β1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure

Abstract

Catecholamines stimulate cardiac contractility through beta(1)-adrenergic receptors (beta(1)-ARs), which in humans are polymorphic at amino acid residue 389 (Arg/Gly). We used cardiac-targeted transgenesis in a mouse model to delineate mechanisms accounting for the association of Arg389 with human heart failure phenotypes. Hearts from young Arg389 mice had enhanced receptor function and contractility compared with Gly389 hearts. Older Arg389 mice displayed a phenotypic switch, with decreased beta-agonist signaling to adenylyl cyclase and decreased cardiac contractility compared with Gly 389 hearts. Arg389 hearts had abnormal expression of fetal and hypertrophy genes and calcium-cycling proteins, decreased adenylyl cyclase and G alpha(s) expression, and fibrosis with heart failure This phenotype was recapitulated in homozygous, end-stage, failing human hearts. In addition, hemodynamic responses to beta-receptor blockade were greater in Arg389 mice, and homozygosity for Arg389 was associated with improvement in ventricular function during carvedilol treatment in heart failure patients. Thus the human Arg389 variant predisposes to heart failure by instigating hyperactive signaling programs leading to depressed receptor coupling and ventricular dysfunction, and influences the therapeutic response to beta-receptor blockade.

Markedly reduced effects of (−)‐isoprenaline but not of (−)‐CGP12177 and unchanged affinity of β‐blockers at Gly389‐β1‐adrenoceptors compared to Arg389‐β1‐adrenoceptors

“…In addition, Liu et al (2003) also reported greater metoprolol-evoked bradycardia in homozygous Arg389 than homozygous Gly389. Furthermore, homozygous Arg389 patients with end-stage heart failure, but not homozygous Gly389 patients, showed significant improvement of the left ventricular ejection fraction when treated with the b-blocker carvedilol (Perez et al, 2003). The more marked effect of atenolol and metoprolol, as well as the selective effect of carvedilol, could be due to higher affinity of these b-blockers for Arg389-b 1 -adrenoceptors than Gly389-b 1 -adrenoceptors.…”

“…Table 2 Potencies of (À)-isoprenaline and (À)-CGP12177 and antagonism by (À)-propranolol (200 nM) on recombinant Arg389-b 1 -adrenoceptors and Gly389-b 1 -adrenoceptors b-adrenoceptor blockade with carvedilol (Perez et al, 2003). Furthermore, b 1 -adrenoceptor blockade with atenolol (Sofowora et al, 2003) and metoprolol (Liu et al, 2003) appears to reduce systolic pressure in Arg389 healthy volunteers but not in Gly389 volunteers.…”

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…46 The association of this allele with antihypertensive response to beta-blocker therapy is less straight forward. Several small studies have revealed positive results with the C allele corresponding to an improved response to beta-blockade as defined by reduction in BP or heart failure endpoints [47][48][49][50][51] . Studies have also illustrated contradictory results where the G allele is associated with more favorable rate control with verapamil and multiple beta-blockers 52 .…”

β-Adrenergic receptor gene polymorphisms and hemodynamic response to dobutamine during dobutamine stress echocardiography

“…In vitro studies have provided evidence for their functional basis, [1][2][3] and these polymorphisms have been implicated in differential response to b 1 -and b 2 -AR antagonists and agonists in numerous studies. Specifically, studies have shown that b 1 -AR genotype is a significant predictor of blood pressure and ejection fraction responses to b-blockers, [4][5][6][7][8] and responses to b 2 agonists have been associated with b 2 -AR polymorphisms. 9,10 Dobutamine is a potent synthetic intravenous inotrope that is principally an agonist at b 1 -AR with mild stimulatory effects at b 2 -AR and a 1 -AR.…”