Background Systemic
inflammation and male
hypogonadism are 2 increasingly recognized "nonconventional" risk factors for
long-QT syndrome and
torsades de pointes (TdP). Specifically, inflammatory
cytokines prolong, while
testosterone shortens the heart rate-corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between
inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men,
testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of
inflammation on QTc. Methods and Results We investigated (1) the levels of
sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and
sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases,
testosterone levels were significantly reduced, but promptly normalized in association with the decrease in
C-reactive protein and
interleukin-6 levels. Reduction of
testosterone levels, which also inversely correlated with 17-β
estradiol over time, significantly contributed to
inflammation-induced QTc prolongation. In men with TdP, both active systemic
inflammation and
hypogonadism were frequently present, with significant correlations between
C-reactive protein,
testosterone, and 17-β
estradiol levels; in these patients, increased
C-reactive protein and reduced
testosterone were associated with a worse short-term outcome of the
arrhythmia. Conclusions During systemic inflammatory activation,
interleukin-6 elevation is associated with reduced
testosterone levels in males, possibly deriving from an enhanced
androgen-to-
estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased
long-QT syndrome/TdP risk in men.