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

Over the past two years, the 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 post-infectious or post-vaccine myocarditis,¹ while females have greater risk for long Covid syndrome;² 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.

While 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 highlight 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.* By natural extension, measures and metrics of human biology frequently vary by sex.* 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 morphologic features such as heart size or even shoe size.* 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.* 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 to males;^3–5 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 (e.g. 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 to males, likely due to a combination of factors including sex differences in biological response, gender differences in patterns of prescribing and/or titrating therapies, and available therapies themselves being functionally inadequate or mismatched for the treatment of female-specific cardiovascular conditions.^3–6,10,11

The 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 non-linear that 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 (e.g. 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 re-tool 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.