Background— Elevated plasma norepinephrine levels are associated with increased mortality in patients and in animal models with chronic heart failure. To test which α₂-adrenoceptor subtypes operate as presynaptic inhibitory receptors to control norepinephrine release in heart failure, we investigated the response of gene-targeted mice lacking α₂-adrenoceptor subtypes (α₂-KO) to chronic left ventricular pressure overload. In addition, we determined the functional consequences of genetic variants of α₂-adrenoceptors in human patients with chronic heart failure.

Methods and Results— Cardiac pressure overload was induced by transverse aortic constriction. Three months after aortic banding, survival was dramatically reduced in α_2A-KO (52%) and α_2C-KO (47%) mice compared with wild-type and α_2B-deficient (86%) animals. Excess mortality in α_2A- and α_2C-KO strains was attributable to heart failure with enhanced left ventricular hypertrophy and fibrosis and elevated circulating catecholamines. The clinical importance of this finding is emphasized by the fact that heart failure patients with a dysfunctional variant of the α_2C-adrenoceptor had a worse clinical status and decreased cardiac function as determined by invasive catheterization and by echocardiography.

Conclusions— Our results indicate an essential function of α_2A- and α_2C-adrenoceptors in the prevention of heart failure progression in mice and human patients. Identification of heart failure patients with genetic α₂-adrenoceptor variants as well as new α₂-receptor subtype–selective drugs may represent novel therapeutic strategies in chronic heart failure and other diseases with enhanced sympathetic activation.