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JAMA Apr 2020Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase. (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial.
IMPORTANCE
Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase.
OBJECTIVE
To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke.
DESIGN, SETTING, AND PARTICIPANTS
Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria.
INTERVENTIONS
Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy.
MAIN OUTCOMES AND MEASURES
The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death.
RESULTS
All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%]).
CONCLUSIONS AND RELEVANCE
Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03340493.
Topics: Aged; Aged, 80 and over; Brain Ischemia; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Reperfusion; Stroke; Tenecteplase; Thrombectomy; Treatment Outcome
PubMed: 32078683
DOI: 10.1001/jama.2020.1511 -
Annals of Medicine Dec 2023Excessive oxygen free radicals and toxic substances are generated in cerebral ischemia-reperfusion (I/R) process. Dexmedetomidine (DEX), a common anesthetic and sedative...
Excessive oxygen free radicals and toxic substances are generated in cerebral ischemia-reperfusion (I/R) process. Dexmedetomidine (DEX), a common anesthetic and sedative drug, can considerably boost glutathione (GSH), which has anti-copper influx effects. Focusing on cuproptosis, the mechanism of DEX in the I/R was revealed. Using the I/R rat model, the effects of DEX and the copper chelator D-penicillamine on cerebral infarct volume, copper levels, mitochondrial respiration and membrane potential, GSH content, and enrichment of cuproptosis functional proteins were examined. The involvement of ferredoxin 1 (FDX1) in the DEX regulatory pathway was verified by overexpressing FDX1 . DEX could significantly reduce cerebral infarction in rats, reduce copper levels, maintain mitochondrial functions, increase GSH, and reduce the content of key proteins related to cuproptosis. These aspects were replicated and revealed that FDX1 overexpression partially reversed the impacts of DEX. Together, cuproptosis occurs in the brain I/R process and DEX can enhance cell survival by blocking the primary pathway mediated by FDX1.KEY MESSAGESDexmedetomidine reduces cerebral infarction in the I/R rat models.Dexmedetomidine reduces cuproptosis in the I/R rat models.FDX1, an upstream of protein fatty acylation, mediates regulation of Dexmedetomidine.
Topics: Animals; Rats; Apoptosis; Brain Ischemia; Cerebral Infarction; Dexmedetomidine; Ferredoxins; Homeostasis; Reperfusion; Reperfusion Injury
PubMed: 37162502
DOI: 10.1080/07853890.2023.2209735 -
Pharmaceutical Biology Dec 2023Metformin (Met) has a protective effect against cardiac ischemia and reperfusion (I/R) injury.
CONTEXT
Metformin (Met) has a protective effect against cardiac ischemia and reperfusion (I/R) injury.
OBJECTIVE
This study uncovered the Met effect on ferroptosis in cardiac I/R.
MATERIALS AND METHODS
Sprague-Dawley rats underwent cardiac I/R treatment (ischaemia 30 min; reperfusion 24 h) (I/R group), and administered intravenously with Met (200 mg/kg) (I/R + Met group). Haematoxylin-eosin staining, Prussian blue staining, immunohistochemistry and transmission electron microscope were conducted on cardiac tissues. H9c2 cells underwent oxygen-glucose deprivation/reoxygenation (OGD/R group) and treated by Met (0.1 mM) (OGD/R + Met group). Adenosine monophosphate-activated protein kinase α (AMPKα) siRNA was transfected into OGD/R-induced H9c2 cells. Cell counting kit-8 (CCK-8) assay, dichloro-dihydro-fluorescein diacetate (DCFH-DA) and JC-1 staining were conducted on H9c2 cells. Ferroptosis-related indicators and gene expression were detected by enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot.
RESULTS
In cardiac I/R rat, Met decreased heart and serum MDA, cardiac and serum non-heme iron, and serum CK-MB and LDH (inhibition rate: 50.0%, 48.8%, 47.6%, 29.5%, 30.6% and 34.7%, respectively), relieved cardiac tissue ferroptosis and mitochondria damage, increased fraction shortening and ejection fraction (157.5% and 146.2% on day 28, respectively), up-regulated AMPKα and down-regulated NOX4 in cardiac tissues. In OGD/R-induced H9c2 cells, Met (0.1 mM) increased cell viability (promotion rate: 170.0%), decreased non-heme iron and MDA (inhibition rate: 30.1% and 47.9%, respectively), relieved ferroptosis, up-regulated AMPKα and down-regulated NOX4. AMPKα silencing abrogated these effects of Met on the OGD/R-induced H9c2 cells.
DISCUSSION AND CONCLUSIONS
Met shows effectiveness in relieving ferroptosis in cardiac I/R. In the future, Met may be an effective drug for relieving ferroptosis in cardiac I/R patients clinically.
Topics: Rats; Animals; Ferroptosis; Rats, Sprague-Dawley; Metformin; Cell Line; Apoptosis; Reperfusion Injury; Myocardial Ischemia; Ischemia; AMP-Activated Protein Kinases; Reperfusion; Iron; Myocytes, Cardiac
PubMed: 37288723
DOI: 10.1080/13880209.2023.2212700 -
Stroke and Vascular Neurology Feb 2024Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) was not inferior to alteplase for ischaemic stroke within 4.5 hours. Our study aimed to investigate... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) was not inferior to alteplase for ischaemic stroke within 4.5 hours. Our study aimed to investigate the efficacy and safety of rhTNK-tPA in patients who had an ischaemic stroke due to large vessel occlusion (LVO) of anterior circulation beyond 4.5 hours.
METHODS AND DESIGN
Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III (TRACE III) is a multicentre, prospective, randomised, open-label, blind endpoint, controlled clinical trial. Patients who had an ischaemic stroke due to anterior circulation LVO (internal carotid artery, middle cerebral artery M1 and M2 segments) within 4.5-24 hours from last known well (including wake-up stroke and no witness stroke) and with salvageable tissue (ischaemic core volume <70 mL, mismatch ratio ≥1.8 and mismatch volume ≥15 mL) based on CT perfusion or MRI perfusion-weighted imaging (PWI) were included and randomised to rhTNK-tPA 0.25 mg/kg (single bolus) to a maximum of 25 mg or standard medical therapy. Specially, we will exclude patients who are intended for direct thrombectomy. All will be followed up for 90 days.
STUDY OUTCOMES
Primary efficacy outcome is modified Rankin Scale (mRS) score ≤1 at 90 days. Secondary efficacy outcomes include ordinal distribution of mRS at 90 days, major neurological improvement defined by a decrease ≥8 points compared with the initial deficit or a score ≤1 on the National Institutes of Health Stroke Scale (NIHSS) at 72 hours, mRS score ≤2 at 90 days, the rate of improvement on Tmax >6 s at 24 hours and NIHSS score change from baseline at 7 days. Safety outcomes are symptomatic intracerebral haemorrhage within 36 hours and mortality at 90 days.
DISCUSSION
TRACE III will provide evidence for the efficacy and safety of rhTNK-tPA in patients who had an ischaemic strokes due to anterior circulation LVO beyond 4.5 hours.
TRIAL REGISTRATION NUMBER
NCT05141305.
Topics: United States; Humans; Tenecteplase; Fibrinolytic Agents; Stroke; Brain Ischemia; Prospective Studies; Treatment Outcome; Ischemic Stroke; Reperfusion
PubMed: 37247876
DOI: 10.1136/svn-2023-002310 -
Redox Biology Aug 2022Ischemic injury to the heart induces mitochondrial dysfunction due to increasing oxidative stress. MG53, also known as TRIM72, is highly expressed in striated muscle, is...
Ischemic injury to the heart induces mitochondrial dysfunction due to increasing oxidative stress. MG53, also known as TRIM72, is highly expressed in striated muscle, is secreted as a myokine after exercise, and is essential for repairing damaged plasma membrane of many tissues by interacting with the membrane lipid phosphatidylserine (PS). We hypothesized MG53 could preserve mitochondrial integrity after an ischemic event by binding to the mitochondrial-specific lipid, cardiolipin (CL), for mitochondria protection to prevent mitophagy. Fluorescent imaging and Western blotting experiments showed recombinant human MG53 (rhMG53) translocated to the mitochondria after ischemic injury in vivo and in vitro. Fluorescent imaging indicated rhMG53 treatment reduced superoxide generation in ex vivo and in vitro models. Lipid-binding assay indicated MG53 binds to CL. Transfecting cardiomyocytes with the mitochondria-targeted mt-mKeima showed inhibition of mitophagy after MG53 treatment. Overall, we show that rhMG53 treatment may preserve cardiac function by preserving mitochondria in cardiomyocytes. These findings suggest MG53's interactions with mitochondria could be an attractive avenue for developing MG53 as a targeted protein therapy for cardioprotection.
Topics: Carrier Proteins; Humans; Ischemia; Lipids; Mitochondria; Myocytes, Cardiac; Oxidative Stress; Reperfusion
PubMed: 35679798
DOI: 10.1016/j.redox.2022.102357 -
The Journal of Thoracic and... Jan 2022
Topics: Animals; Animals, Newborn; Biological Oxygen Demand Analysis; Brain; Cerebrovascular Circulation; Circulatory Arrest, Deep Hypothermia Induced; Hypothermia; Optical Imaging; Oxygen Consumption; Reperfusion; Reperfusion Injury; Spectroscopy, Near-Infrared; Swine
PubMed: 33485655
DOI: 10.1016/j.jtcvs.2020.12.017 -
Cardiovascular Research Jun 2023Recent studies have suggested a key role of intestinal microbiota in pathological progress of multiple organs via immune modulation. However, the interactions between...
AIMS
Recent studies have suggested a key role of intestinal microbiota in pathological progress of multiple organs via immune modulation. However, the interactions between heart and gut microbiota remain to be fully elucidated. The aim of the study is to investigate the role of gut microbiota in the post-ischaemia/reperfusion (I/R) inflammatory microenvironment.
METHODS AND RESULTS
Here, we conducted a case-control study to explore the association of gut bacteria translocation products with inflammation biomarkers and I/R injury severity in ST-elevation myocardial infarction patients. Then, we used a mouse model to determine the effects of myocardial I/R injury on gut microbiota dysbiosis and translocation. Blooming of Proteobacteria was identified as a hallmark of post-I/R dysbiosis, which was associated with gut bacteria translocation. Abrogation of gut bacteria translocation by antibiotic cocktail alleviated myocardial I/R injury via mitigating excessive inflammation and attenuating myeloid cells mobilization, indicating the bidirectional heart-gut-microbiome-immune axis in myocardial I/R injury. Glucagon-like peptide 2 (GLP-2), an endocrine peptide produced by intestinal L-cells, was used in the experimental myocardial I/R model. GLP-2 administration restored gut microbiota disorder and prevented bacteria translocation, eventually attenuated myocardial I/R injury through alleviating systemic inflammation.
CONCLUSION
Our work identifies a bidirectional communication along the heart-gut-microbiome-immune axis in myocardial I/R injury and demonstrates gut bacteria translocation as a key regulator in amplifying inflammatory injury. Furthermore, our study sheds new light on the application of GLP-2 as a promising therapy targeting gut bacteria translocation in myocardial I/R injury.
Topics: Mice; Animals; Gastrointestinal Microbiome; Myocardial Reperfusion Injury; Dysbiosis; Case-Control Studies; Inflammation; Myocardial Ischemia; Coronary Artery Disease; Heart Injuries; Ischemia; Reperfusion; Communication
PubMed: 36715640
DOI: 10.1093/cvr/cvad023 -
International Journal of Molecular... Feb 2023This Special Issue aims to summarize the most up-to-date research on ischemia-reperfusion and organ transplantation [...].
This Special Issue aims to summarize the most up-to-date research on ischemia-reperfusion and organ transplantation [...].
Topics: Humans; Reperfusion Injury; Organ Transplantation; Reperfusion
PubMed: 36834861
DOI: 10.3390/ijms24043450 -
The Journal of Thoracic and... Jun 2021
Topics: Cardiac Surgical Procedures; Heart Ventricles; Heart-Assist Devices; Humans; Myocardial Infarction; Myocardial Reperfusion; Reperfusion Injury; Ventricular Function, Left
PubMed: 32859423
DOI: 10.1016/j.jtcvs.2020.07.078 -
Cerebrovascular Diseases (Basel,... 2021The concept of the ischemic penumbra was defined over 40 years ago by Lindsay Symon and his group and is now an established principle of all acute ischemic stroke... (Review)
Review
The concept of the ischemic penumbra was defined over 40 years ago by Lindsay Symon and his group and is now an established principle of all acute ischemic stroke therapies. These reperfusion treatments rescue threatened, critically hypoperfused brain tissue and have been proven to improve clinical outcomes. We have been fortunate to have observed and played a small part in the penumbral story from its beginnings in the 1970s to its pivotal position today. Over this period, we have witnessed penumbral imaging evolve from positron emission tomography through to magnetic resonance imaging and now predominantly computed tomography perfusion, with the advent of automated imaging facilitating case selection for reperfusion therapies. We and others have conducted clinical trials using penumbral imaging to extend the time window for intravenous thrombolysis and select patients for thrombectomy. Together with the concept of fast- and slow-growing ischemic infarct patterns, this embeds the penumbral principle in everyday clinical management. The opportunity now exists to make penumbral imaging even more portable, affordable, and more widely available using mobile platforms, novel imaging techniques, digital linkage, and artificial intelligence.
Topics: Humans; Ischemic Stroke; Reperfusion
PubMed: 34736251
DOI: 10.1159/000519730