Abstract
Female sex is an independent risk factor for development of torsade de pointes (TdP)-type arrhythmias in both congenital and acquired long QT syndrome (LQTS). In females, QTc interval and TdP risk vary during the menstrual cycle and around delivery. Biological experiments including single-cell current recordings with the patch-clamp technique and biochemical experiments show that progesterone modulates cardiac K+ current and Ca2+ current via the non-genomic pathway of the progesterone receptor, and thus the cardiac repolarization duration, in a concentration-dependent manner. Incorporation of these biological findings into a computer model of single-cell and coupled-cell cardiomyocytes simulates fluctuations in QTc interval during the menstrual cycle with reasonable accuracy. Based on this model, progesterone is predicted to have protective effects against sympathetic nervous system-induced arrhythmias in congenital LQTS and drug-induced TdP in acquired LQTS. A combined biological and computational approach may provide a powerful means to risk stratify TdP risk in women.
Highlights
A growing body of evidence suggests that clinical arrhythmia syndromes emerge as a result of complicated interactions of multiple endogenous and environmental factors
Experiments using multicellular wedge prepatnion indicate that torsade de pointes (TdP) is triggered by early afterdepolarization (EAD) followed by intramural phase 2 reentry, which is based on hetelogeneous prolongation myocardial action potential duration (APD) [3]
Sympathetic nervous system (SNS) stimulation is a critical triggering factor for TdP in LONG QT SYNDROME (LQTS) patients [29], and we examined both the basal condition and the SNS stimulation-mimicked condition with isoproterenol application or with intracellular dialysis of cAMP and okadaic acid (OA)
Summary
A growing body of evidence suggests that clinical arrhythmia syndromes emerge as a result of complicated interactions of multiple endogenous and environmental factors. A combined approach using patch-clamp study and computer simulation study is a powerful means for investigating the influence of multiple interacting factors on the development of clinical symptoms. In this mini-review, we will discuss our recent work using a combined biological and computational approach to predict arrhythmic risks in women. Progesterone is suggested to be responsible for differences in cardiac repolarization duration and in ibutilide-induced QTc prolongation during the menstrual cycle. A Combined Approach Using Patch-Clamp Study one, is strongly suggested to have protective effects against long QT-associated arrhythmias
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