A Scientific Imperative as Seen Through a Sharpened Lens: Sex, Gender, and the Cardiovascular Condition

HomeCirculation ResearchVol. 130, No. 4A Scientific Imperative as Seen Through a Sharpened Lens: Sex, Gender, and the Cardiovascular Condition Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBA Scientific Imperative as Seen Through a Sharpened Lens: Sex, Gender, and the Cardiovascular Condition Natalie A. Bello, C. Noel Bairey Merz and Susan Cheng Natalie A. BelloNatalie A. Bello https://orcid.org/0000-0003-3257-3623 Department of Cardiology (N.A.B., C.N.B.M., S.C.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA. , C. Noel Bairey MerzC. Noel Bairey Merz https://orcid.org/0000-0002-9933-5155 Department of Cardiology (N.A.B., C.N.B.M., S.C.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA. Barbra Streisand Women's Heart Center (C.N.B.M.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA. and Susan ChengSusan Cheng Correspondence to: Susan Cheng, MD, MPH, Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4977-036X Department of Cardiology (N.A.B., C.N.B.M., S.C.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA. Originally published17 Feb 2022https://doi.org/10.1161/CIRCRESAHA.122.320825Circulation Research. 2022;130:433–435Over the past 2 years, the coronavirus disease 2019 (COVID-19) pandemic has led us to step back and reflect on our work as scientists through a new lens. This fresh perspective has forced us to question not only what we thought we knew about infectious diseases, immune-inflammatory responses, and end-organ vulnerabilities but also about the interactions of sex and gender with health and disease. We now recognize that males are more susceptible to severe COVID-19 illness as well as postinfectious or postvaccine myocarditis,1 whereas females have greater risk for long COVID syndrome2; the same etiologic agent leads to many similar and yet some other quite disparate outcomes based on the sex of the infected host. These differences cannot be erased even after accounting for all possible confounders.Although perplexing, such sex differences are not surprising to those of us grappling with parallel conundrums in cardiovascular research. To this end, Dr Jane Freedman and the Circulation Research editorial team have been prescient in recognizing the time is right to take stock of the current state of our understanding of sex, gender, and the cardiovascular condition. At their urging, we enlisted thought leaders from across disciplines to produce this Compendium of updates on current knowledge and key scientific gaps relevant to sex and gender differences in cardiovascular risks and outcomes. The results are both illuminating and timely.As you will read in this Compendium, several key themes emerge. The first set of themes highlights our still nascent understanding of sexual dimorphism in cardiovascular biology. Among these is the recent recognition of genome-wide sex-biased gene expression and related molecular and cellular phenotypes that likely underlie sex-related divergence of phenotypes in both health and disease.14 By natural extension, measures and metrics of human biology frequently vary by sex.11 And yet, our understanding of sex-specific ranges or thresholds for both established and novel cardiovascular biomarkers still lags behind how we readily consider sex differences when interpreting gross morphological features, such as heart size or even shoe size.12,14 Another key theme is the paradoxical finding that when comparing females to males, traditional cardiometabolic risk factors contribute greater risk for the classic cardiovascular diseases but account for a smaller proportion of the total risk.6,7,11,19 In effect, females are more sensitive than males to the effects of certain risk exposures; at the same time, there is evidence of substantial residual risk in females—contributed by either inadequately measured or yet unidentified key factors or both.The second set of themes emerging from this Compendium underscores the need for greater balance to enable more effective approaches to reducing cardiovascular risks in females. One persistent theme is how prevalent cardiac diseases with common features, including heart failure, arrhythmias, and valvular disorders, tend to present phenotypically differently in females compared with males3–5; similarly, prevalent vascular diseases tend to manifest differently when involving each of the major coronary, cerebrovascular, and peripheral arterial vascular beds.6–8 In fact, certain apparently similar ischemic syndromes (eg, chest pain or leg claudication) can arise from relatively distinct pathophysiology in females compared to males.6,8 This fact leads us to recent guidelines9 encouraging avoidance of the term 'atypical' to describe symptoms in females where the preferred adjective should perhaps more accurately be 'understudied'. Not surprisingly, a related theme is the persistent disparities experienced by females compared to males in rates of diagnosis, treatment, and control of conventionally defined cardiovascular conditions, attributable to many factors, including delayed or missed recognition.3,5–8 Finally, and concerningly, is the consistent finding that available cardiovascular interventions are often not similarly effective in females compared with males, likely due to a combination of factors including sex differences in biological response, gender differences in patterns of prescribing or titrating therapies, and available therapies themselves being functionally inadequate or mismatched for the treatment of female-specific cardiovascular conditions.3–6,10,11The scientific imperative is now ever clear. Notwithstanding foundational achievements to date, much of what we currently understand about cardiovascular risk in females stems from predominantly descriptive data on sex differences. For instance, we are still at the beginning stages of appreciating how the diversity and range of proteins, metabolites, and immune-inflammatory markers vary by sex.12–14 We are still at the start of understanding how and why cardiac and vascular diseases can present quite differently in females and males, particularly with aging.11 While continuing to expand our recognition of dissimilarities, we need to press forward and more deliberately interrogate mechanisms as well as implications.11–16 Why do we consistently observe these differences and what do they mean for the future of cardiovascular health in females and males, not only as the population ages but also as previously presumed static entities such as atherosclerosis evolve over time—and as new disease types emerge, especially in the setting of new forms of systemic perturbations and stressors. To understand these important differences, we need to include sex-specific studies across all of our work, rather than treating this approach as part of a niche area of expertise.The scientific imperative is bolstered by historical analogies offered by physics and mathematics, as well as COVID-19. When Einstein described his theory of general relativity in 1915, he initially assumed that because his equations were nonlinear, they could not be solved. Within a year, however, the first of many exact solutions was discovered.17 In 1917, Einstein then adjusted his equations to support another assumption that the universe is static. This assumption was also later proven wrong in 1929 by Hubble, who showed the universe is expanding.18 As we have seen during this pandemic, even the most daunting problems (eg, rapid vaccine development) can prove to be solvable. Moreover, such progress is attainable even while recognizing that the landscape of human disease is expanding and becoming more rather than less complex.The insightful articles in this Compendium, and the broader context of this moment in biomedical history, underscore two inter-related central features of human biology—resilience and diversity. Rather than presenting with exclusively one phenotype or another, cardiovascular manifestations in females and males are not completely binary; they involve areas of commonality as well as difference. Not surprisingly, it is the areas of difference where the knowledge gaps remain the largest.12,15 For instance, when the totality of conventional risk factors is found to account for much less of the total cardiovascular disease risk in females compared to males, then the logical assumption is that there remain some major missing, unmeasured, or as yet undiscovered factors related to sex or gender.16,19 Alternatively, or in addition, it is possible that certain key contributors are being measured inadequately or incorrectly. It could be that we need brand new tools or that we need to retool our usual approaches.15,19 Ultimately, to help stimulate and drive further advances in the field, perhaps a more integrative and progressive perspective might involve considering the areas in urgent need of new knowledge as less about sex and gender differences and more about sex and gender diversity.Needless to say, there is more work to be done, and we expect the best is yet to come.Article InformationAcknowledgmentsWe are grateful to Mallory Heath, MLS, and Kylie Rhoades, for their invaluable assistance in organizing and supporting the collaborative work of multiple authors for this Compendium.Sources of FundingThis work was funded in part by National Institutes of Health grants K23HL136853, R01HL153382, U54AG065141, and U54CA260591; National Center for Research Resources, General Clinical Research Centers (GCRC) grant M01-RR00425, National Center for Advancing Translational Sciences Grant UL1TR000124, the Barbra Streisand Women's Cardiovascular Research and Education Program, the Linda Joy Pollin Women's Heart Health Program, the Erika Glazer Women's Heart Health Project, and the Adelson Family Foundation.DisclosuresN. Bello has served as a consultant for GSK. C.N. Bairey Merz has served as consultant for Sanofi, Abbott Diagnostics, and iRhythm. S. Cheng has served as consultant for Zogenix.FootnotesFor Sources of Funding and Disclosures, see page 434.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Susan Cheng, MD, MPH, Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA. Email susan.[email protected]orgReferences1. Barda N, Dagan N, Ben-Shlomo Y, Kepten E, Waxman J, Ohana R, Hernán MA, Lipsitch M, Kohane I, Netzer D, et al. Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting.N Engl J Med. 2021; 385:1078–1090. doi: 10.1056/NEJMoa2110475CrossrefMedlineGoogle Scholar2. Taquet M, Dercon Q, Luciano S, Geddes JR, Husain M, Harrison PJ. 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Rosenzweig A (2022) The Growing Importance of Basic Models of Cardiovascular Disease, Circulation Research, 130:12, (1743-1746), Online publication date: 10-Jun-2022.Wenger N, Lloyd-Jones D, Elkind M, Fonarow G, Warner J, Alger H, Cheng S, Kinzy C, Hall J and Roger V (2022) Call to Action for Cardiovascular Disease in Women: Epidemiology, Awareness, Access, and Delivery of Equitable Health Care: A Presidential Advisory From the American Heart Association, Circulation, 145:23, (e1059-e1071), Online publication date: 7-Jun-2022. February 18, 2022Vol 130, Issue 4 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.122.320825PMID: 35175842 Originally publishedFebruary 17, 2022 KeywordssexCOVID-19heart disease risk factorsEditorialsgender identityPDF download Advertisement SubjectsCardiovascular DiseaseWomen, Sex, and Gender