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Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Sep 10, 2018

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.

 

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