Circulation September 11, 2018 Issue

Dr Carolyn
Lam:               
We start today's podcast with a few words from our
Editor-in-Chief, Dr Joe Hill.


Dr Joe
Hill:                          
I speak with you today with a heavy heart as we recently lost an
esteemed and beloved colleague, Professor Bongani Mayosi. Bongani
was a pioneering leader, a renowned investigator, Dean of the
Medical School at the University of Cape Town, and an important
member of our Circulation editorial leadership team.


                                               
Bongani had an abiding passion for the under-served, especially
those in his native Africa. He died tragically and suddenly at
the early age of 51, just 10 days after recording the podcast
you're about to hear.


                                               
We mourn the loss of this colleague and our hearts go out to his
family. It is a very poignant moment, as we hear his voice once
again. We grieve deeply, and are reminded of Bongani's towering
achievements and contributions to the betterment of our world.


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.


                                               
CD4-positive T cells play an important role in atherosclerosis,
but their antigen specificity is poorly understood. Today's paper
describes the first study to detect apolipoprotein B peptide 18
specific CD4 T cells in mice and humans. First author Dr Kimura,
corresponding author Dr Ley from La Jolla Institute of Allergy
and Immunology and their colleagues constructed novel P18
tetramers to detect human and mouse APOB-specific T cells and
assayed their phenotypes by flow cytometry. They found that these
P18 specific T cells were mainly anti-inflammatory regulatory T
cells in healthy donors, but co-expressed other CD4 lineage
transcription factors in patients with sub-clinical
cardiovascular disease.


                                               
Immunization with P18 reduced atherosclerotic burden in APOE
deficient mice and induced antigen specific T regulatory cells.
This study therefore, identifies APOB peptide 18 as the first T
regulatory APOtope in human atherosclerosis.


                                               
The next study suggests that testing intracellular calcium
handling in circulating B lymphocytes may be a novel biomarker
for monitoring patients with heart failure. During [inaudible
00:02:47] intracellular calcium is released from sarcoplasmic
reticulum into the cytoplasm through Type II ryanodine receptor
calcium release channels. In heart failure chronically elevated,
circulating catecholamine levels cause pathologic remodeling of
these Type II receptors, resulting in diastolic sarcoplasmic
reticulum calcium leak, thus decreasing myocardial contract
[inaudible 00:03:09]. Similarly, skeletal muscle contraction
requires sarcoplasmic reticulum calcium release and this occurs
through Type I ryanodine receptors. Chronically elevated
catecholamine levels in heart failure cause Type I mediated
sarcoplasmic reticulum calcium leak, thus contributing to
skeletal myopathy and weakness.


                                               
In today's paper, first author Dr Kushner. Co-corresponding
authors Dr Kitsis from Albert Einstein College of Medicine and Dr
Marx from Columbia University, New York hypothesized, that since
circulating B lymphocytes express Type I ryanodine receptors,
they may be a potential surrogate for defects in intracellular
calcium handling due to leaky ryanodine channels in heart
failure. Indeed, they found that circulating B lymphocytes from
humans and mice with heart failure exhibited remodeled Type I
ryanodine receptors and decreased endoplasmic reticulum calcium
stores, consistent with chronic intracellular calcium leak. This
calcium leak correlated with circulating catecholamine levels.
The intracellular calcium leak was significantly reduced in mice
treated with S107, which is a drug that specifically reduces
ryanodine receptor calcium leak.


                                               
Furthermore, heart failure patients treated with LVADs exhibited
a heterogenous response. Thus, Type I ryanodine receptor mediated
calcium leak in B lymphocytes assessed using flow cytometry may
provide a surrogate measure of intracellular calcium handling and
systemic sympathetic burden and therefore represent a novel
biomarker strategy for monitoring the responses in heart failure
therapy.


                                               
Hypouricemia and gout are known to be associated with increased
risk of cardiovascular disease. And xanthine oxidize inhibitors
such as allopurinol and febuxostat are the mainstay of urate
lowering treatment of gout, but do they have different effects on
cardiovascular risk? First author, Dr Jong, corresponding author,
Dr Min from Brigham and Women's Hospital Harvard Medical School
in Boston, Massachusetts, studied a cohort of almost 100,000
older Medicare patients with gout and found that there was,
overall, no difference in the risk of MI, stroke, new onset heart
failure, coronary revascularization are all cause mortality
between patients initiating febuxostat compared to those
initiating allopurinol. However, there did seem to be a trend
toward an increased opiate not statistically significant risk for
all-cause mortality in patients who use febuxostat for over three
years compared to allopurinol use for over three years. The risk
of heart failure exasperation was slightly lower in febuxostat
initiators.


                                               
The final original paper this week provides important
contemporary data on the clinical characteristics in hospital
management and long-term outcomes of patients with acute
myocarditis. Co-corresponding authors, Dr Ammirati and Kamichi,
both from Milan, Italy and their colleagues screened 684 patients
with suspected acute myocarditis and recent onset of symptoms
within 30 days between May 2001 and February 2017 and included
443 patients with acute myocarditis diagnosed either by
endomyocardial biopsy or by increased troponin and edema and late
gadolinium enhancement on cardiac magnetic resonance imaging.
They showed that among these 443 patients, 118 patients or 26.6%
had either left ventricular ejection fraction less than 50%
sustained ventricular arrhythmias or a low cardiac output
syndrome. While, the 73.4% had no such complications.


                                               
Cardiac mortality and heart transplantation at five years was
4.1%, but went up to 14.7% in the patients with complicated
presentation and contrast down to zero percent in the
uncomplicated cases. Similarly, major acute myocarditis related
cardiac events after the acute phase, such as post discharge
death and transplantation, sustained ventricular arrhythmias,
symptomatic heart failure needing device implantation all
occurred in 2.8% at five years, but was much higher in patients
with a complicated presentations at 10.8% versus zero percent in
the uncomplicated presentations. Thus, the authors concluded that
patients with acute myocarditis can be effectively stratified
based on their initial clinical presentation. Patients with left
ventricular ejection fraction less than 50% at the first echo.
Those with sustained ventricular arrhythmias or those with low
cardiac output syndrome are at higher risk of cardiac events
compared to those without these manifestations.


                                               
And that brings us to the end of our summaries. Now, for our
feature discussion.


                                               
With advances in therapy most deaths in people with HIV are now
due to noncommunicable diseases, especially cardiovascular
disease. What does the global burden of HIV associated
cardiovascular disease really look like? Well we're going to get
some answers in today's feature paper. I have with us today the
first and corresponding author of the paper, Dr Anubshaw from
University of Edinburgh, as well as our associate editor, Dr
Bongani Mayosi from University of Cape Town in South Africa.


Dr Carolyn
Lam:               
Welcome to you both. And Anub, what an important question to
examine. Could you tell us how you looked into this question and
what you found?


Dr
Anubshaw:                  
Sure. So, this is a very interesting question from our end and we
had in short idea looking at the risk of cardiovascular disease
in patients with HIV. And there are many studies of it, varying
results. I'm looking at the risk of heart disease and stroke in
patients with HIV. So, what we did was a big systematic review to
extract all the data out there looking at the risk of heart
disease in patients with HIV, we then developed a model that
looked at what the overall risk was and then tried to calculate
the actual burden of cardiovascular disease attributable to
patients with HIV. In some of the work we found, well, primarily
we found that the majority of the burden, as expected in
Sub-Saharan Africa and that is primarily the cause, in prevalence
of HIV is the highest in Sub-Saharan Africa, accounting for about
two thirds of all people living with HIV.


Dr
Anubshaw:                  
The risk of cardiovascular disease with patients with HIV is
twofold higher compared to patients not infected by virus. And
there was not [inaudible 00:10:12] variations in the actual
burden. The majority of the burden in Sub-Saharan Africa and
Southeast Asia.


Dr Carolyn
Lam:               
Wow, Sub-Saharan Africa and Asia Pacific, isn't it? Oh my
goodness, Bongani, your views please on these standing results
from Africa.


Dr Bongani
Mayosi:         Yes. I
think these results are actually very important in the
Sub-Saharan African region, reaching the, at the center of the
HIV/AIDs epidemic in the world. And particularly important now
that we are finding people and are on treatment and that they are
growing older and there's a thriving proportion of people above
the age of 60, they are on HIV infection and therefore the whole
question of cardiovascular disease in these patients has become
very important and clearly now these data suggest that HIV
[inaudible 00:11:08] for cardiovascular disease, but what is more
important [inaudible 00:11:14] they are important [inaudible
00:11:17] for cardiovascular disease, but also a [inaudible
00:11:22]. [inaudible 00:11:23] such as another vascular
condition, which is pulmonary hypertension associated with HIV
detection. [inaudible 00:11:35] with the increase of the number
of people on treatment, these particular conditions are becoming
[inaudible 00:11:43] in the context of how to [inaudible
00:11:48], but is an important condition in the African
continent. So that the overall burden of cardiovascular disease
is likely to be greater than is estimated here because the study
is only estimating atherosclerotic cardiovascular disease.


Dr
Anubshaw:                  
That brings up a very intriguing question, Anub. Could you at all
distinguish between atherosclerotic risk factors and the role
that played versus more HIV specific risk factors, such as the
medication, the degree of HIV control, level of inflammation, for
example? Now, of course in a meta-analysis this may be difficult,
but just your thought.


                                               
You're absolutely right from a meta-analysis point of view it's
very difficult for a couple of reasons. Firstly, we do not have
individual patient level data, so we couldn't really see a
[inaudible 00:12:45] level which patients are on [inaudible
00:12:47] therapy and what their personalized risk factors are.
Varying schools of thought estimated around the candidates that
they need, which kind of portrays a risk of heart disease in the
[inaudible 00:12:59] artery in patients with HIV. And what we
think may be happening there, one that HIV represents a degree of
sub-clinical inflammation that leads to vascular inflammation,
which then leads to accelerated atherosclerosis and there's some
fantastic mechanistic evidence looking at this where, workers
have looked at vascular inflammation in the arteries in patient
HIV can go through control and you do get much more vascular
inflammation. There is some evidence about the fact that the
[inaudible 00:13:31] therapy itself can cause [inaudible
00:13:34] and therefore increase the risk of atherosclerotic
heart disease.


                                               
And finally, some risky behavior is probably much more, have a
look at HIV for example, smoking entered the [inaudible 00:13:46]
etc., etc. and there may be a degree of overlap in terms of or
correlation in terms of risk factors being much more common in
HIV patients, which are more conditional for atherosclerotic
heart disease. I think a combination of all those three things
probably explain the increase risk of atherosclerotic heart
disease and strokes in these patients.


Dr Carolyn
Lam:               
Indeed. Your paper is so important to raise awareness of that
very risk. I mean, if I could please re-iterate, you show very
clearly that people with HIV are the two fold increase risks of
cardiovascular disease and that that global burden had tripled
over the last two decades. I think that your paper really shines
a bright light in this area, that we have to study further
because the clinical implications are enormous aren't they?
Because we're using guidelines developed in non-HIV patients to
perhaps treat these cardiovascular diseases in HIV patients and
there may be other pathophysiologic mechanisms like you just
mentioned. What do you think are the main clinical implications
of your paper?


Dr
Anubshaw:                  
The clinical implication is quite important because what the
burden estimate show is that the majority of burden is in no or
little information and therefore the resource of those
innovations are quite limited, but there's one condition that has
been treated so well in these countries. One of the main success
stories of medicine, over the last two or three decades and how
they've tackled HIV, who runs PEP for has made intrical virals
available so widely in the Sub-Saharan African regions, while
there's other highly prevalent regions. And they set up
logistically clinics to deliver and scare for persons with HIV
and if you and I will see that the survival in these patients
[inaudible 00:15:39] just mentioned. Then, these patients are at
more high risk of other among AIDs related conditions, such as
strokes and heart disease. What you now have in these poor
resource countries or limited resource countries, where clinics
and the logistical support is only set up to deliver
cardiovascular risk prevention strategies and therapy. Which is
not expensive in terms of antihypertensives, in terms of
[inaudible 00:16:06] and in terms of lifestyle factors.


                                               
So, I think there is [inaudible 00:16:10] here that the region
has to further reduce the cardiovascular burden in this
population.


Dr Carolyn
Lam:               
Bongani, you too recognize the very important clinical
implications and in fact invited the editorial by Priscilla Sue
and David Waters from San Francisco General Hospital. I love the
title of it. Is it time to recognize HIV as a major
cardiovascular risk factor? Bongani, what are your thoughts?


Dr Bongani
Mayosi:         I think
it is time we should be considering the HIV as a risk factor for
cardiovascular disease. You know these data arriving from this
[inaudible 00:16:48] are quite compelling and when you look, for
example at that this is a hot study [inaudible 00:16:55] in the
editorial and conferred by HIV, it is almost the same as the
other [inaudible 00:17:02]. I mean if you go into it now that in
fact the European Society of Cardiology it is already [inaudible
00:17:12] in HIV infected individuals with [inaudible 00:17:19].
So, if now may be entering their [inaudible 00:17:27] of
practice, they consider HIV as a significant risk factor for
cardiovascular disease and maybe contribute to bring a drug that
will modify outcome. I do think though that because of the
mechanism of cardiovascular disease it [inaudible 00:17:45] HIV
it is not common on the basis of atherosclerotic disease. In
Africa as an example, we know very well that the patient tend to
[inaudible 00:17:55] with not a lot of traditional risk factors
of cardiovascular disease, in fact, atherosclerotic diseases such
as [inaudible 00:18:07] still have a relatively low level of
[inaudible 00:18:10].


                                               
So, we still, I think need to discover what are the other
[inaudible 00:18:14] mechanisms that are involved, I mean they do
that very much more targeted drug [inaudible 00:18:21] where it
needs to be tested, that don't know our traditional interventions
for reducing risk and preventing cardiovascular disease. So,
there is need for further research here and the mechanisms and
specific intervention. That is the important in this large HIV
infected populations because at the moment there at least 27
million people in the world, living with HIV who already facing a
major public health issue on a global scale.


Dr Carolyn
Lam:               
Exactly and all these new research efforts, paying attention to
this, making sure that we don't underestimate cardiovascular risk
and HIV based on traditional risk calculators. All of this starts
with awareness and with important papers such as yours, Anub.
Thank you so much for publishing that with us at Circulation.


                                               
Well, listeners you know how important this is globally, so
please share this podcast with your colleagues and don't forget
to tune in next week.