FAQ on Sex Differences in Myocarditis
Written by DeLisa Fairweather, PhD
For many years clinicians have noted that sex differences exist in the presence and severity of myocarditis, but only recently has evidence been obtained to substantiate this observation.
Does myocarditis, dilated cardiomyopathy, and heart failure occur more frequently in men than women?
A: Two studies were published finding that women with myocarditis had better myocardial recovery and transplant-free survival than men 1,2. Another study found that men are two-times more likely to develop myocardial fibrosis following myocarditis than women 3. Fibrosis is a scar that develops in the cardiac muscle that makes it more difficult for the heart to pump efficiently and usually leads to dilated cardiomyopathy, or an enlarged heart, and may progress to heart failure. A family of cytokines, or cell signaling proteins, that lead to an interleukin-17 (IL-17)-type immune response have been found in animal models to cause fibrosis that leads to dilated cardiomyopathy after myocarditis (Baldeviano GC, Barin JG, Talor MV, Srinivasan S, Bedja D, Zheng D, Gabrielson K, Iwakura Y, Rose NR, Cihakova D. Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. Circ Res. 2010. 106:1646-55; Wu L, Ong S, Talor MV, Barin JG, Baldeviano GC, Kass DA, Bedja D, Zhang H, Sheikh A, Margolick JB, Iwakura Y, Rose NR, Ciháková D. Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. J Exp Med. 2014. 211:1449-64). Cytokines in this family (i.e., IL-1beta, IL-6) have been found to be elevated in male mice with myocarditis and in men with myocarditis or dilated cardiomyopathy and to be associated with an increased risk of heart failure (Coronado MJ, Brandt JE, Kim E, Bucek A, Bedja D, Abston ED, Shin J, Gabrielson KL, Mitzner W, Fairweather D (2012) Testosterone and interleukin-1β increase cardiac remodeling during acute coxsackievirus B3 myocarditis via serpin A 3n. Am J Physiol Heart Circ Physiol 302:H1726-H1736; Myers JM, Cooper LT, Kem DC, Stavrakis S, Kosanke SD, Shevach EM, Fairweather D, Stoner JA, Cox CJ, Cunningham MW. Cardiac myosin-Th17 responses promote heart failure in human myocarditis. JCI Insight. 2016; 1:e85851). A study of around 300 myocarditis patients found a sex ratio for myocarditis of 3.5 men to 1 woman (Coronado MJ, Bruno KA, Blauwet LA, Tschöpe C, Cunningham MW, Pankuweit S, van Linthout S, Jeon ES, McNamara DM, Krejčí J, Bienertová-Vašků J, Douglass EJ, Abston ED, Bucek A, Frisancho JA, Greenaway MS, Hill AR, Schultheiss HP, Cooper LT Jr, Fairweather D. Elevated Sera sST2 Is Associated With Heart Failure in Men ≤50 Years Old With Myocarditis. J Am Heart Assoc. 2019; 8:e008968), but more research is needed to better understand sex and gender differences in myocarditis and dilated cardiomyopathy. A serum biomarker called soluble ST2 (sST2) was found to be increased in the sera of patients with myocarditis that progressed to heart failure based on New York Heart Association Classification, and those patients were mainly men (Coronado MJ, Bruno KA, Blauwet LA, Tschöpe C, Cunningham MW, Pankuweit S, van Linthout S, Jeon ES, McNamara DM, Krejčí J, Bienertová-Vašků J, Douglass EJ, Abston ED, Bucek A, Frisancho JA, Greenaway MS, Hill AR, Schultheiss HP, Cooper LT Jr, Fairweather D. Elevated Sera sST2 Is Associated With Heart Failure in Men ≤50 Years Old With Myocarditis. J Am Heart Assoc. 2019; 8:e008968). Additionally, most patients with myocarditis and elevated sST2 levels were men under 50 years of age. A summary of sex and gender differences in myocarditis, dilated cardiomyopathy and heart failure is found in the following references (Fairweather D, Cooper LT Jr, Blauwet LA. Sex and gender differences in myocarditis and dilated cardiomyopathy. Curr Probl Cardiol. 2013; 38:7-46; Jain A, Norton N, Bruno KA, Cooper LT Jr, Atwal PS, Fairweather D. Sex Differences, Genetic and Environmental Influences on Dilated Cardiomyopathy. J Clin Med. 2021; 10:2289).
Many differences exist in the normal physiology or function of the heart in men and women 4,5. Likewise, men and women respond very differently to the same type of damage to the heart as can be caused by certain infections or chemicals/drugs 6. Sex steroid hormones like testosterone and estrogen are able to directly influence cardiac inflammation resulting in more inflammation and scarring (or fibrosis) in men and less in women.
How are testosterone levels in men linked to myocarditis?
A: Researchers have found that elevated testosterone levels in males directly promote the type of immune response that leads to increased inflammation, fibrosis, dilated cardiomyopathy and heart failure 7-11. In a model of viral myocarditis testosterone was found to increase myocardial inflammation while estrogen (17beta- estradiol) was found to decrease inflammation during myocarditis (Coronado MJ, Bruno KA, Blauwet LA, Tschöpe C, Cunningham MW, Pankuweit S, van Linthout S, Jeon ES, McNamara DM, Krejčí J, Bienertová-Vašků J, Douglass EJ, Abston ED, Bucek A, Frisancho JA, Greenaway MS, Hill AR, Schultheiss HP, Cooper LT Jr, Fairweather D. Elevated Sera sST2 Is Associated With Heart Failure in Men ≤50 Years Old With Myocarditis. J Am Heart Assoc. 2019; 8:e008968), similar to the findings of clinical myocarditis.
How are women affected by sex hormones and their role in myocarditis?
A: Females are able to clear infections and repair damage without high levels of inflammation and without long-lasting damage (Di Florio DN, Sin J, Coronado MJ, Atwal PS, Fairweather D. Sex differences in inflammation, redox biology, mitochondria and autoimmunity. Redox Biol. 2020; 31:101482, 12. But, similar to atherosclerosis, women develop myocarditis that leads to heart failure in a different way than men (i.e., by different mechanisms). However, women may be more susceptible to certain types of myocarditis, such as autoimmune myocarditis caused by immune-complex deposition in the heart, which may be promoted by estrogen 6. Additionally, pregnant women are at risk of developing peripartum cardiomyopathy, which is a relatively rare form of heart failure that affects women during the last months of pregnancy or the first months after delivery (Douglass EJ, Cooper LT Jr, Morales-Lara AC, Adedinsewo DA, Rozen TD, Blauwet LA, Fairweather D. A Case-Control Study of Peripartum Cardiomyopathy Using the Rochester Epidemiology Project. J Card Fail. 2021; 27:132-142, 13.
Research to understand how sex differences affect myocarditis is a relatively new area of study and should provide critical information that will lead to better diagnosis and treatment of disease.
- McNamara DM, Starling RC, Cooper LT, Boehmer JP, Mather PJ, Janosko KM, Gorcsan J 3rd, Kip KE, Dec GW; IMAC Investigators (2011) Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study. J Am Coll Cardiol58:1112-1118.
- Cooper LT, Mather PJ, Alexis JD, Pauly DF, Torre-Amione G, Wittstein IS, Dec GW, Zucker M, Narula J, Kip K, McNamara DM; IMAC2 Investigators (2012) Myocardial recovery in peripartum cardiomyopathy: prospective comparison with recent onset cardiomyopathy in men and nonperipartum women. J Card Fail18:28-33.
- Cocker MS, Abdel-Aty H, Strohm O, Friedrich MG (2009) Age and gender effects on the extent of myocardial involvement in acute myocarditis: a cardiovascular magnetic resonance study. Heart95:1925-1930.
- Mendelsohn ME, Karas RH (2005) Molecular and cellular basis of cardiovascular gender differences. Science 308:1583–1587.
- Legato MJ, Leghe JK (2010) Gender and the heart: sex-specific differences in the normal myocardial anatomy and physiology. In: Principles of Gender-Specific Medicine (2ndEdition). Legato MJ (Ed). Elsevier, San Diego, USA, pp. 151–161.
- Fairweather D, Petri MA, Coronado MJ & Cooper LT Jr (2012) Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis. Expert Rev Clin Immunol8:269-284.
- Huber SA, Kupperman J, Newell MK (1999) Hormonal regulation of CD4+ T cell responses in coxsackievirus B3-induced myocarditis in mice. J Virol73:4689-4695.
- Huber SA (2005) Increased susceptibility of male BALB/c mice to coxsackievirus B3-induced myocarditis: role for CD1d. Med Microbiol Immunol194:121-127.
- Frisancho-Kiss S, Coronado MJ, Frisancho JA, Lau VM, Rose NR, Klein SL & Fairweather D (2009) Gonadectomy of male BALB/c mice increases Tim-3+alternatively activated M2 macrophages, Tim-3+ T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis. Brain Behav Immun 23:649-657.
- Onyimba JA, Coronado MJ, Garton AE, Kim JB, Bucek A, Bedja D, Gabrielson KL, Guilarte TR, Fairweather D (2011) The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice. Biol Sex Differ2:2.
- Coronado MJ, Brandt JE, Kim E, Bucek A, Bedja D, Abston ED, Shin J, Gabrielson KL, Mitzner W, Fairweather D (2012) Testosterone and interleukin-1β increase cardiac remodeling during acute coxsackievirus B3 myocarditis via serpin A 3n. Am J Physiol Heart Circ Physiol 302:H1726-H1736.
- Huber SA (2008) Coxsackievirus B3-induced myocarditis: infection of females during the estrous phase of the ovarian cycle leads to activation of T regulatory cells. Virology 378:292-298.
- Blauwet LA, Cooper LT (2011) Diagnosis and management of peripartum cardiomyopathy. Heart 97:1970-1981.