Circulation October 15, 2019 Issue

Dr Carolyn
Lam:               
Welcome to Circulation On The Run, your weekly podcast summary
and backstage pass to the journal and it's 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 Greg Hundley, associate editor from the Pauley Heart
Center in Richmond, Virginia at VCU Health.


                                               
Well, Carolyn, we've got a great feature article to discuss later
in our interview today. We're going to compare surgical versus
percutaneous aortic valve replacement, but now with coronary
artery revascularization. So, very exciting results from the
SURTAVI trial.


                                               
So, Carolyn, do you have a couple papers to discuss?


Dr Carolyn
Lam:               
For sure. Actually, it's exactly a couple, and it's a couple of
GWAS papers. The first is a GWAS of the cardiac magnetic
resonance imaging derived left ventricular phenotypes of the UK
bio bank. It comprises almost 17,000 European-UK bio bank
participants without prevalent myocardial infarction or heart
failure. So this was led by professors Petersen and Monroe from
Queen Mary University of London, and colleagues who found that
prognostically important left ventricular imaging phenotypes were
highly heritable, with a heritability of 22 to 39%. A total of 14
genetic susceptibility low PSI, eight of which were unique,
enriched in the cardiac developmental pathways and regulation of
contractile mechanisms were discovered, and the polygenic risk
scores of left ventricular phenotypes were predictive of heart
failure events independently of clinical risk.


Dr Greg
Hundley:            
Well, Carolyn, knowing me and MRI, something I really am
interested in. So tell us a little about what are the clinical
implications?


Dr Carolyn
Lam:               
Well, the findings not only enhance our understanding of the
genetic basis of prognostically important left ventricular
phenotypes in the general population, but they also underscore
the intricate genetic relationship between these endo phenotypes
and the pathogenesis of heart failure. The prioritized genes in
the genome whites significant load size should be followed up in
the functional studies to aid the development of potential novel
therapies in future. The polygenic risk scores of left
ventricular phenotypes may have a role in personalized risk
stratification. But this, of course, is dependent on further
validation of the clinical robustness in future studies.


                                               
I want to skip onto my second GWAS paper, and this time dealing
with bicuspid aortic valve. So, first a little reminder that
bicuspid aortic valve disease is a congenital defect that affects
0.5 to 1.2% of the population, and is associated with
comorbidities including ascending aortic dilatation and calcific
aortic stenosis. To date, while a few causal genes have been
identified, the genetic basis for the vast majority of bicuspid
aortic valve cases remains unknown. Today's paper from Dr
Lipschultz from Medical University of South Carolina reports
novel human genetic based models, which developed bicuspid aortic
valve and aortic stenosis with high penetrance.


Dr Greg
Hundley:            
Very interesting. So, how did the authors do this, Carolyn?


Dr Carolyn
Lam:               
Yeah, it is interesting. What they did is they performed a GWAS
and replication study using cohorts of more than 2,000 patients
with bicuspid aortic valve and more than 2,700 controls, which
identified the primary Celia genes as associated with the
bicuspid aortic valve phenotype. Specifically the most associated
snips were identified in or near genes that are important in
regulating Ciliogenesis through the exocyst, which is a shuttling
complex that chaperone Celia cargo to the membrane. Genetic
dismantling of this exocyst resulted in impaired Ciliogenesis
through the XO CIS, disrupted Ciliogenic signaling, and resulted
in a spectrum of cardiac defects in zebra fish and aortic valve
defects including bicuspid aortic valve, valve stenosis, and
Velveeta calcification in murine models as well. So this data
really supports that the exocyst is required for normal
Ciliogenesis during aortic valve morphogenesis and really
implicates the disruption of Ciliogenesis, and its downstream
pathways may contribute to bicuspid aortic valve and its
associated comorbidities.


Dr Greg
Hundley:            
Wow. Very interesting. Learning more and more about bicuspid
valves through our journal. I'm going to shift Carolyn and talk
about an article from Dr Marc Sabatine from the TIMI study group
at Brigham and Women's hospital. This study performed a
systematic review and a trial level meta regression analysis of
three classes of lipid lowering therapies that reduce
triglycerides to a greater extent than they do LDLC. Fibrates,
Niacin, and Marine derived Omega-three fatty acids and key
inclusion criteria were a randomized, controlled trial that
reported on major vascular events. The study also incorporated
data from a previous Meta-regression of 25 Statin trials, and the
main outcome measure was the risk ratio for major, vascular
events associated with absolute reductions in lipid parameters.


Dr Carolyn
Lam:               
Oh, very interesting. So did the study show that it was
beneficial to lower triglycerides or not?


Dr Greg
Hundley:            
Let me tell you a little more about it. The study encompass
374,358 patients that sustained 46,180 major cardiovascular
events, and in their multi-variable Meta-regression model, that
included terms for both LDLC and triglyceride surrogates for LDL
and VLDL. The risk ratio was 0.8 per one millimole per liter
reduction in LDLC, and 0.84 per one millimole liter reduction in
triglycerides. Therefore, a reduction in non-HDLC, a measure of
atherogenic LDL and VLDL particles, is strongly associated with
lower risk of major vascular events regardless of the lipid
lowering drug class, and triglyceride lowering is associated with
a lower risk of cardiovascular events, but to a lesser extent per
absolute amount of reduction then with LDLC. Interesting, Carolyn
one study reduce it and impacted the study results, and nearly
all non-statin trials did not achieve significant non-HDLC
lowering to detect a clinical difference in major vascular
events. Now how about in regards to Omega- three dose?


                                               
Well, each one gram per day of EPA administered was associated
with a 7% relative risk reduction in major vascular events,
whereas there was no significant reduction in major vascular
events with DHA. So the benefits of Marine-derived Omega-three
fatty acids, particularly high dose EPA, appear to exceed their
lipid lowering effects.


Dr Carolyn
Lam:               
Wow. Interesting. So Greg, take it home for us. What should we do
clinically about this information?


Dr Greg
Hundley:            
Carolyn, developing drugs that achieve large reductions in VLDL
and triglycerides and are targeting patients with high baseline
levels of triglycerides would likely increase the probability of
showing a meaningful clinical benefit, and fibrates could be
considered in patients needing further non-HDLC lowering, being
mindful of side effects, as they should offer clinical benefit
proportional to the degree of non-HDLC lowering, and if a
disproportionate relationship between lipid lowering and
cardiovascular risk reduction is validated in ongoing high dose
Omega-three fatty acid trials, it will support the hypothesis
that confers a unique benefit of this class of agents beyond
simply their lipid lowering.


                                               
How about that?


Dr Carolyn
Lam:               
Very nice Greg and I think very balanced and good clinical take
home messages. Tell us what else is in the mailbag.


Dr Greg
Hundley:            
We have so many interesting articles in Circulation and let me
just run through a quick list of those that are also in this
issue. First, Dr Jere Mitchell, from UT Southwestern, reviews the
50th anniversary of the Dallas Bedrest Study that involve five
20-year-olds that underwent several weeks of bedrest, and he
discusses how this informs many of our thoughts regarding the
benefits of activity today, and one of his major coauthors is Dr
Ben Levine. Our own Josh Beckman reviews the ongoing efforts of
physicians to understand the role of paclitaxel coated stents for
those undergoing peripheral arterial interventions. Dr Berlinde
von Kemp, in our case series, identifies that not all
cardiomyopathy, after delivery, is simply postpartum
cardiomyopathy. In another article, Dr Anurag Agrawal discusses
what's on their mind regarding the use of spirometry as a
cardiovascular disease risk assessment tool, should it be
incorporated into existing cardiovascular disease risk models.


                                               
Then, we have a great letter back and forth discussion from Dr
Junfeng Wang, Dr Daxin Wang, and our own Naveed Sattar in three
separate letters that discussed the relevance of age of onset for
type two diabetes relative to cardiovascular risk. Then, finally
our own Carolyn Lam reviews the role of biomarkers in heart
failure and preserved ejection fraction.


Dr Carolyn
Lam:               
Let's hop on to our feature discussion, shall we?


Dr Greg
Hundley:            
Absolutely.


Dr Greg
Hundley:            
Welcome everyone to the discussion of our featured article today
where we're going to review an excellent study comparing TAVR
versus SAVR in patients with aortic stenosis, but also now
considering simultaneous coronary artery revascularization.
Discussing our article today we have Dr Thomas Engstrøm and then
our own associate editor, Dharam Kumbhani. Well Thomas, welcome
to our podcast featured article discussion. I wonder if you could
start us off with a little background regarding your study. What
were your hypotheses, and then tell us a little about your study
population and your methods.


Dr Thomas Engstrøm:     Now, as you know, up
to 50% of patients that are treated for aortic stenosis have
coronary artery disease, and this may be considered as a
bystander disease to develop disease, but definitely also adds to
the prognosis for the patients. A priority guideline recommends
that if you do SAVR, you'll also have significant coronary artery
disease. What we don't know is if the complete percutaneous
approach is as good as a surgical approach. Maybe do TAVR plus
PCI comply with fiber plus CABG. That's the background for the
study.


                                               
Now, the population involved in this study is the population from
the search TAVR trial, which as you know compared TAVR to SAVR in
patients that were clinically at intermediate risk and in
patients that had severe aortic stenosis. If patient had
additional coronary artery disease with a syntax called Bob 22,
they were excluded from the trial. We are talking about
intermediate risk patients with low syntax score. Of the patients
in the TAVR trial, 20% had additional coronary artery disease and
were resterilized. In the paper, we compare TAVR plus PCI versus
SAVR plus CABG in those patients with significant coronary artery
disease.


Dr Greg
Hundley:            
How did you define the presence or absence of coronary disease?
Just real quickly before we get to your results.


Dr Thomas Engstrøm:     This was at the
discretion of your operator to define where the patients had
coronary artery disease or not. In the paper, patients were
defined as having significant diseases. More than 70% of stenotic
lesions were present in one or more coronary arteries.


Dr Greg
Hundley:            
And so can you tell us, Thomas a little about the results of your
study?


Dr Thomas Engstrøm:     First of all, the
patients that had additional coronary artery disease had a poor
prognosis than those that only had valve substitution, which is
probably not a surprise. Within those that also had coronary
artery disease, TAVR plus PCI appeared to be as good as CABG plus
SAVR in terms of the primary endpoint, which was all because
mortality or disabling stroke after two years. Then, if you dive
more deeply into the endpoint and the number of secondary
endpoints were pre-specified, there were no differences regarding
any stroke myocardial infraction and in total no differences
between what you could call major heart end points. If you look
more into detail of the secondary endpoint, there are subtle
differences. Patients that were in the SAVR plus CABG had more
atrial fibrillation as they also had more acute kidney injury
following that treatment. Whereas, in the TAVR plus PCR, more
patients had vascular complications and of course had the need
for pacemaker implantation. There are differences between the
outcome in the two groups, but not in regard of pre-specified
primary and more important secondary endpoints.


Dr Greg
Hundley:            
Dharam, I was wondering if you could help us think about what
this means for the field in terms of both from aortic valve
replacement, and then also the concomitant management of coronary
disease in patients that require aortic valve replacement.


Dr Dharam Kumbhani:   As Thomas just pointed out, I
think this is a very important question. This comes up all the
time in patients with severe aortic stenosis, being evaluated for
best options, and the guidelines have stayed true to this that if
somebody has concomitant coronary artery disease, then the
guidelines typically would recommend SAVR as the first option
because then they can have CABG at the same time. This study
really seeks to address a very important knowledge gap in the
field, and as he very well pointed out, this does restrict itself
a little in terms of the population, because they couldn't have a
high syntax score, actually an intermediate or high syntax score,
and they need in the trial...I think the main syntax score was
eight or nine. I think that is important, but having said that,
more than 50% of the patients had multi-vessel disease, and it
was really impressive that nearly 15 or 17% still had three
vessel PCI even in this arm.


                                               
I think it's important for people to recognize that although this
was the lowest syntax score, multivessel PCI was still pursued. I
think that's definitely an important takeaway from the strike.
It's a really important trial. It's one of the very few pieces of
information that we have that is prospectively done under the
auspices of a big trial like SURTAVI, and with low risk approval
in and what this means for patients going forward I think will be
very exciting to see how this few devolves.


                                               
Thomas, as this field matures, could you walk us through, in
terms of did you do the valve first and then the coronaries, or
where the coronaries worked on first and then the valve? That's
sort of the first question. Can you walk us through how you make
those decisions?


Dr Thomas Engstrøm:     It was up to the
discretion of the operator whether to do a concomitant procedure,
both PCI and TAVR, or to state the procedures in that way that
PCI was done first, and this could be done up to seven days
before the TAVR. If you compare those two groups, and now numbers
become a little bit few, so we can't be conclusive here. It
appears that patients that had stage procedures did poorer than
those that had concomitant procedures done. Of course, it raises
some questions. The prioritization as to do it in one way or the
other was that through concomitant procedure, you may introduce
too much of stress to the patient. Otherwise, if you do a stage
procedure, it's best to do the PCI first, because the actual
appearance of the valve may make it more difficult and cumbersome
to address the coronary arteries. To sum this up, in the patients
that we have, it appeared that a concomitant procedure is safe.


Dr Greg
Hundley:            
Dharam, tell us, what do you think is the next step forward for
this field? What do see as the next study moving forward here?


Dr Dharam Kumbhani:   I think this study really sets
the stage for, I think future trials where perhaps we would
have... So I'm doing this in this trial. The stratification was
done based on whether or not they need to revascularization. I
think going forward, again with LOTUS approval here and
proliferation of the number of TAVR procedures that are being
offered everywhere, I think it will be helpful. This study would
set the stage for future studies, where I think you would
prospectively have patients with needing an aortic valve
replacement and perhaps even complex revascularization, and how
that was kind of actually the randomization, which is the
stratification strategy, which again was very helpful. These are
really among the first few data that we have of this, but I think
this kind of sets the stage for future investigations in this
space. And then as I briefly alluded to, I think this may help
evolve or this may help in the evolution on the guidelines as
well.


                                               
Thomas, would you like to add anything to that?


Dr Thomas Engstrøm:     Yeah, I completely
echo that. Going back to the old syntax trial, it would be very
interesting to see if PCI holds through, even in high tunes,
syntax scores with newer drug eluting stents, and also of course
the question of the diabetics is totally unsolved in this cohort.
CABG plus SAVR may turn out to be the best solution, but we still
are waiting to see data that can support any of the two
strategies in those patient cohorts.


Dr Greg
Hundley:            
We want to thank Thomas Engstrøm and also our own Dharam
Kumbhani. We look forward to seeing you next week.


Dr Carolyn
Lam:               
This program is copyright American Heart Association, 2019.