DEVELOPMENT OF CARDIOMYOPATHY AND HEART FAILURE IN MICE OVEREXPRESSING B2-ADRENOCEPTORS IN THE HEART. X.M. Gao*, E.A. Woodcock, G.L. Jennings, A.M. Dart and X.J. Du. Baker Medical Research Institute & Alfred Heart Centre, Melbourne The transgenic (TG) mice that carries ~200-fold more b2-adrenoceptors (b2AR) in the heart have markedly enhanced ventricular contractility and heart rate versus non-TG (NTG) littermates. Thus, b2AR overexpression is considered as an approach of gene therapy for heart failure (HF). We studied the TG mice with serial echocardiography to examine whether a long-term b2AR activation might result in cardiac abnormalities. Echo tests were performed at 4,6,9,12 and 15m of age in TG (n=27) and NTG (n=26) mice, using a Sonos 5500 echo machine and a 12 MHz transducer. The survival of mice were monitored and autopsies performed to identify the reason of death. Hearts were analysed histologically. Heart rate levels remain to be higher in TG than NTG mice during 4-15m period. The left ventricular dimensions at diastole (LVIDd) and systole and fractional shortening (FS) were similar between TG and NTG groups at 4 and 6m. During 9~15m, TG mice showed progressive increases in LVD, decline in FS and increase in LV mass (Table), indicating development of ventricular remodelling, HF and hypertrophy. Loss of TG mice, most due to HF, started at 8m and the cumulative mortality was 67% at 12m and 81% at 15m, vs. 4% in NTG group (P<.0001). Postmortem signs included cardiac dilatation, increase in heart weight, severe lung congestion, pleural effusion and chronic thrombus in the left atrium (all P<.001). Widespread interstitial fibrosis, loss of myocytes and myocardial hypertrophy were evident in TG hearts. Conclusion: A long-term b2AR activation at a high level in the heart is detrimental leading to cardiomyopathy and HF. (Table, *P<.05 vs NTG)
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