Sex Hormone Profiles in Patients With Torsades de Pointes Ventricular Tachycardia

Female sex is a well-recognized risk factor for long QT syndrome and torsades de pointes (TdP), likely reflecting the influence of sex hormones on ventricular repolarization. Overall, estradiol prolongs, whereas progesterone and testosterone shorten, heart rate-corrected QT interval. However, no studies have comprehensively evaluated sex hormone levels in male and female long QT syndrome patients developing TdP, nor their implications in terms of clinical outcomes and electrophysiological changes. This study was aimed at determining the sex hormones profiles in male and female TdP patients, and defining their role in this clinical setting. The authors investigated: 1) the levels of sex hormones in a prospective cohort of male and female patients who developed TdP; 2) the relationship between sex hormones and arrhythmia outcome in TdP men and women; 3) the in vitro impact of sex-specific TdP hormone profiles on guinea pig ventricular myocyte and human-induced pluripotent stem cell-derived cardiomyocyte action potential duration, and their modulation by sex-specific hormonal interventions. Over 13 years, 68 TdP patients (42 female) were consecutively enrolled. Compared to control subjects, a differential sex hormone profile was observed in TdP men and women, primarily reduced testosterone in male patients and increased 17β-estradiol in female patients. Within the TdP cohort, lower testosterone in men and higher 17β-estradiol in women were associated with a worse short-term arrhythmia outcome. In vitro reproduction of sex-specific TdP hormone profiles prolonged action potential duration in sex-matched cardiomyocytes, an effect reversed by the addition of testosterone in male patients and progesterone in female patients, respectively. Different sex hormone profiles, primarily low testosterone in male patients and high 17β-estradiol in female patients, are associated with TdP occurrence and outcome in men and women. These endocrine milieus act, at least in part, via direct and reversible effects on cardiac electrophysiology, thereby supporting the antiarrhythmic potential of sex-specific hormonal-modulating therapies.