Feb 15, 2021
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.