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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Now displaying: March, 2019
Mar 25, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, 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, associated editor from the Pauley Heart Center at VCU Health Sciences in Richmond, Virginia.

Dr Carolyn Lam:                A big number of acute ischemic stroke patients receiving endovascular therapy in the United States are receiving this therapy only after inter-hospital transfer. What are the temporal transient outcomes following this inter-hospital transfer? Very important discussion coming right up with our featured paper. But for now, sit back, relax with us. We're going to discuss a couple of papers that we found were interesting in this week's journal.

Dr Greg Hundley:             Very good, so thanks Carolyn. I'll start off, and I'm going to talk a little bit about stress induced cardiomyopathy, and we also know it as takotsubo cardiomyopathy, looking at a paper from Dana Dawson from the University of Aberdeen in the United Kingdom. Takotsubo cardiomyopathy can result in a heart failure phenotype with a prognosis comparable to myocardial infarction.

                                                In this study, the investigators hypothesize that inflammation is central to the pathophysiology in natural history of takotsubo cardiomyopathy. They prospectively recruited 55 patients with takotsubo cardiomyopathy, and 51 age, sex, and comorbidity match control subjects.

                                                During the index event, and at five months of follow-up, the patients with takotsubo cardiomyopathy underwent a cardiac MRI study in which they looked at ultra-small, super paramagnetic particles of iron oxide, or USPIOs, enhancement for detection of inflammatory macrophages in the myocardium. What would the studies show? Patients with acute takotsubo cardiomyopathy had macrophage-mediated myocardial inflammation.

                                                They also demonstrated modulation of peripheral monocyte subsets and increased systemic pro-inflammatory cytokines. This systemic inflammation persisted for five months, and then at that five-month time point, the cardiac MRI evidence of the macrophage presence was diminished.

Dr Carolyn Lam:                Wow, Greg. So this is right up your wheelhouse, isn't it? Can you explain? What are the clinical implications of these MRI findings?

Dr Greg Hundley:             It was really interesting. For the first time, they've linked an ongoing inflammatory process using the USPIO contrast agent with MRI actually going on or operative in the heart, and they associate that with systemic markers in the circulation.

                                                They help us elucidate the mechanisms and the pathogenesis of takotsubo cardiomyopathy, and systemic and myocardial inflammation really may start to now serve as a therapeutic target for patients with acute takotsubo cardiomyopathy.

Dr Carolyn Lam:                Very interesting. From stress-induced cardiomyopathy to early onset myocardial infarction. The first paper I chose really answers the question, "What is the relative prevalence and clinical importance of monogenic mutations, that is, a single mutation that significantly increases risk, versus a polygenic score, which really measures the cumulative impact of many common variants, in early onset myocardial infarction?"

                                                The co-corresponding authors were Doctor Amit Khera and Sekar Kathiresan and both from Massachusetts General Hospital, and they performed deep coverage, whole genome sequencing of more than 2,000 patients from four racial subgroups hospitalized in the United States with early onset myocardial infarction defined as myocardial infarction before the age of 55 years, and compared this to 3,761 population base controls.

                                                What they found was that a monogenic mutation related to familial hypercholesterolemia was identified in 1.7% of the patients, and associated with a 3.8-fold increased odd of myocardial infarction. In comparison, the high polygenic score, which was composed of 6.6 million common DNA variants and defined as the top 5% of the control population distribution, now, that was identified in 10 times as many patients, so 17% of patients, and associated with a similar 3.7-fold increased odds of myocardial infarction.

Dr Greg Hundley:             Interesting. How do we apply this clinically, Carolyn?

Dr Carolyn Lam:                These findings really lay the scientific foundation for the systematic identification of individuals born with a substantially increased risk of myocardial infarction. The important point is both familial hypercholesterol mutations and a high polygenic score are associated with more than three-fold increased odds of an early onset myocardial infarction.

                                                However, the high polygenic score cannot be reliably identified on the basis of elevated LDL cholesterol, and yet has a 10-fold higher prevalence among patients presenting with early onset myocardial infarction. So very intriguing that both groups matter.

Dr Greg Hundley:             Very good. My next paper is from Adrian Hobbs at the London School of Medicine, and is looking at the role of endothelial C type natriuretic peptide as a critical regulator of angiogenesis and vascular remodeling. We know that a central pathway coordinating both neovascularization and ischemic extremities in PAD is driven by vascular endothelial growth factor or VEGF-A4.

                                                But preclinical studies and other large scale clinical trials have been disappointing because administering or using VEGF-A to promote angiogenesis or arteriogenesis in PAD really hasn't occurred. This group focused on endothelial-derived CMP. Why? Because it plays a fundamental role in regulating vascular homeostasis. It controls local blood flow and the resistance vasculature, and systemic blood pressure, and reduces the reactivity of leukocytes and platelets.

                                                So, what were the results? Clinical vascular ischemia was associated with reduced levels of CMP and it's cognate NPR-C. Moreover, genetic and pharmacological inhibition of CNP and NPR-C reduced the angiogenic potential of the pulmonary microvascular endothelial cells and the human umbilical vein endothelial, and it isolated vessels ex vivo.

                                                So, the study really defines a central pathophysiological role for endothelium-derived C type natriuretic peptide via activation of cognate natriuretic peptide receptor C in angiogenesis and in vascular remodeling. Moreover, the work demonstrates the therapeutic utility of pharmacologically targeting NPR-C to restore deficits in these processes following ischemia and injury.

Dr Carolyn Lam:                Interesting, from new mechanisms and targets to good, old, major risk factors for coronary heart disease. Back to the basics but in a really, I think, nicely done paper from Dr Pencina and colleagues from Duke Clinical Research Institute.

                                                Now, their objective in this next paper was to compare the associations of key, modifiable coronary heart disease risk factors with incident coronary heart disease events based on their prognostic performance, the attributable risk fractions and treatment benefits overall and by age.

                                                And so really aiming at quantifying the importance of these major, modifiable risk factors for coronary heart disease. What they did is they used pool participant level data from four observational cohort studies sponsored by the NHLBI, and they created a cohort of more than 22,600 individuals ages 45 to 84 years old who are initially free of cardiovascular disease.

                                                And these individuals were followed for 10 years from baseline evaluation and followed for incident coronary heart disease. They estimated that age, sex and race captured up to 80% of the prognostic performance of cardiovascular risk models. When we add either systolic blood pressure or non-HDL cholesterol, diabetes or smoking to model with the other risk factors, the prognostic performance, as measured by the C index, increased by only 0.004 to 0.013.

                                                However, if you look at it from the attributable risk and absolute risk reduction standpoint, lowering the systolic blood pressure of all individuals to less than 130, or lowering LDL cholesterol by 30% would be expected to lower a baseline, 10-year coronary heart disease risk of 10% to 7% and 8% respectively.

Dr Greg Hundley:             That's a lot of data, Carolyn. Help me synthesize all that.

Dr Carolyn Lam:                This is a take-home message. Although the individual modifiable risk factors contribute only modestly to the overall model prognostic performance, when we eliminate or control these risk factors, they would actually lead to a substantial reduction in total population coronary heart disease.

                                                That's because if we look at the attributable fraction and the absolute risk reductions, we see that they actually really matter. The take-home message too from Dr Pencina was that metrics used to judge the importance of these risk factors should therefore be tailored to the question being asked.

Dr Greg Hundley:             Very good. That was a very nice summary, Carolyn.

Dr Carolyn Lam:                Thanks. Let's move on now to our feature discussion, shall we?

Dr Greg Hundley:             Very good.

Dr Carolyn Lam:                Trials have established that endovascular thrombectomy dramatically reduces disability after acute ischemic stroke due to intracranial large vessel occlusion. In fact, guidelines almost immediately adopted endovascular thrombectomy as a standard of care. However, that has created some problems.

                                                The main one being that hospitals equipped to carry out this procedure are largely limited to tertiary centers in urban areas. This is, of course, important because that means that patients may need to be transferred from another center to receive such treatment.

                                                Today's feature paper discusses this very issue, a terribly important one, and I'm so pleased to have the author with us, Dr Shreyansh Shah from Duke University Medical Center. We have our editorialist, Dr James Grotta who's director of the Mobile Stroke Unit project at Memorial Herman Hospital.

                                                And we have an associate editor, Dr Graeme Hankey from University of Western Australia. So, such an important topic. I think Shrey, could you just jump right in and tell us what your study showed.

Dr Shreyansh Shah:         I'm very excited to present findings of our study, and as a Carolyn mentioned, this study is going to have a very important implication in our country here in US on the creation of systems of stroke. I think the findings are already applicable to other countries also where we are seeing endovascular care getting more and more used.

                                                As Carolyn was talking, endovascular treatment is very important and lifesaving measure. But unfortunately, it is not available at every hospital. Patients are often transferred across different hospital or institution before they can receive this endovascular care.

                                                What we did in our project was we looked at the data from the hospital that's participating in Get With The Guidelines®® Stroke, which is a quality improvement program here in US. It looked at the endovascular thrombectomy used especially in relation to inter-hospital transfer.

                                                What we found was big proportion of patients receiving endovascular care, up to about 43% to 45% of patients, were getting the care after transferring across different hospital. The outcomes in this patient were worse compared to the patient who were receiving endovascular care if they had come directly to the hospital.

                                                While there was no difference in mortality between these two groups, the endovascular care, after inter-hospital transfer, resulted in a higher rate of symptomatic ICH, patients are less likely to be discharged to home, which is the preferred outcome. And patient was also less likely to be able to ambulate independently prior to the hospital discharge.

                                                There was also delay in endovascular care initiation for patient who received this after inter-hospital transfer. I think this particular study highlights the magnitude of this problem, and that's why it's going to be important for people who are studying systems of care. The fact that about 45% of patient had to get inter-hospital transfer before endovascular care tells us that we still need to take significant steps in increasing access to this lifesaving therapy.

Dr Carolyn Lam:                Thank you and indeed James, I really love the editorial you wrote that accompanied this. I mean you highlighted its importance, and you also noted that what was unusual about the paper was that even after controlling for the delay in initiating endovascular thrombectomy, there was still worse outcomes in the patients who were transferred. Could you share some thoughts?

Dr James Grotta:              It is a very timely issue. Now that we have a very effective treatment, the big challenge we have is getting it to the patients as fast as possible. Right now, our system, as is pointed out, means shuffling patients from one hospital to another.

                                                I think that clearly with stroke treatment, any sort of stroke treatment, the faster we deliver it, the better. Other studies have shown that transferring patients is associated with a delay of treatment, and this study showed the same thing.

                                                There was a substantial delay in getting the patients treated if they required a transfer. And as you pointed out, however, this did not explain the entire or was not at least the entire explanation for the worst outcome. So, it is a little bit of a mystery.

                                                I do know from personal experience that transferring patients from hospital to hospital, it's not exactly a black hole, but you lose control of the patient when they're being transferred. These are patients who have large artery occlusions. That means they have their middle cerebral artery is blocked.

                                                And so, the area of brain that's affected is in a very tenuous shape. So, any drop-in oxygen concentration from breathing problems or of any drop-in blood pressure might further worsen the stroke. So, this could happen in transit. So, it's possible that in the process of transfer, these sorts of things happen.

                                                I do think that we do have to be a little bit careful in that by remembering that this was not a randomized comparison, so patients that were treated directly and those that were transferred were not randomized. And so, although they appear to be balanced in a lot of the important variables like their stroke severity, there may be other things that we can't account for that could explain some of the worst outcomes.

                                                I'd like to ask Dr Shah whether he identified any things in ... well, he and his co-authors think might have contributed to some of the worst outcomes.

 Dr Shreyansh Shah:        To answer Dr Grotta's question about what other factors may have played a role in the worst outcome that we saw in patients who were getting inter-hospital transfer, I think as we correctly pointed out, transferring this very sick patient is very tricky. As we know, the hemodynamic instability or variability plays an important role in outcomes of stroke patient.

                                                And it is very likely that during the transfer process, there is not adequate control of their blood pressure variability, their oxygen saturation, and this ends up affecting their brain leading to worst outcome. The other possibilities also, as Dr Grotta was explaining, this is not a randomized control trial.

                                                And although we balance for number of important factors that can affect stroke outcome, there might be a selection bias in transferring patient who are more sicker and also patients who received thrombolysis with TPA but did not improve, while the patient who were directly arriving to the hospitals and getting endovascular care, they received the TPA.

                                                It is possible that they started to improve and still received a thrombectomy at the same time. So that group may have been more favorable in that respect, which could have also played a role in better outcomes with patient who are directly arriving.

Dr Carolyn Lam:                Interesting. And, you know, with the mention of TPA, I really have to bring James back. I loved your mention about potential solution using mobile stroke units. And since you direct one of them, could you tell us what you meant there?

Dr James Grotta:              Yes, of course, I have to state at the outset that I have a little bit of a bias about mobile strokes, and so I do it every day. What a mobile stroke unit is, for those who don't know, it's basically taking the emergency department to the patient.

                                                It's an ambulance with a CT scanner on board and the ability to treat with TPA in the field. But in addition, it's also the CT scanner. We can do CT angio and identify large vessel occlusions on the mobile stroke unit, not to mention the fact that you have a vascular neurologist either in-person or by telemedicine examining the patient.

                                                So clinically, you can make the determination also much more accurately than any sort of pre-hospital stroke scale, whether the patient has a large artery occlusion. That way, you don't have to take the patient to the nearest hospital. You can bypass the nearest hospital, take them right to the thrombectomy center, therefore, avoiding the transfer process.

                                                We've been implementing this in Houston, and there are now about 30 mobile stroke units around the world. The innovation actually started in Germany by Dr Fassbender about a decade ago in Hamburg, Germany. We are conducting a randomized trial, comparing mobile stroke unit care to standard management to see how much better outcomes occur as a result of this faster treatment.

                                                We obviously can treat patients with TPA faster. For example, a similar study from the Get With The Guidelines® a few years ago showed that only 1% of patients treated with TPA in emergency departments get treated within the first hour after symptom onset simply because it takes an hour in the emergency room itself to do the evaluation of the patient and get them treated.

                                                Whereas on our mobile stroke unit, at least a third and probably 40% of the patients we're treating with TPA, we can get treated within that first hour where there may be an exponential better benefit. But we don't yet know really how much that translates to better benefit, and also, of course, mobile stroke units are more intensive in terms of the amount of facilities on board and costs.

                                                So, we need to look at the cost-effectiveness. If it produces only a marginal reduction in disability but costs a fortune, then it's not worth it. But in fact, in our experience, it's pretty practical. We can cover almost the entire City of Houston, which is the fourth largest city in the country, with one mobile stroke unit. When it's well-integrated, it requires careful integration with the fire department and other hospitals in the city.

 Dr Shreyansh Shah:        At those two conferences, I came across a very interesting talk from Dr Grotta's group about rendezvous with the EMS which allows extending their coverage area significantly. I think we definitely need more and more innovative solutions like this where we can identify patients by their origin, whether they have large vessel occlusion or not, and then triage them appropriately at the centers that can perform endovascular therapy. So as a result, we can provide them earlier therapy and hopefully, it will lead to better outcome.

Dr Carolyn Lam:                Thank you Shrey and James for these incredible insights. Now, Graeme, I want you to have the last word and reflections from down under.

Dr Graeme Hankey:        Firstly, just to congratulate Dr Shrey and colleagues on this terrific study that reports a contemporary United States experience, a very broad one across the country, really highlighting how since 2012, until a year ago, there's been a six-fold increase in the number of patients being transferred for endovascular therapy.

                                                And we're all experiencing that around the world. And moreover, since the DAWN trial and the DEFUSE trial were published just over a year ago, which is when this study stopped, there's been an expansion of the window from six hours out to 24 hours.

                                                So, in the last year, which this study doesn't cover, we've seen an exponential increase in the number of people being transferred from rural and remote areas who have had a stroke up to 24 hours ago being considered for endovascular therapy if their CT angiogram at the base hospital shows a large vessel occlusion.

                                                This is likely to be not only internally valid, but externally valid to all of us around the world. It reflects our experience of this avalanche of cases coming. And it's provided a lot of challenges for those who are trying to deliver the service at the tertiary referral center.

                                                And it highlights that nearly half of the cases who are having endovascular therapy are coming from external sites. As Jim has really highlighted in his editorial, it challenges us to reassess the current practice of inter-hospital transfer.

Dr Carolyn Lam:                Thank you so much for publishing this paper with us and the editorial. And listeners, don't forget to tune in again next week. This program is copyright American Heart Association, 2019.


Mar 18, 2019

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

Dr Greg Hundley:             And I'm Greg Hundley, also Associate Editor from the Pauley Heart Center in Richmond, Virginia, VCU Health Sciences.

Dr Carolyn Lam:                How well are we doing with guideline-directed stroke prevention therapy in atrial fibrillation? Well, there are going to be very important results that you need to hear about from Get With the Guidelines Atrial Fibrillation. That's our feature paper coming right up in a future discussion. But first, you've got Greg and I discussing really important papers that we've spotted in The Journal. Greg.

Dr Greg Hundley:             Absolutely, Carolyn. And my favorite kind of follows from that 'cause it's really about left atrial electromechanical remodeling following two years of high intensity exercise training in sedentary middle-aged adults, kind of like me. The studies from Ben Levine at University of Texas Southwestern Medical Center in Dallas. So, what he's driving at here are moderate-intensity exercises associated with a decrease in incidents of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk.

                                                So, in this study, they're looking at the effects of 24 months of high-intensity exercise training on left atrial mechanical as well as electrical remodeling in sedentary, healthy, middle-aged adults. So, he had 61 individuals, their average age was 53.5 years, quite young, who were randomized to 10 months of exercise training followed by 14 months of maintenance exercise and some stretching or stretching and balance control. He also had another group of 14 master's athletes that were added for a comparison and he looked at three of the echocardiograms to assess left atrial and left ventricular volumes and also had signal average EKG's for filtered P-wave durations and atrial light potentials. He made assessments at baseline, so before everyone started, and 10 and 24 months.

Dr Carolyn Lam:                Hold on, hold on. Let's really understand here how much exercise were these sedentary middle-aged adults subjected to.

Dr Greg Hundley:             So, let's talk about that because that was very interesting because a lot of us are out there exercising. So briefly the way he started this, there was an initial phase that was comprised of six months of regressive training during which an increase in the frequency, the duration, and the intensity of exercise, including two high-intensity aerobic interval sessions per week that were prescribed to peak training load. The peak training load included five to six hours of exercise per week that included two interval sessions, at least one being an hour-long session, and then two 30-minute sessions.

                                                Once you got that peak training load, that was sustained for four months and then he made these 10-month measurements as part of his study design. Now following that phase, a 14-month sort of a continuation, all of the 24 months, a 14-month period of maintenance exercise was completed where the frequency of high-intensity intervals was reduced to once per week plus continuous training all the way to that 24-month time point. And during the maintenance phase, participants performed a total of about three hours a week of aerobic exercise.

Dr Carolyn Lam:                Well, don't keep us in suspense now. What did the study show?

Dr Greg Hundley:             So at the 24 month time point of high-intensity exercise, it led to a disproportionate dilation of the left atrium compared to the left ventricle. So, mechanical changes, but no electrical remodeling was seen. And interesting, and remember he had that comparison cohort with master's athletes. Those participants randomized exercise training demonstrated lower absolute left atrial and left ventricular volumes, but a similar left atrial to left ventricular ratio after 24 months of exercise training.

                                                So, what's going on here, if you're middle-aged or young, some of us like to think, and you start one of these aggressive training sessions, you do have some changes mechanically in the shaping of your left atrium and left ventricle, but they're concordant, but no electrical remodeling that was observed in this situation. So, how do those elite athletes develop atrial fibrillation in the electrical remodeling? Don't know. It may be they need a longer duration of exercise. Maybe they start at a different time point because these are relatively sedentary individuals, and maybe their training regimen is very different.

                                                So, more research is needed, but it was interesting that these middle-aged folks that start with this little bit more aggressive regimen really didn't develop the electrical remodeling. So, Carolyn, you've got a couple of papers that are sort of tied together.

Dr Carolyn Lam:                Indeed. A couple of papers centered on lipoprotein little A. Now, we know that lipoprotein little A levels predict the risk of myocardial infarction and this has been shown in populations of European ancestry, however there's very little data available in other ethnic groups. And so, this was addressed by Dr Paré from McMaster University and the Interheart Investigators who looked at more than 6000 cases of first myocardial infarction and more than 6800 controls, all from the Interheart study, and were stratified by ethnicity and included African, American, Chinese, European, Latin American, South Asian, and Southeast Asian ancestries.

                                                Lipoprotein little A concentration was measured in each participant, first using an SA that was insensitive to iso-form size and then iso-form size itself was also assessed by Western Blot in a subset of more than 4200 participants. So, what they found was that lipoprotein little A concentration and iso-form size varied markedly among the ethnic groups. Africans had the highest concentrations with the smallest iso-form size whereas Chinese had the lowest concentrations with the largest iso-form size.

                                                Furthermore, higher lipoprotein little A concentrations were associated with an increased risk of myocardial infarction and carried an especially high population burden in South Asians and Latin Americans. And a high concentration above 15 milligrams per deciliter was associated with significantly increased risk of myocardial infarction in all populations except Arabs and Africans. The iso-form size, on the other hand, was inversely associated with lipoprotein little A concentrations and did not significantly contribute to the risk.

Dr Greg Hundley:             So, Carolyn, how do we use this clinically? I mean, do we measure this in folks?

Dr Carolyn Lam:                Yeah. So, there are two take-home messages. I think one is about the monitoring or measuring and it supports a clinical use of the actual lipoprotein A concentration rather than iso-form size as a marker of myocardial infarction in this ethnically diverse population. But this is, other than Africans and Arabs where, remember that cut off did not seem to associate with a risk of MI's in these two ethnicities. The second take-home is that the effects of clinical interventions that reduce lipoprotein A should be investigated especially in South Asians and Latin Americans where the population attributable risk is really high. And that actually brings me to the second study.

                                                So, we've always been looking for intervention that can reduce lipoprotein A and this current paper is really interesting 'cause it talks about insights from the Fourier trial. So, we may finally have a therapy that can reduce it. Dr O'Donoghue from the TIMI study group and Brigham and Women's Hospital in Boston, Massachusetts and colleagues looked at the relationship between lipoprotein A levels, PCSK9 inhibition, and cardiovascular risk in the Fourier trial, which you remember is a randomized trial of Evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease.

                                                So, they found that patients with a higher concentration of lipoprotein little A were at increased risk of coronary events independent of the LDL concentration. And individuals with a higher baseline LP little A concentration tended to have a greater relative and absolute coronary risk reduction with Evolocumab and therefore a lower number needed to treat. It was as low as four T for individuals with a lipoprotein A above the median versus 105 number needed to treat for those at or below a lipoprotein A level below the median.

Dr Greg Hundley:             So should we start checking this in all our patients now, these lipoprotein little A levels?

Dr Carolyn Lam:                Yeah. So, this issue was discussed beautifully in a company editorial by Dr Thanassoulis from McGill University Health Center. And here he mentions that there remains tremendous clinical inertia honestly for the measurement of lipoprotein A in North America and in fact, worldwide. For this to be successful, we really need to be proactively screening our patients with myocardial infarction and stroke and especially those with premature events or a family history. And particular attention will need to be made on screening individuals with recurrent events despite adequate lipid or LDL lowering who frequently may still have high lipoprotein little A. It's encouraging to know that the most recent version of the US Lipid Guidelines has newly recommended LP little A measurements in select individuals as a risk enhancer and so this should further raise awareness of lipoprotein little A as a risk marker.

                                                Finally, the editorialist mentioned that common misconception that we have a lack of therapeutic options to lower high LP little A. Still, we need to remember that these individuals may obtain significant benefit from more aggressive lifestyle modifications. And now we have these results of this trial that suggest that PCSK9 may be one of the few drugs that can lower lipoprotein little A. And so, the editorialist actually ended with targeting therapy for lipoprotein A is around the corner and a test of this hypothesis is really imminent, so we should watch this space.

Dr Greg Hundley:             Yeah, so it sounds like another wonderment of PCSK9 inhibitors.

Dr Carolyn Lam:                Yeah.

Dr Greg Hundley:             Well Carolyn, let me jump in and finish our chat here talking about iron. This particular paper is from Dr Jean-Sébastien Silvestre from Paris, France, and he's looking at the iron regulator Hepcidin. So, we know that iron deficiency is frequent in patients with coronary artery disease and increases morbidity in those with high risk profiles such as those with diabetes and anemia and then conversely, excess iron is also detrimental to cardiac function. We see this with iron overload cardiomyopathies and as a major co-morbidity in patients with genetic hemochromatosis.

                                                So, among the multiple regulators of iron homeostasis is Hepcidin. It plays an instrumental role in fine-tuning systemic iron trafficking by modulating the transfer of dietary, recycled, and stored iron from intracellular compartments to extracellular fluids. Hepcidin is a catatonic peptide hormone. It's produced primarily by hepatocytes, but also, it's produced in macrophages. So, given the role of Hepcidin to locally regulate cardiac function and that inflammation guides cardiac remodeling after acute MI, the investigators hypothesized that inflammatory macrophages may control cardiac repair through a Hepcidin-dependent mechanism. And until now, the role of Hepcidin in some other cardiac diseases challenged by inflammation hasn't really been explored.

Dr Carolyn Lam:                Huh, interesting. So, what did they find?

Dr Greg Hundley:             Great question and let's lead to the main results of this study. The hormone Hepcidin, they found, was produced by a distinct sub-population of inflammatory cardiac macrophages residing in infarcted heart tissue and the deletion of Hepcidin in macrophages improved tissue remodeling and stimulated cardiomyocyte renewal in both, just as our wonderful basic science studies have, in both adult mice with myocardial infarction, neonatal animals with apical resection and also in human subjects. And so, this study provided novel insights into the complex roles of the immune response during cardiac repair following MI and suggests and deleterious role for the macrophage-derived Hepcidin in cardiac repair.

                                                Interesting, Carolyn. Another role for iron in acute MI and more research to come.

Dr Carolyn Lam:                Indeed. Well, thanks Greg. Let's move on to our feature discussion, shall we?

                                                For our feature discussion today, we are talking about the first results from the Get With the Guidelines atrial fibrillation. That is huge, and I have none other than the first author, Dr Jonathan Piccini from Duke Clinical Research Institute, as well as Dr William Lewis from Case Western Reserve University here to discuss these really important results, so listen up. I think to start with it is such an honor to have you with us, Bill. I mean, as Chair of the Get With the Guidelines atrial fibrillation work group, could you give us a background on how did this start? How far has it come?

Dr William Lewis:             The Get With the Guidelines program started in 2000. Greg Fonarow figured out that if we put in place mechanisms to improve adherence, that we could get people on appropriate therapies. In 2012, there was some focus on atrial fibrillation and I had been participating in the program since 2004 and I kept telling them that A-fib was a big, big problem. And in 2012, they said, "Let's do this," so we built this program to try to improve adherence in atrial fibrillation. Get With the Guidelines is a national, hospital-based, quality improvement program that improves adherence to guidelines over time and it has been very successful at doing that.

                                                So, by 2013 we were ready to start enrolling patients and we started getting patients in the database and we're now up to about 162 hospitals nationwide, in the United States, and we've enrolled about 75000 patients in the program. So, it's been very successful from that standpoint.

Dr Carolyn Lam:                Congratulation. And today we're actually going to be talking about that very question you asked. Adherence. How well are we adhering to guideline-directed stroke prevention therapy for atrial fibrillation? Jonathan, wanna share the key results?

Dr Jonathan Piccini:         I think you're getting exactly to the point of what was the rationale for this study and I think most individuals that are familiar with the field and atrial fibrillation and also clinicians across the world who are treating patients with atrial fibrillation know that most large reports, most nationwide studies have shown that adherence for oral anticoagulation to prevent stroke in patients with atrial fibrillation usually ranges in the 50, 60, 70 percent range at best. And there's been some notable publications in the past several years from nationwide registries that have shown rates as low as 50 percent or lower in high-risk patients. So, one of the main goals of the program, as Bill articulated, was to try and improve the use of oral anticoagulation in patients who had a guideline recommendation. So, patients who had a CHA2DS2-VASc score of two and higher with atrial fibrillation.

                                                And so, looking at over 30000 admissions between 2013 and 2017 and the guidelines A-fib program, we saw that just under 60 percent of patients who had known AF at the time of admission were on oral anticoagulation. And not surprisingly, the patients who were on oral anticoagulation had lower rates of stroke during their hospitalization. But the major finding from the program was that in this quality improvement program, the program was able to improve adherence to oral anticoagulation at discharge from 60 percent to admission all the way up to 93.5 percent in the overall cohort. And if you looked at results over time, adherence improved from 80 percent at discharge all the way to 96 percent and those improvements were sustained in follow up as well.

Dr Carolyn Lam:                Could you tell us, what do you think are the key elements that help this improvement? Is it just because there's a program and people know they're being watched? Is it that there was a change? I mean, when you say oral anticoagulants I bet you mean both Warfarin and the newer oral anticoagulants, so how much did that help? What do you think is the key ingredient here?

Dr Jonathan Piccini:         It was several things. Having visited several of these hospitals and spoken with them about the impact of the program, I think you can't emphasize enough that if you don't measure something, you can't really expect to improve it. So, just the fact that hospitals were having systematic data on their atrial fibrillation patients at discharge illustrating who was and who was not getting oral anticoagulation makes a big difference. Between the program itself and the conferences affiliated with the program and teaching sessions affiliated with the program, there's a heavy emphasis on education of the importance of guideline recommended treatments for atrial fibrillation, so that's a second component.

                                                And then there's an iterative relationship between the sites and the American Heart Association where improvements in the rates of oral anticoagulation are recognized and celebrated. And I think it's not any one thing, in my opinion. I think it's all of those things taken together. And again, Bill, who's been with the program since its inception probably has additional thoughts on that as well.

Dr Carolyn Lam:                Bill, did you expect such remarkable results?

Dr William Lewis:             No. I actually didn't expect 96, but in a previous study where we were looking at patients who had had a stroke in the stroke database, we were able to achieve 93 percent adherence. And so, 96 is remarkable and it's the highest number that's ever been seen in any A-fib program. I was going to mention about the idea of what makes the special sauce, if you will, and I think John put forth a number of items. I think, again, celebrating success, those kinds of things, but I think that docs, by their very nature, are very competitive and when you get a data report that says you're doing x percent and somebody else is doing y percent and their percentage is higher, you tend to get motivated to actually do better. And so, we provide these reports in the program to hospitals so that they can measure their success against other institutions.

Dr Carolyn Lam:                That's such a good idea. And, you know, I practice here in Asia and there aren't these very massive programs that are accepted in many places. So, what do you think is the generalizability of something like this?

Dr Jonathan Piccini:         That's such a critical question because a limitation is that these are hospitals that are saying voluntarily, "We want to commit to the program because we think quality care for atrial fibrillation patients is important." And so, you could argue that, well, these results really don't generalize to your run of the mill hospital in different parts of the world. And I think while that's a limitation, it's also a call for what the next steps are. So, having visited many of these hospitals, these are real hospitals of brick and mortar that face many of the same challenges other health systems and hospitals across the world do and I think the key message is that a hospital that implements these types of interventions is very likely to see the same improvement with their patients. And so, I think that's a very important message and a very positive message for patients all over the US and all over the world.

Dr William Lewis:             I agree. I think it's, not turn-key, it's much more generalizable than we had ever expected. So, community hospitals do this. The American Heart Association is using other Get With the Guidelines programs in China. I think that there is a lot that has to do with the support that's provided by the program and the tools that are made available to them to be able to make it so that you can recreate it in a hospital. I agree, it is more difficult in some hospitals than others.

Dr Carolyn Lam:                John, before we end, what are the take-home messages for clinicians listening out there?

Dr Jonathan Piccini:         I'd have two messages. The first message is that this study shows that with some assistance any healthcare system or hospital can achieve optimal adherence to these medications for their patients and thus in so doing achieve a significant benefit for the public health. And the second message I would have, which isn't necessarily specifically related to the paper, but I think it's equally important, that this is just the beginning for the American Heart Association and the Heart Rhythm Society Get With the Guidelines A-fib registry. Though stroke prevention is obviously just one of many different aspects of quality care for atrial fibrillation and so keep an eye out 'cause you'll be seeing a lot of studies coming out about how Get With the Guidelines A-fib is better informing care and treatment for atrial fibrillation across many different therapy domains, including catheter ablation and rate control and other interventions for rhythm control. And again, on behalf of all the co-authors and the American Heart Association, the Heart Rhythm Society sponsors, we really appreciate to have the opportunity to talk about the program.

Dr Carolyn Lam:                Thank you so much for sharing that with us.

                                                Audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Mar 11, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. 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 and director of the Pauley Heart Center at VCU Health, in Richmond, Virginia.

Dr Carolyn Lam:                So Greg, are ARNI's now going to be used for functional, mitral regurgitation and heart failure? Well, we're going to be chatting all about that with our feature paper, coming right up after these summaries.

                                                Greg, you've got a biggie to start with, haven't you?

Dr Greg Hundley:             Oh yes, Carolyn, I'm really excited about this paper. The senior author Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas and looking at high phosphate diets and their relationship to exercise intolerance. I really felt this was an exceptional study and combining that key that we have, for basic science papers and translation, where we're looking at data from both human and basic science, in both in a single manuscript.

                                                So, this study focuses on inorganic phosphates and they are present in 40-70 percent of the foods, really as a preservative enhancer, in western diets. We see it in colas, meats, dry food mixes, bakery products.

                                                For the human subject component of this study, the investigators examine the relationship between physical inactivity, assessed with ActiGraphs that were worn, and serum phosphate levels. They also obtained MRI measures of cardiac function and participants were recruited from the Dallas Heart Study too.

                                                In animals, they looked at the direct effects of dietary, inorganic phosphate on exercise capacity, oxygen uptake, serum non-esterified fatty acids, and glucose was measured during exercise treadmill tests in mice fed either high inorganic phosphate diets or normal in-organic phosphate diets. And they were on that for 12 weeks.

                                                To determine the direct effect of phosphate on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in the differentiated myotubes were conducted after subjecting those cells to media with high or low phosphate conditions.

Dr Carolyn Lam:                So, what did the study show?

Dr Greg Hundley:             In the human part, among 1603 participants, higher serum in-organic phosphate was independently associated with reduced time spent in moderate to vigorous physical activity and increased sedentary time. And interestingly, there was no association between serum phosphate levels and left ventricular ejection fraction or volumes.

                                                In the animal studies, mechanistic insight was obtained. Compared to controlled diets, consumption of high phosphate diet for 12 weeks did not alter body weight or left ventricular function, thereby confirming what we saw in the human subjects, but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, fatty acid levels, and led to down-regulations of genes involved in fatty acid synthesis.

                                                So, the take-home on this is that the results of this study demonstrate a detrimental effect of dietary, phosphate excess on skeletal muscle, fatty acid metabolism, and exercise capacity, which is independent of obesity and cardiac contractile function.

                                                And as such, dietary in-organic phosphate may represent a novel and modifiable target to reduce physical inactivity associated with the western diet. I think, Carolyn, we're going to see a large number of epidemiologic studies that are going to really look at this as something we might be able to modify in our diet to help impact some of these sedentary lifestyles and the harmful cardiovascular effects that we find associated with that lifestyle.

Dr Carolyn Lam:                Yikes. Remind me again, so phosphates in colas, meats, dried food mixes, and bakery products and so on, the preservative. Wow, you're right; big paper.

Dr Greg Hundley:             It's amazing. It's in 40-70 percent of the food products here in the United States. So, wow. Something really striking. So Carolyn, how about one of the papers that you liked?

Dr Carolyn Lam:                Moving to related cardio metabolic disease, we know that patients with type 2 diabetes and prevalent atherosclerotic cardiovascular disease, there is a tenfold variation in future cardiovascular risk in these patients. The current paper actually analyzes data from EMPA-REG OUTCOME where the authors, led by David Fitchett from St. Michael's Hospital in Toronto, sought to investigate whether the beneficial effects of Empagliflozin, observed in the EMPA-REG OUTCOME trial, varied across the spectrum of baseline, cardiovascular risk.

                                                What they found was that in patients with type 2 diabetes and atherosclerotic cardiovascular disease, the relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE, and heart failure hospitalizations with Empagliflozin versus placebo, were consistent in patients with and without a prior, myocardial infarction, with and without a prior stroke, and across sub-groups by the 10-point TIMI Risk Score for secondary prevention at baseline.

Dr Greg Hundley:             Does this suggest, Carolyn, that we use these inhibitors in all patients with type 2 diabetes?

Dr Carolyn Lam:                Remember the EMPA-REG OUTCOME; all patients had established atherosclerotic cardiovascular disease. This paper really adds to the understanding of the gradient of risk within these patients who had atherosclerotic cardiovascular disease and says Empagliflozin could be beneficial. But remember, there are patients with type 2 diabetes without established, cardiovascular disease and I think there's still equipoise in this primary prevention population.

Dr Greg Hundley:             That was great, Carolyn. Now I'm going to grab another sip of coffee and go onto my next paper.

Dr Carolyn Lam:                Sure, as long as it's not cola. No phosphates.

Dr Greg Hundley:             Right, thank you very much, Carolyn. I'm going to talk about screening for small and medium abdominal aortic aneurysms. This particular study comes from the surveillance of the National Health Service screening program by Dr Earnshaw. Basically, population screening for abdominal, aortic aneurysms has been shown to reduce AAA-related mortality by up to 50%. Most men who screen positive have a AAA below 5.5 centimeters in diameter, and that's really our current referral threshold for treatment. When they have smaller diameter aneurysms they're entered into an ultrasound surveillance program.

                                                In this study, the investigators looked and reviewed those that had small, 3-4.4 centimeter diameter aneurysms or medium ,4.5 up to 5.4 centimeter aneurysms, and they were followed. They were looking at the risk of rupture in these under surveillance.

                                                They had a total of 18,652 men and the risk of rupture overall per annum was 0.03% for men with small, abdominal aortic aneurysms and 0.28% for medium size. That was just below the threshold for the 5-5.4 centimeters, which was 0.4% over time. The risk of abdominal aortic aneurysm surveillance is below .5% per year and that is just below our current referral threshold for surgery, which is 5.5 centimeters.

                                                This is a study that really confirms, Carolyn, that the target mark or diameter that we've selected is appropriate.

Dr Carolyn Lam:                Nice. These just confirm the current guidelines?

Dr Greg Hundley:             Yeah, they do and Gil Upchurch from University of Florida, a surgeon, had a very nice editorial. The point he wants to make is yep, diameter of 5.5 is the threshold, but a couple key points. As patients are coming in for these visits, we need to continue to emphasize to them other factors related to growth of abdominal aortic aneurysms and their rupture. So, tobacco cessation, treatment of your lipids, management of your hypertension.

                                                The other point that he makes, is we really don't need to be operating on those individuals with an abdominal aortic aneurysm diameter of less than 5.5 centimeters. He makes an argument here that's in some countries with fee-for-service reimbursement, up to 30% of AAA repairs are for aneurysms less than this diameter of 5.5 centimeters. This over utilization of resources can add considerable costs to the healthcare system for managing this condition and is unlikely to increase the overall survival of these patients.

                                                A nice study confirming that what we're doing, really in terms of size and diameter, is correct, but also emphasizing this patient population often has a lot of other cardiovascular co-morbidities that we need to aggressively manage. How about your next paper?

Dr Carolyn Lam:                From one very clinically, applicable paper to another. This one answers the question, what's the optimal duration of emergency department and post-emergency department rhythm monitoring among patients with syncope. And the authors, led by Dr Thiruganasambandamoorthy and his colleagues from the Ottawa Hospital Research Institute, prospectively studied adults presenting within 24 hours of syncope at six emergency departments. They collected baseline characteristics, the time of syncope, the time of emergency department arrival, and the Canadian Syncope Risk Score, risk category. They followed subjects for 30 days and adjudicated the primary outcome, which was serious arrhythmic conditions and that includes arrhythmias or interventions for arrhythmias and unexplained death.

                                                Their results showed that the overall arrhythmia risk, and the risk after two hours of emergency department arrival from Canadian Syncope Risk Score, low-risk patients, was indeed very low. Similarly, the overall risk and after six hours of emergency department arrival for medium and high-risk patients was moderate and high, respectively. No low-risk patients suffered ventricular arrhythmia or unexplained death and most of the arrhythmias among the non-low-risk patients occurred within 15 days of the index syncope.

Dr Greg Hundley:             Carolyn, what's the take home message here?

Dr Carolyn Lam:                The results really support brief monitoring in the emergency department for two hours for Canadian Syncope Risk Score low-risk patients, and six hours for medium and high risk patients followed by selective admissions and the results also support a 15-day outpatient monitoring for medium-risk patients at a selected threshold and for all high-risk patients. So very practical advice.

Dr Greg Hundley:             Very good. Until next week, I'm going to watch out for phosphates.

Dr Carolyn Lam:                Indeed, and let's go on now to our featured discussion.

                                                For today's featured paper, we are discussing the results of the PRIME Study and that is Angiotensin Receptor Neprilysin Inhibitor, or ARNIs, for functional mitral regurgitation. A terribly interesting study. So pleased to have with us an author Dr Sung-Hee Shin from Inha University Medical center in Incheon, Korea as well as our associate editor Dr Victoria Delgado from University of Leiden in the Netherlands.

                                                Sung-Hee, what an interesting study. ARNI or Entresto for functional mitral regurgitation. Could you tell us what inspired this study and what did you find?

Dr Sung-Hee Shin:            Our study was the designed to tell if ARNI or functional mitral regurgitation because secondary functional mitral regurgitation was developed as a result of a reduced function. Guideline-directed medical therapy for heart failure would be a mainstay for a therapy.

                                                But despite use of the traditional drugs such as BETA blocker, ACE inhibitor or angiotensin receptor blockers, you know that the functional mitral regurgitation may be common and significant in the person having this functional mitral regurgitation would be related to increased morbidity and mortality.

                                                So, that trial showed that trans-catheter mitral valve repair effectively reduced the function mitral patient and resulted in lower rate of heart related mortality among patients with heart failure and function mitral regurgitation.

                                                In our blind trial, we also tried to tell whether an ARNI is more effective in improving function mitral regurgitation and randomly assigned 118 patients with heart failure and chronic secondary function mitral regurgitation lasting more than six months despite medical therapy and ejection fraction between 25% and 50% to receive either sacubitril/valsartan or valsartan in addition to standard medical therapy for heart failure.

                                                What happened with that change of mitral regurgitation after 12 months which was assessed by means of transthoracic area ways echo. What we observed was that transthoracic area as well as the volume of mitral regurgitation saw a decrease much more effective in the sacubitril/valsartan group than valsartan group.

                                                We also looked at the various other measures of the left ventricle remodeling and showed that the valsartan group had smaller left ventricle volume at 12 months and had a greater reduction of end-diastolic volume index.

                                                Also, among the completers ARNI, for the reduced left ventricle volume and the yearly time than the control group. So, what we think is that these factors might contribute to greater reduction of function mitral regurgitation in patients in the sacubitril/valsartan group.

                                                But our study was a mechanism study, but it was not designed to see outcomes. So further research and data would be necessary to check is this transthoracic echo end point can translate into better outcome in this population.

Dr Carolyn Lam:                Sung-Hee, this is just so interesting to have hypothesized this about functional mitral regurgitation. And not only that, I mean, to my mind, this is the largest echo-based studies of patients before and after Entresto that I can think of. It's nice to know, on top of knowing in paradigm that we can improve outcomes in heart failure reduced ejection fraction, that we now can look at the heart and see what happens in so many dimensions.

                                                So, congratulations.

                                                Victoria, were you surprised by these results? And do you agree with the mechanisms that Sung-Hee suggested?

Dr Victoria Delgado:        I think that this study is very important because in the field of functional mitral regurgitation, there is still a lack of consensus on how to treat these patients, which are very challenging.

                                                If the patient needs revascularization they will be referred for certain. But it still should be CBR mitral regurgitation and moderate and mile mitral regurgitation are not considered.

                                                I think that we discuss often which is the optimal medical therapy or the guidelines based medical therapy but it's not really consensus because the studies before have not been like this one. That large in order to answer a specifically that question.

                                                I think that this article brings an important message and brings more evidence to our field that there is not that much data. So, I think it's very important for that research, in particularly after the research of the co-op and the mitral trial where it seems that the selection of patients is very important in order to identify the patients that will really benefit from those therapies.

Dr Carolyn Lam:                That's such a good point. Going to that selection of patients, Sung-He, you mentioned very carefully the ejection fractions that you allowed up to 50% in these patients. Could you explain how you reasoned the selection of this patient cohort?

Dr Sung-Hee Shin:            The reason why we chose the patients we did, the range of ejection fraction condition, was that we thought the reversibility of the left ventricle mortality and function mitral regurgitation might be more pronounced in these patients.

                                                When we considered the fraction condition in mitral regurgitation with ejection fraction used under [inaudible 00:18:17] LV dysfunction, our inclusive criteria of ejection fraction between 25 to 50% might correspond to ejection fraction of 20 to 40% in patients with mitral regurgitation.

                                                We concluded that if a patient had ejection fraction less than 25% because the reversibility of mortality and function mitral regurgitation might be smaller when all the LV dilation is too extreme and advanced heart failure is already established.

                                                So, I just thing how it can be provided to the patient who have functional mitral regurgitation associated with too extreme LV dilation and LV ejection fraction too.

Dr Victoria Delgado:        I think, Carolyn, it's a very good point what she explained because we are used to select patients based on ejection fraction, in particularly patients with functional mitral regurgitation, ejection fraction is rather misleading because actually it's just a change of volume in the ventricles emptying in a low pressure chamber which is the left atrium.

                                                The moment that you correct that in mitral regurgitation sometimes then you face, or you see, the true ejection fraction of that ventricle. And if we wait too long, we may end up with ventricles that they don't have any more resource in order to improve ejection fraction after repair of the mitral valve.

                                                So, I think that this study is important to also realize that concept. That ejection fraction in patients with functional mitral regurgitation may not be the most accurate parameter to assess the function of that ventricle.

Dr Carolyn Lam:                Yeah. Exactly. And I thought that was a very clever part of the design. I'm glad you explained it and also so glad, Victoria, you invited the editorial by Dr Mullens, who also commented on that. So, just for the audience to understand that ejection fraction up to 50% was included and ejection fraction less than 25% was excluded.

                                                So also, again, very consistent to your prior point, Victoria.

                                                Could I ask you, I think Dr Mullens also spent quite some time talking about the potential mechanisms. What's your take of this Victoria? ARNI for functional regurgitation. How come?

Dr Victoria Delgado:        For me, I'm much more from the side of the imaging point of view. When we have patients with functional mitral regurgitation I always try to see which is the capability that that ventricle has to recover.

                                                Actually, first is always medical therapy, but we know that the [inaudible 00:20:59] only, for example, we just reduced the mitral regurgitation, but they don't really improve the function of that ventricle, while if you reduce the loading conditions of the ventricle in terms of blood pressure as well and favoring remodeling of the left ventricle, you can improve the condition of the mitral valve and reduce the mitral regurgitation.

                                                How valsartan plus sacubitril works differently than valsartan alone that I don't think that I have enough knowledge to explain why but it could be that in a way there is more effective with sacubitril on top of valsartan can improve the loading conditions of the ventricle and improve the, or facilitate, the reversing of morbidity of that ventricle, reducing the mitral regurgitation and that, by itself, could also lead to reversing morbidity.

                                                Like a little bit cardiac resynchronization we'd do, for example, in patients with an ejection fraction below 35% and based on the EEG you have the synchronous fraction of the papillary muscle or the walls of the ventricle which could lead to the mitral regurgitation at the moment that you resynchronize that mitral regurgitation can produce, you reduce part of the volume of the load of the ventricle and that can favor that reversing morbidity.

                                                So, I think that this study raises a lot of questions and I think that further research is needed in order to confirm or to know more how these treatments work.

Dr Carolyn Lam:                Goodness, that was so beautifully explained and in fact, many clues from Sung-Hee's study and the reversal of left ventricle end diastolic volume index greater with those treated with ARNI, the LA size and so on.

                                                But maybe I should ask you, Sung-Hee, in line with what Victoria said, what are the next steps? Do you already know what are the next studies that you're going to be looking at in PRIME?

Dr Sung-Hee Shin:            We're considering mark of monitoring such as NT pro-BNP or using auto imaging models such as echo and cardiac MRI to look at the change of mitral valve regurgitation in more detail.

                                                This kind of study might be very helpful in understanding [inaudible 00:23:15] ARNI in functional mitral patient.

Dr Carolyn Lam:                Yes, that's clever, too. And Victoria, before we end could you maybe give us some take home messages?

Dr Victoria Delgado:        I think that the take home message from this study is that when we have patients with functional mitral regurgitation, we need to think what we can offer to them. Not consider mitral regurgitation just as a base standard. That it's going to respond only to diuretics. No. We need to do something on that left ventricle to help it to improve the function and to avoid the progress to more reduced function.

                                                It's very important to understand the mechanism of the mitral regurgitation and to use the guidelines based medical therapy trying to go step by step in order to optimize the medication of that patient and later on, see all the potential treatments that are available right now such as cardiac synchronization therapy, which we should not forget, and then surgery if the patient needs catheterization and if the patient needs the benefit from mitral valve plasty or eventually, for example, trans catheter mitral valve therapies.

                                                But we should avoid that the patient goes further down into heart failure with very dilated ventricles and very poor function because then probably we may face a point of no return.

Dr Carolyn Lam:                Thank you so much, Victoria. Both you and Sung-Hee mentioned this is a mechanistic study. So many insights. But it's not saying that everybody with functional mitral regurgitation has to be treated this way now. It's calling for more work and it's certainly very, very important study.

                                                Thank you listeners, for listening today as well. 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.


Mar 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 doctor 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 at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                Have you heard of long non-coding RNAs? Well, they are definitely the hot topic and our feature paper today discusses the first demonstration of the importance of a linked RNA in atherosclerotic lesions not just in mice but also in humans. You have to listen on, it's coming up right after our copy chat.

                                                Greg, what are your picks upon the journal this week?

Dr Greg Hundley:             The first paper I wanted to discuss comes from France, and it's basically looking at ambulance density and outcomes after out of hospital cardiac arrest from Florence Dumas from Hôpital Cochin in Paris, France. This manuscript addresses the geographic disparities and survivorship of out of hospital cardiac arrest and the relevance of the patients characteristics versus whether ambulances are equipped with those trained in basic or advanced cardiac life support. So, what they did they had nineteen neighborhoods in Paris, and the number of BLS trained versus ALS ambulances was collected, and the authors assessed that respective associations of socio-economic characteristics of the patient population and the ambulance resources of these neighborhoods and compared those with successful return of spontaneous circulation or risk as the primary end point and then survival of out of hospital discharge as the second end-point.

                                                So, they had 80754 non-traumatic out of hospital cardiac arrests across the Paris area. 42% at ROSK 9% head survival at discharge, and after accounting for the patient's socio-economic status, greater than one and a half advanced cardiac life support ambulances per neighborhood and greater than 4 basic cardiac support basic life support units per neighborhood were associated with ROSK, but only the 1.5 ALS units per neighborhood were associated with survival.

Dr Carolyn Lam:                Oh, interesting Greg. So does this we need more advanced life support units?

Dr Greg Hundley:             So, Paul Dorian from St. Micheal's Hospital in Toronto, Canada wrote an excellent editorial, and one point he made related to these ALS units is that it was really a very small 1.3 adjusted odd ratio for survival to hospital discharge, and it's important to note that although the increase in survival was associated with more ALS units, there were many other variables that were likely important and not recorded in this study. For example, including the time to collapse, to calling for EMS, the time from the call to the deployment of that ALS unit to the scene, the time from collapse to the defibrillation, the total "no flow time" sort of in quotation, which is the total duration of collapse until CPR is started and so I think one of the points in this observational study is there could've been many differences that would've associated with the findings, interesting findings how about one of the papers that you liked?

Dr Carolyn Lam:                So, the paper that I selected here is a first time that a targeted anti-inflammatory therapy has been shown to reduce hospitalization for heart failure and at-risk patients. So, you know that some clinical inflammation associates with an increased risk of heart failure and associates with the worst prognosis in patients with heart failure, and yet, so far, treatments specifically directed at reducing inflammation in patients with heart failure have not been shown to improve clinical outcomes. That's why today's paper is so special and it's from Dr Everett and colleagues from Brigham and Women's Hospital Harvard Medical School in Boston, and basically, the authors looked at CANTOS and tested the hypothesis that the interleukin -1β inhibitor can canakinumab would prevent heart failure hospitalizations and the composite of heart failure hospitalizations on heart failure related mortality in the CANTOS trial.

                                                Now, remember the CANTOS trial randomized more than 10 000 patients with a prior myocardial infarction and with high sensitivity C-reactive proteins at least two or greater, and they were randomized to canakinumab 50, 150, and 300 mg or placebos. Now, before randomization, these participated were asked if they had a history of heart failure and 22% said yes so the current paper actually looks at this stratification of patients who said they had heart failure, and during a meeting follow-up of 3.7 years, 385 patients had a new heart failure hospitalization event. Now, here's the key: the authors found a dose dependent reduction in the risk of hospitalization for heart failure as well as the composite of hospitalization for heart failure or heart failure related mortality among those allocated to Canakinumab.

Dr Greg Hundley:             So, how does this differ from prior attempts targeting inflammation and heart failure? I mean is this ready for prime time thing?

Dr Carolyn Lam:                So, we have to bear a few things in mind here you know. CANTOS was different from a previously published randomized controlled trials, which were basically neutral and that was like of infliximab and etanercept so the drug in CANTOS targets interleukin-1 beta whereas the prior ones targeted the TNF-alpha, and also very importantly, CANTOS did not specifically enroll patients with an established heart failure only. CANTOS patients had to have a history of myocardial infarction and there was no data on their ejection fraction or natriuretic peptides at the time of randomization nor at the time of heart failure hospitalization. So, by the way, we don't know whether there's a differentially effect on hep pef versus hep-ref. So, again difference from the heart failure focused trial previously that used an anti-inflammatory agents.

                                                The other thing: although there was a dose dependent reduction in the risk of hospitalization for heart failure no single dose of Canakinumab compared to the placebo had a statistically significant reduction in the risk of heart failure hospitalization. Only the trend was statistically significant so all in all, this was a pre-specified aim of CANTOS to look at heart failure, the data presented here should really be considered hypothesis generally, but really quite promising. And what about you Greg? What's your other paper?

Dr Greg Hundley:             We're going to switch gears a little bit and shift over to the Jackson heart study. The large longitudinal cohort from Jackson, Mississippi that's recruited to follow for cardiovascular events, and it's an area of the United States where we have some of the highest cardiovascular disease event rates really across the nation so this study focuses on sleep apnea and is the Jackson's heart sleep study. It's a sub-study of this larger Jackson's heart study that involves 913 patients, and the investigators were looking at the association between sleep apnea and blood pressure control among those of a Black race. So, Dayna Johnson of Emerald University is the first author on the paper. What's nice about this sub-study, this sleep sub-study is that there are objective measures using an in-home type III sleep apnea study. They had clinical blood pressure measurements and then anthropometry as opposed to questionnaire derived data that may have been performed in the larger cohort.

                                                And the study determined these associations between moderate or severe obstructed sleep apnea with controlled, uncontrolled and resistant hypertension. So the analytic sample of the individuals with hypertension was 664, and they had an average age of about 64 years. They were predominately women 69%, obese 58%, College-educated at 51%. Among the sample, about a quarter had obstructive sleep apnea, which was untreated and unrecognized in 94% of the participants. That's an interesting point, just right there.

                                                Overall, 48% of the participants had uncontrolled hypertension and 14% had resistant hypertension. So, multiple medications, often four and still unable to control the blood pressure. So the findings participants with moderate or severe obstructive sleep apnea had 2 times higher odds' ratio of resistant hypertension.

Dr Carolyn Lam:                Whoa Greg, that's a huge risk and very important finding. I mean if sleep apnea could be modifiable risk factor perhaps for very important issue among African Americans resistant hypertension. What do you think about clinical implication?

Dr Greg Hundley:             One of the things to be considering now is what are we going to do about that cause as you know CPAP is really the preferred treatment for resistant hypertension, but it's efficacy hasn't been really that well studied in African Americans and CPAP tolerance is low so this study highlights for us potentially new mechanisms for resistant hypertension, but we still got to be thinking about what would be our next therapeutic intervention for this particular patient population. And what about your next study?

Dr Carolyn Lam:                The next study is about Impella support for acute myocardial infarction complicated by cardiogenic shock. Now, we use it all the time, but did you know that to date, there is no large randomized study actually comparing the use of Impella to other contemporary cardiac support devices and medical treatment in stem related cardiogenic shock. So, Dirk Westermann and colleagues from University Heart Center in Hamburg tried to address this knowledge gap by using a multi-national database of patients with acute myocardial infarction complicated by cardiogenic shock and treated with the Impella device and compared in a matched fashion their outcomes to patients from the IABP Shock II trial, which you would recall is a randomized trial which demonstrated similar outcomes between IABP and medical treatment in myocardial infarction in cardiogenic shock.

                                                So, they looked at 237 matched-pairs so remember this was pairs from this registry of acute myocardial infarction with shock and using an Impella matched with IABP shock patients and what they found was that there was no significant difference in 30-day all-cause mortality. Instead, severe or life-threatening bleeding and peripheral vascular complications occurred significantly more often in the Impella group when they limited the analysis to the IABP treated group as controlled versus Impella that was still the same results.

Dr Greg Hundley:             So, Carolyn, there are trying to match patient population from two different studies and they may have confounders in there that we can't account for so why we not able to produce large randomized trials of Impella devices in studies of patients with acute myocardial infarction?

Dr Carolyn Lam:                The rate of acute myocardial infarction complicated by cardiogenic shock has really declined in the past decade. Furthermore, clinical signs of shock really appear in half to three quarter of cases several hours after hospital admission so making randomization before primary PCI of the AMI really very difficult. And finally, many interventional cardiologists believe that there's equipoise that has already been reached on the use of these cardiac assistive devices in patients with cardiogenic shock and this was from registry data, and so if interventionists believe this then they also believe its unethical to randomize these patients in trials. Still, I think that current study to date really causes us to pause and to acknowledge that we really need to evaluate this better and prospective randomize trials of Impella treatment are warranted.

                                                Let's now go to our featured discussion, shall we?

                                                For our featured paper discussion today, we are talking about a basic science paper, and we have none other than the best of the best Dr Charles Lowenstein, our associate editor from University of Rochester Medical Center joining us as well as the first author of a really fantastic paper on long non-coding RNA in a specific type involved in arthrosclerosis and plaque formation. This first author is Sebastian Creamer from Goethe University in Frankfurt.

                                                Charlie, could you start us off by telling us what is a long non-coding RNA? We've heard a lot about this in recent times. What's the big deal about them?

Dr Charlie Lowenstein:  So in the last decade, scientists have learned that your genome, your DNA inside you, every cell codes about 20,000 genes and those 20000 genes encode proteins, but there are another 20000 genes that encode RNA only, RNA that never turns into protein that leaves RNA are an amazing diversity of different kinds of RNA really short micro RNA, longer RNA that defends the host from viruses and long non-coding RNA that have a huge variety of effects regulating genes, turning genes on and off in proliferation and cell growth and inflammation so long non-coding RNAs are increasingly appreciated as an important part of the genome.

Dr Carolyn Lam:                What a perfect set up with that. Sebastian, could you tell us about your study please?

Dr Sebastian Creamer:   Our laboratory was interested in non-coding RNAs for some time and previously, we've found that this specific non-coding RNA MALAT1 regulates endothelial cell functions and because we were interested in analyzing this particular RNA in the disease setting it shows at a risk growth so it's because also we saw that when it's regulated by flow and end of previous cells and so we cross MALAT1 deficient mice to Apoe mice and set them on a high fat diet and analyzed and subtracted in both groups. And while we only saw a modest increase in plaque size in MALAT1 deficient mice, we could appreciate a higher amount of inflammatory cells in plaque of aortic roots in those mice, which let us hypothesize that inflammatory responses was appreciated and is a very important contributor to arthrosclerosis in MALAT1 deficient mice. And to test this, we decided to transplant MALAT1 deficient bone marrow in Apoe knockout mice with MALAT1 and interestingly, we saw that now plaques were significantly larger than compared to mice who received controlled MALAT1 white cell bone marrow, and also inflammatory cells were more prominent in those mice.

Dr Greg Hundley:             Sebastian, this is Greg Hundley. You also did some experiments in human subjects. Could you tell us a little bit about those too?

Dr Sebastian Creamer:   So, because we saw this interesting phenotype, we were very much interested if this also translates into the human setting. Luckily, we got a really nice collaboration receding in Stockholm access to high impact material from patients with arthrosclerosis and what we could see here that MALAT1 expression was down regulated in patients with arthrosclerosis and it also correlated with disease progression. Moreover, in another collaboration, we consolidated those findings with experiments, which showed that human cells have less MALAT1 compared to normal vasculature.

Dr Carolyn Lam:                It all sounds so sensible and logical and so on but let me just frame this for our audience. This is actually the first time that it's been demonstrated. The importance of long non-coding RNA in arthrosclerosis. Charlie, could you tell us a little bit about how significant these findings are?

Dr Charlie Lowenstein:  Sure. So, I'm really interested in the final figure in this paper because there are lots of interesting human data, showing that MALAT1 expressed more in normal than atherosclerotic arteries and also that MALAT1 expression is correlated with fewer major adverse cardiac events so the whole story is a very nice story saying that the expression of this anti-inflammatory link RNA not only has an effect in mice but it can be extended into the human field of arthrosclerosis and inflammation. It's particularly important because there's a lot of attention in the last decade that inflammation drives atherosclerosis, and in light of CANTO trial showing that anti-inflammatory therapy can actually decrease atherosclerosis and decrease cardiovascular events in humans. This is important cause it shows another pathway, which regulates inflammation. Not only in mice, but also in humans, and in the human atherosclerotic setting.

Dr Carolyn Lam:                Amazing. Sebastian, what are the next steps? How far are we away from clinical applications here? What are the next steps to get it in the clinic?

Dr Sebastian Creamer:   So, the very difficult thing is that MALAT1 is down-regulated in atherosclerosis and also therapeutic approaches is very difficult in such a complicated disease like atherosclerosis to actually increase the expression of such a long non-coding RNA. What we are currently working on is to decipher more than the clinical malade-1 is actually influencing atherosclerosis so we have lots of hints or some evidence that adhesion of inflammatory substances altered and the bone marrow activity, which is very important in atherosclerosis and also in other cardiovascular diseases like myocardial infarction is altered so we think that malade-1 might actually influence the resolution of inflammation and when it's lacking, inflammation can be resolved. So, we are now putting somewhat mechanistic studies and finally, we hope that we can find another downstream target like micron AB, we talked about in our paper, which we can directly target in the future.

Dr Charlie Lowenstein:  So, I agree with Sebastian. I think MALAT1 is going to turn out as one of those major link RNAs that controls inflammation possibly controlling the way in which the bone marrow reacts to systemic inflammation and produces cells and then have those cells home in on various inflammatory targets so I think this is an important observation that's going to have not only implications for atherosclerosis but also for other inflammatory diseases.

Dr Carolyn Lam:                Excellent. If you don't mind, I would love to switch tracks a little bit. We find it that very special and we can discuss basic papers with people who can explain it so well because we understand that there's so much work that goes in to these papers and so on. Charlie, could you take behind the scenes a little bit with the editors and tell us what is it that circulation looks for in basic science papers that makes us published?

Dr Charlie Lowenstein:  We get a lot of really good basic science papers, and it's a challenge for the associate editors, and the editors to figure out what's right for circulation and let me use this manuscript as a great example because this is a terrific paper. So, this paper is divided into four sections, and these sections are what we look for in any basic science paper that's going to reach an audience of clinicians who are interested in pathways and therapeutics so this paper has a section on mice. There's a gene in mice that's important then the paper delves into cells what's happening with cells and then a little bit of mechanisms and genes and proteins and then this paper takes the observation back into humans and shows that there's some human and clinical relevance so this is not only a great paper, but it is a classic example of what the associate editors are looking for in a basic science paper that's targeted towards clinicians.

Dr Charlie Lowenstein:  There's some in vivo work with mice, there's some mechanistic work then they take it back to the humans. Plus, of course like anything that comes into circulation, it's going to be novel, interesting and has some important relevance to human cardiovascular disease. This paper that we're discussing is a great example of a paper that we love to publish in a circulation and it's a real tribute to Dr Dimmeler and her team and to Sebastian that they put this paper together and submitted it to us.

Dr Carolyn Lam:                Thank you audience for joining Greg and I today. You've been listening to circulation on the run. Don't forget to tune in again next week.