Association between blood pressure and different antihypertensive drugs with outcome after ischemic stroke: A Mendelian randomization study

Author:

Liu Hanchen1ORCID,Zhang Xiaoxi1,Zhou Yu1,Nguyen Thanh N2ORCID,Zhang Lei1ORCID,Xing Pengfei1ORCID,Li Zifu1,Shen Hongjian1,Zhang Yongxin1,Hua Weilong1,Xu Hongye1,Zhu Xuan1ORCID,Chen Lei1,Zuo Qiao1,Zhao Rui1,Li Qiang1,Dai Dongwei1,Zhang Yongwei1,Xu Yi1,Huang Qinghai1,Liu Jianmin1,Yang Pengfei1

Affiliation:

1. Neurovascular Center, Naval Medical University Changhai Hospital, Shanghai, China

2. Departments of Neurology and Radiology, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

Abstract

Background: Observational studies suggest an association between blood pressure (BP) and functional outcomes in ischemic stroke patients but whether this is causal or due to confounding is uncertain. We used Mendelian randomization (MR) to assess causality, and also explore whether particular classes of anti-hypertensives were associated with a better outcome after ischemic stroke. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drugs from genome-wide association studies (GWAS) on 757,601 individuals. The primary outcome was 3-month dependence or death defined as a modified Rankin Scale (mRS) of 3–6. The secondary outcome was disability or death after 90 days defined as mRS 2–6. Cochran’s Q statistic in the inverse variance weighted (IVW) model, the weighted median, MR-Egger regression, leave-one-single-nucleotide polymorphism (SNP)-out analysis, MR-Pleiotropy Residual Sum and Outlier methods were adopted as sensitivity analyses. To validate our primary results, we performed independent repeat analyses and Bi-directional MR analyses. Results: Genetic predisposition to higher systolic and diastolic BP was associated with disability or death after ischemic stroke in univariable IVW MR analysis (odds ratio (OR) 1.29, 95% confidence interval (CI): 1.05–1.59, p = 0.014; OR 1.27, 95% CI: 1.07–1.51, p = 0.006, respectively). Pulse pressure was associated with both dependence or death and disability or death after ischemic stroke (OR = 1.05, 95% CI: 1.02–1.08, p = 0.002; OR = 1.04, 95% CI = 1.01–1.07, p = 0.009, respectively). Angiotensin-converting enzyme inhibitor (ACEI) and calcium channel blocker (CCB) were significantly associated with improved functional outcomes (dependence or death, OR 0.76, 95% CI: 0.62–0.94, p = 0.009; OR 0.89, 95% CI: 0.83–0.97, p = 0.005). Proxies for β-blockers, angiotensin receptor blockers (ARB), and thiazides failed to show associations with functional outcomes ( p > 0.05). Conclusion: We provide evidence for an association of genetic predisposition to higher BP with a higher risk of 3-month functional dependence after ischemic stroke. Our findings support ACEI and CCB as promising antihypertensive drugs for improving functional outcomes in ischemic stroke.

Funder

Research and Popularization of Appropriate Intervention Technology for the Stroke High Risk Group in China

Shanghai Sailing Program

Naval Medical University Fundamental Research Program

Publisher

SAGE Publications

Subject

Neurology,Neurology (clinical)

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