Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease

Abstract

Registry data worldwide indicate an overall female predominance for pulmonary arterial hypertension (PAH) of 2-4 over men. Genetic predisposition accounts for only 1-5% of PAH cases, while autoimmune diseases and infections are closely linked to PAH. Idiopathic PAH may include patients with undiagnosed autoimmune diseases based on the relatively high presence of autoantibodies in this group. The two largest PAH registries to date report a sex ratio for autoimmune connective tissue disease-associated PAH of 9:1 female to male, highlighting the need for future studies to analyze subgroup data according to sex. Autoimmune diseases that have been associated with PAH include female-dominant systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and thyroiditis as well as male-dominant autoimmune diseases like myocarditis which has been linked to HIV-associated PAH. The sex-specific association of PAH to certain infections and autoimmune diseases suggests that sex hormones and inflammation may play an important role in driving the pathogenesis of disease. However, there is a paucity of data on sex differences in inflammation in PAH, and more research is needed to better understand the pathogenesis underlying PAH in men and women. This review uses data on sex differences in PAH and PAH-associated autoimmune diseases from registries to provide insight into the pathogenesis of disease.

Keywords: Autoimmune disease; Inflammation; Myocarditis; Pulmonary arterial hypertension; Sex differences; Systemic sclerosis.

Fig. 1

Hypothesis for how infections and autoimmune diseases may promote PAH in women and men. Infections and autoimmune diseases like HIV and systemic sclerosis (SSc) are able to cause inflammation, immune complex (IC) deposition, and remodeling in the lung that may lead to pulmonary arterial hypertension. Estrogen increases the risk of developing autoimmune diseases like SSc following infection or other insults by promoting antibody/autoantibody and IC deposition that may contribute to the increased incidence of PAH in women, especially for autoimmune diseases that affect the lung-like SSc. PAH associated with HIV infection occurs more often in men and HIV-associated PAH patients also have myocarditis. Inflammatory mechanisms that drive myocarditis in men following infection may also drive PAH