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

Claire Baudier; Françoise Fougerousse; Folkert W Asselbergs; Mickael Guedj; Michel Komajda; Dipak Kotecha; R. Thomas Lumbers; Amand F. Schmidt; Benoît Tyl

doi:10.3389/fcvm.2023.1148931

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

Claire Baudier, Françoise Fougerousse, Folkert W Asselbergs, Mickael Guedj, Michel Komajda, Dipak Kotecha, R. Thomas Lumbers, Amand F. Schmidt, Benoît Tyl^*

^*Corresponding author for this work

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	1148931
Number of pages	11
Journal	Frontiers in cardiovascular medicine
Volume	10
DOIs	https://doi.org/10.3389/fcvm.2023.1148931
Publication status	Published - 18 Oct 2023

Bibliographical note

Funding:
This study was funded by Servier and BigData@Heart that received funding from the Innovative Medicines Initiative2 Joint Undertaking under grant agreement No 116074, which received support from the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations. FA is supported by University College London Hospitals National Institute for Health Research (NIHR) Biomedical Research Centre. RT is supported by a UK Research and Innovation Rutherford Fellowship hosted by Health Data Research UK (MR/S003754/1). DK is supported by the NIHR (203326 Birmingham Biomedical Research Centre; 130280/132974 DaRe2THINK), and the British Heart Foundation (BHF)/University of Birmingham Accelerator (AA/18/2/34218). The opinions expressed in this paper are those of the authors and do not represent the BHF, NIHR, EU, EFPIA, or the UK Department of Health and Social Care.

Keywords

target validation, drug
Mendelian randomization
adrenergic receptors
alpha-blockers
beta-blockers

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10.3389/fcvm.2023.1148931Licence: Creative Commons: Attribution (CC BY)

BaudierC2023UnravelingFinal published version, 1.46 MBLicence: Creative Commons: Attribution (CC BY)

H2020_COLLAB(IMI-JU)_BIGDATA@HEART
Kotecha, D. (Principal Investigator) & Kirchhof, P. (Co-Investigator)
European Commission
1/03/17 → 28/02/23
Project: Research

Cite this

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title = "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, {\ss}1, and {\ss}2 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 {\ss}1 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 {\ss}2 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 {\ss}1 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.",

keywords = "target validation, drug, Mendelian randomization, adrenergic receptors, alpha-blockers, beta-blockers",

author = "Claire Baudier and Fran{\c c}oise Fougerousse and Asselbergs, {Folkert W} and Mickael Guedj and Michel Komajda and Dipak Kotecha and {Thomas Lumbers}, R. and Schmidt, {Amand F.} and Beno{\^i}t Tyl",

note = "Funding: This study was funded by Servier and BigData@Heart that received funding from the Innovative Medicines Initiative2 Joint Undertaking under grant agreement No 116074, which received support from the European Union{\textquoteright}s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations. FA is supported by University College London Hospitals National Institute for Health Research (NIHR) Biomedical Research Centre. RT is supported by a UK Research and Innovation Rutherford Fellowship hosted by Health Data Research UK (MR/S003754/1). DK is supported by the NIHR (203326 Birmingham Biomedical Research Centre; 130280/132974 DaRe2THINK), and the British Heart Foundation (BHF)/University of Birmingham Accelerator (AA/18/2/34218). The opinions expressed in this paper are those of the authors and do not represent the BHF, NIHR, EU, EFPIA, or the UK Department of Health and Social Care.",

year = "2023",

month = oct,

day = "18",

doi = "10.3389/fcvm.2023.1148931",

language = "English",

volume = "10",

journal = "Frontiers in cardiovascular medicine",

issn = "2297-055X",

publisher = "Frontiers Research Foundation",

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TY - JOUR

T1 - Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure

AU - Baudier, Claire

AU - Fougerousse, Françoise

AU - Asselbergs, Folkert W

AU - Guedj, Mickael

AU - Komajda, Michel

AU - Kotecha, Dipak

AU - Thomas Lumbers, R.

AU - Schmidt, Amand F.

AU - Tyl, Benoît

N1 - Funding: This study was funded by Servier and BigData@Heart that received funding from the Innovative Medicines Initiative2 Joint Undertaking under grant agreement No 116074, which received support from the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations. FA is supported by University College London Hospitals National Institute for Health Research (NIHR) Biomedical Research Centre. RT is supported by a UK Research and Innovation Rutherford Fellowship hosted by Health Data Research UK (MR/S003754/1). DK is supported by the NIHR (203326 Birmingham Biomedical Research Centre; 130280/132974 DaRe2THINK), and the British Heart Foundation (BHF)/University of Birmingham Accelerator (AA/18/2/34218). The opinions expressed in this paper are those of the authors and do not represent the BHF, NIHR, EU, EFPIA, or the UK Department of Health and Social Care.

PY - 2023/10/18

Y1 - 2023/10/18

N2 - 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.

AB - 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.

KW - target validation, drug

KW - Mendelian randomization

KW - adrenergic receptors

KW - alpha-blockers

KW - beta-blockers

U2 - 10.3389/fcvm.2023.1148931

DO - 10.3389/fcvm.2023.1148931

M3 - Article

SN - 2297-055X

VL - 10

JO - Frontiers in cardiovascular medicine

JF - Frontiers in cardiovascular medicine

M1 - 1148931

ER -

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

Abstract

Bibliographical note

Keywords

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Projects

H2020_COLLAB(IMI-JU)_BIGDATA@HEART

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