Rheo-Erythrocrine Dysfunction as a Biomarker for RIC Treatment in Acute Ischemic Stroke

Grethe Andersen45 enrolled

Overview

This study aims to investigate whether Remote Ischemic Conditioning (RIC) improves rheo-erythrocrine dysfunction in acute ischemic stroke

Stroke is a leading cause of death and disability worldwide. Of all strokes, 85% are ischemic strokes caused by a thrombus or an embolus. The additional 15% are caused by hemorrhage. Currently the only approved treatments for ischemic strokes are thrombolysis given within 4.5 hours and thrombectomy performed within 6 hours of symptom onset - in some cases up to 24 hours. The majority of stroke patients are not however eligible for acute reperfusion therapy, mainly due to time constrains and late presentation. Novel neuroprotective strategies available for all stroke patients are thus urgently needed. Remote Ischemic Conditioning (RIC) is a simple intervention in which transient ischemia is induced in an extremity by repetitive inflation-deflation of a blood pressure cuff. It remains uncertain exactly how the protective effect of RIC is transmitted and communicated between the extremity and the brain. Both humoral, immunological and neuronal pathways seem to be involved. Treatment with RIC and has proven to be a safe, feasible and low-cost treatment in clinical settings. Biomarkers of the RIC treatment is a new area of stroke research and are important to establish in order to assess and predict responders of the conditioning treatment. Rheo-erythrocrine dysfunction of the Red Blood Cell (RBC) is a novel biomarker in both ischemic strokes in general and on the effect of RIC. Red Blood Cells with a diameter of 6-8 μm must be highly deformable in order to deliver oxygen to brain tissue by travelling through micro vessels with a diameter of just 2-3 μm. RBC's can carry nitric oxide as NO2-/s-nitrosylated proteins. These proteins improve RBC deformability and induce hypoxic vasodilation thereby improving passage through the microvasculature. RBC's also express Erythrocyte Nitric Oxide Synthase 3, which regulate the rheo-erythrocrine function. Erythrocyte Nitric Oxide Synthase 3 is activated by shear stress and provide an extra source of NO for hypoxic vasodilation. Preliminary data have shown that experimental stroke on mice seems to cause a rheo-erythrocrine dysfunction of the RBC's leading to a loss of deformability. The RBC's become rigid, which can lead to occlusion of micro vessels in the brain and further ischemic damage. Loss of deformability can be measured as a reduced Elongation Index (EI) by ektacytometry and may be attenuated by RIC.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Stroke, Acute Ischemic Stroke Cerebrovascular Disorders Central Nervous System Diseases

Interventions

Remote Ischemic ConditioningDEVICE

RIC is commonly achieved by inflation of a blood pressure cuff to induce 5-minute cycles of limb ischemia alternating with 5 minutes of reperfusion

Sham Remote Ischemic ConditioningDEVICE

Sham Comparator (Sham-RIC)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

STROKE PATIENTS Inclusion Criteria: * Onset to randomization \< 48 hours * Independent in daily living (mRS 0-2) * Legal competent * Ambulatory * Documented ischemic stroke on baseline MRI Exclusion Criteria: * Prior stroke, dementia or other known neurological condition Pregnancy * Contraindications to MRI * Investigators discretion * Known upper extremity peripheral arterial stenosis Diabetes CONTROLS Inclusion Criteria: * Independent in daily living (mRS 0-2) Ambulatory * Legal competent * Non vascular diagnosis (e.g. epilepsy, migraine etc.) Exclusion Criteria * Prior stroke, dementia or other known neurological condition * Pregnancy * Contraindications to MRI * Investigators discretion * Known upper extremity peripheral arterial stenosis Diabetes

Locations (1)

Aarhus University Hospital

Aarhus, Denmark

Outcomes

Primary Outcomes

RBC deformability will serve as a biomarker of the conditioning response and predictor of the clinical outcome in stroke patients.

RBC deformability is measured as Deformability or Elongation Index (DI or EI, Rheoscan AnD-300, RheoMeditech, South Chorea). A higher EI at the optimum viscosity (300 Osmolality) indicates highly deformable RBCs indicative of better microcirculation, while a lower EI indicates rigid RBC's. Briefly, 6 µL of heparinized or EDTA treated fresh blood is mixed with 600-µL of polyvinylpyrrolidone (PVP) solution (300 Osm) and transferred to a disposable kit. The kit is placed inside the laser-assisted ectacytometer for automated read out, data and image collection as per the vendor's instructions.

Time frame: 1 week

RBC deformability will serve as a biomarker of the conditioning response and predictor of the clinical outcome in stroke patients

For measurement of shear stress, 0,5 mL of heparinized or EDTA treated fresh blood is mixed with 600-µL of polyvinylpyrrolidone (PVP) solution (300 Osm) and transferred to a disposable kit. The kit is placed inside the laser-assisted ectacytometer for automated read out, data and image collection as per the vendor's instructions.

Time frame: 1 week

Secondary Outcomes

Nitric oxide quantification using DAF-FM-Diacetate flowcytometry as a biomarker of the conditioning response

Analytical flowcytometry with DAF-FM-Diacetate (4-Amino-5-Methylamino-2',7'-Difluorofluorescein Diacetate) on wholeblood samples

Time frame: 1 week

Nitric oxide quantification using DAF-FM-Diacetate flowcytometry as a predictor of the short term clinical outcome in stroke patients

Analytical flowcytometry with DAF-FM-Diacetate (4-Amino-5-Methylamino-2',7'-Difluorofluorescein Diacetate) on wholeblood samples

Time frame: 1 week

RBC deformability presentation across stroke subtypes

Data from ClinicalTrials.gov

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