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Circulation on the Run

Feb 17, 2020

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.