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

Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH. Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH. Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease

Genetically Predicted Blood Pressure Across the Lifespan: Differential Effects of Mean and Pulse Pressure on Stroke Risk.

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

Multidisciplinary investigations of the diets of two post-medieval populations from London using stable isotopes and microdebris analysis

This paper presents the first multi-tissue study of diet in post-medieval London using both the stable light isotope analysis of carbon and nitrogen and analysis of microdebris in dental calculus. Dietary intake was explored over short and long timescales. Bulk bone collagen was analysed from humans from the Queen’s Chapel of the Savoy (QCS) (n = 66) and the St Barnabas/St Mary Abbots (SB) (n = 25). Incremental dentine analysis was performed on the second molar of individual QCS1123 to explore childhood dietary intake. Bulk hair samples (n = 4) were sampled from adults from QCS, and dental calculus was analysed from four other individuals using microscopy. In addition, bone collagen from a total of 46 animals from QCS (n = 11) and the additional site of Prescot Street (n = 35) was analysed, providing the first animal dietary baseline for post-medieval London. Overall, isotopic results suggest a largely C3-based terrestrial diet for both populations, with the exception of QCS1123 who exhibited values consistent with the consumption of C4 food sources throughout childhood and adulthood. The differences exhibited in δ15Ncoll across both populations likely reflect variations in diet due to social class and occupation, with individuals from SB likely representing wealthier individuals consuming larger quantities of animal and marine fish protein. Microdebris analysis results were limited but indicate the consumption of domestic cereals. This paper demonstrates the utility of a multidisciplinary approach to investigate diet across long and short timescales to further our understanding of variations in social status and mobility

Measurement of the Ratio of b Quark Production Cross Sections in Antiproton-Proton Collisions at 630 GeV and 1800 GeV

We report a measurement of the ratio of the bottom quark production cross section in antiproton-proton collisions at 630 GeV to 1800 GeV using bottom quarks with transverse momenta greater than 10.75 GeV identified through their semileptonic decays and long lifetimes. The measured ratio sigma(630)/sigma(1800) = 0.171 +/- .024 +/- .012 is in good agreement with next-to-leading order (NLO) quantum chromodynamics (QCD)

Effects of vasodilating medications on cerebral haemodynamics in health and disease: systematic review and meta-analysis

Objectives: Vasodilating antihypertensives prevent stroke and potentially cerebral small vessel disease but their effects on cerebrovascular haemodynamics beyond blood pressure lowering are unclear. Methods: We searched PubMed, Medline, Embase, Cinahl, Psychinfo, Health Business Elite and Health Management Information Consortium for randomized studies of vasodilating medications, compared to no treatment or nonvasodilators, that reported effects on cerebral blood flow (CBF), mean blood flow velocity (MFV) or cerebrovascular reactivity. Absolute and standardized mean differences (SMD) were combined by inverse-variance weighted fixed or random-effects meta-analysis stratified by study design, population characteristics and vasodilator class. Results: In 35 studies reporting 57 comparisons, there was a reduction in SBP (4.13 mmHg, 7.55 to 0.71, P ¼ 0.018) but no change in MFV (DMFV 1.11, confidence interval 0.93 to 3.14, P ¼ 0.29, 23 comparisons). MFV increased in patients with underlying conditions (3.41, 0.24 to 6.57, P ¼ 0.04) but not in healthy study participants (1.27, 5.18 to 2.64, P ¼ 0.68), with no differences by vasodilating drug class. Cerebral pulsatility index was reduced across all studies (D pulsatility index 0.04, 0.07 to 0.02, P ¼ 0.001; D pulsatility index - SMD 0.32, 0.47 to 0.16, P and#60; 0.001), except in studies reporting responses to single drug doses (D pulsatility index 0.00, 0.09 to 0.08, P ¼ 0.93). Despite evidence of reporting and publication bias, there was an apparent consistent reduction in CBF with vasodilators (CBF-SMD 0.24, 0.46 to 0.02, P ¼ 0.03) with a significant increase in cerebrovascular reactivity-SMD (0.48, 0.13–0.83, P ¼ 0.007). Conclusions: Despite reducing SBP, vasodilators did not significantly impair absolute CBF but improved cerebrovascular pulsatility and reactivity, suggesting therapeutic potential in preventing stroke and cerebral small vessel disease

Effects of vasodilating medications on cerebral haemodynamics in health and disease: systematic review and meta-analysis

Objectives: Vasodilating antihypertensives prevent stroke and potentially cerebral small vessel disease but their effects on cerebrovascular haemodynamics beyond blood pressure lowering are unclear. Methods: We searched PubMed, Medline, Embase, Cinahl, Psychinfo, Health Business Elite and Health Management Information Consortium for randomized studies of vasodilating medications, compared to no treatment or nonvasodilators, that reported effects on cerebral blood flow (CBF), mean blood flow velocity (MFV) or cerebrovascular reactivity. Absolute and standardized mean differences (SMD) were combined by inverse-variance weighted fixed or random-effects meta-analysis stratified by study design, population characteristics and vasodilator class. Results: In 35 studies reporting 57 comparisons, there was a reduction in SBP (4.13 mmHg, 7.55 to 0.71, P ¼ 0.018) but no change in MFV (DMFV 1.11, confidence interval 0.93 to 3.14, P ¼ 0.29, 23 comparisons). MFV increased in patients with underlying conditions (3.41, 0.24 to 6.57, P ¼ 0.04) but not in healthy study participants (1.27, 5.18 to 2.64, P ¼ 0.68), with no differences by vasodilating drug class. Cerebral pulsatility index was reduced across all studies (D pulsatility index 0.04, 0.07 to 0.02, P ¼ 0.001; D pulsatility index - SMD 0.32, 0.47 to 0.16, P < 0.001), except in studies reporting responses to single drug doses (D pulsatility index 0.00, 0.09 to 0.08, P ¼ 0.93). Despite evidence of reporting and publication bias, there was an apparent consistent reduction in CBF with vasodilators (CBF-SMD 0.24, 0.46 to 0.02, P ¼ 0.03) with a significant increase in cerebrovascular reactivity-SMD (0.48, 0.13–0.83, P ¼ 0.007). Conclusions: Despite reducing SBP, vasodilators did not significantly impair absolute CBF but improved cerebrovascular pulsatility and reactivity, suggesting therapeutic potential in preventing stroke and cerebral small vessel disease

White matter damage due to pulsatile versus steady blood pressure differs by vascular territory: a cross-sectional analysis of the UK biobank cohort study

Small vessel disease is associated with age, mean blood pressure (MAP) and blood pressure pulsatility (PP). We used data from the UK Biobank cohort study to determine the relative importance of MAP versus PP driving white matter injury within individual white matter tracts, particularly in the anterior and posterior vascular territory. The associations between blood pressure and diffusion indices in 27 major tracts were analysed using unadjusted and fully-adjusted general linear models and mixed-effect linear models. Blood pressure and neuroimaging data were available for 37,041 participants (mean age 64+/−7.5 years, 53% female). In unadjusted analyses, MAP and PP were similarly associated with diffusion indices in the anterior circulation. In the posterior circulation, the associations were weaker, particularly for MAP. In fully-adjusted analyses, MAP remained associated with all diffusion indices in the anterior circulation, independently of age. In the posterior circulation, the effect of MAP became protective. PP remained associated with greater mean diffusivity and extracellular free water diffusion in the anterior circulation and all diffusion indices in the posterior circulation. There was a significant interaction between PP and age. This implies discordant mechanisms for chronic white matter injury in different brain regions and potentially in the associated stroke risks