Antihypertensive Drugs for the Prevention of Atrial Fibrillation: A Drug Target Mendelian Randomization Study

Abstract

Background: We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies.

Methods: Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836).

Results: Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10^-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10^-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10^-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10^-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10^-07) on AF risk.

Conclusions: Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention.

Keywords: Mendelian randomization analysis; antihypertensive agents; atrial fibrillation; drug repositioning; epidemiology; genomics; polymorphism, single nucleotide.

Figure 1.

Flow chat for selection of genetic variants for the primary analyses. AABs indicates adrenergic neuron blockers; ACEIs, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; ANBs, alpha-adrenocepter blockers; AntiHTN; all 12 antihypertensive drug classes combined; ARBs, angiotensin-II receptor antagonists; BBs, beta-adrenoceptor blockers; CAAHTN, centrally acting antihypertensives; CCBs, calcium channel blockers; GTEx, Genotype-Tissue Expression; GWAS, genome-wide association study; LDs, loop diuretics; MR, Mendelian randomization; MRAs, mineralocorticoid receptor antagonists; n, number; PSDs, potassium-sparing diuretics and aldosterone antagonists; RIs, renin inhibitors; SBP, systolic blood pressure; SNP(s), single-nucleotide polymorphism(s); Thiazides, thiazides and related diuretics; and VDs, vasodilators.

Figure 2.

Forest plot visualizing the Mendelian randomization analyses between antihypertensive drug classes and atrial fibrillation. Odds ratios represent a genetically determined 10 unit decrease of ln(SBP) through the various antihypertensive drug classes with the odds of atrial fibrillation. AABs indicates adrenergic neuron blockers; ACEIs, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; ANBs, alpha-adrenocepter blockers; AntiHTN; all 12 antihypertensive drug classes combined; ARBs, angiotensin-II receptor antagonists; BBs, beta-adrenoceptor blockers; CAAHTN, centrally acting antihypertensives; CCBs, calcium channel blockers; IVW, inverse-variance weighted; LDs, loop diuretics; n, number; OR, odds ratio; PSDs, potassium-sparing diuretics and aldosterone antagonists; RIs; renin inhibitors; Thiazides; thiazides and related diuretics; VDs, vasodilators.