Background: The β(1)-adrenoceptor (β(1)AR) mediates cardiostimulatory effects of catecholamines in the heart. The Arg389Gly polymorphism of the β(1)AR gene has recently been shown to determine the responsiveness to catecholamines in vitro, and we previously reported that dobutamine induced an augmented contractile response in humans homozygous for the Arg389 allele. The aim of the present study was to evaluate whether the Arg389Gly β(1)AR gene polymorphism influences the responsiveness to β-blocker treatment on cardiac contractility.
Methods: We investigated 30 healthy male volunteers who were genotyped for the Arg389Gly polymorphism and subjected to modified dobutamine stress-echocardiography (DSE) with and without pretreatment with metoprolol controlled release/extended release (CR/XL). Fractional shortening (FS) as a parameter for left-ventricular contractility and heart rate were measured. To control for pre- and afterload effects, rate corrected velocity of circumferential fiber shortening (Vcfc) was calculated.
Results: Homozygous Arg389 carriers had a significantly higher increase in contractility upon dobutamine stimulation than individuals carrying the Gly389 allele. Pretreatment with metoprolol CR/XL prior to DSE blunted the dobutamine-induced increase of FS and Vcfc in homozygous Arg389 carriers to the level of subjects carrying the Gly389 allele. In the latter group, metoprolol had a modest effect on the dobutamine-induced increase in FS at low concentrations of dobutamine, and no significant effect at peak stress (40 μg/kg/min of dobutamine).
Conclusion: The responsiveness to β-blockers with respect to cardiac contractility is determined by the Arg389Gly β(1)AR gene polymorphism. These findings offer a molecular explanation for interindividual differences in the responsiveness to β-blocker treatment in humans.