Mar 8, 2021
This week features two Feature Discussions. In our first feature discussion, Nikkil Sudharsanan and Associate Editor Ntobeko Ntusi as they discuss the article "Variation in the Proportion of Adults in Need of BP-Lowering Medications by Hypertension Care Guideline in Low- and Middle-Income Countries: A Cross-Sectional Study of 1,037,215 Individuals from 50 Nationally Representative Surveys." Then in our second feature discussion, join author Aloke Finn and Associate Editor Jeffrey Saffitz as they discuss the article "Microthrombi As A Major Cause of Cardiac Injury in COVID-19: A Pathologic Study."
One addendum to the Feature Discussion with Drs. Sudharsanan and Ntusi:
· Dr. Sudharsanan wanted to clarify that treatment needs were determined for each country based on multiple blood pressure measurements taken on the day of the survey; however, all the estimates were based on BP measured on just one day, rather than over several weeks as is done in clinical practice. This is related the final question posed in the first Feature Discussion.
TRANSCRIPT BELOW
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Greg Hundley Associate Editor for the Pauley Heart Center in Richmond, Virginia at VCU Health.
Dr. Carolyn Lam:
Guess what, Greg, it's another issue with a double feature. We are going to be discussing microthrombi as a major cause of cardiac injury in COVID-19.
Dr. Greg Hundley:
Yes, Carolyn and our second discussion will be centered on blood pressure lowering in low and middle-income countries. But how about you and I both grab a cup of coffee and jump into the other articles in this issue.
Dr. Carolyn Lam:
Sure thing. I got my coffee and let's start with gestational diabetes. Now, we know that leads to an earlier onset and heightened risk of type 2 diabetes, which is a strong risk factor for cardiovascular disease. But Greg, do you think that attaining normal glycemia following gestational diabetes can ameliorate the access risk?
Dr. Greg Hundley:
Carolyn, that's a really great question. I would think so but how about you tell me what these authors found.
Dr. Carolyn Lam:
Yep. This next paper it's from Dr. Gunderson from Kaiser Permanente, North California and colleagues. They exactly sought to answer the question and realize that it was unclear whether attaining normal glycemia can ameliorate the excess cardiovascular disease risk that's associated with gestational diabetes. So they evaluated gestational diabetes history and glucose tolerance after pregnancy and found out whether or not it was associated with coronary artery calcification in women. The obtained data from the CARDIA study which is a US multicenter community-based perspective cord of young black and white adults age 18 to 30 years at baseline.
Dr. Carolyn Lam:
This is what they found. Women without previous gestational diabetes showed a greater increase in the risk of coronary artery calcification associated with worsening glucose tolerance. However, women with a history of gestational diabetes had a twofold higher risk of coronary artery calcification across all subsequent levels of glucose tolerance. Midlife atherosclerotic cardiovascular disease risk among women with previous gestational diabetes is therefore not diminished by attaining normal glycemia. And this is discussed in an accompanying editorial by Dr. Jennifer Green from DCRI entitled Cardiovascular Consequences of Gestational Diabetes.
Dr. Greg Hundley:
Carolyn, well, sounds like I was wrong but our next paper, it's going to review for us a little bit about IgE. Remember that immunoglobulin associated with itching. So Carolyn immunoglobulin E or IgE belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor in pathological cardiac remodeling and heart failure or a non. So in this study, the investigative team measured serum IgE levels and cardiac IgE receptor expression in diseased hearts from humans and mice.
Dr. Carolyn Lam:
Oh, Greg, I'm itching to find out what this study showed.
Dr. Greg Hundley:
Yes, Carolyn, going from the quizmaster now to is it comedy now? Serum IgE levels were significantly elevated in patients with heart failure as well as in two mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin two infusion. Now, interestingly Carolyn, IgE receptor expression levels were also significantly up-regulated and failing hearts from human and the mouse model.
Dr. Greg Hundley:
Carolyn, the authors found that IgE induction plays a causative role in pathological cardiac remodeling at least partially via the activation of IgE receptor signaling in cardiac myocytes and cardiac fibroblasts. So future studies are needed to determine if therapeutic strategies targeting the IgE receptor axis and as to whether they may be effective for managing IgE mediated cardiac remodeling.
Dr. Carolyn Lam:
Fascinating. I never thought of IgE involved in cardiac remodeling. Now, this next paper really interesting. Regulators are always evaluating the use of non-interventional real-world evidence studies to assess the effectiveness of medical products. The RCT DUPLICATE Initiative was formed to use a structured process to design real-world evidence studies to emulate randomized control trials and compare results. Now, this paper represents the first 10 trials emulations in RCT DUPLICATE, and it's from Dr. Jessica Franklin from Brigham and Women's Hospital and Harvard Medical School in Boston and her colleagues. And they did this to evaluate cardiovascular outcomes of antidiabetic and antiplatelet medications.
Dr. Greg Hundley:
Wow, Carolyn. So how does they do this?
Dr. Carolyn Lam:
So they use patient level claims data from US Commercial and Medicare-PEERS and implemented inclusion exclusion criteria of the trial selected primary endpoints and compare the populations to emulate those of each of the corresponding randomized controlled trials within the trial mimicking populations, they then conducted propensity score matching to control for more than 120 pre-exposure con founders.
Dr. Greg Hundley:
So Carolyn, were they able to emulate their randomized clinical trial results?
Dr. Carolyn Lam:
Now, despite the attempts to emulate the trial design as close as possible, there were still differences between the randomized control trial and the corresponding real-world evidence study population. The regulatory conclusions were equivalent in six of 10 studies. The real-world evidence emulations achieved a hazards ratio estimate that was within the 95% confidence interval from the corresponding trial in 8 of 10 studies. Agreement between the trial and real-world evidence findings varied depending on which agreement metric was used.
Dr. Carolyn Lam:
Interim findings indicated that selection of active comparative therapies with similar indications and use patterns enhance the validity of the real-world evidence. And so, even in the context of active comparators concordance between trial and real-world evidence findings was not guaranteed partially because trials were not emulated exactly. More trial emulations are needed to understand how often and in what context real-world evidence findings will match the trials. And yet these initial findings of RCT DUPLICATE really indicate circumstances when real-world evidence may offer causal insights where trial data is either not available or cannot be quickly or feasibly generated
Dr. Greg Hundley:
Well, Carolyn, that is really interesting findings there because we're all trying to decide what to do with these large data sets and combining the results of millions and millions of data points and very interesting findings in this study. How about we see what else is in the issue?
Dr. Carolyn Lam:
Absolutely. Well, let me start. There's an exchange of letters among doctors Villarreal, Cárdenas Suri, [and] Navarro-Castellanos regarding the Multi-system inflammatory syndrome in children. The ECMO needs and Kawasaki disease likeness. There's also an ECG challenge by Dr. Pillai entitled "A Tale of Two Blocks".
Dr. Greg Hundley:
Well, Carolyn, I've got a very nice In-Depth review from Dr. Van Belle regarding transcatheter aortic valve replacement in bicuspid aortic valve stenosis. And there's a Research Letter from Dr. Lew entitled “Short-Chain Enoyl-CoA Hydratase Mediates Histone Crotonylation and Contributes to Cardiac Homeostasis.” And then finally, Dr. Nordin Hanson from Amsterdam has a very nice piece on the Clinical Implications of Basic Science Research entitled “DAMPening Mortality in COVID19: Therapeutic Insights from Basic Cardiometabolic Studies on S100A8/A9.” Well, Carolyn, how about we check out the double feature.
Dr. Carolyn Lam:
Definitely let's go, Greg.
Dr. Greg Hundley:
Well listeners, we are here for our first feature discussion on this March 9th issue and we have with us Nikkil Sudharsanan from Heidelberg and also our own Associate Editor Ntobeko Ntusi from Cape Town. Welcome gentlemen. Nikkil, could you please describe for us the hypothesis that you wanted to test your study population and your study design?
Dr. Nikkil Sudharsanan:
Yeah, so for our hypothesis, we really wanted to know, depending on which hypertension treatment guideline you chose, what implications does it have at the population level for the number of people in low and middle-income countries that would require treatment or that you would want to place on treatment. And we were really looking at not just one country, but a whole range of 50 low and middle-income countries. And so our study population is actually from this pretty remarkable data source that combines the World Health Organization surveillance data for many countries with other sources of data, to try to create a comparable almost low and middle-income country super dataset that's specifically designed to answer questions around cardiovascular disease. So our study population was really based on population representative samples for each of the 50 countries we considered. And in most of the countries we focused on the adult population. So those ages 30 and above.
Dr. Greg Hundley:
And your total sample was over a million participants, correct?
Dr. Nikkil Sudharsanan:
Yeah, it's a really huge sample. And I think it's a testing to some of these data sources, especially the ones in India and Brazil, but collected just really large sample sizes that contributed to this huge global population.
Dr. Greg Hundley:
Very nice Nikkil. And what did you find?
Dr. Nikkil Sudharsanan:
So the big finding is we actually went into it not knowing how the choice or how strong the choice of a blood pressure treatment guideline would be on the number of people that required treatment and were really surprised to see that we took more treatment guidelines, the 2018 American College of Cardiology, American Heart Association guidelines, the kind of typical 140 by 90 blood systolic diastolic blood pressure threshold that you see as part of a lot of guidelines. The UKs NICE guideline and then the WHO Hearts guideline, which is based on their pen and package of essential non-communicable disease interventions.
Dr. Nikkil Sudharsanan:
And we started a really, really pronounced difference in the proportion and size of the adult population that you would recommend or place under hypertension treatment, depending on which of these guidelines used to decide who gets treatment across these countries. So at the top, we found the American College of Cardiology, American Heart Association guidelines, and for the countries we were considering it put about 27% of women and a really high 35% of men as recommended for blood pressure treatment.
Dr. Nikkil Sudharsanan:
And then very closely followed to that was the 140, 90 threshold. So it was still high, but not as high, I would think it was around 26% of women and 31%. And then between these two guidelines and the UK NICE and WHO Hearts, there was a really big drop-off in how many people would actually be recommended for blood pressure treatment.
Dr. Nikkil Sudharsanan:
The NICE guideline, for example, only have 12% of women and about 16% of men and the WHO Hearts is by far the lowest, which only about 10% of women and 11% of men. So I think our first really striking finding was that this choice is not trivial. And depending on which guideline you actually choose to decide who gets treatment in that country, it has really big implications for how many people in that country are going to need treatment.
Dr. Greg Hundley:
Very good. And Ntobeko, how do you put the results of this study in the context with other research perform to study hypertension?
Dr. Ntobeko Ntusi:
Thank you, Greg. So we know that although more than 80% of the global battle of Cardiovascular Disease, okay. As in low and middle-income countries, the data around respecters for cardiovascular disease has largely come from high-income countries. And the INTERHEART study was really the first publication about 15 years ago to try and address this question. And it was very apparent both in the INTERHEART study as well as the INTERHEART Africa study of hypertension was one of the key respecters not only for my myocardial infraction, but for cardiovascular disease in general.
Dr. Ntobeko Ntusi:
In the INTERHEART study hypertension having a hazard ratio of two and the population attributable risk of 17%. And then the INTERHEART Africa study having a hazard ratio of over six. And this paper is really an important application in my view, showing that in a comparison of over a million individuals from 50 countries, there is great variation in the proportion of individuals that need to be treated for hypertension, based on the choice of guideline and definition of hypertension. And if you look at figure one, this is variable from anywhere from 9% to 35%.
Dr. Ntobeko Ntusi:
The other important contribution of this paper is that the proportion of the population that needs to be treated for hypertension increases with age, which is something that we know but strikingly more than 60% in those over the age of 60 years. And for me, they are really great core key messages that I think are important contributions from this publication. The first one being that the choice of hypertension treatment guideline significantly influences the denominator of what you consider to be hypertensives in your population. The second one is that many people in low and middle-income countries are still unaware of their status of elevated blood pressure and the need for treatment. And I think this is a key point to emphasize.
Dr. Ntobeko Ntusi:
The third important message is that these first two points I've made have got huge implications for the scale-up costs and healthcare system capacity and that countries need to choose definitions for diseases. And this needs to be aligned with national health policy as well as available resources. And then finally, a key part of the discussion, which I asked the author to address was really around our understanding of the barriers to optimal management of blood pressure in low and middle-income countries and how these gaps can be oppressed. And they speak to the economic and human resources, the health policy, the importance of population screening and importantly education at every level.
Dr. Greg Hundley:
Very good. Nikkil I'd like to come back to you and then maybe 20 seconds or so, what do you think is the next study that needs to be performed really in this area of research?
Dr. Nikkil Sudharsanan:
I think there may be two, one is to really build on this in terms of what we showed this is the proportion of people that would require treatment and that's how it varies across these guidelines. I think it's important to also tie that to the resource implications directly, like Dr.Ntusi said, to actually show this guideline would require this many resources versus this many for that guideline. I think that will really help countries in deciding what's actually feasible guideline to implement.
Dr. Nikkil Sudharsanan:
And the second one, which is I think a much more challenging study to do is just a study of all these guidelines are based on mostly data from high-income countries. And even among these high income countries, there's these discussions on what the appropriate level for treatment is and what point you should initiate treatment. And it seems like this really has not been done with low and middle-income country populations. So we're arguing about four different guidelines that were built for high-income country populations. And I think it would be really important to see some sort of trial or long-term observational study actually in terms of averting cardiovascular disease events which guidelines actually makes the most sense for these countries.
Dr. Greg Hundley:
Very good. Ntobeko, anything to add to that?
Dr. Ntobeko Ntusi:
I think I agree completely with Nkkil and I think this paper has a number of really important strengths, and I think those strengths and key contributions have to be taken in the context of one significant limitation and how we interpret these results. And that's the fact that when we normally see a patient in the clinic to diagnose hypertension, we would take two or three blood pressure measurements. In this study, they only took a single blood pressure measurement and that's the basis for the conclusions and for me a key limitation, but nonetheless, I think a very important contribution.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Nikkil Sudharsanan from Heidelberg and Ntobeko Ntusi from Cape town for bringing us this important study, indicating that worldwide there's substantial variation really in the proportion of adults in need a blood pressure lowering medication, depending on which hypertension guideline is used. Well, let's move on now to our second feature discussion.
Dr. Greg Hundley:
Listeners, we are now to our second feature discussion and we have with us Dr. Aloke Finn from the Cardiovascular Path Institute in Gaithersburg, Maryland and our content editor expert for pathology, Dr. Jeff Saffitz from Beth Israel Deaconess. Welcome gentlemen. Aloke, could you describe for us, what was the question you wanted to address with this researching? What was your study design and your study population?
Dr. Aloke Finn:
Great. Greg, thanks for your interest in our article and for highlighting it. We were really interested in understanding what the pathologic causes for cardiac injury were in people hospitalized with COVID-19, as you know, it's been reported in the literature that people with COVID-19 with cardiac injury do worse than those without cardiac injury, but the mechanism is not still well understood. So the study design was really based upon a collaboration with a group from Italy in the Lombardy region, where they had had a terrible outbreak in 2020, as you remember in February. And they had a number of hospitalized. People die from COVID-19 infection, and they too were interested in understanding the pathologic causes of chronic injury. We got IRB approval and those hearts were sent to us during the middle of this pandemic in the February, March time. And we were able to examine 40 of those hearts and report our pathologic findings. And these were unselected cases of hospitalized patients dying of COVID-19.
Dr. Greg Hundley:
That was great. And tell us a little bit what were your study results?
Dr. Aloke Finn:
So we, first of all, did an analysis based upon the presence of myocardial necrosis. So that was the sort of the selection factor, which hearts had myocardial necrosis which parts didn't have myocardial necrosis. We found that 35% of the hearts in this 40 cases had myocardial necrosis. Now, we divided those into the type or pattern of myocardial necrosis. Was it acute myocardial infarction? Was there a large area of infarction greater than one centimeter squared or was there focal myocardial necrosis less than one centimeter squared. It's small areas of focal myocardial necrosis. We've found that most cases of patients dying of COVID-19 with myocardial necrosis had focal myocyte necrosis. Not large areas but small areas of myocyte necrosis. And we looked for the cause of those necrosis, majority of those cases with focal myocyte necrosis had microthrombi as the cause of that necrosis. So that suggests the major mechanism of myocardial injury in COVID-19 patients is microthrombi.
Dr. Greg Hundley:
Very nice. Well, Jeff, let's turn to you. How do we put the results of this study in the context with perhaps other pathologic studies that have been obtained from hearts of individuals that succumb to COVID-19?
Dr. Jeffrey Saffitz:
It's a very important question. And I want to say that at the outset, there have been many papers published focused on the pathologic findings of COVID-19 patients who have come to autopsy. And I have to say that the quality of these papers has been quite variable. In many cases, the pathology being shown is actually post-mortem artifact. In other cases, the interpretation of the pathology is incorrect. And so I think we have to be very careful in a study like this to make sure that what is being reported is actually valid and meaningful in the context of the important clinical questions being posed. And in this case, I can say the pathology was really extremely impressive and very convincing.
Dr. Jeffrey Saffitz:
Another important aspect of this study has to do with the comparison of the composition of the microthrombi that were identified in patients dying from COVID-19 versus patients who have other types of coronary thrombosis, but in a different setting. And here, there were some interesting observations that provide insights, not only into mechanism of thrombosis, but also potential information about how one might want to target antithrombotic therapy in these patients. So I would really like to hear more from Dr. Finn on this interesting aspect of this study.
Dr. Aloke Finn:
Jeff, thanks for your comment and your question. I think I agree with you, this was another interesting aspect of the study. What was done was that were able to examine the constituents of thrombi, different types of thrombi both in the setting of patients who had COVID-19 and non COVID-19 STEMIs as well as microvascular thrombi described in the COVID-19 patients, as well as embolized thrombi that embolized a small microvascular within the heart. And what we essentially found was that these thrombi, that are COVID microthrombi are distinct in their constituents. Distinct in that they had more fibrin and more compliment activation than the other types of thrombi that we're studied. So I do think this begins to unravel the question about how are these thrombi forming and are they different from the type of thrombi we normally treat? And the answer is, yes.
Dr. Greg Hundley:
Very nice, Aloke. What study do you think needs to be performed next in this space? And after you, I'll ask Jeff the same question.
Dr. Aloke Finn:
Greg, I would like to know whether or not therapies like anticoagulant, anti-compliment, antiplatelet therapies can decrease the risk or the effect of the COVID-19 on myocardial injury. Is will we see a benefit to anticoagulant or antithrombotic strategies in the study? I think that is the natural next question to ask.
Dr. Greg Hundley:
Very nice. And Jeff, anything to add?
Dr. Jeffrey Saffitz:
Yeah, well, I'm an experimental pathologist, so I'm always interested in disease mechanisms. And I would like to understand more about how these microthrombi form, the role of endothelial cell injury, the role of cytokine storm and other factors which we know are contributing. I think in the end having a more fundamental understanding of these mechanisms will provide important insights, not only in trying to manage heart disease, but in fact, other organ system disease, which is likely being mediated by a similar mechanism in the kidney and potentially in the brain and other organs as well. So I think this is a great example about how autopsy can provide really critically important information in a new human disease and set the stage for subsequent studies that will really provide important dew information.
Dr. Greg Hundley:
Excellent. Well listeners, we want to thank Dr. Aloke Finn from Gaithersburg, Maryland, Dr. Jeff Savitz from Boston, Massachusetts for this excellent discussion and revealing the pathologic results of 40 hospitalized patients from Italy that expired after COVID-19 highlighting the cause of myocardial necrosis and how it was related to the presence of microthrombi.
Dr. Greg Hundley:
On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.