Dataset Information

Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure.

ABSTRACT:

Background

The effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF.

Methods

Genetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases).

Results

Lower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74-0.93, P = 0.001) and 0.95 (95% CI 0.93-0.97, P = 8 × 10^-6). Conversely, lower α2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05-1.12, P = 3 × 10^-7). No evidence of an effect of lower ß2 activity on HF risk was found: OR 0.99 (95% CI 0.92-1.07, P = 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease.

Conclusions

This study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.

SUBMITTER: Baudier C

PROVIDER: S-EPMC10619754 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure.

Baudier Claire C Fougerousse Françoise F Asselbergs Folkert W FW Guedj Mickael M Komajda Michel M Kotecha Dipak D Thomas Lumbers R R Schmidt Amand F AF Tyl Benoît B

Frontiers in cardiovascular medicine 20231018

<h4>Background</h4>The effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF.<h4>Methods</h4>Genetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pres ...[more]

PMID: 37920183

Similar Datasets

Project description:Heart failure (HF) is a complex syndrome characterized by cardiac dysfunction, Ca2+ mishandling, and chronic activation of the innate immune system. Reduced cardiac output in HF leads to compensatory mechanisms via activation of the adrenergic nervous system. In turn, chronic adrenergic overstimulation induces pro-arrhythmic events, increasing the rate of sudden death in failing patients. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an innate immune modulator that plays a key role in HF progression. NOD1 deficiency in mice prevents Ca2+ mishandling in HF under basal conditions, but its role during β-adrenergic stimulation remains unknown. Here, we evaluated whether NOD1 regulates the β-adrenergic modulation of Ca2+ signaling in HF. Ca2+ dynamics were examined before and after isoproterenol perfusion in cardiomyocytes isolated from healthy and from post-myocardial infarction (PMI) wild-type (WT) and Nod1-/- mice. Isoproterenol administration induced similar effects on intracellular [Ca2+]i transients, cell contraction, and sarcoplasmic reticulum (SR)-Ca2+ load in healthy WT and Nod1-/- cells. However, compared with WT-PMI cells, isoproterenol exposure induced a significant increase in the [Ca2+]i transients and cell contraction parameters in Nod1-/--PMI cells, which mainly due to an increase in SR-Ca2+ load. NOD1 deficiency also prevented the increase in diastolic Ca2+ leak (Ca2+ waves) induced by isoproterenol in PMI cells. mRNA levels of β1 and β2 adrenergic receptors were significantly higher in Nod1-/--PMI hearts vs WT-PMI hearts. Healthy cardiomyocytes pre-treated with the selective agonist of NOD1, iE-DAP, and perfused with isoproterenol showed diminished [Ca2+]i transients amplitude, cell contraction, and SR-Ca2+ load compared with vehicle-treated cells. iE-DAP-treated cells also presented increased diastolic Ca2+ leak under β-adrenergic stimulation. The selectivity of iE-DAP on Ca2+ handling was validated by pre-treatment with the inactive analog of NOD1, iE-Lys. Overall, our data establish that NOD1 deficiency improves the β-adrenergic modulation of Ca2+ handling in failing hearts.

Project description:Growing evidence suggests that heart failure (HF) is associated with an increased risk of depressive disorders and anxiety. However, the existing studies were observational and may have confounded and not reflected true causal relationships. This study collected genetic instruments about HF, depression, and anxiety from publicly available genetic summary data. Two-sample Mendelian randomization (MR) analysis was performed, with inverse-variance weighted designated as the primary approach for determining causal effects. Secondary analyses included MR-Egger regression and the weighted media method. Additionally, we conducted MR pleiotropy residual sum and outlier to address horizontal pleiotropy. Cochran Q test, MR-Egger intercept test, and leave-one-out analysis were used to assess the robustness of the findings. The significance is determined by a P-value below .05. Gene prediction result revealed that HF did not exhibit a significant association with elevated incidence of depression by inverse-variance weighted method no matter HF from the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 0.93-1.18, P = .424 for major depressive disorder, MDD; OR = 1.01, 95% CI = 0.94-1.09, P = .782 for major depression) or the FinnGen Consortium (OR = 1.03, 95% CI = 0.92-1.15, P = .644 for MDD; OR = 1.00, 95% CI = 0.94-1.07, P = .962 for major depression). In contrast, the results of HF on anxiety exhibited inconsistency (OR = 1.60, 95% CI = 1.10-2.31, P = .013 for Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium; OR = 1.42, 95% CI = 0.91-2.21, P = .123 for FinnGen Consortium); however, a combined effect analysis indicated support causal relationship between HF and the risk of anxiety (OR = 1.52, 95% CI = 1.07-2.00, P < .001). Our findings did not reveal evidence to confirm a causal association between HF and depression. However, our results provide support for a causal effect of HF on the risk of anxiety.

Dataset Information

Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure.

Background

Methods

Results

Conclusions

Publications

Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets