Circulation December 22/29, 2020 Issue

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.