Interaction between cardiac sympathetic drive and heart rate in heart failure : Modulation by adrenergic receptor genotype

ObjectivesIn the present study, we aimed to evaluate the effect of adrenergic receptor polymorphisms on the response of myocardium to measured levels of cardiac adrenergic drive, and to evaluate whether polymorphisms of presynaptic adrenoceptors modified the rate of cardiac and systemic release of norepinephrine.BackgroundHeightened sympathetic activity plays an important pathophysiologic role in congestive heart failure (CHF). Recently several functionally relevant polymorphisms of the α2-, β1-, and β2-adrenoceptors have been identified, and specific genotypes have been associated with the incidence or clinical severity of CHF. These adrenoceptors are known to be located both pre-synaptically (α2and β2) and post-synaptically (β1and β2), raising the possibility that their association with clinical measures in CHF could be mediated either by modulation of the cardiac response to a given level of adrenergic drive or by altering norepinephrine release from sympathetic nerve terminals.MethodsWe determined the β1-, β2-, and α2C-adrenoceptor genotype in 60 patients with severe CHF in conjunction with measurement of cardiac and systemic sympathetic activity using the radiotracer norepinephrine spillover method.ResultsWe showed a strong relationship (r = 0.67, p < 0.001) between heart rate and the level of cardiac adrenergic drive, and heart rate for a given level of cardiac adrenergic drive was substantially greater in patients with the Arg/Arg16 β2-adrenoceptor polymorphism (p = 0.02), whereas no such relationship existed for polymorphisms of the β1-adrenoceptor. The genotype of the α2C- and β2-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves.ConclusionsFor the first time, we show that β2-adrenoceptor polymorphisms significantly influence the relationship between heart rate and cardiac adrenergic drive in CHF, but do not affect the rate of norepinephrine release from sympathetic nerve terminals.