The hypothesis that individuals require a double-hit to develop PAH is supported by the findings that illicit drug use increases the risk of HIV-associated PAH, and that BMPR2 mutations increase the risk of fenfluramine-associated PAH.42,43 Men who develop PAH may therefore require several higher-risk hits (e.g., HIV and methamphetamine use), while women who develop PAH may get the disease more easily via causal mechanisms that are not as strongly associated with mortality. The gene discussed is BMPR2; the disease is pulmonary arterial hypertension.