Circulation February 11, 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, associate editor,
director of the Pauley Heart Center at VCU Health in Richmond,
Virginia. Well, Carolyn, our feature article this week relates to
an international multi-center evidence-based reappraisal of genes
reported to cause congenital long QT syndrome. But, before we get
to that, how about if we grab a cup of coffee and start on our
other papers? Do you have one you'd like to discuss?


Dr Carolyn Lam: Yes. My favorite part of the week. So this first
paper really asks the question, "What's the association between
HDL functional characteristics, as opposed to HDL cholesterol
levels, and acute coronary syndrome?" The paper comes from Dr
Hernáez from IDIBAPS in Barcelona, Spain and colleagues who
conducted a case control study nested within the PREDIMED cohort.


Originally a randomized trial where participants followed a
Mediterranean or low-fat diet. Cases of incident acute coronary
syndrome were individually matched one is to two to controls by
sex, age, intervention group, body mass index, and follow-up
time. The authors measure it the following functional
characteristics, which were HDL cholesterol concentration,
cholesterol efflux capacity, antioxidant ability, phospholipase
A2 activity and sphingosine-1-phosphate, apolipoproteins A1 and
A4, serum amyloid A and complement 3 protein.


Dr Greg Hundley: Wow Carolyn, a detailed analysis. What did they
find?


Dr Carolyn Lam: They found that low values of cholesterol efflux
capacity, and levels of sphingosine-1-phosphate and
apolipoprotein A1 in HDL or all associated with a higher risk of
acute coronary syndrome in high cardiovascular risk individuals,
irrespective of HDL cholesterol levels and other cardiovascular
risk factors. Low cholesterol efflux capacity values and
sphingo-1-phosphate levels were particularly associated with an
increased risk of myocardial infarction, whereas HDL antioxidant
or anti-inflammatory capacity was inversely related to unstable
angina.


Now this is significant because it's the first longitudinal study
to comprehensively examine the association of several HDL
function related biomarkers with incident acute coronary syndrome
beyond HDL cholesterol levels in a high-risk cardiovascular risk
population.


Greg Hundley: Very nice. Carolyn. It sounds like function over
just the levels is important.


Dr Carolyn Lam: Exactly, you summarized it well. Well Greg, I've
got another paper and I want to pick your brain first. Is it your
impression that type 2 myocardial infarction, the type that
occurs due to acute imbalance in myocardial oxygen supply versus
demand in the absence of atherothrombosis, do you think that this
type of MI is on the rise? It seems more and more common in my
country.


Dr Greg Hundley: Do we want to say it's on the rise? Certainly by
measuring all these high sensitivity troponins, et cetera, we're
finding, I think, more evidence of type 2 MI. So, all in all,
yeah it probably is on the rise, but likely related to some of
our measurement techniques.


Dr Carolyn Lam: Oh, you are so smart, Greg. Because this paper
that I'm about to tell you about really addresses some of these
issues and it's from corresponding author Dr Gulati from Mayo
Clinic in Rochester, Minnesota. And they really start by
acknowledging that despite being frequently encountered in
clinical practice, the population base incidents and trends of
type 2 myocardial infarction is unknown and long-term outcomes
are incompletely characterized. So they prospectively recruited
5,640 residents of Olmsted County, Minnesota who experienced an
event associated with cardiac troponin T greater than 99th
percentile of a normal reference population, which is greater
than or equal to 0.01 nanograms per milliliter. And this was
between 2003 and 2012, so very careful to talk about which
Troponin T assay exactly to the point you discussed earlier,
Greg. The events were retrospectively classified into type 1
versus type 2 MI using the universal definition.


Dr Greg Hundley: So Carolyn, what did they find?


Dr Carolyn Lam: They found that there was an evolution in the
types of MI occurring in the community over a decade with the
incidence of type 2 MI now being similar to type 1 MI. Adjusted
long-term mortality following type 2 MI is markedly higher than
after type 1 MI and that's driven by early and non-cardiovascular
deaths. Mortality of type 2 MI is associated with a provoking
factor and is more favorable when the principle provoking
mechanism was an arrhythmia compared with postoperative status,
hypotension, anemia or hypoxia. And these findings really
underscore the healthcare burden of type 2 MI and provide
benchmarks for clinical trial design.


Dr Greg Hundley: Very nice, Carolyn. Well, my paper comes from
type 5 long QT syndromes and an analysis. And it's from Dr Jason
Roberts from Western University. Through an international,
multi-center collaboration, improved understanding of the
clinical phenotype and genetic features associated with rare
KCNE1 variants implicated in long QT 5 was sought across 22
genetic arrhythmia clinics and four registries from nine
countries that included 229 subjects with autosomal dominant long
QT five. So there were 229 of those subjects. And then 19
individuals with the recessive type 2 Jervell and Lang-Nielsen
syndrome. The authors compared the effects of clinical and
genetic predictors on a composite primary outcome of definite
arrhythmic events, including appropriate implantable cardioverter
defibrillators shocks, aborted cardiac arrest, and sudden cardiac
death.


Dr Carolyn Lam: Wow. What did they find?


Dr Greg Hundley: Well, several things, Carolyn. First, rare loss
of function KCNE1 variants are weakly penetrant and do not
manifest with a long QT syndrome phenotype in a majority of
individuals. That's a little bit of a surprise. Second, QT
prolongation and arrhythmic risk associated with type 2 Jervell
and Lang-Nielsen syndrome is mild in comparison with the more
malignant phenotype observed for type 1 Jervell and Lang-Nielsen
syndrome. And then number three, all individuals possessing a
rare loss of function KCNE1 variant should be counseled to avoid
QT prolonging medications and should undergo a meticulous
clinical evaluation to screen for long QTS phenotype.


And then finally, Carolyn, the last finding, in the absence of a
long QTS phenotype, more intensive measures, such as beta
blockade and exercise restriction, may not be merited.


Dr Carolyn Lam: Oh, very interesting. Well, I've got one more
original paper and in this, authors describe a new cellular
mechanism linking ischemia-reperfusion injury to the development
of donor specific antibody, a pathologic feature of chronic
antibody-mediated rejection, which mediates late graph loss. This
paper is from corresponding author Dr Jane Witt from Yale
University School of Medicine and colleagues who use humanized
models and patient specimens to show that ischemia-reperfusion
injury promoted elaboration of interleukin 18 from endothelial
cells to selectively expand alloreactive interleukin 18 receptor
1 positive T peripheral helper cells in allograph tissues and
this promoted donor specific antibody formation.


Dr Greg Hundley: Carolyn, here's the famous question. What does
that mean clinically for us?


Dr Carolyn Lam: Aha, I'm prepared. Therapies targeted against
endothelial cell derived factors like interleukin 18 may
therefore block late complications of ischemia-reperfusion
injury.


Dr Greg Hundley: Very nice. Sounds like more research to come.
Well, how about other articles in the issue?


Dr Carolyn Lam: Well, I'd love to talk about a white paper from
Dr Al-Khatib, and it's about the research needs and priorities
for catheter ablation of atrial fibrillation and this is a report
from the National Heart, Lung, and Blood Institute Virtual
Workshop.


Dr Greg Hundley: Well, I've got another arrhythmia paper, so this
is from Professor Michael Ackerman at the Mayo Clinic and its
minor long QT gene disease associations by coupling the genome
aggregation database. It's a harmonized database of 140,000 or
more exomes and genome derived in part from population-based
sequencing projects, with phenotypic insights gleaned from a
large long QT syndrome registry to reassess the strength of these
minor long QT syndrome gene disease associations. Next, Carolyn,
in an on my mind piece, Professor Gerd Heusch from University of
Essen Medical School discusses, how can the many positive
preclinical and clinical proof of concept studies on reduced
infarct size by ischemic conditioning interventions and
cardioprotective drugs be reconciled with the mostly neutral
results in regard to clinical outcomes.


The author discusses the important differences between animal
models that have been used a lot in this ischemia reperfusion and
infarct size reduction science, and then the clinical scenarios
of STEMI in humans as well as the many aspects of coronary
reperfusion. How is that affecting the myocytes? How is that
affecting the microcirculation, et cetera, that must be
addressed? And then finally Carolyn, there is a series of
letters, one from Professor Oliver Weingärtner from
Universitätsklinikum Jena and another from Professor Yasuyoshi
Ouchi from Toranomon Hospital. They're exchanging letters
debating the utility of lipid lowering with Ezetimibe in
individuals over the age of 75 years.


Dr Carolyn Lam: Very nice, Greg. Thanks so much. Shall we now
move to our future discussion.


Dr Greg Hundley: You bet.


Well, welcome everyone. This is our feature discussion and today
we're going to hear more about long QT syndrome. We have Dr
Michael Gollob from University of Toronto and our own associate
editor, Dr Sami Viskin from Tel Aviv Medical Center. Good
morning. Good afternoon, gentlemen. Before we get started with a
discussion of some of the study findings and results, Michael,
could you tell us a little bit about why you performed the study
and what were some of the hypotheses you wanted to test?


Dr Michael Gollob: As you know, long QT syndrome is probably the
most recognized channelopathy associated with sudden cardiac
death in young individuals and adults. And at the present time,
there are 17 genes available for clinical genetic testing in
cases of suspected long QT syndrome. We simply ask the question,
"Is there sufficient scientific evidence to support that each of
these genes are single gene causes of long QT syndrome based on
our contemporary knowledge of genetics and the human genome?


Dr Greg Hundley: Great, Michael. So, can you tell us a little bit
about your study population? How did you go about this and what
was your study design?


Dr Michael Gollob: We designed a methods approach that would
assure that any conclusions that were made from our working group
were not based on the opinions of one or two individuals. We
wanted to ensure that this was a consensus conclusion with
multiple experts in the field including genomic scientists,
genetic counselors, inherited arrhythmia experts, and researchers
in the field. We created three independent teams of genetic
experts to curate the genetic evidence reported in the medical
literature for each of these 17 reported causes of long QT
syndrome. This was essentially an evidence-based approach using a
pre-specified evidence-based matrix or scoring system depending
on the level of evidence, genetic primarily, in the reported
literature for each gene.


Each of these curation teams worked independently of each other
and they were blinded to each other's work and they were tasked
with concluding whether a gene, based on the medical literature
and the resource methodologies, had sufficient evidence for
disease causation. Their classifications would be one of disputed
evidence, limited evidence, moderate evidence, strong or
definitive evidence for claims towards disease causation.
Remarkably, independently, all of these teams reached the same
conclusion. In the end, their summary data was reviewed by a
clinical domain expert panel with individuals with expertise,
particularly in long QT syndrome and other channelopathies. So in
total 19 individuals reviewed all of the literature and the data
presented and came to unanimous conclusions for each gene.


Dr Greg Hundley: Out of the 17, were there some that were more
important than others or was it uniformly all 17 were relevant?


Dr Michael Gollob: Well, I think the most relevant conclusions of
our study are that nine of these genes, more than half of these
genes, were felt not to have sufficient evidence to support their
causation as a single gene cause for typical long QT syndrome. So
nine genes that are currently tested by clinical genetic testing
providers do not have enough evidence to support their testing in
patients with suspected long QT. And to us, that is the most
relevant observation because testing genes that do not have
sufficient evidence for disease causation poses a significant
risk to patient harm and family harm. We concluded that only
three genes had very definitive evidence for causation of long QT
syndrome. Those three genes were KCNQ1, KCNH2, and SCN5A. There
were another four genes that were concluded to have strong or
definitive evidence for unusual presentations of long QT
syndrome. And by that, I mean presentations that typically occur
in the neonatal period and are associated with heart block
seizures or developmental delay or in the case of one of these
genes, Triadin, an autosomal recessive form of the disease.


Dr Greg Hundley: So helping us perhaps what types of genes to
screen for when we have someone with this condition or suspected.
So Sami, can you help us put this into perspective? How does this
study help us in management of this clinical situation.


Dr Sami Viskin: In Circulation, we immediately recognize the
importance of the manuscript, the importance of the study because
unfortunately, there are too many physicians all over who will
accept the results of genetic testing essentially like gospel.
Now it's in the DNA, it's in the genes, so whatever you find must
be true. And too often, clinical decisions on treatment including
ICD implantation have been undertaken based on results of genetic
testing’s; thus are wrongly interpreted. So we recognize
immediately the importance of this paper. We already had a
different study by Dr Gollob and his associates. Again,
reassessing the role of genes in Brugada syndrome. So we were
familiar with this type of analysis.


We recognize the importance and we moved ahead to accept this
paper, it went fairly easily, I think only one revision. At the
same time, we were getting additional paper by other groups. So
in the same issue, we have two more papers, one from Jason
Roberts with the International Long QT Registry of long QT 5,
reaching similar conclusions that this is a gene with very
limited penetrants and another study by the Mayo clinic also
showing that many of the genes who are not the major genes are
overrepresented in the healthy population. So we put all these
three papers together with a very nice editorial by Chris
Semsarian in the same issue. So everything is put in the right
perspective of how we should be looking at all the genes of these
disease in a different way.


Dr Greg Hundley: So as a clinician quickly, how can I use this
information in the issue, perhaps this paper and all three, in
management of patients with either suspected or long QT syndrome?


Dr Michael Gollob: First off, I would emphasize that the
diagnosis of long QT syndrome or any genetic base disease for
that matter, should be based on clinical phenotype and not the
observation of a genetic change, particularly if genes are being
tested that do not have strong evidence for disease causation, as
is the case for the nine genes that we've pointed out in this
manuscript.


So I think clinicians need to be wary of the genetic testing
panels that they are requesting be screened or used in the
assessment of their patients and be knowledgeable that at this
point in time, we really only have three genes with very strong
evidence to support disease causation of the typical form of long
QT syndrome. And that for the most part, these other genes should
not be tested or should only remain in the realm of research.


I think that responsibility extends further than just the
clinician taking care of the patient, but also clinical genetic
testing providers, companies that offer these genetic testing
services. I think they should assume a responsibility to ensure
that they are only offering services for genes that have strong
evidence for disease causation because when they report results
in genes that are not valid for the disease, that only confuses
the care of the patient and that creates a risk of harm to them
if that information is misinterpreted by a physician.


As Dr Viskin or Sami pointed out, we do see patients who are
inappropriately diagnosed. We remove the diagnosis of roughly 10
to 20% of cases in our own clinic. And unfortunately, many of
these patients and their families have suffered undue anxiety.
Some of them have ICDs in place that should not have been there.
So I think overall, the field needs to be aware of what genes are
relevant and what genes still are within the realm of research.


Dr Greg Hundley: Can you tell us just quickly Michael and then
also Sami, what do you see as the next study in this field?


Dr Michael Gollob: We're taking a step back now. The first decade
of this century saw an exponential growth in reported gene
disease associations. And now in the last five or six years,
we've learned a lot about human genetic variation, which has
provided us an opportunity to reflect back on some of these
previous and reported genes as causes for long QT and other
diseases.


So I think many individuals in our field may say, "Well, you
know, this is disappointing. We believed in these genes. We
really thought these genes were causes of long QT." And to that
point I would say, we need more research. If you believe in some
of these genes that have now been considered to have limited or
disputed evidence, research should continue if these remain
plausible candidates for the disease.


So I think future research has to continue. There are probably
still a few other genes that have not yet been discovered. I
think we've got the vast majority. I think in most cases, at
least in our experience, 90 to 95% of cases are explained by the
top three genes. But there are probably other genes out there and
it's always fascinating to learn or discover new genes, but those
sorts of studies have to be done with the correct methodologies
and rigid protocols. Lastly, I think in the future us clinicians
and geneticists and genetic counselors need to work closely with
genetic testing providers to ensure that they are offering
responsible genetic testing services.


Dr Greg Hundley: Sami, do you have anything to add?


Dr Sami Viskin: Just congratulate the authors. I think they did a
very great service to the medical community by pointing out the
limitations of the genetic testing and the way we interpret the
results, and they deserve to be applauded for reminding us that
we have to be careful when we read papers about genetic results
or when we get genetic testing results ourselves.


Dr Greg Hundley: I want to thank Michael from University of
Toronto and Sami from Tel Aviv Medical Center for participating.
And on behalf of both Carolyn and myself, wish you all a great
week and look forward to chatting with you next week.


This program is copyright, the American Heart Association 2020.