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Circulation on the Run


Apr 25, 2022

This week, please join author Vasan Ramachandran and Associate Editor Mercedes Carnethon as they discuss the article "Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study."

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 in Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I'm so excited about today's feature paper. You see, I trained at the Framingham Heart Study and today's feature paper talks about the temporal trends in the remaining lifetime risk of cardiovascular disease among middle aged adults across six decades in the Framingham Heart Study. Truly a landmark study and a discussion nobody wants to miss. But first, let's talk about the other papers in today's issue, and I understand that you've got one ready.

Dr. Greg Hundley:

You bet Carolyn. I'll get started first. Thank you. So my first paper comes from Dr. Daniel Mark from Duke University and it refers to the ISCHEMIA trial.

Dr. Carolyn Lam:

Ooh, could you please first remind us what is the ISCHEMIA trial and are you presenting a substudy, is that correct?

Dr. Greg Hundley:

Right, Carolyn. So the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, or ISCHEMIA, compared an initial invasive strategy with an initial conservative strategy in 5,179 participants with chronic coronary disease and moderate or severe ischemia. And this sub study of the ischemia research program included a comprehensive quality of life analysis.

Dr. Carolyn Lam:

So very interesting. What did they find Greg?

Dr. Greg Hundley:

Right, Carolyn. So this study included 1,819 participants. 907 in the invasive, 912 in the conservative. And collected a battery of disease specific and generic quality of life instruments by structured interviews at baseline. And then at three, 12, 24 and 36 months post randomization, and then finally at study closeout. Now Carolyn, these assessments included an angina related quality of life assessment from the 19 item Seattle Angina Questionnaire, a generic health status assessment, an assessment of depressive symptoms, and for North American patients, cardiac functional status from the Duke Activity Status Index, or DASI. In this study, Carolyn, in terms of results, the median age was 67 years and about 20% were women and about 16% were nonwhite. So Carolyn, getting to the results. The estimated mean difference for the SAQ 19 summary score favored invasive therapy. And remember the SAQ 19 was the Seattle Angina Questionnaire.

Dr. Greg Hundley:

Next, no differences were observed in patients with rare or absent baseline angina. Next, among patients with more frequent angina baseline, those randomized to invasive had a mean point higher score on the SAQ 19 summary score than the conservative approach, with consistent effects across all of the SAQ subscales including physical limitations, angina frequency and quality of life health perceptions. For the DASI, and remember DASI refers to the Duke Activity Status Index, no difference was estimated overall by treatment. But in patients with baseline marked angina, DASI scores were higher for the interventional arm. Whereas patients with rare or absent baseline angina showed really no treatment related differences.

Dr. Carolyn Lam:

Oh, okay. So a lot of results. What's the take-home message, Greg?

Dr. Greg Hundley:

Right, Carolyn. Glad you asked. So in the ISCHEMIA comprehensive quality of life substudy, patients with more frequent baseline angina reported greater improvements in the symptom physical functioning and psychological wellbeing dimensions of quality of life when treated with an invasive strategy. Whereas patients who had rare or absent angina baseline reported no consistent treatment related quality of life differences.

Dr. Carolyn Lam:

Wow. Thank you, Greg. Very interesting indeed. Now from angina to now cholesterol. Now, cholesterol guidelines typically prioritize primary prevention statin therapy based on 10 year risk of cardiovascular disease. Now the advent of generic pricing may in fact justify expansion of statin eligibility. Moreover, 10 year risk may not be the optimal approach for statin prioritization. So these issues were looked at in this next paper by authors led by Dr. Kohli Lynch from Northwestern University and colleagues who estimated the cost effectiveness of expanding preventive statin eligibility, and evaluated novel approaches to prioritization from a Scottish health sector perspective. A computer simulation model predicted long term health and cost outcomes in Scottish adults, age 40 years or more.

Dr. Greg Hundley:

So Carolyn, what did they find?

Dr. Carolyn Lam:

The advent of generic pricing has rendered preventive statin therapy cost effective for many adults. Absolute risk reduction guided statin therapy, which is based on 10 year cardiovascular disease risk and non HDL cholesterol levels, is cost effective and would improve population health. Whereas age stratified risk thresholds were more expensive and less effective than alternative approaches to statin prioritization. So guidelines committees may need to expand statin eligibility and consider new ways to allocate statins based on absolute risk reduction rather than 10 year risk thresholds.

Dr. Greg Hundley:

Very nice Carolyn. Always important, new information regarding statin therapy. Well Carolyn, my next paper comes to us from the world of preclinical science. And Carolyn, as you know, the regenerative capacity of the heart after myocardial infarction is limited. And these authors led by Dr. Tamer Mohamed from University of Louisville previously showed that ectopic introduction of Cdk1, CyclinB1 and Cdk4, CyclinD1 complexes and we'll refer to those now as 4F, promoted cardiomyocyte proliferation in 15 to 20% of infected cardiomyocytes in vitro and in vivo and improved cardiac function after MI in mice. So Carolyn, in this study using temporal single cell RNA sequencing, the investigative team aimed to identify the necessary reprogramming stages during the forced cardiomyocyte proliferation with 4F on a single cell basis. And also using rat and pig models of ischemic heart failure, they aim to start the first preclinical testing to introduce 4F gene therapy as a candidate for the treatment of ischemia induced heart failure.

Dr. Carolyn Lam:

Oh, wow Greg. So what did they find?

Dr. Greg Hundley:

Several things, Carolyn. First, temporal bulk and single cell RNA sequencing and further biochemical validations of mature HIPS cardiomyocytes treated with either LAcZ or 4F adenoviruses revealed full cell cycle reprogramming in 15% of the cardiomyocyte population at 48 hours post-infection with 4F. Which was mainly associated with sarcomere disassembly and metabolic reprogramming. Second Carolyn, transient overexpression of 4F specifically in cardiomyocytes was achieved using a polycistronic non-integrating lentivirus encoding the 4F with each driven by a TNNT2 promoter entitled TNNT2-4F polycistronic-NIL. Now this TNNT2-4F polycistronic-NIL or control virus was injected intra myocardial one week after MI in rats, so 10 per group, and pigs, six to seven per group.

Dr. Greg Hundley:

And four weeks post-injection the TNNT2-4F polycistronic-NIL treated animals showed significant improvement in left ventricular injection fraction and scar size compared with the control virus treated animals. And four months after treatment, the rats that received TNNT2-4F polycistronic-NIL still showed a sustained improvement in cardiac function without obvious development of cardiac arrhythmias or systemic tumorigenesis. And so Carolyn this study advances concepts related to myocellular regeneration by providing mechanistic insights into the process of forced cardiomyocyte proliferation and advances the clinical feasibility of this approach by minimizing the oncogenic potential of the cell factors, thanks to the use of a novel transient and cardiomyocyte specific viral construct.

Dr. Carolyn Lam:

Wow. What a rich study. Thanks so much, Greg.

Dr. Greg Hundley:

Well, Carolyn, how about if we see what else and what other articles are in this issue. And maybe I'll go first. So there's a research letter from Dr. Wu entitled Modeling Effects of Immunosuppressive Drugs on Human Hearts Using IPSC Derived Cardiac Organoids and Single Cell RNA Sequencing. Carolyn, there's an EKG challenge from Dr. Yarmohammadi, entitled “Fast and Furious, A Case of Group Beating in Cardiomyopathy.” And then finally from Dr. Tulloch, a really nice Perspective entitled “The Social Robots are Coming, Preparing For a New Wave of Virtual Care in Cardiovascular Medicine.

Dr. Carolyn Lam:

Oh, how interesting. Well, also in the mail back is an exchange of letters of among Drs. Lakkireddy, Dhruva, Natale, and Price regarding Amplatzer Amulet Left Atrial Appendage Occluder versus Watchman Device for stroke prophylaxis, a randomized control trial. All right. Thank you so much, Greg. Shall we go on to our feature discussion now?

Dr. Greg Hundley:

You bey. Welcome listeners to our feature discussion today. And we're so fortunate we have with us today, Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. Welcome to you both. And Vasan, let's start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address?

Dr. Vasan Ramachandran:

Thank you, Greg, first of all for having me. So we know two facts. One is that heart disease and stroke disease death rates and incidents are declining over the last six decades in the United States. Juxtapose against that is also the observation that there is rising incidence of obesity and overweight, and also a rising burden of diabetes. There are a lot of advances in our ability to treat high blood pressure, high cholesterol, as well as high blood sugar. So we wanted to ask the question, given the historic trends in control awareness of risk factors and their control, interrupted by this escalating burden of obesity, overweight, and diabetes, what is the lived experiences of people over time in terms of the risk of developing heart disease or stroke using a metric we call as the remaining lifetime risk of developing heart disease or stroke.

Dr. Greg Hundley:

The hypothesis you wanted to address?

Dr. Vasan Ramachandran:

The hypothesis we wanted to address was that perhaps the decline in the incidence of heart disease and stroke may have decreased over time given the escalating burden of overweight, obesity and diabetes.

Dr. Greg Hundley:

Very nice. And can you describe for us your study population and your study design?

Dr. Vasan Ramachandran:

Thank you, Greg. So the Framingham Heart Study is one of the oldest running epidemiological studies in the world. We have multiple cohorts. The study began in 1948 with the original cohort, the offspring cohort enrolled in 1971, third generation cohort in 2002, and two minoritized cohorts in the 1990s and 2002. So we have an observation period of different cohorts over a six decade period. So we asked the question, if you were a participant in the Framingham study between 1960 and 1979 and then 1980 to 1999, and then 2000 to 2018, what was your lifetime risk of experiencing a heart disease or stroke in the three different time periods? Is it going down, is it steady or is it going up?

Dr. Greg Hundley:

Very nice. And so, Vasan, describe your study results.

Dr. Vasan Ramachandran:

Look, what we found was if you look at the first, the 20 year period from 1960 to 1979, and compare that with the latest, which is 2000 to 2018, in the initial time period, the lifetime risk of developing heart disease or stroke in a man was pretty high. It was about one in two. And that for a woman was about one in three. So when you come to the latest epoch, what we find that the risk of one in two men had dropped to about one in three men in the latest decade. For women, the risk declined from what was one in three in the earlier epoch to one in four. So approximately there was about a 36% reduction in the lifetime probability of developing heart disease or stroke across the six decade period of observation.

Dr. Greg Hundley:

Very nice. And so help us a little bit, put the context of your results into what that might mean for us today as we are managing patients with atherosclerotic disease.

Dr. Vasan Ramachandran:

Yes, Greg. What it means is that the permeation of the advances in science in terms of the screening of risk factors, awareness of risk factors, medications to lower these risk factors effectively, the clinical trials that have given us these new medications, they may have translated into a reduction in risk over time. That the lived experience of people in the later decades is better in terms of having a lower risk of heart disease or stroke as the consequence of multiple advances that have happened in heart disease and stroke.

Dr. Greg Hundley:

Well, thank you so much Vasan. Well listeners, now we're going to turn to our Associate Editor, Mercy Carnethon. And Mercy, you have many papers come across your desk. What attracted you to this particular paper and how do you put these results really in the context of other science pertaining to risk associated with populations that may have atherosclerotic cardiovascular disease?

Dr. Mercedes Carnethon:

Thanks so much for that question, Greg. And again, Vasan, I really thank you and your team for bringing forth such outstanding research. You know, as cardiovascular disease epidemiologists, we were all raised and taught that what we know about risk factors for cardiovascular disease are based on the Framingham cohort. And so I was really excited to see this very comprehensive piece of work that characterized what the Framingham study has identified and also leverages the unique characteristics of a study that started in 1948.

Dr. Mercedes Carnethon:

So, you know, we're almost 75 years in and actually has the ability that cross sectional studies don't have to look over longer periods of time at risk. And you know, when we think about papers that excite us, that we really want to feature in circulation, they are papers that teach us something new. And I will say there were aspects of this work that confirmed what I had heard but had not seen using empirical data. Namely that the remaining lifetime risks for developing cardiovascular disease were going down over time, and they were going down secondary to better management and recognition of the risk factors that the Framingham cohort study had really been instrumental in identifying in the first place.

Dr. Mercedes Carnethon:

There were surprising elements of the paper. The surprising elements being that I think as you brought up earlier, we were concerned that risk factors that were on the rise, such as obesity, were threatening these increases in life expectancy. And it was really nice to see that the findings held, even in the face of rising risk factors. And just to summarize, what I really like about this piece when we situate it within circulation, where we are addressing clinical treatment factors, where we're also featuring clinical trials and even other epidemiologic studies, is that your work identifies for us the overall context in which the clinicians who read the journal are thinking about managing patients and where we're going. It highlights our successes, but it also really brings up what we need to do next. And I look forward to hearing from you about where you think this may be headed.

Dr. Greg Hundley:

Well, Mercy, you're teeing us up for that next question. Vasan, what do you think is the next study or studies that need to be performed in this space?

Dr. Vasan Ramachandran:

Thank you, Greg and Mercy, for your kind comments. Like I shared, this is a success story for a predominantly white population in the Northeast. We are very much aware about the heterogeneity and the geographic variation in heart disease burden in our country. So one of the success stories interpretation might be this represents the upper bound. What can happen to a population that is compliant with screening of risk factors, awareness of risk factors, treatment and healthcare access. I think the next set of studies should broaden the study population to bring in additional populations that are more diverse, that are also followed up over a period of time to assess and put the current observations in the appropriate context. Do we see similar findings longitudinally in other cohorts with non-white participants? Is it different, is their lived experience different? If so, why? And that could inform us how we can reach the success story and replicate it across the entirety of our country.

Dr. Greg Hundley:

And Mercy, do you have anything to add?

Dr. Mercedes Carnethon:

I do. You know, I really like that focus on broadening to whom these results are applicable. We've undergone a lot of shifts within our country and also around the world. You know, circulation, we have a worldwide readership. I would love to see this sort of work replicated across different countries to the extent that we have the data to do so, recognizing that limitation. But I'd love to see work focus on comparing how these things change in low income countries, middle income and high income countries, so that we can really think about resource allocation and find strategies to try to replicate the successes that we are seeing based on the data from the Framingham heart and offspring studies.

Dr. Greg Hundley:

Excellent. Well listeners, we really appreciate the opportunity to get together today with Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. And really appreciate them for bringing us these epidemiologic data from the Framingham cohort, indicating that over the past decades, mean life expectancy increased and the remaining lifetime risk of atherosclerotic cardiovascular disease decreased across individuals in the cohort, even after accounting for increasing incidences of other cardiovascular risk factors like obesity and smoking. Well 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, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.