Author + information
- aDivision of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio
- bDivision of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- ↵∗Address for correspondence:
Dr. William T. Abraham, Physiology, and Cell Biology, College of Medicine Distinguished Professor, Division of Cardiovascular Medicine, The Ohio State University, 473 West 12th Avenue, Room 110, Columbus, Ohio 43210-1252.
“Men know life too early. Women know life too late. That is the difference between men and women.”
—Oscar Wilde (1)
In Oscar Wilde’s 19th-century play, A Woman of No Importance, the above quote characterizes the moral double standard of the times in reference the Mrs. Arbuthnot having a child out of wedlock. While the recognition of gender differences dates back well before the Victorian era, the formal academic study of gender differences developed more recently following the women’s liberation movement of the 1960s and 1970s. Despite significant cultural changes and the development of formal gender studies programs happening earlier, in medicine women remained so dramatically under-represented that the United States National Institutes of Health (NIH) Revitalization Act was signed into law in 1993 directing the NIH to establish guidelines for including women and minorities in clinical research (2). Consequently, women’s participation in clinical research has improved over the past 25 years. However, a recent analysis demonstrated that increased representation in clinical trials remains suboptimal and is not uniform across cardiovascular disease states. In particular, women remain significantly under-represented in heart failure, coronary artery disease, and acute coronary syndrome trials (3).
In this issue of JACC: Heart Failure, Guistino et al. (4) report a secondary analysis from the Cardiothoracic Surgical Trials Network (CSTN) randomized controlled trial comparing mitral valve (MV) replacement versus MV repair for patients with severe ischemic mitral regurgitation (SMR). They examined sex differences in baseline characteristics and clinical outcomes in patients with SMR undergoing surgery. Of the 251 patients enrolled, 38% were women. Several notable baseline differences were discovered. Despite no difference in age at the time of surgery, women had a higher incidence of diabetes mellitus, hypertension, chronic kidney disease, and thyroid disease. Women also reported worse quality of life as measured using the Minnesota Living with Heart Failure questionnaire. Finally, there were important echocardiographic differences between men and women. Women had smaller left ventricular (LV) volumes (even when indexed for body surface area), smaller mitral valve effective regurgitant orifice area (EROA), MV annulus area, MV tethering area, and shorter interpapillary muscle distance. Conversely, women had a higher ratio of EROA to left ventricular end-diastolic volume (LVEDV), suggesting that the mitral regurgitation (MR) in women is more disproportionate to LV volumes than in men. The EROA/LVEDV ratio finding is particularly important in light of a recently proposed framework of “proportionate and disproportionate” functional MR potentially better characterizing MR for the selection of optimal treatment (5).
After adjusting for baseline characteristics, female gender was still independently associated with higher mortality at 2 years and a higher rate of the composite of death, stroke, MV reoperation, heart failure hospitalization, or increase in New York Heart Association functional class ≥1. Following MV surgery, LV end-systolic volume index improved from baseline in both men and women with no significant gender differences in the percent change. Quality of life (QOL) scores also improved for both men and women at 2 years. However, women had worse overall QOL scores at 2 years adjusting for both baseline characteristics and baseline differences in QOL scores. The study is consistent with other heart failure studies that suggest that women have a higher symptom burden than men even when correcting for comorbidities, suggesting that additional work is needed to understand sex differences in symptom burden (6).
This analysis illustrates important baseline clinical differences between men and women with SMR and potential differences in outcomes following MV surgery. It is an important contribution in light of the ongoing under-representation of women in heart failure and cardiac surgery trials. Yet, despite the thought-provoking findings, this study raises more questions than it provides answers. With more comorbidities and worse baseline QOL, were the women in this analysis “sicker” and as a result the surgery was too late? Is there a comorbidity that confers an unrecognized higher risk in women than in men? Is MV surgery just riskier in women (7)? Additionally, based on the aforementioned conceptual framework of “proportionate and disproportionate” MR, the women in this study should have done better due to their higher EROA/LVEDV, suggesting more disproportionate MR. On the contrary, in the current analysis, patients with smaller EROA/LVEDV ratio had more reverse remodeling, suggesting this hypothesis may not be entirely correct.
Finally, it is important to note that even in this analysis of gender differences, men made up the majority of study participants. Although the original CSTN trial was not designed to evaluate the gender differences, it is discouraging that equal representation continues to lag in clinical trials. There are most certainly gender differences in how SMR manifests, as evidenced by the significant differences in baseline and echocardiographic characteristics in this study, and gender or other individualized definitions of SMR may be needed. But if women cannot even be equally enrolled in clinical trials, how will we ever understand these nuances, let alone translate them to guidelines and clinical practice?
Multiple recent studies of MV interventions have produced both exciting and contradictory results. The MITRA-FR (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) and COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trials sequentially resulted in no benefit and considerable benefit in select patients with MR compared with medical therapy (8,9). How are we to reconcile these outcomes and that seen in the study by Guistino et al.? Collectively, there appears to be encouraging evidence for the benefit for MV interventions in the right patients at the right time. But we remain a long way away from fully understanding which patients benefit and appropriately timing them so they are not too sick or the treatment too late. In particular, further study is needed to know how to assess SMR in women to make sure that, like Oscar Wilde’s character, they do not know life too late. Finally, it is clear that we have a lot more to learn about sex differences in the benefits of various therapies and, as the NIH suggested many years ago, we will not determine the answers unless we study these patients.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Lindenfeld has reported that she is a consultant for Abbott. All other authors have reported that they have no relationships relevant to the content of this paper to disclose.
- ↵Wilde, O. A Woman of No Importance. Available at: https://en.wikisource.org/wiki/Page:Wilde_-_A_Woman_of_no_Importance,_1909. Accessed May 9, 2019.
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