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.

β‐Adrenoceptor activation affects galectin‐3 as a biomarker and therapeutic target in heart disease

“…Cardiac Gal‐3 content is increased in β 2 ‐TG mice at a young age and then it progressively increases with ageing in parallel to the progression of cardiomyopathy, myocardial fibrosis, and inflammation (Nguyen, Su, Kiriazis, et al, ; Xu et al, ). Thus, the progressive increase in cardiac Gal‐3 content in this model is likely to be attributable to the age‐dependent increase in the cardiac densities of inflammatory cells and fibroblasts (Nguyen et al, ; Nguyen, Su, Vizi, et al, ).…”

Stimulation of β‐adrenoceptors up‐regulates cardiac expression of galectin‐3 and BIM through the Hippo signalling pathway

“…Myocardial fibrosis was determined by hydroxyproline assay as previously described (Nguyen et al, 2015). An apical portion of the LV (about 20 mg) was used for the assay with hydroxyproline values converted into total collagen content.…”

Association between heart rate variability indices and features of spontaneous ventricular tachyarrhythmias in mice

“…Progression of cardiomyopathy in the TG model is age‐dependent measured by phenotypes of ventricular dilatation, dysfunction, spontaneous VTA and premature deaths 17‐19 . In this study, mice aged at 9‐10 months were used, because TG mice at this age exhibit severe cardiomyopathy with frequent onset of VTA 7 . There is strong evidence for a relationship between fibrosis and arrhythmogenesis 20 .…”

“…Our previous study showed that the β 2 ‐adrenoceptor ( β 2 ‐AR) transgenic mice (TG) exhibited an age‐dependent development of cardiomyopathy featured by fibrosis, ventricular remodelling, dysfunction, VTA and premature deaths 7 . In this model, the frequency of ventricular ectopic beats (VEBs) and episodes of VT recorded by telemetry is increasing with age: approximately 1000 per hour for VEB and 80 episodes per hour for VT were recorded in TG mice aged 9–11 months 7 . Thus, even a 10‐minute period of ECG recording allows for quantitative evaluation of the severity of VTA …”

“…In this model, the frequency of ventricular ectopic beats (VEBs) and episodes of VT recorded by telemetry is increasing with age: approximately 1000 per hour for VEB and 80 episodes per hour for VT were recorded in TG mice aged 9–11 months 7 . Thus, even a 10‐minute period of ECG recording allows for quantitative evaluation of the severity of VTA …”