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Nov 21, 2016

Carolyn:
Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. [Carolyn Nam 00:00:08], associate editor from the national heart center and Duke National University of Singapore ...

 
 
In just a moment we will be discussing the exciting new results of the [Prague 00:00:21] 18 study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. But first, here's your summary of this week's issue ...

 
 
The first study represents the largest published study on the association between PR interval and cardiac resynchronization therapy with defibrillator versus implantable cardioverter defibrillator and real world outcomes. Dr. Friedman and colleagues from Duke Clinical Research Institute studied 26,451 CRT eligible patients from the National Cardiovascular Data Registry ICD Registry. They found that a PR interval at or above 230 milliseconds was associated with increased rates of heart failure, hospitalizations, or death among CRTD but not ICD patients. The real world comparative effectiveness of CRTD versus ICD was significantly less among patients with a PR interval above 230 milliseconds compared to patients with a shorter PR interval.

 
 
The authors discuss that these findings may be due to the association between a prolonged PR interval and factors associated with lower rates of CRT response such as non-left bundle branch block morphology, ischemic heart disease, or atrial arrhythmias. It could also be due to the association between delayed AV conduction, disordered diastolic filling, and contemporary CRT reprogramming strategies. The take home message is: in CRT patients with a prolonged PR interval, recognize that they are at high risk for poor outcomes and merit close follow up and consideration of AV optimization ...

 
 
The next study is the first adolescent study of serum lipidomics that identifies a new panel of serum glycerophosphocholines that are associated with cardiovascular risk. First author Dr. [Sine 00:02:29], corresponding author Dr. [Palsova 00:02:31], and colleagues from Hospital for Sick Children in University of Toronto recognize that atherogenic dislipidemia is traditionally assessed with high abundance lipids, such as cholesterol and triacylglycerols, which accumulate at millimolar levels in blood. Current advancements in mass spectrometry now allow the discovery and study of new low abundance lipids, which circulate at micro- or nanomolar blood levels. And one such example are the glycerophosphocholine metabolites.

 
 
They studied a population based sample of 990 adolescents with age range 12-18 years using liquid chromatography electrospray ionization mass spectrometry. They identify several novel glycerophosphocholines that were associated with multiple cardiovascular disease risk factors. Mediation analysis revealed that these novel glycerophosphocholines mediated their respective relationships between visceral fat and cardiovascular disease risk factors. Furthermore, a particular glycerophosphocholine shown recently to predict incident coronary heart disease in older adults was already associated with several cardiovascular disease risk factors in these adolescents.

 
 
The clinical implication is that the development of a lipidomics signature that could facilitate early intervention or treatment of those at high risk of cardiovascular disease or monitor response interventions could help triage limited healthcare resources. Furthermore, future research on glycerophosphocholines might improve biological understanding of disease and identify potential drug targets to impede cardiovascular disease development ...

 
 
The next study also describes plasma lipidomic profiles but this time in patients with type 2 diabetes. This study is from first author Dr. [Elchuri 00:04:35], corresponding author Dr. [Meekly 00:04:37], and colleagues from the Baker IDI Heart and Diabetes Institute in Melbourne, Australia. These authors performed a targeted lipidomic analysis using liquid chromatography electrospray ionization tandem mass spectrometry in a case cohort of 3,779 patients with type 2 diabetes and one or more additional cardiovascular risk factors from the advance trial.

 
 
They found that sphingolipids, phospholipids, cholesterol esters, and glycerol lipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model of 14 traditional risk factors and medications improved the prediction of cardiovascular events. The prediction of cardiovascular death was also improved with the incorporation of 4 lipid species to the base model. These results were further validated in a subcohort of type 2 diabetes from the lipid trial. In summary, this important study demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes ...

 
 
The last study sheds new light on the optimal ablation method for atypical atrioventricular nodal reentrant tachycardia or atypical ARNVT. Dr. [Catrisis 00:06:10] and colleagues from Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts study 2,079 patients with AVNRT subjected to slow pathway ablation. In 113 patients, atypical AVNRT or coexistent atypical and typical AVNRT without other concomitant arrhythmias was diagnosed. Ablation data and outcomes were compared to a group of age and sex matched control patients with typical AVNRT. The authors found that in the atypical group slow pathway ablation was accomplished from the right septum in 110 patients and from the left septum in 3 patients. There was no need for additional ablation lesions at other anatomical sites and no cases of AV block were encountered.

 
 
In summary AVNRT, regardless of the type, appears to be successfully ablated by targeting the anatomic area of the slow pathway. When a right septal approach is not successful, the anatopic area of the slow pathway can be ablated from the left septum and so it seems the slow pathway participates in both typical and atypical AVNRT. The take home messages are that catheter ablation at the anatomical area of the slow pathway from the right or left septum may be the treatment of choice for atypical AVNRT. The approach is not associated with an increased risk of inadvertent AV block. The recurrence rate following ablation of atypical AVNRT may not be significantly higher than that seen following the ablation of typical AVNRT.

 
 
Those were the highlights from this week's issues. And now for our feature paper ...

 
 
We're so pleased to have with us today for our podcast interview first and corresponding author of the Prague 18 study, Dr. [Zuzana Motovska 00:08:12] from Charles University in Prague. Welcome Zuzana.

 
Zuzana:
Thank you for having me.

 
Carolyn:
We're also so lucky to have Dr. [Gabriel Stig 00:08:21], associate editor from Paris, and I understand you're even traveling at the moment. Thank you, Gabriel for making the time.

 
Gabriel:
Yes, hello Carolyn, hello Zuzana.

 
Carolyn:
So let me start by congratulating you Zuzana on this first head-to-head comparison study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. And what a lovely study acronym of course, Prague 18. Could you maybe start by describing, in the Czech Republic before your study, how were clinical decisions being made between prasugrel and ticagrelor in these patients?

 
Zuzana:
The current guidelines prefer newer P2Y12 inhibitors over clopidogrel for patients with acute coronary syndromes. Prasugrel and ticagrelor are being increasingly used in patients [with just 00:09:15] primary PCI in Czech Republic. Analysis of our registry documented that doctors did not view these two drugs as interchangeable and prasugrel is a drug associated with a high risk of bleeding. Our data show that safety in terms of bleeding risk was the most important aspect under consideration when choosing one of new agents for an individual patient. The same observation has been reported from other contemporaries from other countries and according to the published subgroup analysis of [stratum 00:09:54] and other studies we have also perceived prasugrel to be a more effective agent for primary PCI. We prefer this drug in patients with a high thrombotic risk.

 
Carolyn:
Could you, maybe now, clearly describe what you did in this study and what were your findings?

 
Zuzana:
The Prague 18 study truly [inaudible 00:10:19] was designed to test the hypothesis on whether one of the newer drugs, prasugrel or ticagrelor, is more effective and safer than the other one in acute myocardial infarctions, which is the primary [treatment 00:10:36] strategy. We randomized the total 1,230 in 14 participating sites. I highlighted hemodynamic instabilities, was not an [excluding 00:10:52] criterion for study participation. The patients were randomized for prasugrel or ticagrelor immediately on hospital arrival and the recommended dosing regiments were used for both drugs. The prasugrel dose was reduced during the maintenance phase in patients over 75 and [reduced vein 00:11:12] was the [sixth 00:11:14] feature around presence of both these parameters was an exclusion criterion.

 
 
So, what we find. Fewer [unsourced 00:11:23] primary endpoint composed of all cause of death or reinfarction show serious bleeding or urgent vessel revascularization within 7 days after randomization or discharge if prior to the seventh day. They did not differ between groups, either for in 4 person prasugrel group and in 4.1 person in ticagrelor group. The appearance of key secondary end point composed of cardiovascular death, nonfatal MI, or nonfatal stroke. Within 30 days did not show any significant difference between prasugrel and ticagrelor, furthermore no significant difference was found in any of the components of the primary and secondary endpoints and also no significant difference was observed in the appearance of definite vein thrombosis [inaudible 00:12:17] days after randomization.

 
 
So the study did not show any difference between ticagrelor and prasugrel in the early phase of a mild [treatable 00:12:26] primary PCI. Because of small sample size the confidence for the estimation of the [interval 00:12:35] of either were quite high, however we identify differences, which are very low in absolute numbers and [inaudible 00:12:45]

 
Carolyn:
That was very nicely explained Zuzana, thank you. Now could you share a little bit more about, were you powered for this analysis and the decision to stop early.

 
Zuzana:
Oh yes, the power analysis was computed for primary endpoint difference of 2.5 person and the needed sample size was estimated at 2,500 patients. The interim analysis led to a decision to terminate the study prematurely because of futility. No significant difference in primary endpoint was found between the two study drugs in the course of the entire randomization process, moreover the difference in appearance of the primary endpoint between the compare groups was declining with a growing number of randomized patients and analyzed on the different 0.1% and this was the decision why we stopped the trial prematurely.

 
Carolyn:
Right. Gabriel could you comment a little bit as the associate editor managing this paper, how do you think it's going to impact practice?

 
Gabriel:
First of all, let me start by congratulating Zuzana and the team of the Prague 18 trial for this academic trial. I think it's really important that we have a clinically led effort to investigate optimal treatments in modern cardiology in general and specifically in acute coronary syndromes. We've known for several years now, through large randomized trials, that the novel P2Y12 agents, ticagrelor and prasugrel, are clearly superior to clopidogrel but we don't know which of the two agents to choose and we know that comparison across trials are fraught with major methodological problems. So with evidence that prasugrel is superior to clopidogrel for PCI treated ACS patients, there was evidence that ticagrelor was superior to clopidogrel for ACS patients in general but we didn't have any rational data on which to base a rational selection process between the two agents.

 
 
Really, I think it's an important issue and often people state that these are delicate differences between agents, and we shouldn't expect that this is going to impact clinical outcomes. Actually it does impact clinical outcomes because we know that those novel agents have had a roughly 20% reduction in major heart outcomes compared to clopidogrel so this is not a moot point. It's not a minute difference, it's a huge difference and it's an important clinical issue. That's my first point, I think it's an important question and I really want to commend the investigators for launching this trial despite not having the support of industry.

 
 
The second point I want to make is I think that the results from the trial are not yet complete because we don't have the one year follow-up and I know that this is planned and the investigators are continuing follow-up of their patient cohort, which I think is going to be important because it's conceivable that differences may emerge over time as was, in fact, the case in some of the previous trials. In [plato 00:15:49] there was a modest difference early on but the curves diverged over time between clopidogrel and ticagrelor so it's conceivable that differences that are absent at 30 days might emerge over time.

 
 
In fact, I have a question for Zuzana. One of the interesting features and important issues that needs to be addressed is ... I know that in some sites in the Czech Republic, because of the out of pocket expenses related to the cost of the novel agents, it was allowed for patients to be switched back to clopidogrel after hospital discharge. Do you have any sense of what is the proportion of patients who are scaled back to clopidogrel instead of prasugrel or ticagrelor after initial index submission?

 
Zuzana:
Thank you Gabriel, it's true the study ... a lot of patients who are unable to bear the cost associated with long term treatment with the study medications and switch to clopidogrel. Therefore, a second goal of the study was to assess the rate, the reason, and also the consequences of switching from a study drug to clopidogrel after the acute phase in the course of 12 months follow-up. We are not focusing on the study completion and analysis that are related to the second study. There are, of course, patients who switch from prasugrel or ticagrelor to clopidogrel also in first 30 days and this proportion was about one third of patients.

 
Gabriel:
The other point I want to make really relates to the power issues and Zuzana already pointed out herself this important issue. The paper is actually accompanied by an excellent and very cogent editorial by Steve [Webiok 00:17:31], who discusses explicitly and in great detail the issue of sample size. We know that the relative difference between the novel agents and clopidogrel is in the range of 20% so we might expect that the difference between the two novel agents themselves, when we compare prasugrel and ticagrelor, might be less. Yet the study was powered for actually a greater relative risk reduction than what was seen in the pivotal trials of prasugrel and ticagrelor compared to clopidogrel. So the study is really on the low end of the power spectrum and I think, as you pointed out Zuzana, it's important to keep in mind that the confidence interval for the relative risk between ticagrelor and clopidogrel both act together on prasugrel, both for the primary endpoint, which is a combination of efficacy and safety, as well as for the key secondary endpoint of efficacy.

 
 
It's really very wide and we can't rule out a major benefit or a major detrimental effect of one agent versus the other. I think this is important to keep in mind because many people equate a neutral result of a trial, a non-significant result, particularly in the [secondary 00:18:36] trial, with lack of difference or clinical equivalence or non-inferiority and I think it's important to remember the readers that this is not a non-inferiority trial, it's not a clinical equivalence trial, it's superiority trial that is actually with a neutral result. It's really and important issue.

 
 
Yet, because it's the first head-to-head comparison, because it's an academic effort independent, and because it's going to report one year outcomes, I think this is a critical effort and the investigators need to be lauded for that. Even if this study isn't powered, it will be able to be pulled in further meta-analysis with other upcoming studies that are similar that also may be underpowered and provide us with a hint of evidence of what might be the best agent to use, which is an every day clinical question. This is a very, very common condition and any unbiased evidence we can get from randomized trials is very valuable ...

 
Carolyn:
Thank you, everyone, for listening to this episode of circulation on the run. Tune in next week ...

 

Nov 14, 2016

Carolyn:
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. In today's podcast interview we will be discussing the ruling in and ruling out of myocardial infarction with the European Society of Cardiology 1-hour algorithm. Stay tuned for a discussion of new data and controversies on this hot topic. Now, here's a summary of this weeks issue.

 
 
The first paper brings us one step closer to the ultimate goal of cardiac tissue engineering. That is to replicate functional human myocardium in vitro. In this study, by first author Dr. Ruan, corresponding authors Dr. Murry and Regnier from the Institute for Stem Cell and Regenerative Medicine and University of Washington, authors recognize that human-induced pluripotant stem cells, or iPSC-derived cardiomyocytes, really provide a cell source for cardiac tissue engineering. However, their immaturity limits their potential applications. Hence, they sought to study the effect of mechanical conditioning and electrical pacing on the maturation of iPSC-derived cardiac tissues.

 
 
They found that after two weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility, tensile strength, construct alignment, cell size, and SERCA2 expression. When electrical pacing was combined with static stress conditioning the tissue showed an additional increase in force production and further increases in expression of RyR2 and SERCA2. These studies really demonstrate that electrical pacing and mechanical stimulation promote the maturation of the structural, mechanical, and force generation properties of iPSC-derived cardiac tissues and constitute a really important contribution to cardiac tissue engineering.

 
 
The next study is the first large-scale, nationwide, population-based investigation of the association between congenital heart defects and any placental measure. This study by Dr. [Matheson 00:02:27] and colleagues from Aarhus University Hospital in Denmark, included all 924,422 live-born Danish singletons from 1997 to 2011. Congenital heart defects was present in 7,569 newborns. The authors compared the mean differences in placental weight between newborns with and without congenital heart defects and found that only three specific subgroups of congenital heart defects were associated with measures of impaired placental growth. These included Tetralogy of Fallot, double outlet right ventricle, and major ventricular septal defects. In these subgroups, the mean deviations from the population mean head circumference and birth weights were reduced by up to 66%, with adjustment for placental weight. In other words, up to two thirds of the deviations in fetal growth, including fetal cerebral growth, may be related to the impaired placental growth. The present work provides an important contribution to the existing knowledge on the association between congenital heart defects and placental anomalies as well as the possible importance for fetal growth in this population.

 
 
The next study provides an up-to-date evaluation of the cost effectiveness of antibiotic prophylaxis in the prevention of infective endocarditis. In this study by first author Dr. Franklin, corresponding author Dr. Thornhill, and colleagues from the University of Sheffield, the cost effectiveness of antibiotic prophylaxis, namely single dose amoxicillin or clindamycin, in patients at risk of infective endocarditis. They did this using, firstly, recent estimates of the effect of antibiotic prophylaxis on infective endocarditis in the English population; secondly, rates of antibiotic adverse drug reactions; and thirdly, estimates of the probability of developing infective endocarditis following dental procedures derived from French data. All this as foundation for analysis of cost and health benefits.

 
 
A decision analytic cost effectiveness model was used based on the decision model by the National Institute for Health and Care Excellence, or NICE, that was used to inform the 2008 guidelines. The authors found that antibiotic prophylaxis was less costly and more effective than no antibiotic prophylaxis for all patients at risk for infective endocarditis. In fact, if antibiotic prophylaxis was reinstated in England for those at moderate or high risk of infective endocarditis, it could save 5.5 to 8.2 million pounds and result in health gains of more than 2,600 quality-adjusted life years. Antibiotic prophylaxis was even more cost effective for those at high risk of infective endocarditis, being cost effective even if only on 1.44 cases of infective endocarditis was prevented per year. In summary, these updated findings really support the cost effectiveness of guidelines recommending antibiotic prophylaxis use, particularly in high risk individuals.

 
 
The last study provides data on long term cardiac mortality among survivors of cancer diagnosed in teenagers and young adults in the largest population-based cohort to date. Furthermore, the study provided, for the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 to 39 years. For example, survivors of Hodgkin lymphoma, lung cancer, acute myeloid leukemia, non-Hodgkin lymphoma, and CNS tumors experience 1.3 to 3.8 times the population-based mortality rates. This study provides important insight into the cardiotoxicity of the treatments given in the past to teenagers and young adults with each individual type of cancer and importantly, provides an initial basis for developing evidence-based follow up guidelines.

 
 
Those were you summaries. Now for our feature interview.

 
 
Our feature paper today discusses the hot and controversial topic of ruling in and ruling out myocardial infarction with the European Society of Cardiology 1-hour algorithm. I'm so excited to have with us the corresponding author of the paper that really represents the first multi-center external validation of these ESC guidelines for MI and the first multi-centered direct comparison of the performance of the algorithm with high-sensitivity troponin I and high-sensitivity troponin T assays. This would be Dr. Martin Than from Christ Church Hospital in New Zealand. Welcome Martin.

 
Martin:
Thank you very much. It's a great pleasure for me to be able to join everybody and talk here.

 
Carolyn:
It's great to have you. We also have with us the editorialist on this paper, Dr. Allan Jaffe from Mayo Clinic, Rochester, Minnesota. Allen, it's so good to hear your voice again.

 
Allan:
Good to talk to you again too, Carolyn.

 
Carolyn:
Finally, we have Dr. Deborah Diercks, Associate Editor from UT Southwestern. Welcome Deb.

 
Deborah:
Oh, it's good to be here and I'm looking forward to the conversation and what we're going to learn from these two gentlemen.

 
Carolyn:
Absolutely. You know what? I'm going to start with Martin. I love the way to set up your paper. You very correctly pointed out that there's a tension in that ED physicians require really high sensitivity to confidently rule out MI and send patients home, whereas cardiologists do not want high proportion of false positives because we don't want false high risk to lead to invasive testing. I just love, if you could start by telling us how the ESC 1-hour algorithm fits into all this and what you were trying to do in your study.

 
Martin:
I heard Deb Diercks on the phone as well, who's a very respected emergency physician in this area, and I think we would both say that we have a certain bias in our perspective on this, which is of course we are the people at the end of the day that have to send people home when they present with chest pain and possible myocardial infarction. We are also, of course, the people that take the fall if there are any mistakes made. Historically, people have not been very kind to emergency physicians who miss such a diagnosis. It's an extremely high source of medical legal action in the United States and, in fact, worldwide. So we're somewhat paranoid as a speciality about missing cases of myocardial infarction because at the end of the day, the worst thing that can possibly happen is for you to send someone home who comes to harm from the very clinical complaint for which they came to you for help. We want to avoid that at all costs and that was the basis behind us trying to put together this paper.

 
 
Soon after the ESC guidelines come back and I returned from London, where they were announced at the conference, to New Zealand, I received quite a lot of phone calls and correspondence saying, "Okay, we see these new ESC guidelines are out. When are we going to start introducing them?". I immediately wanted to say, "Well, the key thing is to understand how they would work, how they would be implemented, and whether they'd work in my own setting" because if we want to implement them in New Zealand or Australasia, we would want to double-check on that first. That's the basis and the philosophy behind the manuscript.

 
Carolyn:
Tell us what you found.

 
Martin:
As Allan will be the first to point out, I think there are a number of flaws in the data we had available to us that allowed us to do this analysis, but based on the concept that when we've surveyed emergency medicine physicians, the sensitivity that was wanted was at least 99% if not higher. We found that neither of the algorithms produced that level of sensitivity, although the algorithm based on hsTnI was very close. I think it's 98.8%, so that was very good. Reasonably wide confidence intervals on that. The hsTnT algorithm performed slightly less well with a sensitivity around 97%. I guess, if I was to start with an a priori question, which is did we reach a standard of 99%, then our answer to this was, in one case, not quite, and the other case, no, we probably didn't. We said that if you wanted to use a metric of negative predictive value, which I know a lot of people do, then there was actually very good negative predictive value in the high 99 percentage range for both pathways.

 
Carolyn:
Do you mind if I stretch you a little bit and ask you to describe exactly what you did in the cohorts? You were saying that there were some imperfections. Maybe you'd like to tell us a little bit about that.

 
Martin:
Absolutely. As always, when you're writing a paper, you look back and you always feel there are far too many imperfections, but I guess the principle one I would say that's been noted is that we had samples done on arrival and the algorithm itself specifies a [inaudible 00:11:43] one-hour second sample. We didn't have those specimens, so we had to base our data analysis on samples done either at 90 minutes afterwards or two hours afterward. It's clearly not being tested exactly as it was written, although one could argue that that slightly delayed sampling is potentially reflective of real life, where it's very hard to hit a one hour mark in a busy emergency department, and two, where the slight delay in getting the samples would actually allow more time for a troponin to rise and therefore give a chance of providing a better sensitivity.

 
 
I think the other I guess key flaw is that of course, the people present to emergency departments at different time frames following the onset of their symptoms. There's been some valid concern raised that algorithms may not necessarily perform as well in very early presenters. In fact, that is something that's being emphasized now in the ESC guidelines.

 
Carolyn:
Right. Allan, I loved your editorial. You did mention a couple of these points. Would you like to maybe clarify your view of this?

 
Allan:
I think that there are two or three terribly important issues. We all would like to have very facile algorithms. Particularly given removing the high sensitivity, the idea would be gee, wouldn't it be nice to have something really simple that works perfectly? If you look at the validation and the way the algorithm has been put together, immediately there are some concerns that people ought to have and that at least we tried to point out, that were important. One of them Martin has already discussed a little bit, which is one looks at most of the validation studies. There are very few patients who are evaluated very early after the onset of their symptoms. That's a potential problem because the overlap, since they use very low values or very small change, that there could be, with people who have real disease, is in those very early presenters. The initial algorithm from the ESC used both a very low level troponin and a set of change criteria. Actually when they published those criteria, they changed that and eliminated, at least for the first three hours, the very low values. If one looks at Martin's study, it was again, the very early patients who potentially may have been missed. I think we need more data before we go ahead and acknowledge that this will be working for those early presenters.

 
 
There are two other problems with the population that we need to be careful about. It's been well known that when you have a negative troponin at six hours all the way back to [Chrisann's 00:14:26] original article in the '90s, that you're pretty safe. The population that you'd like to look at really are the patients who, after two hours in Martin's study, since he took a little bit longer given the logistics that were there in New Zealand and Australia, is the patient who came in at four hours because by six, they're actually meeting that six-hour criteria. When you have a large number of other such patients, you simply add noise and it makes you sensitivity look better, but it's not necessarily the case that that give you that same degree of reassurance that ED physicians would like.

 
 
The third population-related issue is that you'd like to do this in all-comers. The protocol was developed for chest pain patients, but there are a variety of patients in whom we evaluate myocardial infarction in, who may not qualify for that. The patients who are critically ill, for example, who may have Type 2 infarctions. The individuals who may come in who are very elderly, who often don't have chest pain so we don't identify them necessarily as a rule out. Interestingly, if you start thinking about those groups, they tend to have much higher troponin, so they may well skew the cut-offs that are used and change the algorithm.

 
 
In truth, we don't want more than one way of defining myocardial infarction. We only want one algorithm for ruling in and ruling out. Having an all-comers study, in my way of thinking, would be important. In that same regard, let me point out that you can rule out myocardial infarction because you don't have an acutely changing pattern of troponin elevations, but what we really rule in myocardial infarction? You rule in acute cardiac injury. Could be myocarditis, could a apical ballooning. There are a whole variety of other types of disease entities that could be involved and the arbitrary value of 52 that was put in the algorithm really, I think, is much too low for two reasons. One reason, because it didn't include all-comers. A second reason is because of the way in which the comparison between troponin T and I were done. I'll talk about that in just a moment. I would point out that using a different assay, the troponin I assay, in another set of studies, another group from Hamburg has suggested that very different metrics would be much better.

 
 
The final thing to say about extrapolation between the assays, and then I have some suggestions about what would make this better if you want to go there now or we can wait, is the comparison and the way in which the metrics for troponin I were developed really weren't by using troponin I as a gold standard. It was by taking and using troponin T as the gold standard for the diagnosis, then thawing samples many years later, running troponin I, and then extrapolating from the gold standard of troponin T to troponin I. Well, there's several problems with that. Number one is that appropriate comparisons should be fresh samples. Fresh samples. In addition, we believe, from the way in which we think about high sensitivity, which may not be correct, that the troponin I assay should be more sensitive and in [inaudible 00:18:05] fact, in the papers that were done validating this approach or attempting to describe the approach, troponin T was wildly more sensitive than was troponin T. We're extrapolating some data that doesn't sort of fit the way in which the information we have, it would mean all of the troponin I validation studies are incorrect.

 
 
That's where those numbers came from and even more problematic are the change numbers, which are very low. For the troponin T assay, they're three in five between ruling in and ruling out, which if you look at the assay imprecision, is something the assay can't do. Now you're extrapolating them in a very, very loose manor to troponin I and making them even lower. Those are not doable sorts of things. There's a real problem with the way in which the metrics for troponin I, even though it performed well in this circumstance, ended up being developed. I think all of those things need to be taken into account when we look at the results of the study. The results that Martin and his group got are very similar to the other validation studies that have been done because they've all done it pretty much that same way. There's not a surprise that their validation is similar, but I think unfortunately, we didn't have an opportunity to unmask, in a data-driven way, the problems that I just described.

 
Carolyn:
Thank you Allan. Deborah, if you could share your thoughts on this.

 
Deborah:
Martin raises some valid issues. That if something goes out as an algorithm, people want to use it. That use needs to be predicated on does it work in their patient population and is it feasible in the time frame and can it be adopted safely and what the indications are. In the emergency department, the value really is the negative predictive value because we want to be able to safely send people home. That's where rapidity of an evaluation is very important.

 
 
The other issue raised was exactly what Dr. Jaffe talked about. Does the algorithm itself reflect what we really need? Can you validate something that was created by the scientific way, but really a combination of a lot of information? Are the thresholds really valid themselves? That's the challenge with it. I think what you heard here are kind of two issues we struggle with it. We have a very respectable organization putting out an algorithm that is scientifically based and we want to adopt early, but there are questions on both sides of the issue on whether it can be adapted into real-world clinical practice on a global nature where prevalence of disease is different and the patients it'll be applied to vary, whether it's been on time of presentation or overall demographics.

 
 
Also on the scientific side, on the assays itself, are we using the right cutoff? Especially when we're looking at deltas and looking at such a rapid change. It's very nice to hear both of those points so eloquently described today during the discussion.

 
Carolyn:
Thanks Deb. I fully agree. Hence, again, the importance of this paper. Martin, I'd love to hear your responses to Allan's comments and then also share with us, what's the take-home message for you as a clinician? How are you applying what you just found?

 
Martin:
The guidelines are good on the right line, it's just as I said, they may not necessarily translate to all other environments. I guess that's my take-home message to myself, which was if I were to look at my own data from my own center, in Christ Church, and the way it's applied here, if I had applied the ESC guidelines and it had met the metrics which I was satisfied with, which I guess would be a very high sensitivity for me in terms of rule out, then I would actually seriously consider implementing it in my own center. It didn't reach that threshold so now I want to try and refine or explore further how I could allow the guidelines to do that. For example, one way that, and this is in the guidelines, but not necessarily in the flow chart, is the importance of applying clinical judgment and clinical findings with the results of the algorithm. I think that's a very important step in it. For example, if I was going to apply this in my own center, I'd want to be setting out clearly for the doctors concerned, how one would incorporate clinical judgment rather than it being a very subjective thing, which might vary significantly between a junior doctor or a far more experienced one.

 
 
I guess the take home message for me is this. The ESC guidelines are a very important piece of work. They've been robustly developed. For people who want to implement them, I'm no saying don't use them at all. I'm just saying that, you know, just think about carefully how you would use them and check whether you think they're appropriate for your setting.

 
Carolyn:
That's great. Allan, what about you? What are your thoughts on how this may be applied in clinical practice and what more needs to be done?

 
Allan:
I think we need to have a real trial where patients are managed based on the results of these approaches rather than more observational studies. I would argue that those management trials that involve an all-comers sort of population, so we are comprehensive, and should also interrogate whether or not the protocol itself is adequate or whether or not it requires follow-up to meet the metrics that have been proposed. I would point out that in the past, in the studies from the group from New Zealand and Martin Than particularly, have had very, very good follow-up. One at least needs to ask the question whether or not the algorithms that are proposed work perfectly without any follow-up or whether or not follow-up is an important component. We don't know that yet.

 
Carolyn:
Thanks Allan. I'd love to give the final words to Deb. Take home messages?

 
Deborah:
You know, I think that we need to look at this as a positive in that we're looking at time frames that provide a rapid evaluation and the discussion is around safety. As long as we keep focused on appropriate evaluations for the patients and applying the right algorithm to the right patient, we're going to benefit the care of those we're really concerned about. I appreciate the work that both Martin and Allan both have done on really pointing out how we can do that in a great manor.

 
Carolyn:
Thank you, all of you, for joining us today. I mean, it's been such an enlightening conversation. I'm sure the listeners have enjoyed it and thank you listeners for tuning in. Don't forget to tune in again next week.

 

Nov 7, 2016

 

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 for the National heart center and Duke National University of Singapore. Our podcast is really going around the world, and today's feature interview comes to you live from China. Where we will be discussing the prediction of ten year risks of cardiovascular disease in the Chinese population. So now to all our Chinese colleagues out there: Chinese dialect

 
 
First here's your summary of this week's journal. The first study challenges the assumption that all patients with vascular disease are at high risk of recurrent vascular events. First author Dr. Kasenbrud corresponding author Dr. Viceren and colleagues form the University Medical center Utric in the Netherlands, provide new data on the estimation of ten year risk of recurrent vascular events and a secondary prevention population. In other words, in patients with established cardiovascular disease they applied the second manifestations of arterial disease or 'smart' score for the ten year risk prediction of myocardial infarction, stoke or vascular death in more than six thousand-nine hundred Dutch patients with vascular diseases ranging for coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm and poly-vascular disease. Predictors included in the SMART risk score included age, sex, current smoking, diabetes, systolic blood pressure, total cholesterol, HGL cholesterol, presence of coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm, estimated glomariaol fruition rate, high sensitivity CRP and years since the first manifestation of vascular disease. They further externally validated the risk score in more than eighteen thousand four hundred patients with various types of vascular disease fro the TNT ideals Sparkle and Capri trials.

 
 
The overall findings was that the external performance of the SMART risk score was reasonable apart from over-estimation of risk in patients which a ten year risk of more than forty percent. What was striking was the substantial variation in the estimated ten year risk. The median ten year risk of a reoccurring major vascular event was 17 percent but this varied for less than 10 percent in 18 percent to more than 30 percent in 22 percent of patients.

 
 
The authors further estimated residual risk at guideline recommend targets by applying the relative risk reductions form meta-analysis to estimated risks for targets for systolic pressure, LDL, smoking, physical activity and use of anti-thrombotic agents. They found that if all modifiable risk factors were at guideline recommend targets only half of the patients would have ten year risk of less than 10 percent. Even with optimal treatment many patients with vascular disease appear to remain at more than a 20 percent or even more than 30 percent of a ten year risk.

 
 
The take home message is that a single secondary prevention strategy for all patients with vascular disease may not be appropriate. Instead novel risk stratification approaches may be helpful to individualize secondary prevention by identifying high risk patient which may derive the greatest benefit from novel interventions.

 
 

 

 

 

 

 

 

 

 

 
The next study provides experimental evidence that an indigenous-gastro transmitter hydrogen sulfide may potentially be a therapeutic target in diabetic patients with cardiovascular diseases. In this paper by first author Dr. Chen, corresponding author Dr.Kisher and Colleagues from the Louis Cat's school of medicine Temple University in Philadelphia. Authors aim to evaluate the role of hydrogen sulfide deficiency in diabetes induced bone marrow cell dysfunction and to examine the therapeutic effects of restoring hydrogen sulfide production in diabetic bone marrow cells on ischemic high limb injury in diabetic DBDB mice. They further specifically investigated the effects of hydrogen sulfide deficiency on the nitric oxide pathways under conditions of high glucose. They found that bone marrow cells for diabetic DBDB mice had decreased hydrogen sulfide production and lower levels cystathonine gamma lyaze which is the primary enzyme that produces hydrogen sulfide in the cardiovascular system. Administration of a stable hydrogen sulfide donor and over expression of cystathonine gamma lyaze in diabetic bone marrow cells restore their functional and restorative properties. Further more they demonstrated that the therapeutic actions of hydrogen sulfide were mediated by nitric oxide pathway involving endothelial nitric oxide synthase PT495.

 
 
In summary these results support the hypothesis that hydrogen sulfide deficiency plays critical role in diabetes induced bone marrow cell dysfunction and suggests that modulating hydrogen sulfide production in diabetic bone marrow cells may have transformational value in treating critical limbs ischemia.

 
 
The next study reinforces the importance of hypertension as a critical risk factor for inter-cerebral hemorrhage, and suggests that Blacks and Hispanics may be a particularly high risk. In this study by DR. Walsh and colleagues for the University of Cincinnati, authors conducted the largest case controlled study to date on treated and untreated hypertension as a risk factor for inter-cerebral hemorrhage. They also investigated whether there was variation by ethnicity. The ethnic racial variations of inter-cerebral hemorrhage or eriche study is a prospective multi-center case controlled study of inter-cerebral hemorrhage among Whites, Blacks and Hispanics. Cases were enrolled from 42 recruitment cites, controls were matched cases one to one by age, sex, ethnicity and metropolitan area. A total of 958 white, 880 black and 766 Hispanic cases of inter-cerebral hemorrhage were enrolled. Untreated hypertension was more highly prevalent in Blacks at almost 44 percent and Hispanics at almost 47 percent compared to whites at 33 percent. Treated hypertension was a significant independent risk factor and untreated hypertension was substantially greater risk factor for all three ethnic groups and across all locations. There was a striking interaction between ethnicity and risk of inter-cerebral hemorrhage, such that untreated hypertension conferred a greater risk of inter-cerebral hemorrhage in Blacks and Hispanics relative to Whites.

 
 

 

 

 

 

 

 

 

 

 

 
The nest study provides the first prospective multi-centered data on mortality and morbidity in rheumatic heart disease from low and middle income countries. First author Dr. Zulky, corresponding author Dr. Mayoci and authors from Gertrude hospital and University of Cape Town in South Africa present the results of two year follow up of the global rheumatic heart disease registry or remedy study in 3343 children and adults with rheumatic heart disease from 14 low and middle income countries. They found that although patients were young with a median age of only 28 years the 2 year case fatality rate was high at almost 17 percent. The median age at death was 28.7 years. Mortality was higher in low income and low middle income regions compared to upper middle income countries. Independent predictors of death was severe valve disease, more advanced functional class, atrial fibrillation and older age. Where as post primary education and female sex were associated with a lower risk of death. The authors carefully noted that apart from age and gender the independent risk factors for mortality such as severity of valve disease heart failure, atrial fibrillation and low education were all modifiable and thus they called for programs focused on the early detection and treatment on clinical rheumatic heart disease.

 
 
Well that's it for the summaries, now lets go over to China

 
 
For our feature interview today we are going all the way to Beijing at the great Wall meeting where we will be meeting authors as well as editors. So here we have first and corresponding author Professor {Dong Fen Gu} and co-author Professor {Sherliang} both from {Fu Y} hospital Chinese academy of medical sciences in Beijing. Welcome

 
Dr.Gu:
Welcome we are so delighted to be interviewed by you

 
Dr. Carolyn Lam:

 
Thank you so much we are so excited to be talking about your paper predicting the ten year risks of cardiovascular disease in the Chinese population. And here we have as well editor in chief Dr. Joe Hill as well as Dr. Amid Kira digital strategies editor and associate editor. Gentlemen how is it in Beijing? And I hear that you have a Chinese greeting for everyone as well.

 
Joe Hill:
{Ni how} and {nuchme and senchmen}

 
Amid Kira:
I can't top that but I agree with what Joe said

 
Dr. Carolyn Lam:
Dr. Gu, could you please tell us what is it that is so different about cardiovascular disease in China compared to what we heard about in the western world.

 
Dr.Gu:
Okay cardiovascular disease is both leading cause of death in China and in United States as well in European countries. However the patterns for components of cardiovascular disease including coronary arteries and stroke are still quite different in the Chinese populations compared united states. For example there are coronary arteries mortality rate in the united states is along the 100 thousand per year and this is the first leading cause of death in the united states. And for stroke the annual mortality rate is along 36 per 100 thousand in the united states populations. However in china the stroke mortality rate among Chinese populations is around the 160 per 100 thousand, so that almost 3.5 to 4 as high as in untied states. Obviously for our lifestyle in including battery behavior quite different you can easily identify one kind of difference in the united states and the Europe restaurants from Chinese restaurants and some western style restaurants you can figure it out.

 
 

 

 

 

 
And another example, smoking rate is major component for risk of cardiovascular disease it is very high in Chinese adult men. It over 50 percent right now but in the united states in the past 50 years it declined immensely. And around maybe less than around 20 percent and from the previous experiment from studies by Dr. Liu Chin from and my colleague Dr.WU they used the questions for predictions of coronary arteries compared to equations and also use the similar prediction model compares that its chemical cardiovascular disease from the united states population and the Chinese population. That to over estimation if we use the united states produced this kind of equation. So based on this kind of scenario we based on Chinese long term larger scales cohort to precede and study our own prediction model.

 
Dr. Carolyn Lam:
Wow that is really fascinating Dr. Gu and I really could not agree with you more because I sort of trained in the united states for quite some time and then I moved back to Singapore and saw for myself in Asia the tremendously high rates of stroke. I was also very struck by the relative youth of the patients suffering cardiovascular disease and the differences in risk factors, the smoking but not just that, obesity is almost defined on a different scale in our relatively sized smaller Chinese population compared to that in the western. Congratulations to you and your team for a successful amazing effort. Could you or Dr. Yang now just let us know what are your main findings.

 
Dr. Yang:

 

 

 

 

 
Well I think there are 2 major finding for our work. First we developed a new prediction risk model you know after analysis is for high risk score or equations released by AJ and ACC and is some other risk scores. We included 6 conditional risk factors in combination with our previous knowledge that included age, treated or untreated ISBP, total classical, HDLC current smoking and diabetes. So this traditional risk factors were set up as a base model and then we use the predefined statistical to include new additional variables they were Chinese special elements. Finally in our model there were rates as constraints and geographic region which means northern part versus the southern part in China and also organization is rural or urban area. And finally the forth one is family history as a CVD so this for additional variables in our model suggest that we maybe as a Chinese prediction and equations has something special. For example we feel more attention for central obesity in primary prevention in Chinese populations and also you know the norther part and the southern part there are large differences in the risk profiles. And so maybe according to our risk prediction model we pay more attentions for the residence living in northern part in China.

 
 
And then for the second points I think we found that PCE equation which shows for equations was not appropriate to predict ten year risk of in Chinese populations. For example in our revelation cohort we found that our model just slightly over predicts severity risk by 17 percent in Chinese man but when we use the PCE models released form AHA the over-estimation come to 50 percent so maybe equations from western populations are not appropriate to Chinese populations.

 
Dr. Carolyn Lam:
Thank you so much Dr. Yang I mean those are just such important findings applicable to a huge population in china, like you said. And just as important as the second point that the pooled equations derived from western populations may not be the most appropriate for certain other ethnic populations. I think that a very important message and that why we are so proud to be publishing this in Circulation. Could I ask then are you applying these new equations in your personal clinical practice?

 
Dr.Gu:

 
Risk assessment is a fundamental components for prevention of ASSVD. In Chinese we question {turn the PA on} provide a valuable to identify high risk individuals in Chinese populations. And not with just complicated [inaudible 00:18:02] for further analysis. And propose three levels of groups of risk stratification could be identified by cut off 5 percent and 10 percent. So lower risk individuals with predicted activity risk of less than 5 percent should be offered lifestyle wise to maintain the lower risk status. While the moderate risk individual is predicted risk of 5 to 10 percentage for intensive therapeutic lifestyle change wit drug therapy if necessary. For the high individual risk high or large 10 percent teheraph of clinical aliment taken account for physicians recommendation should be required with therapy for the lifestyle modification. Then annually clinic up, including an echocardiographic information for carotid artery back and even for outer [inaudible 00:19:09] CT examinations for coronary artery are recommended. Also blood pressure, lipids, glucose measurement if necessary are suggest according to Chinese guideline. While cardiovascular disease prevention as well as for the epidemic of this kind a lines. For ACVD patients those are different kinds of risk assessment we could know whether their risk profile had been improved or be progressed so that appropriate clinical elements should be taken in clinical practice.

 
Dr. Carolyn Lam:
Thank you very much Dr. Gu so that just show that these findings are immediately clinically applicable and I trust that means you're suing it in your clinics too, and once again were so happy to be publishing this in Circulation so in the rest of the time in going to now direct questions at Joe and Amid.

 
 
How's China been? How are your chopstick skills and any word on how Circulation is being received there?

 
Joe Hill:
Well Carolyn its a delight to be here this is a bustling media that get better and better every year. In about 2 hours we have our first ever Circulation session, we brought several editors here to discuss the types of content that we are looking to publish, the type of work across prevention and population and electrophysiology of heart failure. This is an extraordinary media that is now internationally acclaimed and as we've heard here, the face of cardiovascular disease in Asia is changing. And as you pointed out 60percent of the human race lives in Asia and we want to do everything we can to be here on the ground, in Asia trying to address this curve that is already present and is worsening by the day.

 
Dr. Carolyn Lam:
Amid, you know you've seen the latest statistic on our podcasts and you highlighted that we have quite a number of listeners over there as well. Would you like to tell me how this is all blending it to the digital strategies and anything else you might want to highlight?

 
Amid Kira:
Sure its been an incredible meeting and we get to meet great colleagues like our colleagues today on this podcast and learning so much from this meeting. Our podcast as you pointed out quite a sizable and growing cadre of people in Asia and Japan and China who are listening and we truly want to enhance that as Joe mentioned with the large splurge of cardiovascular disease and the great science that is going on here. Want to make sure that we are able to be apart of that conversation and interact with researcher and clinitions here. In addition to podcast, we are exploring some other options involving social media, specifically in China so stayed tuned in how those develop but we certainly appreciate the importance of being her and interacting where so much of cardiovascular disease and cardiovascular science is occurring.

 
Dr. Carolyn Lam:
That's so great. Joe or Amid now there's a specific we would like to highlight to our listeners the doodle, either of you want to pick that up a bit about blipping the doodle?

 
Amid Kira:
So there is as you know Circulation now has this doodle where we change it periodically and its sort of a fun themed thing. Right now I think it Halloween and we've had several other ones that people have designed to sort of keep thing fresh and light and interesting. There's a new app called blippar which you can download from iTunes or android stores and you can essentially scroll that over with your phone with the doodle and that will take you to new content either table of contents of videos, different kinds of content that it can navigate you to. So I hope people will not only enjoy the doodle kind of anticipate what's next in terms of seasons but will take the time t blip the doodle when they get a chance.

 
Dr. Carolyn Lam:
That great and that blippar- B l I P P A R. You really c should check it out, anyone who is listening to this really check it out you'll be floored. Joe could I just turn the mic to you for any last words about the global outreach of Circulation, I mean its just so amazing that you're there in China

 
Joe Hill:
Well heart disease Carolyn knows no boundaries nor does Circulation. There was a day when cardiovascular disease was largely an issue in the developed world that is long since gone and that's why the study that we are talking about today with these authors is so important because the face of cardiovascular disease is different than in the west, the ways in which it is  evolving id different here than in the west and I like many others foresee an increase a significant increase in the types and prevalence of heart disease here in Asia. for all the reasons that we have been talking about, hypertension, obesity, type two diabetes, smoking the environment all of these challenges I fear are going to lead to a substantial increase in the prevalence of heart disease in Asia and that why we're here on the ground with Circulation in Asia that's why we have one of our major leaders Chong Shong Ma who is here in Beijing. Circulation is in China everyday, it’s in Beijing everyday to try and address this problem.

 
Dr. Carolyn Lam:
And you heard it from our editor and chief, so thank you everyone for listening to this episode of Circulation on run. Tune in next week.

 
 

 

Oct 31, 2016

 

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. Our interview today comes to you live from Rome at the European Society of Cardiology, where I talk to authors of The STICH Trial, about their ten year outcomes that help to answer the question, "Is there such a thing as being too old for coronary artery bypass surgery in heart failure?" But first, here's your summary of this week's journal:

 
 
The first paper provides experimental evidence that hypertension may be a bone marrow disease. In this paper, first author Dr. Wang, corresponding authors Dr. Li and [Sia 00:00:50] from The First Affiliated Hospital of Dalian Medical University in China, recognize that recruitment of leukocytes from the bone marrow to the vascular wall is a key step in the development of hypertension. Numerous factors stimulate this leukocyte migration during inflammation, including chemokines, which are low molecular weight proteins of the cytokine family which activate g-protein coupled receptors and induce migration of neutrophils, monocytes, and macrophages to the damaged vascular wall.

 
 
In this study the authors focus on chemokine receptor CXCR2. Using mouse models with hypertension they found that aortic MRNA levels of CXCR2 and its ligand CXCL1 are elevated in these mice with hypertension. They elegantly demonstrated that mice lacking CXCR2 are protected from blood pressure elevation, vascular inflammation of inflammatory cells, fibrosis, reactive oxygen species formation, NADPH activation and vascular dysfunction in response to either angiotensin 2 or [dolcasalt 00:02:01].

 
 
These results were recapitulated using a novel, allosteric inhibitor of CXCR2. Importantly, they also showed in 30 hypertensive patients compared to 20 normatensive controls that hypertensive patients have increased numbers of circulating CXCR2-positive cells and that there is a correlation between blood pressure and the number of CXCR2-positive cells in the circulation.

 
 
In summary, these findings that CXCR2 inhibition prevents and reverses hypertension and vascular dysfunction in response to multiple hypertensive stimuli really help us to understand the mechanisms involved in CXCR2 action, but also point to a potential clinical use of CXCR2 inhibition for the treatment of hypertension. This is discussed in a beautiful accompanying editorial by Drs. [Montenel 00:02:56] and Harrison.

 
 
The next study suggests that the eyes provide a window to long-term cardiovascular risk. In this paper from first author Dr. [Seidelman 00:03:12], corresponding author Dr. [Solomon 00:03:13] and colleagues from the Brigham and Women's Hospital, authors investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up, and whether they provide incremental value over the 2013 ACCAHA pooled cohort equations in predicting atherosclerotic cardiovascular disease events. They studied 10, 470 men and women from the [Eric 00:03:41] or Atherosclerosis Risk in Community Study who underwent retinal photography at their third visit, which occurred in 1993-1995.

 
 
During a mean follow-up of sixteen years, narrower retinal arterials, but wider retinal venules were associated with long-term risk of mortality and ischemic stroke in both men and women. Coronary heart disease in women was also related to narrower retinal arterials and wider retinal venules independent of the the pooled cohort equation variables. In fact, retinal vessel caliber reclassified 21% of low-risk women as intermediate-risk for atherosclerotic cardiovascular disease events.

 
 
In discussing the clinical implications of these findings, the authors noticed that identification of coronary heart disease is frequently delayed in women and this under-recognition may party be due to the fact that non-obstructive coronary artery disease is more prevalent in women and micro-vascular dysfunction may largely contribute to myocardial ischemia in women. Since the retinal vessels offer an insight into micro-vasculature, adding retinal imaging may be of incremental value to current practice guidelines in risk prediction in low-risk women. This, of course, deserves further study.

 
 
The next study challenges the traditional focus on macro-vascular disease in Type 2 diabetes, namely myocardial infarction, strokes, and peripheral artery disease, and causes us to focus on micro-vascular disease instead. In this paper from first author Dr. [Sorrenson 00:05:33], corresponding author Dr. [Stiehauer 00:05:36], and colleagues from the Maastricht University Medical Center in the Netherlands, authors hypothesized that micro-vascular dysfunction occurs in pre-diabetics, which may explain the increased risk of complications of micro-vascular origin in pre-diabetes and early Type 2 diabetes.

 
 
They studied 2,213 individuals in the Maastricht study, which is population-based cohort study enriched with Type 2 diabetes, and they determined micro-vascular function, measured as flicker-light-induced retinal arterial[inaudible 00:06:12] percentage dilatation, as well as heat-induced skin percentage hyperemia. They found impaired retinal and skin micro-vascular function in pre-diabetics with further deterioration in patients with Type 2 diabetes. Inverse linear associations were found between micro-vascular function and measures of glycemia such as HBA1C, fasting and two-hour post-op glucose levels. All associations were independent of cardiovascular risk factors.

 
 
The clinical implications are that micro-vascular dysfunction in pre-diabetes may at least partially explain the increased risk of complications that are known to be of micro-vascular origin such as retinopathy and albuminuria but also diseases such as heart failure and cognitive decline. The take-home message is that both early hyperglycemia and micro-vascular dysfunction may be considered potential targets for early preventive intervention.

 
 
Well, those were your summaries! Now, let's on to Rome.

 
 
Hello, I'm Dr. Carolyn Lam, associate editor of Circulation, and I am so delighted to be reporting from Rome this time at the European Society of Cardiology. We are discussing the 10-year followup paper on STICH that includes an age analysis that is being featured as a hotline session of clinical trials update. I'm here with the distinguished guest, the first author, Dr. Mark Petchey, from University of Glasgow, the corresponding author Dr. Eric [Moleskus 00:07:51] from Duke University, and the associate editor who managed this paper, Dr. Nancy [Scheitzer 00:07:56] from University of Arizona. Welcome! [crosstalk 00:07:59]

 
 
Right, let's get straight into this. Eric, remind us what it first showed and why there's a need to look at the effective age.

 
Dr. Eric M. :
Thank you Carolyn. Thanks to Circulation and to both of you for really helping us work through this paper. We are very excited that we're being able to feature this work in Circulation. So, a STICH trial is a reminder. Surgical treatment of ischemic heart failure trial has been a 15-year effort actually that started with the first patient enrolled in 2002, enrollment ending in 2007 and at the ACC with the simultaneous fabrication in the journal, we published the 10-year results of the STICH trial, combining medical therapy vs. cabbage plus medical therapy in patients with ischemic cardiomyopathy defined as an EF less than 35%. Coronary disease [inaudible 00:08:51] to cabbage was over 90% having class 2 or greater heart failure systems.

 
 
What we showed in our 10-year results was that cabbage, when added to guideline-directed medical therapy, led to a substantial reduction in all-cause mortality, cardiovascular mortality as well as all-cause plus cardiovascular hospitalization in those patients who were randomized to the cabbage arm. This translated to about an 18 months extension in survival for the cabbage patients over that time period, a 16% relative risk reduction in mortality and nearly a 10% after the risk reduction is all-cause mortality, with the number needed to be treated of approximately 14.

 
 
With those findings, the next question that we want to address rapidly was whether there was an impact by age. This is what we're here to talk about, mostly because everyone recognizes that age is, although something we can't control ... As we age, our risk for everything increases, and clearly heart failure, which is the field that we work in clinically, patients who are older in heart failure have more risks, and worse clinical outcomes in patients who are younger. Whether there would be a benefit that would persist in terms of the treatment in younger as well as older patients was really the subject of this analysis.

 
Dr. Carolyn Lam:
That's great. So maybe, Mark, you could tell us the highlights of the results. Give us an idea, first of all, of the age range that we're talking about, what you looked at. And then- this is definitely going to be an issue if we're talking about age- the relative risks vs. the absolute risk of the different types of outcomes.

 
Dr. Mark P:
Sure. So, the patients in the STICH trial were similar age to a normal heart failure trial. The median age was around 61. What we did to look at the patients we had in the trial, we looked at quartiles, first of all. So the lowest quartile was aged less than 54, and the highest quartile aged more than 67. So we had a fair spread of age. We didn't have many patients, we were very elderly or very old. So 65% were above age 75 and 1% above the age of 80. When we looked at the patients we saw a similar [inaudible 00:11:18] to a usual heart failure trial. The older patients had more co-morbidities, not surprisingly, and they had more... they basically died more often as they got older as we see in every other trial.

 
 
When we started looking at the results, the treatment effects of cabbage, obviously we were very eager to know if the benefits, which Eric's talked about already were seen across all age groups. I think clinicians, when they look at patients for bypass surgery have anxieties around sending older people for bypass surgery. We were thrilled is probably the word to say that we say benefits across all age ranges. So the point has been for us in terms of all-cause mortality were all [less than one 00:11:58]. We saw consistent benefit, or certain across-the-board benefit in terms of all-cause mortality.

 
 
What we did see that we were very interested about were the younger patients got more benefit in terms of all-cause mortality, [inaudible 00:12:12] quite strikingly more. The risk reduction was over 40% for the ... We saw upper age groups having benefits with [hazard issues 00:12:24], risk reductions of, roundabout, the [teens 00:12:28], as in the major overall trial results, the younger patients got particular benefit.

 
 
We then looked at cardiovascular mortality and we saw a slightly different pattern. We saw the benefit was actually quite similar across all age groups. The older patients were getting the similar reduction in cardiovascular mortality as the younger patients. So there's the main take-home findings.

 
Dr. Carolyn Lam:
OK, so by extrapolation then, the younger patients, a greater proportion of their deaths were probably cardiovascular, or there's a bit more of a competing risk, so to speak from non-cardiovascular deaths in the elderly, is that kind of the idea?

 
Dr. Mark P:
Carolyn, that's exactly right. Because the cardiovascular mortality was similar across all age groups, because all people, as we know, die more commonly of non-cardiovascular events, we saw that clearly in the trial the benefits in terms of all-cause mortality weren't quite as much. Just to emphasize, the cardiovascular reduction was consistent across all age groups.

 
Dr. Carolyn Lam:
With bypass compared to medical, yes.

 
Dr. Mark P:
Exactly.

 
Dr. Eric M. :
I think an important aspect to remember and I think STICH reminds us is that even in the oldest population- and although we did these analyses continuously, we described this in quartiles for the purpose of the paper- we have to remember in heart failure patients like these who have coronary disease, cardiovascular death is the most common cause of death, regardless if you're young or old. What happens is that as we get older, there is an increasing rate of non-cardiovascular deaths. It's not surprising to us, that of the findings we found, which is that as the risk of non-cardiovascular deaths increase in the ages, the impact on all-cause mortality is mitigated slightly, while the effect on cardiovascular mortality remains consistent because it's still by far the most common cause, I think more than double the cause even in the oldest group.

 
Dr. Carolyn Lam:
That's a great point. Now I've got to ask something though. What did you do about crossovers? Because this is a 10-year thing. The original results of STICH came out 5 years. You'd expect that there's quite a bit of crossover or no?

 
Dr. Eric M. :
I'll just comment on the effect of crossovers in STICH in general, and then we can focus on the age analyses. What's really interesting is that in STICH approximately over time, over the time period, there was approximately an 18% rate of crossovers. That actually led to, by the intention to treat analysis, a decrease in the effect [inaudible 00:15:15] intention to treat. But when you look at crossovers, the medical therapy patients who were randomized to medical therapy but received cabbage at some point, and the patients who were randomized to cabbage but never did receive cabbage. But actually when you look at as-treated analyses, by the treatment they received, not [inaudible 00:15:36] they were randomized, the effect of cabbage actually increases. The relative risk reduction is about 25% in that group. Thankfully, the effect of crossover into different age quartiles were [inaudible 00:15:51] different. We had the same, relatively the same effect, so there were no, we were [eventually knowing 00:15:57] to make sure that there was no increase in crossover rates in the older vs. the younger and we did not find that. I started the discussion, maybe you can complete it.

 
Dr. Mark P:
Thank you for hitting the nail on the head, Eric, that there weren't many crossovers, but if there were crossovers, if the crossover towards the cabbage, the benefits seemed the be greater and that was seen across all age groups. There was no differential between the older patients and the younger patients.

 
Dr. Carolyn Lam:
You know then, I just want to know what's your take-home message and then I'd really like to hear from Nancy the take-home message we wanted to convey in our journal.

 
Dr. Mark P:
I think for me the take-home message goes back to the fundamental approach to assessing a heart failure patient in a clinic. Over the years there's been a tendency for patients not to investigate and look for coronary heart disease. People tend to focus on medical therapy and device therapy but the coronary arteries have been the poorer cousin. I think we would urge people to think about revascularization by surgery, coronary artery bypass drafting's a treatment for  for heart failure, so certainly, my practice, we look for coronary artery disease more than we think about the patient and weigh out the pros and cons and certainly this analysis was done to give us [granularity 00:17:14] from the perspective of the older person and the young person and the relative benefits. Basically, it's steered me towards looking for coronary artery disease. Also you can inform the patient in the clinic and have discussions with the surgeons about the benefit in terms of the all-cause mortality across the age group, and the cardiovascular mortality as well.

 
Dr. Carolyn Lam:
Yeah, it's consistent. That's brilliant. Nancy, speak on behalf of our journal.

 
Dr. Nancy S.:
So at Circulation, we were very excited to get this paper because as heart failure clinicians, we all struggle with this issue in older patients in particular. When we look and find coronary disease, these tend to be patients with higher surgical risks. Our surgical colleagues are often hesitant to operate. The benefits are perhaps less apparent, and this data's very helpful to show us that in a patient in whom the heart disease is the primary morbidity, surgical revascularization has a clear benefit for these patients.

 
 
I do think that it's important to remember though, that STICH population is a selected population, and probably a little healthier than the average patient we see in clinic. As Mark rightly pointed out, the discussions with surgical colleagues I think can now occur with a greater level of data substantiation and understanding of the true benefits, and then competing risks and morbidities in this patients need to be considered with the reality that surgical revascularization benefits the patients. We're really excited to have worked with you, this fantastic group of authors to get this paper to a point where I think it's really going to have a clinical impact, and that's what we're trying to do. As you know, Carolyn, editorial board at Circ now has published really high-quality science that's going to impact the practice of clinicians seeing patients on a daily basis.

 
Dr. Carolyn Lam:
Thanks so much for that Nancy, and actually I was going to congratulate you gentlemen. In your paper you so humbly said that these are exploratory, I think, and I was actually thinking that we're never going to have a better trial than this and it's something I am personally taking to be clinically applicable in my heart failure patients so congratulations. I'm going to switch tracks a little bit... we're actually going to a simultaneous publication in Circulation from the European Society of Cardiology and I think that's really neat for our journal, Circulation. I want to ask each of you as author perspective and as associate editor who made this happen, what do you think of these simultaneous publications? Were there challenges, what was it like, and what was your experience like?

 
Dr. Mark P:
So I have to confess that usually when we submit papers for review, there is a mixture of trepidation, fear, generally quite negative thoughts. We submitted it, and I've got to say that it was the most interactive, positive experience I've had so far. It was quite clear that was interested in the data, and wanted to publish it in a way that informed the clinical community. They certainly worked with us to make sure the message was honed and as accurate as possible to reflect the results. We were really thrilled. It was a "breakneck pace" is also probably the best way to describe it. We worked day and night actually, but there was phone calls and emails happening in very rapid sequence and lots of responsiveness. I could almost describe it as "fun".

 
Dr. Carolyn Lam:
Kudos to you, Nancy! And from your point of view, was it fun?

 
Dr. Nancy S.:
It actually was fun.

 
Dr. Carolyn Lam:
(laughs)

 
Dr. Nancy S.:
You know, we've all had the experience of- on both sides- being an editor and being an author. Getting a paper, getting reviews, sending it back, getting the revision, it's not quite what you want, reviewing it again, sending it back, getting it back, it's not quite what you want, and then you feel obligated to publish a paper that's not really what you want. What we've decided to do is a much more interactive process to say "We're going to work with you to make this the paper we want to publish. We hope that as authors that's the paper you want to have written." We're doing this on a regular basis at Circulation but this was at hyperspeed, I would say.

 
Dr. Carolyn Lam:
[inaudible 00:21:34] how long?

 
Dr. Nancy S.:
We knew the paper was going to come in. We had been in contact with Eric. I identified reviewers before we even received the manuscript. I identified reviewers who would commit to a 72-hour turnaround. In fact, our reviewers did it in less than 24 hours. Then I looked at it, added to it, called Eric, and we talked it over. And then we sent it back with the formal replies. I think Mark then worked 24/7 to get it back to us very quickly. I worked with one of the senior associate editors; at that point we didn't involve the reviewers. We basically track-changed the paper to make the changes we really thought were necessary at the point. It wasn't a lot but I think they were critically changes. At that point, Mark and Eric were kind enough to accept those changes and the paper was on track for simultaneous publication. I do want to mention that we have simultaneous publication of five different presentations here at ESC in Circulation online which is certainly a record for Circulation and we're really proud of that.

 
Dr. Eric M. :
First of all, I want to think the journal. Really a remarkable, wonderful experience. I've been very fortunate in my career to be in a position to submit simultaneous publications previously, and this was a wonderful- I think it was a 14-day turnaround, it was remarkable. And the responses from the reviewers were outstanding even if they were reviewed in a very short time, and I think the paper definitely improved.

 
 
A general comment about simultaneous publications as you bring it up, I think it's an area of controversy. I think my perspective as a person who does clinical trials, as well as sees a lot of patients, there's an ethical mandate that exists to... Once you have information that you're putting out there, to be in a position, if we think it's clinically impactful, and we feel that the data is mature, to get that into people's hands, all of it, as soon as possible. There's a certainly a difference between what I can speak to in 8-10 minutes on stage with slides that will get distributed anyway across the world, and what, with Nancy's help, we are able to put into journal-wide circulation and really explain the story and give it a full [vetting 00:24:05]. I feel like, from the ethical perspective, being able to push forward with this simultaneous publication is in the best interest of our patients, and it's so exciting to see Circulation now doing this with the European Society, which is a remarkable achievement for this new editorial board, so thank you again.

 
Dr. Carolyn Lam:
You've been listening to Circulation on the Run. Tune in next week for more.

 
 

Oct 24, 2016

 

Carolyn:
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. We have such a special podcast for you today. The entire podcast is going to be a conversation with two very special guests, Dr. Marc Ruel from The University of Ottawa Heart Institute, the guest editor of the surgery themed issue this week. Hi Marc.

 
Marc:
Hello Carolyn. How are you?

 
Carolyn:
Very good. Especially because we also have Dr. Timothy Gardner, Surgeon, Associate Editor from Christiana Care Health System. Welcome back again, Tim.

 
Timothy:
Thank you, Carolyn. Glad to be here.

 
Carolyn:
Marc, could you first give us an overview of the surgery themed issue from your perspective.

 
Marc:
This year as we have had on previous years, we are having a surgery themed issue which comprises what I would argue which is some of the very best cardiac surgical science can offer to the wide readership in the cardiovascular community that served by circulation. This year, we will have a total of ten articles that would be published in circulation, as a section of one of our regular issues and out of those ten, there are five original papers. There's one research letter which is an original research article but in a shorter format and we'll also have one invited perspective paper namely about coronary artery bypass grafting and its future with respect to multi-arterial grafts and the themed issue will be completed by three state of the art papers that deal in a very in depth comprehensive way with some important problems that the cardiovascular community faces from a clinical point of view.

 
Carolyn:
Thanks Marc. That was a beautiful summary of the issue. I couldn't help but notice that there was a theme of coronary artery bypass surgery covering at least four of the papers and I really like your thoughts on that. You covered everything from medical therapy, CABG versus PCI, on versus off-pump, emergency surgery in the setting of shock. Could you go through each of these four papers a little and tell us what was your take home message from each?

 
Marc:
As you said, there are three original research articles and one invited perspective that relate to coronary artery bypass grafting surgery and these encompass the number of clinical problems that are still controversial and certainly I believe they contribute a very, very significant [inaudible 00:02:31] with the wealth of knowledge that the cardiovascular community is looking for at this point. If I may go one by one, just with a very high level overview, if you will. The first one is a paper from the Leipzig Heart Center with first author, [Pieroz Adewalla 00:02:45], which looked at surgery for acute myocardial infarction but accompanied with cardiogenic shock. As you know, many patients undergo surgery in an acute MI context, but surgery for cardiogenic shock is often a very gruesome difficult decision.

 
 
Leipzig Heart Center looked at over 3,000 patients who had an acute MI prior to cardiac surgery for bypass surgery and of these, there were 508 patients who actually had cardiogenic shock due to [valve 00:03:15] failure with myocardial dysfunction and to give you an idea, these patients were quite sick. There's about 40% of the patients who were ventilated prior to surgery or very close to 40%. The timing was quite urgent, those patients were on inotrophes and on vasopressors to support their blood pressure prior to operation. Essentially, what they found is that first the outcomes got better over the last number of years, this is a series that dates back to about the 2000's, so the early 2000's.

 
 
They also favor an approach where they tried to avoid a cardioplegic arrest of the heart. Their favored overall approach is to do what we call on-pump beating heart type of surgery which would be a surgery where the cardioplegia would not be administered to stop the heart but the hemodynamics would be supported for the cardio coronary bypass. They also have over the years since the beginning of this year, is in 2000 ranging up to 2014 of increasing the use of the off-pump bypass surgery and certainly the outcomes have been better and the mortality although high has decreased significantly. It was as high as 40% in the early parts of the cohort if you will and in the latest third of the experience, therefore from 2010 to 2014, the mortality has been down to about 25%.

 
 
Again, these are patients who present with cardiogenic shock. What's also interesting to note is that patients who survive out of hospital still have a significant mortality burden and about 50% of them survive long term. What was interesting is the  Leipzig group is looking at some predictors of bad outcomes in those patients and they found that the serum lactate over four minimal per liter was actually a very robust and multi-variative predictor of a poor outcome after surgery.

 
Carolyn:
That was a great summary of that first paper. You mentioned beating heart surgery and so on. Would you like to comment on next paper that I think was the largest single institution European study comparing on versus off-pump bypass surgery?

 
Marc:
You're absolutely right. This is a paper from England, [inaudible 00:05:25] from Liverpool, where the patients were gathered from and with some contribution from Oxford as well from a statistical and methodological point of view and it's a retrospective cohort study of all isolated CABG patients in Liverpool between 2001 and 2015. These are bypass surgery patients and in total, there were over 13,000 patients who had CABG. About 6,000 patients had off CAB which is off-pump bypass surgery and more than 7,000 had bypass with cardiopulmonary bypass. The median follow up was 6.2 years. What's interesting in this paper is that they essentially found equivalent long term outcomes. As you know, there has been some debate regarding the completions of myocardial revascularization and the long term graft patency with off-pump surgery versus on-pump surgery. Also named conventional CABG.

 
 
What's interesting here is that the benefits of off-pump CABG appear to be seen early on with regards to antiemetic release as stroke rates, etc. Which does correspond to some of what has seen in the randomized controlled studies. However, the long term data is interesting. There's a a nice editorial about this paper written from a group from the Cleveland Clinic with Dr. Joe Sabik as the senior author and essentially it raised a number of good points, although this is an important series, it also shows that the surgeons who are very good at off-pump bypass surgery may overall be slightly technically more skilled at doing bypass surgery in itself and for instance, use more often arterial grafts and have more advanced techniques in their completion of bypass surgeries for their patients.

 
Carolyn:
Right. I'm so glad you mentioned the editorial. I was about to bring that up as well. Switching gears to you very kindly included a paper that talked about medications and the impact of here is the medical therapy on the comparative outcomes between CABG and PCI. Would you like to discuss that paper?

 
Marc:
This is a paper from the Care Registry which has generated some interesting publications in the past. The lead author is Dr. Paul Polinski and there's co-authors, Dr. Herbert Prince and Michael Mack from Dallas as well. This was presented at the science sessions in Orlando last November and it's an interesting paper. Essentially they have looked at large databases, again the Care Registry which comprises eight community hospitals and they look at six month period of performance of CABG and those eight community hospitals. They ended up with over 2,700 patients who were then systematically followed on a regular basis up to 2009 at which time the database was locked.

 
 
They look at various outcomes but also medication use in great detail over that period of time and the interesting perspective that this paper brings is that first, most patients at least in that period were not on optimal medical therapy. The authors used their own predefined definitions of what constitutes optimal medical therapy and this is with regards to adherence to aspirin use, lipid lowering agents, beta blockers and indicates of PCI, dual anti-platelet therapy. As expected but nicely documented in this paper, the outcomes of patients who were not on optimal medical therapy were much worse than those who were and CABG proved to be more robust in patients who were not on optimal medical therapy compared to PCI.

 
 
The differences between CABG and PCI in patients who were on optimal medical therapy tended to vanish. However, a number of caveats here is that only 25% of patients in fact in this cohort were on optimal medical therapy. The vast majority of patients were not considered to be on optimal medical therapy. Therefore, there are considerations of definitions that one has to be aware of and also considerations of statistical power because the group that was on optimal medical therapy was much smaller than the other group. Therefore, the effects, the superiority of CABG over PCI could only be firmly demonstrated in the group was not on optimal therapy, again comprising 75% of patients in this cohort.

 
Carolyn:
I love your summaries and they really show that these are true significant original contributions to that knowledge gaps in coronary artery bypass surgery. To round it all up, you also invited a perspective on novel concepts. Would you like to comment on that paper?

 
Marc:
This is an invited perspective in the view classifications that circulation has which is entitled, "The evolution of coronary bypass surgery will determine relevance as a standard of care for the treatment of multi-vessel CABG." It is authored by three leaders in the field, Dr. Gener, Dr. Gudino, and Dr. Grouw. Dr. Gener has been leading several of what I would call the advanced multi-vessel coronary re-vascularization trials looking for instance at multi-arterial grafts doing numerous anastomosis with two ventral mammary arteries in a wide fashion. He's been a leader of this movement certainly. Dr. Gudino recently published [inaudible 00:10:43] the 20 years of outcome of the radial artery graft and certainly has been one of the pioneers which use of this arterial graft for coronary artery bypass surgery. What the authors provide here is a very nice summary of what the trials have shown so far and they also report as many know that their rate of multi-arterial grafts use in SYNTAX, FREEDOM and I think we will soon see in EXCEL and NOBLE that will be presented this fall, has not been as high as it should have been.

 
 
In the US, it is estimated right now that the rate of use of more than one mammary artery is less than 10% across the nation, and other countries have not performed better than this either. This perspective is a call to improving the quality of multi-vessel coronary artery bypass mainly through the use of multiple arterial re-vascularization. There is also considerations around the hybrid coronary re-vascularization and as well as the use of off-pump versus on-pump surgery.

 
Carolyn:
I am really proud and privileged to have helped to manage one of the papers as associate editors in this issue as well and that is the paper from the group with corresponding author, Dr. Veselik, from Boston Children's Hospital and it centers around patients with congenitally corrected transposition of the great arteries but a management problem that is really increasingly encountered and really needs to be reviewed properly and that is the management of systemic right ventricular failure in these patients. Tim, you were so helpful in looking at this paper as well. Could you share some of your thoughts?

 
Timothy:
Well, this is a somewhat unique situation where a patient with this condition, congenitally corrected transposition of the great arteries may go through early life, in fact may end up as a young adult before this particular condition is identified because if there is no shunting or no cause for cyanosis and heart murmurs and so on early on, the circulations seem to work pretty well until the poorly prepared right ventricle which is the systemic ventricle, starts to fail after years of work carrying the systemic circulation and that is really the focus of the paper. There's been a lot of work and publications and attention to transposition syndromes but this particular one is a condition that may be first encountered by adult heart failure cardiologist who have not had this kind of exposure to congenital heart disease. It's a particularly apt paper to bring this condition to our attention and to demonstrate that really it's the adult heart failure cardiologist who may be managing these patients in their late 20's or 30's, when that systemic right ventricle fails because of a lack of formation to manage the systemic circulation.

 
Carolyn:
Exactly. Written by a group that has one of the most robust experiences in this field, so that also brings to mind another state of the art article in the issue that refers to the hypoplastic left heart syndrome and though it's entitled that and people may think it's rare, I think it's increasingly being seen in the adult cardiology world as well. You want to comment on that one?

 
Timothy:
That actually is one of the main points of this paper that this very, very difficult condition of hypoplastic left heart syndrome that requires staged operations beginning in the neonatal period has now reached the state of surgical accomplishment in medical management where many of these young children are surviving into young adulthood. Albeit, with having had two, or three, or four operations. In a community like ours here in Delaware, where pediatric patients transition to adult services and adult cardiologist sometime around their 20's, it's really important for the entire cardiology community to be aware of what has happened in terms of the successful staged treatment of children with hypoplastic left heart syndrome and that is brought out very nicely by the three authors who look at various accomplishments and different techniques for managing these staged repairs. It is very amazing to someone who has been observing this field for sometime as I have, that many of these children are in fact surviving into young adulthood and will require comprehensive cardiovascular treatment, not just by neonatal specialist but by specialist in adult congenital heart disease.

 
Carolyn:
Exactly, which is why such a timely state of the art articles both of them for this issue. There is another state of the art article that you were handling, Tim, "The Surgical Management of Infective Endocarditis Complicated by Embolic Stroke", now that's an important topic.

 
Timothy:
Absolutely, as we know up to a half or more of patients with infective endocarditis primarily on their left sided heart valves will have cerebral embolic problems and it has really been a dilemma for many of us in terms of optimal timing for the cardiac surgery with respect to the existence of cerebral injury from the embolism, from hemorrhage that may occur, from hemorrhage that may be exacerbated by placing the patient on the heart-lung machine, etc, and this paper really takes an extremely comprehensive, careful and judicious look at all of the evidence that has emerged and it has been a confusing field of evidence as to how to best optimally manage these patients with cerebral involvement from infective endocarditis.

 
 
I think this paper is going to have a big impact. It appears that there are a couple of messages that I took away from this paper. Number one, we really need to use the full panoply of diagnostic opportunities or diagnostic test for characterizing the nature and the extent of the cerebral involvement in these patients and then perhaps even more important, we need to convene what the authors called the infective endocarditis team and that has to include not just the surgeon, the cardiologist and the infectious disease specialist but also the neurologist, the neuro-interventional specialist, the neurosurgeon and so on because all of these specialist need to contribute to the assessment and choosing the optimal timing for these patients.

 
 
That is the central message of the paper. The authors also suggest that we may be getting to the point where we need to update and make sure that the guidelines that we're using are in fact current. Current in the sense that the experience now with advance imaging and with more aggressive management of the neurological or cerebral issues really need to be factored into how best to handle these patients, but I think this paper is going to have a big impact, it's very well written and very thorough.

 
Carolyn:
I agree. In fact all the content we just discussed is just so rich. Congratulations on such a beautiful issue. Marc, do you have any last highlights you'd like our audience to hear about?

 
Marc:
I'd like to also mention two other original research papers that will be featured in the surgery themed issue. One, in keeping with the congenital theme that we had talked about is about the modified [Straun's 00:19:08] procedure for palliation of severe Ebstein's anomaly and this is a series actually from Professor [Straun 00:19:16] himself mostly originating from Children's Hospital Los Angeles and essentially, the series here is that of 27 patients about equal in gender distribution who were operated at seven days of life, between 1989 and 2015.

 
 
It's very interesting that patients did well, the survival at ten years is 76% and most of them have undergone successful Fontan completion. I think this is a very important paper not only because it is an extremely vexing and difficult problem to deal with Esbtein's anomaly but it comes from the innovator of the operation himself with his team and it provides much needed data regarding the long term outcomes of these children with this very difficult solution. I think this will be of great interest and also as we commented before veering into the world of adult cardiology as well, because fortunately most of these patients survive into adulthood.

 
 
The other paper I wanted to touch upon which is also an original research paper that will be in this themed issue, is a paper from the CTSN Group looking at the impact of left ventricular to mitral valve are being mismatched on recurrent ischemic MR after ring annuloplasty and this paper used the free innovative and interesting methods. As some of you may know, there were two large files recently that were conducted by the CTSN looking at either moderate MR at the time of coronary artery bypass grafting or at severe ischemic mitral regurgitation. The randomizations were different when the moderate MR was CABG lone versus CABG post mitral valve repair and the severe MR was mitral valve repair versus mitral valve replacement.

 
 
These studies have led to interesting conclusions that several will know about but what's been interesting in the current study is that they have gathered all patients who underwent mitral valve repair from both studies, original randomized trials and they ended up with about 214 patients who underwent mitral valve repair. The others had moderate or severe MR and basically the point of this study is to look at predictors of failure of mitral valve repair and this is an extremely relevant problem, not only for the cardiac surgical community I would venture, but also for heart failure community and for JV General cardiology community. What the others found is that the most important predictor of recurrent mitral regurgitation after mitral valve repair was something called the left ventricular and systolic diameter to ring size ratio and they provide an algorithm which will have to be tested clinically with regards to whether it is applicable and indeed changes outcome, but this is a very important discovery in the field of ischemic MR and enabling us to hopefully better understand and improve outcomes for patients with this very difficult problem.

 
Carolyn:
I agree. Thank you so much, Marc and Tim for this most insightful discussion. Thank you very much and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next next week for more highlights and features.

 
 

Oct 17, 2016

Carolyn:
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. Have you ever wondered what the clinical implications of very brief episodes of device-detected atrial tachyarrhythmias are? Well, we will be discussing this with novel data from the RATE registry in just a moment. First, here's your summary of this week's journal.

 
 
The first study provides the first evaluation of the Sweden nationwide abdominal aortic aneurysm screening program. Of almost 303,000 men invited for screening, 84% attended. The prevalence of screening detected abdominal aortic aneurysm was 1.5%. After a mean of 4.5 years, 29% of patients with aneurysms had been operated upon with a 30-day mortality rate of 0.9%. The introduction of screening was associated with a significant reduction in aneurysm-specific mortality. The number needed to screen to prevent 1 premature death was 667, while the number needed to operate on to prevent 1 premature death was 1.5.

 
 
Furthermore, the authors showed that their screening program was highly cost-effective in the contemporary setting in Sweden. These findings confirm results from earlier randomized controlled trials in a large population-based setting, and may be important for future healthcare decision-making. This and the diverse requirements for efficient population screening for abdominal aortic aneurysm, from program management to maintaining skills in open repair are discussed in an excellent accompanying editorial by Dr. Cole from Imperial College London.

 
 
The next study looks at thoracic epidural anesthesia and suggests that caution may be needed in patients with or at risk for right ventricular dysfunction. You see, thoracic epidural anesthesia involves blockade of cardiac sympathetic fibers, which may affect right ventricular function and interfere with the coupling between the right ventricle and right ventricular afterload. Dr. Wink and colleagues from the Leiden University Medical Center therefore used combined pressure volume conductance catheters to study the effects of thoracic epidural anesthesia on right ventricular function and ventricular pulmonary artery coupling in 10 patients scheduled for lung resection.

 
 
Thoracic epidural anesthesia resulted in a significant reduction in right ventricular contractility, stroke work, dP/dt max and ejection fraction. This was accompanied by a reduction in effective arterial elastance such that ventricular pulmonary coupling remain unchanged. Clamping of the pulmonary artery increased right ventricular contractility but decreased ventricular pulmonary coupling. These effects of increased afterload were the same before and after thoracic epidural anesthesia. In conclusion, therefore, thoracic epidural anesthesia impaired right ventricular contractility but did not inhibit the native positive ionotropic response of the right ventricle to increase afterload. These findings are clinically relevant for daily practice in cardiothoracic surgery because pulmonary hypertension is frequently encountered, and right ventricular function is an important determinant of early and late outcomes.

 
 
The next study suggests that the use of point of care hemostatic testing may have a place in the management of patients undergoing cardiac surgery. Dr. Karkouti and colleagues of the Toronto General Hospital hypothesized that point of care hemostatic testing within the context of an integrated transfusion algorithm would improve the management of coagulopathy in cardiac surgery, thereby reducing blood transfusion. They therefore conducted a pragmatic multi-center stepped-wedge cluster randomized controlled trial of a point of care based transfusion algorithm in 7,402 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass in 12 hospitals in Ontario, Canada. They found that the trial intervention reduced rate of red cell transfusion with an adjusted relative risk of 0.91 and a number needed to treat of 24.7.

 
 
The intervention also reduced rates of platelet transfusion and major bleeding but had no effect on other blood product transfusions or major complications. These findings that point of care testing improved management of coagulopathy in cardiac surgery support the consideration of their broader adoption in clinical practice.

 
 
The next study provides experimental evidence that brings us one step closer to therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis. In this study from first author Dr. Ortega-Gómez, corresponding author Dr. Soehnlein and colleagues from LMU Munich, authors focus on cathepsin G, which is stored in neutrophil and azurophil granules and discharged upon neutrophil activation. They studied site-specific myeloid cell behavior after high-fat diet feeding or TNF stimulation in the carotid artery, the jugular vein, and cremasteric arterioles and venules in APOE E and Cathepsin G-deficient mice.

 
 
Their studies revealed a crucial role for Cathepsin G in arterial leukocyte adhesion, an effect that was specific for the arteries and not found during venular adhesion. Consequently, Cathepsin G deficiency attenuated atherosclerosis but not acute lung inflammation. Mechanistically, Cathepsin G was immobilized on arterial endothelium, where it activated leukocytes to firmly adhere, engaging endocrine clustering, a process of crucial importance to achieve effective adherence under high-sheer flow.

 
 
Therapeutic neutralization of Cathepsin G specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of Cathepsin G-neutralizing antibodies really allowed the inhibition of atherogenesis in the mice. Taken together, these findings presented evidence of an arterial-specific recruitment pattern centered on Cathepsin G adhesion, thus representing a potential novel strategy and target for the treatment of arterial inflammation. Well, that wraps it up for the summary of this week's journal. Now, for our featured discussion.

 
 
Our feature paper for today discusses the clinical implications of brief device-detected atrial tachycardias and really novel findings from the RATE registry. I'm so happy to be here with the first and corresponding author, Dr. Steven Swiryn from Feinberg School of Medicine, Northwestern University. Hi, Steven.

 
Steven:
Good morning.

 
Carolyn:
We also have with us Dr. Mark Link, associate editor from UT Southwestern. We all know that prolonged episodes of atrial tachycardia or atrial fibrillation are associated with increased risk and that if we anticoagulate those with a high CHA2DS2–VASc score, we can lower the risk of stroke. Now, the European Society of Cardiology guidelines also say that recent data reinforced the assumption that even brief episodes of silent atrial fibrillation may convey an increased risk of stroke. We also know that prior studies have looked at device-detected atrial fibrillation. Steven, I'd really love if you could start by telling us what makes your study different. What was the main thing you were trying to look at?

 
Steven:
Well, one reason it's attractive to use the device population, patients with pacemakers or defibrillators, to look at these issues is because devices have a very high likelihood of detecting episodes of atrial fibrillation whereas symptoms or single 12 EKGs miss a lot of atrial fibrillation, so the sensitivity is much higher, although not perfect. The problem is that very brief episodes of atrial fibrillation are very poorly detected by devices. The specificity of automatic detection is very low, such that all previous studies until the RATE registry have excluded any episode of atrial fibrillation detected by a device less than 5 minutes in duration because they're unreliable. A lot of them turn out to be false positive detections. Our study was designed to evaluate whether even very brief episodes of an atrial tachyarrhythmia might also be associated with risk of clinical events and might or might not warrant anti-coagulation.

 
Carolyn:
Ah, that's interesting, so you really helped to answer how brief is "brief" when we need to talk about device-detected atrial fibrillation. Could you expand on how you actually defined "short episodes" here?

 
Steven:
Right. A short episode for the purpose of the RATE registry was defined as an episode where the electrogram that we scrutinized had both the onset and the offset of the episode within the same electrogram tracing, so although we can't put a specific time duration on it because that wasn't part of the criterion, it's typically less than 20 seconds or so, although not always, whereas a long episode was defined as an electrogram where either the onset and/or the offset was not captured by the device memory and therefore we don't know the duration. Some of those may not have been very long, and some of those may have been extremely prolonged episodes. That allows us to actually scrutinize the electrogram. We looked at 37,530 individual electrograms using 8 teams of adjudicators, each with a physician and a field clinical engineer from the device company so that we could actually say definitively, "Yes, this was atrial fibrillation," or, "No, it wasn't."

 
Carolyn:
This is the first study to really look under that 5-minute limit of atrial tachycardias. What did you find?

 
Steven:
Well, we found that in contrast to prolonged episodes, short episodes of atrial tachyarrhythmias were not associated with an increased risk compared to those without atrial fibrillation of pre-defined clinical events, including death from any cause, heart failure, stroke, hospitalization for atrial fibrillation, and a few other smaller events.

 
Carolyn:
This was over a 2-year follow-up period, is that right?

 
Steven:
The median follow-up was slightly less than 2 years, that's right.

 
Carolyn:
What I really was struck with was also the second finding, the propensity to develop longer episodes. Could you expand on that?

 
Steven:
We reasoned that in the clinic, one might be faced with a short episode was we defined them, and then you don't know what's going to happen for the next 2 years to bring to bear the results of our study. We looked at if your first episode was short, what was your likelihood over the full follow-up of the study of progressing to longer episodes. About 50% of patients who had their first episode as only a short episode progressed to a longer episode over the full follow-up and therefore were in the long category for the rest of the results. Half of them never got a longer episode.

 
 
It was, as one might imagine, if you had your first short episode very early in the study and had a longer follow-up, you were more likely to end up in the long category, and if you had very frequent short episodes, you were also more likely to end up in the long category by the time the full follow-up was over with. Having an initial short episode is not a guarantee that you're never going to get a long episode and that you'll never acquire a consideration of anti-coagulation.

 
Carolyn:
That was a very important message to me as well because it meant that although I can be secure or reassured by these data for very short episodes, I needed to look out for the development of longer episodes, at least that's what your registry showed over 2 years of follow-up. I'm curious, Mark, what were your take-home messages because that leaves us with a bit of a conundrum. What do we do about anti-coagulation in these patients?

 
Mark:
I think this study is a big help to the practicing electrophysiologist and practicing cardiologists. It's a very ledger number of patients with a lot of episodes of afib. It's reassuring to me that the shorter episodes of afib as defined by the study, the individuals did not have a higher incidence of stroke compared to those with no episodes, so it's reassuring and very important clinically as I go through my practice.

 
 
I do look forward to more analyses and more data from this study because although now we know that episodes less than 20 seconds are in all likelihood not going to need anti-coagulation, we still don't know about those from 20 seconds to 5 minutes. Hopefully with more analysis of this study we'll get that answer also.

 
Carolyn:
Steven, do you agree with that?

 
Steven:
We would love to have that. At first glance, you would think that devices would give you all of the data you needed because after all, they're monitoring the patient 100% of the time, but there are difficulties with that because device memory is limited, and you don't get electrograms that go on until the termination of atrial fibrillation even if the device were accurate in determining when that termination was because depending on how the device was programmed and depending on whether it was a more modern device later in the trial or earlier and had more or less memory, it cuts off after a limited amount of time, and you don't see necessarily how long the duration is.

 
 
Now, you can use device-based data. The device gives you its estimate of how long the episode is, but those are not as reliable as adjudicating the electrograms and actually looking at them. Those data would be a little softer than the main results if we get there.

 
Mark:
That was the data that was used for all of the other studies, was [transassert 00:14:51]. It would be comparable to those other studies. I still think it would be very important data that I'd love to see.

 
Steven:
Okay, well, I agree. I think it would be very interesting to look at that and a number of other things. We have a number of other things we could do with this database. There are a number of substudies that are in progress. For example, one interesting one is there were some instances we found, because we actually looked at these electrograms, there's something that we termed "competitive atrial pacing," where the device will pace at times when we as clinicians would not want to pace. For example, pacemaker-mediated tachycardia would be an instance of that, but then you can pace in the atrium inappropriately. There's a rhythm called repetitive non-reentrant ventricular atrial systole, which, although it's exotic to all of us, actually turned out to be fairly common where there's pacing in the atrium that occurs for various reasons when we want it to.

 
 
We actually saw instances where the device itself induced atrial fibrillation. It wasn't that common, but we did see it. We have a substudy that we're working on about the subjective competitive atrial pacing to see how much of that there was and of what, if any, consequence that was. That's one of the things that's been done. Because we scrutinized these so carefully, we tracked morphology and atrial rate at least as a crude estimate, and we have those data, so we could actually evaluate whether if something looks very, very rapid and disorganized as opposed to more organized electrograms at a slower rate, did that make any difference. We don't have any results for those analyses yet. I agree with Mark that the intermediate durations would be interesting to look at.

 
Carolyn:
I agree too, and I'm really grateful for you sharing those thoughts. Very grateful for both of you for your time today. I just have to congratulate you. I completely agree this paper fills an important knowledge gap, and congratulations once again.

 
Steven:
Thank you very much.

 
Mark:
Thank you.

 
Carolyn:
Thank you for listening. You've been listening to Circulation on the Run. Please tune in next week.

 
 

 

Oct 10, 2016

 

Carolyn:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke-National University of Singapore. Today's featured discussion deals with the perspective piece entitled, What I Wish Clinicians Knew About Industry and Vice Versa. Intriguing, isn't it? I can tell you it is one of the best papers I have ever read, so stay tuned. First, here's your summary of this week's journal.

 
 
The first study takes a step towards understanding atrial fibrillation on a more fundamental level by demonstrating that some patients have altered left ventricular myocardial energetics even in the absence of other comorbid diseases. First author, Dr. [Veejay Surendra 00:00:50], corresponding author, Dr. [Cassidy 00:00:53] and colleagues from the University of Oxford studied 53 patients with lone atrial fibrillation undergoing catheter ablation and compared them to 25 matched controls without atrial fibrillation. They did this using sequential studies of cardiac function with magnetic resonance imaging as well as energetics with phosphorus-31 magnetic resonance spectroscopy.

 
 
At baseline, there was subtle but significant left ventricular dysfunction and abnormalities in ventricular energetics in patients relative to controls. Following ablation of atrial fibrillation, left ventricular function measured by ejection fraction and peak systolic circumferential strain improved rapidly with a switch to sinus rhythm but remained at normal at 6 to 9 months. Although pulmonary vein isolation effectively eliminated atrial fibrillation in all the patients in the study, the hearts continued to express an energetic profile consistent with a myopathic phenotype meaning that the ratio of phosphocreatine to adenosine triphosphate was lower in the atrial fibrillation compared to controls irrespective of recovery of sinus rhythm and freedom from recurring atrial fibrillation.

 
 
The clinical implications of these findings are that apparently lone atrial fibrillation may actually be a consequence rather than a cause of an occult cardiomyopathy and that this cardiomyopathy is unaffected by ablation. Of course, future studies are needed to prove this and to examine whether therapeutic strategies that target the adverse cardiometabolic phenotype could reduce atrial fibrillation recurrence. These important issues are discussed in an accompanying editorial by Doctors Hyman and Callans.

 
 
The next study provides experimental evidence that suggests we may finally have an answer to heart failure preserved ejection fraction or HFpEF, and that is the modification of titin. Titin is a sarcomeric protein that functions as a molecular spring and contributes greatly to left ventricular passive stiffness. The spring properties can be tuned through post-transcriptional and post-translational processes and their derangement has been shown to contribute to diastolic dysfunction in patients with HFpEF. The current paper by first author, Dr. Methawasin, corresponding author, Dr. Granzier and colleagues from University of Arizona provide important proof of principal investigation of the effects of manipulation of titin isoforms as a treatment for a transverse aortic constriction murine model of progressive left ventricular hypertrophy leading to HFpEF.

 
 
Conditional expression of a transgene with deletion of the RNA recognition motif for one of the splicing factor, RBM20 alleles, resulted in reduced splicing and a substantial increase in larger more compliant titins that were named super compliant titin. The result was normalization of passive stiffness of isolated muscle strips as well as normalization of left ventricular diastolic function and chamber stiffness as assessed by echocardiography and pressure volume analyses. There were no effects on extracellular matrix stiffness. The authors also showed that other spliced targets of RBM20 did not contribute to the results and thus, the beneficial effects were almost certainly entirely related to the changes in titin isoforms.

 
 
Furthermore, treadmill exercise was used to show that treated animals displayed improved exercise tolerance. In summary, the study showed that increasing titin compliance in this murine model resulted in marked improvement in multiple measures of diastolic function and performance, thus suggesting that titin holds promise as a therapeutic target in HFpEF. This is the discussed in an excellent accompanying editorial by Dr. LeWinter and Dr. Zile.

 
 
The next study adds importantly to evidence that heavy physical exertion and anger or emotional upset may act as triggers of first myocardial infarction. In this paper by first author, Dr. Smith, corresponding author, Dr. Yusuf, and colleagues from the Population Health Research Institute Hamilton Health Sciences and Master University, authors explored the triggering association of acute physical activity, anger, and emotional upset with acute myocardial infarction. They did this in the inter-heart study which was a case control study of first acute myocardial infarction in 52 countries. In the current analysis, the authors used a case crossover approach to estimate odds ratios for acute myocardial infarction occurring within 1 hour of triggers.

 
 
Of 12,461 cases, 13.6% engaged in physical activity and 14.4% were angry or emotionally upset in the case period referring to the 1 hour before symptom onset. Physical activity in the case period was associated with an increased odds of acute myocardial infarction with an odds ratio of 2.3 and a population attributable risk of 7.7%. Anger or emotional upset in the case period was associated with an increased odds of acute myocardial infarction of more than 2.4 odds ratio and a population attributable risk of 8.5%. Importantly, there was no effect modification by geographic region, prior cardiovascular disease, cardiovascular risk factor burden, prevention medications, time of day, or day of onset of acute myocardial infarction.

 
 
Interestingly, the authors did find an interaction between heavy physical exertion and anger or emotional upset with an additive association in participants with exposure to both in the 1 hour prior to the acute myocardial infarction. The take home message, these findings suggest that clinicians should advice patients to minimize exposure to extremes of anger or emotional upset due to the potential risk of triggering an acute myocardial infarction. While heavy or vigorous physical exertion may also be a trigger, this did not refer to just any physical activity and the authors cautioned that this must be balanced against the known well-established benefits of regular physical activity over the long term and clinicians should continue to advice patients about the life-long benefits of exercise.

 
 
The last study provides insights in the molecular mechanism in pulmonary hypertension. First author, Dr. Lee, corresponding author, Dr. Stenmark, and colleagues from the Pediatric Critical Care Meds and CVP Research University of Colorado Denver hypothesized that metabolic reprogramming to aerobic glycolysis may be a critical adaptation of fibroblast in the hypertensive vessel wall, an adaptation that drives proliferative and pro-inflammatory activation through a mechanism specifically involving increased activity of the NADH sensitive transcriptional corepressor, C-terminal-binding protein 1.

 
 
The authors assessed glycolytic reprogramming and measured NADH to NAD+ ratio in bovine and human adventitial fibroblast as well as mouse lung tissues. They found that expression of the C-terminal-binding protein 1 was increased in fibroblast within the primary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with pulmonary hypertension. Furthermore, treatment of fibroblast from the pulmonary hypertensive vessels of hypoxic mice with a pharmacological inhibitor of C-terminal-binding protein 1 led to a normalization of proliferation inflammation and the aberrant metabolic signaling.

 
 
In summary, these result showed that C-terminal-binding protein 1, a transcription factor that is activated by increased free NADH acts as a molecular linker to drive the proliferative and pro-inflammatory phenotype of adventitial fibroblast within the hypertensive vessel wall. Thus, this metabolic sensor may be a more specific target for treating metabolic abnormalities in pulmonary hypertension. Those were your summaries. Now for our feature paper. Our feature today is special on so many levels, and because it's so special, I actually have Dr. Joe Hill, editor-in-chief of circulation from UT Southwestern here today with me. Hi Joe.

 
Joe:
Sure. As always, it's a pleasure to be here with you. This is a new type of content where we solicit thought leaders from a variety of vantage points around the cardiovascular space to provide their perspective on the future of cardiovascular Science in medicine. Rob Califf, the FDA Commissioner, provided his perspective on the regulatory role interfacing with cardiovascular medicine and Science. Victor Dzau who presides over the National Academy of Medicine in the United States did the same, provided a very insightful perspective from his vantage point now, formerly in academia, but now overseeing this advisory board to the policy makers in Congress. Today, we're going to talk about a perspective that emerges from industry, from someone who also has a strong and long history in academia.

 
Carolyn:
That is a perfect lead up. The title of the paper; What I Wish Clinicians Knew About Industry and Vice Versa. Here is the amazing guest that we have today, it's Dr. Ken Stein, Chief Medical Office of Rhythm Management at Boston Scientific. Hi Ken. It is a very, very intriguing title and I'd like you to first describe to us what makes you the person who can talk about being a clinician and going over to the dark side of industry and vice versa?

 
Ken:
Thanks Carolyn and Joe. I think right now just get over my embarrassment at being called a thought leader and being mentioned in the same as Rob Califf and Victor Dzau. I met both of them but I don't think I've ever been mentioned in the same sentence as either them and probably never will be again. Why me to do this? Again very gracious of Joe to invite the submission. My history, I've been in industry now at Boston Scientific for 7 years, and prior to that was an unreformed academic faculty at Cornell. Ever since I did my training, eventually becoming co-director of the EP Lab there for many years. Then 7 years ago, the opportunity came up to leave the cloistered ivory towers of academia and to join industry. It's been a very interesting and I think very productive ride ever since.

 
Carolyn:
I have to tell you that your article is just one of the most well-written pieces I have ever read and I mean that sincerely. You began with the story that everybody asked you this question. Why did you do it? What did you learn? I'm going to ask that of you today. Tell us.

 
Ken:
In the 7 years, I get 2 questions all the time. One is, do you miss practice? The answer is, there are things about practice that I miss very deeply and that is really the engagement that you get with patients and families. I think we always have to remember as caregivers, we're privileged to be able to do what we do. On the other hand is, but I do get an opportunity to participate in decisions now that rather than affect one patient at a time, for better or for worse, affect hundreds of thousands of patients at a time.

 
 
The other question is, what surprised you? What have you learned? What didn't you know about industry? As I thought about it, it's 2 things. It's one that I think in retrospect I was and I think many of us are way too cynical about the motivations of industry, how industry operates. The other shock, if you will, was that it goes 2 ways and there's a lot of cynicism in industry about physician motivations and how physicians operate on a day to day basis.

 
Carolyn:
Really? Do you have any examples of that?

 
Ken:
I'll give you a couple of examples. First, from the point of view of how does industry work and what are the motivations in industry. One of the first decisions that I had to make 7 years ago after joining the company was to issue a recall on one of our products. It actually was a recall that had not yet failed in the field but we had some bench testing that suggested that there was a particular risk to some patients and novel to the industry and the whole thing. This is not go over well with the CEO, but in fact, really the only question people ask is, is this the right decision for patients? That was a really gratifying piece of education to me.

 
 
The flip side of the coin, we did introduce a new battery technology in our fibrillators and CRT devices just before I joined the company that basically doubled the amount of battery capacity that we have in the devices. It's one of the funny things. There are still editorials being written in journals other than circulation, I'll say, that still say that industry will never increase battery longevity of their devices but cost us money because we lose money on device replacements. We've done it and a lot of our competitors are in the process of doing it.

 
 
When I got to the company, what I found is there was a tremendous amount of angst within the leadership of the company. Do doctors do this or are they afraid in a fee-for-service environment to give up what they get doing battery replacements on short-lived devices. Of course that cynicism is unfounded. That doctors have embraced longer, better battery life technology.

 
Joe:
Ken, to hear you say this is interesting and frankly inspiring. You can't pick up a copy of the New York Times right now and not read about some issue around drug pricing and some of the companies that have done the wrong thing with. They've increased prices hundreds of percentage, 400%, even more. To know from your perspective that those are perhaps the exceptional circumstances and that there are many, many companies who of course have to keep a business running but at the same time they truly have the patient at heart. You have said and you said in your piece that as the Chief Medical Officer, you're the voice of the patient at your organization.

 
Ken:
I aim to be. That was the lesson I learned from Don Baim who really ... Don passed away very shortly after I joined the company, who's really a giant in cardiology. I wish that I had been able to spend more time with him as a mentor but that was very important statement he made. Say he's right, there are bad actors, there are bad actors in industry, there are bad actors among physicians, there are bad actors among academics, but that's not generally true. I also want to be careful not to be misconstrued. Skepticism and doubt are important. Cogito ergo sum, it's not just I think, therefore I am, it's probably better understood that I doubt, therefore I think, therefore I am. Skepticism is fundamental to scientific process, but there's this border that you cross over where constructive skepticism turns into destructive cynicism. I'm afraid gets in the way of our ability to work together to better the outcomes, better welfare of patients.

 
Carolyn:
Do you think we've swung from the United States maybe you could give me your opinion to the wrong end of that balance between constructive skepticism and destructive cynicism? Joe, what do you think?

 
Joe:
As someone who has not worked in my own research closely with industry, sometimes I think that we have. I mean, there are certainly many examples. We all know where people have crossed the line and that is profoundly unacceptable, but at the same time, I worry that we've thrown the baby out with the bathwater and some of the things that are uniquely done in academia and some of the things that are uniquely done in industry, a synergy between them across the divide is essential to move this field forward. I think sometimes the boundaries and the bright lines separating them are so distinct and defined that it prevents those source of synergies.

 
Carolyn:
Thank you for that paper that really provides that balanced perspective. The beautiful thing, it's just so personal almost. It feels like we're sitting with you, having a conversation when we're reading that paper. Like now, it's just been an amazing experience having you on this podcast. Do you have any last messages?

 
Ken:
My last words. I again just want to thank you and thank Joe. Has the pendulum swung too far? Thing about pendulums are that they oscillate and I think what's needed is a willingness to watch out that it doesn't swing too far. Is there cynicism? I'll admit, I was flabbergasted and I still flabbergasted that you allowed me to write this piece but I think the fact that you welcomed the piece from someone in industry within the intent of bringing this out, that is the pendulum not going too far. As long as there are voices, editors, journals who are willing to help us articulate points like this, I think that's at least what keeps us in a reasonable balance.

 
Joe:
As Carolyn said, you brought a uniquely human conversational element to this piece. Not everybody would publish a piece in circulation and acknowledge that you are intimated and embarrassed walking into Don Baim's office. That brought us right into your living room and that was powerful.

 
Ken:
Honestly, I wasn't looking for the job. I was more interviewing them to find out what I can about the company, but I did not want to make an ass of myself in front of them. I felt like I was [pieing 00:19:53] for fellowship. I walked in the door and honestly I'm still standing with my hand on the doorknob and he looks up at me and I have to remember his voice, he had that deep sort of growly voice. He said, "Stein, you have no idea what Chief Medical Officer does, do you?" I'm just thinking, do I try to BS my way out of this or do I just give him the God honest truth and turn around and go back to work. I said, "No, Dr. Baim." I couldn't call him [inaudible 00:20:22] and to the end, I told him, "Dr. Baim," I said, "I had no idea." That's when he said, "Your job is to be the voice of the patient within Boston Scientific." He said after that, "You don't need to know anything about business. We know you don't know anything about business. We've got a lot of MBAs and hopefully they do."

 
Carolyn:
Thank you once again for the paper, for this discussion. Thank you both for being here. For all of you who are listening, thank you for joining us again on Circulation on the Run.

 
 

Oct 3, 2016

Carolyn:
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.

 
 
Today, we will be discussing an interesting Danish nationwide cohort study on the return to the workforce following first hospitalization for heart failure, but first here's your summary of this week's journal.

 
 
The first paper addresses a common question asked by patients who have survived an aortic dissection. Will this happen to me again? First author, Dr. Isselbacher, and corresponding author, Dr. Lindsay, and investigators of the International Registry of Aortic Dissection investigated this in the largest systematic analysis to date of patients presenting to hospital with a recurrent aortic dissection.

 
 
In this large registry, the authors identified 204 patients with recurrent aortic dissection and compared these to 3624 patients in the registry with an initial aortic dissection. They found that patients with recurrent dissection were more likely to have Marfan syndrome, but not bicuspid aortic valve. Descending aortic dimensions were greater in those with recurrent dissections than those with only an initial dissection, and this was independent of the sentinel dissection type. In multivariable analysis, the diagnosis of Marfan syndrome was independently predictive of a recurrent aortic dissection with a hazards ratio of 8.6.

 
 
Furthermore, they found that the patient's age at the time of first dissection correlated with the anatomic pattern of aortic involvement. In younger patients, dissection of the proximal aorta tended to be followed by dissection of the distal aorta, whereas the reverse was true among older patients suggesting divergent mechanisms of disease.

 
 
In summary, therefore, this study shows that recurrent aortic dissection while in common does occur and in fact affected 5% of those in this registry. The data really illustrate the importance of syndromic forms of aortic dissection and suggest that occurrence of a recurrent dissection should raise suspicion of a genetic etiology of aortic disease.

 
 
The next study provides pre-clinical data suggesting that counteracting increased hepcidin may be a therapeutic target for treatment of intracerebral hemorrhage. In this study from first author, Dr. Xiong, corresponding author, Dr. Yang, and colleagues from Xinqiao Hospital, the Third Military Medical University in China, parabiosis and intracerebral hemorrhage mouse models were combined with in vitro and in vivo experiments to investigate the roles of hepcidin in brain iron metabolism after intracerebral hemorrhage. Hepcidin in an important iron regulatory peptide hormone that controls cellular iron efflux.

 
 
The authors found that increased hepcidin-25 was found in the serum and astrocytes after intracerebral hemorrhage. In hepcidin-deficient mice with intracerebral hemorrhage, there was improvement in brain iron efflux and protection from oxydative brain injury and cognitive impairment, whereas, the administration of human hepcidin-25 peptide in these mice aggravated the brain injury and cognitive impairment.

 
 
In vitro studies showed that increased hepcidin inhibited intracellular iron efflux in  brain microvascular endothelial cells, but this phenomenon was rescued by a hepcidin antagonist. Additionally, toll-like receptor 4 signally pathway increased hepcidin expression, whereas, a toll-like receptor 4 antagonist decrease brain iron levels and improve cognition following intracerebral hemorrhage.

 
 
In summary, the study showed that increased hepcidin expression caused by inflammation prevented brain iron efflux and aggravated oxidative brain injury and cognitive impairment, thus, counteracting increased hepcidin maybe a mechanistic target to promote brain iron efflux and attenuate oxidative brain injury following intracerebral hemorrhage.

 
 
The next basic science paper provides fascinating insights into the similarities between advanced atherosclerotic lesions and tuberculous granulomas, both of which are characterized by a necrotic lipid core and a fibrous cap. First author Dr. Clement, corresponding author Dr. Mallat, and colleagues from the University of Cambridge Addenbrooke's Hospital in United Kingdom looked at the C-type lectin receptor 4E which has been implicated in the events leading to granuloma formation in tuberculosis.

 
 
The authors hypothesized that the same C-type lectin receptor 4E may be involved in the formation of atherosclerotic lesions as well. They addressed this hypothesis by examining the impact of receptor activation on macrophage functions in vitro and on the development of atherosclerosis in mice. They showed that C-type lectin receptor 4E was expressed within human and mouse atherosclerotic lesions and was activated by necrotic lesion extracts. The receptor signaling in macrophages inhibited cholesterol efflux and induced endoplasmic reticulum stress responses leading to the induction of proinflammatory mediators and growth factors.

 
 
Furthermore, repopulation of LDL receptor-deficient mice with C-type lectin 4E receptor-deficient bone marrow reduced lipid accumulation, endoplasmic reticulum stress, macrophage inflammation, and proliferation within developing arterial lesions that's significantly limiting atherosclerosis.

 
 
In summary, this paper shows that C-type lectin receptor 4E orchestrates major pathophysiologic events during pluck development and progression, and thus, provides a mechanistic explanation for the close association between necrotic lipid core formation and the development of inflammatory advanced atherosclerotic lesions.

 
 
The last paper examined the impact of optimal medical therapy in the dual antiplatelet therapy or DAPT study. In this paper from first author, Dr. Resor, corresponding author, Dr. Mauri, from the Brigham and Women's Hospital in Boston and colleagues, authors sought to assess the impact of optimal medical therapy use on long term patient outcomes and on the treatment benefit and risk of continued dual antiplatelet therapy, and they did this using data from the DAPT study which was a randomized placebo control trial comparing 30 versus 12 months of final prudent therapy on the background of aspirin after coronary stenting.

 
 
Optimal medical therapy was defined as a combination of statin, beta blocker, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker used in patients with an ACC/AHA class 1 indication for each medication. Endpoints included myocardial infarction, major adverse cardiovascular and cerebral vascular events or MACE, and GUSTO moderate or severe bleeding events.

 
 
Of 11,643 randomized patients with complete medication data, 63% were on optimal medical therapy. Between 12 and 30 months, continued final prudent therapy reduced myocardial infarction compared to placebo in both groups and had consistent effects on the reduction in MACE, and an increased bleeding regardless of the optimal medical therapy status. In other words, the P for interaction was nonsignificant for these comparisons.

 
 
Importantly, patients on optimal medical therapy had lower rates of myocardial infarction, MACE, and bleeding compared to patients not on optimal medical therapy. Rates of stent thrombosis in death did not differ. The take home message is therefore, that more emphasis on the use of optimal medical therapy after coronary stenting is needed, but the decision to continue dual antiplatelet therapy beyond 12 months should be made irrespective of the optical medical therapy status.

 
 
Those were your summaries. Now, for our feature paper.

 
 
Our feature paper today discusses a really important, but frankly, often neglected outcome in heart failure, and that is return to the workforce following first hospitalization for heart failure, and I'm really pleased to have the first and last author of this really special Danish paper, Dr. Rasmus Rorth and Dr. Soren Kristensen, both from the University of Copenhagen, here to join me today. Hello, gentlemen.

 
Soren:
Hello and thank you for having us, Carolyn.

 
Rasmus:
Hello.

 
Carolyn:
As a very special third guest, we actually have editorialist, Dr. Martin Cowie from Imperial College London as well. Hi, Martin.

 
Martin:
Hi, Carolyn. Nice to be part of the conversation.

 
Carolyn:
This is going to be so fun. Let's get straight into this. Rasmus, maybe you could start by telling us. This return to work concept is hardly addressed in guidelines, it's so important, and yet, you are one of the first if not the first to take a look at it. What inspired you to do this?

 
Rasmus:
First of all, we are very inspired to work with heart failure because heart failure is a common costly, disabling, and deadly disease, and furthermore, information on young patients with heart failure is vast.  We know that they have a high hospitalization rate and a low mortality rate compared to all the patients. We also know from some of the big trials that young heart failure patients report low quality of life. Therefore, we wanted in this study to examine return to work for a number of reasons.

 
 
First of all, it gives off some information of the patient's performance basis and we get some information of their quality of life and mental status, and one more reason that is not that common for us as clinicians to think about is also for society, the economic burden these patients play in the society, and all of these reasons inspired us to get into this exciting field.

 
Carolyn:
I really appreciated that you did this because the patients that I see here in Asia are on average 10 years younger than the heart failure patients that have been seen in other European registries and so on, so it is a very, very important aspect because my heart failure patients are often the sole breadwinners of families here. Could you, maybe, Soren, share with us what are those unique resources that you manage to look at this in such detail in the Danish registries?

 
Soren:
The unique quality in Denmark is that you have the unique identifying numbers for all the citizens of Denmark and these numbers are not only used in the health systems. They're also used for administrative registries for tax paying and for state funds and pensions. We were able to link information from the hospital discharge registries with information on tax paying and whether or not people are getting pensions. In that way, we could follow all patients who stayed in Denmark at least to see whether or not they were receiving any funds, any pension, or sick leave money, or things like this from the state, or whether they upheld a position. That's what makes the Danish system a bit unique, that we have this ability to track the patients across all the fields of society and also that we have a public health system which all patients are included in, and the private sector is negligible in Denmark.

 
Carolyn:
Wow. Listening to that is making all epidemiologist everywhere really drool. That is such a precious system to look at this. What were your main findings, Rasmus?

 
Rasmus:
Maybe I should explain a bit about the setting. This is a nationwide-based study starting where we identify the patient with the first heart failure hospitalization, 18 to 60 years in the period from 1997 to 2012, and we followed them onwards. In our primary analysis, we only included patients in the workforce, that means either employed or available for the labor market at time hospitalization. That is the setting of the study.

 
Carolyn:
Could you share your main findings and your take home messages?

 
Rasmus:
Our primary outcome of this study is that after one year, 25% of the patients did not return to the workforce and we had a low mortality, only 7% died.

 
Carolyn:
Twenty-five percent didn't return to the workforce?

 
Rasmus:
Yeah, and keeping in mind, Carolyn, these are patients in the workforce at their first hospitalization and also young patients. Our take home patient from this paper is that patient in the workforce at heart failure hospitalization had a low mortality for the high risk of [inaudible 00:13:41] from the workforce at one year of followup. Furthermore, we look at some association effect associated with returning to work, and we found that young age, male sex, and high level of education were associated with high likelihood of returning to work.

 
Carolyn:
Martin, you wrote just a beautiful editorial. I have to say I was chuckling and enjoying it as I read it. I could hear your voice in it. What do you make of these results in the interpretation?

 
Martin:
I was really pleased to see something published by this really important topic that is largely ignored, and as you said in your introduction, the guidelines, if you read them you'll think that nobody of working age ever develops heart failure. There's no mention at all about return to work. There's no mention of the kind of urgent need to be able to provide people with the counseling about the heart failure and how it might impact their work, and also, no interaction, no mention of interaction with employers to tell them, "Yes, this person have this condition, but actually, could do their job or stay in the same job," or "How we can help support them?"

 
 
I think this article which is so good to see graded publish in Circulation and I think we have to see it in the context of other occupational rehabilitation work which shows that if you don't get people back to work quite quickly after a major event in their lives, then you'll never get them back, and that's got huge consequences for them in their mental health, their economic, social, family, and never mind the healthcare system. It's really nice to see this work and I hope many people read it and quote it.

 
Carolyn:
Martin, you've been to Asia. You know that our patients are strikingly young, but I wonder, do you think these results are extrapolatable outside of Denmark?

 
Martin:
I think this comment and not an editorial, Denmark, of course, is a relatively small country. It's wealthy. It's different from the states, but it's very different from Asia as you say, so lots of heart failure patients in Asia are young, of working age, and quite often, their families depend on them.

 
 
I think the tactics may have to be different to different countries, but the general principles are the same that we, as a heart failure team, as heart failure doctors, have to think about the person not just in terms of the left atrium and left ventricle, or even of the whole body function, but actually, what is their role in their family, what are they trying to achieve in life, how can we support them about way, because otherwise, we're really failing our patient.

 
 
I think, in Asia even more than in some wealthy, rich countries where there's a lot of safety nets, it's really important. I'd be interested in your comment, Carolyn, on what you think we can do to improve right across the world in terms of occupational rehab.

 
Carolyn:
First, I think it begins with awareness and that's why I just wanted to tell Soren and Rasmus how much I enjoyed this paper and I will be citing it because I think it's so important especially in the younger heart for the community, but can I ask you, Soren or Rasmus, have these findings changed your practice in any way or to be even more provocative, do you think that maybe return to work should be a benchmark to evaluate heart failure programs?

 
Rasmus:
Martin also points out that, first of all, we need to shed light on this hidden fact of heart failure, and afterwards, I think it's also a very good policy metrics to use in the future to see how our patients do.

 
Carolyn:
Are there efforts in Denmark to improve this as a yardstick?

 
Soren:
I'm quite sure that, by large, it's not really registered who is working, who is not working there. There's not much attention to it. We're all focusing very much on the performance of the patient of the NYHA class and so on, so I think we should put more emphasis on this issue and we should, as Martin also added, that we should discuss with the patients if they could change their job or their positions in some ways to better cope if they lost some of their performance, because we're both think and we both agree with Martin that it's a huge quality of life to be able to maintain your job in one way or the other, and we should definitely put more focus on that, but I'm afraid to say that I don't think we put much focus on it in Denmark at this time, but hopefully, we will.

 
Martin:
I think you're right, the attitude have to change across the world, don't they, and they start with the heart failure team and the patients because I think most doctors and nurses and patients assume diagnosis of heart failure, that means really nothing can be the same again, but we really should be trying to return people to their optimal function, and I'm sure we can do a lot more, but perhaps, we need to upscale the workforce and knowing about the key things about occupational counseling, and maybe also [inaudible 00:18:30] interact with employers a little bit more without patient's permission to give them the confidence to have this person re-enter the workforce in a supported way because I'm sure the employers value many of these people and would be pleased to see them still in the workforce.

 
Rasmus:
Exactly. I even think that could be like a fair way of trying to help the patient by relieving them from their job, which is actually will be a big mistake for some patients [inaudible 00:18:54] as a physician to help them with making sure they don't have to return to their job and fill out the statements and everything, but this may not be the best for the patient.

 
Martin:
Exactly.

 
Carolyn:
Gentlemen, I have enjoyed this conversation so much. Thank you for taking the time to discuss this very important paper.

 
 
You've been listening to Circulation on the Run. Tune in next week for more.

 

Sep 26, 2016

 

Dr. 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 in Duke National University of Singapore.

 
 
Today we will be discussing the first multinational study looking at per-cutaneous device closure of peri-valvular leaks, a topic I'm certain you'll recognize as rapidly developing in cardiology, but first, let me fill you in on the highlights of this week's journal.

 
 
The first paper is a translational study telling us that when transfusing stored red blood cells for hemorrhagic shock, cold transfusing hemopexin and heptoglobin may be beneficial. This study is from first author Dr. Graw, and corresponding author Dr. Zapol and colleagues from the anesthesia center for critical care research at Massachusetts General Hospital and Harvard Medical School.

 
 
These authors reasoned that erythrocytes undergo progressive deleterious changes during storage. Such that, the transfusion of long-stored, packed red blood cells increases plasma levels of cell-free hemoglobin and heme. These are toxic breakdown products of hemolyzed erythrocytes.

 
 
Now, mammals usually synthesize the scavenger proteins: heptoglobin and hemopexin, which bind these toxic extracellular hemoglobin and heme, respectively. The authors therefore, tested the concept of cold transfusion of heptoglobin and hemopexin along with stored red blood cells in their murine remodel of hemorrhagic shock.

 
 
They first showed that resuscitation with long-stored, packed red blood cells produced a higher mortality, higher plasma hemoglobin levels, hemoglobinuria, kidney injury and diffused tissue inflammation, compared to resuscitation with fresh, packed red blood cells. However, when resuscitating hemorrhagic shock with stored red blood cells co-infused with either exogenous human hemopexin or heptoglobin, there was an increased survival and decreased tissue inflammation. Furthermore, co-infusion of heptoglobin with the stored red blood cells, prevented hemoglobinuria and kidney injury. These animal model data warrant further assessment in clinical conditions of severe hemolysis.

 
 
The next study suggests that sickle cell disease, although primarily a blood disease, may also be considered a vascular disease. This is a paper from co-authors Dr. Ranque and Menet from the University Paris Descartes in France, and describe results from the CADRE study. That is, the heart arteries and sickle cell study, which is the World's largest ongoing cohort of sickle cell disease that prospectively recruited more than 3,700 patients with sickle cell disease and 950 healthy controls from Cameroon, Ivory Coast, Gabon, Mali, and Senegal.

 
 
The authors found that mean carotid femoral pulse wave velocity was lower in patients with sickle cell disease, compared to controls and lower in specific hemoglobin phenotypes compared to others. Augmentation index, corrected for heart rate, also increased more rapidly with age in the patients with sickle cell disease, compared to controls, and was higher in patients than in controls. Both carotid femoral pulse wave velocity and augmentation index were independently associated with the glomerular filtration rate and osteonecrosis.

 
 
Augmentation index was also associated with stroke, pulmonary hyper-tension and priapism. Whereas, carotid femoral pulse wave velocity was also associated with microalbuminuria. These findings really under-score the association between sickle cell disease and vascular abnormalities and complications. The prognostic value of these vascular indexes will be assessed during the follow-up of these patients.

 
 
The next paper is a basic science paper suggesting that after sudden cardiac arrest, normalizing calcium cycling, may be a novel approach to improved post-arrest myocardial function. This paper is from co-corresponding authors Dr. Woods, from the Palo Alto Medical Foundation and Dr. Ashley from Stanford University in California.

 
 
These authors developed a rodent model of cardiac arrest using ECMO resuscitation. They used a genetically encoded calcium sensor in a novel fiber optic catheter imaging system to observe calcium-induced calcium release in-vivo before and after resuscitation. They then isolated cardiomyocytes from this model and assessed a mechanical load and calcium cycling simultaneously, using the micro-fiber carbon technique.

 
 
The main finding was of potentiation of calcium-induced calcium release in the post-arrest situation that began in-vivo and was mediated by activation of the calcium calmodulin kinase 2 or CaMKII. Since they also observed that oxidated stress and aldehydic adduct formation were high post arrest, they further tested a small molecule activator of aldehyde dehydrogenase type 2, known as Alda-1, which reduced oxidative stress, restored calcium and c CaMKII homeostasis and improved cardiac function in post-arrest outcomes in-vivo.

 
 
These findings are significant for their potential translational application in post-sudden cardiac arrest, a condition which is really known to have a high mortality.

 
 
The next study reports the results of the DOCTORS Study, standing for Does Optical Coherence Tomography Optimized Results of Stenting. This paper is from Dr. Meneveau from the University Hospital Jean Minjoz and colleagues. The DOCTORS Study is the first randomized control trial testing optical coherence tomography via OCT guided PCI to standard fluoroscopy guided PCI in 240 patients with non-ST-elevation and acute coronary syndromes.

 
 
The first finding was that OCT results directly impacted physician decision making, leading to a change in procedural strategy in half of the cases in the OCT guided group. The primary end-point of functional results of PCI, as assessed by post-PCI, FFR, was modestly improved in the OCT guided group compared to fluoroscopy alone. This improvement appeared to be explained mostly by optimization of the stent expansion. The benefit was obtained at the cost of a longer procedural and fluoroscopy time and more contrast use, but without an increase in peri-procedural myocardial infarction or kidney dysfunction.

 
 
These findings of the DOCTORS study add to the accumulating body of evidence supporting a potential benefit of OCT to guide PCI procedures in acute coronary syndrome. Additional prospective studies with clinical endpoints are warranted. These issues are discussed in an excellent accompanying editorial by Dr. Wijns and Dr. Pyxaras.

 
 
This brings us to the end of our summaries. Now for our feature paper.

 
 
Our featured paper today discusses a problem that we've actually created and that is para-valvular leaks following surgical valve replacement, and we're specifically discussing the role of percutaneous device closure exploring the first multi-national experience form the United Kingdom and Ireland and I'm here with first author, corresponding author as well, Dr. Patrick Calvert from Papworth Hospital in the United Kingdom. Welcome Patrick.

 
Dr. Calvert:
It's a great pleasure to be here, thank you for inviting me.

 
Dr. Lam:
Joining us also is Dr. Dharam Kumbhani, associate editor from UT Southwestern, hi.

 
Dr. Kumbhani:
Hi Carolyn, thanks for having me.

 
Dr. Lam:
Let's get straight into this. It's a problem we've created. How common is it? Why should we care about talking about perivalvular leaks?

 
Dr. Calvert:
You know Carolyn, this is actually quite a common problem. The series we know from previous publications around 5-17% of surgical valves develop leaks. We know in the early experience of TAVR that there was quite a problem with leak, although more recent iterations that's less of a problem. There's a lot of patients out there that have this problem. It's a difficult problem to treat because these are, by definition, high-risk patients and re-operation is not such an inviting thought for them to have. This is something that needs may be a different solution than re-operation.

 
Dr. Lam:
Could you tell us what makes your series special?

 
Dr. Calvert:
Yes, so let's talk about the other series first of all. We had a fabulous series published in 2001 from the Mayo Clinic. That was a single center of excellence where they are really great at doing the procedure, but they gave us great insight of a master class, really if you like, if I had to do the procedure. What is different about our paper is that it's like a real-world experience. It's all the centers that contributed in the United Kingdom and Ireland. It's 20 centers over an 11 year period, in total 308 procedures. It's, if you like, a warts-and-all approach to it. It think that's one way it's a little different.

 
 
I think another way that it definitely stands out is that we are fortunate enough in Europe to have licensed or CE-mark, a number of oblong devices that are a little different in shape. What we do know about these holes is, they tend to be crescentic in shape or at least longer then they are wide. The problem is, if you try to put a circular device in an oblong hole, it's not going to work.

 
Dr. Lam:
Which types of perivalvular leak are you talking about here?

 
Dr. Calvert:
We have approximately 50/50 split between the aortic surgical valve and the micro-surgical valve. Then, about 5% were TAVIs or TAVRs. Then we had a small number of pulmonic valves and one or two around angioplastic rings, so that's the proportions. We had about 57% mechanical valves and 37% bio-prosthetic valves.

 
Dr. Lam:
Wow, first congratulations. That is really important information. I can already imagine. I see those patients too. Dharam, as an interventional cardiologist. What is your take on it. Especially this mention of the oblong devices? They are not FDA approved, so they won't be in the United States, but what did you think of that, managing this paper?

 
Dr. Kumbhani:
I think this is a very tricky subset of patients to treat. As Patrick and his group have shown, that the rates of success can be very high. As you point out, we don't have all the devices that they have in the U.S. A lot of us who do this use more circular devices but they're flexible. The feeling is that they tend to fit in with whatever geometry of the leak is. I do think it would be interesting, and probably more appropriate to have devices that are shaped like these holes are. As Patrick mentioned, they're usually crescentic, or certainly not round.

 
Dr. Lam:
As a non-interventional cardiologist, I didn't realize it was very intricate. Tell us about your main findings.

 
Dr. Calvert:
Our principle findings, and what I think is the most important thing is that, if you're going to do this procedure, you have to achieve a leak at the end of the procedure, or at least in the months that follow-up, that is mild or less. In our series, we showed that those patients that had that, they were independently associated with less deaths and less major adverse cardiovascular events. It's a very clear dichotomy between those groups.

 
 
Of course there's all sorts of reasons why you might be able to achieve a good result in a patient, but we know that if you can do it, those patients will be very much better than the others. In our paper we achieved that in around 75% of patients and they did much better than the others. That is a principle finding. There were another of other factors that were associated independently with death and those also included NYHA classification at follow up, but also creatinine baseline. As I've already eluded to, this is a high-risk chord of patients and there are conventional risk factors that will pre-dispose whether someone's going to do well or not. That's what came out in the multi-variable analysis.

 
Dr. Lam:
Very important clinically. Take home message from your point?

 
Dr. Kumbhani:
I think one of the interesting findings was that only 16% of these PVLs were closed for hemolysis. The vast majority of them were done for symptomatic causes. That probably speaks to the dictum that it's the smaller PVLs that cause hemolysis. I don't know if you have a handle, based on your experience, on that?

 
Dr. Calvert:
When we designed the series, a number of years ago ... When you design a registry you look at the things you're going to collect. Then when you've written the paper you think, "I just wish I had collected some more data." That's one of those things we really wish we looked ... It's fascinating. We do this procedure together and one of the things we're terrified about is taking a big leak, getting rid of heart failure and creating hemolysis.

 
Dr. Kumbhani:
Exactly.

 
Dr. Calvert:
We all have had personal experiences of that happening.

 
Dr. Kumbhani:
Yes.

 
Dr. Calvert:
The data we collected, collected patients who had new hemolysis, requiring transfusion. Therefore, all I can tell you from our series is, that was really quite a small ... It was only 2 or 3% of people who had new hemolysis.

 
Dr. Kumbhani:
After the closure?

 
Dr. Calvert:
After the closure. Of course, about 16 or 17% had hemolysis going into it. It doesn't really tell us any information about what happened to those, unfortunately.

 
Dr. Kumbhani:
One other interesting thing that I wanted to point out. If you look at the PCIs registry, all of, there are about 120 hospitals in it. Is that correct?

 
Dr. Calvert:
That's approximately correct, yes.

 
Dr. Kumbhani:
You had 20 centers that were doing this?

 
Dr. Calvert:
Yes.

 
Dr. Kumbhani:
1 in 6 is doing these in a competent fashion, the PVL closures. I think, as you pointed out, the series are usually single institutions that really specialize in this in the U. S. I think the experience may be a little more consolidated. If you want to just comment on that finding alone?

 
 
The second thing is, is there something different about the intervention training procedure in the U.K. that allows for more interventionists to be comfortable doing this?

 
Dr. Calvert:
I think that's a really great question. I think there's a little to pick apart behind that. I think the first thing to say is that, although there were 20 centers that contributed cases, some of those centers would have definitely had proctors come in to do the cases. This is the entire learning curve. This is every case that has contributed in the U.K. It's watching our learning curve and the lot. There will be a number of centers that have been heavily proctored coming in.

 
 
One thing that's really nice about the U.K., it's a small country. Particularly in this structural community, most people know each other. If you've got a problem, you ring up your friend down the road and say, "You've done a few of these, come and give us a hand." We get that and I do that too, so that's great.

 
 
I think the second thing to say, and I think it's important to say this, our cousins in America are fantastic at doing this procedure. I think they have to be because although the devices are malleable, and they will squash because as we both know, it doesn't matter what the device looks like at the end provided it plugs the hole and is not interfering with the leaflets and it's not falling out. That's fine. I do believe that the oblong devices are more likely to get a good closure. I think therefore, you're less likely to be having to put in 2 or 3 devices in the same sitting. I think that's technically demanding for ... I think it probably is a little more straight forward with the oblong devices.

 
 
I think it is important to say for the record, that there's nothing in this paper that is scientifically proven the oblong devices are better. They trend in their right but, it is a fact of the series of oblong devices. Once they're available, it was 72% and for the total it's about 2/3. It's not a scientific comparison but, we've got these good results with these devices.

 
Dr. Kumbhani:
It would not be a fair comparison but in your database, are you able to do some kind of propensity analysis looking at the oblong versus the other devices? Comparing ventricle leak for example or hemolysis?

 
Dr. Calvert:
We don't have enough breakdown data on hemolysis unfortunately. I think I just need to be careful what I say because a lot of the authors came up with hypotheses about things. I looked at the data and I think when we subgroup too much, it became too small to read to give any careful answers.

 
Dr. Kumbhani:
I see.

 
Dr. Calvert:
I think what would be really fascinating, is when we pool data with other countries because I know there are other countries that are looking at this as well. We might get more information, but that's something we have on the horizon so what this space.

 
Dr. Kumbhani:
That's good.

 
Dr. Lam:
That is fantastic. Thank you Patrick. Thank you Darrin. Seriously, I'm floored. I learned so much from this and I really enjoyed this conversation.

 
 
Thank you very much, and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next week for more highlights and features.

 
 

Sep 20, 2016

 

Carolyn:
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.

 
 
In just a moment, we are going to be discussing the feature paper on results of the RE-LY trial in patients with valvular heart disease. Yes, you heard me right, this means dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. You need to listen to this discussion with first author Dr. Michael Ezekowitz, but first here is a summary of this week's issue.

 
 
In the first study, Dr. Norby and colleagues from the School of Public Heath University of Minnesota assessed trajectories of cardiovascular risk factors and the incidence of atrial fibrillation over 25 years in the ARIC study or the Atherosclerosis Risk in Communities Study. They first assessed the trajectories of cardiovascular risk factors in more than 2,400 individuals with incident atrial fibrillation and more than 6,400 matched controls. Next, they determined the association of those risk factor trajectories with the incidence of new atrial fibrillation among more than 10,500 individuals free of atrial fibrillation at baseline.

 
 
The main finding was that stroke, myocardial infarction and heart failure risk increase steeply during the time close to diagnosis of atrial fibrillation. All cardiovascular risk factors were elevated in atrial fibrillation cases compared to controls more than 15 years prior to the diagnosis. A trajectory analysis showed not only the presence of the risk factors such hypertension and obesity, but also their duration which was more informative in determining the risk of atrial fibrillation compared to a one time clinical measurement.

 
 
Finally, they identified diverse and distinct trajectories for the risk factors findings that carry implications for the different roles of different risk factors in the pathogenesis of atrial fibrillation. The findings of this very significant study also highlight the need to establish preventive strategies that address risk factors decades before atrial fibrillation diagnosis.

 
 
The next study is by first author Dr. van der Valk and corresponding author Dr. Strauss from the Academic Medical Center in Amsterdam. These authors aimed to better understand the underlying mechanisms responsible for atherogenicity of lipoprotein a or LPa. The authors achieved this aim by a combination of three approaches. First, in vivo magnetic resonance imaging using 18F-FDG PET/CT and SPECT to measure atherosclerotic burden, arterial wall inflammation and monocyte trafficking to the arterial wall. Secondly, ex vivo analysis of monocytes using facts analysis, inflammatory stimulation assays and trans endothelial migration assays. Third, in vitro studies on monocytes using an in vitro model for trained immunity.

 
 
Their main findings were that, firstly, individuals with elevated LPa had increased arterial wall inflammation in vivo. Secondly, that monocytes from these individual remain in a long lasting activated state ex vivo, and finally, that LPa elicited a pro-inflammatory response in healthy monocytes in vitro, an effect that was markedly attenuated by removing or inactivating oxidized phospholipids on LPa.

 
 
In summary, this study nicely shows that LPa induces monocyte trafficking to the arterial wall and mediates pro-inflammatory responses through its oxidized phospholipid content. The clinical implications are therefore, that oxidation's specific epitope targeted therapy using for example specific antibodies as single gene antibodies may bear clinical potential to modulate the arthrogenic impact of LPa.

 
 
The final study is from first author Dr. Mazen, and corresponding author Dr. Ouzounian from Toronto General Hospital and University of Toronto in Ontario, Canada. These authors sought to compare the long term outcomes of patients undergoing the Ross procedure compared to mechanical aortic valve replacement in a propensity match cohort study of 208 pairs followed for a mean of 14 years.

 
 
They found long term survival and freedom from re-intervention were comparable between the Ross procedure and mechanical aortic valve replacement. Of note however, the Ross procedure was associated with improved freedom from cardiac and valve related mortality, as well as a significant reduction in the incidence of stroke and major bleeding. This paper provides important evidence that supports continued used of the Ross procedure in properly selected young adult patients in specialized centers.

 
 
What this means is having experienced surgical teams dedicated to mastering the technique and committed to carefully following up the patients for possible late complications. This and more is discussed in a provocative editorial by Dr. Schaff from Mayo Clinic Rochester, Minnesota who provocatively entitled his editorial 'The Ross Procedure: Is it the Preferred Procedure or Double, Double Toil and Trouble?'

 
 
Those were all summaries, now for our featured paper.

 
 
I am so excited to be joined from all over the world to discuss the featured paper today, and that is on the comparison of dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. To discuss this first we have, first and corresponding author, Dr. Michael Ezekowitz from the Sidney Kimmel Medical College at Thomas Jefferson University and Lankenau Medical Center in Philadelphia, as well as from the Cardiovascular Research Foundation in New York. Welcome Michael.

 
Michael:
Thank you very much.

 
Carolyn:
Michael, you're calling from South Africa aren't you?

 
Michael:
I am indeed.

 
Carolyn:
That's wonderful. We're very honored to have Dr. Shinya Goto Sensei, Associate Editor of Circulation from Tokai University Japan. Hello Shinya.

 
Shinya:
Hello Carolyn, thank you very much for your invitation to such an excited podcast. I enjoy podcast every week.

 
Carolyn:
I love this and it is extremely exciting and the most global discussion that we have had so far, with calling in Japan and Singapore and South Africa. Indeed it's because we're discussing a very important problem globally. Michael first, when we talk about the RE-LY trial and the NOAC trials, we're always associating them with non-valvular atrial fibrillation, and yet your topic is discussing valvular heart disease from RE-LY. Can you please start by clarifying that?

 
Michael:
I think the reason we wrote this paper is that there is a misunderstanding of the patient populations that was studied in all the NOAC trials because they were characterized as having non-valvular atrial fibrillation. That's only partially true because in all the trials, patients with mechanical heart valve and hemodynamically significant mitral stenosis were excluded, and yet there were many patients with valvular disease that were included. In the RE-LY trial which is the focus of this particular paper, 25% of the patients had some form of valvular disease that were recruited into the study. So the term non-valvular is misleading.

 
Carolyn:
That is such an important clarification, and it's an issue that I see a lot in Singapore. Frankly, lots of patients with atrial fibrillation have some valve disease even if you exclude prosthetic valves, significant mitral stenosis or valvular heart disease requiring intervention. We're very clear not that this is the patient population you're referring to. Shinya, I want to bring you into this. I see lots of these patients, how about you?

 
Shinya:
The same. Majority of patients have valvular heart disease, small mitral regurgitation is very common. We are excluding only clinically overt mitral stenosis and basically mechanical heart valve in all the newest trials. As Michael pointed out, it is very important to correct misunderstanding. Non-valvular atrial fibrillation, we used in the clinical trial is all atrial fibrillation except clinical overt mitral stenosis and prosthetic for mechanical heart valve.

 
Carolyn:
Exactly. A great foundation for us to get our understand right before we discuss the findings. Michael, could you please give us the top line result and tell us what do the results mean for your own clinical practice?

 
Michael:
Basically, it means that the patients with valvular heart disease that were included in the trial, and these included patients with mitral regurgitation with was the most common lesion, mixed aortic valve disease, tricuspid regurgitation, and also it turned out that there were 192 patients that had mild mitral stenosis. Those with mitral stenosis were presumed to be rheumatic in ideology, and they did have a profile of having rheumatic heart disease, that there were more females, they were younger, there was a high incidence of heart failure and a high incidence of TIA and stroke.

 
 
The bottom line here is whether the patients had mild mitral stenosis or the other forms of valvular disease that I just mentioned, that they benefited in an identical fashion from the 150 milligram BID dose of dabigatran and the one 110 milligram BID dose of dabigatran as those patients without any valvular disease. The bottom line is that clinicians can use dabigatran with equal confidence in these patients with valvular disease as in patients without valvular disease.

 
Carolyn:
Thank you Michael, that was very reassuring and something that is very clinically important. Shinya, I'm going to ask a different question. First, maybe your take on the findings, and secondly, what was it like handling this paper across the globe as the Associate Editor Managing this?

 
Shinya:
That is a very important point. The past as Michael pointed out, this paper is very important to remind the clinician of non-valvular atrial fibrillation is not really non-valvular atrial fibrillation, and there is no difference between valvular atrial fibrillation except mitral stenosis and prosthetic valve. The result is similar to non-valvular atrial fibrillation in regard to the effect of dabigatran or by warfarin. That is the one point I have to assure. As a part, it is very important. We are now including many patients not limited in that North America, Europe. We are participating a huge number of patients from Asia. The results is applicable to the global level. We are now leading in that global evidence-based world and RE-LY is one of the good example for the global trial testing the hypothesis with [inaudible 00:13:58] over warfarin.

 
 
Michael made a very good summary of that, not only limited to RE-LY, he talked about as our trial like ARISTOTLE and the ROCKET trial. All of the NOAC trial include patient who is valvular heard disease, and the exclusion criteria is a little bit different. Michael beautifully summarized that difference in the table, in his paper.  There is a strong intention to publish this paper integration from all the editorial of old member. This is a very nice paper.

 
Michael:
He's been very kind, that's very nice. That's true. In fact, the results in RE-LY were compared in an indirect fashion with the other trials, ROCKET and ARISTOTLE, through have published similar papers on patients with and without valvular heart disease. Just in summary, the bottom line is that this finding in RE-LY is highly reproducible in the other two trials so this is an important finding that is reproducible and true of the three novel agents that had looked at this in detail.

 
 
The other point that was raised is that there were differences in the exclusion criteria in these trials, but at the end of the day, the Europeans and the Americans in terms of guidelines, had fairly similar recommendation. For instance in the United States, it was felt that all patients with valvular disease could be anti-coagulated with the novel agent unless they had rheumatic mitral stenosis, mechanical or bioprosthetic heart valves, or patients that had undergone a prior mitral valve repair. The emphasis was that all other patients could be included.

 
 
The Europeans differed slightly and that they agreed that mechanical prosthetic valve and moderate to severe mitral stenosis should be excluded, but they were somewhat more global in recommending inclusions of all other valvular conditions. There is a slight difference then between the European and the American recommendations and guidelines.

 
Carolyn:
On that note of looking across the world at the guidelines and what these results mean, it really leaves me to congratulate you Michael on such an excellent paper, and Shinya for just managing this paper so well.

 
Michael:
Thank you.

 
Shinya:
Thank you very much for your invitation. Bye-bye.

 
Carolyn:
You've been listening to Circulation on the Run. Thank you for joining us today.

 
 

Sep 20, 2016

 

Carolyn:
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. Have you wondered which anti-platelet agent you should use in your patients with diabetes and coronary artery disease? Well, our feature paper deals with just this topic, so stay tuned, I'll be write back with it's author and associate editor. First, here's your summary of this week's journal: The first paper unravels novel peptides involved in atrial extracellular matrix remodelling in atrial fibrillation. This is work from first author Dr. Barallobre-Barreiro, corresponding author Dr Mayr from King's College London, and colleagues. They used novel mass spectrometry methods to analyze extracellular matrix in human atrial appendages from patients undergoing coronary artery bypass surgery.

 
 
Now, previous proteomic studies have examined the cellular proteome, but this is the first study to comprehensively characterize extracellular matrix proteins in human cardiac tissues, including the identification of glycosylation sites. They found extensive cleavage in the protein core of decorin which is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis and a variety of other extracellular matrix cell signalling molecules. Decorin processing differed between human ventricles and atria and was altered in disease. It's C-terminus which is important for the interaction with connective tissue growth factor was predominantly detected in ventricles compared to atria. In contrast, atrial tissues from patients in persistent atrial fibrillation had higher levels of full length decorin, but also harbored a unique cleavage site that was not found in atrial appendages from patients in sinus rhythm. This unique cleavage site preceded the M-terminal domain of decorin and altered the binding capacity for myostatin, this altering muscle growth.

 
 
The cleaved decorin peptide antagonized myostatin, such that myostatin expression was decreased in atrial appendages of patients with persistent atrial fibrillation and in hearts of decorin-null mice. Furthermore, a synthetic peptide corresponding to this decorin region, those dependently inhibited the response to myostatin in cardiomyocytes and in perfused mouse hearts. This is clinically important because mystatin inhibition has been implicated as a substrate for atrial fibrillation. This study therefore provides first evidence that peptides generated from the cleavage of extracellular matric proteins such as decorin, constitutes a local regulatory mechanism for growth factors in human cardiac tissue.

 
 
The next study looked at therapeutic hypothermia in patients with out of hospital cardiac arrest, and questioned if it may be most effective when induced early during cardiopulmonary resuscitation or CPR, in contrast to prior trials that looked at therapeutic hypothermia induced only after return of spontaneous circulation and hospital admission. This is the RINSE trial from Professor Bernard and colleagues from Ambulance Victoria Australia, which was a multi center randomized controlled trial which assigned adults with out of hospital cardiac arrest undergoing CPR to either a rapid intravenous infusion of up to two liters of cold saline, or standard care. The primary outcome measure was survival at hospital discharge. Secondary end points included return of spontaneous circulation.

 
 
The trial was unfortunately closed early at forty-eight percent of the recruitment target, due to changes in temperature management protocols at the major receiving hospitals. Still, a total of one thousand, one hundred and ninety-eight patients were randomized. Six hundred and eighteen to therapeutic hypothermia during CPR, and five hundred and eighty to standard pre-hospital care. Overall there was no difference in outcomes at discharge. In patients with an initial shockable cardiac rhythm there was lower rate of return of spontaneous circulation in patients who received cold saline compared with standard care. Thus, although this trial was stopped early, the data suggests that induction of mild therapeutic hypothermia using a rapid infusion of large volume intravenous cold saline during CPR did not affect outcomes at hospital discharge and may in fact cause harm in the subset of out of hospital cardiac arrest patients who present with shockable rhythm.

 
 
The last study provides the first generalizable risk score for sudden cardiac death among American adults from the general population without a history of cardiovascular disease. This large study from Dr. Deo of University of Pennsylvania, and colleagues, derived a sudden cardiac death prediction model using the Atherosclerosis Risk in Communities or ARIC cohort, and validated it in the Cardiovascular Health Study or CHS cohort. They found that the twelve independent risk factors in the ARIC study included age, male sex, African American race, current smoking, systolic blood pressure, use of [anti-hypotensive 00:06:00] medication, diabetes, serum potassium, serum albumin, HDO, estimated GFR, and QTC interval. Over a ten year follow up period this model combining these risk factors showed good to excellent discrimination for sudden cardiac death risk. In fact the model slightly outperformed that of the 2013 ACC AHA pooled cohort risk equations.

 
 
Finally, they also showed in the echocardiographic sub-cohort that a left ventricular ejection fraction less than fifty percent was present in only 1.1 percent of these participants and did not enhance sudden cardiac death prediction. This study importantly contributes to the distinguishing of sudden cardiac death risk across the general population, and the results can help target future strategies aimed at sudden cardiac death prevention for the highest risk subgroups in the American general population. That does it for the summaries. Now for our feature paper.

 
 
For our feature paper today we are discussing the super important issue of anti-platelet therapy in type 2 diabetes with coronary artery disease. Joining me today are the corresponding author, Dr. Dominick Angiolillo from the University of Florida College of Medicine - Jacksonville, as well as Dr. Gabriel Steg, Associate Editor from Paris, France. Welcome gentlemen.

 
Dominick:
Thanks for having us.

 
Gabriel:
Hello.

 
Carolyn:
Dominick, I'd really like to start with you. Your paper entitled the OPTIMUS-4 Study, is really a study of the pharmacodynamic comparison of Prasugrel versus Ticagrelor in these patients with type 2 diabetes and coronary artery disease. The whole question is, what was the rationale to look at the pharmacodynamics?

 
Dominick:
As the title of the study says, OPTIMUS-4, it means that there was an OPTIMUS-1, 2 and 3 in the past, which means that there's a lot of thought that went into this and a lot of background information. The rationale for this specific study was that we're all well aware of the fact that patients with diabetes have high platelet reactivity, which may be one of the reasons why they have a higher risk of recurrent atherothrombotic events. Therefore, the need to define ways to optimize their anti-platelet effects, their levels of platelet inhibition. In this specific study we took an approach of looking at the novel, although we cannot call them novel nowadays, but the newer P2Y12 receptor inhibitors Prasugrel and Ticagrelor. Looking at them in a head to head comparison from a pharmacodynamic standpoint to see if one drug would be superior than the other, again, in terms of a platelet inhibitory effect.

 
 
This is the rationale, and just to expand a little bit on this, there's been a perception, again I want to underscore a 'perception' that based on subgroup analysis of the larger clinical trials, that Prasugrel is a superior drug for patients with diabetes. We do know that there's a benefit also with Ticagrelor compared with Clopidogrel, although the absolute risk reductions in the studies led to a perception that Prasugrel would be a better drug. We said to ourselves, "Well, we're never going to have a large scale head to head clinical comparison, why don't we do a head to head pharmacodynamic comparison to see if there are any differences?" This was the overall rationale for conducting this specific study.

 
Carolyn:
That really sets a background perfectly. Tell us about the main findings.

 
Dominick:
The main finding was as follows, we conducted a very detailed pharmacodynamic study, this was a prospective randomized double-blind double-dummy crossover study, with all patients on the background of aspirin therapy. We looked at platelet reactivity, using a variety of assays, I like to say it in every possible salsa that you can imagine. The primary end point which is platelet reactivity at one week into two drugs, using an [ADP 00:10:00] specific assay, actually showed that Ticagrelor was superior to Prasugrel in terms of platelet inhibitory effects. That was the only time point where it was shown, but the study was actually designed to show the opposite, so it was a very interesting finding, while with all the other time points there were no differences between the platelet inhibitory effects between the two drugs.

 
 
The other thing that we did look at, which gives a little bit of a novelty to this study is, we went beyond just looking at ADP induced effects, which is the target for these two drugs, we looked at other signalling pathways which one would not believe to be necessarily affected by P2Y12 inhibitors, and we found these also to be reduced by both drugs to a similar extent.

 
Carolyn:
Fascinating. I'm going to get to your second point a bit later. First, that first finding that surprisingly Ticagrelor appeared to perform better using one of the specific assays and so on, I'd really like Gabriel's opinion there. What do you think is the overall clinical implications or what was the message that the editorial board was hoping to get across to the audience? Because I noticed you invited an editorial as well, a beautiful one written by Dr. [Star-ee-an 11:36] Parker. What was the thinking behind that?

 
Gabriel:
I think this is really a very important paper and I'm delighted that Dominick Angiolillo and his team submitted it to Circulation, in fact to be frank, we invited that paper after seeing his presentation at the ACC earlier this year. The reason that paper caught everybody's attention in the editorial board was that it's addressing a frequent and deadly disease, diabetes, that kills really patients with cardiovascular disease. There's a critical issue in the treatment because of the limitations of Clopidogrel because of the increased platelet reactivity in diabetics, and there's tremendous interest in the novel P2Y12 inhibitors Prasugrel and Ticagrelor, and of course any hint of differences between these agents has major clinical implications. In addition, I think I can state that Dominick's team is really one of the premiere international teams looking at this exact issue, platelet reactivity in diabetics. What they did was really state of the art rigorous clinical investigation by a highly skilled team, looking rigorously at a double blind crossover designed four different assays looking at platelet function and platelet response, looking both at the effect of a loading dose and the maintenance dose.

 
 
To me, the message is not a minute difference between the treatments, in fact I think that even though it's the primary outcome and it does show a slightly greater response with Ticagrelor than with Prasugrel, the overall most of the other assays at the other time points show a consistent good response with both agents. To us, and to me, the message is that the novel agents are clearly superior to Clopidogrel as we've seen in the clinical trials, but they are fairly consistent in their benefit, and it's reassuring to see this not in healthy volunteers but in actual patients with stable coronary artery disease. I think it was really important to show that. Certainly platelet reactivity doesn't summarize entirely the effects of any drug, and there might be platelet independent effects of Ticagrelor mostly and possibly Prasugrel, but I think on the platelet side, I think that this paper really nails it.

 
Carolyn:
I read that editorial and really agree that that puts everything in perspective really well. I particularly like the figure that accompanied the editorial. In case any of our listeners out there don't really remember all the different pathways and how Prasugrel and Ticagrelor and Clopidogrel are metabolized differently, I'd really refer everyone to that figure as well. Just want to pick up on one of the points that both of you mentioned, and that is the non ADP induced platelet reactivity that Prasugrel and Ticagrelor both seem to have an affect on and so on, and if they're so effective, Dominick, is there still a role for aspirin co-administration with these new anti-platelet agents?

 
Dominick:
The study clearly puts a little bit more beef, let's put it this way, to some of the ongoing clinical studies looking at whether we need aspirin in the patients treated with one of these newer P2Y12 receptor inhibitors. There are a series of ongoing studies out there. There's a laundry list, so I'm not going to go into the details. It does highlight that maybe when you have ultimate P2Y12 blockade, which is a key signalling pathway and blocks other responses by virtue of the fact that there's an interplay between this pathway and others, maybe you do not need this additional anti-platelet agent such as aspirin, which we know there's associated with potential bleeding particularly gastrointestinal side effects.

 
 
Having said that, this is not something that I'm advocating at time, but what I am saying is that we'll need to look into the results of the clinical trials. I believe that this study is an additional piece of evidence from an ex vivo standpoint to prior in vitro studies showing that aspirin is not associated with additional platelet inhibitory effects, at least not substantial platelet inhibitory effects. One can say that you may get away with just one of these newer agents. Again, this is based on pharmacodynamic findings, let's just wait for the clinical trial results.

 
Carolyn:
I think that's so fairly put, and I learnt so much just listening to this conversation. Thank you so much for joining me today. Any last words from Gabriel?

 
Gabriel:
Yeah, I'd like to make a couple of points as an Associate editor for Circulation. The first one is, this paper was picked up when we saw Dominick's team's presentation at the ACC, and I think it exemplifies that we really want to pick up the best science from the meetings, either before the meetings and publish it simultaneously as much as possible, but sometimes also at the meetings, so expect to see Circulation Editors at your presentations and maybe you'll seduce them enough with your science that we'll get good science submitted to the journal. The other aspect to it is also that I think with the new editorial board there's really a focus on trying to make the journal very international in it's approach, and I think it's fitting that I am Associate Editor from Europe and I think there's no more international a scientist than Dominick Angiolillo who's not only a good friend but also has been trained in Italy, has practiced in Spain, and now works in the US. I think he embodies how science transcends boundaries and borders. I think there's a definite international outlook to Circulation, and we're looking for great science from anywhere in the world, not solely the US.

 
Carolyn:
Thank you so much Gabriel. Thank you so much Dominick. Thank you listeners for listening today, you've been listening to Circulation on the Run. Don't forget to join us next week for more summaries and highlights.

 
 

Sep 19, 2016

 

Carolyn:
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. Today we will be diving deep into issues of resistant hypertension, adherence to anti-hypertensive medication, and renal denervation. All this by looking closely at new data from the Renal Denervation for Hypertension trial. First, here are your summaries of this week's journal.

 
 
The first paper sought to answer these questions: How can we better re-stratify patients with long QT syndrome type 3? You will remember that as the type caused by a gain of function mutation in the SCN5A sodium channel, and the type that has a more lethal course than types 1 and 2. Another question is, are we sure that beta blockers are effective in type 3 long QT syndrome? Well the current study is by co-first-authors, Dr. Wilde of Academic Medical Center, Amsterdam, and Dr. Moss from University of Rochester School of Medicine and Dentistry, which is the largest multi-center long QT type 3 syndrome cohort described to date.

 
 
This study was designed to identify the risk and therapeutic factors associated with cardiac events in patients. The risk factors evaluated included clinical features such as age, gender, ECG measurements, the mutation type, and the therapeutic effects of beta blockers, other medications, and ICD. In almost four hundred patients with type 3 long QT syndrome, 30% experienced at least one cardiac event; that is syncope, aborted cardiac arrest, or sudden death. The risk of a first cardiac event was directly related to the degree of QT prolongation. Each 10 millisecond increase in QTC up to 500 milliseconds was associated with a 19% increase in cardiac events. Prior syncope doubled the risk of life threatening events. Beta blocker therapy was associated with an 83% percent reduction in cardiac events in females, however the efficacy in males could not be conclusively determined due to low number of events. The take-home message is, in your patients with long QT syndrome type 3, recognize the very high risk sub-population with prolonged QTC and a history of syncope.

 
 
The next paper is a basic science paper that reveals a novel way in which mitochondrial dysfunction may be targeted in heart failure. This paper is from first author Dr. Li, corresponding author Dr. Tian, and colleagues from the Mitochondria and Metabolism Center at University of Washington. These authors previously found that elevation in the NADH to NAD ratio induces mitochondrial protein hyperacetylation, and renders hearts highly susceptible to stresses, and they showed this in a mouse model of primary mitochondrial dysfunction caused by genetic defects. In the current study they defined the molecular intermediaries linking specific NAD sensitive hyperacetylation targets to the development of heart failure, and further demonstrated the relevance of these mechanisms in human heart failure. Specifically, they identified that hyperacetylation of the regulators of mitochondrial permeability transition poor and malate-aspartate shuttle, mediates the increased susceptibility to cardiac stresses. Further, expanding the cardiac NAD pool via pharmacological or genetic approaches normalized the NADH to NAD ratio, and thereby normalized protein acetylation in hypertrophied and failing hearts. Importantly, these measures improved cardiac function and reduced pathological hypertrophy in mice. Thus, the clinical implication is that restoring the NADH to NAD ratio may be an effective and translatable strategy to treat mitochondrial dysfunction in heart failure.

 
 
The next study broadens our considerations of the benefits versus risks of intensive anti-platelet therapy in patients with a prior myocardial infarction, and really suggests that more intensive anti-platelet therapy should be considered, not only to reduce the risks of coronary events, but also to reduce the risk of stroke. This is a paper from Dr. Bonaca and colleagues of the TIMI study group from Brigham and Women's Hospital in Boston, Massachusetts, who investigated the efficacy of ticagrelor, 60 milligrams twice a day, for reducing stroke in patients with a prior myocardial infarction from the Pegasus-TIMI 54 trial.

 
 
You will remember that in the Pegasus-TIMI 54 trial, ticagrelor was already shown to reduce the risk of major adverse cardiovascular events when added to low-dose aspirin in stable patients with prior MI. Of more than 14,000 patients randomized to placebo or Ticagrelor, 213 experienced a stroke, 85% of which were ischemic. 18% of strokes were fatal, and another 15% led to either moderate or severe disability at 30 days. Ticagrelor significantly reduced the risk of stroke, with a hazards ratio of 0.75, and this was driven by a reduction in ischemic stroke. Hemorrhagic stroke occurred in nine patients on placebo and eight patients on ticagrelor. Furthermore, a meta-analysis of four placebo-controlled trials of more intensive antiplatelet therapy in more than 44,800 patients with coronary disease confirmed a marked reduction in ischemic stroke, with a combined hazards ratio of 0.66. Thus this study really broadens our considerations of benefits versus risks of intensive antiplatelet regimens for the long-term secondary prevention in patients with patients with prior myocardial infarction. It really highlights the broader benefits in reducing ischemic stroke, and not just coronary events. In summary, overall, for 1,000 patients initiated on ticagrelor 60 milligrams twice daily for three years, 13 primary endpoint events would be prevented, including approximately five ischemic strokes. This benefit would come at a cost of nine TIMI major bleeds, but no hemorrhagic strokes or fatal bleeds.

 
 
That wraps it up for our summaries! Now for our feature paper. Our feature paper today discusses a really important issue that we face everywhere around the world, and that is the management of resistant hypertension. We're taking a very interesting look at the Renal Denervation for Hypertension trial, because we're actually looking at the adherence to anti-hypertensive therapy, and what we've learned in this trial. I'm so excited because I am sitting right here with first and corresponding author Dr. Michel Azizi, from Georges Pompidou hospital in Paris, France. Hello Michel, thank you!

 
Michel:
Hello, Carolyn. Thank you also for the invitation to discuss about the paper.

 
Carolyn:
We're also so lucky to have the associate editor who handled the paper, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome, Wanpen.

 
Wanpen:
Hi, Carolyn.

 
Michel:
Hi, Wanpen.

 
Carolyn:
This whole issue of resistant hypertension, I'll tell you, to me that means someone who's adequately treated, and despite all the treatment that we can throw at them, they still have a blood pressure that is above a certain level, right?

 
Michel:
Yes.

 
Carolyn:
But your study seems to tell us that that assumption, that everyone's receiving treatment and still having high blood pressure, may need to be questioned, so please tell us a little bit more about what you found.

 
Michel:
This is a clinical trial where we compared the effect of renal denervation to medical treatment, optimal medical treatment. We standardized the anti-hypertensive treatment in the cohort of patients with resistant hypertension, and then we followed them on a monthly basis with home blood pressure monitoring. We also increased the intensity of the treatment every month after randomization between renal denervation against nothing, because this is a probe trial, it is not a double blind trial. We gave them the same treatment in both arms. At the end of the many study we demonstrated that there was 6 millimeter of difference, in terms of ABPM, in favor of renal denervation, against the same medical treatment alone.

 
 
However, because this trial was an open trial, it was open to a Hawthorne effect, and the possibility that patients or doctors behave differently in each arm of the study. Those having renal denervation may be more adherent to the treatment, and those not being given the new therapy, not being really adherent to treatment. This was an issue, so we specified analysis. We also measured drug levels in urine after six months of followup, and also assessed the exposure to each individual using a peptide in urine, which is N-acetyl-serylaspartyl-lysyl-proline (AcSDKP)/creatinine.

 
 
What we found after six months of followup in patients who really participated to this trial, they were willing to participate to the study, they signed an informed consent where it was written that, indeed, we will monitor drug levels. They knew that we would do this. They also knew that we will follow them very carefully every month, et cetera, that we'll provide them home blood pressure monitor for free. They had access to the same doctor, same nurse, same everything. They could arrive at the time they wanted in the morning for being investigated. After six months of followup we found that more than half of these patients did not take correctly their treatment, and even 15% of them, in reality, took zero medication over seven medications. This was a major, major surprise for us in this trial.

 
Carolyn:
I think that's one of the most significant findings, even in a trial setting, that is such a lot of non-adherents, anti-habitants, of therapy. It really makes us question when we say someone has resistant hypertension, is it really that, or do we have just a very non-compliant patient?

 
Michel:
Yes.

 
Carolyn:
Because it can only be worse in the real-world setting, isn't it? Congratulations, that was a very striking message to me as well. What was the other main finding that you wanted to ... ?

 
Michel:
The other finding was that the rate of non-adherence was similar in both arms. That there was absolutely no influence of being randomized to the renal denervation group or the medical treatment group only. This means that the patients were not influenced, and other physicians behaved similarly in both arms. Because at the end you have exactly the same rate of non-adherence to treatment. This is also very important.

 
Carolyn:
Yes, indeed. Wanpen, I was wondering what your thoughts were, and take-home messages from this paper. We definitely thought it was significant in the editorial board because you even commissioned a wonderful editorial by Dr. David Calhoun on this. What are your thoughts?

 
Wanpen:
In the United States, using the same technique, we found as much non-adherence. I think there is a lot that we need to do and to understand what caused non-adherence. The patient should not be the only party that's to blame. I think that the doctor's as much of a culprit here to try to tease out what's the barrier to the treatment. Also, as pointed out by Dr. Calhoun, is that although the trials show improvement in blood pressure in both groups, at the end number of medications of patients in resistant hypertension, they require to take four to five drugs to get the blood pressure under control. I think this is going to be a lifelong continuing medication treatment that the physicians have to face, and to deal with the adherence problem as well. Just lastly, I think that although people believe that doing drug levels is only for research purpose, but many people don't realize that actually many drug levels for anti-hypertensive drugs actually is clinical available and can be ordered. It takes a little bit more effort to order it, but it can be done, and actually our center has been doing that already anyway.

 
Carolyn:
Wow. I cannot say that my center has been doing that in Asia, but I really have to admit that this paper made me think about it. Especially the editorial when he highlights it, the very unique information that is provided by actually measuring the blood levels. Michel, you were nodding your head vigorously when Wanpen was saying that we should not just blame the patient. Tell me, what are your thoughts, and how does this affect your clinical practice?

 
Michel:
I fully agree with Wanpen. We have to now integrate the fact that it's accessible, you can measure drug levels through technology, with mass spectrometry, et cetera. This is very important to integrate and to change our paradigm that we have to put in our brain. We have to monitor drug levels. Using this technology we have to establish a partnership with the patient.

 
 
I think the truth, also, is somewhere, as Wanpen said, we are also culprits. If patients do not take their treatment, okay, there may be some benefit and e have to look why they are not taking pill treatment, but also we are culprits because we don't listen to them, we don't take enough time, et cetera, et cetera. But I think patients should not be only blamed, so it opens a new possibility to discuss with the patient about the fact that we didn't find the drug in levels in their urine, et cetera.

 
 
However, taking into account that there will be this toothbrush effect, that is, "Patient, brush your teeth when you go to see the dentist," you'll take the pills when you go to see the doctor so you can be treated. This is one of the difficulties. However I think it's a new possibility to discuss with the patient of his or her difficulties in taking the pills. It gives us the opportunity to discuss, to take time with our patients.

 
Carolyn:
It's really fascinating, you're talking from a system based in Europe. You're based in Paris.

 
Michel:
Yes.

 
Carolyn:
Wanpen just said that she's doing it, and she's based in the US. Do you now routinely, maybe, monitor these medication levels?

 
Michel:
Yes, yes, yes.

 
Carolyn:
Wow.

 
Michel:
In the hospital we have these mass spectrometer platforms, so we have access to this, and we are working with the house authority to have the reimbursement. Because I think it's important, because if it's not reimbursed there is also a problem.

 
Carolyn:
Of course.

 
Michel:
We are working to see how it could be reimbursed for labs doing these measurements.

 
Carolyn:
But this is for maybe selected resistant hypertensive patients that are difficult to ... ?

 
Michel:
Yes, absolutely. Those very difficult to manage. I think, as a rule of thumb, that after four or five drugs given to the patient, if the patient-

 
Carolyn:
Yeah, we should start questioning, are they taking it.

 
Michel:
If the patients do not have secondary hypertension, we should really start questioning ourself whether they are taking or not the treatment, even if they are looking right in your eyes and telling you, "Yes, doctor, I'm taking all the pills."

 
Carolyn:
Wanpen, how about the reimbursement issues and things like that in the United States? How are you getting it done in your institution?

 
Wanpen:
Actually the coding for doing drug levels, it's actually generic. It's the same coding for Digoxin or Cyclosporine. They actually don't care about what the name of the drug. Strangely, they're coded by the technique, so that's how we go with it, but we have to put in miscellaneous "other" for, we wanted to test for this. That's how we get around it.

 
Carolyn:
Do you do that again routinely, or in selected patients that are difficult to manage hypertensive?

 
Wanpen:
Obviously we have to be selective, so we select from people who we would suspect are non-adherent, but they say they're taking it. But if they already came in and made that they're not taking the drug, there's no point doing that for the clinical purpose. We're doing it for people who we suspect it, and we use it the way ... Actually we shall describe very well, not only just to find what drug they're not taking, because when they're not taking, only about 30% are not taking everything, about 20% not taking one or two drugs. When we drill down to that drug they say, "I have side effects to beta blocker and I don't want to tell my physician that I have problems taking it, but I just not take it." I think that's what led us to pinpoint the problem a little bit better with this technique.

 
Carolyn:
What a lot of practical advice, and congratulations once again for very, very meaningful findings. I learned a lot this time. I don't do this, and so I'm definitely going to think about this much more because of your work. Thank you very much Wanpen, Michel.

 
 
And thank you, listeners, for tuning in this time. Remember, you're listening to circulation on the run. Listen in again next week. Thanks.

 
 

Sep 5, 2016

Carolyn:
Welcome to Circulation On The Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, associate editor from the national heart center and Duke National University of Singapore.

 
 
In just a while, we will be discussing patients with familial hypercholesterolemia after acute coronary syndrome, and the new data in this week's issue that suggests we still need to pay special attention to this group of patients even in the current era of the widespread use of high intensity satins. First here's your summary of this weeks issue.

 
 
The first paper suggests that we may need to look at thyroid function in our risk assessment sudden cardiac death in the general population. This paper is from co primary authors Dr. Chacker in Van Der Burgh and corresponding author Dr. Strecker and colleagues from the Erasmus University medical center in water dom.

 
 
The authors studied the association of thyroid function with sudden cardiac death in more than 10,000 participants of the population based Water Dom study. They found the higher levels of 3T4 were associated with an increased risk of sudden cardiac death even in the normal range of thyroid function. The estimated hazard ratio was 2.28 per one nano-gram per deciliter of 3T4, and these risk estimates did not change substantially even after stratification by age or sex or sensitivity analysis excluding participants with an abnormal 3T4. The absolute 10 year risk of sudden cardiac death increased in youth thyroid participants from 1 to 4% within increasing 3T4 levels.

 
 
Thus this study suggests that 3T4 and additive marker in risk stratifications for sudden cardiac death in the general population. Further research is needed to assess the possible additional benefit of using 3T4 levels to re stratify and prevent sudden cardiac death.

 
 
The next study reminds us that therapies to reduce ischemic events in patients undergoing percutaneous coronary intervention are still really important even in the current era of changing definitions of periprocedural myocardial infarction. This study is from first author Dr. Cavender of University of North Carolina chapel hill and corresponding author Dr. Bach Brigham women's hospital and colleagues.

 
 
The authors looked at more than 11,000 patients randomized to cangrelor or clopidogrel int the champion phoenix trial.

 
 
Cangrelor is an intravenous P2Y-12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention who are not pretreated with with a P2Y-12 inhibitor.

 
 
The authors explored the effects of cangrelor on myocardial infarction using different definitions of myocardial infarction and perform sensitivity analysis on primary endpoint.

 
 
They found that 4.2 percent of patients had a myocardial infarction defined by the second universal definition within 48 hours after undergoing PCI. When the sky definition of periprocedural MI was used, there were fewer total myocardial infarction, but the effects of cangrelor remain significant.

 
 
Finally similar effects were seen when MI's were restricted to those defined with large bio marker elevations or by symptoms of ECG changes. Very importantly patients who had an MI regardless of the definition, were at increased risk of death at 30 days.

 
 
In summary changes in the definition of MI used in the primary endpoint did not affect the overall findings from the champion phoenix trial. This study also reminds us that periprocedural MI remains an important clinical event in the current era. Being associated with increased risks of death at 30 days, and therefore reducing ischemic events in patients undergoing PCI remains very important.

 
 
The final paper describes experimental evidence of a novel treatment approach to hypertension using micro RNA's. This paper is from first author Dr. Lee and corresponding authors Dr. Chinn and Wang from Tong G medical college and Whadrom University of Science and Technology in Wuhan China.

 
 
Micro RNA's are a class of small non-coding RNA's that regulate gene expression at a post transcriptional level. These authors compared the expression of key neucler genoman coded and mitochondrial genoman coded genes involved reactive oxygen species production in spontaneous hypertensive rats and wistar rats. They then used bioinformatics to predict the micro RNA targets followed by biochemical validation using real time PCR and immunial precipitation.

 
 
They first found that there was down regulation of mitochondrial DNA encoded sitoca B in the spontaneous hyper intensive rats, which appeared to directly contribute to the increased mitochondrial reactive oxygen species.

 
 
Next they found that mere 21 a key micro RNA induced into hyper spontaneous rats, was able to trans-locate into mitochondria to counteract the mitochondria pseudonym B down regulation. Finally, they showed that exogenous mere 21 delivered by recombinant adeno associated virus was able to lower blood pressure and attenuate cardiac hypertrophy in the spontaneously hypertensive rat model.

 
 
These findings are striking because they provide experimental support for developing micro RNA based treatments for hypertension.

 
 
Those were your summaries of original papers but before I go, I just have to highlight this in depth review paper in this week's issue, and it is regarding sodium glucose co transported to inhibitors or SLG2 inhibitors in the treatment of diabetes, discussing the cardiovascular and kidney affects potential mechanisms and clinical applications.

 
 
It is a beautiful review article written by first author Dr. Heresphink of the University Medical Center Groningen, corresponding author Dr. Churney from Toronto general hospital and colleagues. Truly a must read, but now here is our featured paper.

 
 
Our featured paper today is on patients with familial hypercholesterolemia after acute cornery syndromes. Today I have with us the first and corresponding author David Nan chin university of Lausanne in Switzerland.

 
 
Hi David, thanks for joining us.

 
David:
Hi, I'm very happy to be here.

 
Carolyn:
As the associate editor who managed this paper we have Dr. Amat Kira and you will recognise him as the digital strategies editor as well from UT Southwestern. Welcome back Amat.

 
Amat:
Thank You Carolyn, happy to be here.

 
Carolyn:
I am really curious about this paper because it speaks of familial hypercholesterolemia that most of us would assume is very rare.

 
 
Now David, I know that you actually published prevalence in a prior paper last year, but could you maybe start by telling us why we should, how common is this in our patients with acute coronary syndrome?

 
David:
In fact we studied patients who is hospitalized with acute coronary syndrome in several university hospitals in Switzerland. Of course we try our best to include all classifications in the study in order to be very protective of the acute coronary syndrome population.

 
 
We found that among patients with acute coronary syndrome, familial hypercholesterolemia was not a rare disease. We found a prevalence of 2-5% which is in fact 10 times higher than what is thought to be in the general population.

 
 
The important point here is that we use very simple clinical catatonia to assist the prevalence of adage. This catatonia includes unbelievable[inaudible 00:08:50] and the family of Bethany of coronary heart disease. This criteria are very easy to use and implement in a clinical practice in the sitting in acute coronary syndrome to detect patients with familial hypercholesterolemia.

 
Carolyn:
Exactly. You did not use molecular diagnosis in your paper, but yet, with these simple criteria there was a very important clinical take home message. Could you tell us about those findings?

 
David:
The question we wanted to answer here is wanted to know what happened to this patient with familial hypercholesterolemia after hospital discharge. We found that patients with familial hypercholesterolemia were an increased risk of recurrence of cornea events within the year after discharge, and this is despite the use of idol science.

 
 
In fact, one year after the coronary syndrome, 7 people found a patient with adage were still using idle studies, which is very good we were quite impressed by these numbers, but they mean[inaudible 00:09:57] one year after the acute coronary syndrome, with one in twenty become affected later.

 
 
Most of these patients were not able to decrease their added cholesterol to lower evens.

 
 
I really think there is clear room for infestation of leamington therapy among these patients. In any of those drugs available from my seeing and very effective to decrease and [inaudible 00:10:25] to substance, but they are very expensive.

 
 
Maybe the best initial strategy, to prescot these drugs, is to target patients with familial hypercholesterolemia after acute coronary syndrome. Because these patients are at high risk of recurrence and most of them cannot achieve their cholesterol level with our studies.

 
Carolyn:
Congratulations for being really the first to show that. This is common and it affects recurrent events. I think actually the first step is to recognize this in our patients which very few of us really do I think.

 
 
Amat from your point of view, knowing the results of this paper how has it changed your clinical practice?

 
Amat:
Absolutely Carolyn. First I congratulate Dr. Nan chin and his colleagues. This was an incredibly important paper, and I think as you pointed out, one of the first to really show us why it is irrelevant to show us why it is relevant to identify FH at the time of an ACS.

 
 
Generally even when I work with my trainees when we talk about FH, everyone is thinking, "Well, we'll just put everyone on statins," and it's well appreciated. We can think about cascades swinging and why it's important to their offspring, but what Dr. Nan chin and his colleagues have certainly highlighted, is that these patients are at higher risks for recurrent ACS and recurrent events, and that's incredibly important as mentioned that tells us that maybe the routine treatment post ACS with high dose statins is not sufficient.

 
 
What's next is the tricky part, do we initiate PCS canine initially, do we add a zedemi upfront. Sort of the next step is the part that's a little bit more tricky, but I certainly see a potential for augmented therapy in these patients up front.

 
Carolyn:
I like the way you said tricky, and that's usually when we call for an editorial isn't it?

 
Amat:
That is correct as we will see with this article.

 
Carolyn:
I really like the title of it, "Diagnosis and Management of Petra Zygas familial hypercholesterolemia too little and too late."

 
 
That was very interesting, but are there any other take home messages from your end David?

 
David:
Maybe one thing we can add ... We are currently trying to change our practice regarding these reasons that we have now. We have now implemented in our casualty department a system that's explaining strategy to identify this patient, to identify patient with asage.

 
 
We have a prevention team that can provide very early during hospitalization additional information for this patient about asage. That's one very important point is to encourage family testing especially for the children of the patient and also to provide concerning for other cardiovascular risk factors. Because we also found that half of these patients with asage were smokers in fact and 40% of them had hypertension.

 
 
Certainly to address the other cardio risk factor in patients with asage so certainly very important. At the end part of what we are doing is we are assured of the patient will an appropriate medical follow up in the primary care setting because it's also very important for management of asage and circular prevention in the primary care setting after discharge.

 
Carolyn:
Wow. Those are excellent points. Very practical advice on screening, management, and really just applying the results of what you found. Congratulations once again.

 
 
Amat I'm going to switch tracks a little bit now. Since we've got you online I really have to ask you a couple of things with your hat as a digital strategies editor.

 
 
Has it been two months since we first chatted even about this podcast which is part of the digital strategies. Let's take stock of it. How are things going?

 
Amat:
Well, so far I think excellent and frankly one of the highlights of our digital strategies is your podcast. It's gotten rave reviews and certainly appreciate all your enthusiasm and your unique take on how to do this. We've also had some excellent work with our social media. We have a revised website which has a lot more real estate for some novel offerings, and I think we certainly can't rule out traditional print media, but those articles that come out online.

 
 
It's been really an exciting time and thinking of novel ways to share new information in a modern era.

 
Carolyn:
Right. Thanks to you really Amat and I would really want to bring out one of the strategies that we may have not talked about so often yet, and that's the "on my mind" vlogs.

 
 
The reason I'm going to bring it up is because last week I was struck by the on my mind article by Milton Packer and it's entitled, "Heart Failure's Dark Secret. Does anyone really care about optimal medical therapy?" That's just awesome. Could you tell us a bit more about this vlog.

 
Amat:
I think you hit the nail on the head there it certainly an edgy and controversial title, and if you think about it that's the purpose of this in most of our academic writing. It's a little bit stiff in following certain para dines, and more formal para view. The purpose here for the on my mind was literally that for someone who is a thought leader to free associate various ideas they have that would be controversial or edgy or may not be accepted down the main stream.

 
 
That's a bit on purpose because we hope to create a dialog around that. If you look on our webpage, there's actually a place where people can add comments or start a dialog saying whether they agree or disagree, or begin an important conversation around these edgy topics.

 
Carolyn:
I think that's the really cool part when we can actually start interacting with our readers and listeners online that way.

 
 
Thank you to my wonderful guests and thank you listeners for listening this week. Don't forget to tune in next week for more highlights and features.

 
 

Aug 29, 2016

 

Carolyn:
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. In just a moment, we will be discussing the very topical subject of wearable cardioverter defibrillators in patients at high risk of sudden cardiac death. Yes, this is the topic of our feature paper which really builds on prior US data using these devices and extends it, now, to a healthcare system outside the United States. First, here's the summary of this week's journal.

 
 
The first paper describes a novel class of mediators that may revolutionize the nonsurgical treatment of limb ischemia. This paper from first author Doctor Jung from University of Louisville School of Medicine and corresponding author Doctor Spite from Harvard Institute of Medicine and colleagues looked at resolvents. Resolvents are a family of lipid mediators synthesized from Omega-3 polyunsaturated fatty acids that promote the resolution of inflammation and have been shown to regulate the transition from inflammation to repair. Now, this is very relevant to limb ischemia because most other mediators that promote revascularization also exacerbate inflammation, thus potentially limiting their therapeutic use in chronic inflammatory diseases such as diabetes.

 
 
To assess the role of resolvents in revascularization and resolution of inflammation, the authors using a Murine model of hindlimb ischemia coupled with Laser Doppler profusion imaging, micro-computed tomography and targeted mass spectrometry. They identified that resolvent D2 is produced in the skeletal muscles of their Murine model of limb ischemia as well as in skeletal muscle biopsies of patients with peripheral artery disease. They showed that resolvent D2 increases tissue profusion by promoting arterial genesis that is collateral artery growth and, importantly, that it rescues defective revascularization in diabetic mice. These findings are important because they could inform the development of novel strategies for the clinical management of limb ischemia.

 
 
The next paper addresses food fortification with folic acid, which we all know prevents neural tube defects but may now even prevent congenital heart defects. This paper is from Doctor [Mule 00:02:53] and colleagues from The Center for Chronic Disease Prevention, Public Health Agency of Canada who studied approximately six million Canadian births from 1990 to 2011 and compared the prevalence rates and temporal trends in congenital heart disease sub-types before and after 1998 when folic acid fortification was mandated in Canada. They quantified the effects of folic acid fortification on the birth prevalence of specific non-chromosomal congenital heart disease sub-types, after controlling for concomitant changes in maternal age, pre-pregnancy diabetes, preterm pre-eclampsia, multiple birth and pregnancy termination. They found that there was an eleven percent reduction in non-chromosomal congenital heart defects following folic acid fortification. Specifically, folic acid fortification was associated with a twenty-seven percent reduction in conotruncal defects, a twenty-three percent reduction in coarctation of the aorta, a fifteen percent reduction in ventricular septal defects and an eighteen percent reduction in atrial septal defects. This large ecological study, therefore, provides evidence of a modest protective effect of folic acid fortification on congenital heart defects.

 
 
The last study suggests that in patients with ischemic cardiomyopathy and right ventricular systolic dysfunction, we should perhaps be taking a look at the mitral valve. This is work from first author Doctor Seib from the Beth Israel Deaconess Hospital and Harvard Medical School, corresponding author Doctor Kwon from the Heart and Vascular Institute of Cleveland Clinic Foundation and colleagues, who looked at over five hundred and fifty patients with ischemic cardiomyopathy, all of whom underwent cardiac MRI. They found that mitral regurgitation, as measured by effective orifice area, was a significant independent predictor of right ventricular ejection fraction. They further found that the relationship between right ventricular ejection fraction and mortality may be affected by mitral valve surgery in that a reduction in right ventricular ejection fraction was associated with increased mortality in non-repaired patients but not in patients who had undergone mitral valve repair.

 
 
The clinical take-home messages are that right ventricular function should be carefully assessed in patients with ischemic cardiomyopathy and if systolic dysfunction is found, patients should be assessed carefully for significant mitral regurgitation as well as other known risk factors such as right bundle branch block, right ventricular scar or a decreased left ventricular ejection fraction. The study suggests that mitral valve surgery may mitigate the relationship between right ventricular rejection fraction and mortality, however further studies are clearly needed.

 
 
Those were the summaries. Now, for our feature paper discussion.

 
 
I am thrilled to be joined by three guests today to discuss the feature paper on wearable cardio defibrillators in patients at high risk of sudden cardiac death. This is a real world experience all the way from Germany. Joining us today we have two authors of the paper, the first and corresponding author Doctor Nadine Visnic as well as author Doctor Ruth Strasser, both from the University of Dresden and Heart Center Dresden in Germany. Welcome, ladies.

 
Ruth:
Hello, how are you?

 
Carolyn:
Very good, thank you.

 
 
We have Doctor Mark Link, Associate Editor from UT Southwestern. Thank you for joining us, Mark.

 
Mark:
You're very welcome.

 
Carolyn:
Mark, let's start with a behind the scenes look. We have data from the United States describing the wearable cardio defibrillator. We have ample data on the implantable cardio defibrillators. What made the editorial board decide that this particular paper from Germany was so important?

 
Mark:
There are a number of aspects that we looked at for this paper. This is exciting new technology that is beginning to impact the daily lives of all the physicians in the states, the wearable defibrillator. This is a very nice prospective study from Germany that looked at a very large group of patients with this wearable defibrillator, gave us real world experience and it also fits in with the circulation mission of becoming a world wide cardiac journal, not just United States journal. We were very interested in the topic. We're very interested in the international collaboration and we're very excited to publish this paper.

 
Carolyn:
I love that. Practicing in a non US system, as well, I found this particularly special about this paper.

 
 
Nadiene, we're all wondering, could you describe the patient population, just so we know the kind of patients that your results are applicable to.

 
Nadine:
The patients included in the register were regular patients we meet in clinic in every day life. No specific selection was made. For legal reason, of course, to analyze the data, they signed informed consent for the register. From April 2010 through October 2013, in total six thousand forty-three patients were using the wearable cardioverter defibrillator in Germany. All of these patients were registered into the life vest network, the registry to record demographic such as gender and age. Also, the cardiovascular indications and defibrillation treatments and daily wear time. The German population consisted of seventy-eight male and twenty-two female patients with median age of fifty-seven years.

 
Carolyn:
Great. What were the indications for the wearable defibrillators?

 
Nadine:
Most of the patients had to reduce the ejection faction by below thirty-five percent or even had experienced ventricular tachycardia as an indication. The largest group we had in our analysis was thirty-seven percent where those with newly diagnosed dilatative cardiomyopathy and ischemic cardiomyopathy accounted for twenty-seven of patients, especially forty days after myocardial infarction or after a high risk PCI or cabbage. Also, in total, we had twelve percent of patients that had an ICD explantation mostly due to infection situation. What is very special on that paper is that ten percent of all our patients had myocardidas as a diagnosis and was reason to use the WCD.

 
Carolyn:
Wow. That does sound very representative of the real world patients that we would put wearable defibrillators on, as well.

 
 
Ruth, could you tell us, what were the main results? Were there any differences by sub-groups?

 
Ruth:
Perhaps, we should first go on the compliance because this is very important to the daily wear time. This was more than twenty-two hours in ninety-four percent of the patients. Many patients who complained about the inconvenience but understanding that this life vest is a potentially life saving and only temporary treatment strategy made it acceptable to ninety-eight percent of the patients. As to the [inaudible 10:52] there is a difference, the younger patients, patients younger than forty-eight years of age or younger, they wear the life vest longer, sixty-six days. While the older patients, older than sixty-eight patients, this was statistically significant, wore it only forty-nine days. This difference was not used to compliance, because you do the description based on the cardiac diagnosis.

 
 
We also observed that the longer the cumulative wear of the life vest was, the longer day hours the patient had the life vest on. They were somewhat accustomed to it. One thing which is very, very important is, that in more than twenty-five percent of the patients, we could save the implantation of a permanent ICD due to the recovery of the ejection fraction. This was especially important for those patients who had the life vest, for example after myocardidas or after myocardial infarction, which is a very large population.

 
 
Also, which is important is that [full 12:06] shock treatment for reasons other then VT occurred only in point four percent, of less than one percent. Whereas those patients were successfully treated, this was one point six percent. They were treated in response to VT and VF. This means the incidence rate was eight point four per hundred patient years. This was even higher in those patients who had the life vest for the explantation. The life vest is very effective. It's a very effective strategy for general patient population with above indications. It can save the implantation, as I said already, in more than twenty-five percent in the population in Dresden itself. We could observe even a reduction of the need of implantation of permanent ICD more than thirty-five percent due to the recovery of the ejection. This is a very important treatment, especially for those patients who have an acute illness.

 
 
The German cohort is the first large cohort outside the US healthcare system. It confirms the overall value of the life vest and treatment pathways in Germany. Also, the cohorts analysis uncovered over two hundred forty-two sustained but self-terminated episodes of VT among seventy life vest patients, so that you have safely not treated because they were still conscious and could still press the response button. We found out that some of the self terminated VT episodes were even longer than eight minutes in duration time. All in all, we could see that the life vest is a device which is safe and which can prohibit shocks, as well.

 
Carolyn:
Thanks, Nadine. [Ruth 14:12]

 
 
Mark, though, for the readers, I'm sure we need to put in perspective, as well, because there are still patients where perhaps an implantable cardio defibrillator is still more important. Could you share some thoughts about that?

 
Mark:
Yeah. I think this is a very interesting, important study, for a number of regards.

 
 
One, is that there was a very high rate of compliance with using the life vest. To leave it on for twenty-three hours a day, for a mean of sixty days, is really quite impressive patient compliance. The data showed that it did recognize and treat VF in a small percentage, but in a important percentage, of people. This data does need to be put in perspective and the randomized trial is currently ongoing. The vest trial, which will randomize people, probably similar population to what the German study did, and look at the life vest performs in that population.

 
 
We look forward to further data from the vest trial and from other trials, that are looking at what the place of the wearable defibrillator will be in the future.

 
Carolyn:
Thank you, Mark and that's perfect take home message for all us out there.

 
 
Thank you, once again, Nadine, Ruth, Mark. It has been wonderful chatting with you.

 
 
To all of you out there, you've been listening to Circulation on the Run.

 
 
Thank you for joining us.

 
 

 

Aug 15, 2016

 

Carolyn:
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. I am so pleased to be joined this week by Dr. Judd Hollander and Dr. Deborah Diercks to discuss a problem that all of us, as cardiologists and emergency department physicians will recognize. This is a feature paper on the state of the art approach to the patient presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome, but first here are the highlights of this weeks issue.

 
 
The first study is from first author's Dr. Wing and Dr. August from Grand Valley State University in Michigan who investigated whether social and physical neighborhood characteristics are related to progression of sub clinical atherosclerosis measured by coronary artery calcium. They studied this in almost six thousand adult participants of Mesa, a multi-ethnic study of atherosclerosis, followed over twelve years. The main result was that increases in density of neighborhood healthy food stores were associated with decreases in coronary artery calcium. This was significant even after adjusting for time varying demographic confiders, time varying behavioral risk factors and depression.

 
 
The next study from Dr. Hess and colleagues from the University of Colorado School of Medicine characterized rates of implantable cardioverter defibrillator or ICD counseling and ICD use among more than twenty-one thousand potentially ICD eligible hospitalized heart failure patients in the Get With the Guidelines heart failure program. This study had several notable findings. First, only twenty-two point six percent of patients received ICD counseling. This means that up to four out of five hospitalized heart failure patients, eligible for ICD counseling, did not receive it. Women were counselled less often than men and racial or ethnic minorities were counseled less frequently than white patients.

 
 
Among counseled patients, a totally of sixty-two point six percent of patients received an ICD or had a documented plan for ICD placement. Women were just as likely as men to receive an ICD, however, ICD used differences by race and ethnicity persisted. The clinical implications of this study are that future quality improvement initiatives should incorporate culturally competent ICD counseling and elevating ICD counseling to a full performance measure and publicly reporting it by sex or race or ethnicity may need to be considered.

 
 
The next paper is from first author Dr. Resconey and corresponding author, Dr. Catalucci and colleagues from the Institute of Genetic and BioMedical Research in Milan, Italy. These authors looked at the voltage dependent [inaudible 00:03:31] calcium channel which is a key mediator of interest [inaudible 00:03:34] calcium entry associated with various cardiovascular conditions such as hypertrophy, atrial fibrillation, hypertension and diabetic cardio myopathy. The author's aim to address the problem that [inaudible 00:03:47] approaches aimed at enhancing calcium current and inotropism in heart failure have also frequently been found to favor arrhythmogenesis and diastolic dysfunction. Thus, limiting their clinical use.

 
 
The novel hypothesis addressed in this study is that a peptidome emetic therapeutic approach may overcome the arrhythmogenic limitations of current channel activator inotropes. To test this hypothesis, the author's used a whole host of methods to dissect new regulatory pathways modulating the [inaudible 00:04:24] tight calcium channel life cycle. This included yeast, two hybrid screenings, biochemical and molecular evaluations, protein interaction essays, fluorescence, microscopy, and structural molecular modeling and functional studies. Having uncovered a novel mechanism involving the [inaudible 00:04:44] tight calcium channel, calcium beta two chaperon, the author's then generated a mimetic peptide that specifically targets this calcium beta two chaperon. Thereby controlling the channel assembly and density of the plasma membrane while preserving its physiological channel function.

 
 
Finally, they showed that delivery of this mimetic peptide into a mouse model of diabetic cardiomyopathy restored calcium balance and recovered cardiac function. This study is so significant because it provides the proof of concept for the exploitation of novel therapy based on mimetic peptide technology. Really opens the field to mimetic peptides being used as innovative therapeutic tools for the treatment of cardiac disease.

 
 
The last study is from Dr. Cammel from the Feil Family Brain and Mind Research Institute in New York and colleagues who studied the association between pregnancy and aortic complications such as dissection or rupture. They used data on all emergency department visits and acute care hospitalizations at nonfederal health care facilities in California and New York between the period of 2005 to 2013. This was a cohort crossover study where they authors defined the period of risk as six months before delivery until three months after delivery. Compared each patient's likelihood of aortic complications during this high risk period to an equivalent control period of two hundred and seventy days exactly one year later.

 
 
Among more than six and a half million pregnancies in almost five million women, they identify thirty-six cases of aortic dissectional rupture during the high risk pregnancy period and nine cases during the control period. This gives the rate of aortic complications a five point five per million patients during pregnancy compared to one point four per million during the equivalent period one year later. Thus, pregnancy was associated with a significantly increased risk of aortic dissectional rupture with an incidence rate ratio of four compared to the control period one year later.

 
 
Furthermore, absolute risks were particularly elevated in those with a documented diagnosis of hypertension or a connective tissue disease. These findings have clinical implications for the counseling of patients at high base line risk of aortic complications and they also further suggest that clinicians may need to have a lower threshold for initiating diagnostic testing for symptoms of a possible aortic dissection or rupture in pregnant or postpartum patients and especially in those with connective tissue disorders or hypertension.

 
 
Our feature paper this week discusses a problem that impacts twenty million patients in North America and Europe every year. What am I talking about? These are patients presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome. Who am I talking with? Well, today we have first author Dr. Judd Hollander from Thomas Jefferson University and Dr. Deborah Diercks associate editor from UT Southwestern. Welcome Judd and Deborah.

 
Dr. Deborah:
Thank you.

 
Dr. Judd:
Thank you.

 
Carolyn:
Let's start with a behind the scenes look at this paper. It's an in depth review that was invited by the editorial team. Deborah, can you tell us how this idea came about?

 
Dr. Deborah:
I think one of the goals of the editorial board of circulation is really to provide great clinical reviews that really could benefit the members. I have a unique aspect in that I'm an emergency physician. This idea was really brought about by discussion of really what can we merge cardiology and emergency medicine with. What would be the most clinically issue we're challenged with right now? You can't get two emergency physicians in a cardiologist's room together without some discussion and challenge around the [inaudible 00:09:11].

 
 
There's been so many changes in the last decade and so much more information about how we can use these in a clinically relevant way. It really fit nicely into a really great review article and I am really happy that we are able to invite Judd who's well known to the US and one of the leaders in the United States in this area and also an international group inviting a cardiologist from Europe and also an emergency physician from New Zealand to participate in it.

 
Carolyn:
Judd, what is the take home message of this in depth review from your point of view?

 
Dr. Judd:
I think the biggest take home message is we have known for decades and decades that if we rely on our clinical judgement we miss too many patients. We send home people that will be having acute coronary syndromes and acute myocardial infraction and the challenge over the last decades of trying to find ways where we're not going to spend a ton of money over admitting people to the hospital because of a fear of missing an event that may happen five percent of the time.

 
 
The beauty of the advances in troponins is we now have troponins that now have increasing sensitivity whether they be the non high sensitivity troponins used in the US or the high sensitivity troponins that are actually used in Europe and the rest of the world. We can use those better [inaudible 00:10:29] and combine them with clinical decision rules to create accelerated diagnostic pathways which is a big term. For now, if we put a blood test together with a structured clinical decision rule, we can, with more than ninety-nine percent negative predictor value, find patients who are safe to send home.

 
Carolyn:
Judd, I really have to congratulate you on such a beautiful paper. You really did cover all of that but what I love most is the way that you've managed to summarize very clearly a whole wealth of information because when you talk about biomarkers, there's so many out there and there's zero hour, one hour, two hours, this score and that score. I'm actually looking at table one now where you show a summary of the biomarkers strategies and then, in table two, you show a summary of the risk scores and then the performance measures of each of these scores. That must have taken quite a lot to put together.

 
Dr. Judd:
I think that's why Deb was very smart and invited authors from around the world. We have Christian Muller from Switzerland and Martin Tann from New Zealand which, literally, means we're all on different time zones and we were able to work around the clock to do that. There as always somebody awake. Getting more series, the nice thing is that my colleagues on this paper are some of the leaders in doing this kind of research. In fact, they are the leaders in doing this kind of research.

 
 
What I think is very challenging for the average cardiologist or the average emergency physician is there have been so many different approaches and many of them actually work. The challenge for us was to try and make it relatively simple so you can choose the approach at your institution and put it into a structured pathway and pick the one that works best for you. You can get a ninety-nine percent negative predicted value using the right essays with samples that the time of presentation and one hour later, you can get a ninety-nine percent negative predictor value at zero and two hours. You can combine it with an accelerated diagnostic pathway and do that at zero and two hours and zero and three hours.

 
 
I think the important thing is you need to figure out what will your clinicians use? Certain clinicians may be very comfortable with one risk score and not another and then they need to combine the timing of testing with the risk score their comfortable with in order for us to achieve the great possibilities we have with these new tasks. I think when you try and do a one size fits all, there are going to be people who push back because they don't like one component of the risk score. Really what we're trying to do and we didn't say everybody should do A, B or C but we present the data on five or six different options and let people choose what is most feasible for them.

 
Carolyn:
How wonderful. Deborah, what were you thinking when you were reviewing this paper and trying to structure it for the clinician out there who wants to use this information?

 
Dr. Deborah:
I think that, overall, we were really impressed by the clarity and the ease that a reader can take this information home. There is so much information out there and there are so many different ways to apply it that we're really impressed how the authors put it in a really pretty clear manner so you can actually see the risk stratification tools that are out there, what they're used with and what type of troponins. Think about your own clinical practice and what you can adapt really based on the evidence that is out there.

 
Carolyn:
I couldn't agree more. Judd, how about this issue of the coronary CT angiogram and where that falls?

 
Dr. Judd:
That's really an interesting question because there's been a lot of publicity and a lot of editorializing in recent years that maybe you can make a decision with your two troponins and your biomarkers and decrease the number of people that need downstream testing. One of the dilemma with this, like I said before, is we know we're not really good at predicting who has acute coronary syndrome based on clinical things and for that reason the European Society guidelines as well as the American AHAACC guidelines have always said you need to do two things. You need to rule out acute myocardial infraction and you need to risk stratify patients for underlying coronary disease. When a patient comes into the emergency department, if I'm going to be guideline compliant with the recommendations in the world, I need to do both things.

 
 
The paper, we summarize really clearly ways you can get out of the woods with biomarket testing and clinical pathways but then you still want to risk strategy for coronary disease. There are sometimes where you might not need that downstream testing but what coronary CTA really lets us do is it makes us more efficient than a stress test. A stress test I like to say is a next day test; although there is data that you can do it when the patient's in the emergency department rapidly. It certainly is not the standard practice.

 
 
There are people afraid of putting people on the treadmill too soon in case they have unstable angina but a coronary CTA lets me look at the coronary arteries, immediately, when they're in the emergency department. There's very few areas in emergency medicine where there are three large randomized control trials that all give the same results. It doesn't say coronary CTA is better than a next day stress test but it does say you can avoid admission and, hence, save some dollars. It says you can send patients home sooner and, hence, save some angst that the patients may feel while they're in that diagnostic indecision area.

 
Carolyn:
That's such a practical summary and, in fact, it really reflects the entire paper which is really so clearly presenting the information. Judd, one last thing, could I check is this correct, in my understanding, that the main difference between this and say the guidelines that you just measured is that what you do here is really give the readers all the information? As you say, allow the readers to choose what suits them best. This is not making recommendations, it's summarizing all the information. Is that right?

 
Dr. Judd:
Yeah, that's exactly right. If you look, I think it's table number four, where we go through each one of the decision aids and how many or what percent of patients actually fit into that decision aid and what the negative predictive value is for that decision aid combined with troponin. Then what type of troponin was used to achieve those results, you'll see that about half the studies are done with, what we call, the contemporary troponin or just the regular sensitivity troponin that we use in the United States. The other half of the data we show is with high sensitivity troponins. It would not be a good idea for somebody creating their quality program in their emergency department to take something that was tested with a high sensitivity troponin and validate it there and then apply it in an emergency department in the United States where we don't have those [inaudible 00:17:18].

 
 
We thought it was critically important to lay out the data and as the high sensitivity troponins come on the market, hopefully in the next year in the US, people can begin with something now and switch to something else later if they want. If we made a recommendation that was firm, the world changes too fast. I don't think we would be doing the best for our patients.

 
Carolyn:
That is such a great statement to end this on. Thank you so much Judd and Deborah. This was an excellent discussion.

 
Dr. Judd:
Thank you.

 
Dr. Deborah:
Thank you.

 
Carolyn:
You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week for more exciting cardiology needs from all over the world.

 
 

Aug 8, 2016

 

Carolyn:
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 National Heart Center and Duke National University in Singapore. Joining me today will be Dr. Katherine Mills and Dr. Andrew Moran to discuss the very striking findings of a new study on global disparities of hypertension prevalence and control, but first, here's the summary of this week's original papers.

 
 
In a study by first author, Dr. [Lu 00:00:42], corresponding author, Dr. Denny, from the Harvard TH Chan School of Public Health in Boston, Massachusetts and colleagues, authors aimed to investigate how the risk of cardiovascular disease is distributed among whites and blacks in the United States and how interventions on cardiovascular risk factors would reduce these racial disparities. To achieve these aims, the authors used a nationally representative sample of more than 6,000 adults, age 50-69 years of age, in the United States and developed a risk prediction model that was calibrated separately for blacks and whites.

 
 
The main results were that were substantial disparities in the risk of fatal cardiovascular disease; 25% of black men and 12% of black women were at high risk of fatal cardiovascular disease compared to only 10% of white men and 3% of white women, respectively. A large proportion of these fatal cardiovascular events among blacks were concentrated among this small proportion of the population. Now, whereas, population wide and interventions focused on single risk factors did not reduce black/white disparities in fatal cardiovascular risk and intervention that focused on high-risk individuals and reduced multiple risk factors simultaneously could indeed reduce black/white disparities in fatal cardiovascular disease by a quarter in men and a third in women.

 
 
These results really emphasize that focusing preventative interventions on the high-risk individuals has a large potential to improve overall cardiovascular health and reduce racial disparities in the United States.

 
 
The next paper is from first author, Dr. Lee, corresponding author, Dr. Federer, from Ohio State University Wexner Medical Center in Columbus Ohio and colleagues who looked at the issue of adenosine-induced atrial fibrillation and aimed to elucidate the molecular and functional mechanisms that may underlie this problem. To achieve this aim they integrated panoramic optical mapping and regional immunoblotting to allow them to resolve the protein expression of the two main components of the adenosine signaling pathway, mainly the A1R and GIRK4. They found that these signaling pathways were 2-3 times higher in the human right atrium compared to the left atrium leading to a greater right atrial action potential duration shortening in response to adenosine.

 
 
Furthermore, they showed that sustained adenosine-induced atrial fibrillation is maintained by re-entrant drivers localized in the lateral right atrial regions with the highest A1R and GIRK4 expression. Finally, the authors demonstrated that selective GIRK channel blockade successfully terminated and prevented atrial fibrillation. Thus, suggesting that the arrhythmogenic effect of adenosine in human atria may be mediated by activating GIRK channels. The take-home message, therefore, is that specific blockade of the GIRK channels may offer a novel mechanism to prevent adenosine mediated atrial fibrillation in patients.

 
 
The next study is from Dr. Nielsen and colleagues from the Copenhagen University Hospital of Bispebjerg in Copenhagen, Denmark, who aimed to assess the optimal blood pressure in patients with asymptomatic aortic valve stenosis. To achieve this aim, the authors used data from the simvastatin, ezetimibe in aortic stenosis or SEAS trial of 1,767 patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease. Outcomes that were studied included all-cause mortality, cardiovascular death, heart failure, stroke, myocardial infarction, and aortic valve replacement. The main findings were that an average diastolic blood pressure above 90 and a systolic blood pressure above 160 millimeters mercury were associated with a poor outcome.

 
 
Furthermore, low systolic blood pressure was also related to adverse outcomes while low average diastolic blood pressure was harmful in moderate aortic stenosis. In summary, the optimal blood pressure, which was associated with the lowest risk of adverse outcomes, were the systolic blood pressure between 130 and 139 and a diastolic blood pressure between 70 and 90 millimeters mercury. The clinical take-home message is that in the scarcity of randomized controlled evidence, these results may assist clinicians in their decisions in blood pressure measurements in patients with aortic stenosis, meaning that a blood pressure above 149D may be treated while a blood pressure lower than 120 systolic or 60 diastolic may be recognized as a warning signal for poor outcomes.

 
 
That was the summary of this week's original papers. Now for a discussion of our feature paper.

 
 
I am so excited to be joined by two guests today to discuss our feature paper entitled Global Disparities of Hypertension Prevalence and Control, a systematic analysis of population-based studies from 90 countries. We are so pleased to have the first author, Dr. Katherine Mills, from Tulane University School of Public Health and Tropical Medicine in New Orleans. Welcome, Katherine.

 
Katherine:
Thank you. Good morning.

 
Carolyn:
And a very special occasion indeed, we have an editorialist joining us, as well, in none other than Dr. Andrew Moran from Columbia University Medical Center in New York. Welcome, Andrew.

 
Andrew:
Good morning. Thank you, Carolyn.

 
Carolyn:
It's wonderful to have you discuss this. This paper has so many key findings that really struck me. If you don't mind, I am just going to summarize some of these. For example, Katherine, you reported globally more than 30% of the adult population, amounting to almost 1.4 billion people have hypertension in 2010, and the prevalence of hypertension was higher in low and middle income countries than in the high income countries, making it, therefore, that approximately 75% of people living with hypertension live in the low and the middle income countries. Yet, hypertension awareness, treatment, and control were much lower in the low and middle income countries compared to the high income countries. That is really striking. Katherine, I'd really love for you to share with us what was the inspiration to look at this and what do you think was the most striking finding?

 
Katherine:
We know that hypertension is a very important risk factor for cardiovascular and kidney disease. It's the leading cause of cardiovascular disease in the world and for premature death. A previous study in our research group found that about 26% of the world's adult population had hypertension in 2000, but since then there really hasn't been any global estimate made. Basically, since 2000, a lot of studies from individual countries and high income countries have shown a leveling off or decrease of hypertension prevalence, but studies from individual low and middle income countries have actually shown an increase in hypertension prevalence.

 
 
Given these trends in individual countries and the importance of hypertension prevalence and treatment and control, to prevent cardiovascular disease, we really wanted to look and see what the disparities were in high income compared to low and middle income countries. I think the most striking findings to me was that we found that over 75% of adults with hypertension globally are in low and middle income countries, and that's over a billion people. We also found that only 7.7% of those people with hypertension and low and middle income countries have controlled hypertension. That represents a huge global public health problem that could lead down the road to a large burden of cardiovascular and kidney disease if it's not effectively addressed.

 
Carolyn:
Katherine, I could not agree with you more because it's actually a living reality that I'm seeing where I come from in Asia. We have just so much hypertension, and what struck me was that from 2000 to 2010, while the prevalence increased here, it decreased in high income countries. Yet, this is where the greatest need is and where the control is the lowest. That was striking. Can you just articulate a bit further how your data now add to the knowledge that was there before your paper?

 
Katherine:
Basically, this is the first paper to show that the prevalence of hypertension is higher in low an middle income countries compared to high income countries. It's the first paper since 2000 to quantify the global burden of hypertension, and it's the first paper to really compare rates of awareness, treatment, and control comparing high income to low and middle income countries.

 
Carolyn:
That is fantastic and really striking. I think that's why the Circulation Editorial Board to invite an editorial by Andrew to discuss this. Andrew, your editorial was entitled Still on the Road to Worldwide Hypertension Control, and even in the first sentence of your editorial, you mention that hypertension is a preventable risk factor, and that's why this is so important. I really like that your first subheading has this big word, action. Maybe you could tell us a bit more. What are the implications of these findings for worldwide hypertension control and actions that we can take?

 
Andrew:
There's a growing attention to noncommunicable diseases worldwide as a lot of maternal and fetal deaths, those rates have improved worldwide, and so really as the world population ages, problems like hypertension and related noncommunicable diseases are becoming a bigger and bigger health problem for people around the world, not just in high income countries. As a matter of fact, recently the World Health Organization set a 25 by 25 goal, meaning to reduce deaths from noncommunicable diseases by 25% by the year 2025. A big part of that effort is going to be an effort to control hypertension. The World Heart Federation has set a goal of improving hypertension control by 25% as part of that overall effort.

 
Carolyn:
Yes. You mentioned that I think in the editorial, as well, but are there some action steps that we could take globally as a community?

 
Andrew:
Yes. It's striking to me as a practicing physician that something so basic as measuring blood pressure and recommending treatment for people with elevated blood pressure, which is so integral to our daily practice in medicine, that we still have so far to go in achieving control both in high income settings and low and middle income country settings. One of the most basic cornerstones of achieving control is proper measurement of blood pressure. I think one of the goal efforts has to involve making sure that primary care settings and even community centers have available well-calibrated and validated blood pressure measurement devices and that people know how to measure blood pressure accurately.

 
 
The other problems that come up with controlling hypertension are for people who have a diagnosis that is accurately made, are they able to follow up with a primary care provider to monitor their blood pressure, and do they have medications available to them that are affordable? It's important to note that especially in low and middle income countries, most people have to pay for their medications out of their own pockets, so the affordability and availability of medications is a really important part of achieving our goals. I think it's important to see that low and middle income countries, even though it can seem like a daunting setting in which to implement improvements in the quality of healthcare delivery, there also important places to experiment with improving the quality of care delivery worldwide.

 
 
For example, the concept of having a community health worker make home visits and reach out into the community was something that was developed in low and middle income countries and now is becoming a popular and effective method of delivering care in all countries worldwide.

 
Katherine:
One thing I would add is that I think we really need collaborations from the international level because so many of these low and middle income countries have very limited healthcare resources, and there still dealing with a lot of infectious diseases, so I think it really is going to take an international effort to address this problem in low and middle income countries.

 
Carolyn:
Thank you so much for joining us for another episode of Circulation on the Run. Tune in next week for more summaries and highlights.

 
 

Aug 1, 2016

Carolyn:
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. Joining on me in just a moment are two guests to discuss a very exciting new category of papers, known as the white paper. The topic for today is an evolution within the field of current day percutaneous coronary intervention that of the treatment of higher risk patients with an indication for revascularization. But first, here is your summary of this week's journal.

 
 
The first study is from first author doctor Jolis and corresponding author doctor Grainger, from the duke clinical research institute in Durham, North Carolina. These authors describe the American Heart Association Mission: Lifeline, STEMI Systems Accelerator. This exciting project represents the largest effort ever attempted in the United States to organize ST segment elevation myocardial infarction care across multiple regions, including 484 hospitals, 1,253 emergency medical services across sixteen regions and involving more than 23,800 patients.

 
 
Indeed, this project aims to organize coordinated regional reperfusion plans so as to increase the proportion of patients treated within guideline goals, that is a first medical contact to devise time of less than 90 minutes for STEMI patients directly presenting to PCI capable hospitals and less than 120 minutes for transferred patients.

 
 
The authors observed that during the study period of July 2012 to December 2013, there was a significant increase in the proportion of patients meeting these guideline goals, including an increase from 50% to 55% of STEMI patients directly presenting via emergency services and from 44% to 48% of those transfer patients. The authors concluded that these improvements, while modest, suggest the potential for reductions in total ischemic time and happily observe corresponding trends towards lower in-hospital mortality compared with the national data towards the end of the measurement period. Indeed, the tickle message is that the findings support continued efforts to implement regional STEMI networks.

 
 
The next study is by first author doctor Hidari and corresponding author doctor Kuang from the Brigham and Women's Hospital in Boston, Massachusetts. They describe the OMEGA-REMODEL randomized clinical trial. This is a multi-center, double-blinded, placebo control trial of 358 participants presenting within acute myocardial infarction who are randomized to six months of high dose omega-3 fatty acids at four grams daily versus placebo.

 
 
Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and following therapy with the primary study in point being a change in left ventricular systolic volume index. Indeed, the authors reported that compared to placebo, patients who received four grams daily omega-3 fatty acids experienced significant improvements in both left ventricular and systolic volume and surrogate measures of non-infarct myocardial fibrosis during the six months of treatment.

 
 
These remodeling benefits further followed a dose response relationship with the rise in the in vivo omega-3 fatty acid levels as quantified by your red blood cell index. They concluded that four grams daily of omega-3 fatty acid is a safe and effective treatment in improving cardiac remodeling in patients receiving current guideline based post-myocardial infarction therapies. Indeed, this does warrant perspective clinical studies.

 
 
The third study is by first author doctor Liu and corresponding author doctor Sia from University of Texas, Houston Medical School and Colleagues, who sought to understand the molecular basis underlying adaption to high altitude hypoxia. By conducting both human high altitude and most genetic studies, the authors identified a novel functional role of CD73-dependent elevations in extracellular adenosin signolin in response to high altitude hypoxia.

 
 
This led to sequential activation of a readthrough site AMP-activated protein kinase, which in turn resulted in increased 2,3-bisphosphoglyceric production and enhanced oxygen release capacity to peripheral tissues. Thus, reducing tissue hypoxia, inflammation and pulmonary injury. These findings have significantly added to our understanding of the molecular mechanisms underlying adaption to hypoxia. Thereby, opened novel therapeutic possibilities for the prevention and treatment of hypoxia related conditions.

 
 
The final study is from first author doctor Yen and corresponding author doctor Chen from the National Taiwan University and Colleagues, who aimed to determine the effect of betel nut chewing and paternal smoking on the risks of early metabolic syndrome in human offspring. The author studied more than 13,000 parent-child trios identified from more than 238,000 Taiwanese aged 20 years or older screened in two large community based screening cohorts.

 
 
The main finding was that pre-fatherhood habits of both betel nut chewing and cigarette smoking led to a 77% and 27% increase in risk of early metabolic syndrome in their offspring respectively. In fact, they even observed a dose-response relationship where the risk was higher with an increase in duration of exposure as well as with earlier age of starting exposure. These findings interestingly suggest that genetic or epigenetic changes due to exposure to both betel nut and cigarette smoking before birth can contribute to early occurrence of metabolic syndrome in offspring. In fact, these findings really support education for avoidance of these habits or cessation of these habits.

 
 
That was your weekly summary. Now, for our feature paper. Our feature paper this week is a white paper regarding the treatment of higher risk patients with an indication for revascularization and evolution within the field current-day percutaneous coronary intervention. To join me in this discussion, I'll have the first and corresponding author doctor Ajay Kirtane from Colombia University Medical Center, New York Presbyterian hospital, as well as doctor [Manus Brelaques 00:08:22], associate editor from UT Southwestern. Welcome, Ajay and Manus.

 
Ajay:
Thanks so much for having us.

 
Manus:
Thanks Carolyn.

 
Carolyn:
Great. Manus, I would love if we could start by talking about the concept of the white paper and what circulation is looking in these white papers.

 
Manus:
Of course. It is a very exciting part of the new circulation which is for topics that are very timely and important, but at the same time there's not enough populous data and populous literature to be able to address it in a more formal systematic review way. The concept is that establish the leaders in the field. I'm going to provide their perspectives which have derived through their clinical practice and be able to inform us of what the current issues are, how can they best be addressed and what are the next steps forward.

 
Carolyn:
That's great, and what a great example to start with with this paper by Ajay. Ajay, maybe I could just start by asking you to make it crystal clear to us the kind of patients you're referring to in this higher risk and the context and the scope of the problem that you're talking about in your paper.

 
Ajay:
Absolutely. First of all, I'm honored that you would consider that's both timely and important and that this will be one of the new papers in the series on behalf of all the [cohorts 00:09:44] is we're really pleased to be able to discuss it. I think the reason that we find this really critical at this juncture is because what we're sort of saying is an evolution in current-day [catlab 00:09:53] practice. There are many patients now who were seen that have either been turned down for cardiac surgery of have highly complex disease that we know merit revascularization.

 
 
In other words, medical therapy has failed for them either from the symptomatic standpoint or because it puts them at too high risk given the complexity of their coronary anatomy and where these lesions are located. Yet at the same time, in order to be able to treat these patients effectively, we need to grasp not only advanced techniques in terms of how to do it, but also need to be able to select the patients appropriately so that they can undergo these procedures safely and to drag the benefit that we'd like to be able to offer them.

 
 
Just one brief thing to mention is that we certainly know that over the past 10 years or so, there's been a lot of criticism of the PCI procedures they could perform, particularly here in the United states. Some of them were perhaps unnecessary or some of them were not necessarily benefiting patients. The good news is we've curtailed a lot of that, but yet at the same with that curtail we've sort of seen a decline in these types of cases that we refer to in the paper where patients really could benefit from revascularization, but for whatever reason or not being offered it.

 
Carolyn:
Listeners might be wondering though, what is the difference between what you're talking about high risk, and we read a lot of papers about complex procedures and complex PCI, you want to make that differentiation just slightly clearer?

 
Ajay:
Sure. I think that complex PCI has been something that carries the historical definition and usually involves lesion subsets like the left main, chronic total occlusion, bifurcations, that require more than just a simple predilatation stent implantation. The concept of procedural risk though while it overlaps with complexity, to some extent actually has other inputs. For instance, the ventricular function of the patient whether or not the other circulation is also compromised, so it's a larger ischemic territory, and similarly some things that were previously complex with an evolution of techniques actually don't offer or confer that much greater risk on patients.

 
 
I would say when I did my fellowship training, left main was something that my heart rate got up for and we were worried about the patient in that respect. Now when we do left mains, it's actually something where we view it as one of the more simple things that we do relative to for instance the retrograde approach to a CTO revascularization. There's been an evolution and there's an overlap of what's complex and what's high risk.

 
Carolyn:
Very nicely put. Could you tell us a little bit about how your paper is structured? I really like for example the way your tables are laid out and so on, but maybe just give an overview?

 
Ajay:
Absolutely. I think we start off with just setting the scope of the problem. Basically, looking at coronary heart disease and the fact that there are subsets of coronary diseases for which has prognosticked the importance to revascularize. For instance, the publication of this ten-year result for the first trial [inaudible 00:12:45] revascularization as a whole. We talk a little bit about the assessment of procedural risk and then we sort of move on in the end to the various areas that interventionalists need to become better trained in order to deal with these types of patients. I have to give credit where credit is due. The tables that you like so much were actually the suggestion of the editors.

 
 
Because of the new theory, Manus had a lot to do with this. I think it's very important for people to understand, at least for this paper the role, the back-and-forth conversation between not only us, but also the editors and the reviewers play in bringing this manuscript to its final form. I really give them credit for it. What's in the tables are not only descriptions of the types of multidisciplinary teams that are needed in order to [affect 00:13:27] that we take of these patients. Also, the techniques that would be useful for interventionalists to know how to use and be [inaudible 00:13:33] to take care of these patients. Finally, a table looking at future directions because it's all good and fine for us to say this is a new area and we're moving into it, but we need to sort of generate the research and the evidence base to really support the treatment that we're trying offer or saying we can offer in the manuscript.

 
Carolyn:
Manus, you have to this describe some of this back-and-forth conversation that went on.

 
Manus:
Ajay, I wish that every author took the comments as well as you did because that's definitely not the case. I must admit that it was a pleasure working with you because again you were so open to all the comments and suggestions even though some were tough ones. I think the interaction and being so open I think made the paper better and we're very, very appreciative for your response to those.

 
Ajay:
I think at the end of the day when you have a new editor team taking over, there are going to be changes and some changes you learn how to grow through and other changes you basically adopt what the previous editors were doing. At least my experience, not to [despair 00:14:29], is the prior circulation editors at all, I actually had a great experience with them as well, but this was novel, and I think it's something that for many authors will find quite nice to experience because there was a lot of back and forth. Some parts were contemptuous, but these were all resolved. I wrote in my response back to the reviewers I really do feel the paper was better as a result.

 
Manus:
I think that's the idea that [inaudible 00:14:51] the language and the whole editorial team is trying to enforce and we're very happy with it and enjoyed.

 
Carolyn:
I couldn't agree more. Actually, Manus I was also going to ask the title is provocative. It says this is an evolution and even in the conclusion of the paper that this could be a new field of coronary interventional procedures. I really love your thoughts. Is this a beginning of a whole new field?

 
Manus:
I personally do believe and many people I think do believe that there's a tremendous evolution that is going on right now, continue to go on in the field compared to the early days of [inaudible 00:15:26] where we did simple angioplasty I think it has come a long way. But I think there is gap between what can be done right now in terms of technical possibilities, in terms of equipment we'll have and improved patients' quality and quantity of life.

 
 
Actually, what is being done because as you heard from Ajay, many of those patients who could benefit do not. Within the environment of trying to stop in a [inaudible 00:15:51] procedure, which is very appropriate, what happened exactly is that those more complex and high risk cases because of the fear of complications or sub-optimal outcomes led to offering less treatment to those complex patients.

 
 
I do believe it's an evolution in the field. I do believe that having access to these techniques, equipment and offering options to the patients and explaining there is benefit ratio can bring the patient's life, make them better and bring the field forward to the next step.

 
Carolyn:
Ajay, do you think you could elaborate a little bit more then on what those next steps you think are and what are the future areas of research?

 
Ajay:
Yeah, I'd certainly be happy to do so. I couldn't agree with Manus more. I know he and I share a lot of beliefs in terms of this. One of the things that's important to recognize is while we can all assess procedural risk, some of these advanced techniques are not commonly shared by all interventionalists here in the United States, particularly if you look at the overall case volumes of many interventionalists in the United States, there are folks who are just not going to have the requisite volume to be able to do complex CTO revascularization with a retrograde approach. For instance, they would bring procedural success rates up around 90%.

 
 
I think that some of this is education. You have to sort of understand what can and cannot be done, what can and cannot be done [faithfully 00:17:08] and what techniques you use or are necessary in order to be able to improve this rate of success. If for instance I can't do the procedure myself, then I need to be familiar with somebody who actually can because if the patient merits revascularization, in other words they could benefit from having a procedure done, they're not a surgical candidate and they could be helped by PCI, then rather than saying, "We should just do medical therapy because I can't do the procedure." The appropriate thing to do is to actually refer the patient to somebody who actually could do the procedure in a safe way and therefore ensure benefit for the patient.

 
 
That's an educational aspect. Some of it relates to training, but I think conceptually we do need to start understanding now that there is a sub-specialization within coronary intervention of interventionalists who are able to offer things that many interventionalists cannot. That's somewhat of a fundamental step many people have to take, but I think it's time to take that step and that was the whole point in writing this paper.

 
Carolyn:
I think that is a very effective first step that now you've brought it to light and we're so proud and privileged to be publishing this paper. Thank you so much Ajay, thank you so much Manus.

 
Ajay:
Thanks so much for having us.

 
Manus:
Thanks Carolyn.

 
Carolyn:
And thank you listeners. You've been listening to Circulation on the Run. Please tune in next week for more highlights and discussions.

 
 

Jul 25, 2016

Carolyn:
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. I am so excited to be joined in just a moment by Dr. Andrea [inaudible 00:00:21] and Dr. Wendy Post to discuss the feature paper this week about leisure-time physical activity and the risk of coronary heart disease in young women. First, here's the summary of this week's issue.

 
 
The first paper, by Dr. Bohula and colleagues at the TIMI Study Group at Brigham and Women's Hospital in Boston, Massachusetts, aim to test the hypothesis that an atherothrombotic risk stratification tool may be useful to identify high-risk patients who have the greatest potential for benefit from more intensive secondary preventive therapy such as treatment with Vorapaxar following a myocardial infarction. As a reminder, Vorapaxar is a first-in-class anti-platelet agent that inhibits thrombin-mediated activation of platelets via the protease activator receptor 1. The authors studied almost 8,600 stable patients with a prior myocardial infarction followed for a median of two and a half years.

 
 
In the thrombin receptor antagonist and secondary prevention of athrothrombotic ischemic events, TIMI 50 trial. They identified nine independent risk predictors which were age, diabetes, hypertension, smoking, peripheral artery disease, prior stroke, prior coronary bypass grafting, heart failure and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rates of cardiovascular death, myocardial infarction or ischemic stroke. Moreover, the net clinical outcome was increasingly favorable with Vorapaxar across the risk groups.

 
 
In summary, this paper provides a practical strategy that could be used by clinicians to assist with risk stratification and therapeutic decision-making regarding Veropaxar use for secondary prevention after myocardial infarction.

 
 
The next paper is by first author Dr. [inaudible 00:02:40] and corresponding authors, Dr. [Gerstein 00:02:43] from the Beth Israel Deaconess Medical Center and Dr. [Carr 00:02:47] from the Broad Institute of Harvard and MIT, who look at aptamer-based proteomic profiling. Now DNA aptamers are [alu 00:02:57] nucleotides of approximately 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. They therefore holds considerable promise for biomarker and pathway discovery in cardiovascular diseases.

 
 
These authors applied a novel technology that uses single-stranded DNA aptamers to measure over 1,100 proteins in a single blood sample. They applied this to a model of planned myocardial injury and that is patients undergoing septal ablation for hypertrophic cardiomyopathy, and they found that 217 proteins were significantly changed in the peripheral vein blood after planned myocardial injury in this derivation cohort. They validated 79 of these proteins in an independent cohort. Furthermore, among 40 validated proteins that increase within one hour after myocardial injury, 23 were also elevated in patients with spontaneous myocardial infarction.

 
 
Finally, the authors applied this to archive samples from the Framingham heart study and showed 156 significant protein associations with the Framingham risk score. This study is so exciting because it highlights any merging proteomics tool that captures a large number of low abundance analytes with high sensitivity and precision, thus providing important proof of principle for future clinical applications and this is discussed in an excellent editorial that accompanies this paper by doctors Graham [Malini 00:04:37], [Lau Enleui 00:04:39] from the University of Ottawa Heart Institute.

 
 
The next paper is by Dr. [Anter 00:04:51] and colleagues from the Beth Israel Deaconess Medical Center in Boston, Massachusetts, who looked at post infarction, reentrant ventricular tachycardia and addressed the problem that in vivo descriptions of ventricular tachycardia circuits are currently limited by insufficient spatiotemporal resolution. The authors therefore utilize a novel, high resolution mapping technology to characterize the electrophysiological properties of these reentrant circuits in 15 swine.

 
 
The main finding was that the zones of slow conduction within the reentrant circuits with the inward and outward curvatures while conduction velocity in the comment channel isthmus itself was nearly normal. The authors further demonstrated that entrainment mapping over estimated the true size of the isthmus. Thus, the conclusion was that high resolution activation mapping of ventricular tachycardia may better guide ablation therapy and ablation at zones of high curvature may be an attractive target for ablation.

 
 
The final papers from first author, Dr. [Tang 00:06:08] and corresponding author Dr. [Fitzgerald 00:06:10] from the University of Pennsylvania Perlman School of Medicine in Philadelphia. These authors studied the cardiovascular consequences of prostanoid I-receptor deletion in microsomal prostaglandin E synthase-1 deficient hyperlipidemic mice. The clinical background to this research question is that inhibitors of cyclooxygenase-2 or Cox-2 are well-known to relieve pain, fever and inflammation by suppressing biosynthesis of prostacyclin and prostaglandin E2.

 
 
However, suppression of these prostaglandins particularly prostacyclin by Cox-2 inhibitors or deletion of the I-prostanoid receptor for prostacyclin is known to accelerate atherogenesis and enhance thrombogenesis in mice. In contrast, deletion of the microsomal prostaglandin E synthase1 has been shown to suppress PGE2 but increase biosynthesis of prostacyclin. It therefore confers analgesia while attenuating atherogenesis and does not predispose mice to thrombogenesis. Therefore, possibly contributing to cardiovascular efficacy.

 
 
In this particular study, therefore, the authors sought to determine the relative contribution of suppressing PGE2 versus augmenting prostacyclin to the impact of depletion of microsomal prostaglandin E synthase-1 in hyperlipidemic mice. The main findings were that augmentation of prostacyclin is the dominant contributor to the favorable thrombogenic profile of microsomal prostaglandin E synthase-1 depletion in these atherosclerotic mice while suppression of PGE2 accounted for the protective effects in atherosclerosis and the exciting clinical take-home message is that inhibitors of the microsomal prostaglandin E synthase-1 may be less likely to cause cardiovascular adverse effects than NSAIDS or specific inhibition of Cox-2. Those were the highlights of this week. Now for our feature paper.

 
 
Our feature paper today is entitled "The frequency, [type 00:08:41] and volume of leisure time physical activity and risk of coronary heart disease in young women" and I am so excited to be joined by two lovely ladies today to discuss this paper. First, the first and corresponding author Dr. Andrea [Comastick 00:08:58] from the School of Public Health of Indiana University Bloomington and Dr. Wendy Post, associate editor from the Johns Hopkins University. Welcome Andrea and Wendy.

 
Andrea:
Hi. Thanks.

 
Wendy:
Thank you so much for having us.

 
Carolyn:
I am just so excited that we are talking about a paper about women being discussed by women. What more could you ask for? I have to say this is a first for Circulation on the Run, which is why I’m just so excited, so let’s get straight into it.

 
 
Andrea, maybe I could just ask you to start by sharing the story of how you and your team came up with some new questions and new data because I’m sure a lot of listeners are thinking there’s a lot of data on exercise and how good it is for cardiovascular health in women already.

 
Andrea:
Yeah, that's a great question. When we started talking about conceptualizing this paper, the first thing was to focus on younger women. Most of the previous work on physical activity and heart disease has been in older adults and that's primarily because it's older adults that have heart attacks. It’s hard to get a large enough study of young women that has enough coronary heart disease events to be able to study this. We were fortunate where we had a large cohort in the nurses health study too of women and because it’s been followed for over 20 years, we had enough events to be able to examine this association.

 
 
We did want to think about, "Okay, what can we add?" because there’s a lot of information about just overall physical activity and health, so what can we do differently? I’m pretty familiar with the physical activity guidelines and really tried to look at what in the guidelines currently and then what could we add? What could be of interest when they start revising the guidelines which is actually going to happen very soon.

 
 
That was when we started focusing on, "Okay, instead of looking at just overall activity, look at intensity, comparing moderate and vigorous." We also wanted to look at frequency of physical activity and looking at frequency but also adjusted for a total time or total amount of physical activity that somebody does. Then we are also, the third thing was that we thought was important was looking at adolescent physical activity.

 
 
We know that kids, unfortunately as they get older and get into their teenage years, their activity declines quite a bit. Looking at how this physical activity during adolescence earlier life impact coronary heart disease risk in adulthood. Those were the three main things that we were focusing on when we first conceptualized the paper.

 
Carolyn:
Nice. Tell us, what did you find?

 
Andrea:
We did find that exercise is just as beneficial in younger woman as it is in older adults, which is great. We also found that moderate intensity exercise is just as beneficial as vigorous intensity exercise, which I think is a really important message to get out there. I think a lot of people, especially those that are really inactive to begin with are completely intimidated about the fact of trying to think about going to a gym or trying to jog or run a marathon or something like that.

 
 
I think really emphasizing that moderate intensity activity is beneficial and we found that walking was actually the most beneficial activity that we looked at in our study, that brisk walking was really really good for everybody and really lowered risk of coronary heart disease.

 
Carolyn:
Hooray.

 
Andrea:
Yeah, and the other thing we found which might be of interest for those that are also extremely busy, especially this target population where a lot of people are moms and working was that frequency didn't seem to matter, that as long as people were exercising for a couple hours a week that they should be that they could accumulate it in a couple times a week or they could do it more frequently, four or five times a week. It didn't seem to matter.

 
Carolyn:
That’s cool. You know what? I think a lot of these things we'll also discuss at the Editorial Board when we're looking at this paper. Wendy, we promised that we would give a backstage pass to the Editorial Board and The Journal, so could you share a little bit about what we talked about there?

 
Wendy:
Well, the Editorial Board was really excited about this paper. We loved the emphasis on young women and the important public health message about how we need to get out there and move and exercise to reduce our risk for cardiovascular disease. As was mentioned, there have been previous studies that also show the benefit of exercise but the Editorial Board especially liked the large sample size, the long duration of follow-up, the number of events that had been accrued that allowed for sophisticated analyses, adjustment for confounders and the very rigorous study design and excellent statistical methods that have been used in this study and so many other studies from the nurses health study, but I think we particularly just loved the message. The message was great.

 
 
We need to get out there and move. We need to tell our patients, especially young women, that now we have data that if you start exercising now, it will help in the future but also the study showed that if you hadn't exercised much in early life that’s starting to exercise more proximal to the event was also important as well.

 
Carolyn:
Thank you Wendy. I also remember that we talked about the lack of interaction with body mass index, and I thought that was a great message. Andrea, could you maybe share a little bit about that?

 
Andrea:
Yeah, this is something that previous investigators have looked at the interaction between body mass index and exercise. Unfortunately, we’ve all found the same thing so it doesn’t seem to matter whether women are normal weight or overweight or obese that they still get benefit when they exercise, and I think that’s really encouraging. I know a lot of people might start to exercise because they really want to drop some weight but just trying to emphasize even if the numbers on the scale aren't changing, that exercise still has all these really great benefits for heart disease and also for many other diseases.

 
Carolyn:
Exactly. Can I just ask both of you and maybe I’ll start with Andrea, what will you do different now both as a woman and as a clinician seeing women now that you know what you do from your data?

 
Andrea:
Well, I’m not a clinician. I’m an epidemiologist so unfortunately I don’t get to see patients and counsel them although I do try to talk to community members as a public health person and really get in the community on board with what we’re talking about. I just try to tell people, I actually talked to a group of people last week, and just trying to say, "Anything is better than nothing and just trying to even start with some short walks." Again, just emphasizing you don’t have to go to a gym or you don’t have to be doing anything that's super strenuous but just do stuff that feels good and just try to get your heart rate up a little bit like going out for a brisk walk. I think that's my main message that I try to tell everybody is at least start with something and get moving a little bit.

 
Carolyn:
I love that. Wendy?

 
Wendy:
I like to emphasize the data about brisk walking. I thought that was great because many of our patients don’t want to join a gym, don’t have the time to join a gym so just getting out and walking is fabulous exercise and now we have the data here that in young women that after 20 years of follow-up, brisk walking was associated with I think it was a 35% reduction in risk for cardiovascular disease during follow-up.

 
 
In addition, I liked the message about the total amount of time that you spend exercising in a week is what’s important. It doesn’t matter whether you divide that into seven days a week to get to that same amount of time or whether you do it in bursts of three days a week, and I think that’s particularly important for the many women who have so many different responsibilities and may not have time every day to go out and exercise. The days that you do have time, just exercise a little bit more those days, so lots of really important messages for our patients and for ourselves.

 
Carolyn:
I really couldn’t agree more and just from my point of view, because I see a lot of patients in Asia and I do acknowledge just like you did, Andrea, in your paper that your data are predominantly in white populations. Still one of the messages I like to get out to the women I see is we have very skinny women and when I see younger women, and I really like emphasizing that, "Hey, just because you’re not struggling with an obesity issue or just because you’re young, it doesn’t mean you don’t need to exercise and that we all should just get moving." Thank you very, very much for that Andrea.

 
Andrea:
Oh, no. It's my pleasure and thank you for having me come on today and talk about this.

 
Carolyn:
Thank you too, Wendy. Do you have any other comments?

 
Wendy:
No, but congratulations on your publication, Andrea.

 
Andrea:
Oh, thank you so much, Wendy. I was really happy to get the message that guys were excited about it. Thank you so much.

 
Carolyn:
You’ve been listening to Circulation on the Run. Thank you for joining us this week and please tune in next week.

 

Jul 18, 2016

 

Speaker 1:
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. Joining me in just a moment are Dr. James Gammie and Dr. Timothy Gardner to discuss our feature paper this week describing the first-in-human clinical experience with a novel transapical beating heart mitral valve repair.

 
 
First, here are the highlights of this week's journal. The first paper is from co-primary authors doctors Yoon, [Tsue 00:00:49], and [Cha 00:00:50] as well as corresponding authors Dr. [Che 00:00:55]  and Dr. Kim from the Seoul National University College of Medicine. These authors examine mechanisms underlying diabetes-induced microvasculopathy, testing the hypothesis that Notch signaling in endothelial cells may play an important role in this condition.

 
 
The authors tested this hypothesis by inducing diabetes in eight-week-old adult mice using intravenous streptozotocin. They then modulated endothelial Notch signaling using chemical inhibitors in both wild type and transgenic mice. Results showed that the Notch ligand called Jagged-1 was markedly increased in endothelial cells of diabetic mice. Using endothelial specific Jagged-1 knocked down mice, they found that blocking Jagged-1 prevented diabetic microvaculopathy. Furthermore, using the induceable endothelium-specific Jagged-1 knocked down mice, blocking Jagged-1 even at four weeks after the establishment of diabetic microvaculopathy could reverse the condition.

 
 
In summary, these findings show that diabetes induces Jagged-1 over expression and suppresses Notch signalling in endothelial cells leading to diabetic microvaculopathy in adult mice. The clinical implications are that dysregulated intercellular Notch signalling may therefore represent a novel molecular target in the treatment of diabetic retinopathy.

 
 
The next study by Dr. Smith and colleagues at the Leiden University Medical Center in the Netherlands evaluated the association between LDL cholesterol variability and four cognitive domains at 30 months in the 4428 participants of the prosper study.

 
 
Results showed that a higher LDL cholesterol variability was associated with lower cognitive test performance for intermediate and delayed memory-related tasks, selective attention, and processing speed. Higher LDL cholesterol variability was also associated with lower cerebral blood flow and greater white matter hyperintensity load in an MRI substudy of 535 patients.

 
 
In addition to being independent of the mean LDL cholesterol levels and of clinically overt cardiovascular diseases, these associations were present both in the placebo and pravastatin treatment [inaudible 00:03:43] of the prosper trial suggesting that the findings did not mearly reflect pleiotropic effects of statins or of nonadherence.

 
 
The study importantly provides the first observational evidence that lipid variability, not just absolute or mean values, but the variability, maybe of importance to neurocognitive function and thus contributes while understanding potential pathways of neurocogniticve decline.

 
 
The next study is by first author, Dr. [Huh 00:04:19], and corresponding author, Dr. Ralph, from the Menzies School of Health Research Charles Darwin University in Australia. These authors aimed to investigate the long term outcomes from acute rheumatic fever and rheumatic heart disease.

 
 
They achieved this aim by using linked data between the rheumatic heart disease register, hospital data, and death register for residents of the northern territory of Australia, and examined 1248 patients with rheumatic heart disease as well as 572 patients with acute rheumatic fever in the period 1997 to 2013.

 
 
The main findings were that in the first year after an acute rheumatic fever episode, the incidents of progression to rheumatic heart disease was 10 times higher than acute rheumatic fever recurrence; 10% of rheumatic heart disease patients had severe disease at diagnosis. The presence of comorbidities was associated with higher incidence of rheumatic heart disease complications and mortality. In particular, comorbid renal failure and hazardous alcohol use accounted for 28% of the access indigenous mortality.

 
 
These findings have global relevance for settings with high acute rheumatic fever, rheumatic heart disease rates and really emphasized the need for integrated chronic disease management strategies for these patients.

 
 
The final paper is by first author Dr Bettencourt, corresponding author Dr. Blankstein, and colleagues from Brigman and Women's Hospital in Boston, Massachusetts. These authors sought to answer the question what is the most appropriate score for evaluating the pretest probability of obstructive coronary artery disease?

 
 
To answer the question, the authors compared the Diamond-Forrester score with the two CAD consortium scores recently recommended by the European Society of Cardiology, and they did this in 2274 consecutive patients without prior CAD referred for coronary CT angiography. CT angiography findings were used to determine the presence or absence of obstructive CAD defined as 50% or more stenosis.

 
 
Here's a refresher of the different probability scores. The Diamond-Forrester score is calculated based on chest pain type such as non-anginal, atypical or typical angina, gender, and age. The first CAD consortium model score called CAD consortium basic is also based on these factors, but was developed using more advanced statistical modeling strategies which were not available when the Diamond-Forrester model was derived. Additionally, the population had a lower prevalence of disease than the original Diamond-Forrester derivation cohort.

 
 
The second CAD consortium score called CAD consortium clinical included the same characteristics as CAD basic, but also included the following clinical risk factors; diabetes, smoking status, hypertension, and dyslipidemia. Moreover, the presence of typical chest pain was weighted less in diabetics compared to nondiabetics in the CAD clinical score.  Results showed that among symptomatic individuals referred for coronary CT angiography, the CAD consortium clinical pretest probability score demonstrated improved calibration and discrimination for the prediction of obstructive CAD compared to the Diamond-Forrester classification.

 
 
Driving home the clinical implications of this, the authors applied these observed differences in pretest probability of obstructive CAD to guidelines-based patient management algorithms and projected that the use of the newest score could decrease the proportion of individuals in whom testing would be recommended and increase the yield of diagnosing obstructive CAD.

 
 
Those were the highlights of these weeks issue. Now, for our feature paper. Our feature paper today is about the first-in-human clinical experience with the transapical beating heart mitral valve repair using a expanded polytetrafluoroethylene chordal insertion device. We're really lucky today to have the first and corresponding author, Dr. James Gammie from the University of Maryland Medical Center as well as Dr. Timothy Gardner, associate editor from Christiana Care Health System to discuss this exciting paper. Welcome, both of you.

 
Tim:
Thank you.

 
James:
Thank you.

 
Speaker 1:
James, may I start with you? What an exciting title, a first-in-human experience, and this is really sounding very reminiscent of our experience with TAVR and aortic stenosis valves. Could I ask you, with so many exciting things, what is it about the results that excited you most?

 
James:
This is an exciting project in that we believe it affords a new treatment option for patients with degenerative mitral regurgitation. We believe that this is a less invasive way of achieving surgical grade reduction of mitral regurgitation. This is a project which has involved a great number of people on our team both within the university and then within Harpoon Medical, as well as our colleagues in Europe to bring this device from an idea which was asked more than a decade ago into a clinical experience.

 
 
It really rose out of our recognition in particularly my own practice that virtually, every patient with degenerative mitral regurgitation could be fixed with ePTFE or Gore-Tex neo-chords, and the question became how can we place neo chords on a prolapsed mitral leaflets without doing open heart surgery?

 
 
We begin working on that in the laboratory a number of years ago and went through a variety of prototypes, and ultimately, came up with this idea where we could use a 3 millimeter shafted instrument with a specially designed wrap of Gore-Tex on a 21-gauge needle such that we could land on the underside of the mitral leaflet, deploy device, and create a specially designed knot on the atrial surface of the leaflet, and that would anchor the ePTFE on the leaflet. We could repeat that a few times transapically and then adjust the length of those chords in real time using transesophageal echo guidance.

 
 
We got this to work in the laboratory and we had hoped that we would have some modest success in humans, but we've been quite pleasantly surprised that it has just worked and we've outlines this initial clinical experience in the manuscript.

 
Speaker 1:
First of all, I'd just like to pick up on the point that this is degenerative mitral regurgitation, so this is limited to the primary mitral regurgitation, not secondary?

 
James:
That's correct and we know that right now, at least in North America, that two-thirds of mitral valve operations are done for degenerative disease. That's correct.

 
Speaker 1:
I think a lot of the audience out there is going to be wondering how this new technique compares to the MitraClip. Could you tell us a little bit more about that?

 
James:
I do MitraClip as well, so I think I'm well positioned to comment on the differences. The Harpoon device right now is still in operation. It does require a small one or two-inch incision. We anticipate it's going to be a thoracoscopic approach in the very near future and then, beyond that, we would hope to extend it to a transcatheter approach. That's one difference.

 
 
The MitraClip now is certainly across the world. It's used predominantly for functional mitral regurgitation. In our own experience, it seems to work best for functional mitral regurgitation and as you know, there are anatomic limitations for MitraClip in degenerative disease. The MiraClip replicates the LCRA surgical approach and I think what we've learned from all the less invasive approaches to treat mitral valve disease is that we have to respect what we've learned from our surgical experience, and we know that the LCRA approach works best when it's combined with an annuplasty ring, and certainly, the MitraClip, again, is mostly this perfunctional MR.

 
 
Another point I'd bring up is that the experience with MitraClip has been that when you place a MitraClip, you get a fairly strong fibrous reaction and in most of the series, it's not been possible to then go back and surgical repair the valve, but you have to do a replacement because you've compromised the leaflets. Our own approach were simply putting Gore-Tex sutures in the leaflets and we believe that one advantage is that we're not burning any bridges, and that you can go back and do an open repair of you had to.

 
 
In our experience, you asked about our results, we had great results in 10 out of 11 of our patients. One patient did require a reoperation. Actually, one of the chords had come untied on the surface in that patient. We were able to go ahead and do a repair and we saw as we had anticipated it based on our animal experience, there was not much compromised to the leaflets.

 
 
One of the advantages of our approach is that we can titrate the length to the Gore-Tex chords to optimize the amount of coaptation and maximize the quality of the repair, and that's something that we can't do an open cardiac surgery, and one of the challenges of mitral valve repair is that you have to figure out how long to make those chords while the heart is arrested and placid, and that's one of the challenges in why mitral valve repair is certainly some degree of an art to doing that.

 
 
What we've found is that the imager is incredibly important, and so we've teamed up with our echocardiography colleagues, and they really provide essential input into the procedure, and it's done not looking directly at the valve, but looking up at the screens. I think as surgeons, with this procedure, we're moving more into almost becoming interventionalists.

 
Speaker 1:
Thank you, James. That was so exciting. Tim, I have to bring you into this now. Now that James has said they're becoming like the interventionalist. Back to my original comment of TAVR and aortic stenosis, are we witnessing history in the making now? You invited an editorial by Dr. Michael Mack and his title was very provocative, Transcatheter Treatment of Mitral Valve Disease. Is it deja vu all over again? What are your thoughts?

 
Tim:
I think this is an exciting report and I think that this is the wave of the future. I agree completely with Michael Mack that we are beginning to see interventions for mitral valve disease that are effective, less invasive, in some instances catheter based, but this is just the beginning. In fact, mitral valve disease is somewhat more complex even than aortic stenosis, but this type of experience and the ingenuity and the technical prowess, and the ability to do this minimally, invasively, and so on really portend a whole new era.

 
 
I agree with Jim. This is sort of the common ground between the interventional structural cardiologist and the surgeon, and we're becoming even more entwined, more collaborative, and more mutually supportive. We are in a new era and I think over those next decade or so, we're going to see this and similar, and even different procedures tried and proven to be useful for the variety of mitral valve disorders that we encounter. Perhaps the era of the full sternotomy for fairly straightforward, single, focused operations will become something of a thing of the past.

 
Speaker 1:
That's beautifully put. James, with that comment, what are the next steps?

 
James:
As we said in the manuscript, this isn't barely experience and we're continuing to learn as we move [inaudible 00:17:07] to the clinical arena. We are currently in the midst of a CE Mark trial in Europe. We rolled it out to eight separate centers. As we approve clinical experience, we will learn more about precisely which patients work best with this approach and we will accrue longer term data. We now have a number of patient out to a year with stable results and so, as the numbers go up, we'll do that, and then we anticipate a randomized trial in the United States in the early to mid portion of 2017 where we'll compare this approach to conventional open cardiac surgery.

 
Speaker 1:
That's fantastic. Thank you so much to both of you, gentlemen, for joining me on our podcast today.

 
Tim:
Thank you.

 
James:
Thank you.

 
Speaker 1:
You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week.

 

Jul 14, 2016

 

 

Dr. 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. Sanjay Kaul and Darren McGuire will be joining me in just a moment to share their perspectives on the EMPA-REG OUTCOME trials. Are the results with empagliflozin in diabetic patients at high risk, are they too good to be true. First, here are the highlights from five original papers in this week's issue.


The first paper is from Dr. Gilboa, from the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention in Atlanta, Georgia, and Dr. Marelli from the McGill Adult Unit for congenital heart diseases in Montreal, Quebec, and colleagues. These authors recognize that because of advancements in care there has been a decline in mortality from congenital heart defects over the last several decades. However, there are still no current empirical data documenting the number of people living with congenital heart defects in the United States.


These authors address this gap in knowledge by using prevalence data from Quebec, Canada, in the year 2010, as a foundation for a mathematical model, and estimated that in the United States in the year 2010, approximately 2.4 million people, including 1.4 million adults, and 1 million children were living with congenital heart defects. This estimate is significant, because it corresponds to a 63% increase in the estimated size of the adult population with congenital heart defects in the United States since the year 2000. This has significant implications for resource allocation for health services delivery that will need to account for this growing population of adults with congenital heart defects.


The second paper is from first author Dr. Tabot, and corresponding author Dr. Liao, from the University of Chicago, and colleagues who aim to understand better the common complication of angiodysplasia leading to nonsurgical bleeding in patients with left ventricular assist devices. The authors studied 101 patients with heart failure, left ventricular assist devices, or orthotopic heart transplants. They found that compared to patients with heart failure, or transplant patients, patients with left ventricular assist devices had elevated serum levels, and endothelial expression of angiopoietin-2, which is a potent angiogenic mediator.


Elevated levels of angiopoietin-2 in these patients increase angiogenesis in vitro, and were associated with bleeding events. Furthermore, they found that increased thrombin levels in left ventricular assist device patients were associated with elevated angiopoietin-2 levels. In aggregate, therefore, the results indicate that high levels of thrombin induced endothelial angiopoietin-2 expression, which may then contribute to angiodysplasia and non-surgical bleeding in patients with left ventricular assist devices. The clinical implications are that clinical studies angiopoietin-2, and factor 12 inhibitors may therefore be indicated to prevent nonsurgical bleeding in patients with left ventricular assist devices.


The third paper is Dr. Gordon from Hasbro Children's Hospital in Rhode Island, and Dr. Kieran from the Dana Farber Cancer Institute in Boston, Massachusetts, and colleagues who addressed the Hutchinson Gilford Progeria Syndrome. An extremely rare, fatal segmental premature aging syndrome, where without specific treatment, death usually occurs at an average age of 14 1/2 years from an accelerated atherosclerosis.


A PRIA single arm clinical trial has demonstrated that the protein farnesyltransferase inhibitor, Lonafarnib, ameliorates some aspects of cardiovascular and bone disease in this syndrome. The current trial sought to further disease outcomes by additionally inhibiting progerin prenylation using pravastatin and zoledronic acid on top of Lonafarnib in 37 participants with the Progeria syndrome. Results showed that the composite primary study outcome of increased rate weight gain and decreased carotid artery echodensity was achieved. Overall, participants experienced increased bone density, size, and structural properties. However, unlike the PRIA single arm Lonafarnib monotherapy trial, mean carotid-femoral pulse wave velocity and mean carotid artery adventitial echodensity were not improved. In addition, rates of carotid and femoral artery plaques and extraskeletal calcifications all increased.


In summary, compared PRIA Lonafarnib monotherapy treatment, additional bone mineral density benefit, but likely no additional additional cardiovascular benefit was obtained with the addition of pravastatin and zoledronic acid. The authors concluded that since increased bone fracture is not a disease feature, the addition of a combination of statin and biphosphonate to Lonafarnib therapy is not recommended for clinical treatment of Progeria syndrome. However, it is reasonable to consider statins if concurrent lipid abnormalities need to be treated.


This paper is accompanied by an excellent editorial by Dr. Francis Collins, who describes our journey in seeking a cure for this rare disease of Progeria.
The fourth paper is by first author, Dr. Grisenti and corresponding author Dr. Tilley from Lewis Katz School of Medicine, Temple University in Philadelphia, and colleagues who aimed to better understand the role of leukocyte expressed beta-2 adrenergic receptors in regulating immune cell responses to acute cardiac injury. The authors achieved this aim by studying wild type mice who were irradiated, and then transplanted either with isoform specific beta adrenergic receptor knock out bone marrow, or wild type bone marrow. These chimeric mice, after full reconstitution then underwent myocardial infarction surgery.


Results showed that immune cell specific beta-2 adrenergic receptor expression was essential to the repair process following myocardial infarction. In the absence of beta-2 adrenergic receptors, vascular cell adhesion molecule-1 expression was increased in leukocytes, inducing their splenic retention following injury, and leading to impaired scar formation, followed by rupture and death. Splenectomy partially restored the beta-2 adrenergic receptor deficient leukocyte infiltration into the heart, but gene therapy to rescue the leukocyte beta-2 adrenergic receptor expression completely restored all injury responses back to normality.


This study is clinically important because it highlights a bit of a tension that we're facing. On the one had, beta adrenergic receptors are known to regulate cardiac function and remodeling following myocardial injury, by their effects through cardiomyocytes. That's why we use beta blockers to prevent, at first, cardiac remodeling. However, the current studies now indicate that inhibition or deletion of the immune cell expressed beta-2 adrenergic receptor causes leukocyte dysfunction, and impaired immunomodulatory responses to myocardial injury.
These results may, therefore, have implications on the use of beta blockers around the time of acute myocardial injury, such as myocardial infarction, or perioperatively. This is really an area that needs further research and understanding.


The fifth paper is by Dr. Herman, from the hospital of the University of Pennsylvania, and colleagues who report on the one year clinical outcomes of SAPIEN 3 transcatheter aortic valve replacement in high risk and inoperable patients with severe aortic stenosis. Now, as a refresher, in the initial partner trial of transcatheter aortic valve replacement for high risk and inoperable patients with severe symptomatic aortic stenosis, there was a demonstration of marked survival advantage compared to medical management ... But a high one year mortality of 24% in the high risk, and 31% in inoperable patients.


More recently, the lower profile SAPIEN 3 prosthesis system has become available. Which has a balloon expandable cobalt chromium frame, with bovine pericardial leaflets, and an external fabric seal. The early 30 day outcomes of this system have been reported, and show a very low rate of adverse events.


The current study now reports the one year survival, and showed that all cause survival was more than 85% for all patients, above 87% in the high risk, and above 82% in the inoperable subgroups. Furthermore, there was a high rate of transfemoral access at 84%, and a high all cause and cardiovascular one year survival in the high risk transfemoral subgroup of 89% and 93%, respectively. Between 30 and 365 days, the incidence of moderate perivalvular aortic regurgitation did not increase. There was no association between mild perivalvular leak and one year mortality. Although, a small increase in disabling stroke occurred.


These results, which likely reflect device iteration and procedural evolution, support the use of Taver as a therapy to consider in high risk and inoperable patients with aortic stenosis.


Those were the highlights from this week's issues, and now for our feature paper. We will be discussing the perspective paper entitled "Is the Mortality Benefit With Empagliflozin in Type 2 Diabetes Too Good to be True?". To discuss this, we have two very special guests. First, Dr. Sanjay Kaul, writer of this paper, and from Cedars-Sinai Medical Center. Second, Dr. Darren McGuire, deputy editor of circulation from UT Southwestern. Welcome, Sanjay and Darren.


Dr. McGuire: Thanks, Carolyn.


Dr. Kaul: Thank you, Carolyn.


Dr. Lam: To start us off, I'd really love if Darren could please introduce this new content category of circulation. Frame of reference section, of which this is one of the papers, a perspective article.


Dr. McGuire: Sure, so we envisioned, as we're evolving circulation to our new editorship, an opportunity for authors, luminaries in the field, to give us in a very encapsulated form, a laser focus perspective on a specific topic. These come in two flavors, the perspectives piece, which this is, is a little more evidence and scientific quantitatively based. Then we'll also have a section called on my mind, which is more of a free-flowing opinion editorial targeting possibly a contentious or controversial issue. These are going to be very short, and hopefully very entertaining, and kind of teasers for the readership of the Journal.


Dr. Lam: Sanjay, you made it very personal, and I like that, too. Share with us how this idea came about.


Dr. Kaul: Well, I was very impressed at the reception that the results of the EMPA-REG outcome trial received at the EAST meeting at Starcom last year. While I was witnessing the applause, I had polar reactions. On one hand, I thought that after nearly five decades of trials with checkered history, with regards to cardiovascular outcomes, here we have for the first time a trial demonstrating not only cardiovascular benefit, but a mortality benefit. I thought maybe it's time to take the trumpets out and sort of herald this holy grail, which we had failed to achieve. On the other hand, realizing that we had been fooled before many times by trials, yielding implausibly large treatments actually, that were never replicated at subsequent trials.


I had a skeptical response to it, and sort of asked this question rather tongue-in-cheek, or maybe used as a rhetorical tool to address whether this mortality benefit was too good to be true.


Dr. Lam: You know, you didn't just question it. You examined the data, and provided even more evidence. That's what I was impressed with in your paper. That table where you provided base factor, as well as a Bayesian analysis. Could you break that down for us, and explain what you found?


Dr. Kaul: Yes, I was trying to sort of examine the strength of the evidence, in terms of the quantitative aspect. Yes, the effect size for the cardiovascular benefit was quite impressive. For the primary endpoint, which was a compositive cardiovascular, death, non-fatal MI, and non-fatal stroke, the p-value was not very robust. It was .04. The p-value tends to overestimate the strength of evidence. I utilized base factor, which basically is a metric that allows the two competing hypotheses to predict the data. Using the base factor, I was able to demonstrate that the alternative hypothesis was stronger than the null hypothesis by eight-fold. The p-value of .04 translated into a base factor of .13. Which is not strong evidence against the null hypothesis. It requires independent confirmation and subsequent trials.


A p-value of .04, while meeting the superiority criteria, would not be sufficient enough to meet the FDA's requirement of substantial effectiveness. Substantial effectiveness just basically means that the FDA requires two trials, each with a p-value less than .05. In 1998, they modified their regulatory requirement, and accepted that one single trial would be sufficient, provided that there would be a persuasive p-value. Persuasive basically is defined as a p-value less than .001.
The base factor allows us to sort of interpret the strength of the evidence, with respect to the primary composite endpoint was not strong enough to meet this requirement. With respect to cardiovascular mortality, as well as all cause mortality, which trumps all other endpoints, it was persuasive enough.


Dr. Lam: What's your conclusion on that?


Dr. Kaul: What is controversial about that was that in the three specified statistical plan, the so-called hierarchical testing strategy, the non-inferiority for three point MACE, followed by non-inferiority for four point MACE, and followed by superiority of three point MACE, and lastly, superiority of four point MACE. Because the p-value of four point MACE superiority was .08, one can argue purely from a statistical perspective that you stop your testing strategy, and any analysis beyond that would be deemed exploratory. Even though cardiovascular mortality and all cause mortality was prespecified, the purist would argue that since you failed superiority for four point MACE, you really can't proceed further. You can analyze, but it will be considered an exploratory analysis.


I sort of wept and said that because Christopher Columbus had prespecified that he will be discovering the route to India, the fact that he stumbled upon America does not mean it doesn't exist because he had not prespecified it. I think all cause mortality is the most meaningful endpoint, and the least subjective measurement error. It meets the key attributes of regulatory decision making. Which it's prespecified, it's highly persuasive, therefore, it meets the replication criteria, and the p-value is so robust that even if you adjust for nearly 100 multiple comparisons, the p-value would still hold. It meets all the regulatory criteria for approval.


Dr. McGuire: Sanjay, let me just chime in here. I think it's also important, not only were these prespecified, but it's important, I think, for readers of these diabetes programs to realize that hospitalization for heart failure ... Although it's not part of the primary outcome ... In virtually every one of these trials, it is prospectively collected, chartered to find, and essentially adjudicated by blind endpoint adjudicators. You know, death is death. Cardiovascular death in these programs are all adjudicated, as well. I think the prospective collection and central adjudication also adds legitimacy to the hospitalization for heart failure are above and beyond the analytic issues.


Dr. Lam: Darren and Sanjay, I hear both of you kind of saying it does look like, even looking at it from different angles, the data do look strong. At the end of the day, Sanjay, you concluded that it does need another trial. Results do need to be replicated. That was your conclusion. I'd love to hear Darren's take on this.


Dr. McGuire: I think what Sanjay is saying there, and I think what we all believe, was we would really love to see this observation with another member or members of the class. We're learning a lot in hindsight based on these observations, and people are exploring potential mechanistic underpinnings. We're learning a lot about the mechanisms of these medications, above and beyond their glucose uric effects. There's a lot of implication about renal physiology and hemodynamics, and altered myocardial metabolism. I think as Sanjay points out in the paper, some of this looks like a possible arrhythmic effect. We have a lot to learn about this mechanism of action, and whether or not this will be unique to impact gliflozin.
It has been publicly announced, Boehringer Ingelheim is planning, they're in the planning phases for heart failure trials with empagliflozin to further explore this signal. I think they will address Sanjay's desire to have some replication in a different patient population. Still, we would love to see these extended into other patient populations. To both extend the use of the medications if they're found, but also provide further confirmation of the observations from EMPA-REG outcome.


Dr. Kaul: Carolyn, let me also add, I used the title as a rhetorical tool, as I stated earlier. I do conclude that the mortality data is not likely to be spurious. In the back of my mind, I still have that 1% skepticism that I would like to eliminate, because the findings were totally unexpected, and unprecedented, as we discussed earlier. If all the pathways, including the mechanistic pathways are aligned, I would have substantial reassurance, beyond any reasonable doubt that the findings are true. That's why I'm asking for replication. Not necessarily by empagliflozin in other trials, but by another molecule within the same class. I think that would be sufficient.


Dr. McGuire: Yeah, and I think it's really interesting to note there, is that I was involved in the early days of some of these drugs as they're being developed. When the other two members of this class went to the FDA, dapagliflozin and canagliflozin, they provided FDA's requirement and meta analysis from all of the phase 2B and 3 trials that had been completed to date. The meta analysis of the cardiovascular outcomes. Both dapagliflozin and canagliflozin had point estimates of cardiovascular death reduction of 30%, and 35%, respectively. When we saw those data, they were based on 25 to 40 total events. We chuckled, thinking this is spurious, from small events being analyzed. That there's no way they would prevent cardiovascular death. Sure enough, you know, you could almost superimpose those point estimate plots from the phase 2B-3 meta analysis, with the ultimate outcomes from EMPA-REG. There's some promising, although again, very statistically imprecise estimates that this may well be a class effect. As many of the listeners will know, there are ongoing cardiovascular outcomes trials for all of these medications. That will come some time in the next year or two.


Dr. Lam: That's fantastic. Thank you both for sharing those perspectives. I mean, I learned so much. I really think, Sanjay, your paper achieved exactly what you had meant for it to achieve, and exactly what circulation was hoping to create the discussion, as well.


Dr. McGuire: Thank you, Carolyn.


Dr. Kaul: Thank you very much.


Dr. Lam: You've been listening to Circulation on the Run. Thank you for listening. Don't forget to join us next week for more highlights and discussions.

 

Jun 29, 2016

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.

I am excited to be joined today by 2 guests and we will be discussing the feature paper on phenotype specific treatment of heart failure with preserve ejection fraction but first here are the highlights from 5 original papers in this week's issue.

(0:42) The first paper by first author doctor Haas, corresponding author Dr. Bidinger and colleagues from Boston Children's Hospital aim to investigate the role of PCSK9 in nephrotic syndrome associated hypercholesterolemia. The authors did this by first looking at 50 patients with nephrotic syndrome and showing that resolution of nephrotic syndrome was associated with a decrease in their plasma cholesterol, as well as a decrease in their plasma PCSK9 levels. They then looked at two mouse models of nephrotic syndrome. One using nephrotoxic serum to induce immune mediated damage of the kidney podocytes. The second, a model of genetic ablation of the kidney podocyte.

In both these models nephrotic syndrome produced hypercholesterolemia and a 7 to 24 fold induction of plasma PCSK9 levels. The authors then went on to look at the effect of knocking out PCSK9 both in the whole body as well as specifically in the liver in these mice. They showed that mice lacking PCSK9 no longer showed the increase in LDL cholesterol with nephrotic syndrome induced by nephrotoxic serum. Thus in summary, podocyte damage triggered mocked inductions in plasma PCSK9 and conversely knocking out PCSK9 in ameliorated this lepodimia in a mouse model of nephrotic syndrome. The cool thing about this data is that they now opened the door to the consideration of PCSK9 inhibitors in patients with nephrotic syndromes associated hypercholesterolemia.

(2:45) The second paper by Dr. Fortis and colleagues from Duke Clinical Research Institute aimed to address an important knowledge gap that has not yet been addressed in the pivotal noac trials or large registries. Which is whether outcomes differ among atrial fibrillation papers with worsening renal function compared with those with stable renal function while taking a noac versus warfarin. The authors looked a this by studying more than 12,600 patients who were treated with rivaroxaban compared to warfarin in the ROCKET AF trial. On treatment worsening renal function was defined as a decrease of more than 20% from screening creatinine clearance measurement any time point during the study.

The main finding was that among patients with on treatment worsening renal function, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin without an increase in the composite leading end point. This is really encouraging to all of us who treat these patients, knowing that it is possible to safely anti-coagulate patients with worsening renal function without excessive bleeding and to know that rivaroxaban may be an alternative to warfarin in these patients. This paper is accompanied by a beautiful editorial on the multifaceted dilemma of renal function and atrial fibrillation by doctors Hijazi and Wellington.

(4:30) The third paper by doctor [inaudible 00:04:32] and colleagues from Massachusetts Journal Hospital describes a randomized controlled trial of an advanced care planing video decision support tool in 246 patients with advanced heart failure. Patients were randomized to an intervention arm which consisted of a six minute video as well as an advanced care planning checklist or to a control arm where patients received only a verbal description of the goals of care. This video began by first introducing to the patient the concept of advanced care planning and then using images to depict the three part goals of care namely, life prolonging care, limited medical care and comfort care. Patients in the intervention arm who were showed the video, were more likely to be informed, to select a focus on comfort and less likely to desire CPR and intubation compared to patients receiving the verbal information only. The clinical application of this finding is that advanced care planning video decision needs can stimulate and supplement patient decision communication. Indeed we need such tools to enhance patients understanding of their goals of care options and to ensure that our patients get care that reflects their well-informed wishes.

(6:10) The fourth paper is by first author Dr. [inaudible 00:06:12] and corresponding author Dr. Lloyd Jones and colleagues from the Northwestern University Feinburg school of medicine in Chicago. These authors provided the first prospective evaluation of atherosclerotic cardiovascular disease outcomes in adults with heterozygous familial hypercholesterolemia in the US population. They did this by using individual pool data from 6 epidemiologic cohorts including more than 68,500 baseline person exams and 1.2 million person years of follow up. They confirmed substantially elevated long term, meaning up to 30 year risks of coronary heart disease and total atherosclerotic cardiovascular disease including stroke in US adults with a familial hypercholesterolemia phenotype defined as LDL cholesterol above 190 milligrams per deciliter. This was associated with an acceleration of coronary heart disease risk by up to 20 to 30 years. These findings were independent of other risk factors and were consistent using various definitions of the familial hypercholesterolemia phenotype.

What are the clinical implications of these findings? This was discussed by Dr. Rodriguez and Dr. [inaudible 00:07:47] in an editorial, the take home message is that there is likely an important long term burden of atherosclerotic cardiovascular disease in phenotypic but unrecognized familial hypercholesterolemia patients in the United States. Current efforts to identify patterns and gaps in the diagnosis and management are well justified. The findings also have implications for risk communication to patients.

(8:20) Finally, the fifth paper is by Dr. [inaudible 00:08:25] and colleagues of the TIMI study group from Brigham and Women's Hospital. These authors looked at the impact of renal function on outcomes with edoxaban and oral factor 10 A inhibitor with 50% renal clearance compared to warfarin in the ENGAGE AF-TIMI 48 trial. In the pre-specified subgroups of granting clearance 30 to 50 and more than 50 ml per minute. The higher dose edoxaban regiment was comparable to warfarin for preventing stroke or systemic embolism and resulted in significantly less major bleeding. In further exploratory analysis, there was a suggestion of lower relative efficacy for prevention of stroke or systemic embolism with the high dose edoxaban regiment, compared to warfarin in the upper range of creatinine clearance beyond 95 ml per minute. Due to lower rates of major bleeding, the net clinical benefit was more favorable with the higher dose edoxaban regiment across the range of creatinine clearance.

In summary, edoxaban demonstrated superior safety and comparable efficacy to warfarin for the prevention of thromboembolic events in many patients with atrial fibrillation. However the authors were careful to note that there was insufficient evidence to allow definitive conclusions to be drawn in patients with normal renal clearance above 95 ml per minute. The authors called for further investigation of optimal dosing of edoxaban in the higher range of creatinine clearance.

(10:14) Those were our highlights now for our feature paper of the week. Phenotype specific treatment of heart failure with preserved ejection fraction, a multi-organ road map. The first author is Dr. [inaudible 00:10:31] from Northwestern University Feinberg School of Medicine in Chicago and colleagues. To discuss this very special paper today I have two guests, one is a corresponding author, Dr. Walter Paulus from the VU, University medical center in Amsterdam as well as Dr. Jarett Berry, associate editor from UT Southwestern. Welcome Walter and Jarett.

Jarett Berry: Thanks Carolyn.

Walter Paulus: Thank you very much Carolyn.

Carolyn Lam: To start us off this is an in depth review paper and it is a really very special type of paper that it's new to Circulation. Jarett could you tell us a little bit about these reviews and how this paper came to be?

Jarett Berry: As we think about the new Circulation and our goals to really make the content of Circulation as clinically relevant as possible, as we think of the different circumstances and clinically challenges faced by practicing physicians, many different topics come to mind and one in particular, therapeutic area heart failure with preserved ejection fraction is one particular type of cardiovascular disorder that has been very difficult to find novel treatments for. As we all know there has been a number of large scale clinical trials that have failed to improve clinical outcomes in these patients, in situations like this what we really need is wisdom and a guide from those with expertise in this area so we can take that wisdom and that perspective and incorporate it into our approach to caring for these patients in a way that can provide a road map moving forward.

This particular review addressing heart failure with preserved ejection fraction was timely in that sense and the choice of author, of course, Walter and his colleagues are leaders in the field in terms of the research and our understanding of HFpEF. With that goal, we're really trying to reach out to these types of investigators for these types of reviews to provide us with a framework to help us think about charging our way forward and we couldn't think of a more appropriate choice to lead that effort other than Walter Paulus.

Carolyn Lam: Thank you so much Jarett, that's so well put and I couldn't agree more. I mean HFpEF is one of those disease syndromes were guidelines haven't changed in years and basically the first sentence is that we don't have outcome improving treatments available. Walter this must have been particularly challenging and I really congratulate you because one of the central figures that I'm so impressed with in this review is actually a clinical application figure and I'm referring to figure 2. Do you think you could tell the readers a little bit more about this?

Walter Paulus: I would like to thank first the editors of Circulation for having given us the opportunity to write this in-depth review. I must admit before answering Carolyn's question that I really enjoy this [inaudible 00:13:37]. We have a very challenging team of co-authors and the most difficult part of the enterprise was to have all the noses directed in the same direction. You have to align very many ideas and it has been a very challenging in-depth but I think it will be teamed out with a, not a compromise but something, a paper where everybody is still happy with its content. This is somehow also reflected in the figure 2 to which Carolyn is alluding.

When we start speaking about the phenotypic diversity, it's very difficult to [inaudible 00:14:13] with a conceptual theme on how we're going to organize therapy when there are many different phenotypes around. I think this is what this figure is all about, it tries to organize the phenotypic diversity and come up with a type of personalized medicine for each phenotype in a very comprehensive way. This figure, in fact, orders the phenotypes, presentation phenotypes and pre-disposition phenotypes with presentation phenotypes on the abscissa and the pre-disposition phenotypes on the ordinate. Then you get a matrix configuration, you start out in the matrix in the left hand corner for the most common phenotype which is metabolic risk combined with [inaudible 00:14:59] congestion. Then you go on and you see that you can have [inaudible 00:15:04] hypertension, then you have additional measures that need to be taken. You can go downwards in the graph and then you'll find out that it might be renal dysfunction and then you find specific measures that have to be taken when renal dysfunction is present.

By combining the ordinate and the abscissa in the matrix, you find a very personalized type of therapy for the individual phenotype. I think this to me what makes the figure that feeling is that it's structured, it's organized, it's something very complex in something which is easily comprehensible.

Carolyn Lam: Walter, I have not seen a figure like this that it's so novel and I know that clinicians will really welcome this because as Jarett so nicely put, it's wisdom and some sort of simplification and yet with in-depth understanding that we so need in the management of this syndrome. Another thing that I thought was very special about your paper is that you tackled head on the divergent results of several recent trials. You described the low nitric oxide, low cyclic guanosine monophosphate cycle that's present in HFpEF but also try to put into context the need trial, the relax trial, top cat and even mention Socrates preserved in all of this. Do you have any quick top line comments, not to give the whole story away because I'm sure readers are now encouraged to look at the paper but on how all of this actually falls into place in your schema.

Walter Paulus: I think how everything falls into place is illustrated in the figure 1. Figure 1 shows a very broad perspective on the problems of HFpEF as it shows HFpEF to be the result of systemic inflammatory state but so far we have focused only on the project manifestations of the systemic inflammatory state [inaudible 00:17:08] cardiac manifestations, which is the stiffness of the myocardium, and the [inaudible 00:17:12] of the myocardium. There are also things going in the pulmonary [inaudible 00:17:16], there are things going on in the skeletal muscle and there are things going on in the kidney. I think that if you do not take these other organs into perspective, then the image you will have from the results of your trials is getting blurred. For instance, we have so many trials about look at the exercise [inaudible 00:17:35] in terms of elevation of [inaudible 00:17:37].

It's my feeling that many patients with HFpEF just get treated diabetic. You see them afterwards again in your [inaudible 00:17:46] patient clinic and they have symptoms of nasal fatigue. They no longer being hindered by the elevation of [inaudible 00:17:52] probably because of the administration of the diabetic but they're still highly symptomatic and they have moved over to another board and that limits the [inaudible 00:18:01] mainly the skeletal muscle. It's of course nicely illustrated already for years by the work of Dalane Kitzman which is one of the co-authors, but still these issues, the same goes for the hypertension, a field in which Carolyn has been very active. There are some patients who are persistent [inaudible 00:18:18] hypertension, I'm intrigued by our classification.

It's clear that these patients have moved to a [three catalyst 00:18:24] type of hypertension and we should pay attention to this and we should try to treat it in a very specific way. Again [inaudible 00:18:33] the failure of our trials is also comprehensible. He have two, [inaudible 00:18:38] focus on the myocardium and we should try to keep a very broad perspective and look at [inaudible 00:18:43] in major broader way. Just to support this point is the result of the Socrates reserve trial which I was very intrigued by it, just listen to the results couple of days ago at the European Heart Failure Society meeting in Florence. Turns out if you give this very [inaudible 00:19:01] patients that there is no change in nature at [inaudible 00:19:05], no change in left atrial dimension, there's no single argument that something is changing in the myocardium. Nevertheless the effort tolerance of the patients was greatly increased and the question is in quality of life, how that has drastically improved? What I think is going on, is that maybe on the dose of the [inaudible 00:19:23] you are using this very [inaudible 00:19:24].

The main effect might be going on the [inaudible 00:19:27] and you just took the wrong end point, you are again focusing very narrowly on the myocardium. I think most of the patients have entered such a trial are relatively stable. You're not going to put in a trial a patient who is unstable, they must be all be treated with diabetics and you shift symptoms from the myocardium to the other organs. I think that the index review which we provide, I think has 2 main issues, that you should have a broad perspective on HFpEF with inclusion of the other organs and secondly, that we provide a matrix configuration for phenotypes specific treatment.

Carolyn Lam: Walter that is beautifully put and Jarett I think I'm speaking on behalf of you too that this paper has really accomplished what our in-depth reviews were aiming to do, which is to provide a clinical perspective and really insightful comments regarding the syndrome. Is there anything else you'd like to add Jarett?

Jarett Berry: Yeah, I just wanted to echo your congratulations and just to really highlight the importance of this figure 2. I think it is an important step for us to begin to take the concept of the heterogeneity the phenotype, whether it's something happening centrally or peripherally and take that heterogeneity and try to incorporate that into our practice pattern. I think that's obviously been discussed in length in literature before but has not been put together in a practical way for practicing clinicians. I just want to echo your comments that Walter and his coauthors have done an important service for all of us as we think about how to take care of our patients with HFpEF.

Carolyn Lam: That's awesome, I think anyone listening is really going to want to take hold of that journal and have a look at both figures, 1 and 2 and read this beautiful paper. Thank you very much Jarett and Walter for your time, today.

Jarett Berry: Thanks Carolyn.

Walter Paulus: Thank you very much Carolyn, [good night 00:21:20].

Carolyn Lam: You've been listening to Circulation on the Run, thank you for listening and don't forget to join us next week for more highlights.

 

 

Apr 27, 2016

Carolyn: Welcome to Circulation on the Run. You're weekly podcast summary and backstage pass to the journal. I'm Dr. Carolyn Lam from the National Heart Center in Duke National University of Singapore. I am thrilled to be your host every week. Joining me today to introduce our podcast are two very very special guests. Dr. Joseph Hill from UT Southwestern is editor and chief of Circulation. Hi Joe.

Joe: Pleasure to be here, Carolyn. Carolyn: Thanks, and your second guest, Dr Amit Kara is also from UT Southwestern and the associate editor for digital strategies of Circulation. Hi Amit.

Amit: Hi, Carolyn. Happy to be here. Carolyn: No Joe and Amit, if you don't mind I'm going to start the ball rolling by sharing my little story of how these podcasts came to be. Now do you guys remember when we first talked about this? All right well I do. Joe: Absolutely. Carolyn: Ha ha because frankly, and I don't know if you know this Joe, it wasn't a very good day for me. I had just landed very early in the morning from a long trip and I was battling jet lag while trying to get a million things done such as unpack, clear my mail, get ready for work. You know, the usual. Of course the thing I needed most was to learn that I also needed to do weekly podcasts for Circulation right. So after our chat I did I suppose what a lot of us do when things seem a little bit overwhelming. I dropped everything and I headed for a run in the gym. But in the gym as always I was trying to multitask as well, so I brought my mobile device for my jog so that I could read my mail at the same time, you know. I can already see the smiles of everyone listening because I know you've done this before. Anyone who's done it will know what a pain it is trying to read while you're bouncing up and down on the treadmill. It was just at this point when I was about to go cross-eyed that the radio in the gym started to play the morning news and the news headlines. I remember thinking to myself, oh wow, how I wish I could have someone read my mail or at least the headlines of the mail to me so that I could get the gist of everything even while I was literally on the run. That's how the Circulation podcast idea came to me and hence it's name, Circulation on the Run. To me it's an audio summary of the headlines of the journal so that you the listener can in 15 minutes get caught up literally on the run or drive or whatever it is you're doing when you'd rather listen than read. Just so you know you haven't missed the big things. But in addition to getting an overview of the issues contents every week, you get main take home messages as a clinician. Because it will be dull to talk to myself every week I will be inviting an author, an editor, of a featured article of particular clinical significance so that we can give you a behind the scenes look of the paper. That is the idea of the Circulation podcast. Joe, how does this fit with your vision of the journal? Joe: Carolyn, I love your story behind the scenes on how this all got started and I really, truly appreciate your energy and leadership here. This is such an important endeavor for where we want to take the journal. In fact, your leadership here illustrates one of the major initiatives that we have started and that is a global footprint of editorial oversight for Circulation. We are afforded an extraordinary privilege here to see the best science as it emerges from all around the world and we want to do everything we can to make sure that the journal meets the needs of the clinicians, the practitioners, and the investigators everywhere in the world. Here you are leading this important initiative from your home base in Singapore. That's exactly what we're looking to foster and develop going forward. Carolyn: Oh Joe thanks so much for that. I really so appreciate this privilege of doing this and it's true that I'm a living example of the journal going global so to speak. I also really like the way you say that with this overwhelming knowledge that we're facing, we do need help to synthesize and synergize that information. Especially in the clinically oriented way. I think you made that very clear to us in your leadership of our editorial board. Thanks for that. Maybe speaking of trying to reach the world, social media and digital strategies play a big roll. Amit maybe you could tell us a little bit more about how the podcasts fit in your larger scheme for the journal. Amit: Absolutely and I just want to echo Joe's comments and thank you, Carolyn, for taking the lead of this important endeavor. We couldn't think of a better person to do so. When we look digital strategies we have to remember that the journal is producing so much valuable content. The authors are working very hard and creating such an immense amount of new knowledge. We have to appreciate that people consume knowledge in different ways. In the current era there's so many different ways to do that. One hand we still have the traditional print journal which is incredibly valuable and important. Has depth of information that certainly many and most people would want to investigate. But the other end of the spectrum we have our bite sized information which is Twitter and Facebook and so forth which certainly helps people sort of prioritize or are able to glean what's exciting that week and then they can go back and do a deeper dive. The podcast fits somewhere in between. I love what you said, Circulation on the Run, you're example was a great one for people who are wanting to consume this information but perhaps in a different way. The audio component and also a time component where they have 10 to 15 minutes to take in this information. Your vision for this is a great one. We'll have a brief component where you will review the weekly articles and people can then learn what's in the journal and what's the most important findings and content that week. Similarly they have the opportunity to really get to know an author and get to know some editors and to really get behind the scenes. This backstage pass if you will. We finally have to remember that we're appealing to a broad audience. People of different ages and around the world. People like to consume information in different ways. We really like to have this as an important part of our offering towards helping people consume this information. Carolyn: Oh Amit. I couldn't have said it better. Thank you so much. Just to be true to ethos. Let me remind everyone that it's going to be a 15 minute podcast and we're going to do our very best to compress all that you need to know into those 15 minutes. I just want to echo what you said that this is only part of the broader strategy and it doesn't mean that the print journal is dead in any way. In fact I am so excited to see the new journal. I don't know about you. It's got a whole new look. It is really really quite good looking, if I might say so. Everyone out there, you're going to expect this new journal on June 29th, 2016. Look out for it. Trust me. You won't be disappointed because there's also a very special little part of the cover that I'd like to discuss before we sign off. That is the doodle. Joe could you tell us a little bit more about the doodle? Joe: As you say the journal look I think is fantastic. It has a clean and modern look to it. The judicious use of color to highlight the different types of content, which as before spans a spectrum of basic science, the definition going forward is vertebrate models, pre clinical models, and disease oriented questions. Starting there, traversing through clinical science, population sciences, health services research, the entire spectrum. Again we are afforded an extraordinary privilege here to help frankly shape the future of cardiovascular medicine. We take that responsibility very seriously. That's why we've recruited an extraordinary team of editors from literally around the world. At the same time, we want to have a little fun. We want to make it fun and engaging as well as very very serious. As part of that, we've launched something that we're calling the Circulation Doodle. That is an idea that leverages the google.com website where I think everyone is familiar with. They, based on an event that occurred that day or week or month, they play around with the visual depiction of the word Google. We're going to do the same thing with Circulation. Every month we will reach out and solicit doodles from artists all around the world. Everyone who's listening to this podcast, I encourage you to think about this. Every month there will be a doodle theme. The first one for July will be Texas. Commemorating the fact that the journal headquarters is moving back to Texas after having been in Boston for 12 years. Previous to that it was under the leadership of Jim Willerson. It's coming back to Texas and the first Circulation doodle depicts a Texas theme. In fact, if you're interested you can find this in the April 25th issue of the journal where in the third of four notes from the incoming editor in that third one on April 25th, we show the first doodle. We're asking people to submit doodles according to monthly themes. The month of August will be vacation. I can tell you start thinking about ways in which you might incorporate a vacation theme in the depiction of the world Circulation for August and the one that comes in that's the best, that the editors like the most, it will be placed on the cover of the print journal and on the website for a full month. We've also conceived themes for the rest of the year all the way through to June of 2017, and in the first issue that comes out from our team, we will list those themes and you'll have plenty of time to start thinking about what you would like to submit. Then in subsequent years, those monthly themes will also evolve. We'd like to get people's ideas about issues that come up related to holidays or national heritage months. Things that we might not know about from our base in the US. We want to do that around the world. It's an opportunity to be creative at the level of themes, and again artistic depiction of the word circulation. Carolyn: I love that. Thank you so much Joe and that just exemplifies that we are all about science and all about having fun at the same time. That was a brilliant introduction to what our podcasts are going to be like as well. Thank you so much Joe and Amit for joining me today. Again, everyone, this was Circulation on the Run. Don't forget, first issue coming out 29th June, 2016.

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