Transient Hypogonadism Is Associated With Heart Rate–Corrected QT Prolongation and Torsades de Pointes Risk During Active Systemic Inflammation in Men

Abstract

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.

Effects of COVID-19 on Arrhythmia

“…Inflammatory factors acting on the peripheral pathway lead to increased left stellate ganglion remodeling, which also leads to the same result [79]. In the male, a systemic inflammatory response is associated with reduced testosterone levels and transient inflammatory hypotestosteronemia, which is significantly associated with an increased risk of long QT syndrome and TdP [80].…”

Fir(e)ing the Rhythm

“…Reduction of testosterone levels, which also inversely correlated with 17-β estradiol over time, significantly contributed to inflammation-induced QTc prolongation. 129 Moreover, in men with TdP, both active systemic inflammation and hypogonadism were frequently present (∼70%-80% of cases), with significant correlations among IL-6, testosterone, and 17-β estradiol levels. 129 …”

Testosterone and Covid‐19: An update

“…Whilst several studies have described an associated of lower T levels to poorer clinical outcomes, it still remains unclear whether reduced T is a marker or a mediator of Covid‐19 severity. Critical illness can cause transient hypogonadism thereby causing a rapid decrease in serum T. 57 , 58 Whilst T deficiency is associated with increased pro‐inflammatory cytokines, 59 inflammatory mediators have also been shown to lower T levels during acute illness via increased metabolic clearance and suppression of gonadal axis. 60 , 61 In a study comparing Covid‐19 patients with non‐Covid‐19 patients with respiratory tract infections and age‐matched healthy controls, TT levels were decreased in both Covid‐19 and non Covid‐19 patients suggesting that hormonal imbalance might be a consequence of critical illness in general.…”

“…Whilst several studies have described an associated of lower T levels to poorer clinical outcomes, it still remains unclear whether reduced T is a marker or a mediator of Covid‐19 severity. Critical illness can cause transient hypogonadism thereby causing a rapid decrease in serum T 57,58 . Whilst T deficiency is associated with increased pro‐inflammatory cytokines, 59 inflammatory mediators have also been shown to lower T levels during acute illness via increased metabolic clearance and suppression of gonadal axis 60,61 .…”