Circulation February 12, 2019 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, director of the Pauley Heart Center from
VCU Health in Richmond, Virginia.


Dr Carolyn
Lam:               
Is income volatility a new cardiovascular risk factor? You have
to stay tuned to hear all about that. But for now, join Greg and
I over a nice little coffee chat, because we're picking up the
journal right here and I'm going to tell you about our two top
picks this week. Greg, you go.


Dr Greg
Hundley:            
Well my top picks, Carolyn, is really pertaining to senescence
and senescent cardiomyocytes. Remember that? Senescence is a
situation where there's a mismatch between energy demand and
supply and so that facilitates the cells transitioning toward
failure. They lose their ability to function. In other parts of
the body, they lose their ability to divide.


                                               
And these investigators assessed altered calcium transfer from
sarcoplasmic reticulum to the mitochondria, because that's being
casually linked to the pathophysiology of aging in heart failure.
Because the advanced glycation end products or AGEs accumulate
through life, the authors thought that maybe this intracellular
glycation would be occurring in aged cardiomyocytes and their
impact on the sarcoplasmic reticulum and mitochondria. So, their
study, they investigated both mice and humans and the found that
ryanodine receptor glycation was associated with more pronounced
calcium leak in mice and also interfibrillar mitochondria
directly exposed to sarcoplasmic calcium release from aging mice
had increased calcium content, compared to those with younger
ones.


                                               
Now we're starting to implicate a mechanism by where senescence
could be important in these mice. But of course, in Circulation
in these wonderful basic science papers that we have, they also
cover a translational human component. And what these group found
is that there were higher levels of advanced glycation end
products and reduced glyoxalase 1 activity present in left atrial
appendages, from those patients that underwent surgery greater
than 75-years-of-age, compared to individuals that were younger.
And also, elderly patients exhibited hyper glycation and
increased mitochondrial calcium content that was associated with
reduced myocardial aerobic capacity due to less respiring
mitochondria.


Dr Carolyn
Lam:               
Wow Greg, that was a huge summary and how nice to link aging or
senescence with AGE or advanced glycation end products.
Seriously, that was new to me. Okay look, bring it home. What are
the clinical implications?


Dr Greg
Hundley:            
What these investigators have done is now identified a previously
unknown pathophysiological mechanism that may facilitate the
transition from healthy, towards failing cardiomyocytes and the
implication is that if you could disrupt that process, maybe you
could halt the aging of cardiomyocytes. You got to be careful
though I think with senescence, just as we know from the general
literature. Senescence is a defense mechanism in cancer therapy,
but it's a protagonist if you will, in aging. More to come in
this field, but very exciting research.


                                               
So Carolyn, tell me about your first paper.


Dr Carolyn
Lam:               
Happily, Greg. I'm going to take us to the cath lab and talk
about functional assessment of epicardial coronary artery
disease. This paper from Dr Koo and colleagues of Seoul National
University Hospital, is the first to validate the physiological
relevance and prognostic implication of all available novel
resting pressure derived indices of coronary stenosis. This
includes indices like resting full cycle ratio or RFR and
diastolic pressure ratio or DPR, and they compared this to
instantaneous wave free ratio or IFR and fractional flow ratio or
FFR.


                                               
What they looked at was more than a thousand vessels in 435
patients and showed that all the resting ... Just the resting.
Not hyperemic but resting pressure divide indices, closely
correlated with each other and showed excellent agreement and the
same discriminatory ability for no FFR. All the indices also
showed a similar pattern of changes to different anatomical and
hemodynamic stenosis severity, regardless of the target vessels
and importantly showed similar diagnostic performance for
myocardial ischemia, defined by gold standard PET derived CFR and
hyperemic myocardial blood flow.


                                               
And finally, they showed that all these indices showed
significant association with the two year vessel oriented
composite clinical outcomes.


Dr Greg
Hundley:            
So, do we still need to do adenosine infusions in the cath lab?


Dr Carolyn
Lam:               
That's exactly what they're trying to drive at, because the major
advantage of these resting indices, for example RFR over IFR, is
that IFR doesn't require identification of a specific landmark or
a specific time point during diastole. They may be simpler to
perform and this first study showing their physiologic relevance
and prognostic implication may enhance adoption of invasive
physiologic assessment in daily clinical practice, which we know
is important and a clinical benefit.


Dr Greg
Hundley:            
Excellent. I tell you, it would sure save time if we could use
indices like that.


                                               
Let me tell you about my next paper. This is from Renato Lopes,
from Duke University Medical Center, in Durham. Also, one of your
affiliates. In all of our cardiovascular/metabolic clinical
trials today, cardiovascular death is a very important outcome.
But what happens when, in doing a study like that and you have an
undetermined cause of death, the US Food & Drug
Administration Guidance indicates that deaths due to undetermined
causes should be rare in well-run clinical trials.


                                               
And so what this group did is they looked at 127,049 enrolled
participants from nine trials and they looked at how deaths were
adjudicated. And across nine clinical cardiovascular trials, in
different therapeutic areas, the proportions of deaths
adjudicated as related to undetermined cause ranged from 7-to-22%
and overall, had an average of 16%. Interestingly, in
multi-variable analysis, death due to undetermined cause, was
associated with the therapeutic area and the year of publication
of the study, and then also several patient factors including:
gender, age, the region of enrollment, and time from enrollment
to death.


Dr Carolyn
Lam:               
Gosh, this is so enlightening. Greg, having been on CECs and
struggle with the adjudication, I really like this paper as well.
But please, tell us all, why should we be concerned about this?


Dr Greg
Hundley:            
Great question, Carolyn. First we might think about, if you're
reading a study, the proportion of deaths due to undetermined
cause should really fall within this range. And have a mean of
maybe 16%. Second, what if there are higher rates due to
undetermined cause? Well, that may indicate there are issues with
the trial quality. And then finally, researchers, whenever
they're doing a study, should really report on the proportion of
deaths where cause was unable to be determined.


                                               
And there was a great editorialist, David Morrow, from Brigham
and Women's Hospital, and really pointed out, you've got a couple
factors here that lead to why there's undetermined cause of
death. Maybe the documents are missing, or you're in a clinical
situation where a subject lives alone, found dead, there's no
autopsy. Uncertain duration. Sometimes there are limits on the
study personnel; their ability to actually go out and acquire the
data so that the team, like what you're on, can actually
adjudicate the information. And a point that's made is really ...
He used the word, doggedness, but with which he consistently
worked toward and tried to get those medical records and pursue
them, because that is very important.


                                               
When we think, well what's the importance of a study like this?
It's valuable to those that perform studies, because as we're
working with our study coordinators, we need to make that
information known to them. If we don't collect the exact cause of
death in these important cardiovascular interventional studies,
we may end up with an improper result. And also, for the
investigative team. A really important study I think, providing
guidance for the first time now about what we should expect in
undetermined cause of death, when we're looking at cardiovascular
trials.


Dr Carolyn
Lam:               
Indeed, and from talking about doing the trials to talking about
a very important trial, I want to take you to The Partner 2
Trials and talk about the cost-effectiveness of Transcatheter
Aortic Valve Replacement, or TAVR, compared to surgical aortic
valve replacement, in patients at intermediate surgical risk.


                                               
Now we already know that TAVR is cost-effective, although not
cost-saving. But cost-effective compared to surgical aortic valve
replacement in those at high surgical risk. But this paper refers
to intermediate surgical risk. And the analysis is from Dr Cohen
and colleagues from Saint Luke's Mid-America Heart Institute, and
it's an analysis of the Partner 2A Randomized Trial and the
SAPIEN 3 Intermediate Risk Registry.


                                               
In summary, they found that TAVR was projected to lower total
costs by $8,000.00 to $10,000.00. And to increase quality
adjusted survival by 0.15 to 0.27 years, compared to surgical
aortic valve replacement over a lifetime horizon.


Dr Greg
Hundley:            
Wow! Carolyn, I've got two questions for you. First of all, how
does TAVR save those costs? And number two, was this true for
everyone? Were there any caveats or special subgroups that this
was really applied to?


Dr Carolyn
Lam:               
The cost savings in a TAVR cohort looked like they were driven by
both a shorter length of stay during the index hospitalization,
as well, as less resource utilization during follow-up. And that
would be in the form of fewer hospital days, as well as fewer
rehabilitation and skilled nursing facility days.


                                               
As for the caveats, you see that the authors did acknowledge that
the long-term durability of the valves involved like the SAPIEN
XT and the SAPIEN 3 valves is still unknown, and so lifetime
costs associated with TAVR, may be higher than we assumed, owing
to the need of more frequent repeat valve procedures for example.


                                               
Now if though, the long-term data demonstrate comparable late
mortality with TAVR, and the surgical aortic valve replacement,
these findings are really significant, because they suggest that
TAVR may become the preferred treatment strategy for patient
populations. Not only based on clinical outcomes, but even based
on economic considerations.


Dr Greg
Hundley:            
It looks like that long-term information is going to be really
critical here, so we'll look for more in this area.


Dr Carolyn
Lam:               
For sure. Wish we could keep chatting, but I think we need to
move to the featured discussion.


Dr Greg
Hundley:            
And now to the very fun segment of our discussion this week at
Circulation on the Run. This is Greg Hundley, from VCU Health.
Director of The Pauley Heart Center. And today we have a
fantastic paper from Adina Zeki Al Hazzouri from Miami,
transitioning to Columbia University. And also, our Associate
Editor, Dharam Kumbhani from the University of Texas,
Southwestern.


                                               
Today's paper, Adina is going to discuss is, Associations of
Income Volatility with Incident Cardiovascular Disease and
All-Cause Mortality in a US Cohort. And what she's done is worked
with the Coronary Artery Risk Development in Young Adult Study,
we also know that as, CARDIA. And it's really a prospective
cohort conducted in urban centers, in Birmingham, Alabama,
Chicago, Illinois, Minneapolis, Minnesota, and Oakland,
California. The goal here was to asses a block of individuals,
younger, aged 23-35 years, identified in the time window of
1990-to-2005 and then followed subsequently to look at income
volatility.


                                               
Adina, we're so excited to have you here. And can you tell us a
little bit more about your study.


Dr Adina Zeki Al Hazzouri: Sure, the motivation for the study is
the fact that we know that income volatility is on the rise. And
what I mean by, income volatility, is the sudden and
unpredictable change in income. And in the health researcher, we
actually do not know as much, what is the effect or the influence
of income volatility on health outcomes, and it is really common,
most of us do experience these sudden or unpredictable changes in
income. Whether they're little dips or little jumps in income. So
they are really common, and I think it's really important to try
to understand what would be their effect on health outcomes.


                                               
We were really interested in specifically understanding their
effect on all-cause mortality and incidents of cardiovascular
disease events, so we took advantage of an ongoing perspective
cohort study. The cardio study that you just mentioned. And what
is really nice about this study is they were really relatively
young back in 1990 when we first had the measure of income. They
were between ages 23-and-35. And they were followed for over
20-years, so we had repeatedly over 10-years, or 15-years,
repeated measures of income. And then we were able then to look
in the subsequent 10-years for incident events, cardiovascular
events and all-cause mortality, and what is also interesting in
this study is that these individuals, given that their age range,
so that they are in the peak of their working years, which makes
it even more interesting in terms of applicability and inference
of those findings that we're making in this study.


                                               
We looked at, as I said, income volatility and we defined it
basically as what is the standard deviation of these percent
changes in income that you experience between the different
visits in the study, which were on average, five years apart. And
once we defined that, then we looked at it with outcome and what
we really found was that those who experienced high volatility
had around a two-fold increased risk of cardiovascular disease,
as well as all-cause mortality.


                                               
We also looked at another measure of income volatility which is
the number of income drops, so how many times you've dropped
significantly, which we defined as a drop of more than 25%. And
that is lower than your average income throughout the study
period. And we found similar results.


Dr Greg
Hundley:            
Adina, what could be the cause of this? What do you think as an
investigative group, is the mechanism behind this finding?


Dr Adina Zeki Al Hazzouri: There could be various mechanisms
playing roles here. Stress is obviously one of the important
mechanisms. If you think about the instability of income, that
instability in income could result in daily stresses, maybe
inability to pay for bills. Also, that resulting in inflammation
in all the stress pathway.


                                               
Also, you could think potentially having this instability could
also maybe hinder access to care, maybe coping mechanisms related
to stress could alter adherence to treatment. Whether maybe
someone has to take daily medications, having those dips or
changes, sudden changes in income, could alter your adherence to
those medications and then subsequently influence your risk for
cardiovascular disease.


                                               
Also, you could think access to health insurance. The social
support, though it's not very well evidenced, but maybe if you've
had always stable income, or low income, you're more likely to
have more resilience. However, when you have these unpredictable
changes, or sudden changes in income, you may not have that
coping mechanism or support ready for you to deal with those
sudden changes.


                                               
These are some of the pathways that we think of that could
potentially be playing a key role here.


Dr Greg
Hundley:            
Very good. Now let's turn to Dharam, our Associate Editor, from
University Texas, Southwestern. Dharam, boy, surprising findings.
A young cohort. I mean, they were 23-to-35 and in the next
10-years of their life they start to experience hard
cardiovascular events. I mean, fatal and non-fatal myocardial
infarction, and also, all-cause mortality. How do you put this in
perspective, related to the workforce, and what do you think this
means for this young population moving forward?


Dr Dharam Kumbhani:   At the outset we obviously want
to congratulate Adina and her group, for this really, very
interesting study in cardiovascular EPY and broadly intersects in
health economics and health policy, as well for obvious reasons.


                                               
Very interesting construct as you pointed out and what does this
mean for younger subjects who experience these income volatility
very early in their life. I think, just like any other EPY study,
I think the perspective is helpful, because although the hazard
ratio for these income volatility is two or higher, the absolute
incidents rates are, again putting that in perspective is
important, and so the absolute incident rates for example is
somewhere between two-to-five, per 1,000 persons. So overall that
impact, that's just helpful to understand what effects this would
have.


                                               
Hopefully, that helps. But obviously, very interesting analysis
and brings up a lot of questions. I think one thing I may add to
what was just mentioned is ... And this was highlighted very
nicely by the editorialist, Dr Spatz, and her colleague from
Yale. About how this is globally in the financial toxicity space,
and there are a number of these indicators that are now being
carefully studied like in this study, such as wealth shock and as
I said, financial toxicity. And how they actually have an impact
on cardiovascular outcomes.


                                               
One of the feelings when you read a paper like this or when you
read studies like this, and in fact this was one of our initial
concerns as well, is to what extent you may have a component, or
significant component of reverse causality. Your, "Patients who
are sicker in some way," or have those culpabilities, be the ones
that have these events is their relationship with other
socio-economic indicators such as employment and how that would
affect income volatility as well.


                                               
I think the authors have done a really terrific job responding to
that. And again, it shows an association obviously we know that,
that doesn't imply that it's cause[owed], but it's a very
interesting association. And that it's helpful to speculate both
on the mechanisms, which were just outlined, and also what this
means from a health policy standpoint. What that would mean for
researchers in the cardiology community, or policy makers, things
like that. So I think this is a very nice analysis and definitely
brings up a lot of discussion points.


Dr Greg
Hundley:            
And a very important paper on multiple fronts. One, we've
identified an issue in young, healthy individuals that could
significantly contribute to adverse cardiovascular events. And
then number two, I really liked your point on how this could
impact public health policy, and maybe even how we need to think
about reducing stress and how we design aspects of the workforce
moving forward, so individuals don't suffer from these
conditions.


                                               
I want to thank, Adina Zeki Al Hazzouri, from Columbia. And our
Associate Editor, Dharam Kumbhani, for these excellent comments.
We look forward to seeing you next week.


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