Abstract 18794: More Than a Biomarker_ANP Modulates Heart Failure, Cardiac Function and Survival in Dilated Cardiomyopathy

Abstract

Although atrial natriuretic peptide (ANP) is an established biomarker for heart failure, there is significant controversy whether ANP modifies or affects the progression of heart failure in patients with reduced contractile function and dilated cardiomyopathy (DCM). Therefore we examined the effects of ANP on survival, heart failure progression, fibrosis and cardiac function in a well-established model of DCM caused by the cardiac-targeted expression of a dominant negative CREB transgene. By comparison to DCM mice with normal ANP levels (DCM, ANP+/+) mice with partial ANP deficiency (DCM, ANP+/-) had reduced survival (p<0.001) and, mice with full ANP deficiency (DCM, ANP-/-), had even greater reductions in survival than those with normal ANP or partial ANP deficiency (p<0.001). Radiography showed that ANP-deficient DCM mice developed more severe heart failure with pleural effusions and pronounced cardiomegaly. These mice showed increased alveolar congestion (22.9±1.5% vs. 57.3±3.2%, p<0.001) and increased heart weights (heart:body weight 0.54±0.04% vs. 0.95±0.05%). ANP-deficient DCM mice showed a more marked reduction in cardiac function as evidenced by decreased EF% (30.7±3.2 % vs. 16.0 ±1.5 %, p<0.001) and enhanced cardiac dilation (LVIDd 4.51±0.11 mm vs. 5.85±0.10 mm, p<0.001; LVIDs 3.9±0.1 mm vs. 5.0 mm±0.2, p<0.001). ANP-deficient DCM mice had more severe cardiac interstitial fibrosis (4.54±0.3 % vs. 12.58±0.62%, p<0.01) and perivascular fibrosis (ratio to lumen area 0.58±0.07 vs. 2.53±0.26, p<0.01) as well as eccentric cardiomyocyte hypertrophy (cross sectional area 662±12 μm2 vs. 905±23 μm2, p<0.001). Levels of cGMP were significantly reduced in ANP-deficient DCM mice (p<0.001). We conclude that ANP profoundly modulates the progression of DCM in mice by reducing the severity of heart failure, improving contractility, reducing ventricular dilation, preventing cardiac fibrosis and extending survival. Thus ANP is not only a key biomarker, but it also modulates the progression of heart failure, cardiac function and remodeling in DCM.