Genes and acquired disease: beta-adrenoceptor polymorphisms and heart failure

The selfish gene has little interest in the welfare of its host after reproduction. This teleological concept, albeit simplistic in the present context, may partly explain why the neuroendocrine compensatory mechanisms that have evolved for congestive cardiac failure, a condition affecting mostly older patients, are fundamentally flawed. One of these misguided compensatory responses is chronic activation of the sympathetic nervous system. This not only causes down-regulation of beta-receptors and their uncoupling from signal transduction pathways (the latter resulting from up-regulation of betaadrenoceptor kinases and increased activity of the G-inhibitory protein Gi ; the former from a reduction in the half-life of beta-receptor mRNA) but is directly cardiotoxic (due possibly to adrenoceptormediated increases in intracellular calcium and altered macromolecular synthesis). The extent of these changes correlates with the degree of adrenergic stimulation. The clinical consequences are a loss of exercise tolerance, progression of left ventricular dysfunction and an increased prevalence of arrhythmia and sudden death. The documented functional and survival benefits of long-term therapy with beta-adrenergic receptor antagonists are final proof positive that nature does not always know best. Given the importance of this system in the pathogenesis of chronic congestive heart failure, it might be predicted that mutations or polymorphisms of betaadrenoceptor genes would modulate survival. Several polymorphisms of the beta2 receptor have been identified. The most impaired variant of these is due to a threonine to isoleucine (Ile) switch at amino acid 164 in the 4th transmembrane domain of the receptor. This receptor demonstrates a small decrease in binding affinity for catecholamines, a substantial decrease in basal and stimulated adenyl cyclase activities due to defective coupling of the receptor to the stimulatory G protein and impaired agonist