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

J Card Fail. 2003 Dec;9(6):469-74. doi: 10.1016/s1071-9164(03)00581-5.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use*
  • Adult
  • Aged
  • Biomarkers / blood
  • Calcium-Binding Proteins / biosynthesis
  • Calcium-Binding Proteins / drug effects
  • Calcium-Transporting ATPases / biosynthesis
  • Calcium-Transporting ATPases / drug effects
  • Cardiomyopathy, Dilated / complications
  • Cardiomyopathy, Dilated / drug therapy
  • Cardiomyopathy, Dilated / genetics
  • Cyclic AMP-Dependent Protein Kinases / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Female
  • Gene Expression Regulation / drug effects*
  • Heart Failure / drug therapy*
  • Heart Failure / etiology
  • Heart Failure / physiopathology
  • Humans
  • Japan
  • Male
  • Middle Aged
  • Myocardial Contraction / drug effects
  • Myocardium / chemistry*
  • Myocardium / pathology*
  • Myosin Heavy Chains / biosynthesis
  • Myosin Heavy Chains / drug effects
  • Natriuretic Peptide, Brain / blood
  • Natriuretic Peptide, Brain / drug effects
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Ryanodine Receptor Calcium Release Channel / drug effects
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Sodium-Calcium Exchanger / drug effects
  • Sodium-Calcium Exchanger / metabolism
  • Stroke Volume / drug effects
  • Treatment Outcome
  • Ventricular Function, Left / drug effects
  • beta-Adrenergic Receptor Kinases

Substances

  • Adrenergic beta-Antagonists
  • Biomarkers
  • Calcium-Binding Proteins
  • RNA, Messenger
  • Ryanodine Receptor Calcium Release Channel
  • Sodium-Calcium Exchanger
  • phospholamban
  • Natriuretic Peptide, Brain
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Myosin Heavy Chains
  • Calcium-Transporting ATPases