A decrease in the density of the beta 1-adrenergic receptor and an increase in the functional activity of the G inhibitory protein Gi accompany human heart failure; however, the molecular and biochemical mechanisms responsible for these changes are unclear.
Cardiac beta 1-adrenergic receptor density was decreased while its dissociation constant (Kd) was not altered in the viable tissue of the left ventricle of the CHF rat, which is consistent with beta-adrenergic receptor downregulation.
A novel missense mution in the beta(1)-adrenergic receptor gene was associated with a decreased mortality risk in patients with congestive heart failure.
In this study, we have identified the cardiac Na(+)-H(+) exchanger (NHE1) as a novel mediator of adrenergically induced heart failure. beta(1)-Adrenergic receptor transgenic mice showed upregulation of both NHE1 mRNA (+140+/-6%) and protein (+42+/-19%).
Patients with heart failure who were hetero- or homozygous for the Gly-49 variant of the beta(1)AR (Gly-49-beta(1)AR) showed improved long-term survival as compared with those with the Ser-49 genotype.
We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the beta(1)-adrenergic receptor would be associated with differences in initial tolerability of beta-blocker therapy in patients with heart failure.
We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.
In this issue of the JCI, Rochais et al. describe how a single amino acid change in beta(1)-AR alters its structural conformation and improves its functional response to carvedilol, a beta blocker currently used in the treatment of HF (see the related article beginning on page 229).
One study of risk for heart failure suggested a synergistic effect of ADRB1Arg389Gly with the insertion/deletion polymorphism in the alpha2C-adrenergic receptor gene (ADRA2C).
Numerous studies have demonstrated that beta(1)- and beta(2)-adrenergic receptor gene (ADRB1 and ADRB2) variants influence cardiovascular risk and beta-blocker responses in hypertension and heart failure.
Multiple polymorphisms act synergistically between the ADRA2C and ADRB1 genes to increase risk of death or cardiac transplant in heart failure patients.
The alpha(2C) Del322-325 polymorphism exclusively or in combination with the beta(1)Arg389 allele is not associated with an increased risk of adverse events in HF.
Therapeutic efficacy of a combination of a beta1-adrenoreceptor (AR) blocker and beta2-AR agonist in a rat model of postmyocardial infarction dilated heart failure exceeds that of a beta1-AR blocker plus angiotensin-converting enzyme inhibitor.
The authors' laboratory has thus pursued genetic variation of the beta(1)-AR gene at the molecular, cellular, physiologic, and clinical levels as the potential basis for interindividual variability in the response to beta-blocker treatment during heart failure.
Such treatment has the potential to enable pharmacogenetics, such as the prevention of 100,000 deaths per year in the USA because of adverse drug reactions or specify treatment in heart failure such at the beta 1 adrenergic receptor polymorphisms.