scholarly journals Design of a randomised, double-blind, crossover, placebo-controlled trial of effects of sildenafil on cerebrovascular function in small vessel disease: Oxford haemodynamic adaptation to reduce pulsatility trial (OxHARP)

2021 ◽  
pp. 239698732110266
Author(s):  
Alastair Webb ◽  
David Werring ◽  
Jesse Dawson ◽  
Alex Rothman ◽  
Amy Lawson ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Small Vessel Disease ◽  
Pde5 Inhibitor ◽  
Cryptogenic Stroke ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Percentage Increase ◽  
Double Blind ◽  
Vessel Disease ◽  
Cerebrovascular Function

Background Cerebral small vessel disease (SVD) is associated with increased cerebrovascular pulsatility, endothelial dysfunction, and impaired vascular reactivity. Vasodilating phosphodiesterase inhibitors may improve cardiovascular pulsatility and reactivity, and potentially reduce progression of SVD. Hypothesis: Sildenafil, a PDE5 inhibitor, will reduce cerebrovascular pulsatility and increase cerebrovascular reactivity compared to placebo, and is non-inferior to cilostazol, a PDE3 inhibitor. Methods OxHARP is a randomised, double-blind, crossover trial of sildenafil 50 mg thrice daily, cilostazol 100 mg twice daily and placebo in 75 patients with mild to moderate small vessel disease and a previous lacunar or cryptogenic stroke or TIA. Participants undergo a physiological assessment at baseline and on each treatment, including transcranial Doppler ultrasound (TCD, DWL DopplerBox) to assess cerebrovascular pulsatility and reactivity to 4–6% carbon dioxide. In up to 60 patients, cerebrovascular pulsatility, perfusion and reactivity will also be assessed by MRI. Outcome measures The primary outcome is difference in middle cerebral artery pulsatility (Gosling’s Pulsatility Index, PI) after 3 weeks of sildenafil versus placebo. Secondary outcomes including non-inferiority of sildenafil vs cilostazol in effects on PI, percentage increase in MCA blood flow velocity and BOLD-fMRI response during inhalation of 4–6% carbon dioxide. Discussion Reduction in cerebral pulsatility and increased cerebrovascular reactivity during treatment with sildenafil would indicate potential benefit to prevent progression of SVD, suggesting a need for trials with clinical outcomes. Trial Registration OxHARP is registered with ClinicalTrials.org, NCT03855332

scholarly journals Cerebrovascular reactivity measurement in cerebral small vessel disease: Rationale and reproducibility of a protocol for MRI acquisition and image processing

2017 ◽  
Vol 13 (2) ◽  
pp. 195-206 ◽  
Author(s):  
Michael J Thrippleton ◽  
Yulu Shi ◽  
Gordon Blair ◽  
Iona Hamilton ◽  
Gordon Waiter ◽  
...  
Keyword(s):  
White Matter ◽  
Grey Matter ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Minor Stroke ◽  
Reactivity Measurement ◽  
Vessel Disease ◽  
History Of

Background Impaired autoregulation may contribute to the pathogenesis of cerebral small vessel disease. Reliable protocols for measuring microvascular reactivity are required to test this hypothesis and for providing secondary endpoints in clinical trials. Aims To develop and assess a protocol for acquisition and processing of cerebrovascular reactivity by MRI, in subcortical tissue of patients with small vessel disease and minor stroke. Methods We recruited 15 healthy volunteers, testing paradigms using 1- and 3-min 6% CO2 challenges with repeat scanning, and 15 patients with history of minor stroke. We developed a protocol to measure cerebrovascular reactivity and delay times, assessing tolerability and reproducibility in grey and white matter areas. Results The 3-min paradigm yielded more reproducible data than the 1-min paradigm (CV respectively: 7.9–15.4% and 11.7–70.2% for cerebrovascular reactivity in grey matter), and was less reproducible in white matter (16.1–24.4% and 27.5–141.0%). Tolerability was similar for the two paradigms, but mean cerebrovascular reactivity and cerebrovascular reactivity delay were significantly higher for the 3-min paradigm in most regions. Patient tolerability was high with no evidence of greater failure rate (1/15 patients vs. 2/15 volunteers withdrew at the first visit). Grey matter cerebrovascular reactivity was lower in patients than in volunteers (0.110–0.234 vs. 0.172–0.313%/mmHg; p < 0.05 in 6/8 regions), as was the white matter cerebrovascular reactivity delay (16.2–43.9 vs. 31.1–47.9 s; p < 0.05 in 4/8 regions). Conclusions An effective and well-tolerated protocol for measurement of cerebrovascular reactivity was developed for use in ongoing and future trials to investigate small vessel disease pathophysiology and to measure treatment effects.

Abstract MP42: Arterial Spin Labeling Imaging Assessment of Cerebrovascular Reactivity in Hypertensive Small Vessel Disease

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Hsin-Hsi C Tsai ◽  
Bo-Ching Lee ◽  
Abel Po-Hao Huang ◽  
Li-Kai Tsai ◽  
Ya-Fang Chen ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Arterial Spin Labeling ◽  
Small Vessel Disease ◽  
Vascular Dysfunction ◽  
Spin Labeling ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Disease Score ◽  
Temporal Lobes ◽  
Vessel Disease

Objective: Cerebrovascular reactivity (CVR) represents the phenomenon that cerebral vessels dilate or constrict in response to vasoactive stimuli, and CVR impairment may contribute to the brain injury caused by cerebral small vessel disease (SVD). We aim to determine the CVR in hypertensive intracerebral hemorrhage (ICH) and to identify its vascular dysfunction. Methods: 21 patients with spontaneous hypertensive ICH (strictly deep or mixed deep and lobar hemorrhages, mean age 62.5 ± 11.3 years) and 10 control subjects (mean age 66.1 ± 6.0) were enrolled for CVR measurement. Each participant received a brain MRI study, and CVR was calculated as cerebral blood flow (CBF) change using arterial spin labeling (ASL) sequence at baseline and 10 minutes after intravenous dipyridamole injection (0.57mg/Kg). Traditional MRI markers for SVD including cerebral microbleed, white matter hyperintensity, lacune and MRI-visible enlarged perivascular space were also evaluated to determine the total small vessel disease score. Results: Hypertensive ICH patients showed reduced CVR in the basal ganglia (CBF change 22.4 ± 22.7% vs. 41.7 ± 18.3, p=0.026), the frontal (15.1 ± 11.9 vs. 26.6 ± 9.9, p=0.013) and the temporal lobes (14.7 ± 11.1 vs. 26.2 ± 10.0, p=0.010) compared to control subjects (Figure). These differences remained significant in multivariable models after adjusting for age, sex, hypertension, diabetes, and hyperlipidemia. Within ICH groups, the CBF change in basal ganglia was significantly correlated with total small vessel disease score (R=-0.58, p=0.006), but not with individual MRI markers. Conclusion: Patients with advanced HTN-SVD demonstrated impaired vasoconstriction after dipyridamole challenge in basal ganglia, frontal and temporal lobes. Our findings provide safe approaches for whole brain CVR mapping in small vessel disease, and identify the potential physiological basis of vascular dysfunction in HTN-SVD.

scholarly journals Arterial Spin Labeling Imaging Assessment of Cerebrovascular Reactivity in Hypertensive Small Vessel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Bo-Ching Lee ◽  
Hsin-Hsi Tsai ◽  
Abel Po-Hao Huang ◽  
Yen-Ling Lo ◽  
Li-Kai Tsai ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Arterial Spin Labeling ◽  
Small Vessel Disease ◽  
Vascular Dysfunction ◽  
Spin Labeling ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Disease Score ◽  
Vessel Disease ◽  
Control Subjects

Objective: Cerebrovascular reactivity (CVR) represents the phenomenon where cerebral vessels dilate or constrict in response to vasoactive stimuli. CVR impairment may contribute to brain injury due to cerebral small vessel disease (SVD). We aimed to determine the CVR in hypertensive intracerebral hemorrhage (ICH) and to identify its vascular dysfunction.Methods: A total of 21 patients with spontaneous hypertensive ICH (strictly deep or mixed deep and lobar hemorrhages, mean age 62.5 ± 11.3 years) and 10 control subjects (mean age 66.1 ± 6.0 years) were enrolled for CVR measurement at least 3 months after the symptomatic ICH event. Each participant underwent a brain MRI study, and CVR was calculated as the cerebral blood flow (CBF) reduction using arterial spin labeling (ASL) between baseline and 10 min after an intravenous dipyridamole injection (0.57 mg/kg). Traditional MRI markers for SVD were also evaluated, including cerebral microbleed, white matter hyperintensity, lacune, and MRI-visible enlarged perivascular space, which were used to determine the total small vessel disease score.Results: Compared to control subjects, hypertensive ICH patients showed reduced CVR in the basal ganglia (CBF reduction 22.4 ± 22.7% vs. 41.7 ± 18.3, p = 0.026), the frontal lobe (15.1 ± 11.9 vs. 26.6 ± 9.9, p = 0.013), and the temporal lobe (14.7 ± 11.1 vs. 26.2 ± 10.0, p = 0.010). These differences remained significant in multivariable models after adjusting for age and sex. Within ICH groups, the CBF reduction in the basal ganglia was significantly correlated with the total small vessel disease score (R = 0.58, p = 0.006), but not with individual MRI markers.Conclusion: Patients with advanced hypertensive SVD demonstrated impaired vasoconstriction after dipyridamole challenge in the basal ganglia and the frontal and temporal lobes. Our findings provide safe approaches for whole-brain CVR mapping in SVD and identify a potential physiological basis for vascular dysfunction in hypertensive SVD.

scholarly journals Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination

2017 ◽  
Vol 13 (5) ◽  
pp. 530-538 ◽  
Author(s):  
Gordon W Blair ◽  
Jason P Appleton ◽  
Zhe Kang Law ◽  
Fergus Doubal ◽  
Katie Flaherty ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Platelet Function ◽  
Dose Escalation ◽  
Small Vessel Disease ◽  
Cerebrovascular Reactivity ◽  
Phase Iii ◽  
Small Vessel ◽  
Isosorbide Mononitrate ◽  
Lacunar Stroke ◽  
Vessel Disease

Rationale The pathophysiology of most lacunar stroke, a form of small vessel disease, is thought to differ from large artery atherothrombo- or cardio-embolic stroke. Licensed drugs, isosorbide mononitrate and cilostazol, have promising mechanisms of action to support their testing to prevent stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke. Aim LACI-1 will assess the tolerability, safety, and efficacy, by dose, of isosorbide mononitrate and cilostazol, alone and in combination, in patients with ischemic lacunar stroke. Sample size A sample of 60 provides 80+% power (significance 0.05) to detect a difference of 35% (90% versus 55%) between those reaching target dose on one versus both drugs. Methods and design LACI-1 is a phase IIa partial factorial, dose-escalation, prospective, randomized, open label, blinded endpoint trial. Participants are randomized to isosorbide mononitrate and/or cilostazol for 11 weeks with dose escalation to target as tolerated in two centers (Edinburgh, Nottingham). At three visits, tolerability, safety, blood pressure, pulse wave velocity, and platelet function are assessed, plus magnetic resonance imaging to assess cerebrovascular reactivity in a subgroup. Study outcomes Primary: proportion of patients completing study achieving target maximum dose. Secondary symptoms whilst taking medications; safety (hemorrhage, recurrent vascular events, falls); blood pressure, platelet function, arterial stiffness, and cerebrovascular reactivity. Discussion This study will inform the design of a larger phase III trial of isosorbide mononitrate and cilostazol in lacunar stroke, whilst providing data on the drugs’ effects on vascular and platelet function. Trial registration ISRCTN (ISRCTN12580546) and EudraCT (2015-001953-33).

scholarly journals Magnetic resonance imaging for assessment of cerebrovascular reactivity in cerebral small vessel disease: A systematic review

2016 ◽  
Vol 36 (5) ◽  
pp. 833-841 ◽  
Author(s):  
Gordon W Blair ◽  
Fergus N Doubal ◽  
Michael J Thrippleton ◽  
Ian Marshall ◽  
Joanna M Wardlaw
Keyword(s):  
Magnetic Resonance Imaging ◽  
White Matter ◽  
Magnetic Resonance ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Resonance Imaging ◽  
Vessel Disease

Cerebral small vessel disease (SVD) pathophysiology is poorly understood. Cerebrovascular reactivity (CVR) impairment may play a role, but evidence to date is mainly indirect. Magnetic resonance imaging (MRI) allows investigation of CVR directly in the tissues affected by SVD. We systematically reviewed the use of MRI to measure CVR in subjects with SVD. Five studies (total n = 155 SVD subjects, 84 controls) provided relevant data. The studies included different types of patients. Each study used blood oxygen level dependent (BOLD) MRI to assess CVR but a different vasoactive stimulus and method of calculating CVR. CVR decreased with increasing white matter hyperintensities in two studies ( n = 17, 11%) and in the presence of microbleeds in another. Three studies ( n = 138, 89%) found no association of CVR with white matter hyperintensities. No studies provided tissue-specific CVR values. CVR decreased with age in three studies, and with female gender and increasing diastolic blood pressure in one study. Safety and tolerability data were limited. Larger studies using CVR appear to be feasible and are needed, preferably with more standardized methods, to determine if specific clinical or radiological features of SVD are more or less associated with impaired CVR.

scholarly journals Cerebrovascular Reactivity Measurement Using Magnetic Resonance Imaging: A Systematic Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Emilie Sleight ◽  
Michael S. Stringer ◽  
Ian Marshall ◽  
Joanna M. Wardlaw ◽  
Michael J. Thrippleton
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Small Vessel Disease ◽  
Pulse Sequence ◽  
Cerebrovascular Reactivity ◽  
Image Processing Technique ◽  
Small Vessel ◽  
Resonance Imaging ◽  
Vessel Disease ◽  
End Tidal

Cerebrovascular reactivity (CVR) magnetic resonance imaging (MRI) probes cerebral haemodynamic changes in response to a vasodilatory stimulus. CVR closely relates to the health of the vasculature and is therefore a key parameter for studying cerebrovascular diseases such as stroke, small vessel disease and dementias. MRI allows in vivo measurement of CVR but several different methods have been presented in the literature, differing in pulse sequence, hardware requirements, stimulus and image processing technique. We systematically reviewed publications measuring CVR using MRI up to June 2020, identifying 235 relevant papers. We summarised the acquisition methods, experimental parameters, hardware and CVR quantification approaches used, clinical populations investigated, and corresponding summary CVR measures. CVR was investigated in many pathologies such as steno-occlusive diseases, dementia and small vessel disease and is generally lower in patients than in healthy controls. Blood oxygen level dependent (BOLD) acquisitions with fixed inspired CO2 gas or end-tidal CO2 forcing stimulus are the most commonly used methods. General linear modelling of the MRI signal with end-tidal CO2 as the regressor is the most frequently used method to compute CVR. Our survey of CVR measurement approaches and applications will help researchers to identify good practice and provide objective information to inform the development of future consensus recommendations.

scholarly journals A Comparison of CVR Magnitude and Delay Assessed at 1.5 and 3T in Patients With Cerebral Small Vessel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Michael S. Stringer ◽  
Gordon W. Blair ◽  
Yulu Shi ◽  
Iona Hamilton ◽  
David A. Dickie ◽  
...  
Keyword(s):  
Disease Severity ◽  
Small Vessel Disease ◽  
Signal To Noise Ratio ◽  
Blood Oxygen Level Dependent ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Blood Oxygen Level ◽  
Rank Tests ◽  
Vessel Disease ◽  
Minor Ischemic Stroke

BackgroundCerebrovascular reactivity (CVR) measures blood flow change in response to a vasoactive stimulus. Impairment is associated with several neurological conditions and can be measured using blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI). Field strength affects the BOLD signal, but the effect on CVR is unquantified in patient populations.MethodsWe recruited patients with minor ischemic stroke and assessed CVR magnitude and delay time at 3 and 1.5 Tesla using BOLD MRI during a hypercapnic challenge. We assessed subcortical gray (GM) and white matter (WM) differences using Wilcoxon signed rank tests and scatterplots. Additionally, we explored associations with demographic factors, WM hyperintensity burden, and small vessel disease score.ResultsEighteen of twenty patients provided usable data. At 3T vs. 1.5T: mean CVR magnitude showed less variance (WM 3T: 0.062 ± 0.018%/mmHg, range 0.035, 0.093; 1.5T: 0.057 ± 0.024%/mmHg, range 0.016, 0.094) but was not systematically higher (Wilcoxon signal rank tests, WM: r = −0.33, confidence interval (CI): −0.013, 0.003, p = 0.167); delay showed similar variance (WM 3T: 40 ± 12 s, range: 12, 56; 1.5T: 31 ± 13 s, range 6, 50) and was shorter in GM (r = 0.33, CI: −2, 9, p = 0.164) and longer in WM (r = −0.59, CI: −16, −2, p = 0.010). Patients with higher disease severity tended to have lower CVR at 1.5 and 3T.ConclusionMean CVR magnitude at 3T was similar to 1.5T but showed less variance. GM/WM delay differences may be affected by low signal-to-noise ratio among other factors. Although 3T may reduce variance in CVR magnitude, CVR is readily assessable at 1.5T and reveals comparable associations and trends with disease severity.

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