Neurovascular Center, Naval Medical University Changhai Hospital, Shanghai, China.
Departments of Neurology and Radiology, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Int J Stroke. 2023 Dec;18(10):1247-1254. doi: 10.1177/17474930231185695. Epub 2023 Jul 12.
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.
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.
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, = 0.014; OR 1.27, 95% CI: 1.07-1.51, = 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, = 0.002; OR = 1.04, 95% CI = 1.01-1.07, = 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, = 0.009; OR 0.89, 95% CI: 0.83-0.97, = 0.005). Proxies for β-blockers, angiotensin receptor blockers (ARB), and thiazides failed to show associations with functional outcomes ( > 0.05).
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.
观察性研究表明，血压（BP）与缺血性脑卒中患者的功能结局之间存在关联，但这种关联是因果关系还是混杂因素所致尚不确定。我们使用孟德尔随机化（MR）来评估因果关系，并探讨特定类别的抗高血压药物是否与缺血性脑卒中后的更好结局相关。
我们从 757601 名个体的全基因组关联研究（GWAS）中选择与收缩压和舒张压以及降压药物基因中降压变异相关的遗传变异。主要结局是 3 个月时的依赖性或死亡，定义为改良 Rankin 量表（mRS）为 3-6。次要结局是 90 天后的残疾或死亡，定义为 mRS 2-6。采用逆方差加权（IVW）模型中的 Cochran's Q 统计量、加权中位数、MR-Egger 回归、单核苷酸多态性（SNP）缺失分析、MR-Pleiotropy Residual Sum and Outlier 方法作为敏感性分析。为了验证我们的主要结果，我们进行了独立重复分析和双向 MR 分析。
单变量 IVW MR 分析显示，遗传易患更高的收缩压和舒张压与缺血性脑卒中后的残疾或死亡相关（比值比（OR）1.29，95%置信区间（CI）：1.05-1.59， = 0.014；OR 1.27，95% CI：1.07-1.51， = 0.006）。脉压与缺血性脑卒中后依赖性或死亡以及残疾或死亡均相关（OR = 1.05，95% CI：1.02-1.08， = 0.002；OR = 1.04，95% CI = 1.01-1.07， = 0.009）。血管紧张素转换酶抑制剂（ACEI）和钙通道阻滞剂（CCB）与改善功能结局显著相关（依赖性或死亡，OR 0.76，95% CI：0.62-0.94， = 0.009；OR 0.89，95% CI：0.83-0.97， = 0.005）。β受体阻滞剂、血管紧张素受体阻滞剂（ARB）和噻嗪类利尿剂的代表药物未能显示与功能结局相关（ > 0.05）。
我们提供了证据表明，BP 的遗传易患性与缺血性脑卒中后 3 个月的功能性依赖风险增加相关。我们的发现支持 ACEI 和 CCB 作为有前途的抗高血压药物，可改善缺血性脑卒中的功能结局。
