Circulation April 4, 2017 Issue

Carolyn:                              
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to The Journal and its editor's. I'm Dr.
Carolyn Lam, associate editor from the National Heart Center and
Duke National University of Singapore. Our Journal this week
features important new data telling us that a common genetic
variant risk score is associated with risk of drug induced QT
prolongation and torsades de pointes.


                                               
First, let's give you your summary of this week's journal. The
first paper provides both clinical and experimental data to show
that the adipokine, retinal binding protein four promotes
atherosclerosis. First author, Dr. Liu, corresponding author, Dr.
Xia and colleagues from Sun Yat Sen University in Guangzhou,
China first evaluated the association between serum retinal
binding four levels and the incidents of adverse cardiovascular
events in a community based prospective cohort and then examined
the effects of retinal protein four gain or loss of function on
macrophage foam cell formation and atherogenesis in an apple
lipase protein E deficient mouse model. They found, in the
clinical cohort study, that base line serum retinal binding
protein four level was an independent predictor of incidents of
adverse cardiovascular events after adjustment for traditional
risk factors.


                                               
In the experimental study's, they showed that retinal binding
protein four promoted macrophage derived foam cell formation
through the activation of scavenger receptor CD36 mediated
cholesterol uptake. In turn dependent on June and terminal kinase
and signal transducer and activator of transcription one, as well
as upstream regulation by the tracing kinase CSRC. These
findings, therefore, support the use of retinal binding protein
four as a novel biomarker for the prediction of cardiovascular
risk. The data also provide insight into the mechanism of action
of retinal binding protein four in the path of physiology of
atherosclerosis.


                                               
The next paper is the first clinical trial, looking at remote
ischemic pre conditioning prior to carotid artery stinting in
patients with severe carotid artery stenosis. Remote ischemic pre
conditioning is a protective, systemic strategy by which cycles
of bilateral limb ischemia are applied briefly to confer
protection from subsequent severe ischemia and distant organs.
First author, Dr. Zhao, corresponding authors, Dr. Ji, and
colleagues from Xuanwu Hospital, Capital Medical University
in Beijing, China performed a proof of concept, single center,
prospective, randomized control trial to assess whether remote
ischemic preconditioning was safe and effective in attenuating
ischemic injury related to carotid artery stinting in 189
patients with severe carotid artery stenosis. Results show that
daily remote ischemic pre conditioning for two weeks, prior to
carotid artery stenting, was feasible, safe, well tolerated, and
may effectively attenuate secondary brain injury as evidence by a
decreased incidence and reduced volumes of new ischemic legions
on magnetic residence imaging performed within 48 hours post
operation. The clinical implications are that if results are
confirmed by future, larger studies, remote ischemic
preconditioning may evolve into a nonpharmacological, neuro
protective method for inhibiting carotid artery stenosis related
cerebral ischemic events.


                                               
This potential for clinical translation in discussed in an
accompanying editorial by Doctors Bell and Yellen, from
University College, London.


                                               
The final paper discusses firefighting and the heart. What's the
link? Well, cardiovascular events are the leading cause of death
amongst firefighters and the risk is known to be substantially
increased during fire suppression duties. In the current study,
first author Dr. Hunter, corresponding author, Dr. Mills, and
colleagues from University of Edinburgh in United Kingdom sought
to understand this link better by assessing the effects of
simulated fire suppression on measures of cardiovascular health
in an open label, randomized cross over study of 19 healthy
firefighters. These firefighters performed a standardized
training exercise in a fire simulation facility or like duties
for 20 minutes. Following each exposure, ex vivo thrombus
formation, fibrinolysis, platelet activation and for armed blood
flow in response to intra-arterial infusions of endothelium
dependent and independent vasodilators were all measured. The
authors found that exposure to extreme heat and physical exertion
during fire suppression activated platelets, increased thrombus
formation, impaired vascular function, and promoted myocardial
ischemia and injury in healthy fire fighters. These finding
provided pathogenic mechanisms to explain the association between
fire suppression activity and acute myocardial infarction in fire
fighters.


                                               
The implications of these findings for prevention are discussed
in an accompanying editorial from Dr. Kales, of Harvard school of
Public Health and Dr. Smith from Skidmore College and University
of Illinois fire service institute.


                                               
Well, those were your summaries. Let's welcome our guests for our
feature discussion.


                                               
Today's feature paper describes a pilot study that shows that a
common genetic variant risk score, is associated with drug
induced QT prolongation and torsades de pointes. This paper is so
interesting to me because I found that the learning points, at
least for me, really extended well beyond the trial itself. I'm
so delighted to have with me the co corresponding authors, Dr.
David Strauss from the US FDA, as well as Dr. Christopher
Newton-Cheh from Massachusetts General Hospital. Welcome,
gentlemen.


David:                                  
Thanks very much, glad to be here.


Christopher:                      
Thank you, Carolyn.


Carolyn:                              
So, I've always thought that common genetic variants identified
via GWAS, for example, are individually very weak effects on
medical traits. For example, systolic blood pressure or in this
case, QT interval. But what I'm so impressed with this study is
that you show, I think for the first time, that even these small
effects can add up to clinically meaningful results that are
testable or demonstrable in a trial. David, could you begin by
telling us a little bit about this trial and what the primary
results were.


David:                                  
In the study, we tested the hypothesis that a weighted
combination of common genetic variants, contributing to the QT
interval at base line, identified through prior GWAS studies, can
predict individual response to multiple QT prolonging drugs. We
performed a genetic analysis of 22 subjects and a secondary
analysis of a randomized, double blind, placebo controlled cross
over trial, that included three QT prolonging drugs, with 15 tie
matched QT and plasma drug concentration measurements. This
allowed us to carefully control for the inter individual
differences in pharmacokinetics and just focus on the
pharmacodynamics so the direct effect of the drug on the heart.


                                               
What we found was, there was a significant correlation between
the weighted combination of common genetic variants, which we
call the genetic QT score, and drug induced QT prolongation. More
specifically, we found that the genetic QT score explained 30
percent of the variability in response to dofetilide, 23 percent
in response to quinidine, and 27 in response to ranolazine.


                                               
We also investigated how response to one QT prolonging drug
predicted the response to other QT prolonging drugs. There were
significant correlations between all the drug/drug relationships
with response to each drug explaining 24 to 29 percent of the
variability in response to each of the other drugs. It's
important to note that QT prolongation, by itself, is not
harmful. The real concern is torsades de pointes, which can
degenerate into ventricular fibrillation and cause sudden death.
So, the test, irrelevant to the common genetic variants in
predicting drug induced torsades, we then went on to examine a
previously published, genome wide association study that included
215 patients with drug induced torsades, compared to 771 ancestry
match controls and that prior study that was previously published
had found that each individual common genetic variant did not
reach genome wide significance, as you suggested, Carolyn.
However, when we applied the weighted combination of common
genetic variants, we found that the genetic QT risk score was
associated with significantly increased risk of drug induced
torsade, explaining 12 percent of the variation in risk.


Carolyn:                              
So, my simplistic understanding was more or less there. That
these genetic risks of these common variants kind of add up. I'm
just curious ... Chris, do you think that this has implications
for even other diseases? That's one question. And then secondly,
I really appreciated your comment about using an intermediate
trait, if you may, of QT interval versus looking at the disease
itself of torsade de pointes. Could you give me comments on both
these things?


Christopher:                      
The study of intermediate traits, such as, quantitative traits
like QT variability on the EKG are, I think very tractable for
the study of genetic bases of underlying physiologic processes
because we can study so many people. So the original genome wide
association study that detected these individually weak genetic
effects could only find them because we studied about 75,000
people who had had genome wide genome typing and QT intervals
measured. It requires such large sample sizes to reach p values
that are able to distinguish true positive associations from
false positive associations, due to the multiple testing burden.


                                               
I think a challenge of what to do with these genetic effects once
they've been reliably detected is that they do have weak effects
and they influence intermediate traits. Nobody really cares
whether their QT interval is three milliseconds longer, or three
milliseconds shorter. What they care about is hard outcomes, or
the likelihood that they'll have a toxic drug response. So, it
was a natural follow on to that work to try to test these
variants, and we knew that based on their weak effects
individually on QT interval in the general population, that it
was unlikely that they would individually explain a significant
portion of either drug response or torsade. Which is why we
aggregated the facts into the weighted score.


                                               
I think we tried to examine what we thought were the most
proximal, clinically relevant outcomes. Specifically, drug
response. QT drug response to drugs that are established to cause
QT prolongation and arrhythmias. Whether the QT score will have
meaningful or detectable impact on drugs that have much weaker
effects on re polarization and risk of torsade, I think, would
remain to be seen.


Carolyn:                              
That's really remarkable.


                                               
David, how about your perspective of the implications of this?
It's so unique that you're actually from the FDA so, why is this
important to the FDA?


David:                                  
As Chris mentioned, the specific application we studied here, a
drug induced QT prolongation and torsade have resulted in the
withdrawal of several drugs from the market both in the US and
worldwide. Many critical drugs remain on the market that are
associated with QT prolongation and torsade…over 100 drugs,
likely. What some people may not be familiar with is that at FDA
we perform research to move new science into the drug review
process and close the gap between scientific innovation and drug
review. Like practicing clinicians, we seek to understand inter
patient variabilities and we conduct research to better evaluate,
benefit, and risk of medications. This is in line with the
broader initiative ... the precision medicine initiative, which
seeks to move away from the traditional “one size fits all”
approach for medical therapy and instead, take into account
specific characteristics of individual patients.


                                               
People are most familiar with this being applied in oncology and
advances in pharmacogenomics have been more limited in other
areas with the exception of the genetic bases of metabolism and
pharmacokinetics  where the traits are often controlled by
one or a few genetic mechanisms, rather than the many mechanisms
responsible for complex traits and diseases, as Chris discussed.
As I mentioned earlier, what was relatively unique about this
study is that we were able to control for the difference in
pharmacokinetics and investigate the inter individual differences
in the direct effect of drugs on the heart, the pharmacodynamics.
We think it's very exciting that a combination of common genetic
variants and aggregate can explain a significant portion of the
inter individual variability and, as Chris mentioned, this is
also important because the incidence of torsade is quite low.
Only a small number of patients will develop drug induced
torsade. It's possible that in the future analysis of a large
number of common genetic variants that can be identified through
genome wide association studies as in this case, may help to
better define the personalized benefit risk profiles for
individual patients.


Carolyn:                              
You've really articulated that remarkably. That's exactly the
excitement I think the entire editorial team shared when we read
your paper. Thank you so much for it. Maybe just one last
question thrown out to both of you, what's the next step? What's
in the future.


Christopher:                      
I think one next step, based on this proof of principle study,
will be to try to test the impact of these genetic risk scores in
real world clinical settings where individual patients with the
diversity of different comorbidities and different drug exposures
are also receiving QT prolonging drugs. Because that will have
the biggest relevance for our patients who faced increased risk
of drug toxicity.


David:                                  
The issue of cardiac safety of drugs is something that is very
important to us at the FDA and we have some parallel initiatives
that, in collaboration with other global drugs ... regulatory
agencies and industry and academic collaborators ... we are
working to develop new cardiac safety evaluation paradigms for
new drugs, or existing drugs, that could even be applied in the
preclinical setting and really focus on the mechanistic base, pro
arrhythmic risk. So, we should have more exciting work coming
forward in the near future for better prediction and
individualized prediction of benefit and risk of medication.


Carolyn:                              
Thank you, listeners, for joining us. You've been listening to
Circulation on the Run. Join us next week.