Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.
BACKGROUND
Beta-blocker therapy may improve cardiac function in patients with idiopathic dilated cardiomyopathy. We tested the hypothesis that beta-blocker therapy produces favorable functional effects in dilated cardiomyopathy by altering the expression of myocardial genes that regulate contractility and pathologic hypertrophy.


METHODS
We randomly assigned 53 patients with idiopathic dilated cardiomyopathy to treatment with a beta-adrenergic-receptor blocking agent (metoprolol or carvedilol) or placebo. The amount of messenger RNA (mRNA) for contractility-regulating genes (those encoding beta1- and beta2-adrenergic receptors, calcium ATPase in the sarcoplasmic reticulum, and alpha- and beta-myosin heavy-chain isoforms) and of genes associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide) was measured with a quantitative reverse-transcription polymerase chain reaction in total RNA extracted from biopsy specimens of the right ventricular septal endomyocardium. Myocardial levels of beta-adrenergic receptors were also measured. Measurements were conducted at base line and after six months of treatment, and changes in gene expression were compared with changes in the left ventricular ejection fraction as measured by radionuclide ventriculography.


RESULTS
Twenty-six of 32 beta-blocker-treated patients (those with complete mRNA measurements) had an improvement in left ventricular ejection fraction of at least 5 ejection-fraction (EF) units (mean [+/-SE] increase, 18.8+/-1.8). As compared with the six beta-blocker-treated patients who did not have a response (mean change, a decrease of 2.5+/-1.8 EF units), those who did have a response had an increase in sarcoplasmic-reticulum calcium ATPase mRNA and alpha-myosin heavy chain mRNA and a decrease in beta-myosin heavy chain mRNA. The change in sarcoplasmic-reticulum calcium ATPase was not present in the patients in the placebo group who had a spontaneous response. There were no differences between those who had a response and those who did not in terms of the change in mRNA or protein expression of beta-adrenergic receptors.


CONCLUSIONS
In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression.
Lowes
Brian D
BD
Division of Cardiology and the Cardiovascular Institute, University of Colorado Health Sciences Center, Denver 80262, USA.
Gilbert
Edward M
EM
Abraham
William T
WT
Minobe
Wayne A
WA
Larrabee
Patti
P
Ferguson
Debra
D
Wolfel
Eugene E
EE
Lindenfeld
JoAnn
J
Tsvetkova
Tatiana
T
Robertson
Alastair D
AD
Quaife
Robert A
RA
Bristow
Michael R
MR
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D000077261:Carvedilol; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006439:Hemodynamics; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D013318:Stroke Volume / Q000187:drug effects; D024723:Ventricular Myosins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases; D008790:Metoprolol