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Circulation on the Run

Jun 15, 2020

Today’s episode discusses issues pertaining to the management of ST-elevation myocardial infarction in low and middle-income countries.

Dr Carolyn Lam and Dr Greg Hundley also discuss the following:

Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation by Sadek et al.
Autoantibody Signature in Cardiac Arrest by Li et al.
Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults by Kim et al.

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, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week is a little bit different from what we've done in the past with original manuscripts, we're going to focus on issues pertaining to the management of ST-elevation myocardial infarction in low- and middle-income countries. Oh my Carolyn, there's so many different things to consider. There are knowledge gaps, how we manage patients, how we get from one center to another, even just defining those centers. And this could be a very nice blueprint for future governments to use in managing these patients. But before we get to that feature, how about we have a little bit of a chat on some of the other articles in the issue?

Dr Carolyn Lam: You bet, Greg. Now, have you ever wondered why do some but not all patients with severe aortic stenosis develop otherwise unexplained reduced systolic function?

Dr Greg Hundley: Yes, I have Carolyn. And I wonder if it happens to do with one of our favorite magnetic resonance spectroscopy measurements, including creatine kinase.

Dr Carolyn Lam: You are just too smart, Greg Hundley!

Dr Greg Hundley: I had the opportunity to manage this one through the whole editorial board review.

Dr Carolyn Lam: Well, Dr Ryder and colleagues from University of Oxford hypothesized that reduce creatine kinase capacity and or flux would be associated with the transition to reduce systolic function in severe aortic stenosis. So they looked at 102 participants recruited into five groups. One, those with moderate stenosis. Two, severe aortic stenosis with ejection fraction above 55%. Three, severe aortic stenosis with ejection fraction less than 55%. Four, healthy volunteers with non-hypertrophied hearts with normal systolic function. And five, patients with non-hypertrophied, non-pressure loaded hearts with normal systolic function who are undergoing cardiac surgery and donating left ventricular biopsies.

Now, all these groups underwent CMR, cardiac magnetic resonance imaging, and 31 phosphorous magnetic resonance spectroscopy from myocardial energetics. And they also had left ventricular biopsies. So Greg, I know you know what they found, and so let me lunge right into it. They found that total creatine kinase capacity was reduced in severe aortic stenosis with median values lowest in those with systolic failure, consistent with reduced energy supply reserve.

Despite this, in vivo magnetic resonance spectroscopy measures of resting creatine kinase flux suggested that ATP delivery was reduced earlier at the moderate aortic stenosis stage, but where left ventricular functions still remain preserved. These findings thus suggest that significant energetic impairment is already established in moderate aortic stenosis and a fall in creatine kinase flux is not per se the cause of transition to systolic failure. However, as ATP demands increase with aortic stenosis severity, this could increase susceptibility to systolic failure. As such, targeting creatine kinase capacity and our flux may be a new therapeutic strategy to prevent or treat systolic failure in aortic stenosis.

Dr Greg Hundley: Very nice, Carolyn. That is a very challenging explanation. And boy, you walked us through it just perfectly. And I'm so glad you're here as an expert in heart failure and transplantation to get us through this next quiz. So Carolyn, can you name several of the primary causes of heart transplant related mortality?

Dr Carolyn Lam: All right. Rejection, infection, malignancy and allograph vasculopathy, of course.

Dr Greg Hundley: Thank you very much, Carolyn. What a wonderful job. So this paper comes from Dr Alexandra Loupy, and the study focused on the etiology of transplant related vasculopathy, the last one that you just named, from a population-based perspective. So 1,310 heart transplant recipients from four academic centers spread across Europe and the United States underwent prospective protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical histological and immunological parameters. The main outcome was prediction for cardiac allograph vasculopathy trajectory.

Dr Carolyn Lam: Interesting. So what did they find?

Dr Greg Hundley: So Carolyn, over a median follow-up post-transplant of about six and a half years, 4,710 coronary angiograms were analyzed, and four distinct profiles for allograph vasculopathy trajectories were observed. These four trajectories were characterized by one, patients without allograph vasculopathy at one year and non-progression over time. And that was about 56% of the patients. Second, patients without allograph vasculopathy at one year and late onset slow allograph vasculopathy progression. And that was about seven and a half percent of patients. Third, patients with mild allograph vasculopathy at one year and mild progression over time. And that was about 23% of patients. And finally, a fourth category, patients with mild allograph vasculopathy at one year and accelerated progression. And that was about 13% of patients.

Dr Carolyn Lam: Huh? So what most predictive?

Dr Greg Hundley: Well Carolyn, six early independent predictors of these trajectories were identified. One, donor age. Second, donor male gender. Third, if the donor used tobacco. Fourth, recipient dyslipidemia. Fifth, class two anti-HLA donor-specific antibodies. And finally, acute cellular rejection greater than 2R. The four allograft trajectories manifested consistently in the US independent cohort with similar discrimination, and in different clinical scenarios, and showed gradients for all caused mortality.

Dr Carolyn Lam: Wow. Okay. So what's the take home message, Greg?

Dr Greg Hundley: Well, because this study identified these four trajectories and their respective independent predictive variables, they provide the basis for a trajectory-base assessment of heart transplant patients for early risk stratification. And therefore, we might be able to develop monitoring strategies and form clinical trials around those to determine the efficacy of perhaps these predictive models.

Dr Carolyn Lam: Thanks. Okay. Well, this next paper focuses on Tet-methylcytosine dioxygenase 2, or TET2.

Dr Greg Hundley: Carolyn, what is that?

Dr Carolyn Lam: Well, I'm glad you asked me before I asked you. So TET2 is a key enzyme in DNA demethylation. And the gene TET2 encodes an epigenetic regulator that demethylates cytosine. Somatic mutations of TET2 occur in cardiovascular disease and are associated with clonal hematopoiesis inflammation and at first vascular remodeling.

The current paper by Dr Archer from Queens University Kingston in Ontario, Canada, and colleagues, is novel because it's the first to examine the role of TET2 in pulmonary arterial hypertension. And they did this by evaluating exome sequencing data from the largest PAH cohort assembled to date, including 2,572 patients in the PAH Biobank. Unlike prior genetic studies, the biobank includes patients with associated PAH. Now, this is important. This is the category that includes patients with connective tissue disease such as scleroderma. This biobank also included non-European ancestry. So these are the novel aspects.

The authors performed gene-specific rare variant association analyses using up to 1,832 cases of European origin from the PAH Biobank, and transcriptomic analysis in an independent cohort to assess TET2 expression.

Dr Greg Hundley: Carolyn, so what did they find regarding to TET2?

Dr Carolyn Lam: In the entire cohort, they identified 12 predicted deleterious variants of TET2 novel to PAH. 75% predicted germline and 25% predicted somatic variants. None of the variant carriers were responsive to acute vasodilator challenge. Now, this is the first time that putative germline TET2 mutations have been associated with a human disease. They also identify ubiquitous downregulation of the expression of TET2 in the peripheral blood mononuclear cells of idiopathic PAH and associated PAH patients.

Finally, they evaluated TET2 depleted mice and demonstrated that they spontaneously developed inflammation, pulmonary vascular obliteration and pulmonary hypertension, thus providing biological plausibility that disorders in this pathway can indeed cause PAH. This is discussed in an editorial by Dr Soubrier from INSERM, entitled, TET2: A Bridge Between DNA Methylation and Vascular Inflammation.

Dr Greg Hundley: Oh wow, Carolyn. Well, let me tell you about a couple other articles in our issue. First, Dr Amr Abbas has a letter to the editor regarding actuarial versus echocardiographic outcomes following TAVR, evaluating gradients, leaks, areas and mortality with responses by Flavin Vincent and from Laurent Fauchier. We have Dr Miguel A. Arias again presenting another EKG challenge for us. Next, professor Giovanni Esposito has a research letter involving PCI rates for ACS during this COVID-19 pandemic. Next, Dan Roden from Vanderbilt has a consensus report related to QTC prolongation during the coronavirus pandemic. And finally, professor Marco Roffi has an on my mind piece related to STEMI and COVID-19 pandemics.

Dr Carolyn Lam: Oh, there is a series of on my mind papers in this week's issue. “The Future of Cardiovascular Prevention: Unprecedented Times,” by Laurence Sperling. “Primary and Secondary Prevention Of Cardiovascular Disease in the Era of Coronavirus Pandemic,” by Erin Michos. “Reperfusion of STEMI in the COVID-19 Era: Is it Business as Usual?” by Dharam Kumbhani.

And finally, we also have a research letter by Dr Lili Jong, addressing immune checkpoint inhibitors which are increasingly applied to a broader range of cancers and their potential toxicity causing myocarditis. And this letter describes the association of timing and dose of cortical steroids in immune checkpoint inhibitor associated myocarditis and cardiac outcomes.

Dr Greg Hundley: How about we discuss how we might want to manage ST-elevation myocardial infarctions in low- and middle-income countries?

Dr Carolyn Lam: You bet. Let's go, Greg.

Dr Greg Hundley: Well listeners, now we get to turn to our feature article. And we're very privileged today to have Dr Chandrashekhar from The University of Minnesota. And he and a large group of authors have put together a paper discussing the resources and infrastructure really necessary to manage ST-elevation myocardial infarction in low- and middle-income countries. Welcome Chandra. So we're going to call him Chandra for short as he is known internationally. Chandra, can you tell us a little bit about this prevalence of STEMI in low- and middle-income countries, and then also about the constitution of your writing group and what you were trying to do to address this issue?

Dr Chandrashekhar: The issue we are trying to address is, as you know, the low- and middle-income countries, there are about 80 plus countries constituting this group, and they account for something like 5.8 billion people around the world. And it's so interesting that 80% of the MIs that happen on the face of this earth are probably happening there, in areas which don't have resources to effectively deal with this condition, unlike the US or European countries and developed countries.

So this group got together to create some outlines of how to optimize care in low- and middle-income countries. And we got together groups which have extensive experience in dealing with this problem. It was a coalition of frontline clinicians as well as major organizations, including the Indian Council of Medical Research, the premier research body in India, a public health foundation of India which is a nongovernmental organization extensively involved in this, The Population Health Research Institute in Canada, the Latin America Telemedicine Infarct Network called LATIN, The Pan African Society of Cardiology and The South African Society of Cardiac Interventions, and an NGO in India called STEMI India. So we took experienced people from a number of different countries and created this group.

Dr Greg Hundley: Very good. Now, were there knowledge gaps or implementation gaps, maybe help distinguish those two terms for us, that you had to address when just starting your effort?

Dr Chandrashekhar: Yeah, absolutely. So let's start with the knowledge gap. As you know, there are excellent guidelines both in the United States, as well as Europe. Of course, there are STEMI guidelines in the UK and Australia and New Zealand, but these guidelines are not very applicable to low and middle income countries due to a number of reasons, due to porosity of resources, due to poverty, overcrowding, lack of infrastructure, and a bunch of other reasons that you can imagine.

So if we recommend somebody needs total balloon time under certain threshold, it's nearly impossible to meet this in most places in the low- and middle-income countries. And so there is a significant amount of implementation gap as well as knowledge gap, because the guidelines that are tailored to Western societies don't fit very easily in low- and middle-income countries. It's like fitting a round peg in a square hole.

So that's why we thought we should create something very focused, right? And there are implementation gaps in the sense infrastructure-based as well as resource-based. And knowledge gaps, for example, we don't know what the dose of dual antiplatelet therapy is optimal in these patients, for example, ticagrelor may have a higher effect in some Asian populations with small body habitus.

Similarly, as you know, statin doses, especially in the far east are much lower than what are prescribed here. So these are the kinds of challenges that we are applying and try to suggest some solutions.

Dr Greg Hundley: It sounds like definitions could differ, management strategies could differ, pharmacologic versus invasive, even centers that would manage the patients. Can you describe some of those issues for us?

Dr Chandrashekhar: Right. So that was the biggest challenge we had. So we had to create some resource infrastructure appropriate management paradigms for low- and middle-income countries. To give you an example, primary PCI, which is something we take for granted within our milieu, if you think about it, you and I probably didn't give thrombolytic therapy in the last 15 years. So this is a day-to-day thing in low- and middle-income countries. Most of the patients either they come so late that they don't get any reperfusion therapy for STEMI, or if they do, thrombolytic therapy is are very common mode of treatment there.

And so we had to create a way for them to get the optimized care. And so we divided the localities into different levels, from level one to level five. Level one being the most remote area and five being the one which is most equipped and can implement all the Western standards and guidelines.

And so we suggest a system of hub and spoke to transfer people from the smaller centers to the big centers, and outline what therapies need to be done at what stage. And one of the things that we emphasize so much is called pharmaco-invasive therapy, where you give thrombolytic therapy if you cannot reach a PCI center in time, and then in the next three to 24 hours, you transport the patient to a center where they can do PCI. And this has been studied in a number of trials showing that it's a very effective strategy. And so these are the kinds of solutions that we try to emphasize.

Dr Greg Hundley: And how about the patients themselves and the doctors that would implement, in terms of education, does your document cover how to reach out to both patients and physicians in these countries to emphasize these new protocols that you and your group have developed?

Dr Chandrashekhar: Absolutely. That's the crucial issue, right? No matter how many guidelines we create, if we can't implement it, they're useless, right? And so we have two parts to this guideline. There's a section devoted to governmental agencies as well as NGOs interested in improving care, STEMI care in low and middle income countries, as well as a section for frontline clinicians, which includes very focused flashcards with definitions and what exactly each level of this center in the hub and spoke model should be doing and how do they transport patients and how do they ensure that adequate pharmacotherapy is instituted? And so we keep repeating this and we also provide some other options of how to communicate with the hub facilities, from the spoke facilities, including use of mobile and social media apps like WhatsApp.

Dr Greg Hundley: Do you have certain recommendations that physicians in the field and patients at home should be aware of, for example, administration of aspirin and things like that?

Dr Chandrashekhar: Absolutely. These are all codified in flashcards, which are going to be printed for distribution to the frontline physicians. And they are also created as wall posters and plastered in this peripheral health centers where essentially the only thing they may have is an old EKG machine and a few drugs like aspirin. And so we have tried to cater to each of this, both in the informational material and what basic pharmacotherapies and equipment these centers should be having. And that's where the governmental part comes. So when governments have to decide how they invest their scarce dollars, they can divide it appropriately based on these recommendations.

Dr Greg Hundley: I like that last statement, it sounds like in addition to physicians and patients that your document may even be useful for governments and organizations delivering the care in these countries, do you want to talk a little bit about where you think this document may go next in that regard?

Dr Chandrashekhar: The best use of this document would be for agencies in different parts of the countries to take this up. And at the last count, there are at least five or six governments which are actively looking at the blueprint that is provided from this document, and to see what parts of this are locally implementable within their environment. And eventually, if it appears that it's applicable to multiple jurisdictions, then perhaps something like WHO could take this and modify it suitably for different localities. We see a lot of potential in this.

Dr Greg Hundley: Well, we are very privileged to have the opportunity to publish this important work. And I wonder here, just in closing, on behalf of your entire author group, are there any words you'd like to leave us with regarding this just monumental effort?

Dr Chandrashekhar: The thing that we can say is we should thank Circulation and its editorial board for working with us. It went through, I think, three revisions and it really made the document much better. And we really thank all of you for allowing us this platform. As you know, this is going to reach a huge part of the medical establishment as an open access article. And hopefully it will help us implement some progressive changes in healthcare in the low- and middle-income countries. And so we really thank Circulation for providing us this platform.

Dr Greg Hundley: Well, listeners, we're going to wrap up here and we're most appreciative to Chandra from The University of Minnesota and his entire author group. On behalf of Carolyn and myself, we wish you a great week and look forward to chatting with you next week. This program is copyright to The American Heart Association, 2020.