Associations between neurovascular coupling and cerebral small vessel disease: A systematic review and meta-analysis.

PURPOSE: The pathogenesis of cerebral small vessel disease (cSVD) remains elusive despite evidence of an association between white matter hyperintensities (WMH) and endothelial cerebrovascular dysfunction. Neurovascular coupling (NVC) may be a practical alternative measure of endothelial function. We performed a systematic review of reported associations between NVC and cSVD. METHODS: EMBASE and PubMed were searched for studies reporting an association between any STRIVE-defined marker of cSVD and a measure of NVC during functional magnetic resonance imaging, transcranial Doppler, positron emission tomography, near-infrared spectroscopy or single-photon emission computed tomography, from inception to November 3rd, 2022. Where quantitative data was available from studies using consistent tests and analyses, results were combined by inverse-variance weighted random effects meta-analysis. FINDINGS: Of 29 studies (19 case-controls; 10 cohorts), 26 reported decreased NVC with increasing severity of cSVD, of which 18 were individually significant. In 28 studies reporting associations with increasing WMH, 25 reported reduced NVC. Other markers of cSVD were associated with reduced NVC in: eight of nine studies with cerebral microbleeds (six showing a significant effect); three of five studies with lacunar stroke; no studies reported an association with enlarged perivascular spaces. Specific SVD diseases were particularly associated with reduced NVC, including six out of seven studies in cerebral amyloid angiopathy and all four studies in CADASIL. In limited meta-analyses, %BOLD occipital change to a visual stimulus was consistently reduced with more severe WMH (seven studies, SMD -1.51, p < 0.01) and increasing microbleeds (seven studies, SMD -1.31, p < 0.01). DISCUSSION AND CONCLUSION: In multiple, small studies, neurovascular coupling was reduced in patients with increasing severity of all markers of cSVD in sporadic disease, CAA and CADASIL. Cerebrovascular endothelial dysfunction, manifest as impaired NVC, may be a common marker of physiological dysfunction due to small vessel injury that can be easily measured in large studies and clinical practice.

Consistencies and Differences in Intermediate Physiological Phenotypes of Vascular Ageing between Ischaemic Stroke Aetiologies.

OBJECTIVE: Arterial stiffness, cerebral pulsatility, and beat-to-beat blood pressure variability partly mediate the relationship between hypertension and stroke, but it is unknown if these intermediate phenotypes of vascular ageing differ between stroke aetiologies. We therefore aimed to characterize differences in these intermediate cardiovascular phenotypes between patients presenting with strokes of different aetiologies. METHODS: In consecutive patients on best medical management 1 month after TIA or nondisabling stroke (Oxford Vascular Study), arterial stiffness (PWV) was measured by applanation tonometry (Sphygmocor), middle cerebral blood flow velocity, and pulsatility index (MCA-PI) were measured by transcranial ultrasound (TCD, DWL Doppler Box), and beat-to-beat BP variability was measured with a Finometer. Differences between patients with large artery (LAS), small vessel (SVD), cardioembolic (CE), or undetermined events were derived, including adjustment for cardiovascular risk factors. Relationships were characterized by mixed linear models. RESULTS: In 909 eligible patients, MCA-PI, PWV, and SBPV were all positively skewed. Mean values were greatest in LAS than CE and lowest in SVD (p < 0.001). However, after adjustment for age, sex, and risk factors, PI was greatest in LAS and lowest in CE stroke, whilst PWV was greatest in SVD and undetermined stroke (p < 0.001). In multivariate linear models, age was more strongly associated with PWV and PI in patients with small vessel stroke than other aetiologies, particularly under the age of 65, but SBPV was only weakly associated with demographic indices in all stroke subtypes. CONCLUSIONS: Intermediate cardiovascular phenotypes of vascular ageing had similar demographic associations between stroke aetiologies, but these were particularly strong in patients with small vessel stroke under the age of 65, implying a potential role of these phenotypes in increasing stroke risk in this patient group.

Consistency of associations of systolic and diastolic blood pressure with white matter hyperintensities: A meta-analysis.

BACKGROUND: White matter hyperintensities are the commonest manifestation of cerebral small vessel disease, associated with stroke, functional impairment, and cognitive decline. They are commonly preceded by hypertension, but the magnitude and clinical importance of this association is unclear. AIMS: Quantify the relationship between blood pressure and white matter hyperintensities across studies. METHODS: PubMed and EMBASE were searched for studies reporting associations between concurrent or historic blood pressure and white matter hyperintensities. Beta coefficients from linear models were extracted, whether standardized, unstandardized, unadjusted or adjusted for age, sex, and cardiovascular risk factors. Beta-coefficients were combined by fixed and random effects meta-analysis, combining standardized beta-coefficients or unstandardized coefficients measured by consistent methods. RESULTS: Twenty-five of 3230 papers were eligible, including 53,392 participants. Systolic blood pressure was significantly associated with white matter hyperintensity volume (WMHV) after maximal adjustment (standardized beta 0.096, 95%CI 0.06-0.133, p < 0.001, I2 = 65%), including for concurrent readings (b = 0.106, p < 0.001) or readings five years previously (b = 0.077, p < 0.001), and for younger or older populations (mean age < 65: b = 0.114; >65 b = 0.069). Unstandardized, adjusted associations were similar for raw WMHV, log-transformed WMHV, or WMHV as percentage of intracranial volume. Unadjusted associations with systolic blood pressure (SBP) were greater (standardized beta = 0.273, 0.262-0.284, p < 0.0001). However, while associations with DBP were weaker than SBP (standardized beta = 0.065, p < 0.001), they were minimally affected by adjustment for age. CONCLUSIONS: A standard deviation increase in SBP is associated with 10% of a standard deviation increase in WMHV, providing the current best estimate of the potential reduction in progression of white matter hyperintensities expected with good control of blood pressure.

Midlife blood pressure is associated with the severity of white matter hyperintensities: analysis of the UK Biobank cohort study.

AIMS: White matter hyperintensities (WMH) progress with age and hypertension, but the key period of exposure to elevated blood pressure (BP), and the relative role of systolic BP (SBP) vs. diastolic BP (DBP), remains unclear. This study aims to determine the relationship between WMH and concurrent vs. past BP. METHODS AND RESULTS: UK Biobank is a prospective community-based cohort of 40-69-year olds from 22 centres, with magnetic resonance imaging in a subgroup of over 40 000 people at 4-12 years after baseline assessment. Standardized associations between WMH load (WMH volume normalized by total white matter volume and logit-transformed) and concurrent vs. past BP were determined using linear models, adjusted for age, sex, cardiovascular risk factors, BP source, assessment centre, and time since baseline. Associations adjusted for regression dilution bias were determined between median WMH and usual SBP or DBP, stratified by age and baseline BP.In 37 041 eligible participants with WMH data and BP measures, WMH were more strongly associated with concurrent SBP [DBP: ß = 0.064, 95% confidence interval (CI) 0.050-0.078; SBP: ß = 0.076, 95% CI 0.062-0.090], but the strongest association was for past DBP (DBP: ß = 0.087, 95% CI 0.064-0.109; SBP: ß = 0.045, 95% CI 0.022-0.069), particularly under the age of 50 (DBP: ß = 0.103, 95% CI 0.055-0.152; SBP: ß = 0.012, 95% CI -0.044 to 0.069). Due to the higher prevalence of elevated SBP, median WMH increased 1.126 (95% CI 1.107-1.146) per 10 mmHg usual SBP and 1.106 (95% CI 1.090-1.122) per 5 mmHg usual DBP, whilst the population attributable fraction of WMH in the top decile was greater for elevated SBP (19.1% for concurrent SBP; 24.4% for past SBP). Any increase in BP, even below 140 for SBP and below 90 mmHg for DBP, and especially if requiring antihypertensive medication, was associated with increased WMH. CONCLUSIONS: WMH were strongly associated with concurrent and past elevated BP with the population burden of severe WMH greatest for SBP. However, before the age of 50, DBP was more strongly associated with WMH. Long-term prevention of WMH may require control of even mildly elevated midlife DBP.

Systolic Blood Pressure and Longitudinal Progression of Arterial Stiffness: A Quantitative Meta-Analysis.

Background Arterial stiffness predicts the risk of cardiovascular events and all-cause mortality and is associated with age and hypertension. However, the magnitude of the relationship between blood pressure (BP) and progression of arterial stiffness is unclear, limiting our understanding of how arterial stiffness mediates clinical effects of hypertension and planning of clinical trials. Methods and Results Medline and EMBASE were searched for prospective studies reporting linear models between baseline BP and progression of arterial stiffness, with and without adjustment for demographic characteristics and baseline stiffness. Standardized and unstandardized ß coefficients for pulse wave velocity were combined by fixed and random effects meta-analysis, weighted by the inverse variance. Of 566 fully reviewed articles from 30, 524 titles, 22 populations from 21 reports were included. In 9 cohorts, there were consistent, adjusted associations between baseline systolic BP and progression of arterial stiffness (11 781 patients; standardized ß=0.041; 95% CI, 0.026-0.055; P<0.001; P value for heterogeneity=0.70), equivalent to a 1.14-m/s increase in standard carotid-femoral pulse wave velocity per decade per 20-mm Hg systolic BP, independent of age. Unstandardized, adjusted associations were similar (1762 patients; ß=0.0047; 95% CI, 0.004-0.006; P<0.001; P value for heterogeneity=0.64), equivalent to a 0.94-m/s increase per decade per 20-mm Hg systolic BP. In limited studies, standardized associations between mean BP and arterial stiffness progression were not significant and heterogeneous (913 patients; ß=0.039; 95% CI, -0.008 to 0.086; P=0.11; P value for heterogeneity=0.03). Conclusions Baseline systolic BP was associated with a clinically important progression of arterial stiffness, independent of age, providing a reference for the potential effect of arterial stiffness in mediating changes in clinical outcomes associated with hypertension and providing a reference value to aid clinical trial design.

Progression of Arterial Stiffness is Associated With Midlife Diastolic Blood Pressure and Transition to Late-Life Hypertensive Phenotypes.

Background Hypertension-associated cardiovascular events are particularly associated with elevated systolic blood pressure (SBP) in late life, yet long-term interactions between SBP, diastolic BP (DBP) and arterial stiffness in development of late-life hypertensive phenotypes remain unclear. Methods and Results In the UK Biobank, we determined associations between arterial stiffness index (ASI), SBP, DBP, and their progression, and transition from normotension (<140/90 mm Hg) to hypertension or elevated ASI (>10 m/s). Associations were determined by general linear and logistic regression, adjusted for cardiovascular risk factors and variability of measurements across follow-ups. Mean values of baseline SBP, DBP, and ASI were determined stratified by deciles of age, blood pressure, and ASI, with CIs determined by bootstrapping. In 169 742 participants at baseline, ASI was more strongly associated with DBP than SBP, before and after adjustment for risk factors (ß: SBP, -0.01 [P<0.001]; DBP, 0.06 [P<0.001]), while DBP was more strongly associated with progression of ASI (n=13 761; ß: SBP, 0.013 [P=0.01]; DBP, 0.038 [P<0.001]). Baseline ASI was associated with increasing SBP during follow-up (ß=0.02, P<0.001) but not DBP (ß=0.0004, P=0.39), but was associated with a younger age of transition from rising to falling DBP (highest versus lowest quartile: 51.2; 95% CI, 49.9-52.3 versus 60.4; 95% CI, 59.6-61.3 [P<0.001]). ASI predicted the development of isolated systolic hypertension (odds ratio, 1.30; 95% CI, 1.22-1.39), particularly after adjustment for measurement variability (odds ratio, 2.29). Conclusions Midlife DBP was the strongest predictor of progression of arterial stiffness, while arterial stiffness was associated with earlier transition to a falling DBP. Prevention of long-term harms associated with arterial stiffness may require more intensive control of midlife DBP.

Physiological correlates of beat-to-beat, ambulatory, and day-to-day home blood pressure variability after transient ischemic attack or minor stroke.

BACKGROUND AND PURPOSE: Visit-to-visit and day-to-day variability in systolic blood pressure (SBP) are associated with an increased risk of stroke, more strongly than variability on 24-hour ambulatory BP monitoring, but underlying physiological mechanisms are unclear. We related potentially relevant physiological characteristics to beat-to-beat, ambulatory, and day-to-day BP variability to identify underlying mechanisms and potential therapeutic targets. METHODS: BP variability (coefficient of variation [CV]) on 1-month home BP monitoring (3 sitting readings, 3× daily), on 24-hour ambulatory BP monitoring, and on 5-minute beat-to-beat monitoring was related to BP reactivity (to mental arithmetic), arterial aging (aortic stiffness: carotid-femoral pulse wave velocity; aortic pulsatility), heart rate variability (CV of normal-to-normal R-R interval), and orthostatic responses. RESULTS: In 223 patients within 6 weeks of a transient ischemic attack or minor stroke, beat-to-beat and home SBP-CVs were associated with response to arithmetic (beat-to-beat odds ratio per SD=1.64; P<0.0001 and home BP monitoring, 1.41; P=0.025), aortic stiffness (1.84; P<0.0001 and 1.31; P=0.04), aortic pulsatility (1.98; P<0.0001 and 1.61; P<0.0001), and heart rate variability-CV of normal-to-normal R-R interval (1.34; P=0.03 and 1.35; P=0.03), independently of age, sex, and aortic BP. Orthostatic BP changes were associated only with SBP-CV on home BP monitoring (0.62; P=0.002). In contrast, no physiological measures were associated with within-day BP variability on awake ambulatory BP monitoring except response to mental arithmetic (1.40; P=0.01). CONCLUSIONS: Beat-to-beat and day-to-day SBP variability, but not variability on ambulatory BP monitoring, had similar physiological correlates, suggesting common underlying mechanisms and identifying potentially treatable targets that may be responsible for the relationship between SBP variability and stroke risk.

Hypereosinophilia and acute bilateral facial palsy: an unusual presentation of a common disease.

A 60-year-old man presented with an acute, pruritic, erythematous rash associated with marked hypereosinophilia (2.34×10(9)/l (0.04-0.40)). There was eosinophilic infiltration on hepatic, bone marrow and lymph node biopsies, with multiple lung nodules and mild splenomegaly. However, extensive investigation excluded parasitic or bacterial causes, specific allergens or the Fip1L1 mutation seen in myeloproliferative hypereosinophilia. Six months into the illness, he developed an acute, left, complete lower motor neurone facial palsy over hours, and an acute right lower motor neurone facial palsy 2 weeks later, without recovery. Over the subsequent 3 months, he developed complex partial seizures, a transient 72-h non-epileptic encephalopathy and episodic vertigo with ataxia. Further investigation showed bilateral enhancement of the VII nerves and labyrinthis on gadolinium-enhanced MR brain scan, cerebrospinal fluid lymphocytosis and neurophysiological evidence of polyradicolopathy. His eosinophil count fell with corticosteroids, hydroxycarbamide, imatinib and ultimately mepolezumab, but without symptomatic improvement. Repeat lymph node biopsy showed Kaposi's sarcoma, leading to a diagnosis of HIV-1 infection with a modestly reduced CD4 count of 413×10(6)/l (430-1690). Hypereosinophila and eosinophilic folliculitis are recognised features of advanced HIV infection, and transient bilateral facial palsy occasionally occurs at the time of seroconversion. This is the first report of a chronic bilateral facial palsy likely due to primary HIV infection, not occurring during seroconversion and in association with hypereosinophilia. This case emphasises the protean manifestations of HIV infection and the need for routine testing in atypical clinical presentations.

The effect of antihypertensive treatment on headache and blood pressure variability in randomized controlled trials: a systematic review.

Antihypertensive drugs reduce headache but it is unclear whether there are differences between drug classes. Calcium channel blockers (CCBs) decrease variability in systolic blood pressure (SBPV) and stroke risk more than other classes, possibly due to decreased vascular tone. If so, there might be a correlation between drug-class effects on variability in SBP and on headache. We determined antihypertensive class effects on SBPV and headache during follow-up in a systematic review of randomized controlled trials. We determined pooled estimates of treatment effect on group variability in BP (variance ratio, VR) and on the odds ratio for headache (OR) by random-effects meta-analysis. Antihypertensive drugs reduced the incidence of headache compared to placebo (OR = 0.75, 95% CI 0.69-0.82, p < 0.0001, 198 comparisons, 43,672 patients), but there was significant heterogeneity between drug classes (p = 0.0007) with a greater effect of beta-blockers compared to placebo (VR = 0.49, 0.33-0.68, p < 0.0001, 16 trials) or all other drug classes (OR = 0.73, 0.62-0.85, p = 0.0002, 49 trials) and a lack of effectiveness of CCBs (vs. placebo-OR = 0.95, 0.79-1.15, 65 trials; vs. other drugs-OR = 1.19, 1.05-1.35, p = 0.009, 101 trials). Drug-class effects on headache were opposite to effects on variability in SBP (vs. other drugs: CCB-VR = 0.81, 0.71-0.85, p < 0.0001; beta-blocker VR = 1.17, 1.07-1.28, p < 0.0001), but were unrelated to differences in mean SBP. Antihypertensive drugs reduce headache but the effect differs between classes, corresponding to their effects on SBPV and the risk of stroke. This may partly be explained by consistent antihypertensive class effects on vascular tone in the peripheral (variability) and cerebrovascular circulations (headache).

Effect of dose and combination of antihypertensives on interindividual blood pressure variability: a systematic review.

BACKGROUND AND PURPOSE: Recent studies have shown that visit-to-visit blood pressure variability is a powerful risk factor for stroke, is reduced by calcium channel blockers and diuretics, and increased by ß-blockers. However, it is unknown whether these effects are dose-dependent and persist in combination with other drugs. METHODS: Cochrane and Medline databases were searched for systematic reviews and randomized controlled trials of antihypertensive drugs. Eligible trials randomized all patients to a combination of drug classes or different doses of the same drug. Baseline and follow-up data for mean (SD) systolic blood pressure (SBP) and diastolic blood pressure were extracted. Differences in interindividual variance (SD2) in blood pressure were expressed as a ratio (VR). Estimates were pooled by random-effects meta-analysis. RESULTS: Calcium channel blockers reduced interindividual variability in SBP when added to another agent (VR, 0.75; 95% CI, 0.64 to 0.87; P=0.0002; 12 trials; 1565 patients) with a smaller reduction with diuretics (VR, 0.85; 0.71 to 1.01; P=0.07; 17 trials; 3217 patients). Adding other agents to calcium channel blockers did not significantly affect SBP variability (VR, 1.06; 0.83 to 1.34; P=0.65; 12 trials; 1460 patients) despite a 5.8-mm Hg reduction in mean SBP. Randomization to a higher dose of calcium channel blockers reduced SBP variability (VR, 0.84; 0.74 to 0.94; P=0.004; 25 trials; 2179 patients), whereas randomization to a higher dose of ß-blockers increased SBP variability (VR, 1.31; 1.01 to 1.69; P=0.034; 6 trials; 486 patients). CONCLUSIONS: Effects of antihypertensive drugs on SBP variability are dose-dependent and persist when used in combinations. Use of a high dose of a calcium channel blocker alone or in combination with other agents is therefore likely to be particularly effective in prevention of stroke.

Effects of ß-blocker selectivity on blood pressure variability and stroke: a systematic review.

OBJECTIVES: ß-Blockers increase variability in systolic blood pressure (SBP), which probably explains their lesser effectiveness in preventing stroke vs myocardial infarction compared with other agents. This increase in variability in blood pressure (BP) may be particularly marked on non-cardioselective agents, potentially calling into question the widespread first-line use of propranolol in migraine with aura, elderly patients with essential tremor or anxiety, and other groups at risk of stroke. METHODS: We determined ß-blocker subclass effects on variability in BP and stroke risk in a systematic review of randomized controlled trials (RCTs) comparing different types of ß-blocker with placebo or other agents. We determined pooled estimates of the effect of treatment on group variability in BP (ratio of the variances [VR]) and on the risk of stroke vs myocardial infarction during follow-up. RESULTS: Compared with other antihypertensives, variability in SBP was increased more by nonselective ß-blockers (VR=1.34, 1.13-1.59, p =0.002, 25 comparisons, 9,992 patients) than by ß1-selective agents (VR=1.09, 95% confidence interval 1.00-1.19, p =0.053, 68 comparisons, 40,746 patients; difference-p =0.038). In direct comparisons, variability in SBP was also significantly lower with ß1-selective vs nonselective ß-blockers (VR=0.81, 0.68-0.97, p =0.03, 18 comparisons, 954 patients). In comparisons with other antihypertensives, the increase in stroke risk with nonselective ß-blockers ([OR]=2.29, 1.32-3.96, p =0.002) was more marked than with ß1-selective agents (OR=1.24, 1.08-1.42, p =0.003, difference-p =0.03), as was the risk of stroke relative to the risk of myocardial infarction: OR=1.50 (0.93-2.42) vs 0.99 (0.82-1.19). CONCLUSION: Use of ß1-selective rather than nonselective agents may be advisable when ß-blockers are indicated for patients at risk of stroke.