ABSTRACT
Acute activation of the sympathetic nervous system acts to increase cardiac output and critical organ perfusion. However, chronic activation, particularly via norepinephrine stimulation of myocyte β1-adrenergic receptors (β1AR) ultimately leads to a deterioration of ventricular function. This phenomenon is accompanied by a number of mechanisms which have positive, compensatory effects as well as deleterious features.1 The seemingly paradoxical improvement of ventricular function by β-blockers used in the treatment of chronic heart failure is due to blunting of this sympathetic drive,2 and indeed norepinephrine (NE) levels are inversely correlated to survival in heart failure.3 Given these adaptive and maladaptive events that occur via the sympathetic nervous system, we considered that genetic variants of adrenergic receptors that alter receptor expression or function, may have relevant physiological consequences in heart failure. The incomplete penetrance in familial cardiomyopathies,4 and extensive interindividual variability of adrenergic regulation in humans,5 the clinical characteristics of heart failure,4,6 and the response to therapy in the syndrome,7-9 also suggest a genetic component to common heart failure syndromes such as ischemic and dilated cardiomyopathies. Concerning the receptors, of the nine adrenergic receptors, six have coding polymorphisms (defined as a genetic variant with an allele frequency of ≥1%), which alter receptor function in recombinant cells.10 Figure 35.1 shows a schematic diagram of adrenergic receptors expressed in the cardiac presynaptic nerve terminal and the myocyte. Sympathetic stimulation is controlled in part by α2AR located in presynaptic nerve termini which regulate NE release at the synapse. The a2AAR subtype controls NE release
from presynaptic nerves undergoing high-frequency stimulation, while the α2CAR inhibits release from low-frequency (basal) stimulation.11 Indeed, the α2A/α2C double knockout mouse develops a catecholamine-mediated cardiomyopathy, indicating that even the nonstressed setting regulation of NE release is critical for normal cardiac function and adaptation.11 Furthermore, the α2CAR knockout, while apparently without pathology in the non-stressed state, develops a marked cardiomyopathy and heart failure after induction of pressureoverload by aortic banding.12 A presynaptic β2AR has also been identified, whose activation is thought to increase NE release.13 At the myocyte, released NE acts primarily at the β1AR, but NE can activate β2ARs (albeit at lower affinity), and both subtypes respond to circulating epinephrine. In this review the salient phenotypes of adrenergic receptor polymorphisms relevant to heart failure, as ascertained in transfected cells or transgenic mice, are summarized, and the consequences of certain polymorphisms in the human disease are discussed.
