Circulation February 16, 2021 Issue

This week, Circulation on the Run highlights the articles that
are part of the Go Red for Women issue. Please join Senior
Associate Editors Sana Al-Khatib and Biykem Bozkurt as they
provide summaries for the articles found in this special 5th
Edition of Go Red for Women.


TRANSCRIPT BELOW


Dr. Sana Al-Khatib:


Greetings. And welcome to this podcast that will showcase the
contents of the Fifth Annual Go Red For Women Issue of
Circulation. I am Sana Al-Khatib. I am a Professor of Medicine at
Duke University and an electrophysiologist. And I am a Senior
Associate Editor for Circulation. And I'm delighted to introduce
my co-editor for this issue, Dr. Bozkurt.


Dr. Biykem Bozkurt:


Thank you, Sana. I'm Biykem Bozkurt, Professor of Medicine from
Baylor College of Medicine in Houston. And I'm also a Senior
Associate Editor at Circulation. And we're delighted to do this
podcast. We'll be covering very exciting articles. We're very
proud of our Go Red For Women Issue.


Dr. Sana Al-Khatib:


And you're exactly right, Biykem. We are indeed excited about the
content that we will be sharing with you. And I will actually
start with a couple of articles, tackling arrhythmias and
covering some important topics in this field. So the first paper
is actually an original research article that summarizes the
results of sex and the outcomes of catheter ablation in the
CABANA trial. And as you know Biykem, CABANA was a randomized
clinical trial of patients who were either older than 65, or if
they were younger than 65. They had to have risk factor, at least
one risk factor for stroke. And those patients who had AFib were
randomized to catheter ablation strategy versus pharmacologic
strategy. In this particular secondary analysis of the CABANA
trial, the authors looked at association between sex and outcomes
of catheter ablation. And this is a really important question in
the field of electrophysiology because several prior studies had
suggested that women may be at an increased risk of adverse
events and complications from invasive procedures.


Dr. Sana Al-Khatib:


So it was really good to see the results of this analysis and
some of their findings were as follows. They enrolled 819 women
in CABANA Biykem, which is a really good number because it
accounted for 37% of patients enrolled in that trial. And this is
something that we all strive to do in terms of enriching clinical
trials with good women representation. And 1,385 of the patients
were men. And compared with men, women had some baseline
characteristics that were different. They were older. They were
more likely to be symptomatic to present with paroxysmal atrial
fibrillation. And when they looked at the outcomes of women, they
found that the risk of complications was actually pretty
infrequent in both sexes. And there was no indication that women
had a higher risk of complications, so that was really reassuring
to see. And you may recall that in the main trial and when they
analyze data based on the intention to treat principle, they
found no significant difference in the primary endpoint between
ablation and pharmacologic therapy.


Dr. Sana Al-Khatib:


And just as a reminder, the primary endpoint was a composite
outcome of deaths, disabling stroke, serious bleeding, or cardiac
arrest. And in this secondary analysis focused on sex
differences, they again found no difference in that primary
outcome between ablation and pharmacologic therapy, regardless of
sex. But when they looked at the risk of recurrent AFib, that was
definitely significantly reduced in patients undergoing ablation.
And that was true for men as well as for women although it seemed
that difference was even larger for men.


Dr. Sana Al-Khatib:


I would have loved to see some data on quality of life Biykem,
but these results are definitely reassuring and certainly
indicate that in our female patients that we see in practice who
are symptomatic with atrial fibrillation, passive ablation should
certainly be considered as one of the treatment options. So with
that in mind, I'm going to switch gears and share with you some
of the results from his second paper in the Go Red For Women
Issue that presented the results of an analysis of the engage a
SME 48 trial. And that analysis aimed to examine the efficacy and
safety of edoxaban in women versus men.


Dr. Sana Al-Khatib:


And this was a really large trial. They included 21,105 patients.
Again, representation of women was pretty good at 38%. And they
enrolled patients with AF who had a chart score of at least two.
And they randomized them either to a higher dose of edoxaban,
lower dose of edoxaban or warfarin. And the primary endpoint of
the trial, where the composite of stroke or systemic embolism
looking at efficacy and ISTH defined major bleeding, looking at
safety. And not surprisingly, there were some differences in the
baseline characteristics between men and women, with women being
older, having lower body weights, more likely to have
hypertension, renal dysfunction, but less likely to have
diabetes, coronary artery disease. What was interesting Biykem,
is that when they looked at the pretreatment endogenous factor Xa
activity, this was significantly higher in women at baseline
compared with men. But when they looked at the treatment effect
of edoxaban, it appeared to be greater in women, such that when
you look at the resulting endogenous factor Xa activity, after a
treating these patients, the end result was actually similar
between the two sexes, two to four hours after the dose.


Dr. Sana Al-Khatib:


But then also when you look at the treatment effect, they found a
similar reduction in the risk of stroke, systemic embolism, and
major bleeding with edoxaban in women versus men. However,
actually women assigned to the higher dose of edoxaban,
experienced a greater reductions in hemorrhagic stroke,
intracranial bleeding and life-threatening or fatal bleeding
compared with men. So these are really important findings, very
interesting findings because, intracranial bleeding,
life-threatening bleeding, really dreaded outcomes of
anticoagulant therapy in patients with atrial fibrillation. So
very exciting results. With this, I will turn over to you Biykem.


Dr. Biykem Bozkurt:


Thank you, Sana. We also have great papers on ischemic heart
disease. There's a fascinating research paper on coronary optical
coherence tomography, and cardiac MRI to determine the underlying
causes of MINOCA, myocardial infarction with non-obstructive
coronary arteries in women. This I find it almost like having a
magical mirror showing exactly what's happening inside the heart,
in the setting of MINOCA, which is seen in approximately six to
15% in my cases and disproportionately affecting women. The
investigators performed coronary optical coherence tomography,
which captures very small micrometers structures with very high
resolution providing information on tissue composition.


Dr. Biykem Bozkurt:


They also did cardiac MRI in approximately 116 women diagnosed
with MINOCA by cat. The optical coherence tomography identifies a
culprit lesion in approximately health, surprise, which was most
commonly plaque rupture. TMR was abnormal in approximately three
quarters with an ischemic pattern in health, non-ischemic pattern
in approximately 20% like myocarditis, takotsubo or non-ischemic
cardiomyopathy with the combined non-ischemic cardiomyopathy with
the combined OCT and MRI, they were able to identify hypothesized
cause for MINOCA in approximately 85%, and they couldn't identify
any abnormality in about 15. Overall with both modalities,
ischemic etiology was determined to be the cause in approximately
three quarters, non ischemic etiology, in about 20% and no
mechanism could be identified as 15%.


Dr. Biykem Bozkurt:


We also had a resource letter, which I find to be quite
complimentary to the topic, this time, examining coronary
vascular response to vasoactive breathing maneuvers in ischemia
with no obstructive coronary arteries or INOCA. This time
assessed by another fancy modality oxygenation sensitive cardiac
MR in female patients with recurrent chest pain, with no
obstructive coronary artery by coronary angiography. By
comparison of 20 women with INOCA, chest pain without any
obstructive disease to 20 age matched healthy volunteers, they
found no differences in LV volumes function, LV mass, or global
oxygenation. But women with INOCA had significantly higher
regional variations in response to these breathing and breath
holding maneuvers, suggesting heterogeneous coronary vasomotor
activity.


Dr. Biykem Bozkurt:


This regional heterogeneity suggested alterations in
microvascular dysfunction, which is rather unique and supports
the concept of the microvascular dysfunction, which may explain
the presence of ischemic symptoms in the absence of epicardial
coronary disease, but also in the absence of global coronary
perfusion abnormalities, which have been reported and have been
discorded in some of the former literature. So this study also
implies a potential role for this perhaps new diagnostic
modality, the oxygen sensitive cardiac MR, to have a potential
investigator role for future clinical studies in patients with
the INOCA. The third patients on the realm of ischemic heart
disease reports analysis, highly awaited analysis on the trends
in returns events, following myocardial infarction among US women
and men by using administrative records from approximately 1.4
million hospitalized patients with MI between the dates of 2008
and 2017.


Dr. Biykem Bozkurt:


And following them for returned to MI CHT events, heart failure
hospitalization, and all-cause mortality within a year post Mi.
The investigator has reported the following, the baseline and
recurrent event rates for MI and coronary heart disease event
rates were higher for men than women. Heart failure
hospitalization rates were higher in women than men. The good
news is though the rates of recurrent MI, recurrent coronary
heart disease events, heart failure hospitalization, all-cause
mortality within a year after MI, declined considerably both in
men and women and with proportionately greater reductions for
women than men. However, this should not create any complacency
because the rates remained still quite high and coronary heart
disease is still the number one killer for both men and women. I
know we have fascinating papers on sex differences in sudden
cardiac arrest. So I will turn the mic to you, Sana for you to
comment on those.


Dr. Sana Al-Khatib:


Thank you very much, Biykem. A really interesting papers that you
presented there. So when it comes to sudden cardiac death, which
is an area that is near and dear to my heart, we actually have
two very interesting papers. The first paper is an original
research article that examined sex differences in outcomes among
resuscitated patients with out of hospital cardiac arrest. And
those were patients who were successfully resuscitated from
arrest and were enrolled in the continuous chest compression
trial. And they applied a rigorous statistical analysis to their
data, looking at this association while adjusting for important
factors. They also looked at DNR status, withdrawal of life
sustaining therapy, order status to see if there are any inner
actions there. And they included 4,875 successfully resuscitated
patients, of whom 1825 were women. Again, good representation of
women here, 37%. And a bit more than 3000 of their patients were
men, against some differences in baseline characteristics between
women and men, with women being older, they were less likely to
receive Bystander CPR and had a lower proportion of cardiac
arrests that were witnessed or had shockable rhythm.


Dr. Sana Al-Khatib:


So when they looked at survival to hospital discharge, that was
significantly lower among women compared with men. So you're
looking at a survival that was 36.3% in men versus 22.5% in
women. So that's actually a really big difference. And it's going
to be important to understand better and look at more granular
data that would account for that difference. They also looked at
the association between sex and survival at discharge, and they
found that this was modified by DNR and withdrawal of life saving
therapy status, such that women had significantly reduced
survival at discharge, among patients who were not made DNR,
didn't have a withdrawal of life support order. And so they
highlight these differences and really push for the need to try
to understand reasons for these so that we can work on improving
prognosis and outcomes for women.


Dr. Sana Al-Khatib:


The second paper is really interesting. This was a research
letter that looked at sudden cardiac arrest in young women. And
although several prior studies have looked at sudden cardiac
arrest in men versus women. This particular one was focused on
young women, defined as women younger than 40 years of age. And
this actually delved into that pair sudden death expertise center
registry, which is a prospective population-based registry that
collects data on cardiac arrest in Paris and its suburbs. And
they looked at those cardiac arrests occurring between 2011 and
2018. Their definition of sudden cardiac arrest was closure. And
they had 14,210 sudden cardiac arrests that were recorded with
1062 young, meaning under 40 years of age victims of whom three
36 were women. And they found that the mean age at the sudden
cardiac arrest was 31.3 years.


Dr. Sana Al-Khatib:


And the interesting findings were as follows, sudden cardiac
arrest was the first manifestation of any underlying disease in
89 cases. So 63%. So that was actually a high number. Of course,
looking at risk factors, those were not surprising in terms of
the presence of hypertension, hyperlipidemia, diabetes,
overweight, smoking, 22 patients had a previous history of
cardiovascular disease. Only 16.5%, were mainly non-ischemic
heart disease. Minority had family history of sudden cardiac
arrest at a young age and under the age of 50. And the vast
majority of those events occurred at home and only five really
occurred in the setting of vigorous exercise or sports. Initial
shockable rhythm was found in 73, meaning 29% paces and so on and
so forth. They really provide more information about the
circumstances of the cardiac arrest that would be really
interesting to look at.


Dr. Sana Al-Khatib:


And finally, when they looked at cardiac etiologies, those were
observed in about 50% of the cases, including non-ischemic
cardiomyopathy, ACS, non-structural heart disease, coronary
syndrome, MINOCA was uncommon, actually only one case and so on
and so forth. So definitely I invite you to delve more into the
content of this paper, to learn more about this condition.
Biykem, I will turn over to you.


Dr. Biykem Bozkurt:


Fascinating results and quite striking. We have a very
interesting study that I think is going to be of interest to our
listeners on which actually portrays what happens to the heart in
the setting of metabolic syndrome during pregnancy. The
investigators want to find out if obesity or metabolic syndrome
could disrupt the physiological adaptive cardiac remodeling that
happens normally during pregnancy. This is an important question
because as you know, Sana, there has been a significant increase
in the prevalence of obesity and metabolic syndrome in women of
childbearing age with more than 30% of females in their
reproductive years being obese. So in this study, investigators
compared pregnant female mice who develop metabolic syndrome
after 50% fat diets to non-pregnant female mice or pregnant
female mice that are non-metabolic and being fed by controlled
diet. And the pregnant mice with metabolic syndrome had increased
cardiac mass, pathological hypertrophy and fibrosis, and up
regulation of fetal genes associated with pathological
hypertrophy.


Dr. Biykem Bozkurt:


And they also showed that the mice had cardiac dysfunction when
challenged by angiotensin two infusion after delivery. So these
suggests that metabolic syndrome or obesity could disrupt the
physiological adaptation that is expected during pregnancy and
may result in pathological cardiac remodeling that could
predisposed not only to future cardiovascular complications, but
also added risk to adverse outcomes during pregnancy.


Dr. Biykem Bozkurt:


Another paper that is, which I find to be very important is drug
discontinuation clinical trials. As you know, women are
underrepresented across cardiovascular clinical trials and in
several observational studies, women have been reported to be
less likely than men to adhere to prescribed medication,
including cardiovascular medications, which may contribute to
worse prognosis. The reasons for this has been unclear. And the
investigators in this study examined the association between sex
and premature study drug discontinuation and withdrawal of
consent in 11 large-scale TIMI trials with approximately 200,000
subjects. After adjusting for baseline differences, women had 22%
higher odds of premature drug discontinuation and withdrawal of
consent. Importantly, this was not explained by differences in
comorbidities neither by reporting of adverse events.


Dr. Biykem Bozkurt:


This is important because we always attributed the differences in
drug discontinuation to the differences in pharmacodynamics and
pharmacokinetic profile and the woman experiencing higher
incidence of adverse drug reaction with cardiovascular drugs.
This was not the case in this study. And moreover the difference
was not restricted to certain medications. It was seen in a wide
range of study drugs, such as antiplatelets, anticoagulants,
lipid-lowering drugs, antidiabetic medications. And also there
was a large sex difference in regional representation. The drug
adherence in North America demonstrated a significantly higher
discontinuation in women than in men. The difference was
relatively modest in Europe, Middle East Africa and Asia. And
there was no difference between the two sexes between men and
women in South and Central America. These results may suggest
that there are potentially attributable reasons due to
differences in access to health care, social, economic, cultural
factors, non study related costs, transportation, family
obligations, as well as concerns about drug safety and confidence
in the healthcare system that may have played a role. Back to
you, Sana.


Dr. Sana Al-Khatib:


Very interesting results, Biykem. So the next paper is actually a
research letter that I really enjoyed reading, looking at sex
differences in blood pressure associations with cardiovascular
outcomes. And what the authors did is they studied more than
27,000 participants. 54% of whom were women. And these people had
no baseline cardiovascular disease, but they had standardized
systolic blood pressure measurements performed in one of four
community-based cohort studies, for example, Framingham, Eric, so
on and so forth. And when they looked at the sex pooled analysis,
the threshold for incident MI and heart failure, was 120 to 129
millimeters mercury and for stroke was 130 to 139. In sex
specific analysis, interestingly though, they observed increasing
cardiovascular disease risk beginning at lower threshold of
systolic blood pressure for women than for men. The incidents of
cardiovascular disease proportionately increased beginning at a
lower range of systolic blood pressure in women compared to men.


Dr. Sana Al-Khatib:


And in multi-variable adjusted analysis, the presence of a
systolic blood pressure of 100 to 109 relative to a systolic
blood pressure of less than 100 was associated with incident
cardiovascular disease in women, but not men. So really
interesting findings. And the authors actually states that maybe
these findings could be related to differences in vascular
anatomy, physiology between men and women, but they say that
taken together their findings along with prior results, suggest
that maybe the possible need for a lower sex specific definition
of optimal systolic blood pressure for women. So really
interesting. So they push for people to really do some research
to validate these findings and explore these ideas further.


Dr. Sana Al-Khatib:


And then the last paper that I will present as to do with sex
stratified, a gene regulatory networks. And basically looking at
these to examine female key driver genes of atherosclerosis. And
what the author said is that for years, we have known about sex
differences in CAD with women developing more stable
atherosclerosis than men. However, the underlying vessel biology
had been unknown, and so they were trying to shed some light on
this. And they integrated female gene regulatory networks with
some single-cell RNA sequencing of the data from human
atherosclerotic plaque and single-cell RNA sequencing of advanced
atherosclerotic lesions in knockout mice.


Dr. Sana Al-Khatib:


And basically what they found is that by comparing sex specific
GRNs, they observed clear sex differences in network activity.
Within the atherosclerotic tissues, genes, more active in females
were associated with missing chemo cells, endothelial cells,
whereas genes, more active in males were associated with the
immune system. And they determined key drivers of these GRNs
being active in female with CAD being predominantly found in
smooth muscle cells. So it was really interesting because they
say, well, if we, based on these novel insights into molecular
mechanisms that underlie sex differences, within atherosclerosis,
perhaps, people can develop sex specific therapeutic targets. So
I thought that was really interesting, Biykem. Back to you.


Dr. Biykem Bozkurt:


Very interesting, indeed. The final paper I want to comment on a
very interesting research letter on temporal trends in proportion
of women, physician speakers at major cardiovascular conferences.
The investigators collected data on approximately 80,000 speakers
from large annual cardiovascular conferences. They selected the
ones that had more than 2,500 attendees, such as ACC, AHA, ESC,
TCT, HRS, and they show that between 2015 and 2019, the
proportion of women speakers increased modestly over time. But
unfortunately the invasive fields such as EP interventional
cardiology had the lowest proportions of women speakers in single
digits. Speaker roles also varied by gender with more men serving
in all the roles than women. Furthermore, all high-profile
interventional on EP talks were given by men. Non-invasive
specialties were more balanced. Women comprise approximately 46
to 50% of high profile speakers in non-invasive conferences. But
across the board, women were poorly presented among late-breaking
clinical trial presentations, almost in all conferences.


Dr. Biykem Bozkurt:


So overall the investigations concluded that though they were
below, but gradually increasing in woman physician speakers at
major cardiovascular conferences all the time. It appears that
more women were often being tasked with giving more
presentations, not more high profile ones. And they underlined
the policy of women in high profile roles and almost near absence
from the podium at late-breaking clinical trial presentations,
reflecting exclusion of women in major roles at national
meetings, underlining the need for structural and cultural
change. So overall, fascinating papers, which we believe will add
significantly to the field. On behalf of my co-editor, Dr. Dr.
Sana Al-Khatib, I would like to thank our contributors, the
authors, co-authors, investigators for their submissions, the
Circulation Staff, a special call out to Sara O'Brien for
creation of a very impactful Go Red for Women Issue, [and] our
editors for making this endeavor successful and our listeners for
joining.


Dr. Sana Al-Khatib:


I also want to thank everyone and thank you Biykem. It was indeed
a pleasure to work with you on this issue. Thank you. And thanks
to all.


Dr. Biykem Bozkurt:


Thank you.


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. The program is
copyright of the American Heart Association, 2021.