Feb. 13, 2023
Please join Circulation Senior Associate Editor Sana Al-Khatib and Associate Editor Mercedes Carnethon as they discuss the seventh Go Red for Women issue of the journal.
Dr. Sana Al-Khatib:
Hello and welcome to the Special Circulation on the Run podcast focused on the seventh Go Red for Women issue of the journal. I am Dr. Sana Al-Khatib. I'm an electrophysiologist at Duke University Medical Center and a senior associate editor for Circulation. I had the pleasure of co-leading this issue with a colleague and friend, Dr.
Dr. Mercedes Carnethon:
Well, I am so pleased to be with you today, Sana. My name is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine. I'm an associate editor at the journal Circulation and extremely excited to join you this year on the seventh issue, as a guest editor for our Go Red for Women Issue. And we've got so many great pieces today, so let's get going.
Dr. Sana Al-Khatib:
Wonderful. So we're very excited to provide you with some highlights of the issue that covers a broad range of topics related to cardiovascular disease in women. In this particular issue, the content is presented as five original research articles, three research letters, five online articles, and one in-depth review article. And like prior podcasts, this year's podcast will only focus on the original research articles, so let's get to it.
The first original research article is titled Exercise for the Prevention of Anthracycline Induced Functional Disability and Cardiac Dysfunction. This was the breast cancer randomized exercise intervention Brexit study. In this trial, the investigators enrolled 104 women who were between 40 and 75 years old and had stage one to three breast cancer. And these women were scheduled for anthracycline based chemotherapy and they randomized them to three to four days per week of aerobic and resistance exercise training for 12 months and they were randomized in one-to-one ratio to either do the exercise or really usual care. Very interesting study Merci, don't you think?
Dr. Mercedes Carnethon:
Absolutely. This is such an important issue, particularly for survivors of breast cancer.
Dr. Sana Al-Khatib:
Exactly. And in this trial, they focused on looking at the following measures, cardiopulmonary exercise testing to quantify the peak VO2 and functional disability, cardiac reserve, quantified using exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output stock volume, standard-of-care echocardiography-derived resting LVEF and global longitudinal strain.
And exercise training was found to attenuate functional disability at four months, which was really interesting, but not at 12 months. But when they looked at it, Merci, in a per protocol analysis, functional disability was found to be entirely prevented at 12 months among participants who adhered to exercise training.
Dr. Mercedes Carnethon:
That is so exciting to hear, especially with the potential to intervene for better outcomes.
Dr. Sana Al-Khatib:
Exactly. And then listen to this, as compared with usual care at 12 months, exercise training was associated with a net plus 3.5 milliliter per kilogram per minute improvement in the peak VO2 that coincided with improvements in cardiac output, stroke volume, LVEF and RVEF reserve, all of them improved, Merci.
Dr. Mercedes Carnethon:
That is such great news. What did the authors have to say about these findings?
Dr. Sana Al-Khatib:
Well, of course they were really excited about these findings because hopefully this will help a lot of patients. Now, when they looked at the exercise training in relation to resting measures of LV function, there didn't seem to be an effect. So they concluded that in women with early stage breast cancer undergoing anthracycline based chemotherapy, 12 months of exercise training did not attenuate functional disability, but it certainly provided clinically meaningful benefits in relation to the peak VO2 and cardiac reserve. So really interesting findings. Obviously I personally would like to see these findings replicated by other studies, but I think these results are promising.
Dr. Mercedes Carnethon:
I'm so excited to be able to feature that important piece in here, especially as more women are living and being treated for breast cancer.
Dr. Sana Al-Khatib:
Indeed. So Merci, I'll turn it over to you to tell us about a couple of your articles.
Dr. Mercedes Carnethon:
Well, I'd love to do two of mine back to back if that's okay with you because they address similar issues. So in one of the first from Dr. Yuan, Liu, and colleagues, they studied the influence of maternal exposure to particulate matter, small, fine, particular matter, and how that influenced the risk of congenital heart defects. We certainly know that congenital heart disease is a significant problem. And what's even more interesting is that the author's site that more than 80% of congenital heart disease has no known cause.
However, prior research does suggest that particulate matter is a plausible environmental exposure that could damage follicular development, disrupt hormone homeostasis, cause inflammation and glucose intolerance. All of those processes could lead to abnormal placentation and fetal development. And so I thought it was really exciting that they would pull together this very large study. And in fact, this isn't the first study to ask this question, but it is one of the largest. It was carried out in China, which is an area with relatively higher levels of pollution.
And the authors did some really cool things. I can't wait to tell you Sana, because I feel as though I rarely get to say NASA was involved in a study that we're featuring here in Circulation. So let me tell you about it.
Not just cardiologists, not just obstetricians and gynecologists, but environmental scientists were involved here and the mean monthly measures of PM 2.5, which is small fine particulate matter, were made via satellite, NASA satellites, and imputation procedures were used that combined a number of meteorologic variables, land use types, road network information, elevations and emissions to train models using machine learning to make estimates of the burden of PM 2.5. Isn't this cool?
Dr. Sana Al-Khatib:
Wow. How interesting. Absolutely.
Dr. Mercedes Carnethon:
Yes. It's probably not something you do every day in your cardiology practice, but it's particularly important for us to be able to get these precise measures of PM 2.5 exposure and what the authors were doing were matching up these units of exposure with the preconception period three months before pregnancy, the first trimester three months after pregnancy, and the entire window to determine how exposures to PM 2.5 during those critical periods for fetal development influenced congenital heart disease and they studied the major causes of congenital heart disease, the major classes using ICD 10 codes.
Dr. Sana Al-Khatib:
Wow. Well, I can't wait to hear the results.
Dr. Mercedes Carnethon:
So the results suggested that in general, the risk of delivering a baby with a congenital heart defect increased by 2% for each 10 nanogram per meter cubed in maternal exposure to PM 2.5 during the preconception period. And this relationship was even stronger preconception than it was during the first trimester. And when they studied different types of congenital heart diseases, the strongest associations were with septal defects. And this was regardless of the exposure window, this was preconception, the first trimester and the entire peri-conception window. I think another really compelling thing about a study of this size, and did I mention that it was 1.4 million births that were studied here during a period of time between 2014 and 2017? 1.4 million births.
Dr. Sana Al-Khatib:
That's a very large study.
Dr. Mercedes Carnethon:
Yes, and one of the benefits of having a study of that size is that you have the opportunity to look at subgroup effects to determine whether there are other characteristics that modify the relationship of the exposure and the outcome in this case PM 2.5 exposure. And what they found was that the relationship of PM 2.5 exposure with congenital heart disease was even stronger for births that took place in northern China or births that happened in areas with a low per capita disposable income. And even more surprising, and I'm not sure if this surprised you, but the relationships were even stronger in births to mothers who were younger than age 35. And that's particularly telling given that many births are obviously happening when women are below age 35.
So I think these findings are just so compelling. I think they are important certainly for our cardiology community, but I think they're also important for policy makers as they consider the implications of air quality and how that affects our long-term health.
Dr. Sana Al-Khatib:
Yeah, no, absolutely. Very important implications here, Merci. I agree.
Dr. Mercedes Carnethon:
Yes. Well, so I was really pleased to feature that article and then in the same issue, if I can continue to hold the microphone here.
Dr. Sana Al-Khatib:
Yes, please.
Dr. Mercedes Carnethon:
In the same issue, we have another paper led by authors from China, Zhang and colleagues, who carried out a study of what happens when women grow up with congenital heart disease and they have their own pregnancies? And so the goal of this particular paper was to look at the influence of pulmonary hypertension, which is a common complication of women with congenital heart disease when they become pregnant, to see how the severity of pulmonary hypertension influences pregnancy outcomes in these women.
Dr. Sana Al-Khatib:
A very important topic. Yeah, I agree, Merci.
Dr. Mercedes Carnethon:
Yes. And so this was carried out in over 2000 pregnant women with congenital heart disease who had completed pregnancies. This was a retrospective analysis. And of those a significant portions, 729 women, had pulmonary hypertension. And these range from mild to moderate to severe. And unfortunately, maternal mortality was an outcome in this study along with birth outcomes among the babies. And what the authors found, I guess, consistent with what one might hypothesize, is that the severity of pulmonary hypertension was associated with adverse outcomes. Those women who had more severe pulmonary hypertension were more likely to experience maternal mortality. They were more likely to experience heart failure and other cardiac complications.
And unfortunately, those risks were as well passed along to the babies where there were more obstetric complications and other adverse events. So it's an unfortunate finding, but I would say that there were a number of bright spots and a few bright spots to this particular study. And their findings were that those women who had follow-up care with a multidisciplinary team, strict antenatal supervision, tended to have a lower likelihood of these adverse events.
Dr. Sana Al-Khatib:
That is so good to know. Of course, I mean, we have thought of that to be the case, but now to have a study showing that is really impactful.
Dr. Mercedes Carnethon:
It certainly is. And especially such a well done study. These aren't common. And so this team managed to find a relatively large sample size so that they could produce robust estimates that we can use and consider when we consider helping women with congenital heart disease manage their developing families. So I really thank you for letting me talk about two of these studies back to back, but I can't hog the microphone. We have so much good work in this episode.
Dr. Sana Al-Khatib:
Yeah, no problem. But it's so good to see more work being done on the adult congenital heart disease, by the way, because this is a growing patient population, and it's great that we were able to feature it in two articles, Merci. So let me present the second paper that I had the pleasure of handling in many ways, this particular paper. First of all, it is a topic that's near and dear to my heart as I am an electrophysiologist and the paper provides data on the comparative effectiveness of left atrial appendage occlusion versus oral anticoagulation bisects in patients with atrial fibrillation. And not only am I interested in the topic, but I actually was the senior author on this paper, and so I really need to acknowledge that and would like to share some highlights of the paper with you.
So in this particular paper, Merci, we analyzed Medicare claims data from 2015 through 2019, and we really focused on patients who were deemed to be eligible for left atrial appendage occlusion.
And we divided them into sex subgroups. And of course, we had to apply robust statistical methodology first in terms of making sure that patients with left atrial appendage occlusion were well-matched in one-to-one ratio to those receiving anticoagulant therapy. Obviously, a lot of selection bias goes into those assignments in clinical practice, and so we needed to make sure to match those groups, and we did that for women and we did that for men. And we were really interested in looking at the risks of mortality stroke or systemic embolism as well as bleeding between these matched groups, so we wanted to compare those risks.
And so among females, we had 4,085 left atrial appendage occlusion recipients, and those were again matched in one-to-one ratio to women who were receiving anticoagulant therapy. And if you look at the subgroup of males, 5,378 were left atrial appendage occlusion recipients. And again, those were similarly matched to men who received oral anticoagulation.
And so of course, after doing the matching, we applied the further adjustment to take care of remaining differences between the groups. So what did we find? We found that left atrial appendage occlusion was indeed associated with a significant reduction in the risk of mortality as well as stroke or systemic embolism and this was true for females and males. And when we looked at the bleeding risk, we found that that risk was significantly greater in left atrial appendage occlusion recipients early after implantation, because as you know, Merci, those people for the first six weeks have to be treated either with anticoagulation or a combination of aspirin and Plavix, and so it's not surprising that bleeding was actually high early on, but really lower after the six week per procedural period for both females and males.
And so what we concluded in this study, which was a real world study, and that's the significance of this because several trials had been conducted, but many of us always raised the questions of, well do the results of the clinical trials apply to the average patient that we see in clinical practice? So many of us would like to see comparative effectiveness analysis being conducted in real world populations, and here we were able to show that left atrial appendage occlusion was associated with a reduction in the risk of death, stroke, or systemic embolism as well as long-term bleeding both in females and males. So really very interesting results that I think should help inform shared decision making discussions with patients.
Dr. Mercedes Carnethon:
Oh, absolutely. I have to say I'm not biased. It's not because you are the senior author, it's because this is just truly excellent work, really a creative design. And I agree with your assessment that doing this sort of real world work is critically important because sometimes we don't have the representation in clinical trials of a distribution of people who would ordinarily be the targets of these types of therapies. And so I really applaud you and your team for really leading an excellent study that I hope people will find extremely useful.
Dr. Sana Al-Khatib:
Well, thank you very much, and I really want to give a lot of credit to the first author, Dr. Zeitler, who has been mentee of mine for many years and has done a great job and really a lot of credit to the rest of the co-authors.
Dr. Mercedes Carnethon:
Well, that's fantastic. I'm glad that I chose the ordering that I did because the final study that I'd like to talk about is in fact a randomized trial. And I think similar to the one that you just described, this is another study that's comparing sex differences. So this particular study led by Coughlan and colleagues describes sex differences in 10-year outcomes after percutaneous coronary intervention with drug-eluting stents. And given the positive impact that drug-eluting stents have had on improving coronary artery disease, I think it's critically important for us to find out whether or not there are any disparities by sex and the types of outcomes that occur following percutaneous coronary intervention. And so in order to address this question, what the authors did was to carry out a pooled analysis of five individual patient data from trials of drug-eluting stints that had at least 10 years of follow up.
And the objective here was to really address the controversy in the field about whether the outcomes were worse for women, which was observed in some studies versus in other studies where there was no difference. And the benefit of using this pool design, again, this sample size, I'm an epidemiologist, I love big samples for what can be done. And in the 9,700 patients that were included in this trial, 24% of them were women. So really it required this type of a meta analytic design in order to have enough women to answer these questions. So the outcomes of interest here included death from all causes, death from cardiovascular disease, MI, stent thrombosis, and revascularization of the target lesion, the target vessel, and the non-target vessel.
So one of the challenges in interpreting findings from prior studies of this question are the concerns that the clinical characteristics of men versus women who underwent PCI were different.
And in fact, in this particular pooled analysis, men were more likely than women to have three vessel disease, and they had a lower, lower mean ejection fraction coming in the characteristics following angiogram and the procedure also showed some differences by sex groups, namely that women had smaller vessel reference diameters before PCI and a smaller minimal luminal diameter after PCI. But men had a longer total stinted length as compared with women. So I'm sure you want to know what ended up happening.
Dr. Sana Al-Khatib:
Please.
Dr. Mercedes Carnethon:
Yes. So when the authors tested their primary hypothesis of sex differences in tenure outcomes, they found that some of the very minor differences in the proportion of women versus men who experience the outcomes of interest were eliminated following adjustment for relevant characteristics, or in fact that women were slightly less likely to experience the outcomes of interest. Specifically women were less likely to experience death from any cause over 10 years, but there was no difference in cardiovascular death as compared with men.
Women though were significantly less likely than men to require repeat revascularization of the target legion, the target vessel, and the non-target vessels over 10 years. But unfortunately, the findings weren't all good. A notable exception was that when the offers examined the one-year event rates, women had a significantly increased likelihood of MI in the first 30 days after PCI. And I'm not sure why this is, but the authors did advance numerous hypotheses to explain their findings. One was that baseline and procedural characteristics varied markedly between men and women, and that the age was a primary confounder of these findings. And this was because they carried out a series of sensitivity analyses where they didn't account for age and when they didn't account for age, women had an increased risk of cardiovascular death through the entire 10 years of follow up. And it's curious why this would happen.
And the observation was thought to be attributable either to women developing CAD later than men in life, or because they're diagnosed later because of decreased physician awareness among women. And that's shocking to hear since we all know that cardiovascular disease is the leading cause of death among women. So I really think that the observations in this large pooled analysis do warrant further study and investigation. And a point that I think we discussed earlier is that the representation of women in clinical trials, we have to have more women in these trials and this was an argument that the authors advanced because then without more women in these trials, we don't have adequate power to investigate these sex differences and to explore reasons behind these sex differences. And so I hope that investigators will really heed these calls so that we can generate the best possible science to inform treatment options for women so that we can maximize our health outcomes.
Dr. Sana Al-Khatib:
No, absolutely. Those are excellent points, Merci, that you make. And we certainly need to make sure that we have more women participating in clinical trials and that to the extent that we can, that patients enrolled in clinical trials are representative of patients that we see in clinical practice. You bring up excellent points. Thank you for that great summary.
Dr. Mercedes Carnethon:
Thank you so much, and thank you really for letting me join you in this special issue. I'm so excited about all of our pieces, not just these original research pieces, but as well our research letters and the rest of our content. I think there's just a lot for our readers to dig into here.
Dr. Sana Al-Khatib:
Yeah, no, absolutely. Merci, it's been a pleasure for me to co-lead this issue with you and I agree while we focus this podcast on the original research articles, the other articles are equally interesting and impactful. So a lot for our readers to enjoy here. So in closing, we want to wholeheartedly thank Dr. Joe Hill, the editor-in-chief for Circulation, Dr. James De Lemos, the executive editor of the Journal and all authors who submitted the research for this issue. We also want to thank the Circulation associate editors and staff who worked so hard to deliver what you are about to experience. We're very excited about this issue and know you will find it very informative and interesting.
This concludes our Go Red for Women issue Circulation on the Run podcast. Thank you so much for listening.
Dr. Mercedes Carnethon:
Thank you.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. 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.
