title: New insights into sexual dimorphism during progression of heart failure and rhythm disorders.
abstract: Neurohormonal imbalance is a key determinant of the progression of heart failure (HF), which results in an elevated risk of mortality. A better understanding of mechanisms involved may influence treatment strategies. The incidence and prevalence of HF are lower in women. We explored sexual dimorphism in the progression of HF using a mice model of neurohormonal-dependent HF. Male and female mice overexpressing the human beta2-adrenergic receptor (TG4 strain) develop HF. We compared TG4 animals with age-matched wild-type controls. Cardiac function was studied in vivo by echocardiography and electrocardiography. Histological studies were performed. Conduction parameters were assessed by intracardiac electrophysiological exploration, as was the occurrence of spontaneous and inducible arrhythmias. The patch-clamp technique was used to determine the cellular electrophysiological profile. The role of hormonal status in HF progression was investigated by surgical gonadectomy. High mortality rate was observed in TG4 mice with a dramatic difference between males and females. Male TG4 mice exhibited intraventricular conduction abnormalities, as measured by infrahisian interval and QRS durations potentially determining reentrant circuits and increasing susceptibility to arrhythmia. The severity of HF was correlated with the degree of fibrosis, which was modulated by the gonadal hormones. Action potentials recorded from male and female left ventricular cardiomyocytes were indistinguishable, although both sexes exhibited delayed repolarization when compared with their wild-type counterparts. In conclusion, female TG4 mice were better protected than males against cardiac remodeling and rhythm disorders. A link between fibrosis, conduction time, and mortality was established in relation with sex hormones.
authors.affiliation: Centre National de la Recherche Scientifique FRE3092, Université François-Rabelais, F-37041 Tours, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.forename: Franck
authors.initials: F
authors.lastname: Aimond
authors.forename: Denise
authors.initials: D
authors.lastname: Poisson
authors.forename: Beili
authors.initials: B
authors.lastname: Zhang
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Véronique
authors.initials: V
authors.lastname: Eder
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.forename: Dominique
authors.initials: D
authors.lastname: Babuty
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D005355:Fibrosis / Q000503:physiopathology; D006321:Heart / Q000503:physiopathology*; D006329:Heart Conduction System / Q000503:physiopathology*; D006333:Heart Failure / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009919:Orchiectomy; D010052:Ovariectomy; D018408:Patch-Clamp Techniques; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D012720:Severity of Illness Index; D012727:Sex Characteristics; D018709:Statistics, Nonparametric
chemical_list: D018343:Receptors, Adrenergic, beta-2