Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy.
OBJECTIVE
Large variability exists in the improvement in left ventricular (LV) function from beta-blocker treatment. We hypothesized that polymorphisms at codon 389 (Arg389Gly) and 49 (Ser49Gly) in the beta1-adrenergic receptor (AR) gene were associated with LV reverse remodeling changes in response to beta-blocker therapy among heart failure patients.


METHODS
We prospectively enrolled 61 beta-blocker naive patients with systolic heart failure. Patients underwent baseline echocardiography followed by metoprolol CR/XL. The dose was doubled on a biweekly basis up to 200 mg/day or attainment of maximum tolerated dose. Echocardiography was repeated after the patient received the target or highest tolerated dose for 3 months.


RESULTS
Among patients with the Arg389Arg genotype, ejection fraction (EF) increased from 23+/-5 to 29+/-10 (P=0.008). Gly389 carriers did not demonstrate any significant change in EF (22+/-9 to 23+/-11; P=0.45). There was a significant between-group difference in EF by genotype (P=0.04). The Arg389Arg genotype was also associated with significantly greater reductions in LV end-diastolic and end-systolic diameters compared to Gly389 carriers. Patients with the Gly49 variant also had a significantly greater reduction in LV end-diastolic diameter compared to Ser49 homozygotes. Multiple regression analysis modeling revealed that the codon 389 polymorphism was a significant predictor of an improvement in EF and both codon 49 and 389 polymorphisms were significant predictors of final LV end-diastolic diameter.


CONCLUSIONS
Heart failure patients with the Arg389Arg genotype and Gly49 carriers had greater improvements in LV remodeling from beta-blocker treatment.
Terra
Steven G
SG
Department of Pharmacy Practice, University of Florida College of Pharmacy, Gainesville, FL 32610, USA.
Hamilton
Karen K
KK
Pauly
Daniel F
DF
Lee
Craig R
CR
Patterson
J Herbert
JH
Adams
Kirkwood F
KF
Schofield
Richard S
RS
Belgado
Bernadette S
BS
Hill
James A
JA
Aranda
Juan M
JM
Yarandi
Hossein N
HN
Johnson
Julie A
JA
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D003062:Codon; D004452:Echocardiography; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011941:Receptors, Adrenergic / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D012044:Regression Analysis; D013599:Systole; D013997:Time Factors; D020257:Ventricular Remodeling
D000319:Adrenergic beta-Antagonists; D003062:Codon; D011941:Receptors, Adrenergic; D018342:Receptors, Adrenergic, beta-1