Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

Circadian and Diurnal Regulation of Cerebral Blood Flow.

Circadian and diurnal variation in cerebral blood flow directly contributes to the diurnal variation in the risk of stroke, either through factors that trigger stroke or due to impaired compensatory mechanisms. Cerebral blood flow results from the integration of systemic hemodynamics, including heart rate, cardiac output, and blood pressure, with cerebrovascular regulatory mechanisms, including cerebrovascular reactivity, autoregulation, and neurovascular coupling. We review the evidence for the circadian and diurnal variation in each of these mechanisms and their integration, from the detailed evidence for mechanisms underlying the nocturnal nadir and morning surge in blood pressure to identifying limited available evidence for circadian and diurnal variation in cerebrovascular compensatory mechanisms. We, thus, identify key systemic hemodynamic factors related to the diurnal variation in the risk of stroke but particularly identify the need for further research focused on cerebrovascular regulatory mechanisms.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

Low-frequency oscillations in the brain show differential regional associations with severity of cerebral small vessel disease: a systematic review.

Background: Cerebral small vessel disease (cSVD) is associated with endothelial dysfunction but the pathophysiology is poorly understood. Low-frequency oscillations (LFOs) in the BOLD signal partly reflect cerebrovascular function and have the potential to identify endothelial dysfunction in cSVD. A systematic review was performed to assess the reported relationships between imaging markers of cSVD and LFOs. Methods: Medline and EMBASE were searched for original studies reporting an association between LFOs and STRIVE-defined imaging markers of cSVD, including: white matter hyperintensities (WMH), enlarged perivascular spaces, lacunes, CADASIL, and cerebral microbleeds, from inception to September 1, 2022. Variations in LFOs were extracted, where available, on a global, tissue-specific, or regional level, in addition to participant demographics, data acquisition, methods of analysis, and study quality. Where a formal meta-analysis was not possible, differences in the number of studies reporting LFO magnitude by presence or severity of cSVD were determined by sign test. Results: 15 studies were included from 841 titles. Studies varied in quality, acquisition parameters, and in method of analysis. Amplitude of low-frequency fluctuation (ALFF) in resting state fMRI was most commonly assessed (12 studies). Across 15 studies with differing markers of cSVD (9 with WMH; 1 with cerebral microbleeds; 1 with lacunar infarcts; 1 with CADASIL; 3 with multiple markers), LFOs in patients with cSVD were decreased in the posterior cortex (22 of 32 occurrences across all studies, p = 0.05), increased in the deep grey nuclei (7 of 7 occurrences across all studies, p = 0.016), and potentially increased in the temporal lobes (9 of 11 occurrences across all studies, p = 0.065). Conclusion: Despite limited consensus on the optimal acquisition and analysis methods, there was reasonably consistent regional variation in LFO magnitude by severity of cSVD markers, supporting its potential as a novel index of endothelial dysfunction. We propose a consistent approach to measuring LFOs to characterise targetable mechanisms underlying cSVD.

Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

Low Heart Rate Is Associated with Cerebral Pulsatility after TIA or Minor Stroke.

OBJECTIVE: Beta-blockers are beneficial in coronary artery disease but less so in stroke prevention and dementia, potentially due to reduced heart rate (HR). Cerebral pulsatility is strongly associated with cerebral small vessel disease (SVD) and may be increased by lower diastolic pressures resulting from longer cardiac cycles. METHODS: Patients 4-6 weeks after TIA or non-disabling stroke (Oxford Vascular Study) underwent 5 minutes continuous monitoring of blood pressure (BP), electrocardiogram (ECG), and middle cerebral artery flow velocity (transcranial ultrasound). Beat-to-beat relationships between HR, blood pressure and Gosling's pulsatility index (MCA-PI) are reported as beta-coefficients from general linear models for each individual. RESULTS: Across 759 patients, average MCA-PI during monitoring was associated with lower HR and diastolic BP (DBP) and greater systolic BP (SBP) (∆MCA-PI per 10 bpm/mmHg: -0.02, -0.04, 0.03, all p < 0.001), with HR particularly associated with low end-diastolic cerebral velocity (0.86, p = 0.014). Beat-to-beat HR was strongly associated with concurrent low DBP and high SBP, potentially mediating the association with greater beat-to-beat cerebral pulsatility (average ∆MCA-PI vs HR/DBP/SBP unadjusted: -0.062, -0.052, 0.0092; adjusted for concurrent BP: -0.039, -0.11, 0.041). The beat-to-beat association between HR and MCA-PI increased with age, beta-blockers, arterial stiffness, low HR (age > 70 + HR < 65 vs age < 70 + HR > 65: -0.081 vs -0.024, interaction p < 0.001), and severe SVD on MRI (age > 70 + severe vs age < 70 + none: -0.087 vs -0.047, interaction p = 0.03), with interactions between age, severe SVD, and low HR synergistically increasing MCA-PI. INTERPRETATION: Low HR is associated with greater cerebral pulsatility in patients with SVD, potentially mediated by lower diastolic blood flow and representing a novel potential treatment target. ANN NEUROL 2022;92:909-920.

New Insights Into Cerebrovascular Pathophysiology and Hypertension.

Despite advances in acute management and prevention of cerebrovascular disease, stroke and vascular cognitive impairment together remain the world's leading cause of death and neurological disability. Hypertension and its consequences are associated with over 50% of ischemic and 70% of hemorrhagic strokes but despite good control of blood pressure (BP), there remains a 10% risk of recurrent cerebrovascular events, and there is no proven strategy to prevent vascular cognitive impairment. Hypertension evolves over the lifespan, from predominant sympathetically driven hypertension with elevated mean BP in early and mid-life to a late-life phenotype of increasing systolic and falling diastolic pressures, associated with increased arterial stiffness and aortic pulsatility. This pattern may partially explain both the increasing incidence of stroke in younger adults as well as late-onset, chronic cerebrovascular injury associated with concurrent systolic hypertension and historic mid-life diastolic hypertension. With increasing arterial stiffness and autonomic dysfunction, BP variability increases, independently predicting the risk of ischemic and intracerebral hemorrhage, and is potentially modifiable beyond control of mean BP. However, the interaction between hypertension and control of cerebral blood flow remains poorly understood. Cerebral small vessel disease is associated with increased pulsatility in large cerebral vessels and reduced reactivity to carbon dioxide, both of which are being targeted in early phase clinical trials. Cerebral arterial pulsatility is mainly dependent upon increased transmission of aortic pulsatility via stiff vessels to the brain, while cerebrovascular reactivity reflects endothelial dysfunction. In contrast, although cerebral autoregulation is critical to adapt cerebral tone to BP fluctuations to maintain cerebral blood flow, its role as a modifiable risk factor for cerebrovascular disease is uncertain. New insights into hypertension-associated cerebrovascular pathophysiology may provide key targets to prevent chronic cerebrovascular disease, acute events, and vascular cognitive impairment.

Blood Pressure Complexity Discriminates Pathological Beat-to-Beat Variability as a Marker of Vascular Aging.

Background Beat-to-beat blood pressure variability (BPV) is associated with an increased risk of stroke but can be driven by both healthy physiological processes and failure of compensatory mechanisms. Blood pressure (BP) complexity measures structured, organized variations in BP, as opposed to random fluctuations, and its reduction may therefore identify pathological beat-to-beat BPV. Methods and Results In the prospective, population-based OXVASC (Oxford Vascular Study) Phenotyped Cohort with transient ischemic attack or minor stroke, patients underwent at least 5 minutes of noninvasive beat-to-beat monitoring of BP (Finometer) and ECG to derive the following: BPV (coefficient of variation) and complexity (modified multiscale entropy) of systolic BP and diastolic BP, heart rate variability (SD of R-R intervals), and baroreflex sensitivity (BRS; Welch's method), in low- (0.04-0.15 Hz) and high-frequency (0.15-0.4 Hz) bands. Associations between BPV or BP complexity with autonomic indexes and arterial stiffness were determined (linear regression), unadjusted, and adjusted for age, sex, and cardiovascular risk factors. In 908 consecutive, consenting patients, BP complexity was inversely correlated with BPV coefficient of variation (P<0.001) and was similarly reduced in patients with hypertension or diabetes (P<0.001). However, although BPV coefficient of variation had a U-shaped relationship with age, BP complexity fell systematically across age quintiles (quintile 1: 15.1 [14.0-16.1] versus quintile 5: 13.8 [12.4-15.1]) and was correlated with markers of autonomic dysfunction (heart rate variability SD of R-R intervals: r = 0.20; BRS low frequency: 0.19; BRS high frequency: 0.26) and arterial stiffness (pulse wave velocity: -0.21; all P<0.001), even after adjustment for clinical variables (heart rate variability SD of R-R intervals: 0.12; BRS low frequency and BRS high frequency: 0.13 and 0.17; and pulse wave velocity: -0.07; all P<0.05). Conclusions Loss of BP complexity discriminates BPV because of pathological failure of compensatory mechanisms and may represent a less confounded and potentially modifiable risk factor for stroke.

Aortic Stiffness, Pulse Pressure, and Cerebral Pulsatility Progress Despite Best Medical Management: The OXVASC Cohort.

BACKGROUND: Increased cerebral arterial pulsatility is associated with cerebral small vessel disease, recurrent stroke, and dementia despite the best medical treatment. However, no study has identified the rates and determinants of progression of arterial stiffness and pulsatility. METHODS: In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), arterial stiffness (pulse wave velocity [PWV]) and aortic systolic, aortic diastolic, and aortic pulse pressures (aoPP) were measured by applanation tonometry (Sphygmocor), while middle cerebral artery (MCA) peak (MCA-PSV) and trough (MCA-EDV) flow velocity and Gosling pulsatility index (PI; MCA-PI) were measured by transcranial ultrasound (transcranial Doppler, DWL Doppler Box). Repeat assessments were performed at the 5-year follow-up visit after intensive medical treatment and agreement determined by intraclass correlation coefficients. Rates of progression and their determinants, stratified by age and sex, were determined by mixed-effects linear models, adjusted for age, sex, and cardiovascular risk factors. RESULTS: In 188 surviving, eligible patients with repeat assessments after a median of 5.8 years. PWV, aoPP, and MCA-PI were highly reproducible (intraclass correlation coefficients, 0.71, 0.59, and 0.65, respectively), with progression of PWV (2.4%; P<0.0001) and aoPP (3.5%; P<0.0001) but not significantly for MCA-PI overall (0.93; P=0.22). However, PWV increased at a faster rate with increasing age (0.009 m/s per y/y; P<0.0001), while aoPP and MCA-PI increased significantly above the age of 55 years (aoPP, P<0.0001; MCA-PI, P=0.009). Higher aortic systolic blood pressure and diastolic blood pressure predicted a greater rate of progression of PWV and aoPP, but not MCA-PI, although current MCA-PI was particularly strongly associated with concurrent aoPP (P<0.001). CONCLUSIONS: Arterial pulsatility and aortic stiffness progressed significantly after 55 years of age despite the best medical treatment. Progression of stiffness and aoPP was determined by high blood pressure, but MCA-PI predominantly reflected current aoPP. Treatments targetting cerebral pulsatility may need to principally target aortic stiffness and pulse pressure to have the potential to prevent cerebral small vessel disease.

Blood Pressure Determinants of Cerebral White Matter Hyperintensities and Microstructural Injury: UK Biobank Cohort Study.

[Figure: see text].

Body Mass Index and Arterial Stiffness Are Associated With Greater Beat-to-Beat Blood Pressure Variability After Transient Ischemic Attack or Minor Stroke.

[Figure: see text].

Progression of Beat-to-Beat Blood Pressure Variability Despite Best Medical Management.

Beat-to-beat variability in blood pressure (BP) is associated with recurrent stroke despite good control of hypertension. However, no study has identified rates of progression of beat-to-beat BP variability (BPV), its determinants, or which patient groups are particularly affected, limiting understanding of its potential as a treatment target. In consecutive patients one month after a transient ischaemic attack or nondisabling stroke (Oxford Vascular Study), continuous noninvasive BP was measured beat-to-beat over 5 minutes (Finometer). Arterial stiffness was measured by carotid-femoral pulse wave velocity (Sphygmocor). Repeat assessments were performed at the 5-year follow-up visit and agreement determined by intraclass correlation coefficient. Rates of progression of systolic BPV (SBPV) and diastolic BPV (DBPV) and their determinants were estimated by mixed-effect linear models, adjusted for age, sex, and cardiovascular risk factors. One hundred eighty-eight of 310 surviving, eligible patients had repeat assessments after a median of 5.8 years. Pulse wave velocity was highly reproducible but SBPV and DBPV were not (intraclass correlation coefficient: 0.71, 0.10, and 0.16, respectively), however, all 3 progressed significantly (pulse wave velocity, 2.39%, P<0.0001; SBPV, 8.36%, P<0.0001; DBPV, 9.7, P<0.0001). Rate of progression of pulse wave velocity, SBPV, and DBPV all increased significantly with age (P<0.0001), with an increasingly positive skew and were particularly associated with female sex (pulse wave velocity P=0.00035; SBPV P<0.0001; DBPV P<0.0001) and aortic mean SBP (SBPV P=0.037, DBPV P<0.0001). Beat-to-beat BP variability progresses significantly in high-risk patients, particularly in older individuals with elevated aortic systolic pressure. Beat-to-beat BPV and its progression represent potential new therapeutic targets to reduce cardiovascular risk.

Reliability, reproducibility and validity of dynamic cerebral autoregulation in a large cohort with transient ischaemic attack or minor stroke.

OBJECTIVE: Cerebral autoregulation (CA) is critical to maintenance of cerebral perfusion but its relevance to the risk of stroke and dementia has been under-studied due to small study sizes and a lack of consensus as to the optimal method of measurement. We determined the reliability and reproducibility of multiple CA indices and the effect of intensive data-processing in a large population with transient ischaemic attack or minor stroke. APPROACH: Consecutive, consenting patients in the population-based Oxford Vascular Study (OXVASC) Phenotyped cohort underwent up to 10-min supine continuous blood pressure monitoring (Finometer) with bilateral middle cerebral artery (MCA) transcranial ultrasound (DWL-Dopplerbox). Un-processed waveforms (Un-A) were median-filtered, systematically reviewed, artefacts corrected and their quality blindly graded (optimal (A) to worst (E)). CA metrics were derived in time-domain (autoregulatory index (ARI), Pearson's Mx, Sx, Dx) and in very-low (VLF) and low-frequency (LF) domains (WPS-SI: wavelet phase synchronisation, transfer function analysis), stratified by recording quality. Reliability and reproducibility (Cronbach's alpha) were determined comparing MCA sides and the first vs. second 5-min of monitoring. MAIN RESULTS: In 453 patients, following manual data-cleaning, there was good reliability of indices when comparing MCA sides (Mx: 0.77; WPS-SI-VLF: 0.85; WPS-SI-LF 0.84), or repeated five minute epochs (Mx: 0.57; WPS-SI-VLF: 0.69; WPS-SI-LF 0.90), with persistently good reliability between sides even in lower quality Groups (Group D: Mx: 0.79; WPS-SI-VLF: 0.92; WPS-SI-LF: 0.91). Reliability was greatest for Pearson's Mx and wavelet synchronisation index, with reasonable reliability of transfer function analyses, but ARI was prone to occasional, potentially defective, extreme estimates (left vs right MCA: 0.68). SIGNIFICANCE: Resting-state measures of CA were valid, reproducible and robust to moderate noise, but require careful data-processing. Mx and wavelet synchronisation index were the most reliable indices for determining the prognostic value of CA in large epidemiological cohorts and its potential as a treatment target.

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.

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 genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-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 white matter hyperintensities (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 ß-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic 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.

Two case reports of distal upper limb weakness following influenza-like illness: an emerging pattern of para-infectious myositis in adults.

BACKGROUND: Myositis is a recognised complication of numerous systemic viral infections including influenza. In adults the typical pattern is characterised by myalgia and marked proximal muscle weakness in upper and lower limbs and resolves slowly over weeks rather than days. CASE PRESENTATION: Here, we describe two male patients with myositis with an unusual distribution of weakness in the distal upper limbs, which both followed a flu-like illness and resolved spontaneously. Both patients had moderate elevations in creatine kinase, extensive negative serological investigations, normal nerve conduction studies and myopathic changes on electromyography. CONCLUSIONS: In the para-infectious context, myositis is an important differential of acute distal upper limb weakness. This unusual pattern of acute muscle weakness should be recognised to avoid unnecessary in treatments. Similar cases in the recent literature in male patients between the ages of 25 to 55 are reviewed and suggest an emerging pattern of para-infectious myositis.

Confounding of Cerebral Blood Flow Velocity by Blood Pressure During Breath Holding or Hyperventilation in Transient Ischemic Attack or Stroke.

Background and Purpose- Breath holding (BH) and hyperventilation are used to assess abnormal cerebrovascular reactivity, often in relation to severity of small vessel disease and risk of stroke with carotid stenosis, but responses may be confounded by blood pressure (BP) changes. We compared effects of BP and end-tidal carbon dioxide (etCO2) on middle cerebral artery mean flow velocity (MFV) in consecutive transient ischemic attack and minor stroke patients. Methods- In the population-based, prospective OXVASC (Oxford Vascular Study) phenotyped cohort, change in MFV on transcranial Doppler ultrasound (ΔMFV, DWL-DopplerBox), beat-to-beat BP (Finometer), and etCO2 was measured during 30 seconds of BH or hyperventilation. Two blinded reviewers independently assessed recording quality. Dependence of ΔMFV on ΔBP and ΔetCO2 was determined by general linear models, stratified by quartiles. Results- Four hundred eighty-eight of 602 (81%) patients with adequate bone windows had high-quality recordings, more often in younger participants (64.6 versus 68.7 years; P<0.01), whereas 426 had hyperventilation tests (70.7%). During BH, ΔMFV was correlated with a rise in mean blood pressure (MBP; r2=0.15, P<0.001) but not ΔCO2 (r2=0.002, P=0.32), except in patients with ΔMBP <10% (r2=0.13, P<0.001). In contrast during hyperventilation, the fall in MFV was similarly correlated with reduction in CO2 and reduction in MBP (ΔCO2: r2=0.13, P<0.001; ΔMBP: r2=0.12, P<0.001), with a slightly greater effect of ΔCO2 when ΔMBP was <10% (r2=0.15). Stratifying by quartile, MFV increased linearly during BH across quartiles of ΔMBP, with no increase with ΔetCO2. In contrast, during hyperventilation, MFV decreased linearly with ΔetCO2, independent of ΔMBP. Conclusions- In older patients with recent transient ischemic attack or minor stroke, cerebral blood flow responses to BH were confounded by BP changes but reflected etCO2 change during hyperventilation. Correct interpretation of cerebrovascular reactivity responses to etCO2, including in small vessel disease and carotid stenosis, requires concurrent BP measurement.

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 = 0.018) but no change in MFV (ΔMFV 1.11, confidence interval -0.93 to 3.14, P = 0.29, 23 comparisons). MFV increased in patients with underlying conditions (3.41, 0.24 to 6.57, P = 0.04) but not in healthy study participants (-1.27, -5.18 to 2.64, P = 0.68), with no differences by vasodilating drug class. Cerebral pulsatility index was reduced across all studies (Δ pulsatility index -0.04, -0.07 to -0.02, P = 0.001; Δ pulsatility index -SMD -0.32, -0.47 to -0.16, P < 0.001), except in studies reporting responses to single drug doses (Δ pulsatility index 0.00, -0.09 to -0.08, P = 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 = 0.03) with a significant increase in cerebrovascular reactivity-SMD (0.48, 0.13-0.83, P = 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.

Prognostic Significance of Blood Pressure Variability on Beat-to-Beat Monitoring After Transient Ischemic Attack and Stroke.

BACKGROUND AND PURPOSE: Visit-to-visit and day-to-day blood pressure (BP) variability (BPV) predict an increased risk of cardiovascular events but only reflect 1 form of BPV. Beat-to-beat BPV can be rapidly assessed and might also be predictive. METHODS: In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (Oxford Vascular Study), BPV (coefficient of variation) was measured beat-to-beat for 5 minutes (Finometer), day-to-day for 1 week on home monitoring (3 readings, 3× daily), and on awake ambulatory BP monitoring. BPV after 1-month standard treatment was related (Cox proportional hazards) to recurrent stroke and cardiovascular events for 2 to 5 years, adjusted for mean systolic BP. RESULTS: Among 520 patients, 26 had inadequate beat-to-beat recordings, and 22 patients were in atrial fibrillation. Four hundred five patients had all forms of monitoring. Beat-to-beat BPV predicted recurrent stroke and cardiovascular events independently of mean systolic BP (hazard ratio per group SD, stroke: 1.47 [1.12-1.91]; P=0.005; cardiovascular events: 1.41 [1.08-1.83]; P=0.01), including after adjustment for age and sex (stroke: 1.47 [1.12-1.92]; P=0.005) and all risk factors (1.40 [1.00-1.94]; P=0.047). Day-to-day BPV was less strongly associated with stroke (adjusted hazard ratio, 1.29 [0.97-1.71]; P=0.08) but similarly with cardiovascular events (1.41 [1.09-1.83]; P=0.009). BPV on awake ambulatory BP monitoring was nonpredictive (stroke: 0.89 [0.59-1.35]; P=0.59; cardiovascular events: 1.08 [0.77-1.52]; P=0.65). Despite a weak correlation (r=0.119; P=0.02), beat-to-beat BPV was associated with risk of recurrent stroke independently of day-to-day BPV (1.41 [1.05-1.90]; P=0.02). CONCLUSIONS: Beat-to-beat BPV predicted recurrent stroke and cardiovascular events, independently of mean systolic BP and risk factors but short-term BPV on ambulatory BP monitoring did not. Beat-to-beat BPV may be a useful additional marker of cardiovascular risk.