Administration of Sex Hormones as Drugs to Attenuate Drug-induced Lengthening of Ventricular Repolarization

Elena Muensterman Tomaselli, Purdue University

Abstract

Background: The heart rate-corrected QT (QTc) interval is the electrocardiogram (ECG) representation of ventricular repolarization. Prolongation of the QTc interval is a marker of increased risk of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia. More than 150 commonly used drugs available in the United States (US) can cause QTc interval prolongation and TdP. Few effective strategies have been developed to reduce the risk of drug-induced QTc interval prolongation and TdP, particularly in patients at high risk. In view of the catastrophic consequences of TdP and the widespread use of QTc interval-prolonging medications (including antimicrobials, antidepressants, and other widely-used drug classes), there is an urgent need to identify strategies to reduce the risk in high-risk populations. The risk of drug-induced QTc interval prolongation and TdP is higher in women than men. Ventricular repolarization occurs more rapidly in men, manifested by shorter QTc intervals, a difference which becomes apparent only after puberty, suggesting that changes in serum sex hormone concentrations are responsible. Post-pubertal differences in QTc intervals may be largely due to the production of testosterone in males, which has been shown to shorten ventricular repolarization. However, although female sex is a risk factor for drug-induced TdP, 29-46% of reported cases have occurred in men. Older age (> 65-68 years) is an independent risk factor for drug-induced QTc interval prolongation and TdP in both men and women. In men, this may be attributable to age-related declining serum testosterone concentrations. Higher serum progesterone concentrations have been associated with shorter QT intervals, and preclinical studies indicate that exogenous progesterone administration may protect against drug-induced prolongation of ventricular repolarization, ventricular early afterdepolarizations and arrhythmias. Tisdale et al have previously shown that administration of oral progesterone at a dose of 400 mg once daily attenuates druginduced QT interval lengthening in young healthy premenopausal women during the menses phase of the menstrual cycle, when endogenous serum estradiol and progesterone concentrations are low. These data provide support for further study of the efficacy, safety and clinical feasibility of oral progesterone administration for reducing the risk of drug-induced QT interval prolongation and TdP in patients with risk factors who require therapy with QT interval-prolonging drugs. However, substantial inter-subject variability was present in this study; some subjects demonstrated a substantial response to progesterone-mediated attenuation of drug-induced QT interval lengthening, while the response was limited or absent in other subjects. Identifying and addressing sources of inter-subject variability in response is essential to optimize future clinical utilization of oral progesterone as a novel therapy to attenuate drug-induced QT interval lengthening in high-risk female patients. In vitrodata indicate that testosterone and progesterone shorten early ventricular repolarization through inhibition of the L-type calcium current (ICa, L) and late ventricular repolarization via enhancement of the slow component of the delayed rectifier potassium current (Iks). However, the in vivo effects of testosterone and progesterone on attenuation of drug-induced early versus late ventricular repolarization are unknown. Recently, the novel ECG biomarkers J–Tpeak (corrected for heart rate as J-Tpeakc) and Tpeak-Tend interval (which does not require heart rate correction) have been shown to be accurate biomarkers to assess exogenous effects on different components of ventricular repolarization. Tpeak-Tend/QT is another biomarker that has been used to characterize transmural dispersion of ventricular repolarization, which is associated with an increased risk of TdP.

Degree

Ph.D.

Advisors

Tisdale, Purdue University.

Subject Area

Endocrinology|Medicine|Pharmacology|Physiology

COinS