Circulation May 17, 2022 Issue

This week, please join author Andrew Stokes as he and
Greg Hundley discuss the Research Letter "E-Cigarette Use and
Risk of Cardiovascular Disease: A Longitudinal Analysis of the
PATH Study (2013–2019)."


Dr. Greg Hundley:


Well, listeners, welcome to this May 17th issue of Circulation on
the Run. And I am Dr. Greg Hundley, associate editor, director of
the poly heart center at VCU Health in Richmond, Virginia. And
this week, Carolyn is away out on vacation and we are going to go
through the summaries together. We have a great feature today on
e-cigarette use and the risk of cardiovascular disease. But
before we get to that, how about we grab a cup of coffee and jump
into some of the other articles in the issue? And the first one
comes to us from the world of clinical science and Dr. Jiaqi
Huang from the National Cancer Institute. Listeners, the
objective of this study was to examine overall and cause-specific
mortality in relation to dietary and serum cholesterol, as well
as egg consumption through the prospective analysis of 27,000 men
in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention or ATBC
Study, and also a systematic review and meta-analysis of several
other cohort studies.


Dr. Greg Hundley:


So, what did the investigators find? Well, first, based on
482,000 person-years of follow-up, the authors identified 22,000
deaths, including 9,110 deaths from cardiovascular disease. Now,
greater dietary cholesterol and egg consumption were associated
with increased risk of overall and cardiovascular disease
mortality. Now, second, from the meta-analysis component of the
study, overall consumption of one additional 50-gram egg per day
was associated with an increased cardiovascular disease risk with
a pooled relative risk of 1.04 with a higher risk of
cardiovascular disease among those from us cohorts where their
pooled relative risk ratio was 1.88, a borderline higher
cardiovascular disease risk in European cohorts with a pooled
relative risk of 1.05, but not an increased cardiovascular
disease risk in the Asian cohorts. So, the results from this
study, which includes an updated meta-analysis, suggest that
there is support for restricted consumption of dietary
cholesterol as really a means to improve long-term health and
longevity.


Dr. Greg Hundley:


Well, let's go to our next article. So, in this next study, we
are going to move from cholesterol risk now to salt substitution.
And this article comes to us from Professor Maoyi Tian from the
Harbin Medical University. Listeners, the Salt Substitute and
Stroke Study, or SSaSS is a five-year cluster randomized
controlled trial and demonstrated that replacing regular salt
with a reduced sodium added or potassium salt substitute reduced
the risk of stroke, major cardiovascular events, and premature
death among individuals with prior stroke or uncontrolled high
blood pressure that lived in rural China. So, this particular
study, a substudy, assessed the cost-effectiveness profile of
this particular intervention.


Dr. Greg Hundley:


So, listeners, what did the study find? Well, there was a mean
follow-up of 20,995 participants that was conducted a little over
four years, and over the period, replacing regular salt with salt
substitute reduced the risk of stroke by 14% and the salt
substitute group had on average 0.054 more quality-adjusted life
years per person. The average costs were lower in the salt
substitute group, and this intervention was dominant. That is
better outcomes at a lower cost for prevention of stroke as well
as for quality-adjusted life-years gained. Now, interestingly
sensitivity analyses showed that these conclusions were robust
except when the price of the salt substitute was increased to the
median and highest market prices identified in China. The salt
substitute intervention had a 95% probability of being
cost-saving and a greater than 99.9% probability of being
cost-effective. A really interesting article.


Dr. Greg Hundley:


Well, now, let's turn our attention to the world of population
science. And in this study, these authors led by Dr. Steven
Lubitz from Massachusetts General Hospital performed a
Genome-Wide Association Study or GWAS of the QT corrected
interval among 84,630 United Kingdom Biobank participants. And
they created a polygenic risk score. Now, among 26,976
participants with whole-genome sequencing and electrocardiogram
data in the Trans-Omics for Precision Medicine or TOPMed program,
they identified 160 carriers of punitive pathogenic, rare
variants in 10 genes known to be associated with the QT interval.


Dr. Greg Hundley:


So, the authors here examined the QTC corrected associations with
the polygenic risk score and with rare variants from the TOPMed
cohort. So, what did they find? They found 54 independent loci by
GWAS in the UK Biobank. 21 loci were novel of which 12 were
replicated in TOPMed. The polygenic risk score comprising over a
million common variants was significantly associated with the QTC
in TOPMed, and carriers of punitive pathogenic rare variants had
longer QTC intervals than non-carriers. Now, 23.7% of individuals
with a QT corrected of greater than 480 milliseconds carried
either a monogenic rare variant or had a polygenic risk score in
the top decile. 3.4% for monogenic and 21% for the top decile of
the polygenic risk score.


Dr. Greg Hundley:


So, listeners, the findings of this study indicate that the QTC
duration in the population is influenced by both rare variants in
genes, underlying cardiac repolarization and polygenic risk, with
a sizeable additional contribution from polygenic risk. And
therefore, comprehensive assessment of the genetic determinants
of QTC prolongation should include incorporation of both
polygenic and monogenic risk.


Dr. Greg Hundley:


Well, listeners, let's turn our attention to the world of
preclinical science. And this next article comes to us from
Professor Junbo Ge from the Department of Cardiology in Zhongshan
Hospital in Fudan University. Well, listeners, after myocardial
infarction, cardiac resident macrophages, which are
self-maintaining in that they originate from embryonic
hematopoiesis are responsible for the efficient clearance and
degradation of apoptotic cardiomyocytes. And that process is
called efferocytosis. Now, efferocytosis is required for
inflammation resolution and tissue repair. However, the
underlying molecular mechanisms of this process really remain
unknown.


Dr. Greg Hundley:


So, as such, listeners, these authors sought to identify the
mechanisms of the continued clearance and degradation of
phagolysosomal cargo by cardiac resident macrophages during
myocardial infarction. Well, what did Dr. Ge and colleagues find?
Several things. First, they identified legumine as a gene
specifically expressed by cardiac resident macrophages, and
legumine deficiency resulted in a considerable exacerbation in
cardiac function, accompanied with the accumulation of apoptotic
cardiomyocytes and a reduced index of in-vivo efferocytosis in
the border area of infarcts. Furthermore, the formation of LC3 to
dependent phagosome around secondary encountered apoptotic
cardiomyocytes was disabled. In addition, legumine deficiency
increased infiltration of MHC to high CCR2+ macrophages, and the
enhancement of recruitment of MHC to low CCR2+ monocytes with
downregulation of anti-inflammatory mediators, such as IL10 and
TGF-beta, and upregulation of pro-inflammatory mediators,
including interleukin-1-beta, Tumor Necrosis Factor alpha, IL6,
and IFN-gamma.


Dr. Greg Hundley:


So, listeners, in summary, the results of this study directly
link efferocytosis to wound healing in the heart and identify
legumine as a significant link between acute inflammation
resolution and cardiac function after infarction. Well,
listeners, also in this issue, we have a wonderful On My Mind
feature from Professor Camlet entitled “A Role for the Vascular
Endothelium in Post-Acute COVID-19.” Well, next, we're going to
head to our feature article on e-cigarette use and the risk of
cardiovascular disease.


Dr. Greg Hundley:


Well, listeners, welcome to our feature discussion today. A very
interesting topic. E-cigarette use and the risk of cardiovascular
disease. And we have with us today the senior author of this
particular manuscript, Dr. Andrew Stokes from the Boston
University School of Public Health in Boston, Massachusetts.
Welcome, Andrew. Andrew, to get started, can you describe some of
the background information pertaining to your study and what was
the hypothesis that you wanted to address?


Dr. Andrew Stokes:


Absolutely, and thank you for having me on the podcast. Despite
the increasing popularity of electronic cigarettes, the long-term
health effects of habitual e-cigarette use remain unclear. Most
of the studies that have been conducted to date are either
cross-sectional or they pertain to small clinical samples. The
goal of the present study was to develop a longitudinal design to
see if e-cigarette use at a point in time was linked to
cardiovascular events over a multi-year follow-up period.


Dr. Greg Hundley:


Very nice. So, your specific hypothesis really pertained to
e-cigarette use, correct?


Dr. Andrew Stokes:


That's right. As a novel product, information on e-cigarette use
and its health effects is lacking, and so our goal was to see if
e-cigarette use was associated with the incidence of clinical
events.


Dr. Greg Hundley:


And so, can you describe for us your study population and your
study design?


Dr. Andrew Stokes:


Absolutely. Data come from the Population Assessment of Tobacco
and Health Study or the PATH Study, which is a nationally
representative cohort study of the non-institutionalized
population containing five annual waves of self-reported data
collected between 2013 and 2019. The initial sample included over
30,000 US adults ages 18 years and older with oversampling of
tobacco users. We excluded respondents who were lost to follow-up
or who had a previous diagnosis of CVD or were missing baseline
exposure information. Ultimately, we ended up with a sample of
just over 20,000 individuals.


Dr. Greg Hundley:


Very nice. And so, what were your study results?


Dr. Andrew Stokes:


So, we had several key findings. One key finding was that,
compared to people who only smoke cigarettes, people who smoke
both traditional cigarettes and used e-cigarettes had no
significant reduction in risk for heart attack, heart failure, or
stroke, nor any cardiovascular disease outcome. This is
significant because many e-cigarette users use both e-cigarettes
and cigarettes in combination. Very few move to exclusive
e-cigarette use. Additionally, we found that those who do move to
e-cigarette use exclusively though, representing a very small
fraction of the cohort, had some evidence of reduction in
cardiovascular harm. However, these results for exclusive
e-cigarette users were not statistically significant, indicating
that additional studies with longer follow-up will be required
before we can make any definitive conclusions about this group.


Dr. Greg Hundley:


Very nice. And did you notice any discrepancy in your results
between either men versus women or between individuals that were
younger in age versus those that may say be 50 years or older?


Dr. Andrew Stokes:


I think both sources of effect modification will be valuable
directions for future research. Unfortunately, samples of
e-cigarette users are quite small and incident events over
follow-up are quite limited. Therefore, the present study did not
pursue or explore these types of stratifications.


Dr. Greg Hundley:


Very good. So, sounds like more research to come forward. Well,
Andrew, how do we put your results really in the context with
other studies evaluating the harmful effects of e-cigarettes?


Dr. Andrew Stokes:


Of course. So, we know from toxicological studies that there are
many constituents of e-cigarette aerosols that are concerning and
have substantial toxicity. We know that the inhalation of
e-cigarette aerosols among young healthy adults induce
inflammation and oxidative stress. Population-based studies from
cross-sectional data sources also suggest evidence of harm.
What's needed are more longitudinal studies with longer follow-up
periods and more incidence events so we can really parse this
risk and identify the magnitude of these harms. Finally, we also
need to understand better whether there's any harm reduction
potential associated with e-cigarette use. E-cigarettes are
currently not an FDA-approved cessation product. Therefore, we do
not recommend their use despite preliminary evidence of potential
harm reduction. We'll need further evidence before we can make
any such conclusions.


Dr. Greg Hundley:


And Andrew, describe for us, and you've started to already, what
series of studies are needed next to be performed in this sphere
of research?


Dr. Andrew Stokes:


Right. So, it's difficult to really identify definitively the
effects of e-cigarette use in the absence of randomized control
trials. However, we can use observational data with target trial
approaches to emulate the clinical trial that we would like to do
if we were able to. So, the next step is really to look at
transitions across products between cigarette and e-cigarette use
and to associate those who switch products, such as from
e-cigarettes to cigarettes or vice versa, to see if those
switches are associated with any harm or harm reduction.


Dr. Greg Hundley:


Very good. Any specific racial or ethnic groups or even social
determinants of health that may need to be targeted with some of
these future studies?


Dr. Andrew Stokes:


That's a great question. So, what we know so far from preliminary
research is that some groups are more likely to switch to
e-cigarettes than other groups. Particularly among current
combustible cigarette users, the rates of switching do vary by
race and ethnicity. Thus, we need further research to understand
why these patterns differ across subgroups and what their
implications may be for health.


Dr. Greg Hundley:


Do you foresee any difficulty in trying to enroll participants
from those other groups as you plan these studies moving forward?


Dr. Andrew Stokes:


The advantage of the current research design is that we're using
a large secondary data set of survey participants who are
enrolled in the Population Assessment of Tobacco and Health
study. Therefore, we are not enrolling patients ourselves and the
response rates are quite high in these surveys.


Dr. Greg Hundley:


Well, Andrew, we hear that some of the inhalants that are mixed
with the inhaled nicotine can be flavors and perhaps have been
approved by the FDA for consumption in the GI tract where,
whatever these additives are, you would think might be broken
down by the digestive system. But if they're inhaled and get into
the lung tissue and the parenchyma, the alveoli, et cetera, do
they perhaps have harmful effects that maybe we're not aware of?


Dr. Andrew Stokes:


Absolutely. E-cigarettes come in thousands of characterizing
flavors including sweet flavors, tobacco flavors, and many other
miscellaneous flavors. As we saw with the outbreak of lung injury
associated with the use of e-cigarettes in 2019, inhaling flavors
can have health effects that are unanticipated based on research
in the GI tract, and therefore, as a next step in this research,
we really need more work to investigate how different flavors are
associated with the incidence of clinical events, whether
cardiovascular or pulmonary conditions.


Dr. Greg Hundley:


Very nice. Well, listeners, we want to thank Dr. Andrew Stokes
from the Boston University School of Health for bringing us this
data from the PATH study, suggesting that combining smoking with
e-cigarette use does not reduce cardiovascular events and that
quitting both products is needed to ensure overall cardiovascular
disease risk reduction.


Dr. Greg Hundley:


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. 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.