title: Spontaneous ventricular tachyarrhythmias in β2-adrenoceptor transgenic mice in relation to cardiac interstitial fibrosis.
abstract: Myocardial fibrosis is regarded as a pivotal proarrhythmic substrate, but there have been no comprehensive studies showing a correlation between the severity of fibrosis and ventricular tachyarrhythmias (VTAs). Our purpose was to document this relationship in a transgenic (TG) strain of mice with fibrotic cardiomyopathy. TG mice with cardiac overexpression of β2-adrenoceptors (β2-AR mice) and non-TG (NTG) littermates were studied at 4-12 mo of age. VTA was quantified by ECG telemetry. The effect of pharmacological blockade of β2-ARs on VTA was examined. Myocardial collagen content was determined by hydroxyproline assay. NTG and TG mice displayed circadian variation in heart rate, which was higher in TG mice than in NTG mice (P <0.05). Frequent spontaneous ventricular ectopic beats (VEBs) and ventricular tachycardia (VT) were prominent in TG mice but not present in NTG mice. The frequency of VEB and VT episodes in TG mice increased with age (P < 0.01). Ventricular collagen content was greater in TG mice than in NTG mice (P <0.001) and correlated with age (r = 0.71, P < 0.01). The number of VEBs or VT episodes correlated with age (r = 0.83 and r = 0.73) and the content of total or cross-linked collagen (r = 0.62∼0.66, all P <0.01). While having no effect in younger β2-TG mice, β2-AR blockade reduced the frequency of VTA in old β2-TG mice with more severe fibrosis. In conclusion, β2-TG mice exhibit interstitial fibrosis and spontaneous onset of VTA, becoming more severe with aging. The extent of cardiac fibrosis is a major determinant for both the frequency of VTA and proarrhythmic action of β2-AR activation.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Central Clinical School, Monash University, Melbourne, Victoria, Australia;
authors.forename: My-Nhan
authors.initials: MN
authors.lastname: Nguyen
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; University of Milan, Milan, Italy;
authors.forename: Diego
authors.initials: D
authors.lastname: Ruggiero
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Central Clinical School, Monash University, Melbourne, Victoria, Australia;
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Yidan
authors.initials: Y
authors.lastname: Su
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia;
authors.forename: Anne
authors.initials: A
authors.lastname: Jian
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; WenZhou Medical University, WenZhou, China; and.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Han
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Physiology, Monash University, Melbourne, Australia.
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Central Clinical School, Monash University, Melbourne, Victoria, Australia; xiao-jun.du@bakeridi.edu.au.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D013610:Tachycardia / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D018343:Receptors, Adrenergic, beta-2; D003094:Collagen
keywords: fibrosis; telemetry; ventricular tachyarrhythmias; β-adrenergic receptor