Circulation March 31, 2020 Issue

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

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

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

Dr Greg Hundley: I wondered that yesterday, Carolyn.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr Greg Hundley: What were your results?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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