Cellular basis of sex disparities in human cardiac electrophysiology.
OBJECTIVE
Sex disparities in electrocardiogram variables and dysrhythmia susceptibility exist, notably in long QT syndrome (LQTS) and Brugada syndrome, but the underlying mechanisms in man are unknown. We studied the cellular basis of sex distinctions in human cardiac electrophysiology and dysrhythmia susceptibility using mathematical models of human ventricular myocytes.


METHODS
We implemented sex differences in the Priebe-Beuckelmann and ten Tusscher-Noble-Noble-Panfilov human ventricular cell models by modifying densities of the L-type Ca(2+) current (I(Ca,L)), transient outward K(+) current (I(to)), and rapid delayed rectifier K(+) current (I(Kr)), according to experimental data from male and female hearts of various species. Sex disparities in transmural repolarization were studied in transmural strands of cells with ion current densities based on canine experimental data.


RESULTS
Female cells have longer action potential duration (APD), steeper APD-heart rate relationship, larger transmural APD heterogeneity, and a greater susceptibility to pro-dysrhythmogenic early afterdepolarizations (EADs) than male cells. Conversely, male cells have more prominent phase-1 repolarization and are more susceptible to all-or-none repolarization.


CONCLUSIONS
Sex differences in I(Ca,L), I(to) and I(Kr) densities may explain sex disparities in human cardiac electrophysiology. Female cells exhibit a limited 'repolarization reserve' as demonstrated by their larger susceptibility to EADs, which, combined with their larger transmural electrical heterogeneity, renders them more vulnerable to tachydysrhythmias in LQTS. Conversely, male cells have a limited 'depolarization reserve', as shown by their larger susceptibility to all-or-none repolarization, which facilitates tachydysrhythmias in Brugada syndrome. These general principles may also apply to dysrhythmia susceptibility in common disease.
Verkerk
A O
AO
Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. a.o.verkerk@amc.uva.nl
Wilders
R
R
de Geringel
W
W
Tan
H L
HL
D000200:Action Potentials / Q000502:physiology*; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000503:physiopathology; D053840:Brugada Syndrome / Q000209:etiology / Q000503:physiopathology; D002478:Cells, Cultured; D004198:Disease Susceptibility; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D008133:Long QT Syndrome / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000502:physiology*; D012727:Sex Characteristics