Jan 31, 2022
Please join senior author Louise Olde Nordkamp, Editorialist Sana Al-Khatib, and Associate Editor Mark Link as they discuss the original research article Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in "Transvenous and Subcutaneous Implantable Defibrillators: An Analysis of All Appropriate Therapy in the PRAETORIAN trial" and the editorial "Just When We Thought the Debate About the Value of Anti-Tachycardia Pacing Was Over Perplexing Results from the PRAETORIAN Trial Emerged."
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, your host and Associate Editor from the National Heart Center and Duke National University of Singapore. And as you can tell, I am sorely missing my co-host, Dr. Greg Hundley, who cannot make it today, but yet I am so excited to tell you about the wonderful papers in today's issue. Now, right after these summaries, we will be discussing appropriate shocks and anti-tachycardia pacing in transvenous and subcutaneous implantable defibrillators. A really interesting analysis from the PRAETORIAN trials. The results may surprise you as they did for me. I really highly recommend you listen to the discussion, important clinical take home messages there. Now, though, let me tell you about some original papers in today's issue. We know that symptomatic children with catecholaminergic polymorphic ventricular tachycardia and that's a mouthful.
Dr. Carolyn Lam:
So, I'll abbreviate it as CPVT. They are at risk for recurrent arrhythmic events, beta blockers decreases risk, but are some types of beta blockers better than others in this regard? That's what coauthors and corresponding authors, Dr. Peltonberg and van de Werf from University Medical Center, Amsterdam and colleagues looked at. Studying 329 patients with RYR2 variant carrying symptomatic children from two international registries of patients with CPVT, these authors found that beta-1 selective beta blockers were associated with a higher risk for arrhythmic events, defined as syncope, appropriate ICD shock, sudden cardiac arrest, or sudden cardiac death. And this was compared with non-selective beta blockers. The difference in non-selective versus beta-1 selective beta blockers was driven by a significantly lower risk for arrhythmic events in patients treated with nadolol compared with metoprolol, bisoprolol, and atenolol. So, what are the clinical implications? Well, symptomatic children with catecholaminergic polymorphic ventricular tachycardia should preferably be treated with nadolol or another non-selective beta blocker such as propranolol should nadolol be unavailable.
Dr. Carolyn Lam:
The next paper deals with the super hot topic of myocarditis-related COVID-19 vaccination in adolescents and young adults. Now, suspected myocarditis temporarily related to COVID-19 vaccination has been reported in adolescents above 12 years old and young adults since the emergency use authorization of the Pfizer COVID-19 vaccine. And this is particularly in male adolescents and young adults. Understanding the clinical course and short-term outcomes of suspected myocarditis following COVID-19 vaccine, of course, has important public health implications in the decision to vaccinate youth. So, these authors led by corresponding author, Dr. Truong from University of Utah and Primary Children's Hospital from Salt Lake City in Utah, retrospectively collected data on patients younger than 21 years old presenting before July 2021 with suspected myocarditis within 30 days of COVID-19 vaccination. And they found that in 139 adolescents and young adults with 140 episodes of suspected myocarditis, 49 of which were confirmed and 91 were probable.
Dr. Carolyn Lam:
And these were at 26 centers. Most patients were male and white with a median age of 15.8 years. Suspected myocarditis occurred in 98% following mRNA vaccine with 94% following the Pfizer vaccine, 91% occurring after the second dose. Symptoms started a median of two days after vaccination. The most common symptom was chest pain. 26 patients or 19% were in the ICU. Two were treated with inotropic vasoactive support and none required ECMO or died. The median hospital stay was two days. So, while the majority of patients with suspected vaccine associate myocarditis had normal ventricular systolic function on echocardiogram, many had abnormal findings suggestive of myocarditis on cardiac MRI in the setting of elevated troponin and electrocardiographic changes. The take home message is that despite lab and cardiac MRI evidence of cardiac injury, the majority of adolescents and young adults with suspected myocarditis following COVID-19 vaccination have rapid recovery of symptoms and a mild clinical course. Further studies are needed to better understand the timing of resolution of myocardial injury, mechanisms of myocardial injury, and the long term outcomes.
Dr. Carolyn Lam:
The next paper is the first study to look at examining the genetic architecture of the plasma protein using whole-genome sequencing in persons of African ancestry and really provides a chance to look at rare ancestry specific variation. Authors led by corresponding author, Dr. Gerszten from Beth Israel Deaconess Medical Center in Boston, Massachusetts performed proteomic profiling of 1,301 proteins in 1,852 black adults from the Jackson Heart Study using aptamer-based proteomics or the SOMAscan. Whole-genome sequencing association analysis was ascertained for all variants with minor allele count of five or greater. Results were validated using an alternative antibody-based proteomic platform, the Olink platform as well as replicated in the multiethnic study of atherosclerosis or MESA, and the HERITAGE family study. A huge amount of work. So, this large study added 114 novel genomic [inaudible 00:07:00] associated with protein levels and an additional 217 novel sentinel variant protein relationships. Novel cardiovascular findings included genetic variant associated with amyloidosis in persons with African ancestry shown to be associated with retinol binding protein four levels, even in those without cardiomyopathy implicating it as a potential biomarker.
Dr. Carolyn Lam:
Taken together, these results provide evidence of the functional importance of variants in non-European populations and suggest new biological mechanisms for ancestry specific determinants of lipids, coagulation, and myocardial function. And this is discussed in an excellent editorial by Professor Dr. Schunkert from German Heart Center, Munich. And the final original paper deals with high-salt intake, which we know to be the leading dietary risk factor for cardiovascular disease. We also know that clinical evidence suggests that high-salt intake is associated with non-alcoholic fatty liver disease. Now, could the two be linked, in other words, could hepatic steatosis induced by high-salt diet mediate cardiovascular damage and how? This is exactly what these authors did. Corresponding author, Dr. Zhu from Army Medical University in Chongqing, Institute of Hypertension in China and their colleagues in an elegant series of mouse experiments demonstrated that reduced SERT three expression in the liver is an important mediator of salt-induced hepatic inflammation and steatosis.
Dr. Carolyn Lam:
High-salt diet inhibits the transcription of SERT three through epigenetic modification mechanisms resulting in the persistence of hepatic inflammation in the liver. Notably, the over expression of SERT three in the liver using an adeno-associated virus eight vector or activation of SERT three by metformin effectively relieved the progression of persistent hepatic damage in mice and thus counteracted salt-induced cardiovascular damage. Taken together, these findings suggest that the MK SERT three pathway may be a promising interventional target for treatment of persistent cardiovascular damage in populations exposed to high-salt diet, and finally rounding up the other papers in today's issue, there's an AHA Update by Dr. Lloyd-Jones on the power of patient stories to inspire us to prevent cardiovascular disease and death, personal reflections on AHAs scientific sessions 2021. There is an On My Mind paper by Dr. Dashwood on 30 years of no-touch saphenous vein harvesting, a timely jubilee gift.
Dr. Carolyn Lam:
There's a Frontiers paper by Dr. Rivard on a tremendous contribution on atrial fibrillation and dementia, a report from the AF Screen Interventional Collaboration. And finally a research letter from Dr. Joe on genetic proliferation tracing revealing a rapid cell cycle withdrawal in pre-adolescents cardiomyocytes. Well, that wraps it up for the summaries. Now, let's go on to our feature discussion.
Dr. Greg Hundley:
Welcome listeners to our feature discussion today on this February one. And we're very excited because we have three individuals that will be discussing this paper, Dr. Louise Olde Nordkamp from Amsterdam, Netherlands, the primary author. Dr. Sana Al-Khatib, who is our editorialist for this paper. And finally, Dr. Mark Link, who is our associate editor. Welcome to you all. Louise, we're going to start with you. Can you describe for us some of the background pertaining to why you formulated this study and then what was the hypothesis that you wanted to address?
Dr. Louise Olde Nordkamp:
Yes. Thank you very much for joining this podcast on our study. Our study was designed because in ICD therapy, antitachycardia pacing, ATP has been developed as a painless method to terminate ventricular arrhythmias, and it might decrease the number of appropriate shocks. But on the other hand, ATP might also be given unnecessarily for VTs that would've been ended spontaneously and might even accelerate VTs. The reported efficacy ranges from 52 to 81%, and some studies have observed even higher mortality in patients treated with ATP. The subcutaneous ICD has been developed 10 years ago approximately, and it's completely extra thoracic. And due to this extra thoracic design, it is incapable of providing pacing therapy including ATP. And this was a pre-specified analysis from the PRAETORIAN trial, which was a randomized trial comparing the transvenous and the subcutaneous ICD. And in this pre-specified secondary analysis, we're aimed to determine the efficacy of ATP, the safety of ATP and shocks by comparing appropriate therapies in both arms. So, both the SICD and transvenous ICD, and specifically, we investigated whether ATP reduced the number of appropriate ICD shocks.
Dr. Greg Hundley:
Very nice. And so describe for us a little bit more the study population and the design particularly of the PRAETORIAN trial.
Dr. Louise Olde Nordkamp:
Yeah. So, we published at PRAETORIAN trial in August 2020, in The New England Journal of Medicine and it was the first randomized trial to compare the subcutaneous ICD with the transvenous ICD in patients with a regular ICD indication, but without a pacing requirement. And in 39 census throughout Europe and US of 849 patients were randomized to either the subcutaneous and transvenous ICD in a one-to-one ratio. And during a median follow up of 49 months, the rate of the primary endpoint composite of device related complications and inappropriate shocks were similar between the subcutaneous ICD and the transvenous ICD arm. But here we looked at the appropriate therapy in the study. So, it was defined as both ATP or shock therapy and appropriate therapy was also defined as therapy for ventricular arrhythmias. The PRAETORIAN trial population in overall was, as I said before, regular ICD population with a median age of 63 years, 20% were female. Two-third of patients had an ischemic cardiomyopathy and 20% of patients had a secondary prevention indication.
Dr. Greg Hundley:
Very nice. And so tell us your study results.
Dr. Louise Olde Nordkamp:
Our findings were that in this trial, there was no significant difference in number of patients with appropriate therapy, so shocks and ATP. There were 86 patients in the SICD group and 78 patients in the transvenous ICD group. But patients in the subcutaneous ICD group were one and a half times more likely to be treated with at least one shock. So, if we look at shocks only, and that has a hazard ratio of 1.52 and that was statistically different of significance between the groups. The first shock efficacy was similar in the SICD and in the transvenous ICD. And the first ATP attempt successfully terminated 46% of all monomorphic VTs, but it accelerated through arrhythmia in 9.4%. And although, ATP successfully terminated 46% of all monomorphic VTs, the total of number of shocks, as I said before, was not statistically different between the two groups.
Dr. Louise Olde Nordkamp:
So, we looked at discrete episodes where ATP does reduce the number of appropriate shocks. But when we looked at storm episodes, which was defined as more than three shocks within 24 hours, we saw that there was a higher number of shocks in the transvenous ICD arm, despite a randomized design of the trial and the distribution of shocks between the discrete and the storm episode was there for opposites in the SICD, in the transvenous ICD. So, there was a high number of shocks in storm episodes in the transvenous ICD group, which can partly explain by the number of patients and electrical storms in this group, because there was 10 patients with an SICD who had an electrical storm and there were 18 patients with a transvenous ICD who had an electrical storm. So, patients with appropriate therapy had therefore almost twofold increased risk of an electrical storm in the transvenous ICD arm.
Dr. Greg Hundley:
Very nice. Listeners, next, we're going to turn to the associate editor for this paper, Dr. Mark Link, and Mark, you have many papers come across your desk. What attracted you to this particular manuscript?
Dr. Mark Link:
Thanks, Greg. And thanks, Louise for contributing this papers. We were really very happy to have it. And the reason that we were happy to have it is that this is a very important question in our clinical practice. That is, should we give a patient a subcu ICD or a transvenous ICD? Then, there are risk and benefits of both. It's a discussion that I have multiple times a week with patients. And so getting data on the efficacy of shocks and the efficacy of ATP is very, very important for us as we will discuss this with our patients. So that's why we really like this paper, because we thought it was very clinically relevant to our readership and to the practicing EP community.
Dr. Greg Hundley:
Very nice. Next listeners, we're going to turn to our editorialist, Dr. Sana Al-Khatib from Duke University and Sana, help us put the results of this study in perspective with other research in the field of both subcutaneous and transvenous pacing.
Dr. Sana Al-Khatib:
Yeah, no, absolutely. I'd like to start by congratulating the authors on this paper, I really enjoyed reading it and thank you for sending it to circulation. I also enjoyed writing the editorial. So, certainly this paper provided results that have challenged some of the findings of prior studies, in the sense that several prior studies had shown that antitachycardia pacing reduces the risk of shocks, improves patients outcomes. And that's not at the expense of them having syncope or having adverse events. And this was the case in those trials even for faster ventricular tachycardia. So in this particular study, they excluded patients with slower ventricular tachycardia, but I would also say that several of the prior studies had looked at antitachycardia pacing for faster VT and showed better outcomes.
Dr. Sana Al-Khatib:
And so, this study certainly makes us question some of those findings, but really I feel like it will be a great impetus for different researchers to look at this question in relation to the newer generation of transvenous ICDs as well as even potentially looking at the combination of the subcutaneous ICD with perhaps leadless pacemakers that could deliver antitachycardia pacing, which is an area of research that we're going to hear more about.
Dr. Greg Hundley:
Very nice. And Sana, that really leads us into our next round of questions with our panelists. We'll start with you first, Louise, what do you see is the next focus of research that'll be performed in this space?
Dr. Louise Olde Nordkamp:
So, I think the efficacy and also the potential harm of ATP should be studied more thoroughly. So, I think a randomized trial with ATP as a main focus, because this was a secondary analysis, is the first step to do. And moreover as Dr. Al-Khatib already mentioned is that new innovations are ongoing with a leadless pacemaker in addition to a subcutaneous ICD and these clinical results will be gathered in the coming months and years. And that is really interesting to look at as well.
Dr. Greg Hundley:
And Mark, can you share your thoughts?
Dr. Mark Link:
Yeah. This study brings up many questions, tying in the leadless pacemaker with the subcu ICD is certainly one that's being explored by a number of manufacturers right now, ways to make shocks less painful also would be very critical. I mean, I think that the storms often are because of the catecholamine surges that occur with shocks, if you could make shocks less painful, that would be very keen. And that's been a focus of some researchers for quite some time without good results at the time. And then, increasing the efficacy of ATP because there was a signal here that ATP could, what did generate faster VPs and VFs. And so, the prevention of that I think is very crucial.
Dr. Greg Hundley:
Very nice. And Sana, do you have anything to add?
Dr. Sana Al-Khatib:
Yeah, no, absolutely. I completely agree with what was said. I truly feel that this is an area where we're going to see a lot of research being done. We have new algorithms of antitachycardia pacing, Greg, that are being developed and incorporated into devices that use machine learning, which is really exciting. So, trying to look at hard outcomes related to those and comparing them with, as I mentioned, the subcu ICD combination with a leadless pacemaker would be really interesting. And then, this whole question about the electrical storm, I commend the authors for looking at that, but as they pointed out this was a secondary analysis and the numbers that they had were pretty small. So, trying to look at those findings in a larger population of patients really designed to look at that question would be important.
Dr. Greg Hundley:
Very nice. Listeners, we want to thank our electrophysiology panelists today, Dr. Louise Olde Nordkamp, Dr. Sana Al-Khatib, and Dr. Mark Link for bringing us the results from this trial indicating that really there was no difference in observed shock efficacy of the subcutaneous compared with the transvenous ICDs. 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.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinion expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.