A frequent Gene Polymorphism Affecting the Heart-rate Response to Carvedilol

Abstract

b-adrenoceptor antagonists, known as b-blockers, are a cornerstone in the treatment of the most prevalent cardiovascular syndromes, including heart failure, ischemic heart disease, atrial fibrillation and hypertension. Their beneficial effects are explained by competitive antagonism at b1-adrenoceptors, the dominant adrenergic receptors expressed in cardiac myocytes. By contrast, antagonism at b2-adrenoceptors accounts for side effects (e.g., vasospasm [‘cold extremities’], bronchospasm and hypoglycemia) and contraindications, such as asthma bronchiale. Accordingly, the majority of currently prescribed second-generation b-blockers (e.g., metoprolol, bisoprolol and atenolol) preferentially act at b1-adrenoceptors, that is, they possess higher affinity towards b1than b2-adrenoceptors (‘b1-selective b-blockers’). Carvedilol is a thirdgeneration b-blocker, which is generally classified as nonselective, but, in fact, has a 13-fold-higher affinity for human b2than b1-adrenoceptors [1]. Carvedilol is also a potent a1-adrenoceptor antagonist [2], which balances the constrictive effect of b2-blockade, and has antioxidant effects of unknown relevance. Moreover, carvedilol directly blocks spontaneous diastolic Ca release from cardiac ryanodine receptors, an activity thought to suppress ventricular arrhythmias, for example in heart failure, where the ryanodine receptor is thought to be ‘leaky’ [3,4]. Finally, carvedilol has unusually slow dissociation kinetics, that is, it ‘sticks to adrenoceptors’, which causes a longer time of action than predicted from its plasma half-life [5]. The b1-adrenoceptor gene (ADBR1) exhibits a frequent SNP that causes a change of Arg at position 389 to Gly [6]. Approximately 40 and 7% of Caucasians are heterozygous and homozygous for the rarer Gly389 variant, respectively. The polymorphism has gained much attention because, when overexpressed at very high levels