Circulation April 26, 2022 Issue

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.