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COVID-19, the Female Immune Advantage, and Cardiovascular Impact

Published:December 29, 2020DOI:https://doi.org/10.1016/j.mayocp.2020.12.021
      To The Editor:
      The article by Ritter and Kararigas
      • Ritter O.
      • Kararigas G.
      Sex-Biased Vulnerability of the Heart to COVID-19.
      is a welcome addition to the coronavirus disease 2019 (COVID-19) medical literature, as significant physiologic variations across multiple systems exist between the sexes, yet are often neglected.
      • Ritter O.
      • Kararigas G.
      Sex-Biased Vulnerability of the Heart to COVID-19.
      Although we applaud the hypotheses on differing male and female responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, with emphasis on cardiac vulnerabilities, some additional key potential mechanisms with respect to the role of the “sex hormones” estradiol, progesterone, and testosterone require consideration.
      Estradiol supports immune system modulation, amplifying innate and humoral immune responses, whereas testosterone is overall an immunosuppressant, in particular inhibiting differentiation of naive CD4+ T cells into T helper type 1 cells, impeding cell-mediated immunity. Estradiol helps initiate a robust innate immune response to pathogens via augmented toll-like receptor 7 (TLR7), an endosomal innate immune sensor recognizing RNA viruses such as SARS-CoV-2, inducing a type 1 interferon response, suppressing viral replication, and amplifying host antiviral response.
      • Vikse J.
      • Lippi G.
      • Henry B.M.
      Do sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression explain increased severity and mortality of COVID-19 in males?.
      Subsequently, estradiol helps switch to a state of inflammatory resolution and healing. Progesterone also has substantial immunomodulatory effects on female immune systems.
      • Mauvais-Jarvis F.
      • Klein S.L.
      • Levin E.R.
      Estradiol, progesterone, immunomodulation, and COVID-19 outcomes.
      These significant hormonal effects may result in dramatic sex differences in immune response to infection, and in turn, likely alter inflammatory-mediated cardiovascular impacts from SARS-CoV-2.
      All immune cells have receptors for estradiol, enabling direct immunomodulation. This is complemented by the influence of estradiol on the renin-angiotensin-aldosterone system (RAAS), a second important immunomodulatory system.
      • White M.C.
      • Fleeman R.
      • Arnold A.C.
      Sex differences in the metabolic effects of the renin-angiotensin system.
      Severe acute respiratory syndrome coronavirus 2 uses angiotensin-converting enzyme 2 (ACE2) as a functional receptor to infect cells, destroying its anti-inflammatory capabilities in the process. Females replete with estradiol have greater number and functionality of ACE2, likely a factor in their greater ability to handle SARS-CoV-2 infections. Additional estradiol-mediated RAAS modulatory actions provide further cardiovascular protection. Despite SARS-CoV-2–induced ACE2 deficiency, estradiol supports an anti-inflammatory state by facilitating angiotensin II binding to the angiotensin 2 receptor, rather than the angiotensin 1 receptor. This alternative binding promotes vascular vasodilation and inhibits cardiac remodeling, in contrast to angiotensin 1 receptor binding that facilitates vasoconstriction and additional pro-inflammatory actions (Figure).
      Figure thumbnail gr1
      FigureSex hormones and their impact on effects of angiotensin II.
      In addition to advantageous hormonal differences, females possess 2 X chromosomes, further contributing to the “female immune advantage.” Although the “extra” X chromosome is deactivated, more than 10% of the second X chromosome genetic material, most related to immune function, stays active throughout a woman’s life.
      • Schurz H.
      • Salie M.
      • Tromp G.
      • Hoal E.G.
      • Kinnear C.J.
      • Moller M.
      The X chromosome and sex-specific effects in infectious disease susceptibility.
      For example, the TLR7 gene is found on the X chromosome and escapes X inactivation, resulting in higher expression levels in females. Additionally, during embryonic times in females, both X chromosomes remain active for a short while, resulting in epigenetic modifications, further enabling females to better survive infections. Females likely evolved to better withstand viral infections, and understanding all contributing factors is essential to optimizing care.
      We greatly appreciate this article’s focus on the sex differences involved in immune responses and subsequent CV risk related to the current COVID-19 pandemic. Heightened awareness that such differences exist will hopefully foster expanded research into the significant inherent immune variances between males and females, and between reproductive and postmenopausal women, with the goal of pragmatically and successfully improving medical care.

      References

        • Ritter O.
        • Kararigas G.
        Sex-Biased Vulnerability of the Heart to COVID-19.
        Mayo Clin Proc. 2020; 95: 2332-2335
        • Vikse J.
        • Lippi G.
        • Henry B.M.
        Do sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression explain increased severity and mortality of COVID-19 in males?.
        Diagnosis(Berl). 2020; 7: 385-386
        • Mauvais-Jarvis F.
        • Klein S.L.
        • Levin E.R.
        Estradiol, progesterone, immunomodulation, and COVID-19 outcomes.
        Endocrinology. 2020; 161: bqaa127
        • White M.C.
        • Fleeman R.
        • Arnold A.C.
        Sex differences in the metabolic effects of the renin-angiotensin system.
        Biol Sex Differ. 2019; 10: 31
        • Schurz H.
        • Salie M.
        • Tromp G.
        • Hoal E.G.
        • Kinnear C.J.
        • Moller M.
        The X chromosome and sex-specific effects in infectious disease susceptibility.
        Hum Genomics. 2019; 13: 2

      Linked Article

      • In Reply — COVID-19, the Female Immune Advantage, and Cardiovascular Impact
        Mayo Clinic ProceedingsVol. 96Issue 3
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          We thank Gersh and colleagues1 for their letter in response to our article "Sex-Biased Vulnerability of the Heart to COVID-19.”2 In fact, we are pleased to see that our article is fulfilling its purpose of drawing attention to a topic little explored, putting forward notions and hypotheses for the field to contemplate.
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      • Sex-Biased Vulnerability of the Heart to COVID-19
        Mayo Clinic ProceedingsVol. 95Issue 11
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          Coronavirus disease 2019 (COVID-19) is a quickly evolving public health emergency. Currently, actual death rates associated with COVID-19 cannot be calculated with accuracy. Among other things, this is due to availability of testing modalities and selection procedures for testing, as well as asymptomatic disease, all leading to undetected cases, thereby impacting the estimation of death rates. Nevertheless, on the basis of data released from several countries and a recent study using a multinational COVID-19 registry,1 despite similar infection rates or even in some cases more female than male infections, men appear to be disproportionately affected by COVID-19 and at higher risk of mortality than women.
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