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.
Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients with reduced ejection fraction (HFrEF) who have the beta<sub>1</sub>-adrenergic receptor (ADRB1) Arg389Arg genotype.
Data from our study suggest that the β adrenoreceptor Gly 49 allele of the β1 -adrenergic receptorSer(49) Gly polymorphisms may increase the risk of ICD shock in patients with heart failure, independent of beta-blocker dosage.
Downregulation of β(1)- adrenergic receptors (β(1)-ARs) and increased expression/function of G-protein-coupled receptor kinase 2 (GRK2) have been observed in human heart failure, but changes in expression of other ARs and GRKs have not been established.
During long-term carvedilol therapy, CHF patients with the Arg/Arg genotype of the ADRB1 gene were observed to have a more pronounced decrease in the functional class of heart failure, a significant increase in left ventricular ejection, and a decrease in left ventricular end-systolic and end-diastolic sizes as compared with patients with the Gly/Arg genotype.
GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype.(ClinicalTrials.govNCT01970501).
Impact of the β-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between β adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study.
In conclusion, patients with heart failure and reduced ejection fraction that are homozygous for ADRB1 Ser49 were significantly more likely to experience LVEF recovery than Gly49 carriers.
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%).
Long-term treatment with angiotensin I-converting enzyme inhibitors attenuates the loss of cardiac beta-adrenoceptor responses in rats with chronic heart failure.
More consistent to mammalians, adult zebrafish developed significant heart failure in concert with β1-AR downregulation, and GRK2 and brain natriuretic peptide (BNP) upregulation in response to prolonged, 14d ISO-stimulation.
Multiple polymorphisms act synergistically between the ADRA2C and ADRB1 genes to increase risk of death or cardiac transplant in heart failure patients.
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.
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).