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Background Cardiac resynchronization therapy (CRT) improves echocardiographic measures of ventricular structure and function in the failing heart. To determine whether or not these changes are representative of true biologic reverse ventricular remodeling or simply an artifact of an improved contraction pattern, we evaluated changes in myocardial gene expression typical of reverse remodeling before and after chronic CRT. Methods and Results Optimally medically treated patients with nonischemic heart failure meeting standard clinical criteria for CRT were enrolled. Before implantation of a CRT device, baseline echocardiogram and endomyocardial biopsies were obtained. These studies were repeated after 6 months of CRT. Using quantitative reverse-transcriptase polymerase chain reaction, the amount of messenger RNA for selected genes regulating contractile function (sarcoplasmic reticulum Ca 2+ ATPase, α- and β-myosin heavy chain [MHC] isoforms, phospholamban [PLB]), and pathologic hypertrophy (β-MHC and atrial natriuretic peptide [ANP]) was determined from biopsy samples. Changes in gene expression (baseline to 6 months) were determined and correlated to changes in echocardiographic remodeling parameters. Ten patients were enrolled in the study, with 7 completing both baseline and follow-up biopsies and echocardiograms. On average, a significant increase was observed in α-MHC and PLB gene expression from baseline to 6 months ( P = .016 for both). β-MHC levels tended to decrease with CRT ( P = .078). Increased α-MHC levels correlated best with decreases in left ventricular end-diastolic dimension ( P = .073, r = –0.71) and reductions in mitral regurgitation. No significant correlation between ejection fraction and gene expression was found. Conclusions These changes in myocardial gene expression support the occurrence of reverse remodeling during chronic CRT. The changes are similar to those reported previously with β-blockade, but were seen on top of standard drug therapies for heart failure.