Circulation February 18, 2020 Issue

Dr Biykem Bozkurt: I am Biykem Bozkurt, Professor of Medicine
from Baylor College of Medicine, Senior Associate Editor for
Circulation and today, I'm joined with Sana Al-Khatib, Professor
of Medicine from Duke University, Senior Associate Editor of
Circulation, for the podcast for the fourth annual Go Red for
Women issue for Circulation. As all our listeners are aware,
cardiovascular disease is a leading cause of death among women,
but we have significant gaps in our awareness and treatments, and
with a recognition of these disparities for cardiovascular care
in women, AHA has launched a Go Red for Women campaign back in
2004. We have made great strides, and despite the improvement in
awareness, significant gaps persist and adverse trends are
emerging for cardiovascular disease in women.


With such recognition, in 2017, Circulation launched the annual
Go Red for Women issue, dedicated to cover transformative
science, exciting new treatment strategies, recent
epidemiological trends, and with an intent to close the gaps and
eliminate the disparities for cardiovascular care in women. This
is the fourth Go Red for Women issue and we have an exciting
portfolio that we'd like to share with our readers and listeners.
In this issue, we have quite a few important papers. The first
two that we would like to start with are going over the
epidemiologic trends. Sana, do you want to walk us through the
two papers that we have on myocardial infarction and sudden
cardiac death?


Dr Sana Al-Khatib: I would love to start with the paper on sudden
cardiac death, which is very fitting. That's what I focus most of
my work on. This particular paper actually looked at sudden
cardiac death as the first manifestation of heart disease in
women, and it was focused on the Oregon sudden unexpected death
study, the timeframe for which was between 2004 and 2016 and what
they really wanted to do is to assess sex specific trends in
sudden cardiac death incidence. And so they focused on out of
hospital, sudden cardiac death cases among adults during that
time period.


And they divided that 12-year period from February 2004 to
January 2016 into three four-year intervals, 2004 to 2007, 2008
to 2011 and 2012 to 2015. And they really looked at these trends
among women and men and they found that there were 2,938 sudden
cardiac deaths, 37% of who were women. And they found an
interesting U-shaped pattern of risk of sudden cardiac death with
Anader in 2011. An increase in the years that followed 2011 so
regarding that rebound, the rates really increased in 2013 and
2015. And when they specifically looked at women, they found that
the rates of sudden cardiac death declined by 30% between the
first and second four year time period and increased by 27%
between the second and third period.


Interestingly, the subsets with sudden cardiac death as the first
manifestation of heart disease, accounted for 58% of the total
rebound in sudden cardiac death incidence from period two to
three but there was no change in the incidence over time for
sudden cardiac death occurring among people with preexisting
heart disease. For men actually sudden cardiac death also
declined from the first to the second period, but not as much as
in women and also increased between the second and third periods.
Again, not as much as we saw in women. Subsets of sudden cardiac
death occurring in the setting of identifiable heart disease was
responsible for 55% of the rebound in overall sudden cardiac
deaths incidence. Certainly some significant differences between
men and women. Very exciting findings.


Then if we actually turn our attention to the second study
looking at sex specific trends in acute myocardial infarction,
this particular analysis, Biykem, was done within an integrated
healthcare network between 2000 and 2014 and they picked the
Kaiser Permanente Southern California network. They were able to
identify 45,000 plus acute MI hospitalizations between 2000 and
2014 and they found that age and sex standardized incident rates
of AMI declined from 2000 to 2014. And they found that a decline
for women was actually more so than in men. And in fact for men
it was pretty much stable. And they found that the incidence of
hospitalized MI had declined, however, declines are slowing among
women compared with men in recent years.


That's actually identified some unmet care needs among women that
hopefully can meet people and investigators to tailor their
approaches to try to close those gaps and disparities in care.
With that, let me actually turn it back to you to potentially
talk about to cardiovascular risk assessments in women.


Dr Biykem Bozkurt: With the recognition of the disparities and
the recent emerging trends of adverse outcomes, especially in
younger women, there has been a focused attention in how to
assess risk, cardiovascular risk in women. There is a very
comprehensive review by Salim Virani and colleagues who's
addressing the cardiovascular risk assessment for women. As our
listeners will recall in 2018, ACC/AHA cholesterol professional
guidelines specified risk enhancing factors such as premature
menopause or preeclampsia for women. And if present, in
borderline or intermediate risk patients, would elevate the 10
year risk to a higher category. But now with a recognition of
many more risk factors, Virani and colleagues are proposing a
more comprehensive cardiovascular risk assessment for women. And
these include the risk factors that are not only identified in
the 2018 ACC/AHA cholesterol guidelines, but additional such as
gestational hypertension and diabetes or adverse pregnancy
outcomes such as preterm delivery, small birth for gestational
age or placental abruption or infarct or premature menarche or
premature menopause, primary ovarian failure or pregnancy loss
and additionally inflammatory disorders such as lupus, rheumatoid
arthritis, psoriasis and history of cancer and cancer related
therapies.


And they formulate this in a nice and well tabulated fashion. And
all these risk factors are summarized table one which I think
most of our listeners and readers will refer to. And they also
come up with a nice approach. What shall we do? And how shall we
detect that risk? First recommendation they have is that we
should obtain a comprehensive obstetric and gynecological history
from all women. And if these risk factors are present, then we
should then screen for other traditional risk factors early and
frequently and then treat for modifiable risk factors such as
hypertension, hyperlipidemia, diabetes, metabolic syndrome, and
also implement aggressive lifestyle modification with strategies
such as management of blood pressure control, reduction of blood
sugars, remaining active eating, healthy, losing weight, and not
smoking. Which is summarized as life's simple seven which is an
AHA initiative that summarizes healthy lifestyle as life's simple
seven.


And very complimentary to Virani’s review paper, we had another
wonderful paper that is titled Life's Simple Seven and health by
Jacqueline Kulinski who reminds us that not only these seven
factors but breastfeeding for postpartum mothers is an important
approach to reduce cardiovascular risk. Breastfeeding is not only
beneficial for the newborn infants but for the mother as it's
been associated with reduction in risk of myocardial infarction,
stroke, cardiovascular disease hospitalization rates, future
development of diabetes, hypertension, and even mortality. And
this paper elaborates on potential mechanisms such as increases
in metabolic expenditure, enhancement of insulin sensitivity,
reduction in cholesterol, greater mobilization of fat stores and
reversal of elevated triglycerides and cholesterol that's seen
during pregnancy.


It also emphasizes the importance of recognition and education of
women because currently only about 25% of women are exclusively
breastfeeding at six months and US has one of the lowest
breastfeeding rates among industrialized countries. And we do
have disparities according to race and income and black infants
and infants living in rural areas in Southeast USA are less
likely to be breastfed. And there is definitely increased
recognition for importance and but it's also important to be able
to accommodate and facilitate breastfeeding for mothers.
Currently the paper emphasize that all 50 states now have laws
allowing women to be able to breastfeed in public or private
locations. But again, there definitely is a necessity for
increased awareness and education.


On that end, there is also a great paper covering the news
release announcing the partnership between American Heart
Association and American College of Gynecology and Obstetricians
in promoting risk identification and reduction of cardiovascular
disease in women through collaboration between obstetricians and
gynecologists. In 2018, AHA and American College of Gynecology
issued a call for action for both specialists to team up and
increase screening for cardiovascular disease by obstetricians
and provide education and appropriate referrals. And I think this
initiative is going to increase the opportunities for young women
whose primary care provider solely could be an obstetrician, who
potentially will get screened for cardiovascular disease and if
they have these risk factors, will potentially be able to be
offered lifestyle modification, message and intervention
strategies.


These, I think, three very complimentary papers are enhancing our
recognition for the new risk profile that needs to entail getting
a comprehensive obstetric and gynecological history in all women.
And in the event we recognize either of these risk factors
including the traditional risk factors or obstetric and
gynecological risk factors such as pregnancy related
complications or preeclampsia or other additional special risk
factors such as autoimmune disorders and cancer, then we will
need to heighten our awareness for lifestyle modification, risk
management, and earlier treatment and closer monitoring.


That brings us to another important risk profile, which is cancer
for women. And Sana, I know we do have two great papers related
to cancer topic. If you could elaborate on those.


Dr Sana Al-Khatib: I'm really excited about these papers. As you
pointed out, Biykem, that cardio oncology is a field that is
really expanding and so it was really very gratifying to get
these two papers. The first paper had to do with a comparison
between aromatase inhibitors and Tamoxifen in women with breast
cancer in terms of their association with the risk of
cardiovascular outcome. And this particular study was done in the
United Kingdom and they studied women though with newly diagnosed
breast cancer initiating hormonal therapy, either with everyone
at aromatase inhibitors or Tamoxifen between 1998 and 2016. And
the study outcomes that they were interested in included
myocardial infarction, ischemic stroke, heart failure, and
cardiovascular mortality.


And they actually had a sizable patient population with 23,000
plus patients included in this analysis of whom close to 18,000
initiated treatment with either an aromatase inhibitor or
Tamoxifen. And they found that the use of aromatase inhibitors
was associated with a significantly increased risk of heart
failure and cardiovascular mortality compared with Tamoxifen and
that aromatase inhibitors seemed to have a trend towards
increased risk of myocardial infarction, ischemic stroke.
Although those differences were not statistically significant.
They actually concluded that aromatase inhibitors were associated
with an increased risk of heart failure and cardiovascular
mortality compared with Tamoxifen and that there were trends
toward increased risks also of MI and ischemic stroke. And so
they really want clinicians and patients to be aware of these
findings when they are trying to make decisions about treatment
for breast cancer.


We have another really interesting study, Biykem, that was
actually a randomized control trial that studied the effect of
exercise therapy dosing schedule on impaired cardiorespiratory
fitness in patients with primary breast cancer. And so this
randomized trial enrolled 174 post-menopausal patients who were
randomly allocated to one of two supervised exercise training
interventions, delivered either using a standard linear test or
nonlinear test. And they had a control group of just stretching.
They did some stretching. And they did the trial over at periods
of 16 consecutive weeks and the primary endpoint was change in
the VO2 level, PCO2 level from baseline to post intervention.


They had a couple of other secondary endpoints and their results
were interesting. They found no serious adverse events during the
trial, but they actually found that 40% of patients in both
exercise dosing regimens were classified as responders. And they
concluded that short term exercise training independent of dosing
schedule was associated with modest improvements in
cardiorespiratory fitness in patients previously treated for
early stage breast cancer. Really interesting, a smaller study,
not really looking at hard endpoints yet. It's still important
because I believe that it is going to form the basis for more
studies and more research in this important field, Biykem.


With this, I'd like to turn it over to you to talk about elevated
body mass index in young women.


Dr Biykem Bozkurt: And this is another fascinating study, a large
study from Sweden. It involved more than 1.3 million young women.
Average age was 27. It was a national prospective cohort. The
recruitment was between 1982 and 2014. What they did was they
measured the baseline of weight of women in early pregnancy in
the first trimester, actually the first antenatal visit before
they could gain any weight related to the pregnancy. With their
BMI measurement at baseline, then they followed these patients
for approximately 30 years and associated this baseline BMI with
future developments or dilated cardiomyopathy or any
cardiomyopathy. They looked at that dilated cardiomyopathies,
hypertrophic cardiomyopathies, these other cardiomyopathies such
as alcoholic cardiomyopathy and others.


Interestingly, elevated body mass was associated with future
development of dilated cardiomyopathy. A very similar finding was
reported in former studies for adolescent men, but we didn't have
this finding for young women. This study provides evidence that
elevated BMI, even if it is only in the overweight range, is
associated with future development of dilated cardiomyopathy. In
the past we had numerous studies demonstrating overweight or
obesity status being associated with future development of
clinical heart failure, clinical symptoms of heart failure, but
this is one of the largest scale population based cohorts
demonstrating the association with dilated cardiomyopathy.


And interestingly, these women at baseline did not have the usual
other confounders or comorbidities associated with future
development of cardiomyopathy. The risk of diabetes and
hypertension was less than 1% at baseline. Very interestingly,
BMI by itself, independent of all these other variables was
associated with future risk. And of course the higher the BMI
was, the higher the risk was. The highest risk was for those with
morbid obesity or BMI over 35 and in those patients the risk was
increased by about five fold.


Sana, we talked about the disparities for women. Where are we
with women participation in cardiovascular trials? And how do we
looked globally overall regarding the disparity of cardiovascular
diseases in woman?


Dr Sana Al-Khatib: These are really important questions, Biykem.
Let me first start with a study that will be in the Go Red for
Women issue on women's participation in cardiovascular clinical
trials. They looked at that. Between 2010 and 2017, which is a
very important topic as you know, Biykem. And so what they did
here is they actually assessed the participation of women in
completed cardiovascular trials that were registered in clinical
trials between 2010 and 2017. And they parked calculated the
female to male ratio for each trial to determine the prevalence
adjusted estimates for participation of women. And so they kind
of defined it as participation prevalence ratio. And so they said
that they were able to identify 740 completed cardiovascular
trials including more than 860,000 adults of whom 38% were women.
And they talked about how the median female to male ratio of each
trial was 0.501 overall and varied by age group and type of
intervention and region and trial size and funding sponsors.


Actually, these are really interesting findings. In the interest
of time, I'm not going to delve into all those details, but I
think it would be really interesting for people to read that and
look at this more carefully. But they found that relative to
their presence in the disease population, the participation
prevalence ratio of women versus men actually was a higher than
0.8 for hypertension, pulmonary arterial hypertension and lower
for arrhythmia, coronary artery disease, acute coronary syndromes
and heart failure trials. And they found that in the most recent
time period, that they defined between 2013 and 2017, they saw a
significant increase in the participation and prevalence ratios
for stroke and heart failure trials compared to other periods.
They concluded, not surprisingly, that among cardiovascular
trials in the current decade, men still predominate overall, but
that the representation of women actually is improving,
especially when it comes to studies related to stroke and heart
failure. That's what's really interesting, Biykem.


The other point that you were very nicely raised had to do with
sex differences in primary and secondary prevention of
cardiovascular disease. And the one study that we have in our
issue, Biykem, was actually done in China. I really like this
global reach of our issue. I presented a study that was done in
the UK. You presented a study done in Sweden. This particular one
was done in China and they conducted a community based survey of
adults in seven geographic regions of China between 2014 and
2016. They really wanted to determine sex differences in the
primary and secondary prevention of cardiovascular disease. And
they looked at different factors in terms of age, education
level, area of residence. And they had more than 47,000
participants of whom 61% were women. And they found that 5,454
had established cardiovascular disease, 57% of whom were women
and 9,532 had a high estimated 10 year cardiovascular disease
risk. And of those, 71% were women. And they found that only
about 49% of women versus 39%, 60% of men were on any kind of
blood pressure lowering medications, lipid lowering medications,
antiplatelet therapy for primary and secondary prevention.


And they found that women with established cardiovascular disease
were significantly less likely than men to receive blood pressure
lowering medications, lipid lowering medications, antiplatelet
therapy, so on, so forth. And that woman with established
cardiovascular disease had better blood pressure control but less
well controlled NVM cholesterol, were less likely to smoke and
achieve physical activity targets. Conversely, women at high risk
of cardiovascular disease were less likely than men to have their
blood pressure LDL cholesterol, body weight controlled, despite
the higher use of blood pressure lowering medication. Really
interesting gaps in care that this study highlights that
hopefully can form the basis for interventions to try to address
those disparities.


And then as you know, we actually have a couple of research
letters on the representation of women in editorial boards of
major general and subspecialty cardiology journals, publishing
clinical research. In this particular study, they actually found
significant disparities where women were less represented among
deputy associate editors and more so in European journals
compared with US journals, general cardiology journals. Although
editorial board membership was actually similar between Europe
and the US, and they found that over 20 years, women deputy
associate editors representation increased significantly for our
journal, Biykem, Circulation. That was really very encouraging to
see. And women editorial board membership increased for
Circulation and for JACC without a significant change for the
American Journal of Cardiology. That was really nice to see.


The one thing that was notable was in terms of women serving as
editors-in-chief, we're still lagging behind in a big way, but
I'm hoping that this particular study and several other studies
that may get published in the future, will highlight these gaps
and hopefully will lead to increased representation of women on
editorial boards.


And finally we have an interesting study looking at the
representation of women and men among training programs where
they looked at the AAMC data and they were interested in looking
at training in general cardiovascular disease medicine as well as
for adult cardiology sub-specialties. And they also looked at
pediatric cardiology by the way. And they found that in 2017 to
2018, among all adult cardiology trainees, only 21% were women.
79% were men. And among trainees in the different adult
cardiology subspecialties, the representation was actually pretty
poor in interventional cardiology, where only 10% of the trainees
were women. And for electrophysiology, my own sub specialty, were
only 11.6% of the trainees were women. Really interesting
findings, the representation for advanced heart failure and
transplant like your specialty, Biykem, women constituted 31% of
the trainees and women did better when it came to adult
congenital heart disease representing 47% of the training.


Really interesting trends and they concluded that in this review
of ACG and the accredited training program, they found that
cardiology ranked second for the most under representation of
women, preceded as only by orthopedic surgery. And the sub
specialty trends that I shared with you were really interesting.
Hopefully as we see more of these publications, we'll be able to
as a community come together and think about what are the
barriers to more representation of women in these training
programs? And how can we overcome these failures to encourage
more women to go into this wonderful specialty of cardiology and
the different sub-specialties, including procedural
sub-specialties? Back to you, Biykem.


Dr Biykem Bozkurt: Thank you Sana. Very interesting findings
indeed. Another fascinating study that we have in our issue is a
study that provides us some insights on peripartive
cardiomyopathy and potentially the role of natriuretic peptides
during pregnancy.


This is an experimental study that involved natriuretic peptide
receptor knockout in mice in which natriuretic peptides would not
work. And the investigators demonstrated that these mice, during
the postpartum lactation period, had elevated aldosterone levels,
evidence of expression of pro inflammatory mediators such as
IL-6, cardiac hypertrophy, fibrosis, left ventricular
dysfunction, and even increased mortality. And interestingly,
they were able to abrogate the effects of the lactation by use of
mineralocorticoid receptor antagonists. With MRA use, there was
evidence of reduction in LVH and reduction in inflammatory
mediators.


There is a great editorial by Denise Hilfiker-Kleiner, who
addresses the potential hypothesis of the role of unbalanced
oxidative stress with prolactin in peripartum cardiomyopathy. And
that the natriuretic peptides can be protected. And raises the
question whether there could be a role for augmenting the
natriuretic peptides further by use of sacubitril/valsartan. Or
as was demonstrated in this study by you as a mineralocorticoid
receptor antagonists in the postpartum period. And she also
questions why in this experimental model, the detrimental effects
were not seen during pregnancy but only in the postpartum
lactation period.


Overall, very interesting papers. And finally we have an
inspiring piece in our past or discovery section. It's an
interview with Barbara Casadei, the President of European Society
of Cardiology. She goes in a very detailed fashion over her
career path, what she considers as the critical reasons for her
success and how she envisions to shape the future of women in
cardiology.


Dr Sana Al-Khatib: We would like to thank everyone who submitted
their research and their work for this issue and congratulate the
authors and investigators who were successful in getting their
work published. Thank you very much.


Dr Biykem Bozkurt: We thank you for tuning in to our podcast. We
hope that you'll enjoy our fourth issue for the Go Red for Women
as we continue to highlight some of the best science for
cardiovascular disease in women. Thank you.


This program is copyright, the American Heart Association 2020.