Heterozygous alpha 2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction.

OBJECTIVE: Feedback regulation of norepinephrine release from sympathetic nerves is essential to control blood pressure, heart rate and contractility. Recent experiments in gene-targeted mice have suggested that alpha(2C)-adrenoceptors may operate in a similar feedback mechanism to control the release of epinephrine from the adrenal medulla. As heterozygous polymorphisms in the human alpha(2C)-adrenoceptor gene have been associated with cardiovascular disease including hypertension and chronic heart failure, we have sought to characterize the relevance of alpha(2C)-gene copy number for feedback control of epinephrine release in gene-targeted mice. METHODS: Adrenal catecholamine release, basal hemodynamics and susceptibility to develop heart failure after transverse aortic constriction were tested in mice with two copies (+/+), one copy (+/-) or no functional alpha(2C)-adrenoceptor gene (alpha(2C)-/-). RESULTS: Heterozygous alpha(2C)-receptor deletion (alpha(2C)+/-) resulted in a 43% reduction of adrenal alpha(2C) mRNA copy number and in a similar decrease in alpha(2)-receptor-mediated inhibition of catecholamine release from isolated adrenal glands in vitro. Urinary excretion of epinephrine was increased by 74+/-15% in alpha(2C)+/- and by 142+/-23% in alpha(2C)-/- mice as compared with wild-type control mice. Telemetric determination of cardiovascular function revealed significant tachycardia but no hypertension in alpha(2C)-adrenoceptor-deficient mice. alpha(2C)+/- mice were more susceptible to develop cardiac hypertrophy, failure and mortality after left-ventricular pressure overload than alpha(2C)+/+ mice. CONCLUSION: Adrenal alpha(2)-mediated feedback regulation of epinephrine secretion differs fundamentally from sympathetic feedback control. A single adrenoceptor subtype, alpha(2C), operates without a significant receptor reserve to prevent elevation of circulating epinephrine levels. This genetic model may provide an experimental basis to study the pathophysiology of alpha(2C)-adrenoceptor dysfunction in humans.

Alpha2C-adrenoceptor polymorphism is associated with improved event-free survival in patients with dilated cardiomyopathy.

AIMS: The sympathetic nervous system plays a central role in cardiac growth but its overstimulation is associated with increased mortality in patients with chronic heart failure. Pre-synaptic alpha2-adrenoceptors are essential feedback regulators to control the release of norepinephrine from sympathetic nerves. In this study we tested whether a deletion polymorphism in the human alpha2C-adrenoceptor gene (alpha2CDel322-325) affects progression of heart failure in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: We genotyped and phenotyped 345 patients presenting with DCM in the heart transplant unit of the German Heart Institute, starting in 1994. Patients were treated according to guidelines (99% ACEI, 76% beta-blockers) and were followed until December 2002 or until a first event [death, heart transplantation, or implantation of a left ventricular assist device (LVAD) for a life-threatening condition] occurred. Mean follow-up time was 249 weeks (4.9 years) in event-free patients and 104 weeks (2 years) in patients with events. During follow-up, 51% of the patients exhibited an event: death (18%), implantation of LVAD as bridging for transplantation (7%), or heart transplantation (25%). By Kaplan-Meier analysis, DCM patients with the deletion variant Del322-325 in the alpha2C-adrenoceptor showed significantly decreased event rates (P=0.0043). Cox regression analysis revealed that the presence of the deletion was associated with reduced death rate (relative risk: 0.129, 95% CI: 0.18-0.9441, P=0.044) and event rates (relative risk: 0.167, 95% CI: 0.041-0.685, P=0.012). CONCLUSION: Alpha2C-adrenoceptor deletion may be a novel, strong, and independent predictor of reduced event rates in DCM patients treated according to guidelines.