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Tadalafil may improve cerebral perfusion in small-vessel occlusion stroke-a pilot study.

ABSTRACT: New treatments for cerebral small-vessel disease are needed to reduce the risk of small-vessel occlusion stroke and vascular cognitive impairment. We investigated an approach targeted to the signalling molecule cyclic guanosine monophosphate, using the phosphodiesterase 5 inhibitor tadalafil, to explore if it improves cerebral blood flow and endothelial function in patients with cerebral small-vessel disease and stroke. In a randomized, double-blinded, placebo-controlled, cross-over pilot trial (NCT02801032), we included patients who had a previous (>6?months) small-vessel occlusion stroke. They received a single dose of either 20?mg tadalafil or placebo on 2 separate days at least 1?week apart. We measured the following: baseline MRI for lesion load, repeated measurements of blood flow velocity in the middle cerebral artery by transcranial Doppler, blood oxygen saturation in the cortical microvasculature by near-infrared spectroscopy, peripheral endothelial response by EndoPAT and endothelial-specific blood biomarkers. Twenty patients with cerebral small-vessel disease stroke (3 women, 17 men), mean age 67.1?±?9.6, were included. The baseline mean values ± standard deviations were as follows: blood flow velocity in the middle cerebral artery, 57.4?±?10.8?cm/s; blood oxygen saturation in the cortical microvasculature, 67.0?±?8.2%; systolic blood pressure, 145.8?±?19.5?mmHg; and diastolic blood pressure, 81.3?±?9.1?mmHg. We found that tadalafil significantly increased blood oxygen saturation in the cortical microvasculature at 180?min post-administration with a mean difference of 1.57?±?3.02%. However, we saw no significant differences in transcranial Doppler measurements over time. Tadalafil had no effects on peripheral endothelial function assessed by EndoPAT and endothelial biomarker results conflicted. Our findings suggest that tadalafil may improve vascular parameters in patients with cerebral small-vessel disease stroke, although the effect size was small. Increased oxygenation of cerebral microvasculature during tadalafil treatment indicated improved perfusion in the cerebral microvasculature, theoretically presenting an attractive new therapeutic target in cerebral small-vessel disease. Future studies of the effect of long-term tadalafil treatment on cerebrovascular reactivity and endothelial function are needed to evaluate general microvascular changes and effects in cerebral small-vessel disease and stroke.

SUBMITTER: Olmestig J

PROVIDER: S-EPMC7530832 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Tadalafil may improve cerebral perfusion in small-vessel occlusion stroke-a pilot study.

Ölmestig Joakim J Marlet Ida R IR Hansen Rasmus H RH Rehman Shazia S Krawcyk Rikke Steen RS Rostrup Egill E Lambertsen Kate L KL Kruuse Christina C

Brain communications 20200220 1

New treatments for cerebral small-vessel disease are needed to reduce the risk of small-vessel occlusion stroke and vascular cognitive impairment. We investigated an approach targeted to the signalling molecule cyclic guanosine monophosphate, using the phosphodiesterase 5 inhibitor tadalafil, to explore if it improves cerebral blood flow and endothelial function in patients with cerebral small-vessel disease and stroke. In a randomized, double-blinded, placebo-controlled, cross-over pilot trial ...[more]

PMID: 33033800

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Project description:It is important to understand the microbial features of the cerebral thrombus and its clinical relevance in stroke patients, of which data were scarce. We aimed to investigate the microbial features of cerebral thrombi retrieved via thrombectomy in stroke patients with large vessel occlusion (LVO) and their correlations with 3-month mortality. In a prospective cohort study, thrombus samples were collected during mechanical thrombectomy in LVO stroke patients with successful revascularization at a tertiary hospital. Oral, fecal, and isolated plasma samples were collected within 12 h of admission. The microbial compositions of all samples were compared using 16S rRNA gene amplicon next-generation sequencing. Fluorescent in situ hybridization (FISH) was used to detect bacteria in thrombus samples. The primary outcome was 3-month mortality. Perioperative adverse events (AEs) within 48 h were also recorded. Bacterial DNA was detected in 96.2% of thrombus samples from 104 patients, and clusters of bacterial signals were seen in the thrombi with FISH. Compared with fecal and oral samples, the thrombus microbiota was mainly characterized by excessive enrichment of Proteobacteria, mainly originating from plasma. The bacterial concentrations, dominant bacteria, and distribution patterns differed in thrombi obtained from cardioembolic and large-artery atherosclerotic strokes. Higher abundances of Acinetobacter and Enterobacteriaceae were associated with a higher risk of perioperative AEs, and a higher abundance of Acinetobacter was independently associated with a higher risk of 90-day mortality. This study demonstrated the presence of bacteria in cerebral thrombi retrieved with thrombectomy in LVO strokes, with some bacteria associated with patients' prognoses. IMPORTANCE In this study, we (i) checked for the presence of bacteria in cerebral thrombi in over 95% of the LVO stroke patients using 16S rRNA sequencing, in contrast with periprocedural control samples that are bacteria negative; (ii) visualized clusters of bacterial signals in the thrombi using FISH; and (iii) cultivated Lactobacillus vaginalis, Bacillus cereus, and Kocuria marina in the bacterial culture of the tissue fragment solution of thrombus aspirates. We found excessive enrichment of Proteobacteria in the thrombi, mainly originating from plasma, as indicated with fast expectation-maximization microbial source tracking (FEAST). Different bacterial concentrations, dominant bacteria, and distribution patterns were found in thrombi obtained from cardioembolic and large-artery atherosclerotic LVO strokes. There was an association between higher abundances of Acinetobacter and Enterobacteriaceae in the thrombi and a higher risk of perioperative adverse events and an association between a higher abundance of Acinetobacter in the thrombi and a higher risk of 90-day mortality.

Project description:ObjectivesWe aim to investigate whether cerebral small vessel disease (cSVD) imaging markers correlate with deep medullary vein (DMV) damage in small vessel occlusion acute ischemic stroke (SVO-AIS) patients.MethodsThe DMV was divided into six segments according to the regional anatomy. The total DMV score (0-18) was calculated based on segmental continuity and visibility. The damage of DMV was grouped according to the quartiles of the total DMV score. Neuroimaging biomarkers of cSVD including white matter hyperintensity (WMH), cerebral microbleed (CMB), perivascular space (PVS), and lacune were identified. The cSVD score were further analyzed.ResultsWe included 229 SVO-AIS patients, the mean age was 63.7 ± 23.1 years, the median NIHSS score was 3 (IQR, 2-6). In the severe DMV burden group (the 4th quartile), the NIHSS score grade (6 (3-9)) was significantly higher than other groups (p < 0.01). The grade scores for basal ganglia PVS (BG-PVS) were positively correlated with the degree of DMV (R = 0.67, p < 0.01), rather than centrum semivole PVS (CS-PVS) (R = 0.17, p = 0.1). In multivariate analysis, high CMB burden (adjusted odds ratio [aOR], 25.38; 95% confidence interval [CI], 1.87-345.23) was associated with severe DMV scores. In addition, BG-PVS was related to severe DMV burden in a dose-dependent manner: when BG-PVS score was 3 and 4, the aORs of severe DMV burden were 18.5 and 12.19, respectively.ConclusionThe DMV impairment was associated with the severity of cSVD, which suggests that DMV burden may be used for risk stratification in SVO-AIS patients.Clinical relevance statementThe DMV damage score, based on the association between small vessel disease and the deep medullary veins impairment, is a potential new imaging biomarker for the prognosis of small vessel occlusion acute ischemic stroke, with clinical management implications.Key points• The damage to the deep medullary vein may be one mechanism of cerebral small vessel disease. • Severe burden of the basal ganglia perivascular space and cerebral microbleed is closely associated with significant impairment to the deep medullary vein. • The deep medullary vein damage score may reflect a risk of added vascular damage in small vessel occlusion acute ischemic stroke patients.

Project description:IntroductionCerebral small vessel disease (SVD) is one of the leading causes of stroke; each neuroimaging marker of SVD is correlated with vascular risk factors and associated with poor prognosis after stroke. However, longitudinal studies investigating the association between comprehensive SVD burden scoring system, "total SVD score" - which encompasses the established neuroimaging markers of lacunae, cerebral microbleeds (CMBs), white matter hyperintensities (WMH) including periventricular hyperintensities, and perivascular spaces in basal ganglia- and clinical outcomes are limited. The aim of this study is to determine the association between SVD burden and long-term prognosis in patients with ischemic stroke.Methods and designThis prospective, single-center, observational study enrolled patients with acute ischemic stroke, including cerebral infarction and transient ischemic attack. Magnetic resonance imaging scans were performed, and then total SVD score (range, 0-4) was calculated. We recorded baseline characteristics and evaluated the relationships of long-term outcomes to SVD neuroimaging markers and total SVD score. Stroke recurrence was thought as primary outcome. Hazard ratios (HRs) of events during follow-up were calculated using Cox proportional hazards modeling with adjustments for age, sex, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and smoking. Cumulative event rates were estimated using the Kaplan-Meier method.ResultsConsecutive 564 acute ischemic stroke patients were enrolled according to inclusion and exclusion criteria. A total of 467 participants with first-ever ischemic stroke were analyzed (median age 75.0 [interquartile range, 64.0-83.0] years, 59.3% male). Total SVD score was 0 point in 47 individuals (12.0%), 1 point in 83 (21.2%), 2 points in 103 (26.3%), 3 points in 85 (21.7%), and 4 points in 73 (18.7%). Twenty-eight recurrent stroke events were identified during follow-up. Total SVD score ≥ 2, presence of CMBs, and moderate-to-severe WMH were associated with increased risk of recurrent stroke events (HR 9.31, 95% confidence interval [CI] 2.33-64.23; HR 2.81, 95% CI 1.08-7.30; HR 2.90, 95% CI 1.22-6.88, respectively).ConclusionThe accumulation of SVD biomarkers as determined by total SVD score offered a reliable predictor of stroke recurrence. This study established a firm understanding of SVD prognosis in clinical settings.

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Tadalafil may improve cerebral perfusion in small-vessel occlusion stroke-a pilot study.

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Tadalafil may improve cerebral perfusion in small-vessel occlusion stroke-a pilot study.

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