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Circulation on the Run


Dec 21, 2020

This week's episode features author Peter Schwartz and Associate Editor Sami Viskin as they discuss the article "Exercise Training-Induced Repolarization Abnormalities Masquerading as Congenital Long QT Syndrome."

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's 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 at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to learn a little bit more about long QT syndrome and whether or not those that are athletes should continue exercise training. Maybe some can and before, we thought that they couldn't. But before we get to that, how about we take a look at some of the other papers in this issue.

Dr. Carolyn Lam:

Wow, that was a good hook, Greg. But yes, I want to tell you about this first paper, which is all about weight loss and changes in body composition. So, we know that intentional weight loss is associated with a lower risk of heart failure and atherosclerotic cardiovascular disease, especially among patients with type 2 diabetes. However, what is the contribution of baseline measures and longitudinal changes in fat mass versus lean mass and waist circumference to that risk of heart failure and myocardial infarction in patients with diabetes?

Dr. Carolyn Lam:

Well, investigators led by Dr. Pandey from UT Southwestern and colleagues evaluated more than 5,000 adults from the Look AHEAD Trial without prevalent heart failure. Fat mass and lean mass were predicted using validated equations and compared with DEXA measurements in a subgroup. Adjusted Cox models were then used to evaluate associations of baseline and longitudinal changes in fat mass, lean mass, and waist conference over one and four years follow up with the risk of overall heart failure, HFpEF, and HFrEF and myocardial infarction.

Dr. Greg Hundley:

Interesting, Carolyn. So, what did they find?

Dr. Carolyn Lam:

So, among patients with type 2 diabetes and who were overweight or obese, fat mass and lean mass could be estimated using anthropometric equations with good overall agreement compared with DEXA, so that's the first finding. Next, a decline in fat mass and waist conference, but not lean mass, were each significantly associated with a lower risk of heart failure, but not myocardial infarction.

Dr. Carolyn Lam:

Furthermore, a decline in waist circumference was significantly associated with a lower risk of HFpEF, but not HFrEF. Fatness and waist circumference may represent key modifiable targets for lifestyle interventions to reduce the risk of heart failure with preserved ejection fraction in type 2 diabetes. Cool, huh?

Dr. Greg Hundley:

Yeah. Very nice, Carolyn. Well, my first paper comes from Professor Davide Capodanno, and it's examining self-expanding bioprostheses for TAVR. So, Carolyn, there are few randomized trials comparing these bioprostheses for transcatheter aortic valve replacement or TAVR, and no trials have compared TAVR bioprostheses with the supra-annular design. So, this SCOPE 2 trial was designed to compare the clinical outcomes of the ACCURATE neo and the CoreValve Evolut valves.

Dr. Greg Hundley:

Now, it's a randomized trial performed at 23 centers in six countries between April 2017 and April 2019. And patients greater than 75 years with an indication for transfemoral TAVR as agreed by the heart team were randomly assigned to receive treatment with either the ACCURATE neo, so there are 398 of those patients, or the CoreValve Evolut bioprostheses, also 398 patients. The primary endpoint powered for non-inferiority of the ACCURATE neo valve was all-cause death or stroke at one year. The key secondary endpoint powered for superiority of the ACCURATE neo valve was new permanent pacemaker implantation at 30 days.

Dr. Carolyn Lam:

Okay. So, what were their results?

Dr. Greg Hundley:

Well, Carolyn, the transfemoral TAVR with the self-expanding ACCURATE neo did not meet non-inferiority compared to the self-expanding CoreValve Evolut in terms of all-cause death or stroke at one year. And was associated with a lower incidence of new permanent pacemaker implantation. In secondary analyses, the ACCURATE neo was associated with more moderate or severe aortic regurgitation at 30 days and cardiac death at 30 days and one year. Cardiac death at 30 days was 2.8% versus only 0.8% with the CoreValve Evolut. And moderate or severe aortic regurgitation at 30 days was 10% versus only 3% and they were significantly increased again in that ACCURATE neo group.

Dr. Carolyn Lam:

Wow. Okay. Thanks for that, Greg. Well, my next paper is from the basic science world. Dr. Colucci from Boston University Medical Center and colleagues tested the hypothesis that sarco/endoplasmic reticulum, calcium ATPase or SERCA, which is a major regulator of calcium homeostasis in the heart, whether or not it plays a critical role in mediating mitochondrial calcium and mitochondria-dependent apoptosis in response to reactive oxygen species.

Dr. Carolyn Lam:

So, in adult rat ventricular myocytes expressing an oxidation-resistant mutant of SERCA in which the cysteine-674 was replaced by serine. Mitochondrial calcium and the rise in mitochondrial calcium to exposure to an oxidant were decreased as was apoptotic myocyte death by mitochondrial pathways. Mice with the same SERCA mutation were protected from adverse cardiac remodeling, apoptosis, and progression to heart failure following chronic aortic constriction.

Dr. Greg Hundley:

Mm-hmm (affirmative) Carolyn, so this is another one where I get to ask you, what were the take home messages and what were the clinical implications?

Dr. Carolyn Lam:

I thought you'd ask that, Greg. So, these findings indicate that by contributing to sarcoplasmic reticulum calcium load, the chronic oxidative activation of SERCA may play a critical role in promoting the adverse effects of hemodynamic overload leading to pathologic remodeling. These findings illustrate the importance of post-translational modifications of SERCA and raise the possibility that the expression of a redox-insensitive form of SERCA may be of value in the treatment of heart failure.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next paper also comes from the world of basic science and looks into the mediators of atrial fibrillation. So, as some background, Carolyn, ibrutinib is a Bruton's tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. But it also increases the risk of atrial fibrillation, which remains poorly understood.

Dr. Greg Hundley:

So, the investigators performed electrophysiologic studies on mice treated with ibrutinib to assess the inducibility of atrial fibrillation. In human subjects, again, one of the strengths of some of these basic science papers in Circulation, the pharmacovigilance database or VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of atrial fibrillation.

Dr. Carolyn Lam:

Oh, that's really interesting, Greg. So, it seems like these authors were working toward understanding the mechanism of atrial fibrillation in those receiving ibrutinib. So, what did they find?

Dr. Greg Hundley:

Right, Carolyn. So, the authors found that using chemoproteomic profiling they were able to identify a short list of candidate kinases that was narrowed by additional experimentation, leaving C-terminal Src kinase or CSK, as the strongest candidate for ibrutinib-induced atrial fibrillation. Cardiac-specific CSK knockouts in mice led to increased AFib, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AFib associated with kinase inhibitors blocking CSK versus non-CSK inhibitors with reporting odds ratio of eight. So, Carolyn, perhaps CSK inhibition is the mechanism by which ibrutinib leads to atrial fibrillation.

Dr. Carolyn Lam:

Wow. That is convincing. Well, there are other really nice papers in today's issue. First, there's a research letter by Dr. Iglesias on the effects of fentanyl versus morphine on ticagrelor-induced platelet inhibition in patients with STEMI, the PERSEUS randomized trial. There's also a research letter by Dr. Young entitled the characteristics and outcome of COAPT eligible patients in the MITRA-FR trial. Another research letter by Dr. Zhang on specific modified mRNA translation system.

Dr. Greg Hundley:

Very nice, Carolyn. Well, I've got an exchange of letters by Dr. Spal, Whitlock, and Kebabs regarding the article, Impact of Left Atrial Appendage Exclusion on Short-Term Outcomes in Isolated Coronary Artery Bypass Graft Surgery. And then our own Mark Link discusses changes for practicing physicians regarding the new AFib guidelines.

Dr. Greg Hundley:

And finally, Dr. Vera Bittner has a perspective piece on the new 2019 ACC/AHA Guidelines on the primary prevention of cardiovascular disease. So, this new primary prevention guideline two fills a critical gap by pulling together and updating, as appropriate, guidance on nine topic areas of risk assessment, diet, exercise and physical activity, obesity, type 2 diabetes mellitus, blood cholesterol, hypertension, smoking cessation, and aspirin use.

Dr. Carolyn Lam:

Nice. Well, Greg, guess what? That brings us to the last issue in 2020. Can you believe it, Greg? It's been just so great working with you. It's been such a privilege working with Circulation. And, drum roll, new for 2021, Circulation on the Run is returning with a new format. Watch out for it. Let me give you a hint, it's going to come with a double feature per issue. Isn't that great, Greg?

Dr. Greg Hundley:

Absolutely. Some of the things that you hear folks really enjoy those opportunities we have with authors to review their papers. Well now, with many of the issues next year, we'll have two feature discussions.

Dr. Carolyn Lam:

Exactly. So, you've been listening to Circulation on the Run, but we've been listening to you, too. So, join us again in 2021 for our new features and new format. Thanks.

Dr. Greg Hundley:

And yes, Carolyn, but first, we've got to go and listen to this issue's feature discussion and talk about that long QT syndrome, exercise training-induced repolarization abnormalities. They can masquerade, perhaps, as long QT syndrome.

Dr. Carolyn Lam:

Cool.

Dr. Greg Hundley:

Welcome, listeners, to our feature discussion today. And we're very fortunate, we have Prof. Peter Schwartz from Istituto Auxologico Italiano in Milan and our own associate editor, Dr. Sami Viskin from Tel Aviv Medical Center. And we're going to be reviewing exercise training induced repolarization abnormalities, masquerading as congenital long QT syndrome. Well, first Peter, we'd like to start with you. And could you tell us, or provide us with some of the background information of why you wanted to perform this study and what hypothesis did you want to address?

Prof. Peter Schwartz:

The background is a very simple and I've been involved in the long QT syndrome since exactly 50 years. And as a partial result of that, I developed the idea that usually I... despite my making many errors in many areas, usually I don't miss the diagnosis of long QT syndrome. As a matter of fact, the study that you're publishing now is the result of a complete serendipity. It was not planned. We had to no hypothesis. It simply started because at one point I entered the impression that we might've made a diagnostic error and this bothered me very much.

Prof. Peter Schwartz:

It all started about eight, 10 years ago. When in some cases of our patients in whom we had made a clear diagnosis of long QT syndrome. At their yearly controls, we found that the LQT had been completely normalized. So I was pretty upset about it because I couldn't understand it. And my first reaction a natural reaction was to blame my associates, "We have made a mistake. You've did an error. There was an error in measurement." But as a matter of fact, there were no errors.

Prof. Peter Schwartz:

So I start thinking, "What the hell is going on here?" Now we are in a fortunate position because due to my long standing activity in the long QT syndrome, we are a referral center for all cases or most cases in Italy where people are suspected have the long QT syndrome. In Italy by law, anyone who wants to practice any type of sport at an amateur level or pro-competitive level, needs to have an eligibility certificate. So they have to go to sport doctors and it eases when the problems arise because not infrequently these doctors with somewhat limited experience in diagnosing prolongation and abnormalities in the QT intervals, are worried to make a mistake because a mistake can be a fatal one if the subject allow them to practice pause or die suddenly on to field. So they tend to refer them to us.

Prof. Peter Schwartz:

And so the advantage in my position was that we had a large number of these kids or young people coming to us. When I started to realize that it was not one accident, but another accident, another situation where these young people who clearly had to stop training in an intensive way, because they will no longer allowed by the sport doctors to practice sport. And the normalization of the T-wave abnormalities of the QT interval. I said, "Well, I mean, there must be something here."

Prof. Peter Schwartz:

So we start collecting the data, increasing the numbers, and I think it should be evident there was no design. I mean, it was a clinical observation that was evolving with time, but with adequate numbers. And then of course at one point we start following it more carefully, everything. And these led to the actual numbers that, in my opinion, were sufficiently strong to junior agents in need to publish it and to give a message because essentially this situation in one in which is very possible that even good and experienced doctors make a mistake. And the mistake could be a very bad thing, because if you miss the long QT syndrome and there is, of course, the patient is at risk of dying. But if you leave it, someone is affected and he is not affected, you are affecting his or her quality of life because they cannot practice sport, you generate anxiety. So a proper diagnosis is important. This was the basis of our study.

Dr. Greg Hundley:

Very good. So, it sounds like you're going to be performing a cohort study. Can you describe for us a little more specifically, how many subjects did you include? And who did you include in this cohort? And what measurements did you address?

Prof. Peter Schwartz:

So essentially we looked at the consecutive cases, sent to us by sport doctors with a suspicion of long QT syndrome. They were, if I remember, correctly 310 such individuals about 100 were found not to have the long QT syndrome. And these doctors were concerned they made the wrong measurement and measurement error. All the things that happened that are very well-known. About the remaining 200 in, I think about 120, we had a genetic confirmation of the long QT syndrome. We found disease causing mutation. So, that was pretty clear.

Prof. Peter Schwartz:

Then we had a group of individuals who are genotype-negative. We know very well. I mean, I proposed this thing in 1979, 1980, confirmed it in 1999, that there are some individuals affected by the long QT syndrome. But whoever I did a normal QT interval and that's a possibility, who are genotype-negative.

Prof. Peter Schwartz:

So, it's not surprising that in some cases we have genotype-negative individuals, but with a pattern so clear in terms of long QT syndrome that will make it to diagnosis. Within this group of genotype negative, there was another, let's call it a subgroup. I think it was about 15, 18% of the entire group who were genotype-negative, no family, sorry, neither had an event, a typical, absolutely typical electrocardiographic pattern with a fairly long QT interval QTc in the range of 490. So clearly prolonged significant repolarization abnormalities.

Prof. Peter Schwartz:

But when they were stopped in terms of exercise within three, four or five months, their pattern normalized completely, the QTc went back to normal, repolarization abnormalities disappeared. So this is the group on which we did focus and focusing for the next studies. And in some of them, when we told them, "You don't have the long QT syndrome, is a reaction that we interpret is due to the mechanical stretch of your heart because of very intense exercise training."

Prof. Peter Schwartz:

Some of them did return to practice sport in a very intensive way and all these patterns reappeared again, proving, I think this was the most important point. I mean, shows that you can go back and forth if you stretch the heart in this way, the abnormalities reappear.

Prof. Peter Schwartz:

So this is the essence of the study that carries in my opinion, a number of practical implications, because I think that now, when we are dealing with these youngsters, where we would be making a complete diagnosis. In some cases, I actually started even beta blockers, which is... I mean, afterwards it turns out to be an error and it bothers me, because I don't like to make an error with these patients. But they were so clear. I mean, I could have bet anything that they are affected by the long QT syndrome. But within four or five, six months, they were completely back to normal.

Prof. Peter Schwartz:

So the essence of the studies that we think the youngsters who practice intensely sport, some of them react to these physiological similar situation in an abnormal way. In analogies like with the food allergy. I mean, if you take something that bothers you and the point is, then you just avoid it. With exercise, of course is more difficult for other reasons, but probably it's the quantity of exercise.

Prof. Peter Schwartz:

Now, one change I've observed in recent years is that for youngsters practicing sports, a lot of things have changed. I've done a lot in sports myself soccer, tennis before moving toward golf. But in our days we were just playing, yes, we were playing a lot. But what has changed now is that all these kids have a trainer. They are sent for regular exercise two hours a day, five days a week. And that is probably too much for some of them.

Prof. Peter Schwartz:

So we need to recognize that there are certain individuals who, for whatever reason, I suppose that there is a genetic predisposition tend to react to these excessive amount of exercise training with abnormalities in their electrocardiogram. And for them, probably the logical thing is to reduce the amount of exercise. I would not stop it completely, they should reduce the dose and then have probably a normal life.

Prof. Peter Schwartz:

This is also raises the analogy with drug-induced long QT syndrome. When you have a parent in normal individuals who take any drug that contains an IKr blocker and they could develop to a certain point and the long QT syndrome. Now the situation with exercise is probably not so severe. I don't think the risk is so high, but clearly it is people have a tendency to react to  possibly a variety of stimuli with QT prolongation. so they should be more careful about it.

Dr. Greg Hundley:

You know, I'll tell you, I think the world thanks you for your just observational skills and working through that whole situation that you observed in a very precise, organized fashion to bring us this interesting result. Well, Sami, can you help... Obviously this caught your eye as an associate editor at Circulation. What else attracted you to this study? And how would you like to comment on what Dr. Schwartz has just provided to us?

Dr. Sami Viskin:

Well, in Circulation, we were immediately attracted to this study, especially coming from Peter. Peter has been a pioneer in the entire area for long QT for many, many years. We call him Mr. QT because of his contributions to the field. So we're immediately interested in the paper, which is fascinating. It came a few months after we had reviewed a different paper that deals with patients who have the positive-phenotype, for long QT syndrome and have negative-genotype.

Dr. Sami Viskin:

That was a paper published in the July issue of Circulation with senior author Connie Bezzina. They performed a genome-wide association study to 1,800 patients with long QT, and they compared them with 10,000 healthy individuals. And what they found in these patients who represented 11% of the entire long QT syndrome population was that even though they do not have mutations, they tend to have several genetic variance together. None of them is severe enough to cause the disease but present by itself when they were in their group together in a single individual, then they create the phenotype of long QT syndrome, which is as severe as the phenotype of those who have bona fide mutations.

 

Dr. Sami Viskin:

So, that article was like the background for this one. And in fact, one of the arguments one could do is that the athlete's described by Peter could just have phenotype-positive, genotype-negative long QT, but what Peter would make sure to stress is that they do have electrocardiogram, but not only they do not have symptoms, they have a low pre-test probability of having the disease because they were discovered by screening and also they have a negative family history. So it's a different group of individuals what Peter is describing here. And time will tell. I mean, I'm sure we will be seeing more publications on this, and I will tell you, it's probably that we just looking at a new form of acquired long QT syndrome. Time will tell.

Dr. Greg Hundley:

Very nice. Just briefly, both gentlemen, maybe in 20 seconds or so, what do you think is the next study that needs to be performed in this new group that's been discovered?

Prof. Peter Schwartz:

Greg, we have already started the next study. We are going to compare 700 relatively younger athletes who have intensive exercise and who have a completely normal QTc and completely normal T wave to all our subjects that have defined these phases in our study that performing a similar level of exercise show these changes. And then we are collecting their DNA, and we're going to have an whole exome study for the possibility of identifying some genetic markets that might predispose to something like this.

Prof. Peter Schwartz:

One possibility that I'm interested in is the possibility that the underlying mechanism, maybe something related to the so-called sex activated trainers, which might lead to an increase in intracellular calcium and produces alterations. There are other possibilities, but this is one. And in doing this study, we are also going to begin to look at echocardiography and imaging to see if there are different patterns in terms of mechanics that might contribute to explain.

Prof. Peter Schwartz:

So the point is that on the one hand we wanted and we did confirm the clinical data. So, we know that we are dealing with a factor and we think that's a fact as practical implications for management. Now, the next questions, which I wish to attack as well is why is it, what is the underlying mechanisms?

Dr. Greg Hundley:

Very good, Sami.

Dr. Sami Viskin:

That exactly the direction we were expecting to see if they have a similar polygenic risk score factor as in the study by Bezzina.

Dr. Greg Hundley:

Very nice, well listeners, this has been a wonderful discussion. And we also want to thank Dr. Peter Schwartz for all of his efforts for many years in this area of long QT syndrome and bringing this new finding to light that there is now an observation that not necessarily are all long QTs. Number one of the 300 subjects, 100 actually didn't have it. And then there are some that are phenotype-positive, but not genotype-positive. And we have more to learn about the variance that swings with the presence of the long QT after strenuous exercise. Well, on behalf of Carolyn and myself, we want to thank Peter, thank Sami Viskin and wish all of you a great week. And we will catch you next week on the Run.

 

This program is copyright the American Heart Association, 2020.