Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

Age-specific sex-differences in cerebral blood flow velocity in relation to haemoglobin levels.

INTRODUCTION: Cerebral blood flow (CBF) declines with age and abnormalities in CBF are associated with age-related cerebrovascular disease and neurodegeneration. Women have higher CBF than men, although this sex-difference diminishes to some extent with age in healthy subjects. The physiological drivers of these age/sex differences are uncertain, but might be secondary to age and sex-differences in haemoglobin (Hb) level. Hb levels are inversely correlated with CBF, are lower in women, and decline with age in men, but the interrelations between these factors have not been explored systematically either in healthy subjects or across the full age-range in patients with vascular risk factors. We aimed to determine the age-specific interrelations between sex, Hb, and CBF velocity in a large cohort of patients with cerebrovascular disease. PATIENTS AND METHODS: In patients with a recent transient ischaemic attack or minor stroke (Oxford Vascular Study) and no ipsilateral or contralateral stenosis of the carotid or intracranial arteries, we related peak-systolic velocity (PSV) and other parameters on transcranial Doppler ultrasound (TCD) of the middle cerebral artery to sex, age, Hb and vascular risk factors. RESULTS: Of 958 eligible subjects (mean age/SD = 68.04/14.26, 53.2% male), younger women (age < 55 years) had higher CBF velocities than men (mean sex difference in PSV at age < 55 years = 16.31 cm/s; p < 0.001), but this difference declined with age (interaction p < 0.001), such that it was no longer significant at age 75-84 (∆PSV = 3.26 cm/s; p = 0.12) and was reversed at age ⩾ 85 (∆PSV = -7.42 cm/s; p = 0.05). These changes mirrored trends in levels of Hb, which were higher in men at age < 55 (∆Hb = 1.92 g/dL; p < 0.001), but steadily decreased with age in men but not in women (interaction p < 0.001), with no residual sex-difference at age ⩾ 85 (∆Hb = 0.12 g/dL; p = 0.70). There was an inverse correlation between Hb and PSV in both women and men (both p ⩽ 0.01), and the sex-difference in PSV at age < 55 was substantially diminished after adjustment for Hb (∆PSV = 6.92; p = 0.036; ∆PSV = 5.92, p = 0.13 with further adjustment for end-tidal CO2). In contrast, the sex difference in PSV was unaffected by adjustment for systolic and diastolic blood pressure, heart rate, and vascular risk factors (history of hypertension, diabetes, hyperlipidaemia and smoking). DISCUSSION: CBF velocity is strongly correlated with Hb level at all ages, and sex-differences in CBF velocity appear to be explained in major part by age-related sex-differences in Hb.

Reduced Left Atrial Rotational Flow Is Independently Associated With Embolic Brain Infarcts.

BACKGROUND: Up to 25% of embolic strokes occur in individuals without atrial fibrillation (AF) or other identifiable mechanisms. OBJECTIVES: This study aims to assess whether left atrial (LA) blood flow characteristics are associated with embolic brain infarcts, independently of AF. METHODS: The authors recruited 134 patients: 44 with a history of ischemic stroke and 90 with no history of stroke but CHA2DS2VASc score ≥1. Cardiac magnetic resonance (CMR) evaluated cardiac function and LA 4-dimensional flow parameters, including velocity and vorticity (a measure of rotational flow), and brain magnetic resonance imaging (MRI) was performed to detect large noncortical or cortical infarcts (LNCCIs) (likely embolic), or nonembolic lacunar infarcts. RESULTS: Patients (41% female; age 70 ± 9 years) had moderate stroke risk (median CHA2DS2VASc = 3, Q1-Q3: 2-4). Sixty-eight (51%) had diagnosed AF, of whom 58 (43%) were in AF during CMR. Thirty-nine (29%) had ≥1 LNCCI, 20 (15%) had ≥1 lacunar infarct without LNCCI, and 75 (56%) had no infarct. Lower LA vorticity was significantly associated with prevalent LNCCIs after adjustment for AF during CMR, history of AF, CHA2DS2VASc score, LA emptying fraction, LA indexed maximum volume, left ventricular ejection fraction, and indexed left ventricular mass (OR: 2.06 [95% CI: 1.08-3.92 per SD]; P = 0.027). By contrast, LA flow peak velocity was not significantly associated with LNCCIs (P = 0.21). No LA parameter was associated with lacunar infarcts (all P > 0.05). CONCLUSIONS: Reduced LA flow vorticity is significantly and independently associated with embolic brain infarcts. Imaging LA flow characteristics may aid identification of individuals who would benefit from anticoagulation for embolic stroke prevention, regardless of heart rhythm.

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.

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.

Cerebral hemodynamic effects of early blood pressure lowering after TIA and stroke in patients with carotid stenosis.

BACKGROUND: Effects of early blood pressure (BP) lowering on cerebral perfusion in patients with moderate/severe occlusive carotid disease after transient ischemic attack (TIA) and non-disabling stroke are uncertain. AIMS: We aimed to evaluate the changes in transcranial Doppler (TCD) indices in patients undergoing blood pressure lowering soon after TIA/non-disabling stroke. METHODS: Consecutive eligible patients (1 November 2011 to 30 October 2018) attending a rapid-access clinic with TIA/non-disabling stroke underwent telemetric home blood pressure monitoring (HBPM) for 1 month and middle cerebral artery velocities measurements ipsilateral to carotid stenosis on TCD ultrasound in the acute setting and at 1 month. Hypertensive patients (HBPM ⩾ 135/85) underwent intensive BP-lowering guided by HBPM unless they had bilateral severe occlusive disease (⩾ 70%). Changes in BP and TCD parameters were compared in patients with extracranial moderate/severe carotid stenosis (between 50% and occlusion) versus those with no or mild (< 50%) stenosis. RESULTS: Of 764 patients with repeated TCD measures, 42 had moderate/severe extracranial carotid stenosis without bilateral severe occlusive disease. HBPM was reduced from baseline to 1 month in hypertensive patients both with versus without moderate/severe carotid stenosis (-12.44/15.99 vs -13.2/12.2 mmHg, respectively, p-difference = 0.82), and changes in TCD velocities (4.69/14.94 vs 2.69/13.86 cm/s, respectively, p-difference = 0.52 for peak systolic velocity and 0.33/7.06 vs 1.75/6.84 cm/s, p-difference = 0.34 for end-diastolic velocity) were also similar, with no evidence of greater hemodynamic compromise in patients with stenosis/occlusion. CONCLUSION: There was no evidence of worsening of TCD hemodynamic indices in patients with moderate/severe occlusive carotid disease treated with BP-lowering soon after TIA/non-disabling stroke, suggesting that antihypertensive treatment in this group of patients is safe in the acute setting of TIA clinics.

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.

Age-specific cerebral haemodynamic effects of early blood pressure lowering after transient ischaemic attack and non-disabling stroke.

INTRODUCTION: There is limited knowledge of the effects of blood pressure (BP) lowering on cerebral haemodynamics after transient ischaemic attack (TIA) and non-disabling stroke, particularly at older ages. We aimed to evaluate changes in transcranial Doppler (TCD) haemodynamic indices in patients undergoing early blood pressure lowering after TIA/non-disabling stroke, irrespective of age. PATIENTS AND METHODS: Among consecutive eligible patients attending a rapid-access clinic with suspected TIA/non-disabling stroke and no evidence of extra/intracranial stenosis, hypertensive ones underwent intensive BP-lowering guided by daily home telemetric blood pressure monitoring (HBPM). Clinic-based BP, HBPM, End-tidal CO2 and bilateral middle cerebral artery (MCA) velocity on TCD were compared in the acute setting versus one-month follow-up; changes were stratified by baseline hypertension (clinic-BP≥140/90) and by age (<65, 65-79 and ≥80). RESULTS: In 697 patients with repeated TCD measures, mean/SD baseline systolic-BP (145.0/21.3 mmHg) was reduced by an average of 11.3/19.9 mmHg (p < 0.0001) at one-month (133.7/17.4 mmHg), driven by patients hypertensive at baseline (systolic-BP change = -19.0/19.2 mmHg, p < 0.001; vs -0.5/15.4, p = 0.62 in normotensives). Compared with baseline, a significant change was observed at one-month only in mean/SD MCA end diastolic velocity (EDV) (0.77/7.26 cm/s, p = 0.005) and in resistance index (RI) (-0.005/0.051, p = 0.016), driven by hypertensive patients (mean/SD EDV change: 1.145/6.96 cm/s p = 0.001, RI change -0.007/0.06, p = 0.014). Findings were similar at all ages (EDV change - ptrend=0.357; RI change - ptrend=0.225), including 117 patients aged ≥80. EDV and RI changes were largest in 100 patients with clinic systolic-BP decrease ≥30 mmHg (mean/SD EDV change = 2.49/7.47 cm/s, p = 0.001; RI change -0.024/0.063, p < 0.0001). CONCLUSION: There was no evidence of worsening of TCD haemodynamic indices associated with BP-lowering soon after TIA/non-disabling stroke, irrespective of age and degree of BP reduction. In fact, EDV increase and RI decrease observed after treatment of hypertensive patients suggest a decrease in distal vascular resistance.

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].

Age and sex distribution of beat-to-beat blood pressure variability after transient ischemic attack and minor stroke: A population-based study.

BACKGROUND: Beat-to-beat blood pressure variability is associated with increased stroke risk but its importance at different ages is unclear. AIMS: To determine the age-sex distribution of blood pressure variability in patients with transient ischemic stroke or minor stroke. METHODS: In consecutive patients within six weeks of transient ischemic stroke or non-disabling stroke (Oxford Vascular Study), non-invasive blood pressure was measured beat-to-beat over five minutes (Finometer). The age-sex distribution of blood pressure variability (residual coefficient of variation) was determined for systolic blood pressure and diastolic blood pressure. The risk of top-decile blood pressure variability was estimated (logistic regression), unadjusted, and adjusted for age, sex, and cardiovascular risk factors. RESULTS: In 908 of 1013 patients, excluding 54 in atrial fibrillation and 51 with low quality recordings, residual coefficient of variation was positively skewed with a median systolic residual coefficient of variation of 4.2% (IQR 3.2-5.5) and diastolic residual coefficient of variation of 3.9% (3.0-5.5), with 90th centile thresholds of 7.2 and 7.3%. Median systolic residual coefficient of variation was higher in patients under 50 years (4.5 and 3.0-5.3) compared to 60-70 years (4.1 and 3.2-5.2), but rose to 4.5% (3.5-6.9) above 80 years, with an increasingly positive skew. The proportion of patients with markedly elevated blood pressure variability in the top-decile increased significantly per decade (OR 1.72, p < 0.001), after adjustment for sex and risk factors. CONCLUSIONS: Median beat-to-beat blood pressure variability fell in midlife, reflecting loss of physiological, organized blood pressure variability. However, rates of markedly elevated blood pressure variability significantly increased with greater age, suggesting that blood pressure variability may be particularly important in older patients.

Physiological determinants of residual cerebral arterial pulsatility on best medical treatment after TIA or minor stroke.

Cerebral arterial pulsatility is strongly associated with cerebral small vessel disease and lacunar stroke yet its dependence on central versus local haemodynamic processes is unclear. In a population-based study of patients on best medical managment, 4-6 weeks after a TIA or non-disabling stroke, arterial stiffness and aortic systolic, diastolic and pulse pressures were measured (Sphygmocor). Middle cerebral artery peak and trough flow velocities and Gosling's pulsatility index were measured by transcranial ultrasound. In 981 participants, aortic and cerebral pulsatility rose strongly with age in both sexes, but aortic diastolic pressure fell more with age in men whilst cerebral trough velocity fell more in women. There was no significant association between aortic systolic or diastolic blood pressure with cerebral peak or trough flow velocity but aortic pulse pressure explained 37% of the variance in cerebral arterial pulsatility, before adjustment, whilst 49% of the variance was explained by aortic pulse pressure, arterial stiffness, age, gender and cardiovascular risk factors. Furthermore, arterial stiffness partially mediated the relationship between aortic and cerebral pulsatility. Overall, absolute aortic pressures and cerebral blood flow velocity were poorly correlated but aortic and cerebral pulsatility were strongly related, suggesting a key role for transmission of aortic pulsatility to the brain.

Increasing Blood Pressure Variability Predicts Poor Functional Outcome Following Acute Stroke.

INTRODUCTION: Increasing blood pressure variability has been reported following acute stroke, but there is uncertainty about how best to measure it and about the impact on prognosis following acute ischaemic stroke and transient ischaemic attack. METHODS: Enhanced casual blood pressure and ambulatory blood pressure monitoring were completed at baseline (≤48 h post symptom onset). Blood pressure variability was defined by standard deviation and coefficient of variation of systolic, diastolic, mean arterial pressure, and pulse pressure. Modified Rankin scale score ≥3 described poor functional outcome assessed at 1- and 12-months post-stroke. Multivariable logistic regression models incorporating blood pressure variability measurement and other factors were performed, and odds ratio and 95% confidence intervals reported. RESULTS: 232 patients were recruited; 45 were dependent at 1-month, and 37 at 12-months. Dependent patients were more likely to be older, with a higher burden of pre-morbid conditions, and with increased blood pressure variability. Enhanced casual standard deviations of diastolic blood pressure [1.19 (1.02 to 1.39)] and mean arterial pressure [1.20 (1.00 to 1.43)] predicted dependency at 1-month. Predictors of 12-month dependency included: enhanced casual standard deviation of mean arterial pressure [1.21 (1.0-1.46)]; 24 h ambulatory monitor standard deviations of diastolic blood pressure [2.30 (1.08-4.90)] and mean arterial pressure [1.72 (1.09-2.72)], and the coefficient of variation of mean arterial pressure [1.76 (1.05-2.94)]; day-time ambulatory monitor coefficient of variation of systolic blood pressure [1.44 (1.02-2.03)] and mean arterial pressure [1.46 (1.02-2.08)]; and night-time ambulatory standard deviation of diastolic blood pressure [1.65 (1.03 -2.63)], and the coefficient of variation of mean arterial pressure and [1.38 (1.00- 1.90)] and pulse pressure [1.29 (1.00-1.65)]. CONCLUSION: Increasing blood pressure variability is independently and modestly associated with poor functional outcome at 1- and 12-months following acute stroke.

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.

Prognosis of Cryptogenic Stroke With Patent Foramen Ovale at Older Ages and Implications for Trials: A Population-Based Study and Systematic Review.

Importance: Patent foramen ovale (PFO) closure may prevent recurrent stroke after cryptogenic transient ischemic attack (TIA) or stroke (TIA/stroke) in patients aged 60 years or younger. Patent foramen ovale is associated with cryptogenic stroke in the older population, but risk of recurrence is unknown. Data on prognosis of patients receiving medical treatment at older ages (≥60 years) are essential to justify trials of PFO closure. Objective: To examine the age-specific risk of recurrence in patients with cryptogenic TIA/stroke with PFO. Design, Setting, and Participants: A prospective study was nested in the population-based Oxford Vascular Study between September 1, 2014, and March 31, 2019, with face-to-face follow-up for 5 years. A total of 416 consecutive patients with a diagnosis of cryptogenic TIA or nondisabling stroke, screened for PFO at a rapid-access TIA/stroke clinic, were included. A systematic review and meta-analysis of cohort studies reporting on ischemic stroke recurrence after cryptogenic TIA/stroke in patients with PFO who were receiving medical therapy alone, or with PFO vs no-PFO was conducted. Sample size calculation for future trials on PFO closure was performed for patients aged 60 years or older. Exposures: Patent foramen ovale and age as modifiers of risk of recurrent stroke after cryptogenic TIA/stroke in patients receiving only medical therapy. Main Outcomes and Measures: Risk of ischemic stroke recurrence in patients with cryptogenic TIA/stroke and PFO receiving medical therapy only, and in patients with vs without PFO, stratified by age (<65 vs ≥65 years), as well as sample-size calculation for future trials of PFO closure in patients aged 60 years or older. Results: Among the 153 Oxford Vascular Study patients with PFO (mean [SD] age, 66.7 [13.7] years; 80 [52.3%] men), recurrent ischemic stroke risk (2.05 per 100 patient-years) was similar to the pooled estimate from a systematic review of 23 other studies (9 trials and 14 observational studies) (2.00 per 100 patient-years; 95% CI, 1.55-2.58). However, there was heterogeneity between studies (P < .001 for heterogeneity), owing mainly to risk increasing with mean cohort age (meta-regression: R2 = 0.31; P = .003). In the pooled analysis of 4 studies including patients with or without PFO, increased risk of stroke recurrence with PFO was seen only at age 65 years or older (odds ratio, 2.5; 95% CI, 1.4-4.2; P = .001 for difference; P = .39 for heterogeneity). The pooled ischemic stroke risk was 3.27 per 100 patient-years (95% CI, 2.59-4.13) in 4 cohorts with mean age 60 years or older. Assuming the more conservative 2.0 per 100 patient-years ischemic stroke risk in the PFO nonclosure arms of future trials in patients aged 60 years or older, projected sample sizes were 1080 per arm for 80% power to detect a 33% relative risk reduction. Conclusions and Relevance: The findings of this study suggest that age is a determinant of risk of ischemic stroke after cryptogenic TIA/stroke in patients with PFO, such that trials of PFO closure at older ages are justified; however, projected sample sizes are large.

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.

Age-dependent association of white matter abnormality with cognition after TIA or minor stroke.

OBJECTIVE: To investigate if the association between MRI-detectable white matter hyperintensity (WMH) and cognitive status reported in previous studies persists at older ages (>80 years), when some white matter abnormality is almost universally reported in clinical practice. METHODS: Consecutive eligible patients from a population-based cohort of all TIA/nondisabling stroke (Oxford Vascular Study) underwent multimodal MRI, including fluid-attenuated inversion recovery and diffusion-weighted imaging, allowing automated measurement of WMH volume, mean diffusivity (MD), and fractional anisotropy (FA) in normal-appearing white matter using FSL tools. These measures were related to cognitive status (Montreal Cognitive Assessment) at age ≤80 vs >80 years. RESULTS: Of 566 patients (mean [range] age 66.7 [20-102] years), 107 were aged >80 years. WMH volumes and MD/FA were strongly associated with cognitive status in patients aged ≤80 years (all p < 0.001 for WMH, MD, and FA) but not in patients aged >80 years (not significant for WMH, MD, and FA), with age interactions for WMH volume (p interaction = 0.016) and MD (p interaction = 0.037). Voxel-wise analyses also showed that lower Montreal Cognitive Assessment scores were associated with frontal WMH in patients ≤80 years, but not >80 years. CONCLUSION: MRI markers of white matter damage are strongly related to cognition in patients with TIA/minor stroke at younger ages, but not at age >80 years. Clinicians and patients should not overinterpret the significance of these abnormalities at older ages.

Alkalinization with potassium bicarbonate improves glutathione status and protein kinetics in young volunteers during 21-day bed rest.

BACKGROUND & AIMS: Physical inactivity is associated with lean body mass wasting, oxidative stress and pro-inflammatory changes of cell membrane lipids. Alkalinization may potentially counteract these alterations. We evaluated the effects of potassium bicarbonate supplementation on protein kinetics, glutathione status and pro- and anti-inflammatory polyunsaturated fatty acids (PUFA) in erythrocyte membranes in humans, during experimental bed rest. METHODS: Healthy, young, male volunteers were investigated at the end of two 21-day bed rest periods, one with, and the other without, daily potassium bicarbonate supplementation (90 mmol × d-1), according to a cross-over design. Oxidative stress in erythrocytes was evaluated by determining the ratio between reduced (GSH) and oxidized glutathione (GSSG). Glutathione turnover and phenylalanine kinetics, a marker of whole body protein metabolism, were determined by stable isotope infusions. Erythrocyte membranes PUFA composition was analyzed by gas-chromatography. RESULTS: At the end of the two study periods, urinary pH was 10 ± 3% greater in subjects receiving potassium bicarbonate supplementation (7.23 ± 0.15 vs. 6.68 ± 0.11, p < 0.001). Alkalinization increased total glutathione concentrations by 5 ± 2% (p < 0.05) and decreased its rate of clearance by 38 ± 13% (p < 0.05), without significantly changing GSH-to-GSSG ratio. After alkalinization, net protein balance in the postabsorptive state improved significantly by 17 ± 5% (p < 0.05) as well as the sum of n-3 PUFA and the n-3-to-n-6 PUFA ratio in erythrocyte membranes (p < 0.05). CONCLUSIONS: Alkalinization during long-term inactivity is associated with improved glutathione status, anti-inflammatory lipid pattern in cell membranes and reduction in protein catabolism at whole body level. This study suggests that, in clinical conditions characterized by inactivity, oxidative stress and inflammation, alkalinization could be a useful adjuvant therapeutic strategy.

Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock.

Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-hr gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover (MuRF-1, Atrogin-1). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in gene expression and metabolite fluctuations.

Age and sex-specific associations of carotid pulsatility with small vessel disease burden in transient ischemic attack and ischemic stroke.

Background Although large artery stiffness has been implicated in the pathogenesis of cerebral small vessel disease, whether carotid pulsatility, a convenient surrogate marker of arterial stiffness, is similarly associated with global burden of small vessel disease is unknown. Aims To determine the age and sex-specific associations of carotid pulsatility with global burden of small vessel disease. Methods We studied consecutive patients with transient ischemic attack or non-disabling ischemic stroke from the Oxford Vascular Study who had a brain MRI and carotid duplex ultrasound during 2002-2014. We determined clinical correlates of common carotid artery (CCA) and internal carotid artery (ICA) pulsatility index (PI) and their associations with the total small vessel disease score on MRI, stratified by age (median = 72). Results In 587 patients, correlates of CCA and ICA-PI were both independently associated with age, diabetes, and premorbid mean pulse pressure after adjustment for age, sex, and cardiovascular risk factors (all p < 0.05). ICA-PI was strongly associated with small vessel disease markers and burden, particularly lacunes, in patients aged<70 (age and sex-adjusted odds ratio of top vs. bottom pulsatility index quartile: 5.35, 1.95-14.70, p = 0.001; increasing small vessel disease score: 2.30, 1.01-5.25, p = 0.048), but not in patients aged ≥ 70 ( p > 0.05). No associations between CCA-PI with small vessel disease score were noted at any age. In 94 consecutive patients who also received transcranial Doppler ultrasound, strong associations between middle cerebral artery (MCA)-PI and an increasing small vessel disease score were noted (unadjusted OR-MCA: 4.26, 1.45-12.55, p = 0.009; ICA: 2.37, 0.81-6.87, p = 0.11; CCA: 1.33, 0.45-3.96, p=0.61). Conclusions ICA and MCA-PI are associated with global small vessel disease burden, especially in individuals aged<70 and may be causally related.