Oh. Interesting, Greg. So what did the authors find in the study and how did these findings equate with obesity and hypertension?

Dr Greg Hundley: Well, they found that hyposialyation of the Fc glycan on IgG is identified as a key contributing factor in obesity induced hypertension. And therefore low levels of IgG Fc glycan sialylation may identify individuals at greater risk of developing hypertension. In addition, the degree of sialylation of IgG may predict the relative response of an individual to any hypertensive therapy.

Dr Carolyn Lam: Nice. So my next paper is from Dr Al-Lamee from Imperial College, London, and colleagues who studied the ability of a pre-randomization stress echocardiographic score to predict the placebo-controlled efficacy of PCI within the ORBITA trial. Now as a reminder, the primary results of the ORBITA trial showed us smaller than expected effect size of PCI in comparison with placebo in single vessel stable coronary artery disease on the primary end point of change in treadmill exercise time.

Now in the current study, 183 patients underwent dobutamine stress echo cardiography before randomization, and they found that the degree of ischemia assessed by dobutamine stress echo cardiography predicted the placebo-controlled efficacy of PCI on patient reported angina frequency.

Dr Greg Hundley: Hmm. Very interesting. So help me out again, Carolyn. What's the clinical importance of this?

Dr Carolyn Lam: Ah, so this study really provides the first placebo-controlled evidence of an association between stress echo cardiography, ischemia, and the magnitude of placebo-controlled benefit attributable to PCI. And the greater the downstream stress echo cardiography abnormality caused by the stenosis, the greater the reduction in symptoms from PCI. That's the take home.

Dr Greg Hundley: Oh wow. Very interesting. You know, especially we perform so many stress echo cardiograms. What a great relationship to unfold and present. Well, Carolyn, I'm going to walk through several other important publications in this issue of the journal. The first is from Dr Peter Eckman from the Minneapolis Heart Institute, and he provides an In-Depth review of veno-arterial extra corporal membrane oxygenation, or VA-ECMO, for cardiogenic shock and it's beautifully written for the busy clinician. Robert Platt, PhD, and colleagues discuss in an On My Mind piece the fact that those with adverse cardiovascular sequelae during pregnancy may require development of new cardiovascular risk prediction models. The hypertension or the diabetes that occurs during pregnancy, perhaps we need to incorporate that into our prediction models.

Next. Our own associate editor Torbjørn Omland provides results in a research letter from the peace trial relating the relationship between smoking and high sensitivity troponin T levels. Dr Allen Sniderman from McGill University Health Center writes a letter to Welsh and Associates regarding their study of the UK bio bank database and measures of HDLC. A paper we discussed just a few weeks ago. Dr Derek Chew from the DCRI and Durham North Carolina has another EKG challenge for us. And Dr Tracy Hampton provides an updated news report regarding cardiovascular disease from several recently published articles in the world of basic science. And then finally Dr Thomas Krieg from the University of Cambridge has a nice piece regarding clinical implications of targeting succinate metabolism in ischemia reperfusion injury.

Well, Carolyn, what a great slate, but I can't wait to get to that feature discussion related to prosthetic valve endocarditis.

Dr Carolyn Lam: Me too. Let's go.

Our feature discussion today is really the first paper that describes adjudicated evaluation of prosthetic valve endocarditis in patients with transcatheter and surgical aortic valve replacement. Very unique and valuable data from the partner's trial. I'm so pleased to have with us the corresponding author, Dr Wael Jaber from Cleveland Clinic as well as our associate editor, Dr Manos Brilakis from UT Southwestern. So Wael, very unique question. Could you please tell us how you went about doing this? And I suppose in this setting, the first question on everyone's mind is how did you make this diagnosis of prosthetic valve endocarditis?

Dr Wael Jaber: Actually we saw this as an opportunity that probably we should never miss. I think this is one of the rarer instances where we can objectively not only look at SAVR data but also TAVR data. And over the past maybe seven years, eight years, we started getting here as a referral center patients with TAVR endocarditis for surgery. And we never thought we'd start seeing these weird organisms, different bugs. Of course this is a population that's frail or elderly, but we never had any idea if they behave similarly to SAVR or differently than SAVR in our previous experience with SAVR endocarditis.

So we planned this actually about maybe five years ago, but we didn't have the data because you know the partner trials were undergoing another evolution by going to lower and lower risk population. So we pose this question about a year and a half ago to CRS by asking them, can you provide us with the data on all the endocarditis in partner.

The idea was not only to answer one question but to answer multiple questions. So the first question was in the modern era, what happens in SAVR? All the SAVR endocarditis information we have so far as you will know has been from mainly single center studies or even when we learn about it from multiple centers sites, usually IN European studies, the Swedish registry, the Danish registry, and these are usually limited by the fact that there are a multicenter. The adjudication is at the site what endocarditis happened. So that was the first question. Then the second issue for us was, does TAVR, because of the unusual access to the heart and the fact that we dilate the valve, post dilate the valve, their paravalvular AI, they could be micro-fractures of the refis. This is provide a different opportunity for these bugs to form on the valve, and do they behave differently?

And the third question was, is there any difference between SAVR and TAVR incidence of endocarditis? And bugs. And the final question was what happens to patients when they develop endocarditis in the current decade. Do they do well? Especially for septic endocarditis or do they succumb to their illness? And also this is how we came up with a strategy to answer all these questions.

Dr Carolyn Lam: Very nice. So Wael, could you just expand a little bit more about how the diagnosis or adjudication of prosthetic valve endocarditis was done? And then tell us please, what did you find?

Dr Wael Jaber: All the partner patients, the records were sent to a central place. So the ECHOS first were educated at central places. We were one of those centers. Other places were Columbia University, MedStar and Quebec, the group in Quebec. So all the ECHOS were adjudicated centrally. So that's first, as far as from the echo side of calling it endocarditis or not.

On the clinical side, again, all the records and the forms were sent to a central adjudication committee, CDC group. We served at the Cleveland Clinic as the CDC for most of these trials and actually even for the current trials. So they were sent and they were adjudicated according to the Duke criteria. Which is, you know, the most, probably, reliable way still today to adjudicate these.

And then there was the CDC and the echo core labs were separate. So the people who have information from the CDC did not have access to what's going on in the core lab and vice versa. So these were independently adjudicated as far as echocardiographic evidence and clinical evidence. And then they were fed into it. So by the end, when you hold it on a Duke criteria endocarditis, the echo was fed after the fact, not before. So this is in general how it happened. So all the events were educated centrally, not at the site. And the ECHOS, the same thing, were adjudicated centrally.

Dr Carolyn Lam: Fantastic. And I would love to hear the results.

Dr Wael Jaber: The first question was, what's the incidence of endocarditis? And we decided because of the way these trials were done, to report the incidents as you would see in the results section, to report the incidents of endocarditis per 1000 person year because of the imbalances in follow up and the competing risk for death from other reasons. So we found in general that the incidents of endocarditis was 5.2 endocarditis events per 1000 patients per year in the TAVR side and 4.1 in the SAVR side with a non statistically significant difference. More importantly, we found out that once you develop endocarditis, unfortunately most of these patients succumb to the illness and are dead after the diagnosis. So the risk of dying after developing endocarditis is 4.4 times higher than patients who did not have endocarditis in the trials. In all the trials.

Now there's some caveats here. First, these are trials with different patient populations, as you well know. Starting with partner with the inoperable patients moving on to the most modern S3 trial, which was on the lowest kind of side of population. So we have totally different population groups. Some of them had prolonged hospitalizations before and after, so this should be taken with a little bit of caution.

However, if you look at some of the individual trial data, we found that incidents of endocarditis at least have a trend towards a reduction of incidence of endocarditis over time going from partner, the initial experience with partner, all the way to the modern era.

Dr Carolyn Lam: That is so great. Manos, you know, as an interventional cardiologist yourself, could you tell us how important these results are? Does it affect your practice?

Dr Emmanouil Brilakis: Thanks again, Carolyn. I would like to congratulate Wael for a phenomenal paper. I think it's a very timely study and addresses one of the common concerns there is about whether TAVR does predispose people to more risk for endocarditis. Although again, the opposite grade was kind of low at 0.5% a year. I think this may be a little more than people are commonly seeing in the setting of TAVR, and I think the paper is a good reminder that this is something we should always be mindful and watching. Although typically we'll discuss with the patient about the risk of stroke or access complications, but the risk of infection may not be as well emphasized. And based on this one question I would have is about what can we do if there is something that could potentially lower that risk? I understand the limitations of retrospective study, but are there any recommendations that you have based on the study? Should give more aggressive antimicrobial therapy? Any other biotic prophylaxis or anything else that can be done to reduce the risk of endocarditis in those patients?

Dr Wael Jaber: Actually this is the question we raised. Unfortunately we did not. So the guidelines did not catch up with what we know. So if you look right now, like I was reviewing this paper that came up last month from the Swedish Registry for Endocarditis, it came out in Europe in the European Heart Journal, and one of the questions they raised is how to address, in the editorial, how to address the risk of endocarditis and prophylaxis in this population. There are no standards for that. This is one aspect of it. We need first an update of the guidelines of how to address this issue.

The second question is we do not have any idea, unfortunately, about duration of antibiotics. How the antibiotics prophylaxis were given before the procedure, like as we do right now commonly in surgery, and after the procedure in these patients. We do not know that. Like right now, at least at our center, if you go in for aortic or mitral valve surgery or any valve surgery, you have to have a dental clearance before you start, before you go to surgery. I don't know if this was rigorously applied in the setting of TAVR, and I think it would be a good idea to apply it to make sure that there are no dental, phosphide or potential infections and things like that. So I think it's a multi-front battle to get these patients to the lowest risk possible. I don't think there's one single silver bullet here.

Dr Emmanouil Brilakis: So thanks again, Wael for addressing this. I agree that there's a lot of information to be gained understanding the intricacies of endocarditis prophylaxis. And building on this, let's say another patient develops endocarditis as you've shown in your 170 patients in the study. It was fascinating that staph aureus was actually less common than it was for surgical valves, which has been shown in other studies as well. So you think this affects the choice of the biotic prophylaxis? And then also if the patient develops endocarditis, I understand many people who are not candidates for surgery, but from the ones who did actually undergo surgery, what are the outcomes encouraging?

Dr Wael Jaber: This is a fascinating question actually. This is one of the reasons we had... There was a delay for us in getting the paper out from when we presented it as an abstract at TCT a year and a half ago, is we didn't know. We wanted to answer that question. The second part of the question is how many patients went to surgery? And unfortunately, very few patients. So less than a handful of patients end up going to surgery. And we do not know why. So this is the dilemma here. Is why the rate of referral to surgery for redo surgery was very low.

Was it because these patients were the sickest of the sick? Maybe it is because we waited too long and we did not treat them the same way. We should have treated prosthetic valve endocarditis, which is surgery to be offered as soon as possible because there's no really antibiotic cure for that. So we do not have the answer for that because these very few patients went to surgery and actually I think of those who went to surgery, even the mortality there even was similar to people who did not go to surgery. But we cannot speculate on that because the very few patients.

As far as the bug involved, I think this could be a reflection of the antibiotics given at the time of the procedure, so probably we're covering that very well. But if you notice from the paper, most of the infections happen more than 30 days after the procedure. Whether this is something that was acquired because these patients are more likely to end up in the hospital again for other reasons, whether these patients had endocarditis because they have more instrumentation down the road... Remember this is a population in general above the age of 65 which would require colonoscopies, frequent urinary tract issues, and other procedures.

So we know that we're covering very well, at least I can speculate, we're covering very well for the first 30 days because very few patients had endocarditis right after the procedure, but we're not covering probably after the 30 days. And that remains to be studied. And the worrisome thing is to try to treat these patients with prophylactic antibiotics for a long time and then end up with bug resistance and things like that. Now the CDC issued a big warning about this yesterday. I am not comfortable to speculate from this small number of patients on how to treat for prophylaxis, but I'm comfortable to say probably patients should be sent to surgery as soon as possible after developing endocarditis, especially prosthetic valve endocarditis because the outcomes are dismal.

Dr Emmanouil Brilakis: And do you think... Let's say patient is not a candidate for surgery and gets endocarditis, and I presume they get into prolonged therapy. There were some patients like this that did okay, right? So there is some hope even for those patients.

Dr Wael Jaber: I feel like I'm the cup half full here because if you look at the mortality curves here, we're talking about north of 95% death in this population. So the people who survive this must be very few people survive. So probably about seven patients who survive. So the mortality was 96% at six months versus 46%. So there are very few people who survived that event. Maybe I should go back now and figure out what was the quality of life after survival. So I don't think the picture we have right now is very rosy as far as the way we're managing endocarditis.

Dr Carolyn Lam: Manos, I'm going to give you the final parting words from this very interesting discussion. I mean what do you think are the take home messages and future directions from here?

Dr Emmanouil Brilakis: I agree that this is a phenomenal landmark study and my key takeaways are the same ones that Dr Jaber presented before. But the main thing is, on the consent process, who can tell the patients there is about 0.5% per year. So it's not zero, but it's very high either. The second thing is that this choice between TAVR versus SAVR, that should not have to do with the risk of infection because as it was shown very convincingly, it was very similar to the two groups. And number three that everything possible should be done to prevent this because if you do get infection, the outcomes are not very good.

Dr Carolyn Lam: Thank you so much Manos, Wael. Thank you so much audience for joining us today. You've been listening to Circulation on the Run. Tune in again next week.

This program is copyright American Heart Association 2019.


Dec 2, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia, from VCU Health.

Dr Carolyn Lam: You know what, Greg, I may have a hoarse voice today and I'm a little bit scratchy, but my goodness, I couldn't be more excited about this issue. It's the TCT issue.

Dr Greg Hundley: Well Carolyn, I cannot wait to discuss with our listeners the feature article that compares Apixaban and a P2Y12 inhibitor without Aspirin, versus regimens with Aspirin in patients with AFib who have ACS, whether managed medically or with PCI, or also those undergoing elective PCI that experience regimens that include vitamin K antagonists, aspirin, or both, but more to come later. Carolyn, should I start with my first discussion article and we grab a cup of coffee?

Dr Carolyn Lam: You bet, Greg.

Dr Greg Hundley: So my first article is from Seung-Jung Park from the Asan Medical Center at the University of Ulsan College of Medicine. So Carolyn, here's our first quiz question. In terms of Ticagrelor, have studies been performed in those from Asia evaluating bleeding risk?

Dr Carolyn Lam: You know, I have to admit, Greg, I'm not totally familiar with the literature, but I do know that it's a very important question for us practicing in Asia. We have a perception that the bleeding risk, especially intracranial bleeding, may be higher in Asians.

Dr Greg Hundley: Absolutely. Well, in this multicenter trial, 800 Korean patients hospitalized for acute coronary syndromes with or without ST elevation, and intended for invasive management, were randomly assigned to receive in a one to one ratio, Ticagrelor with a 180 milligram loading dose, and then 90 milligrams twice daily, or Clopidogrel with a 600 milligram loading dose and 75 milligrams daily thereafter, and the primary safety outcome was clinically significant bleeding, which was a composite of major bleeding or minor bleeding according to the PLATO outcomes criteria at 12 months.

Dr Carolyn Lam: Oh, so what did they find?

Dr Greg Hundley: Well Carolyn, at 12 months, the incidence of clinically significant bleeding was higher in the Ticagrelor group than in the Clopidogrel group. So it was 11.7% versus 5.3, and that included major bleeding and fatal bleeding. They were also higher in the Ticagrelor group. The incidents of death from cardiovascular causes, myocardial infarction or stroke, was not significantly different between the Ticagrelor group and the Clopidogrel group, although there was a strong trend toward a higher incidence in the Ticagrelor group with a P value of 0.07. So consequently, Carolyn, these results identified safety concerns regarding bleeding complications of standard dose Ticagrelor in East Asian, Korean patients with acute coronary syndromes, and therefore large adequately powered randomized trials are needed to determine the optimal antithrombotic regimen in this patient population.

Dr Carolyn Lam: Very important data for our patients, as is this next paper, which really examines the cost effectiveness of transcatheter mitral valve repair versus medical therapy in patients with heart failure and secondary mitral regurgitation. Now, these are results from the COAPT trial. As a reminder, the COAPT trial demonstrated that edge-to-edge transcatheter mitral valve repair using the MitraClip resulted in reduced mortality and heart failure hospitalizations and improved quality of life when compared with maximally tolerated guideline directed medical therapy in patients with heart failure and three to four plus secondary mitral regurgitation.

In the current paper, first author Dr Baron from Lahey Hospital and Medical Center in Burlington, Massachusetts and St. Luke’s Mid America Heart Institute in Kansas City, as well as corresponding author Dr Cohen from University of Missouri, Kansas City, and their colleagues used data from the COAPT trial to perform a formal patient level economic analysis of the COAPT from the perspective of the US healthcare system, and they found that although the follow up costs were lower with the MitraClip compared with guideline directed medical therapy, and lower by more than $11,000 per patient. However, the cumulative two year costs remain higher by about $35,000 per patient with the transcatheter mitral valve repair, and this is all due to the upfront costs of the index procedure. Now when in trial survival, health, utilities, and costs were modeled over a lifetime horizon, transcatheter mitral valve repair was projected to increase life expectancy by 1.13 years, and quality adjusted life years, or QALYs, by 0.82 years at a cost of $45,648, yielding a lifetime incremental cost effectiveness ratio, or ICER, of $40,361 per life year gained, and $55,600 per QALY gained.

Dr Greg Hundley: Very interesting. So how do we interpret these results for clinical practice?

Dr Carolyn Lam: Ah, good question. So in order to place this in context, perhaps the most comparable case is the use of transcatheter aortic valve replacement, or TAVR. So based on the partner 1B trial, the ICER for TAVR, compared to medical therapy, was $61,889 per QALY gains. So this is very similar to what you just heard as the ICER for the transcatheter mitral valve repair. The cost effectiveness is also comparable for other commonly used treatments such as the implantable cardiac defibrillators for biventricular pacing, and was interestingly substantially more than the cost effectiveness of continuous flow LVADs, for example, and this is really discussed in a beautiful editorial by Dr Bonow, Mark, and O'Gara, and in this editorial, I think it's really important that they say the cost effectiveness projections really need to be placed in the context of continuing uncertainties regarding the interpretation of COAPT compared to that of the MITRA-FR trial, which reported no benefit of transcatheter mitral valve replacement compared to medical therapy, and so they warn that the current cost effectiveness analysis is not a carte blanche for interventional cardiologists to dramatically escalate their use of MitraClip procedure, and the data do support the thoughtful and deliberate use of this potentially life lengthening procedure in carefully selected patients and under very careful circumstances. You've got to read their editorial.

Dr Greg Hundley: That sounds excellent, Carolyn. I really like that, putting that editorial that puts that data in perspective. Well, my next study really emanates from the ABSORB III trial, and it's from Dr Dean Kereiakes at the Christ Hospital Heart and Vascular Center. The manuscript addresses the long-term cardiovascular event rates among bioresorbable vascular scaffolds and drug eluting metallic stents.

Dr Carolyn Lam: Greg, remind me, what were the results of the original ABSORB trial?

Dr Greg Hundley: Right, Carolyn. So the ABSORB III trial demonstrated non-inferior rates of target lesion failure, cardiac death, target vessel myocardial infarction, or ischemia driven target lesion revascularization at one year with the bioresorbable vascular scaffolds compared with cobalt chromium everolimus-eluting stents, but between one year and three years, and therefore the cumulative to 3 year time point, the adverse event rates, particularly for target vessel myocardial infarction and scaffold thrombosis, were increased with this bioresorbable vascular scaffold.

Dr Carolyn Lam: Ah, I see. Okay, so this current study evaluated the outcomes from three to five years beyond the implantation?

Dr Greg Hundley: Exactly. So what this study did is they looked at an interval of time between three and five years out, and they found reductions in the relative hazards for the bioresorbable vascular scaffolds compared to the common coated stents, and that particularly occurred for target lesion failure, either cardiac death or target vessel MI or ischemia driven target revascularization when compared to the earlier zero to three year time period. So therefore Carolyn, the authors conclude that improved scaffold design and development techniques to mitigate that zero to three year bio resorbable vascular scaffold risk may enhance the late benefits that one sees in this three to five year time point, because of the complete bioresorption.

Dr Carolyn Lam: So that's interesting Greg. Well, my next paper is kind of related. It is the first report of a randomized comparison between magnesium based bioresorbable scaffold and sirolimus-eluting stent in this clinical setting of STEMI with one year clinical and angiographic follow-up. So this study is from the Spanish group, Dr Sabaté and colleagues from the Interventional Cardiology Department and Cardiovascular Institute in Barcelona in Spain, and they found that at one year when compared to the sirolimus-eluting stent, the magnesium based bioresorbable scaffold demonstrated a higher capacity of vasal motor response to pharmacological agents, either endothelium, independent or dependent, at one year. However, the magnesium based bioresorbable scaffolds were also associated with a lower angiographic efficacy, a higher rate of target lesion revascularization, but without thrombotic safety concerns.

Dr Greg Hundley: Wow, Carolyn, very interesting, and Dr Lorenz Räber and Yasushi Ueki wrote a very nice editorial on this whole topic of bioresorbable scaffolds, and they wonder about some of the unfulfilled prophecies. Great for our readers to put these two articles together. Now, how about in that mailbox, Carolyn? What have you got in there?

Dr Carolyn Lam: First there's a research letter by Dr Kimura entitled Very Short Dual Antiplatelet Therapy After Drug-eluting Stent Implantation in Patients with High Bleeding Risk, and that's insights from the STOPDAPT-2 trial. There's another research letter by Dr Lopes entitled The Hospitalization Among Patients with Atrial Fibrillation and a Recent Acute Coronary Syndrome, or PCI, Treated with Apixaban or Aspirin, and that's insights from the AUGUSTUS trial. A very interesting perspective piece by Dr Rob Califf entitled The Balanced Dysfunction in the Health Care Ecosystem Harms Patients, a really, really interesting read, especially those working in the U.S. healthcare system. An ECG challenge deals with fast and slow, long and shorter. I would love to give you a clue to what it is. It's got to do with the atrial ventricular nodes, but I'll let you take a look and test yourself. There’re highlights from the TCT by Drs Giustino, Leon, and Greg Stone, and finally there's Highlights from the Circulation Family of Journals by Sara O'Brien.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a couple reviews. Richard Whitlock in a primer provides a nice historical review of anticoagulation for mechanical valves. How do we get here in anticoagulating this particular patient population? Next, Dr Mark Brzezinski from Brigham Women's Hospital in the Harvard Medical School in an on my mind piece provides very elegant figures, beautiful figures, demonstrating inadequate angiogenesis within the fibrous cap of atherosclerotic plaques, and indicates this could be a source or thought of as a contributing factor toward plaque rupture. What an issue, and I can't wait to get onto that featured discussion.

Dr Carolyn Lam: For our featured discussion today, it is a super-hot topic, and a question that comes up again and again in clinical practice. What is the right antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome, not just those treated with PCI, but also in those treated medically? Well guess what? We're going to have answers right here. I'm so pleased to have with us Dr Renato Lopes, who's a corresponding author from Duke Clinical Research Institute and our associate editor, Dr Stefan James from Uppsala University in Sweden. Wow. Very, very important question here. Renato, could you just start by outlining what is the AUGUSTUS trial?

Dr Renato Lopes: The AUGUSTUS trial was basically one of the four trials trying to give an answer, or help answering about the antithrombotic therapy in patients with anti fibrillation and/or NACS and/or PCI. So in other words, this combination of patients undergoing PCI who require antiplatelet therapy and also patients with AFib who requires anticoagulation therapy, and in summary, what the AUGUSTUS trial did was randomize patients to Apixaban versus VKA, or aspirin placebo in a double blind fashion, and this was a two by two factorial design. So these were basically the two questions that we wanted to answer. Is Apixaban better than VKA, and is it safe to drop aspirin from this treatment strategy? Remembering that everybody received a P2Y12 inhibitor for at least eight months. So this was basically the design of the AUGUSTUS trial, trying to answer two questions in the same study, a two by two factorial design.

Dr Greg Hundley: Very, very nice. And Renato, if I could, I mean I said it in the intro, but may I make sure I got it right. This is the only trial in the field that included patients with ACS that was managed medically. So that's a very important group of patients that we still don't know what the best regimen is, is that right?

Dr Renato Lopes: That is correct. The other trials, the PIONEER, the RE-DUAL PCI and the VPCI, they only included patients undergoing PCI, and when we designed the trial, we thought that it would be important to also include the whole spectrum of ACS, including not only the PCI treated patients, but also the medically managed patients.

Dr Greg Hundley: Well, super. So could you tell us now what were the results?

Dr Renato Lopes: So first, in terms of the breakdown, we found that the breakdown of the PCI, ACS versus elective PCI, was really nice. We had about 60% of the trial being ACS patients, and about 39%-40% elective PCI, and then within the PCI, I think that our results pretty much reflect practice in a lot of parts of the world, which was about 39% medically managed and about 61% PCI treated patients. So to begin with, I think a very nice breakdown that gives us power to look at these three separate groups: ACS medically managed, ACS PCI treated, and also elective PCI, which allows us to understand the whole spectrum of coronary disease in patients also with AFib, and in summary, what we showed for the primary endpoint, which was clinical major or relevant non-major bleeding. Let's start with the Apixaban versus VKA comparison, and we show that Apixaban was safer than VKA in all three groups, in the ACS medically managed, in the PCI treated patients, and also in the elective PCI patients.

There was no significant direction for those three subgroups, although it was borderline 0.052, just showing maybe a little bit less pronounced results in the elective PCI group, but nonetheless, I would say that in general, very consistent, and in terms of Aspirin for the primary endpoint, also no difference, no interaction among those three groups. In other words, as we increase substantially the risk of bleeding about two folds in all the three groups, ACS medically managed, PCI treated patients, and elective PCI patients, with about again, two fold increase in bleeding compared to placebo. If we go to ischemic events, again, that's our hospitalization and other that are ischemic events. In terms of Apixaban versus VKA, the results were very consistent with the overall trial among these three groups, and in terms of as ACS versus placebo, the results also for the ischemic events were also similar among the three groups. So again, reassuring that the main results of the trial were very consistent, regardless how patients were managed in terms of the ACS, medically or through PCI, and also included in the elect PCI group.

Dr Carolyn Lam: Thank you for explaining that so well. Stephan, I would love for you to take us under the hood. What were the editors thinking when we saw this paper, why we're highlighting it now, and what do you think are the implications?

Dr Stefan James: The AUGUSTUS trial was unique in many aspects. I think Renato highlighted a few of them. As he told, there have been several similar trials without the other DOAX, factor 10A inhibitors and the dabigatran, but the AUGUSTUS trial was larger. It includes, as you mentioned previously, patients with ACS and medical management, and it also was designed as a two by two factorial design. So it actually asks two different questions and made two different randomizations, both anticoagulation with the two different agents, Warfarin versus Apixaban, but also Aspirin versus placebo, and so it's possible from this trial to understand more of the different aspects of treating patients, these complex patients with atrial fibrillation, NACS or PCI, and gave the study group and us an opportunity to better understand all these complexities. So with that, I'd like to turn to Renato and try to, with that background that I just outlaid, and you just try to make us understand what are the clinical implications of these aspects of the trial and the treatment of Apixaban and Aspirin in these patients?

Dr Renato Lopes: I think we were in the area that we desperately needed randomized data, because basically until five years ago, the standard of care of treating these patients was the classic triple therapy with Aspirin, Clopidogrel, and Warfarin, and this was based on no randomized trials and all observational data, and we know how problematic this is, and this field has evolved tremendously almost year after year since the PIONEER trial, since the RE-DUAL trial, and this year, we had AUGUSTUS and ENTRUST and I think now, as Mike Gibson used to say, that we have about 2.8 million different combination of antithrombotic strategies to treat these patients because we have different anticoagulants, different anti-platelets, different doses, different durations, different types of stents, which makes it really impossible for physicians or for any guidelines to contemplate all these options. So we really needed a few trials to at least try to give a few options that are evidence based and not just based on low quality of data, and I think now, if you look at the Augustus results, and the totality of the data from all these trials, which now is about almost 11,000 patients all together, actually almost 12,000 patients all together.

I think that what we know today is that yes, the initial period in hospital for some time it's important to use Aspirin. I think this is an important point to highlight, Stephan, that Aspirin still needs to be used for the acute treatment, and I would say at least for the first few initial days while patients are still in the hospital, but then by the time of discharge, which sometimes might be five days, six days, seven days, I think that now the totality of data show that it's reasonable to drop Aspirin for most patients.

So based on the AUGUSTUS results, what we show is that if you're going to use anticoagulation as Apixaban at the dose that is approved for stroke preventions in atrial fibrillation, combined with a P2Y12 inhibitor without Aspirin after the initial period, you have the best outcomes in terms of lower rates of bleeding, lower rates of hospitalizations, and we don't have to pay a cost in terms of ischemic events when we actually drop Aspirin and keep only the NOAC, in this case was Apixaban, plus a P2Y12 inhibitor, which most of the time was Clopidogrel, and here with AUGUSTUS, we basically show that this is true for patients with AFib and ACS, irrespective of the management with medical managing, with medical therapy, or with PCI. So I think that's an additional piece that that is true irrespective of how we're going to treat your ACS patient, or if the patient basically underwent elective PCI, and I think we learned today that the classic treatment therapy of VKA plus Aspirin plus P2Y12 inhibitor, so in other words, the triple classic triple therapy should generally be avoided.

Dr Stefan James: Thank you Renato. I think that that was a very complete answer in this complex arena. I'd like just to mention that of course the AUGUSTUS, as well as the other trials, have their limitations, as all trials. Although it was large, it was powered for safety, for bleeding events, and it was not powered for ischemic events. Having said that, we still want to look at ischemic events and clinical outcomes, and to what degree do you think we can do that? What conclusions can we draw from an ischemic point of view because of the fact that the trial was underpowered for that interpretation?

Dr Renato Lopes: That is a great question, Stephan, and in fact, if we look at events like stent thrombosis, they are very rare, and if you really want to attack a significant difference between Aspirin versus placebo in patients having stent thrombosis, we're really going to need a trial with about 30-40,000 people, which would be not feasible and not doable. So we need to be cautious when we analyze those events in the power trial for ischemic events. Nonetheless, there was a signal, if you look at all trials, and even in the meta-analysis that we published recently, that dropping Aspirin probably increased the risk of ischemic events, not in a statistically significant fashion, but nonetheless, this trend exists. The signal exists. So probably keeping Aspirin, add some protection for ischemic events, primarily stent thrombosis and myocardial infarction. The problem is a tradeoff. The problem is that the cost of adding aspirin is too high.

So now the question to us, Stephan, is to look further into our data and in the combined data sets that we're trying to work with the other authors and try to identify, okay, Aspirin really increased the risk of bleeding, but is there a group of patients who might benefit from a little bit longer Aspirin? So that's the first question. Who are those patients? May be complex PCI, maybe bifurcation lesions, maybe multiple lesions, multiple stents, and second, if we decide to give Aspirin longer, how much longer should we give? Because again, the cost is very high in terms of bad bleeds. So we are trying now to identify what is the trade off, and who most benefit from keeping Aspirin longer, and for how long in a way the cost might be worth it to pay in exchange of potentially save some ischemic events? And with that, we can further refine the treatment that I think I highlighted before. For most patients, I think what I said before is probably reasonable. We can drop Aspirin by the time of discharge after a few days, but for a few patients, for some patients, it might be wise to keep Aspirin a little bit longer, and we are trying now to identify first, who those patients are and second, form how much longer should we keep Aspirin, since the 40,000 patient trial is very unlikely to happen.

Dr Stefan James: I like his interpretation, Renato, although I wanted to highlight that there are limitations, I think this trial is extremely informant for clinicians. We learned a lot how to treat these very complex patients with complex treatments.

Dr Carolyn Lam: No, I couldn't have agreed more. I mean quoting Mike Gibson, 2.8 million combinations. Well, at least we've talked about some of them here and had a very clear take home message, although with the caveats that we were discussing. Thank you so much, Stefan and Renato. This was really a great discussion, and thank you audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2019.


Nov 25, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage passes to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature article really starts to look at micro-circulatory dysfunction and abnormal coronary perfusion during exercise that can be associated with myocardial ischemia. I hear you're anxious to hear about it, but why don't we go to your article first.

Dr Carolyn Lam: Here we go. This first paper I'd like to tell you about reports a novel cardiac kinase as a potential regulator in heart failure.

Dr Greg Hundley: Now remind me, Carolyn, I got to take me back a little bit. What are cardiac kinases?

Dr Carolyn Lam: Ah, I thought you would ask. Cardiac kinases are known to play a critical role in the development of heart failure and represent potential trackable therapeutic targets. Now to identify novel cardiac kinases involved in heart failure, the corresponding authors, Dr Hind Lal from University of Alabama at Birmingham and colleagues, employed an integrated transcriptomics and bioinformatics analysis and identified homeodomain-interacting protein kinase 2 or HIP kinase 2, as a novel candidate kinase. Now this is the first study to define the role of HIP kinase 2 in cardiac biology. In essence, they performed a series of mouse experiments that showed that cardiac HIP kinase 2 expression is elevated in adults compared to embryonal and neonatal stage of mouse experiments, but down regulated in failing hearts.

Deletion of HIP kinase 2 in the cardiomyocytes led to decreased cardiac function in adulthood. The cardiac effect of HIP kinase 2 correlated to its gene expression level and impaired ERK signaling was discovered as the main driver of HIP kinase 2 deficient phenotype by enhancing apoptosis. Taken together these findings really suggest that cardiomyocyte HIP kinase 2 is required to maintain novel cardiac function via ERK signaling.

Dr Greg Hundley: All right, Carolyn, my favorite question, what does this mean for us clinically?

Dr Carolyn Lam: Two points, first since HIP kinase 2 is protective in cardiomyocytes, gene therapy using HIP kinase 2 could be a potential therapeutic method of heart failure treatment in future. Secondly, because inhibition of HIP kinase 2 has been proposed as a therapeutic approach for certain cancers and for renal fibrosis, these results suggest that caution needs to be taken for the potential cardiotoxicity of HIP kinase 2 inhibition in the adult heart. Interesting.

Dr Greg Hundley: Yeah. Very nice. Well, I'm going to switch gears a little bit Carolyn and talk about ablation for atrial fibrillation. And the corresponding author of this paper is Jason Andrade from Vancouver General Hospital. In his study, they randomly assigned 346 patients with drug-refractory paroxysmal atrial fibrillation to A, contact force guided RF ablation, B, four-minute cryoballoon ablation or C, two-minute cryoballoon ablation and they followed the patients for 12 months. Now the primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmias, whether that be AFib, aflutter, atrial tachycardia, between days 91 and 365 after the ablation or a repeat ablation procedure at any time. And the secondary endpoints included freedom from symptomatic arrhythmia and AF burden.

Dr Carolyn Lam: Interesting clinical question. What did the results show?

Dr Greg Hundley: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring, was 54, 52 and 52% with each of those therapies respectively. One-year freedom from symptomatic tachyarrhythmia defined by continuous monitoring was 79, 78 and 73% with those therapies respectively. No difference statistically in either.

Dr Carolyn Lam: Right. No significant difference in those outcomes but what about AF burden or side effects?

Dr Greg Hundley: Right, Carolyn. Well, compared to the pre-ablation monitoring period, AF burden was reduced by a median of 99%, 99.9% and 98.4% in each of the three therapies. No significant difference. And serious adverse events occurred in two patients in the CF-RF group, in six patients in Cryo with four minutes and in seven patients with Cryo in two minutes. Again, no significant difference between those groups.

Dr Carolyn Lam: Greg, were there any significant difference in these techniques?

Dr Greg Hundley: Well, Carolyn, that contact force RF group at a significantly longer procedure duration but a significantly shorter fluoroscopy exposure. And the P was 0.001 versus the cryoballoon group. In summary, in this multicenter, randomized, single blinded trial, contact force RF ablation, and two different regimens of cryoballoon ablation, resulted in no difference in one-year efficacy, which was 53% by time to first recurrence, but 98% burden reduction as assessed by continuous cardiac rhythm monitoring. A new study in patients with ablations looking at these new techniques and for many reasons they're very similar.

Dr Carolyn Lam: Very interesting. My next paper also has to do with atrial fibrillation. Now we know that numerous skills exist for classification of major bleeding events in patients with atrial fibrillation who are anticoagulated. Now there are limited data comparing the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. And so Dr Bergmark from the TIMI study group and colleagues analyzed bleeding outcomes according to the ISTH, TIMI GUSTO and BARC bleeding scales in the ENGAGE AF-TIMI 48 trial of edoxaban versus warfarin. And they found that among patients with atrial fibrillation at risk for stroke, there was an approximately four-fold difference in the frequency of the most severe bleeding events across these commonly used bleeding scales. Further, the relative safety of edoxaban as compared with warfarin tended to increase with greater severity of bleeding.

Dr Greg Hundley: Interesting Carolyn. Tell me, what's the take home message from this study?

Dr Carolyn Lam: This analysis reminds us that the currently available and commonly used bleeding scales differ in important ways. The analysis shows us that one size does not fit all and that the most appropriate bleeding scale really depends on the clinical setting and the intervention being investigated. For patients particularly concerned about bleeding, these results should provide additional reassurance about the safety of the DOX. Finally, this analysis also illustrates how the differential effect of edoxaban compared to warfarin on bleeding, impacts the assessment of net clinical benefit. Now this is discussed in an editorial by John Alexander and Adam Nelson who highlight that one of the most interesting findings was the statistically significant and graded amplification of edoxaban safety compared to warfarin with more severe bleeding.

Greg, perhaps now's a good time, tell us what else is in this issue of the journal?

Dr Greg Hundley: Happy to do so. Ben Freedman from the University of Sydney discusses in a white paper concurrent thoughts from the AF, another atrial fibrillation paper, AF screen international collaboration, which summarizes existing evidence and knowledge gaps on searching for an AFib post-stroke using ECG monitoring. And Carolyn, our own James de Lemos suggests in an on my mind piece that subdividing type two MI into different based on etiology could lead to improved forecasting of events. In a perspective article, Tommy Wang from Vanderbilt revisits the polypill and discusses why we need population-based approaches in the precision medicine era.

Dr Carolyn Lam: Wow. Super interesting. And how about letters? What's in the mailbox?

Dr Greg Hundley: Oh gosh, Carolyn. It's really full this week. There are multiple letters ranging from science, to responses, to prior inquiries. It is really interesting to read these responses and the authors going back and forth and having that open discussion for us. And so Brody Slostad first has his own research letter that reviews unicuspid aortic valves, the demographics, comorbidities, and echocardiographic features and long-term outcomes. Darren Casteel from UC San Diego discusses blood pressure lowering by the antioxidant resveratrol is counterintuitively mediated by oxidation of the cyclic GMP dependent protein kinase. And there's a nice response by Dr Joseph Burgoyne from Kings College London. Finally, there's a letter by Daxin Wang and his associates from Yangzhou University regarding the article targeting filament A reduces macrophage activity in atherosclerosis and there's a corresponding response from Levent Akyürek event accurate from the Institute of Biomedicine. Great mailbox this week, Carolyn. How about now we go on to our feature discussion?

Dr Carolyn Lam: Oh boy, I can't wait. Thanks Greg.

How does coronary microvascular dysfunction relate to exercise physiology or inducible myocardial ischemia? Well, we are going to be talking all about that in the next few minutes and that's because our feature paper this week is the first study to really directly assess coronary blood flow during exercise in patients with microvascular dysfunction. And to compare these changes with high resolution perfusion imaging. We're really pleased to have with us the first and corresponding author, Dr Divaka Perera from Kings College London, as well as our associate editor Dharam Kumbhani from UT Southwestern. Welcome gentlemen and Divaka. Could you start by telling us what makes your study unique? What did you do? What did you find?

Dr Divaka Perera: As you said, microvascular dysfunction is being recognized as quite a common cause of angina. In fact, about 40% of patients who present to the Cath lab for a diagnosis of angina are found to have nonobstructive coronary artery disease, and a significant proportion of these are thought to have microvascular dysfunction. The definition of microvascular dysfunction has been based on demonstration of impaired coronary flow reserve, but what we haven't known is whether the Cath lab measurements that are made actually correlate with exercise maladaptation. Bearing in mind that these patients experience symptoms during exercise and whether there's actually demonstrable ischemia in these patients who don't have obstructed coronary artery disease. Our study's unique in that we were able to measure directly exercise physiology during cardiac catheterization and we were able to stratify patients upfront on the basis of their coronary flow reserve and then in a blinded fashion assess whether these patients who did or didn't have augmentation of flow reserve had ischemia.

Dr Carolyn Lam: Divaka, could you give us a detailed picture of what that meant? These patients were sitting with catheters and then riding bikes or give us a picture of what you did.

Dr Divaka Perera: Right. This is a setup we've been working on for the last 10 years or so to make sure that we have a reproducible and safe protocol that can be carried out in a Cath lab. A patient who was referred for diagnostic angiography, this may have been the first investigation they were having, or they may have had some form of noninvasive testing beforehand. These patients would undergo angiography via the right radial artery with their arm extended out to the side. And then during angiography when the time was right to assess this condition, they would carry out supine bicycle exercise. And that was a bike that was mounted onto the Cath lab table. During all of this, we would measure intracoronary pressure and flow velocity using this combo tipped wire which could give us distal coronary pressure and Doppler flow velocity and we were able to do this throughout the condition of exercise.

Dr Carolyn Lam: That's cool, but then how did the MRI come in then?

Dr Divaka Perera: Right. The MRI was actually done at a different visit and in that situation, we only carried out vasodilator testing. We also do exercise patients in the MR scanner, but we haven't included any of those data in this current paper. Patients would have two visits at least as part of this research protocol.

Dr Carolyn Lam: Maybe now with that background, tell us what you found.

Dr Divaka Perera: The first and most important finding was that patients are classified in the Cath lab on the basis of a coronary flow reserve below 2.5. The flow reserve threshold of 2.5, actually have demonstrable ischemia on a stress profusion myocardial magnetic resonance imaging scan. 82% of patients in the MVD group, the microvascular dysfunction group had inducible ischemia compared to just 22% of controls. This was mirrored by quantitative myocardial profusion reserve data as well, where the ability to augment overall myocardial blood flow was significantly diminished in patients with MVD. And perhaps most interestingly, their exercise pathophysiology was dramatically different to that of controls.

In the healthy heart, the heart actually becomes more efficient during exercise. We were able to quantify the proportion of accelerating and decelerating waves by carrying out a technique called wave intensity analysis on the data I've just described, on the physiology data that I've just described. And by doing that we were able to quantify the proportion of accelerating waves to decelerating wave energy. In the healthy heart, as we exercise the proportion of accelerating wave energy increases and we've termed that profusion efficiency. Now in stark contrast when you have MVD, the heart actually becomes less efficient and the profusion efficiency decreases. This is a normal finding and really told us that cath lab measurement based on the response to vasodilators seems to identify a population who have maladaptation during exercise and demonstrable ischemia on scanning.

Dr Carolyn Lam: Wow. Dharam, could I now ask you to help frame these results in the context of what's known or not known about microvascular disease?

Dr Dharam Kumbhani: I want to congratulate the Divaka and his group. I think this is very interesting analysis. It's really a new paradigm about what is now understood to be more and more of a common issue. It seems like a lot of work, even for the patient population that was enrolled. And I think done in an incredibly thoughtful way. Having said that, I guess what I'd like to understand as a card carrying interventionalist myself, I imagine that some of this may be perhaps in need of validation. And so do you think that this study and in some of the two distinct phenotypes that you describe that this will need to be demonstrated in other labs and other situations?

Dr Divaka Perera: Absolutely. I think we have demonstrated is a proof of concept that we can assess these patients in the Cath lab and then shown that firstly, the measurement of CFR and the classification of patients on the basis of CFR does identify a group with distinct pathophysiology, but that that doesn't tell the whole story because your CFR can be diminished for one of two broad reasons. That there's an abnormality of resting flow or an abnormality of hyperemic or flow at maximum stress. Now, the traditional paradigm of microvascular dysfunction has been that these patients will all have, or the majority will have, diminution of stress flow. Or that they might have an inability to reduce their microvascular resistance during stress.

What we have found in contrast is that actually two thirds of patients who have impaired flow reserve have impaired flow reserve because of an abnormality of rest perfusion. One third only conform to that traditional paradigm, and this, as you've rightly pointed out, is something that's going to need further investigation. It's very exciting and it might mean that we have a basis on which to try different therapies, for instance. That those therapies might be pathophysiologically stratified, but it needs a lot of work and I'm sure you won't be surprised to know that we've already embarked on that next stage of work to validate and take this forward.

Dr Dharam Kumbhani: Let's say you were able to validate this paradigm and you indeed are able to stratify patients with microvascular disease. What you have defined as a functional and a structural endotype. Do you believe that if this were validated and established further from a diagnostic standpoint in labs across other places, what kind of diagnostic testing do you imagine that this would require?

Dr Divaka Perera: At the most basic level Dharam, I think we need to get interventional cardiologists and any cardiologist doing diagnostic angiography to realize that the finding of unobstructed coronary artery disease isn't the final answer. It actually begins a whole chapter of investigation and if we can at least get people to think about doing a physiology study in a way analogous to what's happened when we find equivocal amounts of coronary artery disease that you'd reach for a pressure wire and do a functional test. If we can introduce that paradigm once we find normal or unobstructed coronary arteries in a patient with classical symptoms, that would be step number one. The next step will be that we'll have across the board a harmonized means of classifying these patients and by looking at microvascular resistance as well as coronary flow reserve, we might be able to identify endotypes that behave differently and need different forms of therapy. Once we've got that in place, then we have a basis to carry out large registries and large trials in a systematic fashion.

Dr Dharam Kumbhani: Let me just clarify that. You don't envision that let's say this all gets validated. Do you envision that labs that do CFR measurements would then in addition need to have the ability to do exercise testing as well?

Dr Divaka Perera: No, I don't think so. I think exercise testing requires a really carefully evolved set up and it's not practical to unleash this onto world at large. But it generates hypotheses and examines concepts which can then be translated. I think routine use of microvascular function testing will rely on response to vasodilators and these will be endothelium independent techniques such as an adenosine and possibly as a second stratum, endothelium dependent methods as well. Perhaps using graded acetylcholine infusions. But it would be vasodilator testing in the Cath lab rather than exercise.

Dr Dharam Kumbhani: Got it.

Dr Carolyn Lam: Fascinating. Wait, Divaka, just to be sure that the audience got this. You talked about the two endotypes, a structural and functional and the structural one is the one that has a low flow to begin with. The functional is the one that the hyperemic flow is the one that's mainly impaired. Is that correct? Just checking.

Dr Divaka Perera: Let me just clarify. Those patients that we've termed to have functional MVD have elevated resting flow, but actually essentially normal flow at stress. In contrast, those who have structural MVD have essentially normal resting flow but have an inability to augment their peak flow. The net result appears to be the same in the sense that they all have demonstrable ischemia on noninvasive testing, but the mechanisms are different and therefore the therapies that we direct towards these patients may also need to be different.

Dr Carolyn Lam: Very nicely put. Thank you. And if the audience, you still didn't get that, pick up the paper and read it. But say, one last question because you kind of teased us just now and said, actually we are going on with next steps and so on. What are the next steps? Maybe from you and then Dharam.

Dr Divaka Perera: I think the next step is to assess whether this sort of stratification allows us to treat patients more efficiently. To deliver subtype stratified therapy. And we need to assess this with reference to meaningful clinical outcomes, so quality of life, exercise-based indices, et cetera, before we get onto looking at large numbers and then looking at cardiovascular outcome data.

Dr Carolyn Lam: Great. And Dharam, maybe I'll let you have the closing words.

Dr Dharam Kumbhani: We're understanding a lot more about what is always been an enigma for clinicians as far as having patients who present with very typical symptoms, either stable or unstable symptoms and have no coronary artery disease. I want to congratulate the authors on really trying to dig deeper into this and helping us with this very difficult patient population.

Dr Carolyn Lam: Thank you, Dharam. Thank you Divaka. And thank you listeners for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

This program is copyright American Heart Association 2019.


Nov 18, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And, I'm Greg Hundley, Associate Editor, Director of the Poly Heart Center of VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature articles, very interesting, discussing hypertrophic cardiomyopathy and sudden death in young individuals. But, let's save all the details for later and start in on our coffee chat. So, Carolyn, have you got a paper that you'd like to start with?

Dr Carolyn Lam: I have, and it's a basic science paper. It's one that details the contribution of get this, M-C-U-B. Now this is a paralogue of the poor forming sub-unit MCU in mitochondrial calcium, uniporter regulation and function. Now, this paper shows, for the first time, MCUB's relevance to cardiac physiology, and it's from corresponding author Dr Elrod from Center of Translational Medicine, Louis Katz School of Medicine at Temple University in Philadelphia, and their coauthors, who showed, in a series of elegant work, that MCUB is absent from the uniporter complex in the homeostatic heart. But it's incorporated into the mitochondrial calcium uniporter following ischemic injury and thus represents an endogenous mechanism to limit mitochondrial calcium overload during stress.

Interestingly, the increased incorporation of MCUB into this mitochondrial calcium uniporter is too little and too late to limit acute cell death following ischemic reperfusion injury but may limit cell loss during chronic stress.

Dr Greg Hundley: So Carolyn, tell me what are the clinical implications of this important finding?

Dr Carolyn Lam: Well, simply put, MCUB represents a novel therapeutic target to modulate mitochondrial calcium uptake in disease states speech during mitochondrial calcium overload such as myocardial infarction and heart failure.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got another basic science paper and it involves Protein Kinase N and how that promotes stress induced cardiac dysfunction through phosphorylation of myocardin-related transcription factor A and disruption of its interaction with actin. This comes from the corresponding author Mikito Takefuji from Nagoya University Graduate School of Medicine. So Carolyn protein phosphorylation of course, is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes, in response, extracellular and intracellular signals. The RHOA-associated protein kinase, or ROCK Rho-kinase, in effect, are regulated by the small GTPS RHOA causes pathological phosphorylation of proteins resulting in cardiovascular diseases. RHOA also activates Protein Kinase N, however, and the role of PKN in cardiovascular disease remains unclear.

Dr Carolyn Lam: Ah, okay. So with that background, what did these authors find, Greg?

Dr Greg Hundley: Great question, Carolyn. What they found is that PKN inhibits the binding of MRTFA to G-actin by phosphorylating MRTFA and activating SRF mediated expression of cardiac hypertrophy and also fibrosis associated genes. Also, they showed that cardiomyocyte specific PKN1 and PKN2 double deficient mice are resistant to pressure overload and ANGII induced cardiac dysfunction.

Dr Carolyn Lam: Wow. There's a lot of letters in what you just said. So could you just tell us how does this impact heart failure research and management?

Dr Greg Hundley: So Carolyn, this PKN family appears to play a role in regulating hypertrophy and fibrosis in the heart and therefore could serve as a unique target for therapeutic interventions for heart failure in the future. And so maybe it's going to make its way your way.

Dr Carolyn Lam: Well, okay, well this next paper definitely is making its way my way and it focuses on the Sodium Glucose Co-transporter two inhibitors or SGLT-2 inhibitors, which we know lower cardiovascular events in patients with type two diabetes, but whether they promote direct cardiac effects as in that we can see in cardiac structure and function actually remained unknown until today's paper. And this is from Dr Subodh Verma and Dr Kim Connelly, these co-corresponding authors from St. Michael's Hospital and University of Toronto and their colleagues.

And they sought to determine if empagliflozin causes a decrease in left ventricular mass in patients with type two diabetes and coronary artery disease. So this was a six month double blind randomized placebo controlled trial. If individuals with type two diabetes, coronary artery disease and relatively normal left ventricular mass index. The primary outcome was six month change in left ventricular mass index to body surface area from the baseline and measured by cardiac magnetic resonance imaging and they found that the empagliflozin allocated group exhibited a significant reduction in left ventricular mass index compared with the placebo group.

Dr Greg Hundley: Wow, Carolyn. We have been hearing a lot about empagliflozin in the last several issues. How does this article differentiate what we do or maybe even change our practice?

Dr Carolyn Lam: Well, you know what? It enhances our understanding which is important. We knew about the events. Now we perhaps understand a little bit more of what it may be doing actually to the heart in terms of cardiac structure and function. The so the decrease in left ventricular mass associated with empagliflozin may explain and contribute to the cardiovascular benefits observed in patients with type two diabetes and coronary artery disease who are treated with SGLT-2 inhibitors. Now it's interesting the way we've gone like reverse translation in this, haven't we? Observing the events and then trying to find the mechanism. And this is in fact discussing an editorial by Mark Petrie and titled SGLT-2 Inhibitors: Searching for Mechanisms in the Wake of Large Positive Randomized Trials.

So Greg, after that, maybe you could tell us what else resides in this week's issue.

Dr Greg Hundley: Oh my goodness, Carolyn. Well, there's quite a bit. First Paola Erba from Pisa, Italy provides a nice In-Depth review of the use of echocardiography, radioisotope imaging and computed tomography for the assessment of patients with endocarditis. In another article, Wayne Batchelor and Rebecca Ortega and their colleagues discuss a Perspective piece, several strategies to improve enrollment of racial and ethnic minorities into clinical cohorts and trials addressing cardiovascular disease.

And of course we have our mailbox. And first is Dr Diamantis Tsilimigras from The Ohio State University, and he responds to a letter by Moris et al regarding the article: Effects of Arteriovenous Fistula Ligation, or cardiac structure and function in kidney transplant recipients.

Barry Borlaug from Mayo clinic discusses the importance of right ventricular volume loading and high output heart failure with arteriovenous fistulas.

And Carolyn, our own Joe Hill and a first author Dan Tong coauthor a letter pertaining to whether female sex is protective in a preclinical model of heart failure with preserved ejection fraction.

And then finally Toby Coates from Australia responds to several inquiries related to a prior publication regarding a published article involving the effects of arteriovenous fistula ligation on cardiac structure and function, again in kidney transplant recipients.

There's an On My Mind piece from Dr Heinrich Taegtmeyer from McGovern Medical School at The University of Texas Health Science Center at Houston, or UT Health, relating to characteristics of past prominent investigators. What makes them tick? What contributes to their long-term success and sharing their catch with others? And it's interesting Carolyn, because he compares the vast community of cardiovascular investigators to those that are like anglers or fisherman. Their passion is kind of like the allure of catching just one more. And in so doing, they like to share their catch with others.

Dr Carolyn Lam: That is hilarious. I don't think I've ever wanted more to be a fisherman or angler myself. Well that's great, Greg. Thanks and let's carry on with our feature discussion, shall we?

Dr Greg Hundley: Absolutely.

Welcome everyone to our feature discussion and we're going to discuss hypertrophic cardiomyopathy and sudden cardiac death and the relationship to exercise. And our study comes from Ontario and our lead investigator is Dr Paul Dorian from St. Michael's Hospital, and we also have our associate editor Mark Link from Dallas, Texas. Welcome gentlemen. And Paul, I'll start with you, tell us a little bit, what was the hypothesis and what were the aims that you were trying to accomplish with this particular study?

Dr Paul Dorian: Our hypothesis was that the likelihood of sudden death in patients with hypertrophic cardiomyopathy may be less than has previously been supposed. In brief, the community that looks after patients with HCM, we'll call it for short, is faced with a major challenge in knowing what the actual rate of sudden cardiac death is and it seems to be a little bit of a moving target. Over the last decade, I think that most clinics that look after these patients were faced with what appears to be a less and less frequent likelihood of sudden death in these mostly young patients that we follow. And because we have the opportunity to study this using a well-established prospective coroner database with autopsy results in all sudden deaths in Ontario in young individuals, that we have the opportunity to test our hypothesis that this sudden death rate is lower than had previously been suspected.

Dr Greg Hundley: It sounds like younger patients and trying to investigate the cause of sudden cardiac death. Can you tell us a little bit more about your study population and what was your study design?

Dr Paul Dorian: We had the fortune of being able to use the Coroner of Ontario database. Ontario has about 13 million population and by the longstanding design, almost all patients under the age of 45 who suffer out of hospital, sudden cardiac death receive a full coroner investigation and then 90% of them, it's an autopsy which includes a cardiac autopsy by a qualified forensic pathologist. And in the case of cardiac hypertrophy, the cases are re-reviewed by a specialized cardiac forensic pathologist. So we have very extensive, if you like, detective work, CSI-type information on virtually everybody who dies out of hospital suddenly including those individuals among them who have hypertrophic cardiomyopathy.

And what we did was we reviewed every single case of unexpected sudden death, looking for the specific diagnosis of cardiac hypertrophy or HCM. We verified the accuracy of our numbers by also using, for at least portions of our follow-up, the complete emergency medical services database for about 7 million people, mostly from Toronto. And this included all patients who had a 9-1-1 call for documented cardiac arrest. So we were able to verify that we missed essentially no patients without a hospital cardiac arrest who then died suddenly.

Dr Greg Hundley: Give us a little bit more about the numbers. So what was the age range of your study population, perhaps the gender and breakdown, things like that?

Dr Paul Dorian: We looked at individuals under the age of 45 but the median age was 36 for all of our patients. About 85% of the patients with documented HCM were male, 83% to be precise. And a pretty small minority of them. Had comorbidities that we would expect including hypertension, diabetes, et cetera. 11% were on beta blockers, and a small proportion had atrial fibrillation. So these are generally healthy individuals, or at least they had had relatively little interaction with the healthcare system and about half of these individuals had previously been diagnosed clinically with HCM and the rest had not been diagnosed as far as we could tell, or at least there was no medical record of them having been diagnosed with HCM.

Dr Greg Hundley: And what was the total number of individuals in this study? And then tell us a little bit about your study results.

Dr Paul Dorian: The total number of individuals who had definite HCM was about 45 we had 31 patients who were not known to have HCM who had definite HCM, which we defined as having myocardial disarray on cardiac microscopy and another 13 who are not known to have HCM. And then we had about another 10 patients who we thought had possible HCM because they had autopsy with hypertrophy but didn't have disarray. And a few patients that were diagnosed with HCM but didn't have autopsy. So the total population was approximately 50 patients and this is out of a total population of estimated population of about 140,000 HCM person-years using the widely estimated prevalence of HCM of one in 500.

Dr Greg Hundley: And what did you find?

Dr Paul Dorian: The bottom line, if you like, is that the annual incidence of unexpected sudden death, this would be out of hospital sudden death, was many folds lower than would've been expected based on prior publications and on prior risk calculators that are used by many physicians who for these patients. If your readers or the listeners just want single numbers, the total number of both definite probable and possible HCM related sudden death, this is the most sort of conservative estimate, would be approximately 0.4 per thousand person-years. So this would be less than one per thousand. This would be one half of one 10th of 1% so less than one per thousand per year. Patients with HCM will have sudden death. If we take the most conservative definitions.

Dr Greg Hundley: Now, could you tell whether these sudden deaths were related to exercise? That was sort of one of the feature questions.

Dr Paul Dorian: Absolutely. That's how we were of course, very interested so we defined both exercise as somebody died or doing sport or observed during exercise. I should emphasize that the coroners do extremely careful digging if you like into the circumstances. They interview paramedics, police, they have the police and paramedic report, they interview physicians, relatives, so they do a very thorough assessment of course as best as could be told after the fact. 65% of the sudden deaths occurred at rest and 18% occurred during light activity and about 10% occurred during exercise.

Dr Greg Hundley: Very good. I want to turn over to Mark now. This is Dr Mark link from University of Texas Southwestern in Dallas. Mark, how can we put the results from this study in the context of other studies relating to implementation of defibrillators in patients with hypertrophic cardiomyopathy?

Dr Mark Link: This study brings up a lot of issues and I want to applaud Paul and his gang for doing this. The data is very good. The autopsies are very good. So the quality of the data is excellent and the incidence of sudden death for a hypertrophy is lower than any other study that we've seen. And there are a number of possible reasons for that. Well, you know, one is that the Toronto group was using autopsied determined HCM or most other studies were kind of a mixed bag of clinical and autopsy and newspaper reports and all sorts of things. So the Toronto data is going to be probably the most accurate. The other issue, or the other question I think that could lead to a low incidence, is the denominator, in that there were estimated to be more hypertrophy in Toronto than there actually are. They use the commonly accepted one in 500 and I think that's a reasonable number across all sorts of populations that we see, but is it possible that maybe the one in 500 number isn't true for Toronto?

You know, I've heard one person explain this is that patients with HCM can't stand the cold weather. So they left Toronto, but it is a much lower number than we've seen in regards to sudden death. A couple of other things I think are very interesting in this study. One is that if you looked at the individuals that got ICD shocks for ventricular arrhythmias is there was about as many people as died suddenly, arguing that the Toronto physicians can actually in many ways predict who would benefit, predict which hypertrophy would benefit from an ICD. Since many of these hypertrophies didn't have appropriate ICD shocks. And I also found fascinating that more of the deaths occurred during rest or light activity than exercise. We all tend to think that HCM causes its sudden death with exercise. And what this study's telling us is that's not true that more sun deaths are during rest and light activity. So there's a lot of very interesting insights that come out of this manuscript in this data.

Dr Greg Hundley: Just following up on your last point, are there any inferences regarding activity in this patient population that we should take away from these study results?

Dr Mark Link: I think if you look at the early newspaper reports and they're in there as reports of the incidence of HCM, sudden deaths during sports. So it was because of that, that everyone associated HCM with death during sports. But you have to remember those studies didn't include athletes that died at night. Athletes that died during dinner. They only included athletes that died during sports. So we were missing a large percentage of the hypertrophs dying. And I think we sort of infer that it was exercise that was dangerous, but in fact there's really not that much data that would support that exercise is dangerous for patients with HCM.

Dr Greg Hundley: Interesting. So I'll maybe ask Mark first and then come back to you, Paul. Do you think there are tools that could be available, either blood testing or perhaps other imaging that could help identify which HCM patients may benefit from a defibrillator? Do these results help us in any way make that decision?

Dr Mark Link: Unfortunately, I don't think this study offers us any clues into which patients should get defibrillators. And clearly there are other data that look at risk factors for sudden cardiac death in hypertrophic cardiomyopathy. And one of the things that has come out over the last 10, 15 years is that magnetic resonance imaging, and in particular the scar burden magnetic resonance imaging may actually offer additional prognostic information to our traditional respect for stratification grade CM.

Dr Greg Hundley: Paul, do you have anything to add?

Dr Paul Dorian: Just a couple of things if I may. I think on that last point I completely agree with Mark. Of course we didn't have data on MRI, but the greater the scar burden, the greater our index of suspicion. It is interesting that 57% of the cases of sudden death had asymmetric septal hypertrophy, so we can at least hypothesize that it is possible that patients with septal hypertrophy as opposed to concentric hypertrophy may be at higher risk.

The one thing I might want to highlight for the listeners is that it would seem to me based on our data and based on our suspicions, is that there's probably a difference in the risk in patients who are discovered incidentally. In other words, somebody has an echocardiogram or an ECG for reasons unrelated to their heart and then HCM is discovered and these might be asymptomatic patients as opposed to patients that tend to be followed in specialized clinics who often are sent there because they have some symptoms or there's some specific signal that they have a clinically evident HCM. So I wouldn't want listeners to conclude that the risk is necessarily this low in patients that are transferred to a clinic because of disarray or atrial fibrillation or electro regurgitation or some other manifestation of a hypertrophic cardiomyopathy.

Dr Greg Hundley: Paul, I want to start with you first. What study do you think should follow yours? What's the next study?

Dr Paul Dorian: What I'd like to see, and this is technically feasible although practically challenging, is to use the big data approach and combine in one large database, all echocardiograms done in a large geographic area. All electrocardiograms done in a large geographic area with supplemented with clinical information and do, over a long period of time, a prospective study looking at all patients with cardiac hypertrophy, particularly asymmetric hypertrophy or suspected to have HCM to look at the long-term outcomes. And this should be feasible because most echocardiograms today are uploaded if you like, into a database.

Dr Greg Hundley: Very nice and Mark, how about you?

Dr Mark Link: I have similar opinion. Any one of the most important things in HCM is being able to predict who would benefit from a defibrillator, and currently our ability to risk stratify is woefully inadequate. It lacks sensitivity and specificity. And so with a larger population of HCM patients, and I think Paul's correct followed prospectively, not retrospectively, with the kind of data that we would want to be complete, including echo. Now, MRIs would be fantastic, but there's just no way that's practical, but to have echoes and EKGs and clinical factors and be followed prospectively really to hone down which patients would benefit from a defibrillator, and which patients would not benefit.

Dr Greg Hundley: Well listeners, this has been a great discussion and we want to thank Dr Paul Dorian from the St. Michael's hospital for providing this paper to Circulation and sharing these results with us and also our associate editor, Dr Mark Link from Dallas, Texas and both have emphasized in this study that those individuals with HCM, while we often see them on the sports programs and whatnot, having their, experiencing their event during activity, they also occur within activity.

For Carolyn and myself, we wish you a great week, and we look forward to talking with you next week in our next chat. Bye now.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.


Nov 11, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, we are going to have a great discussion coming right up regarding intensive versus standard ambulatory blood pressure control and its effects on cerebrovascular outcomes in older people. It's the INFINITY trial, but that's all I'm going to tell you for now because I want to hear all about your picks for this week's journal first.

Dr Greg Hundley: Absolutely Carolyn and I can't wait to hear about that discussion regarding hypertension. My first paper though is about titin and it comes from Dr Charles Murry from the University of Washington. The giant sarcomere protein titin is important in both heart health and disease as mutations in the gene encoding for titin are the leading cause of familial dilated cardiomyopathy. The uneven distribution of these mutations within titin motivated the authors of this article to seek a more complete understanding of this gene and the isoform it encodes in cardiomyocyte sarcomere formation and function.

Dr Carolyn Lam: Cool. What did these investigators find?

Dr Greg Hundley: Using genetically engineered human induced pluripotent stem cell derived cardiomyocytes, the authors experimentally confirmed that the gene encoding for the giant sarcomere protein titin includes an internal promoter and start site. This internal start site encodes for the isoform Cronos, which the authors demonstrate support some sarcomere formation in these human induced pluripotent stem cell derived cardiomyocytes.

Dr Carolyn Lam: Oh, nicely summarized. What are the clinical implications Greg?

Dr Greg Hundley: Well, Carolyn identification that Cronos titin, a previously unstudied form of titin is necessary for normal human cardiomyocyte function could be contributing to some of these titinopathies that are relevant for some patients with dilated cardiomyopathy.

Dr Carolyn Lam: Cool. Mine has to do with heart failure as well and presents new results regarding heart failure and heart failure related outcomes from the EXSCEL trial.

Dr Greg Hundley: Carolyn, what was the EXSCEL trial? What did it find?

Dr Carolyn Lam: Ah, so as a reminder, EXSCEL was the largest glucagon-like peptide-1 receptor agonist or GLP-1 receptor agonist trial reported to date where once weekly, exenatide had a neutral effect on hospitalization for heart failure with no differential treatment effect on major adverse cardiovascular events or MACE, by baseline heart failure status. However, the question remains, what about exenatide's effects on secondary endpoints based on the heart failure status? This is from Dr Rob Mentz and colleagues from Duke Clinical Research Institute who aim to explore the effects of exenatide on secondary outcomes in patients with and without baseline heart failure and test the effects of exenatide on recurrent heart failure hospitalization events.

Now they found that out of more than 14,750 EXSCEL participants, 16% had heart failure at baseline and when stratified by the presence or absence of baseline heart failure, there was no observed reduction in all cause death with exenatide in patients with baseline heart failure. While the risk of mortality was reduced with exenatide in the no heart failure group. And that was a significant interaction P value of 0.031. Similar results were observed for the combined outcome of all cause death or heart failure hospitalizations.

Now regarding recurrent heart failure hospitalizations, 450 patients experienced at least one hospitalization for heart failure, but there were 713 hospitalization heart failure events in total. The effect estimate that included the recurrent events was separately, statistically significant while the primary analysis based on just first events was not.

In conclusion in EXSCEL, the use of exenatide in patients with or without heart failure was well tolerated, but the benefits of exenatide on reduction in all cause death and first heart failure hospitalization were attenuated in patients with baseline heart failure. Now this is accompanied by a great editorial by Bruce Neil and Claire Arnett who caution against using post talk subgroup analysis, but the interaction of exenatide tout with baseline heart failure, it's interesting, although should be treated with caution until confirmed by findings from another trial.

Dr Greg Hundley: Very nice Carolyn, especially a nice issue regarding heart failure and I'm going to steer a little bit away from that and talk about atrial fibrillation duration and CHA2DS2-VASc scores. Putting those two together and this article comes from Rod Passman from Northwestern University. Studies of patients with cardiovascular implantable electronic devices show a relationship between atrial fibrillation duration and stroke risk though the interaction with a CHA2DS2-VASc score is poorly defined. The objective of their study was to evaluate rates of stroke and systemic embolism in those patients with cardiovascular implantable electronic devices as a function of both the CHA2DS2-VASc2 score and A-fib duration.

Dr Carolyn Lam: Interesting. What did the authors do?

Dr Greg Hundley: They had 21,768 non-anticoagulated cardiovascular implanted electronic device patients from the Optum electronic health record, de-identified database from 2007 to 2017 and they link those to the Medtronic CareLink TM database of CIEDs capable of continuous AF monitoring. Now the age averaged about 69 years and 63% were men and they found that increasing a fib duration, and of course increasing CHA2DS2-VASc2 score were both significantly associated with annualized risk of stroke and systemic embolism. These rates were low however, in those individuals with CHA2DS2-VASc2 scores of zero to one, regardless of the device detected a fib duration.

Dr Carolyn Lam: Ah. Were there any particular threshold values that seemed important?

Dr Greg Hundley: Great question, Carolyn. Yes, the stroke risk crossed an actionable threshold defined as greater than 1% per year in those with CHA2DS2-VASc2 score patients of two or more with greater than 23 and a half hours of a fib or those patients with CHA2DS2-VASc2 scores of three or four with greater than six minutes of a fib duration or finally in those individuals with CHA2DS2-VASc2 scores greater than five even if they had no atrial fibrillation.

Dr Carolyn Lam: Wow. Very nice clinically relevant conclusions here. Thanks Greg. I'm going to tell you what else is in this issue. There's also a research letter by Dr Rosenmeier entitled, “Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin 6 Receptor Dependent Mechanism.” And this is a cardiac analysis of a double blind randomized controlled trial in abdominal obese humans. We have an on my mind paper by Dr Delbridge entitled “HFpEF, It's Time to Explore the Role of Genetic Heterogeneity in Conferring Phenotypic Variability.” And this discusses among other things, the role of induced pluripotent stem cells and functional studies of bioengineered HFpEF patient derived cardiac micro tissues that could potentially enable several important questions to be answered for the first time. There's an ECG challenge as well by Dr Naru Kanya, and it's really interesting. It's a hiccup artifact. If you haven't heard about that, you should take a look. And finally cardiology news by Dr Kuhn and it's entitled, “Nourishing Native American Communities by Increasing Access to Traditional Food.” A very interesting paper right there.

Dr Greg Hundley: Carolyn, I have a few papers. Robert Gerszten provides a perspective piece regarding emerging affinity reagents for high throughput proteomics, sort of an emerging field, everyone doing proteomic studies, we have to pay a special attention to the reagents that are being used. And then Andrew DeFilippis from University of Louisville as well as Johns Hopkins reviews important concepts related to the definition of MI.

Dr Carolyn Lam: Is this pertaining to that fourth universal definition of MI?

Dr Greg Hundley: Yes, Carolyn. Absolutely. And basically in this white paper, the authors review the epidemiology, risk factor associations and diagnostic tools that may assist in differentiating between non-ischemic myocardial injury, type 1 MI and type 2 MI. And then finally from Suowen Xu from the University of Rochester, there's a letter discussing the CCN family of matricellular proteins CCN 1, CCN 2 and CCN 3, that are mechano-sensitive proteins that are differentially regulated by sheer stress, the frictional force exerted by blood flow in our vessels. Well Carolyn, that's a great issue. How about we move on to our feature article?

Dr Carolyn Lam: Let's go Greg.

For our feature discussion today we are talking about intensive versus standard ambulatory blood pressure control and that effect on cerebral vascular outcomes in older people or the INFINITY trial. Very, very important stuff and I'm so pleased to be with the corresponding author, Dr William White from Calhoun Cardiology Center in University of Connecticut School of Medicine. Dr White, thank you so much for being here. Could you maybe set up already the background of what you were thinking when you started this trial? Especially given the results that we know from SPRINT and SPRINT mind. Could you perhaps comment on how this INFINITY trial is different?

Dr William White: We started work in this area about 15 years ago and we initially were interested in interactions among vascular risk factors including ambulatory blood pressure, lipids and other sort of thrombotic factors and so forth with the development of small vessel disease in the brain that led to these fairly classic images on MRI called white matter hyperintensity lesions. And we learned from a prospective cohort study that we started about 15 years ago, that there was a very strong relationship between ambulatory blood pressure and the development and progression of these white matter hyperintensity lesions on MRI, but not very nice relationship with the clinical blood pressures measured in the standard office practice.

We decided to pursue a clinical trial, a randomized clinical trial in which we would evaluate different levels of ambulatory blood pressure versus the development of the small vessel disease as imaged by MRI, but very importantly we also wanted to link it to functional outcomes because this was in older people, typically in their late seventies, eighties and even nineties in which cognitive impairment begins to develop. There's problem with mobility, bladder function and things of that nature. And since our funder was always the National Institute of Aging of the NIH, there's a great deal of interest in more than just the vascular risk factors and even the cerebral vascular disease that we would detect on the MRI. That was the background of why the study got developed the way it did.

Dr Carolyn Lam: That's so interesting. You've already pointed out ways that this was very different from SPRINT OR SPRINT MIND in looking at ambulatory instead of clinic blood pressure and I suppose in the population you selected, out of curiosity, you mentioned that your prior work showed a relationship between white matter hyperintensity on MRI and perhaps future dementia. In which direction? And is there any basis to suspect low, too low blood pressure may also be bad in these older people who already have microvascular brain disease?

Dr William White: Absolutely. Very important point. When we look at our prospective cohort which was about a 100 older people, we followed for four years without any intervention. This was just a mixture of normal tensive and hypertensive individuals. Some on meds, some not on meds. But we did show that when you got too low or if you stay too low during those four years with a systolic blood pressure of under 115 on a 24-hour blood pressure monitor, it seemed like there was an almost like U shaped relationship with progression of white matter disease. Below 115 there was more accrual of white matter disease. Above 150 there was a systolic blood pressure, there was also a greater accrual, but in between about 125 and 145 we weren't really sure if there was going to be a difference. And that there was the target is that everybody's talking about for clinical measurement, so we decided to pursue that in this study to determine if we could figure out whether or not there was a sweet spot for the desk blood pressure without getting into trouble with hypotensive symptoms.

Dr Carolyn Lam: Nice. Thank you for drawing that up so nicely. Now I get it that you chose the targets that you did, which just for everyone, just a reminder, it was a 24 hour mean systolic blood pressure by ambulatory blood pressure control and the two targets were 130 millimeters mercury and less versus 145 millimeters mercury and less. With that, could you please tell us the results?

Dr William White: Right. We called the 130 or less systolic group, the intensive treatment group and the 145, the standard group. We focused on the primary endpoint was changes in mobility parameters in conjunction with changes in white matter hyperintensity lesion growth. And after a period of about three to four months of randomization, post randomization, we achieved a 24-hour systolic blood pressure about 128 millimeters of mercury in the intensive treatment group and 144 in the standard group. And we maintained a pretty good separation in blood pressure, ambulatory blood pressure throughout the three years of treatment. Now the changes in gait speed, which was one of our primary parameters for mobility actually turned out not to be different between the treatment groups. That is intensive versus standard. However, the changes in the accrual of light matter hyperintensity volume was smaller in the intensive treatment group of a 0.29% versus a 0.48% in the standard treatment group. That was significant at a P value of 0.03.

We actually also had a pre-specified sensitivity analysis, sort of a per protocol analysis that allowed us to look at people who stayed in their sort of assigned treatment groups based on blood pressure throughout the three years of the trial. And in that circumstance, there was actually a stronger separation because these are people who stayed clearly at 130 or less than about 145 throughout the three years and now the differences were approximately 0.23% in the intensive group and 0.58% in the standard group. And now the P value is smaller, .0028.

I think we proved in the study that maintaining a systolic blood pressure on the ambulatory recorder over 24 hours of 130 or less benefited patients by reducing the accrual of white matter hyperintensity lesions by about 40% relatively speaking compared to a standard ambulatory blood pressure value of a 145. One of course caveat is that after that happened within three years, but we did not see the expected benefit on mobility or on most of the cognitive parameters either. And while we were a little bit surprised about that, when we went back and analyzed our situation with where people started from as far as this particular cohort of patients, they might've been a little on the healthy side compared to some other studies. A very educated group, very compliant with everything that they did. And probably three years was just not long enough to show the result of this white matter hyperintensity benefit on some of the functional outcomes.

Dr Carolyn Lam: That's really interesting and I'm glad you sort of tackled head on that sort of apparent dissociation between the clinical end points and the MRI end point. Could I also ask, wouldn't those findings also be consistent with SPRINT and SPRINT MIND?

Dr William White: In many ways our results were consistent with SPRINT MIND, a sub-study on the SPRINT MRI sub-study. Of course, just let me mention the differences between the two studies. Of course, SPRINT was very large but there are sub-studies were not as large as the parent study. The MRI study had about 300 plus patients randomized into it, but the measurement of blood pressure was done in the standard clinical fashion and used that digital device that was able to take measurements without somebody present in the exam room. Though they were a bit lower than what I would have seen on an ambulatory monitor during the day time. And their goals were 120 systolic versus 140, whereas ours were an ambulatory systolic of 135 and 145.

But the results were actually comparable because they showed a benefit with regards to lesser accrual of white matter hyperintensity volume in the intensive group versus this banner treatment group. But they also showed no differences after 3.4 years in the incidence of dementia. And they also showed in a separate study, no differences in gait speed in the population who are in intensive versus standard treatment. One would say that results were really actually comparable despite the age differences and the blood pressure measurement differences. And I think both studies really point to the fact that lower systolic blood pressures in older people should be our target because it's safer actually then than maintaining people in the 140s.

Dr Carolyn Lam: Maybe the follow-up period was not long enough. Could it be possible too that maybe blood pressure control should start earlier in life. Could that be it? And then also, could you give us an idea of the kinds of changes, the magnitude of the change on MRI that you see for those of us that don't think about this all the time, is this a big change considered for your cohort or is it a little change?

Dr William White: I think it's true that these people started out around 81 years old in this trial and so by the time they got to that age and had systolic hypertension for probably as many as 20 years, that some of the damage that was done was obviously permanent and we don't really know how long it took for that to accrue. What we did know is that with three years of intensive treatment, we benefited patients by reducing the continued growth or confluency of these small vessel lesions in the brain. Now the range in the amount of damage varies from about half a percent of the overall brain volume to about 5%, so a 10-fold magnitude difference in our cohort.

And as a result of that, certainly somebody who's got about two to 3% of their brain occupied by better hyperintensity lesions or damage is going to have a great deal more functional disability than somebody who's .5%. I think we have to look at the outliers as well as the mean and median changes that we saw. The mean changes are not huge. The difference between 0.2 and 0.6% for example, in our protocol analysis, 0.4% to me it's clinically relevant because I know that that means that there are some people who went up by a percent or two over the years versus the standard versus the intensive treatment group. That's a big difference in an individual over that period of time.

Dr Carolyn Lam: Yeah, I'd hate to think that I'm losing 1% of my brain.

Dr William White: Yeah. Plus it's also where it's located because the lesions are typically around the ventricles of the brain and it's exactly where neurons are going sort of posteriorly to anteriorly to transmit information. For example, from the visual center to the sort of spatial motor cortex. And when those are interrupted, even if it's in one or 2% of the tissue, it can cause substantial difficulties for people. And it's for both the flow of cognitive information as well as this flow of a mobility and balance. I think that it is very relevant, but the gray matter is affected much less by this compared to the white matter. But there are still studies that show that gray matter sort of follows in line with that so that of course also enhances thought processes and cognitive function as well.

Dr Carolyn Lam: Wow. I love the way you explained that. Very important question would of course be the safety and tolerability of this more intensive approach. Any comments there?

Dr William White: Our sponsor, the National Institute of Aging did recruit a data safety monitoring board that was independent from the study for all the years. Impressively over the course of this trial, even though there wasn't a large sample, it was a 199 people, we saw a significant benefit in the intensive group for cardiovascular events, so there were less admissions for heart failure. There were less myocardial infarctions, there was less strokes. All these kinds of things that we worry about in our patients as they get older with vascular disease was reduced by about 75% in the intensive treatment arm versus the standard arm. As far as the events that we were concerned about, such as falls and syncope and presyncope and things of that nature, they were virtually identical in the intensive treatment group and `the standard treatment group. When you take that into consideration, along with the fact that you're reducing the accrual of small vessel disease in the brain, it's clear that this population, even though they're older, would benefit from a lower systolic blood pressure.

Dr Carolyn Lam: Oh my goodness. Thank you so much, Dr White. That was a beautiful summary. That is the take home message right there.

Listeners, I'm sure you agree with me. Thank you so much for joining us this week, and don't forget to tune in again next week.

This program is copyright American Heart Association 2019.


Nov 4, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and    backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, this issue is super exciting. It's the ESC simultaneous publication issue, isn't it? So the original papers were simultaneous publications at the European Society of Cardiology meeting this year.

Dr Greg Hundley: Oh, wow. Carolyn can't wait to get to these. So Carolyn, later we're going to listen to the authors of this feature discuss the association between ICD use and all-cause mortality in a contemporary heart failure reduced ejection fraction cohort and examine relevant subgroups. So Carolyn, I'm going to get started with my first paper and it's a randomized trial of one hour, one-hour deponent T protocol and suspected acute coronary syndromes and it's a rapid assessment in emergency rooms and it's from professor Derek Chew from Flinders Medical Center. High sensitivity troponin assays promise earlier discrimination of MI, yet the benefits and harms of this improved discriminatory performance when incorporated within rapid testing protocols with respect to subsequent testing and clinical events has not been evaluated in an in-practice, patient level, randomized study. So this multicenter study evaluated the non-inferiority of a zero to one hour, zero to one-hour, high sensitivity troponin T protocol compared with a more traditional zero to three-hour mask, high sensitivity troponin T protocol in those suspected with ACS.

Dr Carolyn Lam: Interesting. So what did the study show?

Dr Greg Hundley: So participants in the zero to one-hour arm were more likely to be discharged from the ED quicker and that would be expected. So 45% versus the standard arm, which was 32%. Also their median ED length of stay was shorter, and we would expect that. Four and a half versus five and a half hours. Those randomized to the zero to one-hour protocol were less likely to undergo functional cardiac testing. The zero to one-hour high sensitivity troponin T protocol was not inferior to standard of care and among patients discharged from the ED, the zero to one-hour protocol had a negative predictive value of 99.6% for 30-day death or MI. So Carolyn, how about your first study?

Dr Carolyn Lam: Well, from MI risk stratification to heart failure risk stratification. I'm going to tell you about a paper describing the TIMI Risk Score for heart failure in diabetes, which is a novel integer base clinical risk score for predicting hospitalization for heart failure in patients with type two diabetes. This is from Dr Mark Sabatine and the TIMI study group who developed a clinical risk score for heart failure hospitalization in more than 8,200 patients with type two diabetes in the placebo arm of saver TIMI 53, as well as externally validated this score in more than 8,500 patients with type two diabetes in the placebo arm of declare TIMI 58.

They found that five clinical variables were independent risk predictors of heart failure hospitalization. These were prior heart failure, history of atrial fibrillation, coronary artery disease, estimated GFR, and urine albumin-to- creatinine ratio, a simple integer base score from zero to seven points. Using these predictors identified a more than 20 full gradient of heart failure hospitalization risk in both the derivation and validation cohorts with high SES statistics. Although the relative risk reductions with dapagliflozin were similar for patients across the risk scores, the absolute risk reductions were greater in those with higher baseline risks.

Dr Greg Hundley: Wow, Carolyn. So tell us what are the clinical implications of this really thorough study?

Dr Carolyn Lam: In summary, the risk score had excellent discrimination in two large clinical trial cohorts. It was well calibrated, and it identified a strong gradient of increasing absolute reduction in risk of heart failure hospitalization with the SGLT two inhibitor dapagliflozin. So by using this TIMI Risk Score for heart failure in diabetes, which is a simple validated clinical risk score, clinicians could better educate patients about their risk for heart failure hospitalizations and could perhaps better identify those patients who have a greater absolute risk reduction in heart failure risk with SGLT two inhibitors.

Dr Greg Hundley: Very good, Carolyn. Well, I'm going to go back to the world of troponins and talk about a paper from Nicholas Mills from University of Edinburgh. And in this study, they evaluated the safety and effectiveness of risk stratification thresholds of high sensitivity troponin in patients with suspected acute coronary syndrome. 48,282 consecutive patients with suspected ACS were enrolled in a multicenter trial from 10 hospitals within Scotland and they're pre-specified secondary and observational analyses. They compared the performance of the limit of a detection of less than two nanograms per liter versus the optimized stratification threshold of less than five nanograms per liter using the Abbott high sensitivity troponin I assay. Patients with myocardial injury at presentation with less than two hours of symptoms or with ST segment elevation myocardial infarction were excluded and the negative predictive value was determined in all patients in subgroups for a primary outcome of MI or cardiac death within 30 days. And they had a secondary outcome that was MI or cardiac death at 12 months.

Dr Carolyn Lam: Nice. So Greg, which threshold of troponin was the optimal one?

Dr Greg Hundley: So the negative predictive value for the primary outcome was 99.8% and 99.9% in those with cardiac troponin I concentrations of less than five or less than two nanograms per leader respectively. At both thresholds, the negative predictive value was consistent in men and women across all age groups. Although the proportion of patients identified at low risk fell with increasing age. Compared to patients with cardiac troponin I concentrations of greater than five nanograms per liter but less than the 99th percentile, the risk of MI or cardiac death at 12 months was 77% lower in those with less than five nanograms per liter and 80% lower in those with less than two nanograms per liter. So in conclusion, use of risk stratification thresholds for high sensitivity cardiac troponin I identified patients with suspected acute coronary syndrome in at least two hours of symptoms at low risk presentation irrespective of both age and sex.

Dr Carolyn Lam: Very nice. Well, more risk stratification in this next paper, which really evaluated the application of the 2018 ACC AHA Cholesterol Management Guideline recommendations for additional lipid lowering therapies in patients with established atherosclerotic cardiovascular disease and residual dyslipidemia despite maximum tolerated Statin who were enrolled in the ODYSSEY OUTCOMES trial. Now, just as a reminder, the 2018 US Cholesterol Management Guidelines recommend additional lipid lowering therapies for secondary prevention in patients with LDL above 70 or non-HDL above a hundred despite maximum tolerated Statin therapy.

Such patients are considered at very high risk based on a history of more than one major atherosclerotic cardiovascular disease event or a single event and multiple high-risk conditions. So in this paper from Dr Matt Roe from Duke Clinical Research Institute and colleagues, they found that in the ODYSSEY OUTCOMES trial, patients classified as very high risk by these 2018 ACC AHA guidelines and either because of a history of multiple atherosclerotic cardiovascular events or a single event, which is a trial qualifying acute coronary syndrome and multiple high risk conditions, these very high risk patients had more than double the risk of recurrent cardiovascular events as compared to patients classified as not very high risk.

 They further looked at the association of Alirocumab with outcomes and found that Alirocumab was associated with a consistent relative risk reduction in both risk categories. But the absolute risk reduction for major adverse cardiovascular events was numerically greater, although not statistically different, in the very high-risk group versus those not at very high risk and among patients at very high risks with multiple prior events versus a single prior event.

Dr Greg Hundley: Wow, Carolyn. Can you put all this together? This is a lot of information in this study.

Dr Carolyn Lam: Yes, so it would appear that the application of the new ACC AHA 2018 guideline recommendations for risk stratification and the use of additional lipid lowering therapies in patients with established cardiovascular disease clearly identifies patients at very high risk of recurrent cardiovascular events after an acute coronary syndrome and these patients may derive substantial benefit from additional lipid lowering therapy, for example, with a PCSK nine inhibitor.

Dr Greg Hundley: Very nice, Carolyn. Well, let me just finish off with what other articles we have in this ESC featured issue of our journal. So Jonathan Stamler and John Lundberg in separate letters discuss findings related to whether hemoglobin beta 93 cystine is not required for export of nitric oxide bio activity from the red blood cell. And in additional separate letters, Doug Lewandowski and Heng-Chen Yao discuss preservation of ACL CoA and attenuation of pathological and metabolic cardiac remodeling through selective lipid trafficking. In a perspective piece, Blake Thomson from the University of Oxford discusses what Medicare for all in the United States can mean for US medical research and provides lessons from the United Kingdom. In a letter from the United States, Gregory Marcus from University of California San Francisco discusses incident atrial fibrillation among American Indians in California and then both Marco Bergonti from University of Milan and Derek Chew from University of Calgary present two separate cases in our ECG challenge feature. Well, Carolyn, what a great issue and how about we turn to our feature discussion?

Dr Carolyn Lam: Yes, let's go. Thanks, Greg.

Dr Greg Hundley: Welcome, everyone, to our feature discussion today we have Gianluigi Savarese from Karolinska Institute in Stockholm, Sweden and our own associate editor, Sana Al-Khatib from Duke University. We're going to be discussing implantable cardioverter defibrillators in their mortality and looking at a more recent take on this relative to some of the previous published studies. So Gianluigi, I'd like to start with you. Could you tell us a little bit about the hypothesis and why you wanted to perform your study?

Dr Gianluigi Savarese: Yes. Basically we design our study based on three main considerations. First one is recent studies show that the advance in heart-failure therapies have impact patients' risk profile leading to roughly 40% reduction risk of sudden cardiac death in HFrEF and RCTs on ICD use for primary prevention of sudden cardiac death and rural patients more than 20 years ago and thus, nowadays the beneficial prognostic effects of ICD may be different due to the improved risk profile in this population.

The second consideration was that efficacy of ICD patients with heart failure with non-ischemic cardiomyopathy patients receiving a contemporary heart failure therapy as being a question in Danish trial and the third consideration is that efficacy of ICD in elderly is still debated due to findings again from the Danish trial showing a significant reduction in all-cause death associated with ICD use in patients age younger versus older than 70 years old. Based on these considerations, we decided to assess the use of ICD for primary prevention propose in a contemporary and selected FRF population and to assess the association between ICD use and outcomes in such a population.

Dr Greg Hundley: So it sounds like we're doing an update on the utility of ICDs. Can you tell us a little more about your study population and your study design and then let's hear a little bit about your results.

Dr Gianluigi Savarese: Sure. First of all, I would like to first highlight of course the observational natural of this study. Our analysis is performed using data from the Swedish Heart Failure Registry, which is a large enough select court of heart failure patients, enrolling patients regardless of ejection fraction. So today we have roughly around 70,000 patients. And of course for the current analysis we select the patients with HFrEF. There were around 15,000 patients with the HFrEF who were eligible for ICD use for primary prevention according to the ESC guidelines. A study design, we used propensity score matching design in order to try to address the issue of potential compounders. Of course this is a very important point in observational studies. So basically, we amassed patients receiving the ICD versus those not receiving ICDs. And we assessed the association between ICD use and all-cause death and cardiovascular death and we accessed one year and five-year outcome.

Dr Greg Hundley: And so what were some of those results?

Dr Gianluigi Savarese: What we observed is that there was a statistically significant 25 relative risk reduction in all-cause mortality in ICD recipients versus those who didn't receive an ICD within one year and there was also a 12% reduction erased within five years. And we also serve a statistically significant 29% reduction in risk of cardiovascular mortality within one year. But we were not able to observe any association for cardiovascular mortality within five years. We thought it was particularly relevant to have subgroup analysis in our studies since there are so many questions regarding ICD use in specific subgroups, which are, for example, older versus younger patients, those with versus without ischemic heart disease, males versus the females and so on. So what we observed was that results in terms of all-cause mortality were consistent in all of the subgroups considered such as patients older versus younger than 70 years old, versus those without history of ischemic heart disease and those with versus without concurrent CRT use.

Dr Greg Hundley: What about the frequency of implanting ICDs? Was the frequency expected in your results?

Dr Gianluigi Savarese: We add that only 10% of our patients received an ICD at the baseline. This person's age is quite low in particular. If we compare these with other studies in US for example, or also in other European countries and basically, we can only speculate about the underuse of ICD in primary prevention propose. First of all, a certain proportion of ICD underuse may be explained by the fact that we could not assess whether life expectancy was longer than one year, and this is one of the eligibility criteria for ICD according to the guidelines.

Then another point is that in Sweden, the majority of heart failure patients are seen by primary care physician and general practitioners who may have less knowledge and acceptance of device therapy and then higher perception of contraindication. In our previous analysis, we showed that patients not seen by cardiologists have lower likelihood of receiving an ICD and use of devices is higher in centers who do implants, CRT, ICD. So this may be some of the explanation that I can anticipate that some more analysis will follow where we will try to assess the predictors for an under use of ICD for primary prevention.

Dr Greg Hundley: Well, thank you very much. Sana, now we're going to turn to you and help us put this study in perspective to what we have already found or observed in other prior studies related to implantation of cardio defibrillators.

Dr Sana Al-Khatib: As was mentioned earlier, I was the handling associate editor for this paper, so I really enjoyed the handling it and writing an editorial on it. The main points that I wanted to touch on are number one, the significantly low or reduced utilization rate of ICDs. So as was mentioned, the 10% of this patient population received a primary prevention ICDs. Even if you account for some of the new ones is that you can't estimate life expectancy. You can't capture granular clinical data on these patients. So of course some of the non-use of ICDs may have been appropriate. I think 10% by anyone's definition is still pretty low and I'm very encouraged to hear that there are plans to look at predictors of non-use, the characteristics of those patients and hopefully the office can build on their findings and try to implement some strategies to improve the utilization of this life saving therapy.

The other thing that I wanted to touch on is clearly the results are positive in favor of the implantable cardioverter defibrillator. Showing that it significantly reduces all-cause mortality within one year, within five years, certainly reduces cardiovascular mortality within one year. As was mentioned, the reduction in cardiovascular mortality within five years was not significant and to me that is probably mostly explained by competing causes of death in this patient population, but I also cannot rule out the possibility of some mis-classification of causes of death, which is not uncommon. I do want to commend the authors for the great and robust methods that they applied in their analysis. As was mentioned, this was a comparative effectiveness research using observational data. These kinds of analyses can be pretty challenging, but the authors defined their patient population very clearly. They used propensity score matching. In fact, they took it a step further by doing a negative control analysis, meaning looking at hospitalizations for renal failure, for pneumonia, respiratory infections, things like that that you don't expect to be affected by the ICD and they found no difference in that.

And that is amazing to kind of see this level of analysis that I believe really lends their results more credibility. It is important though to keep in mind that when you have 10% of patients getting an ICD, I suspect that this was a highly selected patient population and most likely people who were thought to benefit the most from ICDs were implanted with an ICD. And yet, as I said, that given the robustness of the methods that they use, I actually believe the results. I think the results are credible.

The one last point that I want to comment on is the subgroup analyses that were mentioned. Absolutely important subgroups to look at from a clinical perspective. But I point out the fact that when you start looking at subgroup analyses, and especially when you have a smaller sample sizes and lower event rates that it makes you start thinking about, "Well, are these results valid? Are they believable?" I mean, even honestly, in the setting of a randomized clinical trial, I look at subgroup analyses as hypothesis generating. So I liked that they included those just to kind of really emphasize the importance of looking at these subgroups. But I certainly would not put too much weight on the subgroup analysis results, but overall great results and congratulations to the authors.

Dr Greg Hundley: Fantastic overview, Sana and Gianluigi. So on behalf of Carolyn Lam and myself, we wish you a great week and we look forward to speaking with you next week.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.


Oct 28, 2019

Dr Carolyn Lam:  Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:  I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today involves bleeding and new cancer diagnosis in patients with atherosclerosis and it emanates from Dr John Eikelboom from McMaster University who addresses the question of whether incident GI or GU bleeding when treating cardiovascular disease with anticoagulation is associated with incident cancer. Now, that's a common occurrence that we see frequently clinically, and I'm really interested to hear those results.

Dr Greg Hundley:  How about we start with our articles. And Carolyn, maybe I'll go first this time and my first paper is on mapping and ablation of ventricular fibrillation associated with early repolarization syndrome and it's from Professor Nademanee from Chulalongkorn University. Carolyn, this multicenter study evaluated mapping and ablation of ventricular fibrillation substrates and VF triggers in early repolarization syndrome, also called ERS or J wave syndrome, JWS, among 52 ERS patients for women who are averaged age 35 years with recurrent ventricular fibrillation episodes. Ablations were performed on one. VF substrates defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials and two VF triggers.

Dr Carolyn Lam:  So... What did they find?

Dr Greg Hundley: So first there were two phenotypes of ERS/JWS. Group one included those with late depolarization abnormalities with the underlying mechanism of high-amplitude J wave elevation that predominantly resided in the right ventricular outflow tract and the right ventricular inferolateral epicardium. They served as excellent targets for ablation. And two, the other was with a pure ERS devoid of VF substrates, but with VF triggers that are associated with Purkinje sites. The catheter ablation of the arrhythmogenic substrates with late depolarization abnormalities was very effective in preventing VF recurrence in group one patients and ablation of VF triggers emanating from the Purkinje system was effective in treating the group two patients.

Dr Carolyn Lam:  Wow, thanks Greg. My first paper is a first randomized double-blind placebo-controlled trial examining the early effects of SGLT2 inhibitors on clinically important endpoints in patients with heart failure and reduced ejection. Recall that outcome trials in patients with type 2 diabetes have demonstrated reduced hospitalization for heart failure with SGLT2 inhibitors. However, few of these patients had heart failure and those that did were not really fully well characterized.

Dr Carolyn Lam:  So DEFINE-HF was an investigator-initiated multicenter randomized controlled trial of heart failure patients with left ventricular ejection fraction less than 40, New York Heart Association Class II to III, GFR above 30, and elevated natriuretic peptides. This DEFINE-HF was published by Dr Kosiborod from St. Luke's, Mid America heart Institute and colleagues. In total, 263 patients were randomized to dapagliflozin 10 milligrams daily or placebo for 12 weeks. There was a dual primary outcome and the first was mean NT-proBNP and the second proportion of patients with a five or more point increase in heart failure disease specific health status on the Kansas City Cardiomyopathy Questionnaire or KCCQ overall summary score or a 20% or more decrease in NT-proBNP.

Dr Carolyn Lam:  So here's what they found. There was no significant difference in average six and 12 weeks adjusted NT-proBNP with dapagliflozin versus placebo. However, for the second dual primary outcome of a meaningful improvement in KCCQ overall summary score or NT-proBNP, significantly greater proportions of patients treated with dapagliflozin experienced clinically meaningful improvements in heart failure-related symptoms, functional status, and quality of life or natriuretic peptides compared to placebo, and these results were consistent among patients with or without type 2 diabetes.

Dr Greg Hundley:  Wow, Carolyn, another sort of feather in the cap for SGLT2 inhibitors. What are the clinical implications specifically for this study?

Dr Carolyn Lam:  Yeah, I couldn't agree with you more Greg, and these findings in particular suggest that dapagliflozin may have a favorable effect on improving disease-specific health status after 12 weeks of treatment in patients with heart failure and reduced ejection fraction. These beneficial effects of dapagliflozin may potentially extend to patients with or without type 2 diabetes. Interesting that the first primary outcome of NT-proBNP was not significantly different. I'm sure we'll hear more.

Dr Greg Hundley:  Very good. Well, my next paper comes from Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center and it really relates to therapeutic modulation of the immune response in arrhythmogenic cardiomyopathy. Carolyn, inflammation is a prominent feature of arrhythmogenic cardiomyopathy, but whether it contributes to the disease phenotype is not really known. So in this study, the authors sought to define the role of inflammation and the pathogenesis of arrhythmogenic cardiomyopathy by characterizing NF kappa beta signaling in ACM models both in vitro and in vivo and in cardiomyocytes from patient-induced pluripotent stem cells.

Dr Carolyn Lam: Wow, that sounds like a lot of work. So what did they find?

Dr Greg Hundley:  First they found that NF kappa beta signaling is activated in cardiac myocytes in arrhythmogenic cardiomyopathy. Second, BAY 11-7082, a small molecule inhibitor of NF kappa beta signaling prevented development of major features of the disease phenotype. And third, cardiac myocytes express large amounts of inflammatory cytokines and chemotactic molecules in arrhythmogenic cardiomyopathy, reflecting activation of an innate immune response in the heart.

Dr Greg Hundley:  So Carolyn, clinically important features of ARVC or arrhythmogenic cardiomyopathy, myocardial injury and arrhythmias are driven by activation of an immune response in the heart. And the results of this study suggest that Anti-inflammatory drug therapy should be studied to determine if it could be an effective mechanism-based strategy to reduce myocardial damage and risk of sudden death in patients with arrhythmogenic cardiomyopathy.

Dr Greg Hundley:  So Carolyn, how about the other articles in this issue? Can you tell us a little more about them?

Dr Greg Hundley:  Oh, I would love to. We have a primer from Dr Weissgerber entitled Reveal, Don't Conceal Transforming Data Visualization to Improve Transparency, and this primer really outlines strategies for selecting the correct type of figure based on a study design, sample size, and type of variable. It examines techniques for making effective dot plots, box plots, and violin plots and illustrates how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. A really nice primer.

Dr Greg Hundley: We also have a perspective from Dr Verma entitled More Credence for SGLT2 Inhibition. Talk about even more feathers in the SGLT2 inhibitor cap.

Dr Greg Hundley: There's an On My Mind article from Dr Godier on specific antidotes for direct oral anticoagulant reversal. Is it a case closed or a cold case? Dr Godier really concludes with saying that the availability of specific antidotes provides in itself reassurance, but whether DOAC reversal translates into clinical improvements remain unknown and this leaves clinicians in kind of an awkward position and the case is not closed. Read more. It's a very nice piece.

Dr Greg Hundley: We also have a research letter from Dr Mills very interestingly showing that endothelial progenitor cells do not are originate from the bone marrow. Very interestingly, Dr Mills systematically studied the origin of endothelial progenitor cells in people with sex-mismatched bone marrow transplantation using two complimentary methods and found that all the clones formed from single cells were actually derived from the recipient rather than from the donor bone marrow, thus suggesting that endogenous neovascularization in the heart is driven by tissue resident endothelial progenitor cells without a direct contribution from bone marrow cells. A very important piece because it goes against prior pieces and it's consistent with others, so do read this research letter.

Dr Greg Hundley: Finally, there's a cardiovascular key series from Dr Uriel and title It's All About the Tissue and it's a rare case of acute cardiogenic shock.

Dr Greg Hundley: Wow, Carolyn, what great summaries and articles we have in this issue, but how about now we go and learn a little bit more about that GI tract in our feature article?

Dr Carolyn Lam: You bet, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion and today we're going to meet with Dr John Eikelboom from McMaster University in Ontario, Canada and our own associate editor, Dr Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. The feature discussion paper focuses on the development of lower gastrointestinal bleeding or genitourinary bleeding that may occur in patients with cardiovascular disease that are receiving anticoagulant therapy.

Dr Greg Hundley: So first John, I was wondering, could you tell us a little bit about the hypothesis and why you wanted to conduct this study?

Dr John Eikelboom:  Intriguingly, we set out to do a trial of antithrombotic therapy in cardiovascular disease and our intent originally was not to look at cancer specifically in relation to bleeding. In fact, normally in our cardiovascular trials we don't even collect cancer. But the background story is that there is a hypothesis and there are data that aspirin protects against gastrointestinal cancer and in the COMPASS trial we were testing a regimen that omitted aspirin. So we were concerned that by omitting aspirin this might lead to an increase in cancer. So as a safety measure we very carefully collected all types of cancer during this trial. We were very much reassured that none of the antithrombotic regimens were associated with an increase in cancer, but then we noticed there was a very high rate of cancer diagnosis, about 4% during the course of the trial, and cancer was as common as cardiovascular events. This observation prompted a secondary analysis to see who was having the cancer and in particular with our interest in bleeding where the bleeding identified patients who were subsequently diagnosed with cancer.

Dr Greg Hundley: Can you tell us a little bit about the design of your study and your study population?

Dr John Eikelboom:  The COMPASS trial was designed to test whether an antithrombotic regimen containing rivaroxaban might be more effective than aspirin in preventing cardiovascular events. We included people with chronic coronary artery disease or peripheral artery disease who were randomized to one of two rivaroxaban regimens or aspirin. The results of this main analysis have been previously published the rivaroxaban regimen was associated with more bleeding than aspirin and in particular more gastrointestinal bleeding. Of course, it was more effective than aspirin in reducing the composite of cardiovascular death, stroke, or myocardial infarction. So in this analysis, we then drilled down on the bleeding story and in particular on the gastrointestinal or genitourinary bleeding because bleeding into a hollow viscus has previously been identified as a marker of cancer risk.

Dr Greg Hundley: And who did you include in this study?

Dr John Eikelboom:  We included people with chronic coronary or peripheral artery disease, that is people who were some time away from an acute event. They were more or less stable, although the term chronic is probably better. They were on effective secondary prevention strategies. They'd be your typical patient that a cardiologist, an internist, a vascular specialist, or a neurology would see in their outpatient clinic, an ambulatory patient, where the focus of the clinician would be on cardiovascular prevention.

Dr Greg Hundley: And how many subjects were in your study? Was this a large study?

Dr John Eikelboom:  The study included 27,395 patients from 33 countries and 602 centers, so yes, a large study with a very broad inclusion criteria. This result therefore also is very widely applicable to the secondary prevention cardiovascular populations.

Dr Greg Hundley: So what did you find? What were your results?

Dr John Eikelboom:  We found that there are several highlights. The first, as I've already alluded to, new cancer diagnosis was found in one of 25 people of comparable frequency to the composite of cardiovascular death, MI, or stroke. So that's the first finding. The second funding was that bleeding was very common, that is any bleeding, major or minor, about 10% of the population during an average of two years of follow-up. Then the third and the most relevant finding to our report is that bleeding was a powerful predictor of a new cancer diagnosis.

To describe that a little bit more carefully, among those with bleeds about 10% were diagnosed with a new cancer of any type. And then when we look specifically at gastrointestinal bleeding, it's again around the same proportion of those with GI bleeding who are diagnosed with gastrointestinal cancer but compared with those who did not have gastrointestinal bleeding, those with gastrointestinal bleeding had a twentyfold increased hazard. In other words, the GI bleeding was a very powerful predictor of news GI cancer diagnosis.

Likewise, genitourinary bleeding was a very powerful predictor of new genitourinary cancer diagnosis, about a thirtyfold increased hazard. And when we separated out the urinary bleeding that was the most powerful predictor about a hundredfold increase. And the converse, if we look at bleeding in other areas, they was an association with cancer, but it was much weaker, and this really focuses the attention on bleeding into a hollow viscus, GI tract, the genitourinary tract, and in particular the urinary tract, and it sends up a red flag for clinicians if you bleed into these areas there is a very great increase in the hazard of new cancer diagnosis.

Dr Greg Hundley:  Fantastic, John. So just two quick points and then we wanted to ask Shinya to help us put this study in perspective. The average age of the patients, what was that in this study, what was the gender breakdown, and then did you find any more frequent association of cancer with genitourinary bleeding in men versus women?

Dr John Eikelboom:  The average age was 68 and about one fifth where women, so that is pretty typical of cardiovascular trials, although an area of separate interest because women were relatively underrepresented. Of course, that's another story. In terms of cancer prediction, we didn't separately explore this in men and women and indeed the cancers were dominated by the urinary tract and the GI tract with far fewer genital tract cancers. So we're not really in a position to answer that question. I do accept that very important consideration because clearly, we're going to investigate differently in a man compared with a woman if they have genitourinary tract bleeding.

Dr Greg Hundley:  Well, Shinya, we appreciate having the opportunity to speak with you as an associate editor of Circulation. How do we implement or interpret this data in the context of administration of both aspirin as well as other anticoagulant strategies?

Dr Shinya Goto:  This paper is very important. I mean, that we are cardiologists, we believe we are very away from that cancer, but John and COMPASS group demonstrated cancer is much commonly occurred than we expected, almost similar rate as cardiovascular death within two year in patients recognized coronary artery disease and peripheral artery disease. They are on antiplatelet or anticoagulant agent aspirin, 2.5 milligram b.i.d. of rivaroxaban, plus over 5 milligram b.i.d. of rivaroxaban alone. So CAD/PAD patient on antithrombosis, we have to care about cancer.

And as John beautifully pointed out, if the patient experienced bleeding, like GI tract bleeding, we have to care seriously about hidden GI tract cancer. If a CT scan found GU bleeding, it is an important sign of concealed genitourinary tract cancer. We are very close, so it's a kind of bridging discipline. Cardiology should be close to oncology. As John pointed out, the patient at 68 average age, not so old, it's typical of age of the patient treated by cardiologist. But you know, the message is strong: We have to be careful about the cancer and we have to be careful especially if we found anything in GI tract or GU, so the message is clear.

Dr Greg Hundley:  Well, thank you Shinya. Shinya, I wanted to ask you, what do you think is the next study to be performed in this area of investigation?

Dr Shinya Goto:  If we conducted a cardiovascular trial, it would be nice to add cancer as an endpoint, especially for long-term trial.

Dr Greg Hundley:  John, do you have any perspectives? Where do you see your research going in this area over the next five years?

Dr John Eikelboom:  In addition to the very important point raised by Shinya, I think there are two additional considerations. The one is we need to better understand whether the apparently earlier diagnosis of cancer that can be achieved by exploring bleeding in these cardiovascular patients can improve clinical outcome. We certainly hope that this is good news for patients because we hope to be able to diagnose cancer earlier. The second big question is if we were more diligent in screening for bleeding and in particular occult bleeding in the cardiovascular patient, would that lead or help us to diagnose the cancer earlier?

Dr Greg Hundley:  Well listeners, we've had a great discussion from Dr John Eikelboom from McMaster University in Ontario, Canada, and our own Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. They have highlighted to us this important study result indicating an association of detection of cancer when we observe gastrointestinal and genitourinary bleeding after treatment with both anticoagulant and antithrombotic therapy.

And so for Carolyn Lam and myself, Greg Hundley, we wish you a great week and we look forward to catching you On the Run next week.

Dr Carolyn Lam:  This program is copyright American Heart Association 2019.

Oct 21, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Dr Greg Hundley, associate editor for Circulation, from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article, this issue reminds us of the importance of the physical exam in patients with heart failure and reduced ejection fraction involving those that were enrolled in the PARADIGM-HF. Remember a trial of sacubitril/valsartan versus ACE inhibition in those with a reduced ejection fraction? Can't wait to hear more of the discussion of the importance of that physical exam. Carolyn, how about you talk about your first article?

Dr Carolyn Lam:                I will because this first paper reports a novel ventricular tachycardia or VT ablation strategy guided by a voltage independent mapping display during sinus rhythm.

Dr Greg Hundley:             Well, Carolyn, since many of us don't do VT ablations every day, how about a little background on this one first?

Dr Carolyn Lam:                Substrate modification during sinus rhythm is actually the mainstay ablation strategy for scar related VT. With the recent trend being more extensive ablation, aimed to homogenize the entire scar region. These authors are led by Dr Tung from the University of Chicago Medicine Center for Arrhythmia Care, and colleagues. They had hypothesized that a greater understanding of the nature and characteristics of the scar would be most prone to reentry, may actually improve the precision and yield of ablation. Now, they had previously demonstrated that sites critical for reentrant VT localized to regions of activation slowing during sinus rhythm or so-called deceleration zones rather than regions with latest activation. In the current study, they aim to prospectively assess the outcomes of VT ablation guided primarily by targeting these deceleration zones identified by propagational analysis of ventricular activation during sinus rhythm.

Dr Greg Hundley:             Interesting. What did they find, Carolyn?

Dr Carolyn Lam:                They studied 120 patients with scar related VT who are prospectively enrolled in the U Chicago VT ablation registry between 2016 and 2018, who underwent 144 ablation procedures for scar related VT. They performed high density mapping during baseline rhythm and identified the deceleration zones which all localized to successful termination sites in 95% of cases. The median total radio frequency application duration was 29 minutes to target the deceleration zone, representing ablation of 18% of the low voltage area. At a mean of 12 months, 70% freedom from VT recurrence was achieved with an overall survival rate of 87%. A novel voltage independent high-density mapping display may further identify the functional substrate for VT during sinus rhythm and guide targeted ablation thus obviating the need for extensive radio frequency delivery.

Dr Greg Hundley:             Fantastic, Carolyn.

                                                Well, my first paper is from Professor Mark Nicolls from Stanford University. It's entitled Phenotypically Silent Bone Morphogenic Protein Receptor 2 or Bmpr2 mutations, that predispose rats to inflammation induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. While being the most common inherited risk factor for pulmonary arterial hypertension, Bmpr2 germ line mutations only result in disease in 20% of mutation carriers. A finding that suggest a second hit is required to elicit vascular pathology. Transgenic mouse models of Bmpr2 mutations were developed in this study to better understand the relationship between these phenotypically silent gene mutations and the predisposition to pulmonary arterial hypertension.

Dr Carolyn Lam:                Huh. What did they find Greg?

Dr Greg Hundley:             In this new two hit model of disease, Bmpr2 mutant rats subjected to pulmonary inflammation, developed severe pulmonary arterial hypertension with vascular remodeling and the pulmonary arterial endothelial cell transformation that occurred did so in three phases. An initial apoptosis phase induced by exogenous LTB4. Second, a proliferative phase relying on P38 mediated noncanonical TGF-beta signaling. And then finally a terminal inflammatory phase in which pulmonary arterial endothelial cells utilized the canonical TGF-beta pathway, expressed mesenchymal markers and produced LTB4, IL6 and NF-kappa beta signaling molecules. The clinical implications include that in phenotypically silent Bmpr2, haploinsufficient individuals, a second hit of pulmonary inflammation may put them at risk for subsequently developing pulmonary arterial hypertension. And this lung inflammation while usually self-limited may cause durable and inflammatory vascular lesions in these genetically susceptible patients.

Dr Carolyn Lam:                Wow, that is super interesting. Thanks Greg for that great summary.

                                                Well, my next paper really looks at the temporal trends in survival after pediatric in hospital cardiac arrest in the United States. This is from Dr Holmberg from Beth Israel Deaconess Medical Center and colleagues who performed an observational study of hospitalized pediatric patients who received CPR from January 2000 to December 2018 and were included in the Get With the Guidelines resuscitation registry.

Dr Greg Hundley:             Carolyn, what did they find?

Dr Carolyn Lam:                They found that survival has improved for pediatric events requiring CPR in the US with a 19% absolute increase in survival for in hospital pulseless cardiac arrests and a 9% absolute increase in survival for non-pulseless events between 2000 and 2018. However, survival from pulseless cardiac arrest appeared to have reached a plateau following 2010. The increase in survival over time is reassuring and perhaps provides some evidence for the progress of quality improvement efforts. However, given the plateau and survival following 2010, there is a continued need for clinical focus and new interventions to improve outcomes of pediatric in hospital cardiac arrests. And Greg, are you now going to tell us what's in the mailbag?

Dr Greg Hundley:             Absolutely Carolyn. Professor Wei, from Harvard, provides a new perspective on using the restricted mean survival time difference as an alternative to the proportional hazards model and hazard ratios for analyzing risk in clinical cardiovascular studies. In another article, Eric Peterson from Duke provides a white paper discussing randomized clinical trials versus EMR extracted data to inform new therapies in cardiovascular disease. And he really reviews what are the issues we need to overcome using these EMR strategies? And on my mind piece from Dr Glenn Levine from Baylor, discusses the role of psychological wellbeing as it relates to cardiovascular disease. And then we have a large series of letters in this issue.

                                                First, Otmar Pfister and Kari Nytrøen, each have letters regarding high intensity interval training. Dong-Vu Nguyen, asked for several points of clarification regarding the utility of BNP assessments in syncope and whether other metrics incorporating clinical information could be useful. There's a corresponding response from Christian Müller from the PRICIPLE study with great discourse. And then finally an important research letter from Dr Rodés-Cabau in Quebec, evaluates the left atrial occlude or thrombus occurrence among eight centers in Canada and in this letter provides data that suggests thrombi can occur in those that have implanted left atrial occluders and raises considerations for anticoagulation of these patients. Great set of letters in this issue of the journal.

Dr Carolyn Lam:                Absolutely Greg and thanks for sharing that. Let's go onto our feature discussion.

Dr Greg Hundley:             You bet.

                                                Welcome everyone to discussion of our featured article and today we have Senthil Selvaraj from University of Pennsylvania and our own Mark Drazner, associate editor at Circulation from the University of Texas Southwestern and we're going to be discussing some very interesting results regarding the physical exam as they've been generated from the PARADIGM heart failure trial. And remember that's a prospective comparison of an Angiotensin Receptor-Neprilysin inhibitor with an angiotensin converting enzyme inhibitor to determine the impact of those two therapies on all-cause mortality and also morbidity in heart failure. Senthil, welcome to this discussion. We're very excited to have the opportunity to discuss your article and I wonder before we get started, could you tell us a little bit about the background and the hypothesis for why you wanted to perform the study and then afterwards tell us a little bit about the study population and the methods.

Dr Senthil Selvaraj:          I think the impetus for this study torn out of the fact that we do the clinical exam so often, and I think like many cardiology clinicians in the community, we perform this so often, but we don't know what the actual impact is of performing the clinical exam. What I wanted to understand and the primary motivation was to really understand what the change in the physical exam meant in terms of subsequent prognosis. Does decreasing congestion actually relate to improved cardiovascular outcomes? I think this is an area that is hard to study by randomized controlled trials. In my opinion I think there is not so much equipoise in performing a trial of decongestion versus no decongestion. I think this is sort of one way that we can understand epidemiologic methods, whether lowering congestion improve outcomes.

                                                I had a number of other interesting analysis. I think the first is we've had a number of studies that have evaluated the physical exam, but I think that an updated analysis in a population receiving contemporary management was particularly important, particularly given the fact that the risk rad versus insignificantly in the past couple of decades essentially related to improvements in therapy. The second is we formed the physical exam in conjunction with a number of other additional forensic markers in the use of validated risk scores that to understand those and have utility above and beyond this. For instance, can I just check a natural aside and will that be doing a physical exam. And I think while that's easier, I don't know that that necessarily is the right thing to do. And that was another motivation.

Dr Greg Hundley:             What was your overall study design and your study population?

Dr Senthil Selvaraj:          The overall study design was to use the PARADIGM-HF cohort. And in our analysis, we did a time updated analysis, which is different than many other analyses previously done. That means that every single point that a patient goes into a clinical trial visit, we updated their physical exam, possible because the study investigators did perform an exam at each of these visits. And so what we did was we used the physical exam and number of signs of congestion as the time bearing covariate and looked at its relationship to outcomes, but also just as importantly why might think decreasing congestion or changing congestion has really stuck out as very important about to want to feel better. And I anything quantifying that relationship while it's intuitive I think is also very important.

Dr Greg Hundley:             And just remind us who's in PARADIGM heart failure? Well what was the study population? And just very quickly the randomization arms?

Dr Senthil Selvaraj:          PARADIGM-HF was a randomized controlled international multicenter trial of patients with heart failure ejection fraction which has been defined in this study as less than or equal to 40%, near two, three or four symptoms, elevated natriuretic peptides, depending on the trial compared an angiotensin converting enzyme inhibitor and Angiotensin Neprilysin inhibitor to control valsartan.

Dr Greg Hundley:             Tell us what were your study results? And how did they pertain to the outcomes that were gathered in PARADIGM-HF?

Dr Senthil Selvaraj:          We first divided our cohort based upon the total number of signs and as might imagine increasing congestion was associated with a number of adverse clinical features. We then looked at the association between the number of signs and the efficacy outcomes, which included a primary composite outcome of time to heart failure, hospitalization as well as cardiovascular mortality and then we individually looked at those as well as all-cause mortality. And as we show in our paper, there was really a striking relationship between time updated times of congestion as well as all of the efficacy adjusted for baseline natriuretic peptides which are available in all of our participants in PARADIGM-HF as well as MAGGIC risk score and New York Heart Association class to get at the question of whether improving congestion, where the relationship congestion above and beyond symptoms is still valid.

                                                The other thing that we did is because we only looked at natriuretic peptides at baseline is that we've formed a sub study where we evaluated, since you had natriuretic peptides during follow-up as well at the one month visit and eight month visit and compare the utility of signs of congestion and outcomes and you can still see that there was a significant relationship in this sub analysis. The participants would complete NP data. We further looked at relationship and congestion and quality of life and there is a significant relationship such that for every sign of congestion that you decrease, there is a five-point increase in KCCQ, the quality of life score which some have considered to be a clinically significant increase in times of congestion.

                                                We also looked at the relationship between the treatment arm and reduction of congestion as sacubitril/valsartan was associated with significant reduction in clinical congestion, which has mirrored its impact on natriuretic peptides as well. And finally to understand whether reducing congestion was actually associated with improved outcomes, we entered both the baseline congestion and change of congestion into models that looked at the relationship with outcomes and found that change of congestion was a very strong predictor of outcomes even after baseline congestion, which we interpreted to mean that reduction in congestion was a mutable factor, and that reducing congestion is actually associated with improved outcomes.

Dr Greg Hundley:             Signs of congestion on the physical exam, you had JVD, peripheral edema, rales, and then an S3 and so you're adding those up and making a score. And so when one of those particular findings dropped off in terms of score, that's what you're indicating by change in congestion, is that correct?

Dr Senthil Selvaraj:          That's really correct. We analyzed this in two methods. The first is a dichotomous presence of a physical exam science. As you said, the presence or absence of JVD, the presence or absence of a DMO rales and an aspirate. The investigators also graded two of those signs of congestion, which included a DMN rale that we formed a complimentary analysis where we created a sign score where we gave partial credits to gradations of the physical exam and we saw very similar outcomes as well.

Dr Greg Hundley:             Mark Drazner at UT Southwestern has done a lot looking at the importance of our physical exam and assessing patients with heart failure. Mark, how do you feel the results of this study compare with previously published works?

Dr Mark Drazner:             Thanks Greg. First, always a pleasure to join you on this and I do want to congratulate Dr Selvaraj and his team on this outstanding paper to generate considerable enthusiasm among the editorial team and reviewers I'd say. It's a really interesting study for several fold and you've heard a lot of the important methods by Dr Selvaraj already. I would just highlight there've been a number of previous studies that have looked at markers of congestion from physical exam and showed that they had prognostic utility, but a major question that has been addressed to me personally and I think in the field, does that add any independent information beyond just sending BMPR natriuretic peptide level measurement?

                                                And this analysis here as you've heard, one of the big advances was that they were able to adjust for natriuretic peptide levels and showed that the exam or the markers of congestion did add independent prognostic information. I think that's an important step forward, as is bringing the relevance again about the markers of congestion and prognostic utility to patients being receiving the most modern-day therapy including ARNI therapy, which is unparalleled opportunity because of the PARADIGM trial to look at that question. I think those two are really set this paper. I think this is going to be a standard, this is the standard for assessing prognostic utility congestion in heart failure by far in the literature in my opinion.

Dr Greg Hundley:             What we're saying is that our following the patients and identifying these physical exam changes during an initiation of ARNI therapy can be really helpful in determining that particular patient's long-term prognosis. Coming back to both of you, maybe first Mark and then we'll come back to Senthil, what do you see is the next study in this field? Both in terms of new therapies in heart failure and the relationship of physical exam and then also perhaps just briefly some thoughts on ARNI therapy.

Dr Mark Drazner:             I think this paper highlights the incredible importance of congestion in modern day therapy. And there are a number of other studies that looked at this recently, including there's an analysis of TOPCAT preserved heart failure showing again congestion being linked to adverse outcomes. I think that question is resolved that even in modern day therapy. The next step in my opinion is to understand why clinical congestion, the pathway from clinical congestion to adverse outcomes. What are the links? Can we target those links to try to interrupt that cycle? And what is the most effective way to achieve decongestion? We heard that now ARNI appears to be a mediator of decongestion and we need more work on that I think. I would say looking at the pathway from congestion to adverse outcomes and then what is the optimal way to decongest our patients.

Dr Greg Hundley:             Very good. Senthil, do you have anything to add to that?

Dr Senthil Selvaraj:          I think that's great. I completely agree with Dr Drazner on this. I think one question would be to understand truly as Dr Drazner said, the optimal way to decongest patients and so for instance, the way that we have traditionally done this is by increasing diuretic. There are a number of experimental and novel ways that we can decongest patients. I think one unanswered question actually is does increasing a diuretic potentially at the expense of activating the renin angiotensin aldosterone access, actually afford benefit if you decongest patients. It's an analysis that I think is ripe and timely and not been adequately addressed. I think that that would be one potential way to go. And the second is, I think as you mentioned in clinical trials, I think clinical congestion may not be an outcome, a pre-specified outcome of course. But I do think that it is an important outcome aside from just looking at decreases in other surrogate markers such as natriuretic peptides. It's easy to perform. It's collected on many investigator visits during these trials and therefore these are ripe analyses.

Dr Greg Hundley:             Listeners, we look forward to speaking with you next week and have a great week.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.


Oct 14, 2019

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia at VCU Health.

                                                Well, Carolyn, we've got a great feature article to discuss later in our interview today. We're going to compare surgical versus percutaneous aortic valve replacement, but now with coronary artery revascularization. So, very exciting results from the SURTAVI trial.

                                                So, Carolyn, do you have a couple papers to discuss?

Dr Carolyn Lam:                For sure. Actually, it's exactly a couple, and it's a couple of GWAS papers. The first is a GWAS of the cardiac magnetic resonance imaging derived left ventricular phenotypes of the UK bio bank. It comprises almost 17,000 European-UK bio bank participants without prevalent myocardial infarction or heart failure. So this was led by professors Petersen and Monroe from Queen Mary University of London, and colleagues who found that prognostically important left ventricular imaging phenotypes were highly heritable, with a heritability of 22 to 39%. A total of 14 genetic susceptibility low PSI, eight of which were unique, enriched in the cardiac developmental pathways and regulation of contractile mechanisms were discovered, and the polygenic risk scores of left ventricular phenotypes were predictive of heart failure events independently of clinical risk.

Dr Greg Hundley:             Well, Carolyn, knowing me and MRI, something I really am interested in. So tell us a little about what are the clinical implications?

Dr Carolyn Lam:                Well, the findings not only enhance our understanding of the genetic basis of prognostically important left ventricular phenotypes in the general population, but they also underscore the intricate genetic relationship between these endo phenotypes and the pathogenesis of heart failure. The prioritized genes in the genome whites significant load size should be followed up in the functional studies to aid the development of potential novel therapies in future. The polygenic risk scores of left ventricular phenotypes may have a role in personalized risk stratification. But this, of course, is dependent on further validation of the clinical robustness in future studies.

                                                I want to skip onto my second GWAS paper, and this time dealing with bicuspid aortic valve. So, first a little reminder that bicuspid aortic valve disease is a congenital defect that affects 0.5 to 1.2% of the population, and is associated with comorbidities including ascending aortic dilatation and calcific aortic stenosis. To date, while a few causal genes have been identified, the genetic basis for the vast majority of bicuspid aortic valve cases remains unknown. Today's paper from Dr Lipschultz from Medical University of South Carolina reports novel human genetic based models, which developed bicuspid aortic valve and aortic stenosis with high penetrance.

Dr Greg Hundley:             Very interesting. So, how did the authors do this, Carolyn?

Dr Carolyn Lam:                Yeah, it is interesting. What they did is they performed a GWAS and replication study using cohorts of more than 2,000 patients with bicuspid aortic valve and more than 2,700 controls, which identified the primary Celia genes as associated with the bicuspid aortic valve phenotype. Specifically the most associated snips were identified in or near genes that are important in regulating Ciliogenesis through the exocyst, which is a shuttling complex that chaperone Celia cargo to the membrane. Genetic dismantling of this exocyst resulted in impaired Ciliogenesis through the XO CIS, disrupted Ciliogenic signaling, and resulted in a spectrum of cardiac defects in zebra fish and aortic valve defects including bicuspid aortic valve, valve stenosis, and Velveeta calcification in murine models as well. So this data really supports that the exocyst is required for normal Ciliogenesis during aortic valve morphogenesis and really implicates the disruption of Ciliogenesis, and its downstream pathways may contribute to bicuspid aortic valve and its associated comorbidities.

Dr Greg Hundley:             Wow. Very interesting. Learning more and more about bicuspid valves through our journal. I'm going to shift Carolyn and talk about an article from Dr Marc Sabatine from the TIMI study group at Brigham and Women's hospital. This study performed a systematic review and a trial level meta regression analysis of three classes of lipid lowering therapies that reduce triglycerides to a greater extent than they do LDLC. Fibrates, Niacin, and Marine derived Omega-three fatty acids and key inclusion criteria were a randomized, controlled trial that reported on major vascular events. The study also incorporated data from a previous Meta-regression of 25 Statin trials, and the main outcome measure was the risk ratio for major, vascular events associated with absolute reductions in lipid parameters.

Dr Carolyn Lam:                Oh, very interesting. So did the study show that it was beneficial to lower triglycerides or not?

Dr Greg Hundley:             Let me tell you a little more about it. The study encompass 374,358 patients that sustained 46,180 major cardiovascular events, and in their multi-variable Meta-regression model, that included terms for both LDLC and triglyceride surrogates for LDL and VLDL. The risk ratio was 0.8 per one millimole per liter reduction in LDLC, and 0.84 per one millimole liter reduction in triglycerides. Therefore, a reduction in non-HDLC, a measure of atherogenic LDL and VLDL particles, is strongly associated with lower risk of major vascular events regardless of the lipid lowering drug class, and triglyceride lowering is associated with a lower risk of cardiovascular events, but to a lesser extent per absolute amount of reduction then with LDLC. Interesting, Carolyn one study reduce it and impacted the study results, and nearly all non-statin trials did not achieve significant non-HDLC lowering to detect a clinical difference in major vascular events. Now how about in regards to Omega- three dose?

                                                Well, each one gram per day of EPA administered was associated with a 7% relative risk reduction in major vascular events, whereas there was no significant reduction in major vascular events with DHA. So the benefits of Marine-derived Omega-three fatty acids, particularly high dose EPA, appear to exceed their lipid lowering effects.

Dr Carolyn Lam:                Wow. Interesting. So Greg, take it home for us. What should we do clinically about this information?

Dr Greg Hundley:             Carolyn, developing drugs that achieve large reductions in VLDL and triglycerides and are targeting patients with high baseline levels of triglycerides would likely increase the probability of showing a meaningful clinical benefit, and fibrates could be considered in patients needing further non-HDLC lowering, being mindful of side effects, as they should offer clinical benefit proportional to the degree of non-HDLC lowering, and if a disproportionate relationship between lipid lowering and cardiovascular risk reduction is validated in ongoing high dose Omega-three fatty acid trials, it will support the hypothesis that confers a unique benefit of this class of agents beyond simply their lipid lowering.

                                                How about that?

Dr Carolyn Lam:                Very nice Greg and I think very balanced and good clinical take home messages. Tell us what else is in the mailbag.

Dr Greg Hundley:             We have so many interesting articles in Circulation and let me just run through a quick list of those that are also in this issue. First, Dr Jere Mitchell, from UT Southwestern, reviews the 50th anniversary of the Dallas Bedrest Study that involve five 20-year-olds that underwent several weeks of bedrest, and he discusses how this informs many of our thoughts regarding the benefits of activity today, and one of his major coauthors is Dr Ben Levine. Our own Josh Beckman reviews the ongoing efforts of physicians to understand the role of paclitaxel coated stents for those undergoing peripheral arterial interventions. Dr Berlinde von Kemp, in our case series, identifies that not all cardiomyopathy, after delivery, is simply postpartum cardiomyopathy. In another article, Dr Anurag Agrawal discusses what's on their mind regarding the use of spirometry as a cardiovascular disease risk assessment tool, should it be incorporated into existing cardiovascular disease risk models.

                                                Then, we have a great letter back and forth discussion from Dr Junfeng Wang, Dr Daxin Wang, and our own Naveed Sattar in three separate letters that discussed the relevance of age of onset for type two diabetes relative to cardiovascular risk. Then, finally our own Carolyn Lam reviews the role of biomarkers in heart failure and preserved ejection fraction.

Dr Carolyn Lam:                Let's hop on to our feature discussion, shall we?

Dr Greg Hundley:             Absolutely.

Dr Greg Hundley:             Welcome everyone to the discussion of our featured article today where we're going to review an excellent study comparing TAVR versus SAVR in patients with aortic stenosis, but also now considering simultaneous coronary artery revascularization. Discussing our article today we have Dr Thomas Engstrøm and then our own associate editor, Dharam Kumbhani. Well Thomas, welcome to our podcast featured article discussion. I wonder if you could start us off with a little background regarding your study. What were your hypotheses, and then tell us a little about your study population and your methods.

Dr Thomas Engstrøm:     Now, as you know, up to 50% of patients that are treated for aortic stenosis have coronary artery disease, and this may be considered as a bystander disease to develop disease, but definitely also adds to the prognosis for the patients. A priority guideline recommends that if you do SAVR, you'll also have significant coronary artery disease. What we don't know is if the complete percutaneous approach is as good as a surgical approach. Maybe do TAVR plus PCI comply with fiber plus CABG. That's the background for the study.

                                                Now, the population involved in this study is the population from the search TAVR trial, which as you know compared TAVR to SAVR in patients that were clinically at intermediate risk and in patients that had severe aortic stenosis. If patient had additional coronary artery disease with a syntax called Bob 22, they were excluded from the trial. We are talking about intermediate risk patients with low syntax score. Of the patients in the TAVR trial, 20% had additional coronary artery disease and were resterilized. In the paper, we compare TAVR plus PCI versus SAVR plus CABG in those patients with significant coronary artery disease.

Dr Greg Hundley:             How did you define the presence or absence of coronary disease? Just real quickly before we get to your results.

Dr Thomas Engstrøm:     This was at the discretion of your operator to define where the patients had coronary artery disease or not. In the paper, patients were defined as having significant diseases. More than 70% of stenotic lesions were present in one or more coronary arteries.

Dr Greg Hundley:             And so can you tell us, Thomas a little about the results of your study?

Dr Thomas Engstrøm:     First of all, the patients that had additional coronary artery disease had a poor prognosis than those that only had valve substitution, which is probably not a surprise. Within those that also had coronary artery disease, TAVR plus PCI appeared to be as good as CABG plus SAVR in terms of the primary endpoint, which was all because mortality or disabling stroke after two years. Then, if you dive more deeply into the endpoint and the number of secondary endpoints were pre-specified, there were no differences regarding any stroke myocardial infraction and in total no differences between what you could call major heart end points. If you look more into detail of the secondary endpoint, there are subtle differences. Patients that were in the SAVR plus CABG had more atrial fibrillation as they also had more acute kidney injury following that treatment. Whereas, in the TAVR plus PCR, more patients had vascular complications and of course had the need for pacemaker implantation. There are differences between the outcome in the two groups, but not in regard of pre-specified primary and more important secondary endpoints.

Dr Greg Hundley:             Dharam, I was wondering if you could help us think about what this means for the field in terms of both from aortic valve replacement, and then also the concomitant management of coronary disease in patients that require aortic valve replacement.

Dr Dharam Kumbhani:   As Thomas just pointed out, I think this is a very important question. This comes up all the time in patients with severe aortic stenosis, being evaluated for best options, and the guidelines have stayed true to this that if somebody has concomitant coronary artery disease, then the guidelines typically would recommend SAVR as the first option because then they can have CABG at the same time. This study really seeks to address a very important knowledge gap in the field, and as he very well pointed out, this does restrict itself a little in terms of the population, because they couldn't have a high syntax score, actually an intermediate or high syntax score, and they need in the trial...I think the main syntax score was eight or nine. I think that is important, but having said that, more than 50% of the patients had multi-vessel disease, and it was really impressive that nearly 15 or 17% still had three vessel PCI even in this arm.

                                                I think it's important for people to recognize that although this was the lowest syntax score, multivessel PCI was still pursued. I think that's definitely an important takeaway from the strike. It's a really important trial. It's one of the very few pieces of information that we have that is prospectively done under the auspices of a big trial like SURTAVI, and with low risk approval in and what this means for patients going forward I think will be very exciting to see how this few devolves.

                                                Thomas, as this field matures, could you walk us through, in terms of did you do the valve first and then the coronaries, or where the coronaries worked on first and then the valve? That's sort of the first question. Can you walk us through how you make those decisions?

Dr Thomas Engstrøm:     It was up to the discretion of the operator whether to do a concomitant procedure, both PCI and TAVR, or to state the procedures in that way that PCI was done first, and this could be done up to seven days before the TAVR. If you compare those two groups, and now numbers become a little bit few, so we can't be conclusive here. It appears that patients that had stage procedures did poorer than those that had concomitant procedures done. Of course, it raises some questions. The prioritization as to do it in one way or the other was that through concomitant procedure, you may introduce too much of stress to the patient. Otherwise, if you do a stage procedure, it's best to do the PCI first, because the actual appearance of the valve may make it more difficult and cumbersome to address the coronary arteries. To sum this up, in the patients that we have, it appeared that a concomitant procedure is safe.

Dr Greg Hundley:             Dharam, tell us, what do you think is the next step forward for this field? What do see as the next study moving forward here?

Dr Dharam Kumbhani:   I think this study really sets the stage for, I think future trials where perhaps we would have... So I'm doing this in this trial. The stratification was done based on whether or not they need to revascularization. I think going forward, again with LOTUS approval here and proliferation of the number of TAVR procedures that are being offered everywhere, I think it will be helpful. This study would set the stage for future studies, where I think you would prospectively have patients with needing an aortic valve replacement and perhaps even complex revascularization, and how that was kind of actually the randomization, which is the stratification strategy, which again was very helpful. These are really among the first few data that we have of this, but I think this kind of sets the stage for future investigations in this space. And then as I briefly alluded to, I think this may help evolve or this may help in the evolution on the guidelines as well.

                                                Thomas, would you like to add anything to that?

Dr Thomas Engstrøm:     Yeah, I completely echo that. Going back to the old syntax trial, it would be very interesting to see if PCI holds through, even in high tunes, syntax scores with newer drug eluting stents, and also of course the question of the diabetics is totally unsolved in this cohort. CABG plus SAVR may turn out to be the best solution, but we still are waiting to see data that can support any of the two strategies in those patient cohorts.

Dr Greg Hundley:             We want to thank Thomas Engstrøm and also our own Dharam Kumbhani. We look forward to seeing you next week.

Dr Carolyn Lam:                This program is copyright American Heart Association, 2019.


Oct 7, 2019

Dr James de Lemos:        My name is James de Lemos. I'm the executive editor for Circulation and I'll be filling in today for Carolyn Lam and Greg Hundley, and delighted to host the podcast for the annual cardiac surgery themed issue. I'm joined today by Tim Gardner from the University of Pennsylvania who leads the surgical content in Circulation year-round, as well as by Dr Marc Ruel, who's the guest editor for this issue and the Chief of Cardiac Surgery at the University of Ottawa and has really led the development of this issue. Marc, Tim, welcome.

Dr Timothy Gardner:      Thank you.

Dr Marc Ruel:                    Thank you. Good afternoon.

Dr James de Lemos:        And Marc, thanks for all you've done to bring this issue home again this year. It's really wonderful to see this thing develop. Why don't you start us off and tell us how this issue came together and what the purpose of this is? Why do we publish a specific issue focused on cardiac surgery?

Dr Marc Ruel:                    We're really delighted that Circulation has taken the stance as the cardiovascular community's premier cardiovascular journal. I think as an important piece of this is the fact that cardiovascular surgery already has a resurgence intermediate with importance despite new percutaneous options and medical therapies available. There's more and more patients who find himself in need advance path if you will, of an advanced cardiovascular disease and surgery can be performed with safer and better outcomes constantly.

                                                So, I think this issue obviously aims to gather the very best of cardiovascular surgery, not only including cardiac surgery, but also there's actually one of the papers on peripheral vascular surgery.

Dr James de Lemos:        We'll start Tim with you if you don't mind. I'd like to talk about two papers. One from Stanford that focuses on inter-facility transfer of Medicare patients with Type A dissection and then a research letter that studies hospital volume effects with abdominal aortic aneurysm surgery from Salvatore Scali and colleagues at the University of Florida. Can you walk our readers through these papers and lead the discussion on these?

Dr Timothy Gardner:      The first paper focused on inter-facility transfer of Medicare recipients with Type A dissections. First off, underlines the fact that this is a very difficult, serious condition with mortality rates in this series there ranging between about 22 and 30%. And the purpose of the study was to analyze how these Medicare patients with acute aortic Type A aortic dissections are managed and whether the effect of high or low volume hospital experiences influences the mortality. As I think we might expect, patients who receive care at high volume aortic surgery centers have a lower mortality. Then the question is, what is the effect of transfer from a low volume or from a hospital without aortic surgery capabilities? What is the net effect there? The benefit of care and a high volume hospital is pretty clear. The mortality rate is significantly lower and the need to transfer or the actual fact of transfer does not increase the risk to the patient.

                                                It's an interesting challenge because we do know that patients with acute aortic dissection, if their repair or surgery is delayed, we'll have a predictable accumulating mortality. However, what this study shows is that the benefit of transfer and the importance of experience with this complicated aortic surgery. And it really brings up this very challenging issue of regionalization, of acute care or specialized care.

                                                We really struggle with this in so many aspects of surgical care, medical care in general, but especially procedural care. We realize that we need to be able to provide emergency care in many areas and we don't want to suggest that that smaller hospitals may not be able to care for patients with acute complex illnesses. But on the other hand, if transfer can be accomplished and if the availability of high volume experience can be achieved, that this is something that we really need to look at carefully. I think that this study brings that into pretty good view.

Dr Marc Ruel:                    James, I think that Tim has already captured the essence of this paper. The results are impressive in this excellent series and the really carefully led analysis. This is an important paper and it's very thought provoking.

                                                There’re two clans among surgeons. Those that believe that every cardiac surgeon who was named as such should be able to perform safely aortic dissection repair and another client and somewhat sustained or supported by the data from this paper that says that this is a special expertise that should be or regionalized and put through centers of excellence. So this paper would support the latter theory.

Dr James de Lemos:        The next paper, which was a research letter, sort of adds fuel to this fire of regionalization, doesn't it? At least insofar as we're talking about the more complex procedures.

Dr Timothy Gardner:      Yes, this paper studies the hospital volume effects on surgery for abdominal aortic aneurysms, an even more common and somewhat less lethal, but very morbid condition. And this analysis of center volume for care of these patients is complicated even a little bit more because as we know, endovascular repair of abdominal aortic aneurysms is now the most common form of treatment.

                                                Interestingly, in looking at the outcomes in a variety of centers with varying volume procedural volumes, there was no difference in outcomes when endovascular repair was done, but there was inverse relationship between volume and outcomes after classical surgical repair. This really highlight a change that's occurring in vascular surgery where, with endovascular repair being done more commonly, surgeons are having less exposure unless experience with open repairs. This is particularly a challenge for training programs where you have a surgical resident or fellow for two years and he or she may experience relatively few open repairs.

                                                So, this again, the data seems to suggest that higher volume vascular surgery centers, where the numbers of open repairs are done, have better results and that this is not nearly as much, in fact, it wasn't an issue for endovascular treatments, but it again highlights the procedure of volume outcomes relationship. I think this is something we're going to have to deal with both in terms of optimizing patient care, even considering when we're training new or young avascular surgeons, they may have to move to different centers to ensure that they have the kind of exposure to classical surgical treatment for those complex patients who are not candidates for endovascular repair.

Dr James de Lemos:        Let's change gears. We've been talking about two systems of care issues, but let's get back to the complicated patient themselves and talk about a paper Mark from Kato and Pellikka from Mayo Clinic, focusing on hemodynamic and prognostic impact of concomitant mitral stenosis in patients undergoing surgery or TAVR for Aortic Stenosis.

Dr Marc Ruel:                    As you say, this is an intricate clinical problem that we not uncommonly meet when we provide care for patients who have severe aortic stenosis. These are not young patients. These patients in this particular series of 190 patients with severe aortic stenosis, they also had some significant degree of mitral stenosis. These are patients that had a mean age of 76 years. I think we've all encountered these patients estimations, so someone has severe aortic stenosis and has some form of calcific mitral stenosis. And indeed in this series, more often than not, the vast majority of those patients had calcific MS as opposed to a Rheumatic MS. So, a different type of pathology probably to what we see in the elderly patients coming in with some degree of inflow obstruction.

                                                So, the authors took their 190 patients, mostly from the Mayo clinic, but also from Tokyo, about five patients contributed from Japan, and matched in one to two with some controls who also had the same degree of severe aortic stenosis, the same age, same gender, same left ventricular ejection fraction, but didn't have mitral stenosis. And then compare their fate over a couple of years. Essentially, what the authors found is that in patients with severe MS, which was defined as a trans-mitral gradient of equal or higher than four millimeters of mercury, the midterm survival was decreased. The hazard of death was increased by about 90% or so. And there was also a classification, the sub classification based on the fate of the patient with regards to the echocardiographic findings, as to whether the patient truly had mitral stenosis at the time of presentation. So prior to the aortic valve replacement or whether the patient had pseudo-mitral stenosis. How the authors classify this, is those patients in whom the mitral valve area remained less than two centimeters square before and after aortic valve replacement were classified as having true mitral stenosis.

                                                The authors provide a number of maybe predictors, if you will, or correlates perhaps a more appropriately termed as such, of patients who would be generally believed as having true mitral stenosis. And these included, for instance, in the mitral valve area was less than 1.5 centimeters square at the time of presentation, if calcium involved at both the anterior and the posterior leaflet on echo. And there was also the concept of Andler excursion. So, basically the distance between the apex and the analyst of the mitral Valve, half of the patients had true mitral stenosis and the other half saw an increase in the mitral valve area above two centimeters squares after aortic valve replacement.

                                                I think still that we don't have an answer to the question as to whether the mitral valve should already be intervened upon in this series. It was an observational series, so there's no arm where the mitral valve was actually intervened on, and we know that often this intervention is not easy to do if it's by TAVR, there's not a lot we can do on the aortic valve and if it's at surgery, often these patients may have extensive mitral annular calcification, which is not an easy undertaking to fix at the time of surgery.

                                                So, whether these patients, even the ones with true MS are better served by just addressing the aortic valve or adding a mitral valve intervention in addition to the AS treatment still remains an unresolved or unanswered question. But I think this paper helps tremendously with regards to identifying patients who may have the true mitral stenosis concomitant problem at the time of presentation with a severe AS.

Dr James de Lemos:        This was news for me actually. The high prevalence of pseudo MS in this context, I think many of us are very familiar with this with aortic stenosis and low output, but to see this in the context of serial valve lesions was really instructive for me. Tim, what are your thoughts?

Dr Timothy Gardner:      I think this is a really important observation to remind ourselves of in this TAVR era. If you have the heart open and you're doing the aortic valve replacement and you notice this, you can get a picture of this severity of the mitral stenosis or the mitral valve involvement, but I think that in the TAVR era, this finding, this possibility of significant mitral stenosis related to a more severe aortic stenosis has to be accounted for and taken into account.

Dr James de Lemos:        Excellent. The next paper I'd like to talk about is another original article from Shudo and Joe Wu at Stanford. Remarkable series really of almost a thousand heart-lung transplants that were done and reported in UNOS. Tim, can you walk us through this paper and its implications?

Dr Timothy Gardner:      heart-lung transplantation was done first at Stanford and actually by one of my close colleagues. Bruce Reitz in 1981. It was a really an operation and in the tradition of the innovation there in transplant surgery at Stanford. The operation, primarily for patients with end stage lung and heart disease, was done reasonably often at adventuresome and well-experienced transplant centers in the eighties and nineties and it's used less often today because we found that even in patients with end stage lung disease and concomitant ventricular failure that many of those patients can be treated successfully with double lung transplantation.

                                                So, that has resulted in a decline in use of heart-lung block transplantation. The other problem is that as they mentioned in the article that a donor becomes available and you can get two or three patients treated by taking the individual lungs and the heart for three recipients rather than using the whole block for one. That's been another reason why it's been harder to get these heart-lung blocks. But for some patients with end stage heart disease and irretrievable lung disease, this is a great option. There's a few patients with end stage congenital heart disease who have developed irretrievable Eisenmenger's complex with severe pulmonary irreversible form of hypertension who are still candidates for this, but this analysis of the 30 year experience at Stanford and using the UNOS database as well is very interesting and shows the importance of donor selection as a really significant effector of outcomes.

Dr James de Lemos:        Yeah, well I was also struck by the recipient factors too. It looks like selection in both directions is so important. The group that was remarkable to me was the markedly poor outcomes in the group that had heart-lung transplant after ECMO, that five times increase in mortality. That really struck a chord, particularly given what we're seeing now with ECMO accelerating somebody's status on wait lists. I don't know Mark or Tim, do you want to comment?

Dr Timothy Gardner:      That's a very useful observation and where an individual patient ends up on the acuity list as a potential recipient with UNOS rules, it is ECMO support does get them to a higher level of urgency and yet, as is shown in this series, the morbidities or co-morbidities associated with a patient who requires ECMO support prior to transplantation is pretty consequential. And as you said, those were the features of the recipient, the degree of co-morbidities or co-morbidity complications also impact the outcome.

                                                We're still struggling to find the best way to deal with rescue patients both with mechanical support and with transplantation, organ transplantation, and even in the case of heart failure, with destination therapy with mechanical devices, we're still struggling in an area where the challenges are high, and the best practices are not always as well clarified as we would like.

Dr Marc Ruel:                    And I would echo those concerns. I think the prohibitive results that we see after ECMO reflect the reality that there's not a lot of intermediate therapies available for patients who require heart-lung transplants. We have them for the heart now. We can move from ECMO and not go directly to an LVAD or to a transplant because we have implantable axial devices that can be put in percutaneously and basically can arrest the inflammatory response and the major cascade derangements that we see with ECMO.

                                                Unfortunately that is not available to replace both the heart and lungs, so I think there's still some medical advances, surgical advances that are necessary to bridge the gap because that gap right now is real and it's not a gap, it's a cliff.

Dr James de Lemos:        Great discussion gentlemen. Let's talk next Marc, about a research letter that was a case series from Cleveland Clinic from Donnellan and Desai, focusing on a fairly large group of individuals that had received mediastinal radiation therapy previously and then underwent valve surgery for radiation-induced valve disease.

Dr Marc Ruel:                    We were happy to receive this research letter from the Cleveland Clinic because clearly that institution, and maybe a few others around the world, have a special expertise in dealing with the uncommon, but very, very challenging issue of patients with the surgical radiation-induced mitral valve disease. And in fact, radiation-induced carditis. On average, these were patients who were seen about 17 years after their chest irradiation and I guess the main message that can be seen from this paper is that there's often multiple cardiac issues in those patients. They don't just have, for instance, a single valve, in this case the mitral valve, being affected. But the vast majority all tolled of around 80, 85% of patients required not only either another valve, but valve plus bypass or bypass surgery to be performed as well.

                                                So, there are clearly patients where there's been a lot of physical/irradiation damage, not only to the mitral valve, but to the entire heart. It's also, when you look at this series of these 146 patients, you can see that many had an increase in the right ventricular systolic pressure on echo and probably some degree of RV dysfunction as certainly we've seen episodically in our practices.

                                                So, hospital mortality outcomes are pretty good, but the results are humbling. 51% mortality at 2.8 years. And these patients were on average 60 years of age. So looking at U.S. life tables, when someone's 60 years, I've made it to 60, they usually have at least another 20 years on average to live. But these unfortunate patients, despite their cardiac operation performed, having been performed safely, have about an 18% death rate per year.

                                                I think the jury's still out as to which are clear indications to offer these patients surgeries with the humbling results that we see even at a center of excellence by the Cleveland Clinic. But I think this is a foray into a very difficult cardiac problem for which there was limited literature before and certainly that's something that's very relevant as we refer to very advanced cardiac surgical therapies for patients with advanced disease.

Dr James de Lemos:        Mark, you're actually a coauthor on our State-of-the-Art piece, evaluating arterial grafts and CABG, reviewing after the publication of art and radial. What were the main conclusions from your review and interpretation?

Dr Marc Ruel:                    Essentially, there's a discrepancy right now with regards to the use of multiple arterial grafting. The observational series have almost uniformly showed that patients who receive multiple arterial grafts live longer and do better, et cetera, but I think this has to be taken for what it is. There's an inherent indication bias or confounding by indication that goes into allocating that therapy to patients who are perceived to have the potential to do well in the long-term. There may also be an expertise bias at the institutions that provide this and those patients may be receiving better secondary medical therapy or guidelines directed medical therapy, etc. So, maybe a halo effect that comes into play.

                                                In counterpart, the randomized control trials of which the latest was the arterial revascularization trial. Now available with data at 10 years, have shown essentially very little difference which regards to the use of multiple arterial grafts on long-term outcomes. Even looking at cardiac-specific outcomes like myocardial infarction. Actually the more compelling data came from their Radial Alliance, also led by Mario Gaudino who is the author of this, State of the Art paper.

                                                The conclusion of the article is that we need a trial and we need to include the radial artery. The answer may not necessarily lie with the use of mammary arteries, but it may be that the radial artery is more user friendly and more robust. So the new ROMA trial has been designed with that in mind. Comparing one arterial graft versus as many arterial grafts, as long as it's more than one in the test group that the surgeon wants to use. And the surgeon, she or he can use the right internal thoracic artery or radial artery in order to complete the revascularization.

                                                That trial is ongoing. Enrollment is on track and hopefully should provide answers to this very relevant question.

Dr James de Lemos:        You know that discussion about the limitations of clinical trials, Tim, I think leads really nicely into the frame of reference you received from Eugene Blackstone and Cleveland Clinic, doesn't it?

Dr Timothy Gardner:      Yeah, and it was really an article worth everybody reading. It's a short opinion piece and he points out the fact that we really have competing standards for choosing therapy. Sort of the standard traditional evidence based medicine, evidence-based medical care versus precision medicine which focuses on individual patients risk factors and so on. It's sort of the average treatment effect that we may be able to demonstrate well in randomized clinical trials versus real world experience with various therapies based on the risk profile of the patient. It's a really excellent article and as many of us know Gene Blackstone is a very thoughtful student of statistics in surgery and this is, I think, an excellent article. I'm really grateful for his doing this opinion piece for us.

Dr James de Lemos:        The last opinion piece we have is from Mike Farkouh in the group in Toronto. Can you just give the readers and listeners a bullet about what they might expect in that piece?

Dr Marc Ruel:                    I think it's one of the remaining big questions, if you will, in myocardial revascularization as to what should be done with diabetic patients in multi-vessel coronary artery disease who have an acute coronary syndrome and require revascularization. A very well written piece and certainly that instructs what probably the next five years we'll see in terms of big study questions in coronary REVASC.

Dr James de Lemos:        First I'd like to recognize Sarah O'Brien from the Circulation Editorial Office for her tremendous work for pulling this issue together. She's really the glue that brings this issue together every year and thank as well Marc, for your leadership again of this effort and Tim for your ongoing leadership at circulation with our cardiac content and vascular content as well as liaisoning with our surgical colleagues.

                                                Dr Marc, you get the last word. Can you please summarize the thoughts you'd like to leave our listeners with?

Dr Marc Ruel:                    Thank you, James, for your generous comments and also for your support of cardiovascular surgery in and of the team issue. I think again, we have a fantastic issue this year and we really want to gather the very best of cardiovascular surgery and we want to get the highest impact papers. Circulation is home for the best data, the best outcome, say the most interesting answers to important clinical questions that are around cardiovascular surgery.

                                                There's definitely an editorial desire to help with the best of cardiovascular surgery science. And I think I want to again launch a call to cardiac surgical investigators and cardiovascular and surgical investigators in general to consider circulation as your home.

Dr Timothy Gardner:      Yes. And if I could just add to that, not only are we interested in a surgery-themed issue annually that really highlights some of the best articles that we have to publish, but we also want some of the best surgery science during the course of the year. And just remind our surgeon colleagues that the particular advantage to having a paper published in circulation is the exposure of that study to a broad cardiovascular community. Not just surgeons, the predominant readership obviously of circulation, or cardiologists and other cardiovascular specialists. So that's the big advantage you get by having your best work published in circulation. We'd love to see more of it.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.


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