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Stroke and Vascular Neurology Oct 2023Stroke is the second-leading cause of death and the leading cause of disability in much of the world. In particular, China faces the greatest challenge from stroke,... (Review)
Review
Reperfusion and cytoprotective agents are a mutually beneficial pair in ischaemic stroke therapy: an overview of pathophysiology, pharmacological targets and candidate drugs focusing on excitotoxicity and free radical.
Stroke is the second-leading cause of death and the leading cause of disability in much of the world. In particular, China faces the greatest challenge from stroke, since the population is aged quickly. In decades of clinical trials, no neuroprotectant has had reproducible efficacy on primary clinical end points, because reperfusion is probably a necessity for neuroprotection to be clinically beneficial. Fortunately, the success of thrombolysis and endovascular thrombectomy has taken us into a reperfusion era of acute ischaemic stroke (AIS) therapy. Brain cytoprotective agents can prevent detrimental effects of ischaemia, and therefore 'freeze' ischaemic penumbra before reperfusion, extend the time window for reperfusion therapy. Because reperfusion often leads to reperfusion injury, including haemorrhagic transformation, brain oedema, infarct progression and neurological worsening, cytoprotective agents will enhance the efficacy and safety of reperfusion therapy by preventing or reducing reperfusion injuries. Therefore, reperfusion and cytoprotective agents are a mutually beneficial pair in AIS therapy. In this review, we outline critical pathophysiological events causing cell death within the penumbra after ischaemia or ischaemia/reperfusion in the acute phase of AIS, focusing on excitotoxicity and free radicals. We discuss key pharmacological targets for cytoprotective therapy and evaluate the recent advances of cytoprotective agents going through clinical trials, highlighting multitarget cytoprotective agents that intervene at multiple levels of the ischaemic and reperfusion cascade.
PubMed: 37832977
DOI: 10.1136/svn-2023-002671 -
EuroIntervention : Journal of EuroPCR... Nov 2023Reperfusion therapy is challenging in the elderly. Catheter-directed therapies are an alternative for higher-risk pulmonary embolism (PE) patients if systemic...
BACKGROUND
Reperfusion therapy is challenging in the elderly. Catheter-directed therapies are an alternative for higher-risk pulmonary embolism (PE) patients if systemic thrombolysis (ST) is contraindicated or has failed. Their safety has not been evaluated in specific vulnerable populations.
AIMS
We aimed to assess the safety of reperfusion therapies in elderly and frail patients in the real world.
METHODS
In the US Nationwide Inpatient Sample from 2016 to 2020, we identified hospitalisations of patients ≥65 years with PE and defined a frailty subgroup using the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnosis indicator. We investigated reperfusion therapies (ST, catheter-directed thrombolysis [CDT], catheter-based thrombectomy [CBT], surgical embolectomy [SE]) and their associated safety outcomes (overall and major bleeding).
RESULTS
Among 980,245 hospitalisations of patients ≥65 years with PE (28.0% frail), reperfusion therapies were used in 4.9% (17.6% among high-risk PE). ST utilisation remained stable, while the use of catheter-directed therapies increased from 1.7% in 2016 to 3.2% in 2020. Among all hospitalisations with reperfusion, CDT, compared to ST, was associated with reduced major bleeding (5.8% vs 12.2%, odds ratio [OR] 0.58, 95% confidence interval [CI]: 0.49-0.70); these results also applied to frail patients. CBT, compared to SE, was also associated with reduced major bleeding (11.0% vs 22.4%, OR 0.63, 95% CI: 0.43-0.91), but not among frail patients. These differences were particularly significant in patients with non-high-risk PE. Differences persisted for overall bleeding as well.
CONCLUSIONS
Catheter-directed therapies may be a safer alternative to classical reperfusion therapies for elderly and frail patients with PE requiring reperfusion treatment.
Topics: Humans; Aged; Thrombolytic Therapy; Fibrinolytic Agents; Frailty; Treatment Outcome; Pulmonary Embolism; Hemorrhage; Reperfusion
PubMed: 37767997
DOI: 10.4244/EIJ-D-23-00399 -
Annals of Clinical and Translational... Nov 2023This study aimed to investigate whether treatment with adjunct intravenous tirofiban is associated with improved outcomes following successful reperfusion in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study aimed to investigate whether treatment with adjunct intravenous tirofiban is associated with improved outcomes following successful reperfusion in patients with intracranial atherosclerotic stroke.
METHODS
Patients with intracranial large artery atherosclerotic (LAA) stroke and an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3 from the Effect of Intravenous Tirofiban versus Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke (RESCUE BT) trial were included. The primary outcome was the difference in proportion of independent functional outcome (modified Rankin score of 0-2 at 90 days). Safety outcomes included the rates of symptomatic intracranial hemorrhage (sICH) and 90-day mortality.
RESULTS
Among the 382 patients with intracranial LAA stroke and successful reperfusion, 175 patients (45.8%) were treated with intravenous tirofiban and 207 (54.2%) with placebo. The proportion of patients with independent functional outcome at 90 days was 54.3% (95 out of 175) with tirofiban and 44.0% (91 out of 207) with placebo (adjusted odds ratio [aOR], 1.58; 95% CI, 1.02-2.44; p = 0.04). Intravenous tirofiban was not significantly associated with an increased risk of sICH (12/175 [6.9%] vs. 11/207 [5.3%]; aOR, 1.41; 95% CI, 0.59-3.34; p = 0.44) or 90-day mortality (21/175 [12.0%] vs. 34/207 [16.4%]; aOR, 0.71; 95% CI, 0.38-1.31; p = 0.27).
INTERPRETATION
Among patients with acute intracranial LAA stroke and successful reperfusion following endovascular thrombectomy, adjunct intravenous tirofiban was associated with a higher rate of independent functional outcome, without higher rates of sICH or mortality. Confirmatory randomized trials in these patients are desirable.
Topics: Humans; Tirofiban; Fibrinolytic Agents; Brain Ischemia; Treatment Outcome; Stroke; Intracranial Hemorrhages; Arteries; Reperfusion
PubMed: 37649303
DOI: 10.1002/acn3.51891 -
Journal of Cardiovascular Development... Nov 2023Reperfusion therapy in the form of intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) has revolutionised the field of stroke medicine. Atrial... (Review)
Review
Reperfusion therapy in the form of intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) has revolutionised the field of stroke medicine. Atrial fibrillation (AF) patients constitute a major portion of the overall stroke population; however, the prevalence of AF amongst acute ischemic stroke (AIS) patients receiving reperfusion therapy remains unclear. Limitations in our understanding of prevalence in this group of patients are exacerbated by difficulties in appropriately diagnosing AF. Additionally, the benefits of reperfusion therapy are not consistent across all subgroups of AIS patients. More specifically, AIS patients with AF often tend to have poor prognoses despite treatment relative to those without AF. This article aims to present an overview of the diagnostic and therapeutic management of AF and how it mediates outcomes following stroke, most specifically in AIS patients treated with reperfusion therapy. We provide unique insights into AF prevalence and outcomes that could allow healthcare professionals to optimise the treatment and prognosis for AIS patients with AF. Specific indications on acute neurovascular management and secondary stroke prevention in AIS patients with AF are also discussed.
PubMed: 37998516
DOI: 10.3390/jcdd10110458 -
Free Radical Biology & Medicine Aug 2023Ischemia-reperfusion injury is a critical liver condition during hepatic transplantation, trauma, or shock. An ischemic deprivation of antioxidants and energy...
Ischemia-reperfusion injury is a critical liver condition during hepatic transplantation, trauma, or shock. An ischemic deprivation of antioxidants and energy characterizes liver injury in such cases. In the face of increased reactive oxygen production, hepatocytes are vulnerable to the reperfusion driving ROS generation and multiple cell-death mechanisms. In this study, we investigate the importance of hydrogen sulfide as part of the liver's antioxidant pool and the therapeutic potency of the hydrogen sulfide donors sodium sulfide (NaS, fast releasing) and sodium thiosulfate (STS, NaSO, slow releasing). The mitoprotection and toxicity of STS and NaS were investigated on isolated mitochondria and a liver perfusion oxidative stress model by adding text-butyl hydroperoxide and hydrogen sulfide donors. The respiratory capacity of mitochondria, hepatocellular released LDH, glutathione, and lipid-peroxide levels were quantified. In addition, wild-type and cystathionine-γ-lyase knockout mice were subjected to warm selective ischemia-reperfusion injury by clamping the main inflow for 1 h followed by reperfusion of 1 or 24 h. A subset of animals was treated with STS shortly before reperfusion. Glutathione, plasma ALT, and lipid-peroxide levels were investigated alongside mitochondrial changes in structure (electron microscopy) and function (intravital microscopy). Liver tissue necrosis quantified 24 h after reperfusion indicates the net effects of the treatment on the organ. STS refuels and protects the endogenous antioxidant pool during liver ischemia-reperfusion injury. In addition, STS-mediated ROS scavenging significantly reduced lipid peroxidation and mitochondrial damage, resulting in better molecular and histopathological preservation of the liver tissue architecture. STS prevents tissue damage in liver ischemia-reperfusion injury by increasing the liver's antioxidant pool, thereby protecting mitochondrial integrity.
Topics: Mice; Animals; Antioxidants; Hydrogen Sulfide; Reactive Oxygen Species; Chemical and Drug Induced Liver Injury, Chronic; Liver; Reperfusion Injury; Ischemia; Glutathione; Peroxides; Reperfusion; Lipids
PubMed: 37105418
DOI: 10.1016/j.freeradbiomed.2023.04.012 -
Redox Biology Nov 2023Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective...
Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective actions of extracellular adenosine against ischemia/reperfusion (I/R) are well-established, the role of cellular adenosine in protection against I/R remains unknown. Here we investigated the role of cellular adenosine in epigenetic regulation on cardiomyocyte gene expression, glucose metabolism and tolerance to I/R. Evans blue/TTC staining and echocardiography were used to assess the extent of I/R injury in mice. Glucose metabolism was evaluated by positron emission tomography and computed tomography (PET/CT). Methylated DNA immunoprecipitation (MeDIP) and bisulfite sequencing PCR (BSP) were used to evaluate DNA methylation. Lentiviral/adenovirus transduction was used to overexpress DNMT1, and the OSI-906 was administered to inhibit IGF-1. Cardiomyocyte-specific ADK/IGF-1-knockout mice were used for mechanistic experiments.Cardiomyocyte-specific ADK knockout enhanced glucose metabolism and ameliorated myocardial I/R injury in vivo. Mechanistically, ADK deletion caused cellular adenosine accumulation, decreased DNA methyltransferase 1 (DNMT1) expression and caused hypomethylation of multiple metabolic genes, including insulin growth factor 1 (IGF-1). DNMT1 overexpression abrogated these beneficial effects by enhancing apoptosis and decreasing IGF-1 expression. Inhibition of IGF-1 signaling with OSI-906 or genetic knocking down of IGF-1 also abrogated the cardioprotective effects of ADK knockout, revealing the therapeutic potential of increasing IGF-1 expression in attenuating myocardial I/R injury. In conclusion, the present study demonstrated that cardiomyocyte ADK deletion ameliorates myocardial I/R injury via epigenetic upregulation of IGF-1 expression via the cardiomyocyte adenosine/DNMT1/IGF-1 axis.
Topics: Mice; Animals; Myocytes, Cardiac; Epigenesis, Genetic; Adenosine; Insulin-Like Growth Factor I; Positron Emission Tomography Computed Tomography; Ischemia; Myocardial Reperfusion Injury; Mice, Knockout; Apoptosis; Reperfusion; DNA; Glucose
PubMed: 37725888
DOI: 10.1016/j.redox.2023.102884 -
Neurology International Aug 2023Atrial fibrillation (AF) significantly contributes to acute ischaemic stroke (AIS), yet its precise influence on clinical outcomes post-intravenous thrombolysis (IVT)...
Atrial fibrillation (AF) significantly contributes to acute ischaemic stroke (AIS), yet its precise influence on clinical outcomes post-intravenous thrombolysis (IVT) and post-endovascular thrombectomy (EVT) has remained elusive. Furthermore, the overall prevalence of AF in AIS patients undergoing reperfusion therapy has not been clearly determined. Employing random-effects meta-analyses, this research aimed to estimate the pooled prevalence of AF among AIS patients undergoing reperfusion therapy, while also examining the association between AF and clinical outcomes such as functional outcomes, symptomatic intracerebral haemorrhage (sICH) and mortality. Studies comparing AF and non-AF patient groups undergoing reperfusion therapy were identified and included following an extensive database search. Forty-nine studies (n = 66,887) were included. Among IVT patients, the prevalence of AF was 31% (Effect Size [ES] 0.31 [95%CI 0.28-0.35], < 0.01), while in EVT patients, it reached 42% (ES 0.42 [95%CI 0.38-0.46], < 0.01), and in bridging therapy (BT) patients, it stood at 36% (ES 0.36 [95%CI 0.28-0.43], < 0.01). AF was associated with significantly lower odds of favourable 90-day functional outcomes post IVT (Odds Ratio [OR] 0.512 [95%CI 0.376-0.696], < 0.001), but not post EVT (OR 0.826 [95%CI 0.651-1.049], = 0.117). Our comprehensive meta-analysis highlights the varying prevalence of AF among different reperfusion therapies and its differential impact on patient outcomes. The highest pooled prevalence of AF was observed in EVT patients, followed by BT and IVT patients. Interestingly, our analysis revealed that AF was significantly associated with poorer clinical outcomes following IVT. Such an association was not observed following EVT.
PubMed: 37755356
DOI: 10.3390/neurolint15030065 -
Cardiovascular Research Apr 2024Ischemia/reperfusion (I/R) injury is an important complication of reperfusion therapy for acute myocardial infarction, extremely compromising the cardiac benefits of...
AIMS
Ischemia/reperfusion (I/R) injury is an important complication of reperfusion therapy for acute myocardial infarction, extremely compromising the cardiac benefits of revascularization, however, specific and efficient treatment for cardiac I/R injury is still lacking. Isthmin-1 (ISM1) is a novel adipokine, and plays indispensable roles in regulating glycolipid metabolism and cell survival. The present study aims to investigate the potential role and molecular mechanism of ISM1 in cardiac I/R injury using gain- and loss-of-function approaches.
METHODS AND RESULTS
Cardiac-specific ISM1 overexpression and silence were achieved using an adeno-associated virus serotype 9 system, and then these mice were subjected to I/R surgery, followed by biochemical test, echocardiography and histopathologic examinations, etc. Meanwhile, neonatal rat cardiomyocytes (NRCMs) with ISM1 silence or overexpression also received simulated I/R (sI/R) injury to further verify its role in vitro. The potential downstream pathways and molecular targets of ISM1 were screened by RNA-sequencing. We also treated injured mice and NRCMs with recombinant ISM1 (rISM1) to explore whether supplementation with ISM1 was sufficient to protect against I/R injury. Furthermore, acute myocardial infarction patients with percutaneous coronary intervention (PCI) and paired healthy controls were included to reveal the clinical relevance of circulating ISM1. Cardiac-specific ISM1 silencing aggravated while ISM1 overexpression alleviated I/R-induced acute cardiac injury and cardiac remodeling and dysfunction. Mechanistically, ISM1 targeted αvβ5 integrin to facilitate the nuclear accumulation of nuclear transcription factor Y subunit alpha, transcriptionally increased soluble guanylyl cyclase beta subunit expression, and eventually enhanced cGMP generation. Besides, we confirmed that treatment with rISM1 before or after reperfusion could confer cardioprotective effects in mice. Clinically, lower ISM1 levels post-PCI was associated with worse outcome in patients.
CONCLUSION
ISM1 can protect against cardiac I/R injury through cGMP-PKG signaling pathway, and it is a promising therapeutic and predictive target of cardiac I/R injury.
PubMed: 38637328
DOI: 10.1093/cvr/cvae077 -
Cell Communication and Signaling : CCS Aug 2023Acute myocardial infarction has long been the leading cause of death in coronary heart disease, which is characterized by irreversible cardiomyocyte death and restricted... (Review)
Review
Acute myocardial infarction has long been the leading cause of death in coronary heart disease, which is characterized by irreversible cardiomyocyte death and restricted blood supply. Conventional reperfusion therapy can further aggravate myocardial injury. Stem cell therapy, especially with mesenchymal stem cells (MSCs), has emerged as a promising approach to promote cardiac repair and improve cardiac function. MSCs may induce these effects by secreting exosomes containing therapeutically active RNA, proteins and lipids. Notably, normal cardiac function depends on intracardiac paracrine signaling via exosomes, and exosomes secreted by cardiac cells can partially reflect changes in the heart during disease, so analyzing these vesicles may provide valuable insights into the pathology of myocardial infarction as well as guide the development of new treatments. The present review examines how exosomes produced by MSCs and cardiac cells may influence injury after myocardial infarction and serve as therapies against such injury. Video Abstract.
Topics: Humans; Exosomes; Apoptosis; Myocardial Infarction; Myocytes, Cardiac; Mesenchymal Stem Cells
PubMed: 37580705
DOI: 10.1186/s12964-023-01227-9 -
Cerebrovascular Diseases (Basel,... Mar 2024Traditionally, non-contrast computed tomography (CT) alone was used in the initial assessment of acute ischaemic stroke patients mainly to exclude haemorrhage or... (Review)
Review
BACKGROUND
Traditionally, non-contrast computed tomography (CT) alone was used in the initial assessment of acute ischaemic stroke patients mainly to exclude haemorrhage or alternative pathology.
SUMMARY
Late-window (beyond 6 hours) and recent large-volume endovascular mechanical thrombectomy (MT) trials integrated CT Perfusion (CTP) imaging to guide MT and/or intravenous thrombolysis (IVT) decision-making in stroke patients.
KEY MESSAGES
In current clinical practice, many patients are being excluded from reperfusion therapy due to a lack of data from urgent investigations to assess cerebral vasculature and perfusion. Here, we explore the potential benefits of CTP incorporated into the initial CT protocol assessment of stroke patients.
PubMed: 38508150
DOI: 10.1159/000537729