Suppressive Effect of the Gly389 Allele of the .BETA.1-Adrenergic Receptor Gene on the Occurrence of Ventricular Tachycardia in Dilated Cardiomyopathy.

Abstract

ilated cardiomyopathy (DCM) is characterized by ventricular dilatation and depressed myocardial contractility, resulting in progressive refractory congestive heart failure and sudden death from ventricular arrhythmias (mainly ventricular tachycardia (VT) and subsequent ventricular fibrillation). 1 A structural increase in ventricular volume (cardiac remodeling) has been viewed as not only an adaptive consequence of initial myocardial damage, but an important determinant of the progression of heart failure. Although risk stratification of cardiac remodeling and ventricular arrhythmias in DCM is an important issue in clinical practice, the factors that lead to cardiac remodeling or induction of VT are not well defined.The adrenergic nervous system, especially through -1-adrenergic receptor ( 1-AR) activation, appears to be of major importance not only in the genesis or progression of cardiac remodeling but also in induction of VT. 2 In transgenic mice, cardiac overexpression of human 1-AR produced an overtly cardiomyopathic phenotype and ultimately chamber dilatation and systolic dysfunction. 3 Clinical evidence has accumulated of the beneficial effect of blockade of 1-AR on cardiac remodeling and prognosis in Circulation Journal Vol.66, August 2002 patients with heart failure caused by DCM or myocardial infarction. 4,5 In the CIBIS-II study, bisoprolol, a highly selective 1-AR blocker, improved the survival rate in patients with heart failure and more importantly, also showed that bisoprolol reduced sudden death most likelycaused by lethal ventricular arrhythmia and hospital admissions for malignant ventricular arrhythmia. 6 The MERIT-HF study showed that metoprolol, a selective 1-AR blocker, also reduced sudden death in patients with heart failure. 7 Accordingly, it seems reasonable to suppose that the signals mediated by 1-AR play an important role in the arrhythmogenesis of heart failure.Beta-1-AR is encoded by a gene comprising a single exon located on chromosome 10q24-26 and consists of 477 amino acids. 8 To date, 18 genetic variants of the single nucleotide chain have been identified. Although 17 of these are located at the coding region, amino acid changes occur only in 7 variants (Ser49Gly, Ala59Ser, Arg389Gly, Arg399Cys, His402Arg, Thr404Ala and Pro418Ala). 9 None of these regions other than the 389 residue have been implicated in the precise function of the 1-AR. The Arg389Gly variant is located at the interface between the last transmembrane helix and the intracellular tail, adjacent to the phosphorylation sites and thought to be critical for Gprotein coupling and subsequent cell signaling. Interestingly, functional studies using transfected fibloblasts indicated that the Arg389 1-AR had approximately 3-fold the adenylyl cyclase activity of the Gly389 1-AR when stimulated by isoproterenol. 10 Therefore, it is quite possible that the Arg389Gly polymorphism functions as either a gene for susceptibility for DCM (role in the emergence of DCM) or a modifier gene (role in the evolution/prognosis Beta-1-ad...

Common ß-adrenergic receptor polymorphisms are not associated with risk of sudden cardiac death in patients with coronary artery disease

“…2,[8][9][10][11][12] Two common nonsynonymous single nucleotide polymorphisms (SNPs) in each of the single-exon β1AR and β2AR genes are observed: β1AR Ser49Gly and Arg389Gly, and β2AR Gly16Arg and Gln27Glu, the latter two of which are in linkage disequilibrium (LD). 13 Carriers of the β1AR Gly49 allele are associated with a better survival in congestive heart failure (CHF) 14 , while the β1AR Gly389 allele is associated with a lower risk for VT. 15 β2AR Gly16Arg and Gln27Glu result in altered receptor downregulation and trafficking in transfected cells. 16 Recent evidence also suggests a role of these β2AR SNPs in survival and pharmacogenetic response to β blockers following acute coronary syndrome (ACS) 17 , and in the risk for out-of-hospital sudden death.…”

Genetic polymorphisms and heart failure

“…Several studies used unconditional statistical methods for data analysis, despite the fact that they matched their cases and controls on population characteristics. 25,31,34,37,64,71,85 This may underestimate the effect of the polymorphisms studied, as it will bias the results toward the null hypothesis.…”

“…85 Others have confirmed the lack of an association with heart failure occurrence. 34,81,86 Small and colleagues 81 did find a significant interaction between the ␣ 2c Del322-325 variant and the ␤ 1 Arg389 allele in heart failure susceptibility. An impaired exercise performance was demonstrated in patients with ischemic or idiopathic dilated cardiomyopathy, who were homozygous for Gly389 compared to Arg389 homozygotes, with an intermediate level of performance in heterozygotes.…”

“…33 Two small studies in 90 Czech and 84 Turkish subjects did, however, not detect an association between heart failure phenotype and ACE genotype. 24,26 Studies in Japanese 28,34 and Chinese patients 35 failed to associate this polymorphism with heart failure phenotype, whereas studies in blacks were contradictory. Candy et al 30 found an association between DD genotype and reduced cardiac function and increased cavity size in South African patients with cardiomyopathy, whereas others did not.…”

“…88 In contrast, a study in Japanese cardiomyopathy patients showed a protective effect of the Gly389 allele in susceptibility to ventricular tachycardia. 34 Few studies have been published on the Ser49Gly polymorphism. A study in dilated cardiomyopathy demonstrated that 5-year transplant-free survival was worse in Ser49 homozygotes than in patients with the Ser49Gly variant.…”