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

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. The Cochran’s Q statistic in the Inverse variance weighted (IVW) model, the weighted median, MR-Egger regression, leave-one-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 (OR=1.29, 95%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.

Exploring causal association between circulating inflammatory cytokines and functional outcomes following ischemic stroke: A bidirectional Mendelian randomization study

“…The modified Rankin Scale (mRS) was used to evaluate the functional outcomes in the 3 months after IS. A lower mRS score (0-2) indicates a better functional outcome (n = 3741), and a higher score (3)(4)(5)(6) indicates an adverse functional outcome (n = 2280). This study used the results adjusted for age, gender, ancestry, and baseline stroke severity for the primary MR analysis.…”

“…Aside from traditional risk factors such as blood pressure, smoking, and sleep [3][4][5], as an indispensable part of the pathophysiology of stroke, inflammation assumes a pivotal role in the pathogenesis and prognosis of the disease [6]. Several cytokines and growth factors are involved in the regulation of inflammatory responses [7].…”