Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial.

RATIONALE: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question. AIMS: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO. METHODS: This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial. STUDY OUTCOMES: Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted. SAMPLE SIZE: Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm. DISCUSSION: By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00.

Blood volume flow in the superficial temporal artery assessed by duplex sonography: predicting extracranial-intracranial bypass patency in moyamoya disease.

OBJECTIVE: Superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery is an important therapy for symptomatic moyamoya disease. Its success depends on bypass function, which may be impaired by primary or secondary bypass insufficiency. Catheter angiography is the current gold standard to assess bypass function, whereas the diagnostic value of ultrasonography (US) has not been systematically analyzed so far. METHODS: The authors analyzed 50 STA-MCA bypasses in 39 patients (age 45 ± 14 years [mean ± SD]; 26 female, 13 male). Bypass patency was evaluated by catheter angiography, which was performed within 24 hours after US. The collateral circulation through the bypass was classified into 4 types as follows: the bypass supplies more than two-thirds (type A); between one-third and two-thirds (type B); or less than one-third (type C) of the MCA territory; or there is bypass occlusion (type D). The authors assessed the mean blood flow velocity (BFV), the blood volume flow (BVF), and the pulsatility index (PI) in the external carotid artery and STA by duplex sonography. Additionally, they analyzed the flow direction of the MCA by transcranial color-coded sonography. US findings were compared between bypasses with higher (types A and B) and lower (types C and D) capacity. RESULTS: Catheter angiography revealed high STA-MCA bypass capacity in 35 cases (type A: n = 22, type B: n = 13), whereas low bypass capacity was noted in the remaining 15 cases (type C: n = 12, type D: n = 3). The BVF values in the STA were 60 ± 28 ml/min (range 4-121 ml/min) in the former and 12 ± 4 ml/min (range 6-18 ml/min) in the latter group (p < 0.0001). Corresponding values of mean BFV and PI were 57 ± 21 cm/sec (range 16-100 cm/sec) versus 22 ± 8 cm/sec (range 10-38 cm/sec) (p < 0.0001) and 0.8 ± 0.2 (range 0.4-1.3) versus 1.4 ± 0.5 (range 0.5-2.4) (p < 0.0001), respectively. Differences in the external carotid artery were less distinct: BVF 217 ± 71 ml/min (range 110-425 ml/min) versus 151 ± 41 ml/min (range 87-229 ml/min) (p = 0.001); mean BFV 47 ± 17 cm/sec (range 24-108 cm/sec) versus 40 ± 7 cm/sec (range 26-50 cm/sec) (p = 0.15); PI 1.5 ± 0.4 (range 1.0-2.5) versus 1.9 ± 0.4 (range 1.2-2.6) (p = 0.009). A retrograde blood flow in the MCA was found in 14 cases (9 in the M1 and M2 segment; 5 in the M2 segment alone), and all of them showed a good bypass function (type A, n = 10; type B, n = 4). The best parameter (cutoff value) to distinguish bypasses with higher capacity from bypasses with lower capacity was a BVF in the STA ≥ 21 ml/min (sensitivity 100%, negative predictive value 100%, specificity 91%, positive predictive value 83%). CONCLUSIONS: Duplex sonography is a suitable diagnostic tool to assess STA-MCA bypass function in moyamoya disease. Hemodynamic monitoring of the STA by US provides an excellent predictor of bypass patency.

Pattern of Activated Pathways and Quality of Collateral Status in Patients with Symptomatic Internal Carotid Artery Occlusion.

BACKGROUND: Internal carotid artery occlusion (ICAO) is an important risk factor for stroke. Cerebral hemodynamics in patients with ICAO depends on the individual capacity to activate sufficient collateral pathways. Therefore, the assessment of intracranial collaterals is essential for the acute and long-term management of these patients and accurate estimation of further stroke risk. METHODS: Acute stroke patients with unilateral ICAO were prospectively enrolled. We assessed the following collaterals by transcranial color-coded sonography (TCCS): the anterior and posterior communicating artery (ACoA, PCoA), the ophthalmic artery (OA), and leptomeningeal collaterals of the posterior cerebral artery (LMC). We subdivided the flow pattern of the Doppler spectrum in the middle cerebral artery (MCA) into 3 categories: (1) good, (2) moderate, and (3) bad according to the hemodynamic effects on the ipsilateral MCA flow. Finally, we compared the individual TCCS results with the stroke pattern detected on CT or MRI scan. RESULTS: One hundred thirteen patients (age 66 ± 12 years; -female 24) were included. The collateral status was good, moderate, and bad in 59 (52%), 37 (33%), and 17 (15%) patients, respectively. The ACoA collateral was most frequently activated (81%), followed by the OA (63%), the PCoA (53%), and the LMC (22%). The quality of the collateral status was determined by the type (p = 0.0003) but not by the number (p = 0.19) of activated collateral pathways. Good collateral function was highly associated with primary collaterals (ACoA > PCoA). Best parameter for a good collateral status was an antegrade flow in the OA, indicating a high blood supply via the communicating arteries. CONCLUSIONS: TCCS allows the assessment of intracranial collaterals and their hemodynamic capacity. Prevalence of collateral sufficiency in ICAO seems to be higher than previously reported. ACoA cross flow is essential for the optimal hemodynamic compensation of ICAO. Antegrade OA flow indicates good collateral status.

Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice.

In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.

Impact of AT2-receptor stimulation on vascular biology, kidney function, and blood pressure.

The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors within the renin-angiotensin system, which mediate tissue-protective actions such as anti-inflammation, antifibrosis, and antiapoptosis. In recent years, several programs have been launched in order to develop drugs that act as agonists on the AT2R or MAS to take therapeutic advantage of the protective and regenerative properties of these receptors. This review article will focus on recent data obtained in preclinical animal and in vitro models with new AT2R-agonistic molecules (Compound 21 and ß-amino acid substituted angiotensin II) and with relevance for blood pressure (BP) regulation or hypertensive end-organ damage. These data will include studies on vasodilation/vasoconstriction in isolated resistance arteries ex vivo, studies on kidney function, studies on vascular remodeling, and studies that measured the net effect of AT2R stimulation on BP in vivo. Current data indicate that although AT2R stimulation causes vasodilation ex vivo and promotes natriuresis, it does not alter BP levels in vivo acutely - at least as long as there is no additional low-dose blockade of AT1R. However, AT2R stimulation alone is able to attenuate hypertension-induced vascular remodeling and reduce arterial stiffening, which in more chronic settings and together with the natriuretic effect may result in modest lowering of BP. We conclude from these preclinical data that AT2R agonists are not suitable for antihypertensive monotherapy, but that this new future drug class may be beneficial in combination with established antihypertensives for the treatment of hypertension with improved protection from end-organ damage.