Sex and gender differences in myocarditis and dilated cardiomyopathy

Abstract

Heart failure due to nonischemic dilated cardiomyopathy (DCM) contributes significantly to the global burden of cardiovascular disease. Myocarditis is, in turn, a major cause of acute DCM in both men and women. However, recent clinical and experimental evidence suggests that the pathogenesis and prognosis of DCM differ between the sexes. This seminar provides a contemporary perspective on the immune mediators of myocarditis, including interdependent elements of the innate and adaptive immune response. The heart's acute response to injury is influenced by sex hormones that appear to determine the subsequent risk of chronic DCM. Preliminary data suggest additional genetic variations may account for some of the differences in epidemiology, left ventricular recovery, and survival between men and women. We highlight the gaps in our knowledge regarding the management of women with acute DCM and discuss emerging therapies, including bromocriptine for the treatment of peripartum cardiomyopathy.

Figure 1. Sex hormone effects on the immune cell response

Antigen presenting cells, such as mast cells, dendritic cells and monocyte/macrophages, in mice and humans express androgen receptors (AR) and estrogen receptor-α/β (ERα/β). Men express higher AR levels on macrophages than women. Estrogen via ERα/β has a well known ability to activate B cells, resulting in increased antibody (Ab) and autoAb levels and to drive T helper (Th)2 responses, while testosterone via the AR decreases Ab levels and drives Th1 responses.

Figure 2. The effect of testosterone on myocardial inflammation leading to fibrosis and dilated cardiomyopathy (DCM)

Testosterone increases mast cell and macrophage numbers in the heart and Toll-like receptor (TLR)4 expression on mast cells and macrophages. Mast cell release of interleukin (IL)-4 induces alternative activation of macrophages to induce M2 macrophages that express TLR4 and release IL-1β. Elevated testosterone and IL-1β during acute myocarditis increase serpin A3n levels in the heart, which, along with transforming growth factor (TGF)- β₁, causes fibroblasts to produce collagen over the subsequent 4 weeks resulting in fibrosis and the development DCM.

Figure 3. LVEF at baseline and at 6 months for men, peripartum cardiomyopathy (PPCM) women and non-PPCM women

Label on each bar represents the mean left ventricular ejection fraction (LVEF) for the subset ±standard deviation. LVEF was significantly greater in PPCM women at baseline (p = 0.04) and at 6 months (p = 0.007). Men at all points had the lowest LVEF, while non-PPCM women had intermediate LVEF levels. Reproduced with permission from Cooper et al. 2012 (7).