Role of beta-adrenergic receptor gene polymorphisms in the long-term effects of beta-blockade with carvedilol in patients with chronic heart failure.
BACKGROUND
Beta-blockers are mainstay of current treatment of heart failure (HF). Beta-adrenergic receptors (AR) single nucleotide gene polymorphisms (SNPs) may influence the sensitivity and density of beta-AR. We assessed the relation between three common beta-AR SNPs and the response to carvedilol administration.


RESULTS
We studied 183 consecutive patients with chronic HF due to ischemic or nonischemic cardiomyopathy, a LV ejection fraction (LVEF) < or = 0.35, not previously treated with beta-blockers. Each patient underwent gated-SPECT radionuclide ventriculography, cardiopulmonary exercise testing and invasive hemodynamic monitoring at baseline and after 12 months of carvedilol administration at maintenance dosages. The beta1-AR gene Arg389Gly and the beta2-AR gene Arg16Gly SNPs were not related to the response to carvedilol administration. Homozygotes for the Glu27Glu allele showed a greater increase in the LVEF, compared to the other patients (+13.0 +/- 12.2% versus +7.1 +/- 8.1% in the Gln27Gln homozygotes, and 8.3 +/- 11.4% units in the Gln27Glu heterozygotes; p = 0.022 by ANOVA). Glu27Glu homozygotes also showed a greater decline in the pulmonary wedge pressure both at rest and at peak exercise. Gln27Glu SNP was selected amongst the determinants of the LVEF response to carvedilol at multivariable analysis, in addition to the cause of cardiomyopathy, baseline systolic blood pressure and the dose of carvedilol administered.


CONCLUSIONS
Beta1-AR Arg389Gly and beta2-AR Arg16Gly SNPs are not related to the response to carvedilol therapy. In contrast, the Gln27Glu SNP is a determinant of the LVEF response to this agent in patients with chronic HF.
Metra
Marco
M
Institute of Cardiology, Department of Experimental and Applied Medicine, University of Brescia, Italy. metramarco@libero.it
Covolo
Loredana
L
Pezzali
Natalia
N
Zacà
Valerio
V
Bugatti
Silvia
S
Lombardi
Carlo
C
Bettari
Luca
L
Romeo
Alessia
A
Gelatti
Umberto
U
Giubbini
Raffaele
R
Donato
Francesco
F
Dei Cas
Livio
L
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D000077261:Carvedilol; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010101:Oxygen Consumption / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D011412:Propanolamines / Q000494:pharmacology* / Q000627:therapeutic use*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000077261:Carvedilol