Apr 5, 2021
For this week's Feature Discussion, please join authors Igor Klem, Pasquale Santangeli, Mark N.A. Estes III, and Associate Editor Victoria Delgado as they discuss, in a panel forum, the articles: " The Relationship of LVEF and Myocardial Scar to Long-Term Mortality Risk and Mode of Death in Patients with Non-Ischemic Cardiomyopathy," "Prognostic Value of Non-Ischemic Ring-Like Left Ventricular Scar in Patients with Apparently Idiopathic Non-Sustained Ventricular Arrhythmias," and "Cardiac Magnetic Resonance Imaging in Nonischemic Cardiomyopathy: Prediction Without Prevention of Sudden Death."
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 in Richmond, Virginia. Well Carolyn, this week we've got another sort of double feature with a forum and our focus is going to be on myocardial scar that's observed with late gadolinium enhancement during cardiovascular magnetic resonance and the two author groups we'll be discussing the impact of that scar on the development of ventricular arrhythmias. But before we get to that, how about we grab a cup of coffee and jump into the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
I certainly would. Although I have to say, can't wait for the double feature. I love those, and this is right up your alley too. All right. But first, the first paper I want to talk about provides new randomized trial information regarding the benefits of catheter ablation in atrial fibrillation in patients who also have heart failure. Now, this is a sub-study of the CABANA trial.
Dr. Greg Hundley:
So Carolyn, remind us a little bit about the CABANA trial first.
Dr. Carolyn Lam:
I thought you might ask. Well, CABANA randomized 2,204 patients with atrial fibrillation who were 65 years or older or less than 65 with one or more risk factors for stroke at, it was huge at 126 sites, and they were randomized to ablation with pulmonary vein isolation or drug therapy. Now of these, 35% of 778 patients had New York Heart Association Class II or higher at baseline, and really formed the subject of the current paper. Although this sub-study was not specifically designed to evaluate patients with heart failure with preserved ejection fraction, about 91% of the patients with a clinical diagnosis of heart failure participating in CABANA for whom such data on injection fraction were available, really had an ejection fraction of above 40% and fully 79% had an ejection fraction above 50%. So excitingly, this is really majority talking about, have HFpEF. Now, what did they find well in patients with New York heart Association Class II or III heart failure at trial entry, most of whom did not have a reduced ejection fraction.
Dr. Carolyn Lam:
There was substantial clinical outcome benefits with the ablation over drug therapy with a 36% relative reduction in the primary composite endpoint of death, disabling stroke, serious bleeding or cardiac arrest. Benefits were evident for both all-cause mortality and atrial fibrillation reduction. However, the effects on heart failure hospitalization were small and not significant. Authors also caution that these results should not be viewed as practice changing until they are reproduced in a confirmatory trial of ablation in the same population. And this is beautifully discussed in an editorial by Lynda Rosenfeld and Alan Enriquez from Yale University School of Medicine.
Dr. Greg Hundley:
Oh, wow. Thanks Carolyn. Well, my first paper comes from the world of basic science and it's from Professor Thomas Braun, from the Max Planck Institute for Heart and Lung Research. So Carolyn, vascular smooth muscle cells show a remarkable phenotypic plasticity allowing acquisition of contractile or synthetic states, but critical information is missing about the physiological signals that promote formation and maintenance of contractile vascular smooth muscle cells in vivo. So BMP-9 and BMP-10 are known to regulate endothelial quiescence after secretion from the liver and right atrium. And these investigators are studied the role of BMP-9 and 10 for controlling formation of contract, all vascular smooth muscle cells.
Dr. Carolyn Lam:
Greg, talking about vascular smooth muscle cells always reminds me of their role in pulmonary hypertension, am I right?
Dr. Greg Hundley:
Yes, Carolyn. So these investigators found that in mouse models, BMP-9 and BMP-10 act directly on vascular smooth muscle cells for induction and maintenance of their contractile state, and surprisingly the effects of BMP-9 and 10 in vascular smooth muscle cells are mediated by different combinations of BMP type 1 receptors in a vessel bed specific manner. And therefore, just as you suggest, Carolyn, these results may offer new opportunities to manipulate blood pressure in the pulmonary circulation.
Dr. Carolyn Lam:
Thank you, Greg. Well, my next paper provides the first proof of principle of gene therapy for complete correction of Type 1 Long QT syndrome.
Dr. Greg Hundley:
Ah, so tell us a little bit about Type 1 Long QT syndrome, Carolyn.
Dr. Carolyn Lam:
Okay. Well Type 1 long QT syndrome is caused by loss of function variants in the KCNQ1 and coded potassium channel alpha sub-unit. And that is essential for cardiac repolarization providing the slow delayed rectifier current. Now no current therapies target the molecular cause of this Type 1 long QT syndrome. Well, this study from Dr. Michael Ackerman colleagues from Mayo Clinic Rochester really established a novel dual component suppression and replacement KCNQ1 gene therapy approach for Type 1 long QT syndrome. And it's the type that contains the KCNQ1 short hairpin RNA to suppress endogenous expression and a codeine altered short hairpin RNA immune copy of this KCNQ1 for gene replacement.
Dr. Carolyn Lam:
So this very novel approach rescued the prolonged action potential duration in inducible pluripotent STEM cell cardiomyocytes derived from four patients with unique Type 1 Long QT syndrome, causative, KCNQ1 variants. So it's super cool. Just go have a look.
Dr. Greg Hundley:
Well, thanks Carolyn.
Dr. Carolyn Lam:
I want to also tell you about other things in the mail bag. We have ECG Challenge by Dr. Dai on “Severe Arrhythmia Caused by a Chinese Herbal Liqueur. What's the Diagnosis?” I'm not going to tell you. You have to go see. We have Dr. Karen Sliwa writing a beautiful Joint Opinion paper from the World Heart Federation and American College of Cardiology, American Heart Association, and European Society of Cardiology on "Taking a Stand Against Air Pollution, the Impact on Cardiovascular Disease."
Dr. Greg Hundley:
Well, thanks Carolyn. So I've got a couple other articles. First Professor Yacoub has a global rounds describing and working towards meeting the challenges of improving cardiovascular health in Egypt. Those are really interesting features to learn about cardiovascular care worldwide. Next there's an In Depth article by Professor Thum entitled, "Therapeutic and Diagnostic Translation of Extracellular Vesicles in Cardiovascular Diseases, Roadmap to the Clinic." And then finally, a Research Letter from Dr. Bottá entitled, "Risk of Coronary Artery Disease Conferred by Low Density Lipoprotein Cholesterol Depends on Apologetic Background." Well, Carolyn, what a great issue and how about now we proceed on to that double feature?
Dr. Carolyn Lam:
Oh, I can't wait. Thanks Greg.
Dr. Greg Hundley:
Well, listeners, we are here for a really exciting feature discussion today that's going to focus on imaging, in particular magnetic, resonance imaging, and some new findings in that era and how those findings may pertain to ventricular dysrhythmias. With us today, we have Dr. Igor Klem from Duke University who will be discussing a paper, Dr. Pasquale Santangeli from University of Pennsylvania, our own associate editor, Dr. Victoria Delgado from Leiden and an editorialist, Dr. Mark Estes from UPMC in Pittsburgh. Welcome to all of you. Well, Igor, we're going to start with you. Could you tell us what was the hypothesis for your study and what was your study population in study design?
Dr. Igor Klem:
Yes. Good morning, Greg and thanks for the invitation. We wanted to know if you have a patient who you diagnosed with non ischemic cardiomyopathy based on clinical grounds and you refer him for a cardiac MRI study with contrast, what is the additional information that you get from the MRI study? And so we wanted to compare, and that's primarily related to the findings on scar imaging with late gadolinium enhancement. And we wanted to compare that to one of the most robust clinical parameters in cardiology, which is left ventricular ejection fraction, and in particular using a cutoff of 35%, which somehow in our clinical management has sort of as established as a break point for many clinical decisions.
Dr. Igor Klem:
And so we created a registry among three centers of patients who undergo a cardiac MRI study, where we found an LVEF of less than 50% and we followed them for a number of outcomes. One is all caused death. And then we wanted to separate a little bit the events into those who have cardiac mortality to look at a little epidemiology because in those patients, we have two major adverse events: one as heart failure related mortality. One is arrhythmia related mortality.
Dr. Greg Hundley:
And how many subjects did you include?
Dr. Igor Klem:
We included about a thousand patients from three centers and coming to the major findings of our study, we found that both left ventricular ejection fraction, as we know, is a robust marker of all cause mortality and cardiac death. And so it was the presence of myocardial scar on cardiac MRI. But the major difference was in relation to the arrhythmic events. We founded left ventricular ejection fraction in particular, when we use the 35% cutoff actually had very little predictive power to inform us who is at risk of arrhythmic events. In contrast, there was a very strong and robust relationship or multiple statistical methods to stratify patients who are at risk for sudden cardiac death, appropriate ICD shock, as well as arrhythmic cardiac death.
Dr. Greg Hundley:
Very good. Well, Pasquale understand you also performed a research study utilizing cardiovascular magnetic resonance. Could you describe for us your hypothesis as well as what was your population and your study design?
Dr. Pasquale Santangeli:
Thank you, Greg. And of course, thanks to the editor for the interest in our paper. I need to thank also the first call authors Daniele Muser and Gaetano Nucifora for putting together a registry of 70 institutions throughout the U.S., Europe, and Japan and the our hypothesis came from a clinical need. We do know that patients with idiopathic ventricular re we ask, which includes not sustain a weakness like PVCs or non-sustained VT. Very few of them, but there is a group of them that have a higher risk of ending malignant and up comes in terms of your ethnic events over follow-up. And prior studies have shown that by doing an MRI and showings and the detecting scar related announcement, there is an increase with how we make events of a follow-up. However, if you do look at those studies late, an answer's been reported in up to 70% of these patients, which you never view is a highly practical way of re-stratifying these patients, because you have a risk factor that is present 70% of those, then it's hard to use it for clinical decision-making.
Dr. Pasquale Santangeli:
So in this registry, which you put it again at 686 patients with panel data idiopathic, not sustained ventricular arrhythmias, which were defined by a normal WBC gene status, a normal echocardiogram and a normal stress test. We looked at whether there is a specific pattern of late announcement. So how basically I believe lands, and it looks on the MRI, they may predict better or outcomes over follow-up. And again, we use a composite and Pauline the full cost mortality, but associated cardiac arrest due to ventricular fibrillation or a hemodynamically unstable BP, or in a subgroup of patients that underwent ICD therapy. We also looked at, I approve SED shocks.
Dr. Pasquale Santangeli:
The groups were divided in three different categories. The first one, which is a larger group of 85% of patients and no late announcement. The second group, the one with late announcement, which represents the remaining 50% of 15% of patients, we divided it into a ring light pattern, which was defined as that word says, as a ring like distribution of the lead announcement in the mid-market segments, which involves a three consecutive continuous segments in a short axis view. It looks like really at least half the ring or three-quarters of the ring.
Dr. Pasquale Santangeli:
And the other group is the one that had the leader announcement without a ring light pattern. And it's interesting that the third and the latest announcement was not that similar between the ring light and the one without ring light late announcement. What we did find though for our follow-up the patient with a ring light pattern, a significantly higher rate of the primary composite endpoint, which happened in the median follow-up about 61 months so it was quite long. And the composite outcome occurred in 50% of patients in the ring light group versus 19% in the no ring light a positive announcement group and a 0.3%. So really, really rare in patients. So then concluded that of course, late announcement does provide some information in general, particularly the type of announcement that increases the risk significantly. Probably although this has to be confirmed prospective fashion patient with a ring light pattern may benefit from other forms of interventions, including potentially defibrillator therapy in a prophylactic fashion.
Dr. Greg Hundley:
Very nice. So now listeners, we're going to turn to our associate editor. One of the imaging experts here at Circulation, Dr. Victoria Delgado. Victoria, you see a lot of papers come across your desk and as an imaging expert, what attracted you to these two papers? And what do you think are their significance?
Dr. Victoria Delgado:
Thank you, Greg. I think that these two papers are important because right now, if we follow the clinical guidelines, we decide implantation. For example, of an ICD based on the ejection fraction, and we see that in many patients based on ejection fraction, they may not benefit ever from an ICD because they don't have arrhythmias. What other patients who do not meet the criteria often injection fraction below 35%. They may have still arrhythmias. So the article by Igor highlights the relevance of the amount of burden of late government Huntsman with CMR, in patients with non ischemic cardiomyopathy, which are sometimes very challenging patients on how to decide when we implant an ICD or not. We need sometimes to base the decision on genetics.
Dr. Victoria Delgado:
If we have an on the other hand, the paper of Pasquale, these were patients with normal echocardiogram. So what patient, having arrhythmias where we don't see on echocardiogram, that is the first imaging technique that we usually use to evaluate these patients. We don't see anything, but CMR can give us more information in terms of structural abnormalities and particularly not only the burden of scar, but also the pattern of the scar. And we have seen in other studies that for example, not only for ICD implantation, but for ventricular tachycardia ablation. The characteristics of that scar and some areas where these are short of panel that can be targeted for that ventricular tachycardia ablation can lead to much more precise treatment if you want of these patients.
Dr. Greg Hundley:
Thank you, Victoria. So it sounds like listeners we're hearing late gadolinium enhancement, regardless of EF could be forecasting, future arrhythmic events. And then also the pattern of late gadolinium enhancement, where contiguous segments in a ring-like fashion may also offer additional prognostic information. Well, now we're going to turn to our editorialists and as you know, listeners at Circulation, we'll bring in an editorialist to really help put things together and uniquely here today, we have Dr. Mark Estes, who is really not an imager per se, but like many of us uses the information from imaging to make clinical decisions. Mark, how do you see this late gadolinium enhancement as perhaps a new consideration for placement of devices?
Dr. N.A. Mark Estes:
Greg, that's one of the key questions. There's no doubt, not only based on these two studies, which extend our prior information about LGE and patients with valid and non ischemic cardiomyopathies that scar burden is important in predicting not only total mortality, but arrhythmic events. All of the criteria that were used in the original ICD studies, which include the definite, the Skuid half Danish and made it our it trials use only ejection fraction and functional status, no imaging. These are legacy trials. Now, many of them, a decade or more older. And the treatment of advanced heart failure has progressed to the point that the total mortality is dramatically lower than it was at the time of these studies. In some instances down to 4 or 5% per year. The studies are important in that they identify a subgroup of patients with low ejection fractions, less than 35%, who might qualify for ICDs, who are unlikely to benefit.
Dr. N.A. Mark Estes:
They also identify a group of patients with preserved ejection fraction greater than 35%, less than 50 in whom the risk of sudden death may be substantial. And it extends prior observations about patchy, mid Meyer, cardio wall fibrosis, subendocardial, subepicardial and important ways. But the key issue here, and it was alluded to with Pasquale's comments about prospective validation, is that when one has a risk stratifier and identifies a high risk population that has to be linked to an unequivocal therapy, it improves survival. And we don't have that link quite yet.
Dr. N.A. Mark Estes:
Prospective randomized trials are unlikely to be done in the low ejection fraction because they would probably be considered unethical. Given the trials that have shown the benefit you can't randomize to defibrillator versus an implantable loop recorders. I think the future really lies in risk stratification for people with preserved ejection fractions greater than 35%, less than 50 using LG in that patient population. Currently, I think the best information we can give to clinicians is to stick with the AHA guidelines, which is PF less than 35% with dilated, nonischemic class II symptoms who have had optimal medical therapy for at least three months using perhaps in that patient population LGE for shared decision-making in patients about the magnitude of the risk. And I think that's as far as we can go pending future studies, and there is one which we can discuss later on the CMR study at just that preserved ejection fraction LGE randomizing to defibrillator versus ILR.
Dr. Greg Hundley:
Thank you, Mark. So listeners just really quickly, let's go back to each of our experts and ask them, you know, in 20 seconds, Igor, Pasquale, Victoria, and Mark, what's the next study that needs to be performed in this space? Igor, we'll start with you.
Dr. Igor Klem:
Well, number one, following on Mark's comment on the less than 35% population, I think that it's unlikely that they're randomized clinical trial is ethical in this population, but we may consider a wealth of registry data by now that shows that there is a subgroup of patients who have a lower risk or lower benefit from an ICD. I think in the preserved ejection fraction above 35%, maybe up to 45%, 50%. That's an interesting study that's coming up. Maybe there's more trials that can provide us that robust information that we need today in order to change the guidelines to risk stratify, not based on the LVF, but on the presence of scar or maybe subgroups of scar.
Dr. Greg Hundley:
Pasquale?
Dr. Pasquale Santangeli:
Yes. So I think of course, one of the major studies is the one already alluded by this, which is a prospective study that links as specific therapy like ICD or even additional risk factors like we've been using program's stimulation some of these patients to further risk for the five to see what they can benefit.
Dr. Pasquale Santangeli:
Based another one that I think is important for the study that we did is a mechanistic more study to understand why the ring light pattern was there, as opposed to other patterns. We do believe we think that some of these patients may have an initial form of lb dominant arrhythmogenic paramount. There wasn't really a detective before and ran. Now, if we actually extending our study and have a registry to try to screen also the family members or patients with ring light pattern to understand whether there is a familiar component to it, because really we do not see this type of pattern that commonly and it'd been associated with lb dominant. Magnetic kind of alpha in some others, small studies.
Dr. Pasquale Santangeli:
So that's the other part to dig in a little bit more into the field type for these patients to understand why one pattern versus another happens and whether that gets main to, to explain why there's a higher risk in one population versus another.
Dr. Greg Hundley:
Victoria.
Dr. Victoria Delgado:
Yeah. Following what has been said. I think that from the imaging point of view, we are always criticizing in a way that we increase the burden or the cost of healthcare. But I think that these studies or any randomized study where MRI or echo is used in order to design a therapy and show the value of using that imaging technique to optimize the health care costs is important. So I will not add much on which sort of populations, but probably patients within non ischemic cardiomyopathy with preserved ejection fraction that do not fulfill the recent scores, for example, in hypertrophic cardiomyopathy to be implanted with an ICD. But probably if we see a lot of scar on a AGE where specific patterns that can help to decide which are the patients that have benefited from an ICD implantation, for example.
Dr. Greg Hundley:
Thank you. And finally Mark.
Dr. N.A. Mark Estes:
But I think all the major points have been hit here. And unfortunately we have a bit of a dilemma. And that dilemma is that these legacy trials for ICDs, which selected based on low ejection fraction and functional class II were done at a time when contemporary heart failure treatment was not as good as it currently is pharmacologically. And it's been reflected with a lower total mortality. When the mortality in this patient population gets down to the 4 and 5% per year, it's unlikely that any intervention for prevention of sudden death is going to impact on that total mortality.
Dr. N.A. Mark Estes:
So I do think that the registries hold a lot of promise, giving us insights into the subgroup of patients that previously would have been selected for defibrillators who may not have as much benefit or who may benefit the most. And I think that they will play an important part in perhaps refining the risk stratification with greater sensitivity and specificity in the patient population, less than 35%. I think the CMR guide trial is going to be a critical trial and looking at ICDs in the patient population between 35 and 50%, but we need to be mindful of one thing. And that in the Danish trial, they get a sub study looking at about 240 patients using LGE. And they found that ICD in patients with LGE that was positive, did not make a difference in survival or total mortality. So again, we need to get the data. I think the best clinical practice has come out of the best clinical evidence. You'll clearly be limitations to what we can do, but I think in the future, we'll have much better data to make these judgment calls.
Dr. Greg Hundley:
Very good. Well listeners, we want to thank our panelists, Dr. Igor Clem, Pasquale, Santangeli, Victoria Delgado, and Dr. Mark Estes for this wonderful discussion related to magnetic resonance imaging, late gadolinium enhancement, and how it may be useful in identifying those at risk for future arrhythmic events. On behalf of both Carolyn and myself, want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.