Fibrinolysis and Remote Ischemic Conditioning: Mechanisms and Treatment Perspectives in Stroke

2021 ◽  
Author(s):  
Andreas Engel Krag ◽  
Rolf Ankerlund Blauenfeldt
Keyword(s):  
Acute Stroke ◽  
Intravenous Thrombolysis ◽  
Vascular Lesions ◽  
Stroke Recurrence ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Neuroprotective Therapy ◽  
Prevention And Treatment ◽  
Endogenous Fibrinolysis

AbstractStroke is a leading cause of death and disability. Intravenous thrombolysis and mechanical thrombectomy have greatly improved outcomes in acute ischemic stroke (AIS). However, only a minority of patients receive reperfusion therapies, highlighting the need for novel neuroprotective therapies. Remote ischemic conditioning (RIC), consisting of brief, intermittent extremity occlusion and reperfusion induced with an inflatable cuff, is a potential neuroprotective therapy in acute stroke. The objective of this narrative review is to describe the effect of RIC on endogenous fibrinolysis and, from this perspective, investigate the potential of RIC in the prevention and treatment of stroke. A systematic literature search was performed in PubMed, and human studies in English were included. Seven studies had investigated the effect of RIC on fibrinolysis in humans. Long-term daily administration of RIC increased endogenous fibrinolysis, whereas a single RIC treatment did not acutely influence endogenous fibrinolysis. Fifteen studies had investigated the effect of RIC as a neuroprotective therapy in the prevention and treatment of stroke. Long-term RIC administration proved effective in reducing new cerebral vascular lesions in patients with established cerebrovascular disease. In patients with acute stroke, RIC was safe and feasible, though its clinical efficacy as a neuroprotectant is yet unproven. In conclusion, a single RIC treatment does not affect fibrinolysis in the acute phase, whereas long-term RIC administration may increase endogenous fibrinolysis. Increased endogenous fibrinolysis is unlikely to be the mediator of the acute neuroprotective effect of RIC in stroke patients, whereas it may partly explain the reduced stroke recurrence associated with long-term RIC treatment.

Long-term neurological, vascular, and mortality outcomes after stroke

2018 ◽  
Vol 13 (8) ◽  
pp. 787-796 ◽  
Author(s):  
Ravinder-Jeet Singh ◽  
Shuo Chen ◽  
Aravind Ganesh ◽  
Michael D Hill
Keyword(s):  
Acute Stroke ◽  
Recurrent Stroke ◽  
Intravenous Thrombolysis ◽  
Stroke Recurrence ◽  
Stroke Survivors ◽  
Acute Stroke Care ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Stroke Treatment

Background Despite improved survival and short-term (90-day) outcomes of ischemic stroke patients, only sparse data exist describing the sustained benefits of acute stroke care interventions and long-term prognosis of stroke survivors. Aim We review the contemporary literature assessing long-term (5 years or more) outcomes after stroke and acute stroke treatment. Summary of review Acute stroke unit care and intravenous thrombolysis have sustained benefits over longer follow-up, but few data exist on the long-term outcome after endovascular thrombectomy (EVT). A large proportion of stroke survivors face challenges of residual disability and neuropsychiatric sequelae (especially affective disorders and epilepsy) which affects their quality of life and is associated with poorer prognosis due to increase in stroke recurrences/mortality. Nearly, a quarter of stroke survivors have a recurrent stroke at 5 years, and nearly double that at 10 years. Mortality after recurrent stroke is high, and half of the stroke survivors are deceased at 5 years after stroke and three fourth at 10 years. Long-term all-cause mortality is largely due to conditions other than stroke. Both stroke recurrence and long-term mortality are affected by several modifiable risk factors, and thus amenable to secondary prevention strategies. Conclusions There is a need for studies reporting longer term effects of acute interventions, especially EVT. Better preventive strategies are warranted to reduce the vascular and non-vascular mortality long after stroke.

scholarly journals Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning

2018 ◽  
Vol 315 (1) ◽  
pp. H150-H158 ◽  
Author(s):  
Marie Hauerslev ◽  
Sivagowry Rasalingam Mørk ◽  
Kasper Pryds ◽  
Hussain Contractor ◽  
Jan Hansen ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Glyceryl Trinitrate ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rat Myocardium ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Human Endothelium

Remote ischemic conditioning (RIC) protects against sustained myocardial ischemia. Because of overlapping mechanisms, this protection may be altered by glyceryl trinitrate (GTN), which is commonly used in the treatment of patients with chronic ischemic heart disease. We investigated whether long-term GTN treatment modifies the protection by RIC in the rat myocardium and human endothelium. We studied infarct size (IS) in rat hearts subjected to global ischemia-reperfusion (I/R) in vitro and endothelial function in healthy volunteers subjected to I/R of the upper arm. In addition to allocated treatment, rats were coadministered with reactive oxygen species (ROS) or nitric oxide (NO) scavengers. Rats and humans were randomized to 1) control, 2) RIC, 3) GTN, and 4) GTN + RIC. In protocols 3 and 4, rats and humans underwent long-term GTN treatment for 7 consecutive days, applied subcutaneously or 2 h daily transdermally. In rats, RIC and long-term GTN treatment reduced mean IS (18 ± 12%, P = 0.007 and 15 ± 5%, P = 0.002) compared with control (35 ± 13%). RIC and long-term GTN treatment in combination did not reduce IS (29 ± 12%, P = 0.55 vs. control). ROS and NO scavengers both attenuated IS reduction by RIC and long-term GTN treatment. In humans, I/R reduced endothelial function ( P = 0.01 vs. baseline). Separately, RIC and long-term GTN prevented the reduction in endothelial function caused by I/R; given in combination, prevention was lost. RIC and long-term GTN treatment both protect against rat myocardial and human endothelial I/R injury through ROS and NO-dependent mechanisms. However, when given in combination, RIC and long-term GTN treatment fail to confer protection. NEW & NOTEWORTHY Remote ischemic conditioning (RIC) and long-term glyceryl trinitrate (GTN) treatment protect against ischemia-reperfusion injury in both human endothelium and rat myocardium. However, combined application of RIC and long-term GTN treatment abolishes the individual protective effects of RIC and GTN treatment on ischemia-reperfusion injury, suggesting an interaction of clinical importance.

Abstract MP56: Nitric Oxide-Therapy but Not Remote Ischemic Conditioning is Cerebroprotective in Stroke: A Study in Mouse Model of Endothelial Dysfunction and Hypertension

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Syed M Zaidi ◽  
Md Nasrul Hoda ◽  
Farid Ahmed ◽  
Heba Alkhatabi ◽  
Muhammed H Al Qahtani
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Statistical Significance ◽  
Intravenous Thrombolysis ◽  
Once Daily ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Stroke Models ◽  
Endogenous Protection ◽  
Endothelial Nitric Oxide

Background: Remote Ischemic Conditioning (RIC) was found effective in stroke models, likely via increased endothelial nitric oxide (NO); yet RIC failed to improve clinical outcomes ( NCT02342522 ; NCT02189928 ). We anticipated that comorbidities neutralize the benefits of RIC in stroke. Hypothesis: NO-therapy but not RIC is vasculoprotective in hypertensive stroke. Methods: Aged (18±1-mo old) S100A1-hets mutant (S100A +/- ) and wild-type (WT) mice were used. As needed, mice were treated with RIC, s-nitrosoglutathione (GSNO) reductase inhibitor (GRI; 5 mg/kg nebulized once daily for 2-wks), GSNO (100-ug/kg; nebulized once daily at 2h post-TES), and/or intravenous thrombolysis (IVT; 10mg/kg at 4h post-TES). Stroke and outcome measures were performed as mentioned below. Statistical significance was determined at P &lt 0.05. Results: S100A +/- compared to WT-type mice showed significantly higher mean arterial pressure (MAP) and lower plasma-NO, supporting a hypertensive phenotype with endothelial dysfunction in S100A +/- mice. In photothrombotic stroke (PTS), RIC significantly improved cerebral blood flow (CBF), behavior and reduced infarction in WT but not in S100A +/- mice at 48h. GRI in S100A +/- mice enhanced plasma NO, improved behavior and CBF, and reduced infarction significantly as compared to vehicle-treated S100A +/- at 48h post-PTS. RIC with GRI did not produce additive protection in S100A +/- mice at 48h post-PTS, demonstrating that the preservation of NO-pool with GRI protects against stroke, but RIC is not effective to enhance this endogenous protection in hypertensive mice. Moreover, GSNO nebulization but not RIC enhanced PbtO 2 , reduced BBB-leakage and brain hemoglobin (Hb)-content at 24h after thromboembolic stroke with and without IVT. Conclusions: NO-therapies but not RIC is effective in hypertensive stroke. RIC- and NO- therapies need further validation in comorbid stroke before embarking on the clinical trial.

Our Efforts for Ideal Stroke Prevention and Treatment in Japan

Stroke ◽  
2022 ◽  
Author(s):  
Takenori Yamaguchi
Keyword(s):  
Cardiovascular Disease ◽  
Primary Prevention ◽  
Acute Treatment ◽  
Low Dose ◽  
Dual Antiplatelet Therapy ◽  
Intravenous Thrombolysis ◽  
Short Review ◽  
Prevention And Treatment ◽  
Cardiovascular Center

In the present short review for the Sherman Award, Dr Yamaguchi introduces studies at the National Cerebral and Cardiovascular Center, Osaka, which included development of intravenous thrombolysis using low-dose alteplase that was officially approved in Japan, long-term dual antiplatelet therapy using cilostazol together with aspirin or clopidogrel, and others. He also discusses efforts to ensure the passage of the “Stroke and Cardiovascular Disease Control Act,” the aims of which are better primary prevention, better acute treatment, rehabilitation, and secondary prevention of stroke for people living in Japan.

Effect of long-term remote ischemic conditioning on inflammation and cardiac remodeling

2019 ◽  
Vol 53 (4) ◽  
pp. 183-191 ◽  
Author(s):  
Kasper Pryds ◽  
Michael Rahbek Schmidt ◽  
Mette Bjerre ◽  
Steffen Thiel ◽  
Jens Refsgaard ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning

scholarly journals Preventing Ischemic Cerebrovascular Events in High-Risk Patients With Non-disabling Ischemic Cerebrovascular Events Using Remote Ischemic Conditioning: A Single-Arm Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Shimeng Liu ◽  
Zongen Gao ◽  
Ran Meng ◽  
Haiqing Song ◽  
Tianping Tang ◽  
...  
Keyword(s):  
High Risk ◽  
Stroke Prevention ◽  
Stroke Recurrence ◽  
Large Sample Size ◽  
Cerebrovascular Event ◽  
Secondary Stroke Prevention ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Minor Ischemic Stroke ◽  
Cerebrovascular Events

Background: Secondary stroke prevention after a high-risk, non-disabling ischemic cerebrovascular event needs to be enhanced. The study was conducted to investigate whether remote ischemic conditioning (RIC) is effective in preventing recurrent ischemic events within 3 months.Methods: This was a four-center, single-arm, open-label Phase IIa futility trial (PICNIC-One Study). Adult patients (≥18 years of age) who had an acute minor ischemic stroke (AMIS) with a National Institutes of Health Stroke Scale score ≤ 3 or a transient ischemic attack (TIA) with moderate-to-high risk of stroke recurrence (ABCD score ≥ 4) within 14 days of symptom onset were recruited. Patients received RIC as adjunctive therapy to routine secondary stroke prevention regimen. RIC consisted of five cycles of 5-min inflation (200 mmHg) and 5-min deflation of cuffs (45 min) on bilateral upper limbs twice a day for 90 days.Results: A total of 285 patients met the study criteria, of which 167 provided signed informed consent and were enrolled. Data from 162 were analyzed with five subjects excluded. Recurrent AIS/TIA occurred in 6/162 (3.7%) patients within 3 months, with no occurrence of hemorrhagic stroke. The top three adverse events were upper limb pain (44/162, 27.2%), petechia (26/162, 16.0%), and heart palpitation (5/162, 3.1%). About 68 (42.0%) subjects completed ≥ 50% of 45-min RIC sessions.Conclusions: RIC is a safe add-on procedure and it has a potential benefit in reducing recurrent cerebrovascular events in patients with high-risk, non-disabling ischemic cerebrovascular events as the risk of stroke/TIA events is lower than expected; however, its compliance needs to be improved. Our study provides critical preliminary data to plan a large sample size, randomized controlled clinical study to systematically investigate the safety and efficacy of RIC in this population.

Comparison of outcome and interventional complication rate in patients with acute stroke treated with mechanical thrombectomy with and without bridging thrombolysis

2016 ◽  
Vol 9 (3) ◽  
pp. 229-233 ◽  
Author(s):  
Ralph Weber ◽  
Hannes Nordmeyer ◽  
Jeffrie Hadisurya ◽  
Markus Heddier ◽  
Michael Stauder ◽  
...  
Keyword(s):  
Acute Stroke ◽  
Functional Outcome ◽  
Mechanical Thrombectomy ◽  
Independent Predictor ◽  
Intravenous Thrombolysis ◽  
Favorable Outcome ◽  
Complication Rates ◽  
Modified Rankin Scale

BackgroundNo randomized trial has investigated the effect of mechanical thrombectomy (MT) alone in patients with acute stroke. There are conflicting results as to whether prior intravenous thrombolysis (IVT) facilitates subsequent MT, and data in patients treated with MT alone owing to contraindications to IVT are limited.ObjectiveTo compare consecutive patients treated with MT alone or with preceding IVT in a large tertiary neurointerventional center, with special emphasis on contraindications to IVT.MethodsRetrospective analysis of 283 consecutive patients with acute ischemic stroke treated with MT in a tertiary neurovascular center over 14 months. Data on characteristics of periprocedural times, recanalization rate, complications, and long-term functional outcome were collected prospectively.ResultsInformation on prior IVT and functional outcome was available in 250 patients. Mean (SD) follow-up period was 5.7 (5.1) months and 105 (42%) patients received both IVT and MT. No significant differences were found in successful recanalization rates (Thrombolysis in Cerebral Infarction (TICI) 2b/3, 73.8% vs 73.1, p=0.952), complication rates, and long-term favorable outcome (modified Rankin Scale 0–2, 35.2% vs 40%, p=0.444) between patients receiving MT plus IVT and those receiving MT alone. A favorable outcome in patients directly treated with MT alone who were eligible for IVT was achieved in 48.2%. Thrombectomy was safe and resulted in a favorable outcome in 32% of patients with absolute contraindications to IVT.ConclusionsPreceding use of IVT was not an independent predictor of favorable outcome in patients with acute stroke treated with MT and complication rates did not differ whether or not IVT was used. MT is safe and achieved a favorable outcome in one-third of patients with stroke ineligible for IVT.

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