Sex, cardiovascular disease, and the inequities of COVID-19.

COVID-19 created a global stress that caused people to band together to help each other through difficult circumstances and stimulated international research efforts to create safe and effective vaccines on an unprecedented schedule. At the same time, the threat posed by SARS-CoV2 widened gaps in societies, exposing inequities including access to healthcare, job security, and economic stability. Among the most widely recognized crevice of discrimination was the unequal impact COVID-19 had on the sexes (1).

It is fitting that in a special call for papers dedicated to sex differences, this issue of American Journal of Physiology-Heart and Circulatory Physiology includes a paper by Hernandez-Hernandez et al. (2) on how cardiovascular disease differentially impacts COVID-19 mortality in males and females, with intriguing findings about a possible role for menopause. Work like this study is crucial to understand the inequities of this global health challenge and develop solutions that balance the scales of care. But this study goes beyond the male-female divide of the COVID-19 pandemic and brings in sociological and economic components that are necessary considerations to correct systemic imbalances that skew health risks toward more vulnerable segments of society.

Early in the COVID-19 pandemic, it became clear that some of the most significant risk factors for serious illness and mortality were preexisting cardiovascular disease or risk factors and male sex. As individual risks, cardiovascular disease and male sex have been firmly established, but the combination of cardiovascular risk and patient sex has only been specifically examined in a few small-scale studies. The work by Hernandez-Hernandez et al. (2) is a significantly larger study; it included 28,929 patients hospitalized for COVID-19 in Mexico between 27 February 2020 and 28 May 2020. Reflective of the lower hospitalization rates in women, only 35.41% of patients were women. Data confirm earlier reports showing that men had higher rates of COVID-19 mortality, intensive care admission, and intubation. Paradoxically, women hospitalized for COVID-19 had significantly higher rates of cardiovascular disease, hypertension, diabetes, and obesity, all risk factors for COVID-19 mortality. In a subanalysis of patients hospitalized for COVID-19 who had cardiovascular disease, women had an increased risk of mortality compared with men with cardiovascular disease. Interestingly, the relationship between cardiovascular risk factors and COVID-19 mortality was only significant in women over 52 yr, a delineation that approximates the onset of menopause.

The connection between cardiovascular disease and COVID-19 mortality in older women is an intriguing finding that could shed light on why COVID-19 mortality is generally lower in women. But this study goes beyond connecting epidemiological points and provides important insight into the broader issues of inequality and COVID-19 mortality.

The Global Health 50/50 website shows an overall balance of SARS-CoV2 infections between the sexes, but an imbalance in hospitalization, intensive care, and mortality that skews toward males (https://globalhealth5050.org/the-sex-gender-and-covid-19-project/the-data-tracker/, retrieved 12 August 2022). The reasons for an advantage in women diagnosed with COVID-19 are not clear, although fundamental sex differences in the immune system and response to infection have been proposed to play important roles. Females have two X chromosomes that contain several genes which encode proteins and micro-RNA important for innate and adaptive immunity, whereas the Y chromosome encodes several immune-suppressive genes. Partial escape of X-chromosome inactivation yields biallelic expression in women that could provide an immunological advantage (3). These chromosomal differences may be supplemented with hormonal gene regulation that also provides protection for females. Estrogens regulate ACE2 in a manner that could limit SARS-CoV2 infection, whereas androgens regulate TMPRSS2 expression to the disadvantage of males.

The study by Hernandez-Hernandez et al. (2) bolsters the arguments for the role of estrogens in COVID-19 mortality in women. The correlation between the decline in ovarian estrogens in women around the expected age of menopause and a rise in COVID-19 mortality that is exacerbated by cardiovascular disease reinforces the importance of these steroid hormones as protective agents. In further support of a hormonal role, previous research uncovered evidence suggesting that oral-contraceptive use may mitigate the risk of serious illness or death with SARS-CoV2 infection (4).

The postdischarge prognosis for women with COVID-19, however, is vastly different. A prospective assessment of 6-mo mortality and cardiovascular outcomes during the first COVID-19 wave confirmed that while male sex was a risk factor for in-hospital deaths, multivariate analysis revealed that females with COVID-19 were 2.6-times more likely than males to have a major adverse cardiovascular event after hospital discharge (5). The reasons for higher adverse outcomes in women are not clear, but Renda and colleagues speculated that females possess protection against the initial infection that is not available in males, but in the long-term, this protection wanes and is overwhelmed by the extensive damage caused by SARS-CoV2, resulting in a delay rather than mitigation of adverse outcomes.

Despite the immunological advantage females have responding to SARS-CoV2, the work by Hernandez-Hernandez and colleagues found that as women with cardiovascular disease age, the potential for mortality rises to create a risk that is greater than men of similar ages. Specifically, they reported that the risk to women appears only after 52 yr of age. As noted in the study, 52 yr is the average age at which women in Mexico enter menopause, but it should be noted that menopausal status was not explicitly identified in patient records.

The loss of estrogens and their protection might explain a normalization of the risk to levels of similarly aged males, but the data show that in combination with cardiovascular disease, the chances of COVID-19 mortality are higher in women of >52 yr than in men in the same age bracket. The basis for increased mortality is not clear although previous research offers possible explanations.

The inflammatory reaction to COVID-19 increases the risk of thrombosis, and the cytokine storm produced by infection can damage cardiac myocytes and endothelial cells. A stronger immune response in women initially protects during infection but can drive chronic injury if activation continues after viral clearance. Studies in animal models of menopause (6) and postmenopausal women (7) show that proinflammatory cytokine levels increase with menopause to create a low-grade inflammatory state. The addition of a proinflammatory stressor like cardiovascular disease could raise levels closer to a pathological threshold, which is then exceeded with infection. Estrogens limit the cytokine storm that mediates damage and this control is lost with menopause (8). In short, the heightened immune response in premenopausal women protects against infections and their complications, whereas postmenopausal disruptions, including in the heart itself, prime the immune system for a heightened or poorly controlled cytokine response that becomes problematic.

Hernandez-Hernandez et al. (2) show that in a Mexican population of hospitalized patients with COVID-19, women have higher rates of most cardiovascular conditions or risk factors than men, with the exception of smoking. These data reflect the overall Mexican population where women have slightly higher rates of cardiovascular disease. The higher rates of cardiovascular disease, which are known risk factors for COVID-19 mortality, may explain the higher mortality in postmenopausal women when estrogens that protect against infection and cardiovascular disease are lost.

One interesting point that is presented in the study by Hernandez-Hernandez et al. (2) is the lower rates of intensive care unit (ICU) care and intubation in female patients overall. With lower mortality in women, it is expected they have lower rates of ICU admission and intensive care options like intubation. What is not included in the study are data about care in the cohort of patients >52 yr of age. There is a vast body of evidence in the literature showing that women with cardiovascular disease are less likely to receive treatments that are timely, intensive, and guideline-driven. Whether excess COVID-19 mortality in postmenopausal women with cardiovascular disease is the result of substandard care or an underestimation of risk remains unanswered.

In their paper exploring sex differences in COVID-19 outcomes, Hernandez-Hernandez et al. (2) include another variable that influences health, i.e., economics. Just as inequities based on sex have adverse impacts on health, so too do economic disparities. A World Heart Federation study examined clinical outcomes of 5,313 patients with COVID-19 from 40 hospitals across 23 countries between June 2020 and September 2021 (9). Almost one-third of patients had cardiovascular disease. Mortality rates did not directly correlate with country income status, although on average, rates were higher in lower-resourced regions. Interestingly, the risk of major adverse cardiovascular events was two to three times higher in lower-income countries compared with high-income regions. Of relevance to the current study, Prabhakaran et al. (9) found that upper-middle income countries like Mexico had the highest rates of in-hospital deaths and a postdischarge mortality rate that was twice the level of high-income countries.

Disparities in health outcomes based on national resources are a significant threat. The global cardiovascular disease epidemic undoubtedly worsened the COVID-19 pandemic by draining valuable resources and serving as a confounding risk for adverse outcomes. These risks are disproportionately borne by groups who are most vulnerable, including women, the economically disadvantaged, and ethnic/cultural minorities. Data from lower-income countries in studies like the one by Hernandez-Hernandez et al. (2) are critical to understand the risks of COVID-19 in these regions and its complication by risk factors like cardiovascular disease. This information allows for national and regional differences in risk factors and outcomes to be identified and understood and effective strategies, including economic interventions, to be designed and implemented.

The focus on a predominantly Hispanic cohort in a country where they make up a majority of the population provides important insights into ethnic differences in adverse outcomes of COVID-19 and the role of cardiovascular risks. Minority populations often experience discrimination in the form of reduced access to health care and a poorer standard of living, which contribute to greater health risks and adverse outcomes. Collecting data on Hispanics within a country where they comprise a majority and are, therefore, relatively free of discrimination based on ethnicity provides an important focus on biological variations that occur in Latin-American populations and how these differences impact COVID-19 outcomes.

The complicating role of cardiovascular disease on COVID-19 mortality is generally understood based on data collected primarily from Caucasian and Asian populations, which may not be widely applicable. In fact, arguments for important ethnic differences include work from Italy that revealed a novel allelic variant in TMPRSS2, which is more frequent in Italians than East Asians (10). Such a difference could be a significant factor in the differential outcomes and risks reported by studies that focus on European participants and underscores the importance of examining risk factors that may be unique to specific populations. The work by Hernandez-Hernandez et al. (2) lays important groundwork by collecting data in an ethnic population that is often overlooked in other studies where they comprise a minority and examining their outcomes in an environment that is not complicated by cultural discrimination.

Hernandez-Hernandez et al. (2) present important information about the complex relationship between COVID-19, cardiovascular disease, and sex in a Latin-American population. Going forward, several areas should be the focus of further development or new exploration. These include collecting data from women on their menopausal status and use of hormone therapies, such that a more accurate picture of the connections between menopause, estrogens, and COVID-19 mortality might be developed. Data from later waves of the COVID-19 pandemic would help assess the evolution of the global response and our ability to manage the complexity of risk factors. Critical questions about the recognition of sex as a risk factor should be investigated, as well as sex differences on the impact of more effective therapies and risk reduction tools such as vaccines. Finally, expansion of the risk period to include a longer recovery phase is quickly emerging as a priority. The impact of chronic conditions like long COVID and the recognition of sex differences is of importance not only for individuals who are experiencing this phenomenon but also for the development of long-term treatment and management plans.

GRANTS

W.G.P. is supported by Heart and Stroke Foundation of Canada Grant G-21–0031543 and Natural Sciences and Engineering Research Council of Canada Grant RGPIN-2018–04732.

DISCLOSURES

W.G.P. is a Heart and Stroke Foundation of Canada/Health Canada Senior Career Investigator for Improving the Heart and Brain Health for Women in Canada and Ontario co-lead for COVID-19 Resources Canada.

AUTHOR CONTRIBUTIONS

W.G.P. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.