Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Georgakis, Marios K.; Gill, Dipender; Webb, Alastair; Εvangelou, Εvangelos; Elliott, Paul; Sudlow, Cathie; Dehghan, Abbas; Malik, Rainer; Tzoulaki, Ioanna; Dichgans, Martin

doi:10.1212/wnl.0000000000009814

Cited by 83 publications

(91 citation statements)

References 57 publications

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“… 44 Of note, we found no evidence for an association between either genetically predicted MAP or PP and lobar ICH. Unlike deep ICH, lobar ICH is related to cerebral amyloid angiopathy and the absence of an association signal between blood pressure and lobar ICH is consistent with observational 46 and genetic 7 data.…”

Section: Discussionsupporting

confidence: 84%

“… 5 , 6 We recently showed that high genetically predicted systolic blood pressure (SBP) and diastolic blood pressure (DBP) are associated with all major ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke), as well as with deep, but not lobar ICH. 7 While these results support a causal association of elevated blood pressure with the main stroke subtypes, it remains unclear how these associations vary across the lifespan, 8 , 9 given the hemodynamic changes that take place as a result of aging. 10 …”

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confidence: 92%

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Genetically Predicted Blood Pressure Across the Lifespan

Georgakis¹,

Malik²,

Protogerou

et al. 2020

Hypertension

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Hypertension is the leading risk factor for stroke. Yet, it remains unknown whether blood pressure pulsatility (pulse pressure [PP]) causally affects stroke risk independently of the steady pressure component (mean arterial pressure [MAP]). It is further unknown how the effects of MAP and PP on stroke risk vary with age and stroke cause. Using data from UK Biobank (N=408 228; 38–71 years), we selected genetic variants as instruments for MAP and PP at age ≤55 and >55 years and across age deciles. We applied multivariable Mendelian randomization analyses to explore associations with ischemic stroke, intracerebral hemorrhage, and their subtypes. Higher genetically predicted MAP was associated with higher risk of ischemic stroke and intracerebral hemorrhage across the examined age spectrum. Independent of MAP, higher genetically predicted PP only at age >55 years was further associated with higher risk of ischemic stroke (odds ratio per-SD-increment, 1.23 [95% CI, 1.13–1.34]). Among subtypes, the effect of genetically predicted MAP on large artery stroke was attenuated, whereas the effect of genetically predicted PP was augmented with increasing age. Genetically predicted MAP, but not PP, was associated with small vessel stroke and deep intracerebral hemorrhage homogeneously across age deciles. Neither genetically predicted MAP nor PP were associated with lobar intracerebral hemorrhage. Beyond an effect of high MAP at any age on ischemic and hemorrhagic stroke, our results support an independent causal effect of high PP at older ages on large artery stroke. This finding warrants further investigation for the development of stroke preventive strategies targeting pulsatility in later life.

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Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 92%

Genetically Predicted Blood Pressure Across the Lifespan

Georgakis¹,

Malik²,

Protogerou

et al. 2020

Hypertension

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“…For validity, we further checked and selected SNPs also related to SBP in the latest UK Biobank summary statistics of people of European ancestry in Pan UKBB. The strength of each genetic variant was assessed from the F -statistic obtained using an established approximation as previously [ 16 ]; only genetic variants with F -statistic > 10 were used. Details concerning these genetic variants are in Additional file 1 : Table S2.…”

Section: Methodsmentioning

confidence: 99%

“…Details concerning these genetic variants are in Additional file 1 : Table S2. ACE inhibitors, ARBs, and renin inhibitors have only one proxy, given the insufficient power [ 17 ], as previously [ 16 ] we did not include them for the categorical outcome, i.e., albuminuria. To increase the number of genetic variants available, in sensitivity analysis, we included correlated genetic variants with r 2 < 0.8, taking into account their correlations obtained from 1000 Genomes European panel using “ld_matrix.” We used Steiger filtering which enables inference of the causal direction, by calculating and comparing the variance explained by the genetic instrument in kidney function and in blood pressure [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…We conducted the analysis by drug class and also by drug target within each drug class and combined the estimates for all drug classes to obtain the overall association of genetic proxies for antihypertensive drugs with kidney function. We also assessed the association of genetic predictors of SBP, identified from a GWAS of SBP without adjustment for antihypertensive medication or BMI (Additional file 1 : Table S1) [ 16 , 19 ], with kidney function.…”

Section: Methodsmentioning

confidence: 99%

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Using Mendelian randomization study to assess the renal effects of antihypertensive drugs

Zhao

Schooling

2021

BMC Med

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Background Angiotensin-converting enzyme (ACE) inhibitors and/or in combination with calcium channel blockers (CCBs) are generally recommended as the first-line antihypertensive therapy for people with hypertension and kidney dysfunction. Evidence from large randomized controlled trials comprehensively comparing renal effects of different classes of antihypertensive drugs is lacking. Methods We used a Mendelian randomization study to obtain unconfounded associations of genetic proxies for antihypertensives with kidney function. Specifically, we used published genetic variants in genes regulating target proteins of these drugs and then applied to a meta-analysis of the largest available genome-wide association studies of kidney function (estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and albuminuria). Inverse variance weighting was used as the main analysis and to combine estimates from different sources. Results Genetically predicted ACE inhibition was associated with higher eGFR (effect size 0.06, 95% confidence interval (CI) 0.008, 0.11), while genetic proxies for beta-blockers were associated with lower eGFR (− 0.02, 95% CI − 0.04, − 0.004) when meta-analyzing the UK Biobank and CKDGen. Genetic proxies for CCBs were associated with lower UACR (− 0.15, 95% CI − 0.28, − 0.02) and lower risk of albuminuria (odds ratio 0.58, 95% CI 0.37, 0.90) in CKDGen. The associations were robust to using different analysis methods and different genetic instruments. Conclusions Our findings suggest the reno-protective associations of genetically proxied ACE inhibitors and CCBs, while genetic proxies for beta-blockers may be related to lower eGFR. Understanding the underlying mechanisms would be valuable, with implications for drug development and repositioning of treatments for kidney disease.

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Blood Pressure after Successful Endovascular Therapy: A Systematic Review and Meta‐Analysis of Randomized Control Trials

Gharaibeh,

Aladamat,

Mierzwa

et al. 2024

Annals of Neurology

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ObjectiveThere are limited data evaluating the optimum blood pressure (BP) goal post mechanical thrombectomy (MT) and its effect on outcomes of patients with large vessel occlusions (LVO). The objective of this study was to compare the efficacy and safety of intensive versus conventional BP control after reperfusion with MT via a systematic review and meta‐analysis of randomized controlled trials (RCTs).MethodsWe searched PubMed and Embase to obtain articles related to BP control post MT through September 2023. The primary outcome was functional independence (modified Rankin Scale [mRS] 0‐2) at 3 months, while secondary outcomes included excellent outcome (mRS 0‐1), symptomatic intracranial hemorrhage (sICH), and mortality.ResultsFour RCTs with 1,566 patients (762 randomized into intensive BP control vs. 806 randomized into conventional BP control) were included. Analysis showed that there was a lower likelihood of functional independence (mRS 0‐2: odds ratio [OR]: 0.68, 95% confidence interval [CI] 0.51–0.91, p = 0.009) in the more intensive treatment group compared with the conventional treatment group. There was no statistically significant difference in achieving excellent outcome (mRS0‐1: OR: 0.82, 95% CI: 0.63–1.07; p = 0.15), risk of sICH or mortality.InterpretationThis systematic review and meta‐ analysis Indicates that in patients who achieved successful MT for acute ischemic stroke with LVO, intensive BP control was associated with a lower likelihood of functional independence at 3 months without significant difference in likelihood of achieving excellent outcome, sICH risk, or mortality. ANN NEUROL 2024

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Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes

Cited by 83 publications

References 57 publications

Genetically Predicted Blood Pressure Across the Lifespan

Genetically Predicted Blood Pressure Across the Lifespan

Using Mendelian randomization study to assess the renal effects of antihypertensive drugs

Blood Pressure after Successful Endovascular Therapy: A Systematic Review and Meta‐Analysis of Randomized Control Trials

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