Circulation May 22, 2018 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. Our featured discussion
today centers on the challenges of cardiovascular disease risk
evaluation in people living with HIV infection, an important
discussion coming right up after these summaries.


                                               
The first original paper this week provides experimental evidence
that nicotinamide riboside could be a useful metabolic therapy
for heart failure. First author Dr. Diguet, corresponding author
Dr. Mericskay, from University Paris-Sud investigated the
nicotinamide adenine dinucleotide or NAD homeostasis pathways in
the failing heart. They found that an expression shift occurs in
both murine and human failing hearts in which the nicotinamide
riboside kinase two enzyme, which uses the nucleoside
nicotinamide riboside was strongly up-regulated for NAD
synthesis.


                                               
Nicotinamide riboside supplemented diet administered to murine
models of dilated cardiomyopathy or pressure overloaded induced
heart failure restored the myocardial NAD levels and preserved
cardiac function. Nicotinamide riboside increased glycolysis as
well as citrate and Acetyl-CoA's metabolism in these
cardiomyocytes. Thus, nicotinamide riboside supplemented diet may
be helpful in patients suffering from heart failure and may help
them to cope with the limited myocardial ATP supply by restoring
NAD coenzyme levels and its associated signaling.


                                               
In the single ventricle reconstruction trial, one year
transplant-free survival was better for the Norwood procedure
with the right ventricle to pulmonary artery shunt compared with
the modified Blalock‒Taussig shunt in patients with hypoplastic
left heart and related syndromes. In the paper in this week's
journal, authors compare transplant-free survival and other
outcomes between these groups at six years. First and
corresponding author Dr. Newburger from Children's Hospital
Boston and her group showed that the right ventricular pulmonary
artery shunt group had similar transplant-free survival at six
years, but required more catheter interventions before the Fontan
procedure.


                                               
Right ventricular ejection fraction, New York Heart Association
class and complications did not differ by shunt time. Cumulative
incidences of morbidities by six years included 20% with a
thrombotic event, 15% with a seizure, and 7.5% with a stroke.
These data therefore emphasize the importance of continued
follow-up of the cohort, and the need to find new strategies to
improve the long-term outlook for those with single ventricle
anomalies.


                                               
The next paper presents results of the CREATIVE trial, which
stands for Clopidogrel Response Evaluation and Anti-Platelet
Intervention in High Thrombotic Risk PCI Patients). First and
corresponding author Dr. Tang from Fuwai Hospital National Center
for Cardiovascular Diseases, Chinese Academy of Medical Sciences
and Peking Union Medical College conducted a head-to-head
comparison of the safety and effectiveness of intensified
anti-platelet therapies either a double dose clopidogrel or
adjunctive cilostazol and conventional strategy in 1078 post-PCI
patients at high thrombotic risk as identified
thromboelastography, which is a platelet function test.


                                               
The primary outcome was the incidence of major adverse cardiac
and cerebral vascular events at 18 months post-PCI they find as a
composite of all cause death, myocardial infarction, target
vessel revascularization, or stroke. The authors found that the
primary end point occurred in 14.4% of those in the conventional
strategy. 10.6% in those given double dose clopidogrel alone. And
8.5% in those also given adjunctive cilostazol. Now, although
both intensified anti-platelet strategies achieved increased
platelet inhibition, only the triple strategy with adjunctive use
of cilostazol significantly reduced adverse events in the
long-term follow-up.


                                               
No increased rates of major bleeding was found with the
intensified anti-platelet therapy regimes. Thus, in patients with
low responsiveness to clopidogrel as measured by
thromboelastography, the intensified anti-platelet strategies
with adjunctive use of cilostazol significantly improved the
clinical outcomes without increasing the risk of major bleeding.


                                               
The final original paper sheds light on the prevalence and
predictors of cholesterol screening awareness and statin
treatment among American adults with familial
hypercholesterolemia or other forms of severe dyslipidemia. First
and corresponding author Dr. Bucholz from Boston's Children's
Hospital and their colleagues used data from the National Health
and Nutritional Examination Survey, and showed a high prevalence
of screening and awareness above 80%. However, there were
relatively low rates of statin use among individuals with
familial hypercholesterolemia at 52.3%.


                                               
And even lower rates among those with severe dyslipidemia at
37.6%. The discrepancy between the prevalence of cholesterol
screening and treatment was most pronounced in younger patients,
uninsured patients, and patients without a usual source of
healthcare. This study highlights an imperative to improve the
frequency of cholesterol screening and statin prescription rates
to better identify and treat this high risk population.
Additional studies are needed to better understand how to close
these gaps in screening and treatment.


                                               
And that brings us to the end of our summaries. Now for our
feature discussion. The natural history of infection with HIV has
completely changed with the use of potent antiretroviral
therapies. We now know that people living with HIV actually have
morbidity and mortality patterns that really resemble the general
population, especially with regards to cardiovascular disease,
which is very prominent in this population. And I suppose it's
this that has led to the assumption perhaps that risk prediction
tools and intervention strategies that we apply in the general
population may be used in patients living with HIV.


                                               
Is this the case however? Well, this week's feature discussion is
going to be so enlightening. And it's so important we are talking
across the world here, from South Africa to the United States,
and of course with me here in Singapore. I am so pleased to have
the authors of this week's feature paper and they are none other
than Dr. Virginia Triant from Massachusetts General Hospital, Dr.
Ralph D’Agostino from Boston University. And our associate
editor, Dr. Bongani Mayosi from University of Cape Town. Thank
you so much for joining me for today's exciting discussion.
Virginia, could I ask you to first describe your study?


Dr Virginia
Triant:            
As you mentioned in the introduction, we have found that patients
infected with HIV have an increased risk of cardiovascular
disease. That includes both myocardial infarction and stroke
compared to age-matched controls in the general population. And
extensive data has suggested that the etiology of this increased
risk is related both to traditional cardiovascular risk factors,
as well as novel risk factors that are specific to HIV infection.
And these include chronic inflammation in the immune activation.
So consequently, it remains relatively unknown whether
established cardiovascular risk prediction functions are accurate
for patients with HIV because they include only risk factors that
are traditional factors and they don't reflect the complete
mechanism that we know is at play in cardiovascular disease
associated with HIV.


                                               
So in our study, we assess the performance of three established
cardiovascular risk prediction functions, two Framingham
functions, and then the ACC/AHA pooled cohort's equations and we
applied this to a longitudinal HIV infected cohort that was
comprised of men. And we investigated the performance of the risk
scores in terms of comparing regression coefficients,
discrimination and calibration, which are standard metrics in
cardiovascular risk prediction. So I'll briefly summarize our
overall results as a start. We found that overall, the risk
prediction functions underestimated risk in our group of
HIV-infected men.


                                               
We found that discrimination was modest to poor, and this was
indicated by low c-statistics for all of the equations. And we
also found that the calibration or the agreement between observed
or predicted risk was also poor across the board for all three
risk prediction functions. So our results suggests that simply
taking the risk prediction functions and transporting them to an
HIV infected group may actually result in mis-classification in
terms of patient risk. And in underestimation of cardiovascular
risk.


Dr Carolyn
Lam:               
Well, Virginia, beautifully summarized of a beautiful paper. But
perhaps at this point, we should take a step back and ask
ourselves how exactly were these risk prediction scores
originally developed. And I can't imagine asking a better person
than Ralph. Ralph, could you take us on a jaunt along history and
tell us how were those Framingham risk scores developed in the
first place? Who are they supposed to be applied to? And did
these results surprise you?


Dr Ralph D’Agostino:      After the
second World War, what was becoming quite clear is things like
cardiovascular disease were becoming very prominent. Things like
infections and what have you, we were developing all sorts of
ways of handling them with medicines and so forth. But with
cardiovascular disease, it's a thing that progresses slowly over
the years and it starts wiping out people. And back in those
days, one out of three men between the ages of 30 and 60 had some
kind of cardiovascular event. Women weren't that bad off, but
they were pretty bad off also. And so what happened is the
American government and the American Heart Institute set up this
study in Framingham, where they took a third of the individuals
between the ages of 30 and 60 and actually followed them. They
took values of variables like blood pressure, cholesterol, things
they thought might be useful.


                                               
And took values on them. And they had to come back every two
years and after as time went on, they took the data after six
years, after 10 years they took the data, and started to look at
how each individual's blood pressure related to cardiovascular
disease. Does cholesterol, and the answer was yes. And then I
started getting involved and we were developing these
cardiovascular functions where you could actually take an
individual, take their measurements now, and make a prediction
that had a lot of validity, good discrimination, high
predictability over what was going to happen in ten incidents and
then the government, the US Government, started having guidelines
and what we did is we ran a study where we took a number of
different studies in the US, different cardiac studies, the ARIC
studies, number of 'em, and we thought applying our functions how
well would they do. And it turned out that for whites in the
country, the Framingham functions did very well.


                                               
But Japanese-Americans in the country, it over-predicted. Then we
found out that you could make a calibration adjustment and what
we've gone to, like in China, we have a big study where we had a
function and Framingham function it over-predicted but
calibration adjustment would make enough corrections and so now
with Jeanne and the HIV, our hope was that you could take these
functions and see how they work on the HIV population. When we
did it we were quite well aware, because people have been looking
at different things, there's something beyond the original
cardiovascular risk. And what the paper shows, quite nicely,
these cardiovascular risks do have some relationship but they
don't explain enough. The HIV population have a much bigger
burden and a simple calibration adjustment just isn't going to
work. We need new variables, we need new insights on what to add
to these functions.


Dr Carolyn
Lam:               
Thank you so much for that. That's just such important part of
history because I have to thank you for those equations. We apply
those definitely in our Asian cohorts with that calibration
factor. But I was just reflecting as you were telling that story
of how we've come full circle now to actually talk about an
infection again. It's the midst of an infection, like HIV
infection, that we're now testing these equations once again.
What better than to ask than Bongani, you're in the epicenter, if
I may, of HIV infection. What do you think of the applicability
of these findings to the patients you see?


Dr Bongani
Mayosi:         Yes.
These findings are clearly of great interest to us here in the
Sub-Saharan African region because it is really the epicenter HIV
pandemic. We found population, in terms of risk factors for
arteriosclerosis disease still remains low although there clearly
derives, for example, in the incidence of myocardial infarction
that's being detected in a number of the leading centers now. And
with HIV we have observed cases of myocardial infarction while
they tend to be younger men who almost always smoke and who get a
lot more of a thrombotic episodes.


                                               
When you catch them on a thrombotic load, you do not find
arteriosclerosis disease. It's going to be important, I think, as
we move forward to make sure that as we develop risk functions
that will predict cardiovascular disease in patient HIV that the
African epidemiological context is completed teaching that HIV
affects younger people, affects large numbers of women, but that,
quite clearly, is associated with decreased cardiovascular event
and stroke and stroke is well demonstrated. But in terms of
actually looking at the risk factor this population was still in
the early day and certainly in future studies would have to have
a major contribution of the African cohort.


Dr Carolyn
Lam:               
That's true, Bongani, but may I ask how would you, perhaps,
advise your African colleagues now to look at these data? Then
I'd also like to turn that same question over to you, Virginia.
What do we do? What's the clinical take home message of these
findings?


Dr Bongani
Mayosi:         I think
the message is true that HIV infection is associated with the
increased risk of cardiovascular event, there's no doubt about
that. That there are some risk factors that can carry through,
such as the smoking population but it's important for all
clinicians to be aware of that. The ordinary risk you find in
using Framingham and other established risk functions is not
going to give us all the information that we need. So that
recommendation should come through we need to know that risk
factors are unknown, that they're important and we need to learn
more about these patients in order to give us a perfect
prediction of what will happen in the future.


Dr Virginia
Triant:            
I think the findings have a lot of clinical relevance. This
suggests, I think, that there are a lot of clinical implications
for any patient who has novel cardiovascular risk factors that
may not be accounted for in heart functions. And what our
findings suggest is that if functions don't reflect the actual
composition of risk factors in the population, that can result in
misclassification and thus we underestimate risk, we might miss
high-risk individuals, high-risk patients who would benefit from
aggressive risk reduction but are not currently receiving it.
This is a real clinical challenge as sit in clinic and we pull up
the scores and calculate them for our patients, whether that is a
trustworthy number or whether we should, perhaps, thinking that
it's higher, thinking that it's different than what we're seeing
for predicted 10-year risk. I think what this suggests is that
the functions may need to be further tailored to different
populations and sub-populations to reflect the actual composition
of risk factors in that population. Even within HIV patients and
populations, the risk factors in South Africa might be different
than those in Boston, with different relative contributions.


                                               
One of the next stepped planned for our team is to actually look
at developing, new risk functions which are tailored to HIV and
incorporating both HIV itself as a risk factor, as well as HIV
specific variables and to attempt to see if we can improve the
performance of these functions for HIV populations. Perhaps HIV
or HIV related factors might become sort of a new cardiovascular
risk equivalent and we can serve patients in this population as
higher cardiovascular risk baseline. I also just wanted to
mention, briefly, that I think that there are important clinical
implications beyond HIV that extend to other chronic inflammatory
conditions. Inflammation is increasingly recognized as important
in cardiovascular risk and this way HIV can serve as a prototype
population. But these results are likely to extend to a lot of
different populations who have chronic inflammation for different
reasons.


Dr Carolyn
Lam:               
That's a great point, Virginia. As I'm listening, I'm wondering
is there no end to this because now we say HIV and then we put
other inflammatory diseases, then we say, "Well, women may be
different from men," and then different ethnicities may be
different. I think gonna be going closer and closer to precision
risk prediction, if I might say. Could I just pick your brain
here? What do you think the future is? Where's the room for
machine learning approaches for risk prediction, individual
almost down to that level? What do you think?


Dr Ralph D’Agostino:      I think you're
right on target. In some sense, the functions we have there's a
sort of massiveness about it, when you come to view this
population, back in the 50s and 60s and so forth, cardiovascular
disease was such a major ... it still is a major problem ... such
a major problem you identify some of the real items like the
blood pressure and cholesterol, and you attack and develop
functions on that and you'd find that you're affecting positively
a huge number of individuals, but now as, like Jeanne was saying,
and others have been saying, you start focusing, you've got this
massive group of individuals who should have their blood pressure
controlled and what have you, but if you go into HIV, you go into
a number of other populations and so forth, there are other
things that are driving these disease and driving the
manifestations of the disease. It isn't that blood pressure isn't
important, it's that there's other things that are important. And
so it's machine learning and so forth and deep learning that
you're gonna have to be dealing with manifestations on very high
levels and maybe even get into genetics.


                                               
Look in the cancer field ... I do a lot of work with the FDA ...
look at the cancer field now; how it's so genetically driven in
terms of a lot of the drugs the so-called biomarkers, which are
basically driven by uniqueness in populations. I think that's
definitely going to be, or is the future of these cardiovascular
functions.


Dr Carolyn
Lam:               
Okay audience. You heard it, right here. These are exciting
times. In the meantime, thank you so much for this precious,
valuable piece of work. Virginia, Bongani, Ralph, it was great
having you on the show.