Abstract
BACKGROUND: Elevated plasma norepinephrine levels are associated with
increased mortality in patients and in animal models with chronic
heart failure. To test which alpha2-adrenoceptor subtypes operate
as presynaptic inhibitory receptors to control norepinephrine release
in heart failure, we investigated the response of gene-targeted mice
lacking alpha2-adrenoceptor subtypes (alpha2-KO) to chronic left
ventricular pressure overload. In addition, we determined the functional
consequences of genetic variants of alpha2-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 alpha2A-KO (52%) and alpha2C-KO (47%) mice compared with wild-type
and alpha2B-deficient (86%) animals. Excess mortality in alpha2A-
and alpha2C-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 alpha2C-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 alpha2A- and alpha2C-adrenoceptors in the prevention
of heart failure progression in mice and human patients. Identification
of heart failure patients with genetic alpha2-adrenoceptor variants
as well as new alpha2-receptor subtype-selective drugs may represent
novel therapeutic strategies in chronic heart failure and other diseases
with enhanced sympathetic activation.
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