Changes in myocardial gene expression associated with beta-blocker therapy in patients with chronic heart failure

Abstract

Background: The left ventricular functional recovery by beta-blocker therapy is now attributed to time-dependent biologic effects on cardiomyocytes.

Methods and results: To elucidate the cellular mechanism of these biologic effects, we treated 9 patients with dilated cardiomyopathy for 4 months with beta-blockers and examined the gene expressions linked to an improvement of left ventricular ejection fraction (EF). Gene expressions of the biopsied right ventricular endomyocardium were assessed by real-time reverse transcription-polymerase chain reaction. A decrease in beta-myosin heavy chain (1.23+/-0.49 versus 0.86+/-0.45, P<.05) was observed 4 months after the administration of beta-blockers. The expression levels of both sarcoplasmic reticulum Ca(2+) ATPase (SERCA) (0.80+/-0.28 versus 1.39+/-0.44, P<.01) and phospholamban (PLB) (0.49+/-0.08 versus 0.88+/-0.34, P<.05) increased, whereas the expression levels of Na(+)-Ca(2+) exchanger (NCX), beta-adrenoreceptor kinase 1, and ryanodine receptor 2 were unchanged. The SERCA/NCX ratio (0.68+/-0.14 versus 0.96+/-0.33, P<.05) also increased. The increase in SERCA mRNA expression correlated with the degree of changes in EF (%deltaEF) (r=0.679, P<.05), and none of changes in these genes expression correlated with changes in the plasma brain natriuretic peptide concentration.

Conclusions: The functional recovery resulting from beta-blockers may be associated with the restoration of the unfavorable gene expression that controls Ca(2+) handlings in the failing heart.