Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy

The medical treatment of chronic heart failure has undergone a dramatic tra nsition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta -adrene rgic receptor (beta AR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocyte s from failing hearts show changes in beta AR signaling and excitation-cont raction coupling that can impair cardiac contractility but the role of thes e abnormalities in the progression of heart failure is controversial. We th erefore tested the impact of different manipulations that increase contract ility on the progression of cardiac dysfunction in a mouse model of hypertr ophic cardiomyopathy. High-level overexpression of the beta (2)AR caused ra pidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a p eptide inhibitor of the beta AR kinase 1 not only prevented systolic dysfun ction and exercise intolerance but also decreased cardiac remodeling and hy pertrophic gene expression. These three manipulations of cardiac contractil ity had distinct effects on disease progression, suggesting that selective modulation of particular aspects of PAR signaling or excitation-contraction coupling can provide therapeutic benefit.