Spontaneous ventricular tachyarrhythmias in β2-adrenoceptor transgenic mice in relation to cardiac interstitial fibrosis

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 beta(2)-adrenoceptors (beta(2)-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 beta(2)-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 similar to 0.66, all P < 0.01). While having no effect in younger beta(2)-TG mice, beta(2)-AR blockade reduced the frequency of VTA in old beta(2)-TG mice with more severe fibrosis. In conclusion, beta(2)-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 beta(2)-AR activation.