Abstract 5501: Reduced Coronary Reserve as a Mechanism in Beta-Adrenergic Receptor Mediated Cardiomyopathy and its Rescue by Adenylyl Cyclase Type 5 Knockout
Reduced coronary reserve (CR) is a cardinal feature of human cardiomyopathy, but it has not been studied extensively in mouse models of cardiomyopathy, potentially because of difficulties inherent to measuring CR in such a small heart. The first goal of this study was to determine if reduced CR is a potential mechanism involved in a transgenic (Tg) mouse model of cardiomyopathy, induced by cardiac overexpression of beta2-adrenergic receptors (beta2-AR Tg). Older beta2-AR Tg mice (16–17 months, n=7) developed cardiomyopathy, as reflected by decreased LV ejection fraction (LVEF, 50±7%), and increased fibrosis (5.2±0.4%) and apoptosis (3.8±0.6%). CR was obtained by measuring LV coronary blood flow at baseline and with adenosine (160 microg/kg/min) induced hyperemia using high resolution ultrasound (Vevo 770). CR was significantly decreased in beta2-AR Tg (1.8±0.2) compared with wild type (WT) (3.0±0.3, n=6). The next goal was to determine if the rescue of the beta2-AR Tg cardiomyopathy resulted in a rescue of reduced CR. Since adenylyl cyclase type 5 knockout (AC5 KO) mice are protected against catecholamine stress and the development of heart failure (HF), and exhibit enhanced CR (3.7±0.4, n=5), we hypothesized that mating these mice with beta2-AR Tg might rescue the cardiomyopathy. Older (16–17 months, n=4) bigenic mice (beta2-AR Tg x AC5 KO) demonstrated a rescue of cardiomyopathy, as reflected by normalized LVEF (71±1%) and levels of apoptosis (0.11±0.01%) and fibrosis (1.09±0.33%), similar to WT. In these mice, CR was also normalized (3.4±0.6). Reduced CR in beta2-AR Tg cardiomyopathy is similar to that observed in large mammalian models, and in patients with cardiomyopathy. Thus, this mechanism is important to consider in mouse models of cardiomyopathy, in general, and also in particular for the mechanism of the rescue of the beta2-AR Tg cardiomyopathy by AC5 KO.