A multiscale computational modelling approach predicts mechanisms of female sex risk in the setting of arousal-induced arrhythmias

The Journal of Physiology
Pei-Chi YangColleen E Clancy

Abstract

This study represents a first step toward predicting mechanisms of sex-based arrhythmias that may lead to important developments in risk stratification and may inform future drug design and screening. We undertook simulations to reveal the conditions (i.e. pacing, drugs, sympathetic stimulation) required for triggering and sustaining reentrant arrhythmias. Using the recently solved cryo-EM structure for the Eag-family channel as a template, we revealed potential interactions of oestrogen with the pore loop hERG mutation (G604S). Molecular models suggest that oestrogen and dofetilide blockade can concur simultaneously in the hERG channel pore. Female sex is a risk factor for inherited and acquired long-QT associated torsade de pointes (TdP) arrhythmias, and sympathetic discharge is a major factor in triggering TdP in female long-QT syndrome patients. We used a combined experimental and computational approach to predict 'the perfect storm' of hormone concentration, IKr block and sympathetic stimulation that induces arrhythmia in females with inherited and acquired long-QT. More specifically, we developed mathematical models of acquired and inherited long-QT syndrome in male and female ventricular human myocytes by combining effec...Continue Reading

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Citations

Jan 31, 2019·Cardiovascular Research·Mary BarberJoe-Elie Salem
Feb 25, 2020·Circulation Research·Pei-Chi YangColleen E Clancy
Aug 7, 2018·Frontiers in Physiology·Haibo NiEleonora Grandi
Dec 17, 2019·Circulation. Arrhythmia and Electrophysiology·Michael B LiuZhilin Qu
May 1, 2018·Frontiers in Physiology·Laura L PerissinottiSergei Y Noskov
Apr 9, 2018·Current Treatment Options in Cardiovascular Medicine·Lingjin MengOlujimi Ajijola
Jun 26, 2018·Frontiers in Physiology·Eleonora GrandiBlanca Rodriguez
Dec 18, 2020·Biophysical Journal·Zhaoyang ZhangZhilin Qu
Nov 19, 2020·CPT: Pharmacometrics & Systems Pharmacology·Meera VarshneyaEric A Sobie
Jun 2, 2021·Journal of Molecular and Cellular Cardiology·Kevin R DeMarcoIgor Vorobyov

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Methods Mentioned

BETA
dissection
hormone replacement therapy

Software Mentioned

MATCH
SWISS
GAAMP
Schrödinger
MODEL
pCLAMP
Maestro suite
NAMD2
XP

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