P330Progressive development of dilated and hyperkinetic cardiomyopathy in transgenic mice with cardiac expression of adenylyl cyclase

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Abstract

Background

Heart failure(HF) is associated with the desensitization of beta-adrenergic signaling transduction resulting in a decrease of cAMP bioavailability, the critical regulator contractile function. Consistently, reversing or bypassing beta-adrenergic desensitization in animal models of HF led to symptomatic improvement; young mice (2-4 mo-old) over-expressing calcium/calmodulin activated adenylyl cyclase type 8 (AC8TM) showed an improved beta-adrenergic reactivity which enhanced -cAMP synthesis, -PKA activity and -contractile function (Lipskaia, 2000). We now explore whether the beneficial effect of adenylyl cyclase over-expression on cardiac function is modified throughout aging.

Methods and Results

Cardiac function of AC8TM was monitored from 2 to 16 months of age by echocardiography. No difference in basal cardiac function was detected in young mice (2-6 month old). Starting at 8 months, echocardiography revealed a progressive increase in left ventricular size evaluated by LV end-diastolic(ED) and end-systolic(ES) dimensions; and a decrease of LV ejection fraction and fractional shortening (FS) compared to their littermates. At end-point, AC8TM exhibited an increased heart weight/tibia length ratio (1.02 ± 0.13 vs 0.77 ± 0.11,p < 0.01). Histological examination revealed an increase in interstitial fibrosis and higher cardiomyocytes cross-sectional area (μm2: 204.65 ± 48.55 vs. 100.86 ± 5.05, p < 0.01). Echocardiography in aging mice showed a decrease in systolic function(FS%:49.47 ± 5.43 vs 24.56 ± 4.96,p < 0.05), an increase in in LVED (cm: 0.49 ± 0.04 vs 0.37 ± 0.03 p < 0.01) and LVES diameters (cm: 0.37 ± 0.05 vs 0.19 ± 0.03, p < 0.01). Invasive hemodynamic measurements showed an increase in heart rate (HR, b/min:629 ± 68 vs 487 ± 86, p < 0.01) with enhanced systolic (dP/dt max: 8869 ± 4421 vs 5293 ± 1107, p < 0.01) and diastolic (-dP/dt min:7476 ± 3800 vs 4994 ± 1208,p < 0.01) ventricular function. Furthermore, during hemodynamic recording, arrhythmias were recorded in 7 out of 12 AC8TM, vs none in WT; ECG analysis is underway. Altogether, this study lead us to conclude that increasing cAMP/PKA signaling, here by the over-expression of adenylyl cyclase, causes a progressive alteration of cardiac function leading to dilated and hyperkinetic cardiopathy.

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