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.

Sex Differences in Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis.

Background: Cerebral small vessel disease (SVD) is a common cause of stroke, mild cognitive impairment, dementia and physical impairments. Differences in SVD incidence or severity between males and females are unknown. We assessed sex differences in SVD by assessing the male-to-female ratio (M:F) of recruited participants and incidence of SVD, risk factor presence, distribution, and severity of SVD features. Methods: We assessed four recent systematic reviews on SVD and performed a supplementary search of MEDLINE to identify studies reporting M:F ratio in covert, stroke, or cognitive SVD presentations (registered protocol: CRD42020193995). We meta-analyzed differences in sex ratios across time, countries, SVD severity and presentations, age and risk factors for SVD. Results: Amongst 123 relevant studies (n = 36,910 participants) including 53 community-based, 67 hospital-based and three mixed studies published between 1989 and 2020, more males were recruited in hospital-based than in community-based studies [M:F = 1.16 (0.70) vs. M:F = 0.79 (0.35), respectively; p < 0.001]. More males had moderate to severe SVD [M:F = 1.08 (0.81) vs. M:F = 0.82 (0.47) in healthy to mild SVD; p < 0.001], and stroke presentations where M:F was 1.67 (0.53). M:F did not differ for recent (2015-2020) vs. pre-2015 publications, by geographical region, or age. There were insufficient sex-stratified data to explore M:F and risk factors for SVD. Conclusions: Our results highlight differences in male-to-female ratios in SVD severity and amongst those presenting with stroke that have important clinical and translational implications. Future SVD research should report participant demographics, risk factors and outcomes separately for males and females. Systematic Review Registration: [PROSPERO], identifier [CRD42020193995].

Associations Between White Matter Hyperintensity Burden, Cerebral Blood Flow and Transit Time in Small Vessel Disease: An Updated Meta-Analysis.

Cerebral small vessel disease (SVD) is a major contributor to stroke and dementia, characterized by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 systematic review, identifying 30 new studies, 27 cross-sectional (n = 2,956) and 3 longitudinal (n = 440). Cross-sectionally, 10/27 new studies (n = 1,019) included sufficient data for meta-analysis, which we meta-analyzed with 24 previously reported studies (n = 1,161), total 34 (n = 2,180). Our meta-analysis showed that patients with lower CBF had worse WMH burden (mean global CBF: standardized mean difference (SMD): -0.45, 95% confidence interval (CI): -0.64, -0.27). Longitudinally, associations between baseline CBF and WMH progression varied: the largest study (5 years, n = 252) found no associations, while another small study (4.5 years, n = 52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found that CBF was lower in WMH than in normal-appearing white matter in an additional meta-analysis (5 cross-sectional studies; n = 295; SMD: -1.51, 95% CI: -1.94, -1.07). These findings highlight that relationships between resting CBF and WMH are complex. Further longitudinal studies analyzing regional CBF and subsequent WMH change are required to determine the role of CBF in SVD progression.