Carolyn Lam, MBBS, PhD

Circulation June 8, 2021 Issue

Circulation June 8, 2021 Issue

This week's podcast features author Nicholas Mills and Guest Editor Allan Jaffe as they discuss the article "High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial." ( Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke-National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor/Director of the Pauley Heart Center and VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to examine cardiac troponin, high-sensitive cardiac troponin, and its association with myocardial infarction. But first, before we get to that, how about we grab a cup of coffee and start in and review some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I would love that. The first paper brings up the problem of stroke, remaining a devastating complication of transcatheter aortic valve replacement or TAVR. Now, this stroke risk has persisted despite refinements and the technique and increased operator experience, while cerebral embolic protection devices have been developed to mitigate this risk data regarding their impact on stroke and other outcomes after TAVR are limited. Dr. Carolyn Lam: Dr. David Cohen from Cardiovascular Research Foundation in New York and colleagues performed an observational study using data from the STS-ACC TVT registry, including more than 123,000 patients from almost 600 sites who underwent elective or urgent transfemoral TAVR between January 2018 and December 2019. Dr. Greg Hundley: Wow, Carolyn, this sounds like a really good use of the registry. What were the results? Dr. Carolyn Lam: Indeed, in this nationally representative observational study, the authors did not find an association between embolic protection device use for TAVR and in-hospital stroke in their primary instrumental variable analysis. And that's a technique designed to support causal inference from observational data with site-level preference for embolic protection device use within the same quarter of the procedure as the instrument. Dr. Carolyn Lam: However, they found a modestly lower risk of in-hospital stroke in their secondary propensity weighted analysis. These findings provide a strong basis for large-scale randomized control trials to really test whether embolic protection devices provide meaningful clinical benefit for patients undergoing TAVR. And this is discussed in a nice accompanying editorial by Dr. Tam and with Wijeysundera from University of Toronto. Dr. Greg Hundley: Very nice Carolyn. Well, my first paper comes to us from Professor Hua Zhang from Shanghai Children's Medical Center. Cyanotic congenital heart disease is a complex pathophysiological condition involving systemic chronic hypoxia and some cyanotic congenital heart disease patients are chronically hypoxic throughout their lives which heightens their risk of heart failure as they age. Dr. Greg Hundley: Hypoxia activates cellular metabolic adaptation to balance energy demands by accumulating hypoxia-inducible factor 1-Alpha. And Carolyn, this study aims to determine the effect of chronic hypoxia on cardiac metabolism and function in cyanotic congenital heart disease patients and its association with age. The authors investigated the role of hypoxia-inducible factor 1-Alpha in this process, and the potential therapeutic targets for this were explored. Dr. Carolyn Lam: What did they find Greg? Dr. Greg Hundley: In cyanotic congenital heart disease patients maladaptation of cardiac metabolism occurred during puberty, along with impaired cardiac function. In cardiomyocytes, specific HIF1-Alpha knockout mice, chronic hypoxia failed to initiate the switch of myocardial substrates from fatty acids to glucose, thereby inhibiting ATP production and impairing cardiac function. Increased insulin resistance during puberty suppressed myocardial HIF1-Alpha and was responsible for cardiac metabolic maladaptation in animals exposed to chronic hypoxia. Dr. Greg Hundley: Pioglitazone significantly reduced myocardial insulin resistance, restored glucose metabolism, and improved cardiac function in pubertal chronic hypoxia animals. And so, Carolyn, perhaps future studies could test whether pioglitazone administration during puberty might improve cardiac function in cyanotic congenital heart disease patients. And this article is nicely accompanied by an editorial from Professor Ghofrani. Dr. Carolyn Lam: That's really interesting. For the next paper we're going from cyanotic congenital heart disease to plain old hypertension asking the question, What is the association of blood pressure classification using the 2017 ACC/AHA blood pressure guideline with risk of heart failure and atrial fibrillation? Well, this question was addressed by Dr. Kaneko and colleagues from University of Tokyo who performed analysis using a nationwide health claims database collected in the JMDC claims database between 2005 and 2018. Now note, this was more than 2 million patients followed for a mean of more than a thousand days in whom more than 28,000 incident heart failure, and more than 7,700 incident atrial fibrillation events occurred. Dr. Greg Hundley: Carolyn, this is a really large cohort a lot of events. What did they find here? Dr. Carolyn Lam: Among adults not taking anti-hypertensive medications and with no prevalent history of cardiovascular disease, stage one and stage two hypertension, according to the 2017 ACC/AHA blood pressure guidelines was associated with a higher incidence of heart failure and atrial fibrillation. The population attributable fractions for heart failure associated with stage 1 and stage 2 hypertension were 23.2% and 51.2% respectively. The population attributable fractions for atrial fibrillation associated with stage 1 and 2 hypertension were 17.4% and 34.3% respectively. The categorization based on 2017, ATC/AHA blood pressure guidelines may improve risk stratification for identifying adults at high risk for heart failure and atrial fibrillation. Dr. Greg Hundley: Wow Carolyn. Really useful data and something I love about our journal, a transition from a large cohort study on hypertension, and now we're going to delve into the world of preclinical science and talk about myocardial hypertrophy. Carolyn, exercise can induce physiological myocardial hypertrophy and former athletes can live five to six years longer than non-athletic control suggesting a benefit after regression of physiological myocardial hypertrophy. Dr. Greg Hundley: Accordingly, these authors led by Professor Yulin Liao from Nanfang Hospital and Southern Medical University hypothesized that anti-hypertrophic memory exists after physiologic myocardial hypertrophy has regressed increasing myocardial resistance to subsequent pathological hypertrophic stress. In this study, C57BL, six mice were submitted to 21 days of swimming training to develop physiological myocardial hypertrophy. Then after termination of the swimming events and exercise, the physiological myocardial hypertrophy regressed within a week. And these physiological myocardial hypertrophy regression mice termed the exercise preconditioning group or HP, and then sedentary mice as a control group underwent transverse aortic constriction, or a sham operation and were observed for four weeks. Dr. Greg Hundley: Finally, in these two groups, cardiac remodeling and function were evaluated using echocardiography invasive left ventricular hemodynamic measurements and histological analysis. Dr. Carolyn Lam: Wow. Exercise induced and I hypertrophic memory in the heart. That is so cool. Greg, could you summarize what they found? Dr. Greg Hundley: Yeah. And how about that exercise stimulus? The mice were swimming. Carolyn, these authors found that exercise-induced physiological myocardial hypertrophy can produce cardioprotective effect. And this cardioprotective effect continues to exist after the physiological myocardial hypertrophy subsides. And it's termed a phenomenon exercise hypertrophy preconditioning. Dr. Greg Hundley: Now, mechanistically, the investigators found that exercise hypertrophy preconditioning up regulates the expression of the long noncoding RNA Mhrt779 by increasing the three methylation of histone 3 at the A4 promoter of Mhrt779. Dr. Greg Hundley: Carolyn, also cardiac overexpression are knocked down of Mhrt779 respectively enhanced or weakened the anti hypertrophy effect of exercise hypertrophy preconditioning. The clinical implications of this research are that these results will likely stimulate further research into the mechanisms of exercise hypertrophy preconditioning, and Mhrt779 may be a potential therapeutic target for myocardial heart hypertrophy and heart failure in clinical practice. Dr. Carolyn Lam: Wow. Thanks so much, Greg. That was an incredible summary. Dr. Carolyn Lam: Let me tell you what else is in today's issue. There's an exchange of letters amongst doctors Mehmood Donkor, and Westermann regarding the article “Left Ventricular Unloading is Associated with Lower Mortality in Cardiogenic Shock Patients Treated with Venal Arterial Extracorporeal Membrane Oxygenation.” There's an ECG Challenge by Dr. Bhasin regarding “A Young Woman with Palpitations. Is It a Poison or Is It a Reality?” Dr. Carolyn Lam: In Cardiology News by Tracy Hampton, she describes new research, revealing mechanisms behind exercise-induced heart damage, new details behind muscle injury repair, and new insights on plasma membrane rupture during cell death. Very interesting. A new section there. There's a Perspective piece by Dr. Passman on “’Pill in the Pocket?’ Anticoagulation for Atrial Fibrillation. Is That Fiction, Fact, or Foolish?” Dr. Greg Hundley: Great, Carolyn. Well also in the mailbag, there's a Frontiers and medicine piece from Professor Rohatgi entitled “HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research.” And then finally, Carolyn, a Research Letter from Professor Felker, entitled Probabilistic Re-adjudication of Heart Failure Hospitalization: Events in the Paragon-HF Study.” Well, Carolyn, what a great group of articles summarized. How about now we proceed to that feature discussion? Dr. Carolyn Lam: Let's go Greg. Dr. Greg Hundley: Well, listeners. We are now to our featured discussion today and we have with us one of our associate editors who has submitted a paper, Dr. Nick Mills from Edinburgh, Scotland. And then we have a guest editor. Sometimes he's been a feature author, but now he's serving as a guest editor, Dr. Alan Jaffe from Rochester, Minnesota. Welcome gentlemen. Dr. Greg Hundley: Well, Nick, could you start us off first and describe for us the hypothesis that you wanted to test, and then maybe also provide a little bit of context or background around the study that you and your team have just performed. Dr. Nicholas Mills: Thanks, Greg. I've been working for about a decade trying to understand how we can get the value from high-sensitivity cardiac troponin in our clinical practice. We've tried a number of different approaches to implement them for the benefit of patient care that I'm particularly proud of this trial. What we'd recognized that I think with the rollout of these assays across Europe and more recently in America is that they're excellent tests, but they do generate some diagnostic uncertainty in clinical practice. Dr. Nicholas Mills: But as we've got used to using them, we've learned that actually their major strength is that the confidence that they bring in ruling out myocardial infarction rather than ruling it in. And they allow us to make really early decisions often with a single test at the point of arrival, where we can say with absolute confidence that a patient does not have acute coronary syndrome and it's unlikely to have a problem in the next 30 days or one year based on just how low that high sense of high-sensitivity cardiac troponin result is. And I've been a strong advocate for using these tests in that way for some time. But the limitation has been that much of the work in this field has been observational. And so the patients were actually managed accordingly because of uncertain pathways. And there's always been some uncertainty as just how effective they are when in clinical practice, whether using these approaches are safe. And so we designed the Historic Trial to address that definitively in our hospitals in Scotland. Dr. Greg Hundley: Very nice Nick. So what was the study population and what was the design for this Dr. Nicholas Mills: Thanks Greg. So we use an interesting study design set wage cluster, randomized controlled trial, where rather than randomizing individual patients and randomized hospitals in Scotland, in order to do a trial like this, you need very detailed infrastructure because we wanted to enroll every consecutive patient, attending our emergency departments with symptoms, suspicions of acute cardiac syndrome. We embed it so into our care path, which allows our clinicians to enroll patients for us. We were keen to enroll all consecutive patients because we wants to be confident that our findings were truly generalizable at any included patients with complex comorbidities presenting that of ours who were sick unwell, which is often not the case; they've been observational studies. We randomized hospitals and follow up patients with acute coronary syndrome up for a year in order to determine whether the implementation of already changed clinical care and that was safe and did not lead to recurrent and in the future. Dr. Greg Hundley: Very nice. So Nick, in this randomization of hospitals, how many total patients did you encounter and then what were your study results? Dr. Nicholas Mills: So we enrolled 31,492 consecutive patients. I've crossed all seven hospitals implementing our early relapse pathway, reduced length of stay overall in the hospital. By just over three hours, we increased the proportion of patients who are directly discharged home from the emergency department by more than 50%. So that overall 71% of patients attending hospital with possible acute coronary syndrome were able to be discharged from the emergency department rather than being admitted unnecessarily for further investigations. But the critical result was, was that major change in the care pathway safe. We had a non-inferiority design. We had a very small number of safety outcomes at 30 days, and it was difficult to prove non-inferiority, but the event rate favored the implementation there. Dr. Nicholas Mills: They will have pathway with the 0.4% of patients we attend within 30 days of heart attack or dying from heart disease for our implementing it and 0.3% in and crucially, we followed everyone up for a year and were able to demonstrate that the safety outcome was not increased in those that we are able to that pathway one year with absolute confidence. And furthermore, there was no difference in re attendance or an all-cause mortality. We the two different arms of the trial. So we concluded that the early relapse pathway was effective and safe, and that using this approach we'd have major benefits from patients who can avoid unnecessary for healthcare providers in terms of reducing actual cost limitations. Dr. Greg Hundley: Fantastic. Well listeners, we're now going to turn to our guest editor, Dr. Alan Jaffe, and Alan, could you help us put into perspective these new data regarding high sensitivity, proponent, and also comment what attracted you to this article so much so that you feel it's needs to be published and circulated worldwide in the literature? Dr. Allan Jaffe: One of the important areas in the field of biomarkers is the movement just finally occurring. And Nick has been the forefront of this, of starting to do randomized trials. Observational data is just that it's observational. The patients are not created based on the information that is by the biomarkers. Patients can be missed if you're missing a sample, you exclude those patients. In addition, most observational trials, try and get informed consent. And by getting informed consent often miss the sickest patients. So what's desperately needed by the field. And which is just now starting with two or three ongoing randomized trials is just that a randomized trial where the investigators are forced to use the data, to manage the patient. And by using the step wedge design that Nick and his group has used in other trials as well, they guarantee that they don't miss patients either. Dr. Allan Jaffe: So that it's comprehensive and takes all into account. This is terribly important to then validate things like in this instance, the rule-out pathway. And I think these data do substantially confirm the fact that a single sample rule-out strategy using the cutoff value that Nick had previously established as optimizing the percentage of the population that can be included works well. It is unfortunate that the way in which they design their trial mist and design their non-inferiority outcome for safety was such that they ended up not finding significance to that. But I agree with Dr. Mills in the sense that the outcome adverse effects were so low, that despite that I think there's very important and reasonable data that this strategy is also safe. Dr. Greg Hundley: Very good. Well, Nick, thinking forward, what do you feel is the next study that needs to really be performed in this area? Dr. Nicholas Mills: I completely agree with everything Alan said. I think there's lots of really interesting approaches to find a group diagnosis, risk stratification of this really common condition. We need trials that demonstrate these approaches actually influence care and outcomes. For me, the challenge remains how to really harness these great tests to route the ruler of my cognitive function. I run about ads of patients with elevated cardiac troponin added due to an underlying condition that is an acute coronary syndrome. And we're starting to think about ways in which we can individualize our decision-making a little bit moving to walk away from binary thresholds, because values are influenced by age, by sex, by comorbidities like renal disease and preexisting heart failure about heart disease. Dr. Nicholas Mills: And by incorporating some of these patient factors into the interpretation of cardiac troponin. I think we can give clinicians better guidance on who to treat early with antiplatelet therapies and who needs invasive investigation than just simply saying that the troponin concentration is all positive or negative. And it's our challenge, I think, is how to harness that information, make it workable in clinical practice, and then demonstrate that by doing so we actually target effective therapies better, and that it makes a difference for patient care. So this is where we're working on at the moment. And I hope that in due course, we'll be able to do randomized trials in this space and that will move things forward again. Dr. Greg Hundley: Alan, do you have anything you'd like to add to that? Dr. Allan Jaffe: Yes. I think we're in a new era. We are finally starting to see there are now two or three randomized trials. It is time that the biomarker diagnostic studies graduate to a higher level of evidence, meaning randomized controlled trials. Nick is leading the way in that regard and I suspect and hope that subsequent trials, although observational trials may help inform which ones we should do, but that subsequent trials will continue to be randomized and generate the more robust data that randomized trials are capable of generating. Dr. Greg Hundley: Well, thank you both. And Nick, thank you for bringing us this research and also Alan, for evaluating it and providing this commentary today. It's quite exciting to have really this new information produced from a randomized trial, which evaluated the utility of a low high sensitivity treponema value in patients presenting to hospitals with chest pain syndromes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit  

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