Effect of the Blood Pressure and Antihypertensive Drugs on Cerebral Small Vessel Disease: A Mendelian Randomization Study

BACKGROUND: Previous studies yielded conflicting results about the influence of blood pressure (BP) and antihypertensive treatment on cerebral small vessel disease. Here, we conducted a Mendelian randomization study to investigate the effect of BP and antihypertensive drugs on cerebral small vessel disease. METHODS: We extracted single-nucleotide polymorphisms for systolic BP and diastolic BP from a genome-wide association study (N=757 601) and screened single-nucleotide polymorphisms associated with calcium channel blockers, thiazides, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers from public resources as instrumental variables. Then, we chose the genome-wide association study of white matter hyperintensity (WMH; N=18 381), cerebral microbleed (3556 cases, 22 306 controls), white matter perivascular space (9317 cases, 29 281 controls), basal ganglia perivascular space (BGPVS; 8950 cases, 29 953 controls), hippocampal perivascular space (HIPPVS; 9163 cases, 29 708 controls), and lacunar stroke (6030 cases, 248 929 controls) as outcome data sets. Subsequently, we conducted a 2-sample Mendelian randomization analysis. RESULTS: We found that elevated systolic BP significantly increases the risk of BGPVS (odds ratio [OR], 1.05 [95% CI, 1.04–1.07]; P =1.72×10 −12 ), HIPPVS (OR, 1.04 [95% CI, 1.02–1.05]; P =2.71×10 −7 ), and lacunar stroke (OR, 1.41 [95% CI, 1.30–1.54]; P =4.97×10 −15 ). There was suggestive evidence indicating that elevated systolic BP is associated with higher WMH volume (β=0.061 [95% CI, 0.018–0.105]; P =5.58×10 −3 ) and leads to an increased risk of cerebral microbleed (OR, 1.16 [95% CI, 1.04–1.29]; P =7.17×10 −3 ). Elevated diastolic BP was significantly associated with higher WMH volume (β=0.087 [95% CI, 0.049–0.124]; P =5.23×10 −6 ) and significantly increased the risk of BGPVS (OR, 1.05 [95% CI, 1.04–1.06]; P =1.20×10 −16 ), HIPPVS (OR, 1.03 [95% CI, 1.02–1.04]; P =2.96×10 −6 ), and lacunar stroke (OR, 1.31 [95% CI, 1.21–1.41]; P =2.67×10 −12 ). The use of calcium channel blocker to lower BP was significantly associated with lower WMH volume (β=−0.287 [95% CI, −0.408 to −0.165]; P =4.05×10 −6 ) and significantly reduced the risk of BGPVS (OR, 0.85 [95% CI, 0.81–0.89]; P =8.41×10 −19 ) and HIPPVS (OR, 0.88 [95% CI, 0.85–0.92]; P =6.72×10 −9 ). CONCLUSIONS: Our findings contribute to a better understanding of the pathogenesis of cerebral small vessel disease. Additionally, the utilization of calcium channel blockers to decrease BP can effectively reduce the likelihood of WMH, BGPVS, and HIPPVS. These findings offer valuable insights for the management and prevention of cerebral small vessel disease.