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Cardiovascular Drugs and Therapy Apr 2022The present study was to determine whether OP2113 could limit myocardial infarction size and the no-reflow phenomenon in a rat myocardial ischemia/reperfusion model.
PURPOSE
The present study was to determine whether OP2113 could limit myocardial infarction size and the no-reflow phenomenon in a rat myocardial ischemia/reperfusion model.
METHODS
Rat heart-isolated mitochondria (RHM) were used to investigate mitochondrial respiration and mitochondrial reactive oxygen species (mtROS) generation both in normal conditions and in ischemia/reperfusion-mimicking conditions (using high concentrations of succinate). Human skeletal muscle myoblasts (HSMM) in culture were used to investigate the cellular intermittent deprivation in energy substrates and oxygen as reported in ischemia/reperfusion conditions. In vivo, rats were anesthetized and subjected to 30 min of left coronary artery occlusion followed by 3 h of reperfusion. Rats were randomized to receive OP2113 as an intravenous infusion starting either 5 min prior to coronary artery occlusion (preventive), or 5 min prior to reperfusion (curative), or to receive vehicle starting 5 min prior to coronary artery occlusion. Infusions continued until the end of the study (3 h of reperfusion).
RESULTS
RHM treated with OP2113 showed a concentration-dependent reduction of succinate-induced mtROS generation. In HSMM cells, OP2113 treatment (5-10 μM) during 48H prevented the reduction in the steady-state level of ATP measured just after reperfusion injuries and decreased the mitochondrial affinity to oxygen. In vivo, myocardial infarct size, expressed as the percentage of the ischemic risk zone, was significantly lower in the OP2113-treated preventive group (44.5 ± 2.9%) versus that in the vehicle group (57.0 ± 3.6%; p < 0.05), with a non-significant trend toward a smaller infarct size in the curative group (50.8 ± 3.9%). The area of no reflow as a percentage of the risk zone was significantly smaller in both the OP2113-treated preventive (28.8 ± 2.4%; p = 0.026 vs vehicle) and curative groups (30.1 ± 2.3%; p = 0.04 vs vehicle) compared with the vehicle group (38.9 ± 3.1%). OP2113 was not associated with any hemodynamic changes.
CONCLUSIONS
These results suggest that OP2113 is a promising mitochondrial ROS-modulating agent to reduce no-reflow as well as to reduce myocardial infarct size, especially if it is on board early in the course of the infarction. It appears to have benefit on no-reflow even when administered relatively late in the course of ischemia.
Topics: Animals; Rats; Coronary Artery Disease; Coronary Circulation; Coronary Occlusion; Disease Models, Animal; Ischemia; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Oxygen; Succinates
PubMed: 33555510
DOI: 10.1007/s10557-020-07113-7 -
Cardiovascular Research May 2022Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the...
AIMS
Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury.
METHODS AND RESULTS
We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis.
CONCLUSION
Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.
Topics: Cathepsins; Humans; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Percutaneous Coronary Intervention; Reperfusion; ST Elevation Myocardial Infarction; Treatment Outcome
PubMed: 34132807
DOI: 10.1093/cvr/cvab204 -
Neurological Research Aug 2019The damage caused by ischemic stroke is mostly refractory to medical therapies and amounts to a substantial degree of mortality and morbidity in the world. The core... (Review)
Review
The damage caused by ischemic stroke is mostly refractory to medical therapies and amounts to a substantial degree of mortality and morbidity in the world. The core tenet of treatment for acute ischemic stroke (AIS) is to save 'reversible' ischemic tissue (ischemic penumbra) as quickly as possible within a limited therapeutic time window. The neuroprotective effect of hypothermia has been proven previously in a large number of animal experiments and clinical trials. Some of these animal and human studies have shown that pre-reperfusion hypothermia can reduce myocardial infarction and improve clinical outcomes. However, to date, there is little research about hypothermia before reperfusion in the animal model and human study of AIS. This review will explore possible benefits of the application of pre-reperfusion hypothermia in the setting of AIS.
Topics: Animals; Brain Ischemia; Humans; Hypothermia, Induced; Myocardial Reperfusion Injury; Stroke; Treatment Outcome
PubMed: 31030645
DOI: 10.1080/01616412.2019.1609160 -
Journal of Cardiovascular Pharmacology... Mar 2020Remote ischemic conditioning is the phenomenon whereby brief, nonlethal episodes of ischemia in one organ (such as a limb) protect a remote organ from ischemic necrosis... (Review)
Review
Remote ischemic conditioning is the phenomenon whereby brief, nonlethal episodes of ischemia in one organ (such as a limb) protect a remote organ from ischemic necrosis induced by a longer duration of severe ischemia followed by reperfusion. This phenomenon has been reproduced by dozens of experimental laboratories and was shown to reduce the size of myocardial infarction in many but not all clinical studies. In one recent large clinical trial, remote ischemic conditioning induced by repetitive blood pressure cuff inflations on the arm did not reduce infarct size or improve clinical outcomes. This negative result may have been related in part to the overall success of early reperfusion and current adjunctive therapies, such as antiplatelet therapy, antiremodeling therapies, and low-risk patients, that may make it difficult to show any advantage of newer adjunctive therapies on top of existing therapies. One relevant area in which current outcomes are not as positive as in the treatment of heart attack is the treatment of shock, where mortality rates remain high. Recent experimental studies show that remote ischemic conditioning may improve survival and organ function in shock states, especially hemorrhagic shock and septic shock. In this study, we review the preclinical studies that have explored the potential benefit of this therapy for shock states and describe an ongoing clinical study.
Topics: Animals; Humans; Ischemic Preconditioning; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Recovery of Function; Risk Factors; Shock, Cardiogenic; Shock, Hemorrhagic; Treatment Outcome
PubMed: 31823646
DOI: 10.1177/1074248419892603 -
Life Sciences Apr 2021Cardiac tissue ischemia/hypoxia increases glycolysis and lactic acid accumulation in cardiomyocytes, leading to intracellular metabolic acidosis. Sodium bicarbonate... (Review)
Review
Cardiac tissue ischemia/hypoxia increases glycolysis and lactic acid accumulation in cardiomyocytes, leading to intracellular metabolic acidosis. Sodium bicarbonate cotransporters (NBCs) play a vital role in modulating intracellular pH and maintaining sodium ion concentrations in cardiomyocytes. Cardiomyocytes mainly express electrogenic sodium bicarbonate cotransporter (NBCe1), which has been demonstrated to participate in myocardial ischemia/reperfusion (I/R) injury. This review outlines the structural and functional properties of NBCe1, summarizes the signaling pathways and factors that may regulate the activity of NBCe1, and reviews the roles of NBCe1 in the pathogenesis of I/R-induced cardiac diseases. Further studies revealing the regulatory mechanisms of NBCe1 activity should provide novel therapeutic targets for preventing I/R-induced cardiac diseases.
Topics: Acidosis; Animals; Astrocytes; Bicarbonates; Coronary Artery Disease; Heart; Heart Diseases; Humans; Ischemia; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocytes, Cardiac; Reperfusion Injury; Sodium; Sodium-Bicarbonate Symporters
PubMed: 33539911
DOI: 10.1016/j.lfs.2021.119153 -
European Heart Journal Nov 2021The aim of this study was to determine the contemporary use of reperfusion therapy in the European Society of Cardiology (ESC) member and affiliated countries and...
AIMS
The aim of this study was to determine the contemporary use of reperfusion therapy in the European Society of Cardiology (ESC) member and affiliated countries and adherence to ESC clinical practice guidelines in patients with ST-elevation myocardial infarction (STEMI).
METHODS AND RESULTS
Prospective cohort (EURObservational Research Programme STEMI Registry) of hospitalized STEMI patients with symptom onset <24 h in 196 centres across 29 countries. A total of 11 462 patients were enrolled, for whom primary percutaneous coronary intervention (PCI) (total cohort frequency: 72.2%, country frequency range 0-100%), fibrinolysis (18.8%; 0-100%), and no reperfusion therapy (9.0%; 0-75%) were performed. Corresponding in-hospital mortality rates from any cause were 3.1%, 4.4%, and 14.1% and overall mortality was 4.4% (country range 2.5-5.9%). Achievement of quality indicators for reperfusion was reported for 92.7% (region range 84.8-97.5%) for the performance of reperfusion therapy of all patients with STEMI <12 h and 54.4% (region range 37.1-70.1%) for timely reperfusion.
CONCLUSIONS
The use of reperfusion therapy for STEMI in the ESC member and affiliated countries was high. Primary PCI was the most frequently used treatment and associated total in-hospital mortality was below 5%. However, there was geographic variation in the use of primary PCI, which was associated with differences in in-hospital mortality.
Topics: Cardiology; Europe; Hospitals; Humans; Myocardial Reperfusion; Percutaneous Coronary Intervention; Prospective Studies; Registries; ST Elevation Myocardial Infarction; Treatment Outcome
PubMed: 34389857
DOI: 10.1093/eurheartj/ehab342 -
Trends in Cardiovascular Medicine Nov 2020Acute myocardial infarction (MI) is a major cause of death worldwide. Although timely and successful reperfusion could reduce myocardial ischemia injury, limit infarct... (Review)
Review
Acute myocardial infarction (MI) is a major cause of death worldwide. Although timely and successful reperfusion could reduce myocardial ischemia injury, limit infarct size, and improve ventricular dysfunction and reduce acute mortality, restoring blood flow might also lead to unwanted myocardial ischemic-reperfusion (I/R) injury. Pre-clinical studies have demonstrated that multiple approaches are capable of attenuating the myocardial I/R injury. However, there is still no effective therapy for preventing myocardial I/R injury for the clinical setting. It is known that myocardial I/R injury could induce cardiac autonomic imbalance with over-activated sympathetic tone and reduced vagal activity, in turn, contributing to pathogenesis of myocardial I/R injury. Cumulative evidence shows that the enhancement of vagal activity, so called vagus nerve stimulation (VNS), is able to reduce injury and promote recovery of injured myocardium. Therefore, VNS might be a potentially novel strategy choice for preventing/attenuating myocardial I/R injury. In this review, we describe the protective role of VNS in myocardial I/R injury and related potential mechanisms. Then, we discuss the challenge and the opportunity of VNS in the treatment of acute myocardial I/R injury.
Topics: Animals; Apoptosis; Heart; Humans; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress; Treatment Outcome; Vagus Nerve; Vagus Nerve Stimulation
PubMed: 31740206
DOI: 10.1016/j.tcm.2019.10.011 -
Molecules (Basel, Switzerland) Apr 2022Ischemia-reperfusion myocardial damage is a paradoxical tissue injury occurring during percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI)... (Review)
Review
Ischemia-reperfusion myocardial damage is a paradoxical tissue injury occurring during percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) patients. Although this damage could account for up to 50% of the final infarct size, there has been no available pharmacological treatment until now. Oxidative stress contributes to the underlying production mechanism, exerting the most marked injury during the early onset of reperfusion. So far, antioxidants have been shown to protect the AMI patients undergoing PCI to mitigate these detrimental effects; however, no clinical trials to date have shown any significant infarct size reduction. Therefore, it is worthwhile to consider multitarget antioxidant therapies targeting multifactorial AMI. Indeed, this clinical setting involves injurious effects derived from oxygen deprivation, intracellular pH changes and increased concentration of cytosolic Ca and reactive oxygen species, among others. Thus, we will review a brief overview of the pathological cascades involved in ischemia-reperfusion injury and the potential therapeutic effects based on preclinical studies involving a combination of antioxidants, with particular reference to resveratrol and quercetin, which could contribute to cardioprotection against ischemia-reperfusion injury in myocardial tissue. We will also highlight the upcoming perspectives of these antioxidants for designing future studies.
Topics: Antioxidants; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Percutaneous Coronary Intervention; Quercetin; Reperfusion Injury; Resveratrol
PubMed: 35458766
DOI: 10.3390/molecules27082564 -
Biomedicine & Pharmacotherapy =... May 2024Propofol, a commonly used intravenous anesthetic, has demonstrated potential in protecting against myocardial ischemia/reperfusion injury (MIRI) based on preclinical... (Meta-Analysis)
Meta-Analysis Review
Propofol, a commonly used intravenous anesthetic, has demonstrated potential in protecting against myocardial ischemia/reperfusion injury (MIRI) based on preclinical animal studies. However, the clinical benefits of propofol in this context are subject to debate. We conducted a systematic search across eight databases to identify all relevant animal studies investigating the preventive effects of propofol on MIRI until October 30, 2023. We assessed the methodological quality of the included studies using SYRCLE's bias risk tool. Statistical analysis was performed using STATA 15.1. The primary outcome measures analyzed in this study were myocardial infarct size (IS) and myocardial injury biomarkers. This study presents a comprehensive analysis of 48 relevant animal studies investigating propofol's preventive effects on MIRI. Propofol administration demonstrated a reduction in myocardial IS and decreased levels of myocardial injury biomarkers (CK-MB, LDH, cTnI). Moreover, propofol improved myocardial function parameters (+dp/dtmax, -dP/dtmax, LVEF, LVFS), exhibited favorable effects on inflammatory markers (IL-6, TNF-α) and oxidative stress markers (SOD, MDA), and reduced myocardial cell apoptotic index (AI). These findings suggest propofol exerts cardioprotective effects by reducing myocardial injury, decreasing infarct size, and improving heart function. However, the absence of animal models that accurately represent comorbidities such as aging and hypertension, as well as inconsistent administration methods that align with clinical practice, may hinder its clinical translation. Further robust investigations are required to validate these findings, elucidate the underlying mechanisms of propofol, and facilitate its potential translation into clinical practice.
Topics: Propofol; Animals; Myocardial Infarction; Myocardial Reperfusion Injury; Oxidative Stress; Biomarkers; Anesthetics, Intravenous; Humans; Apoptosis
PubMed: 38640712
DOI: 10.1016/j.biopha.2024.116629 -
Biomedicine & Pharmacotherapy =... Jun 2024Ischemic heart disease invariably leads to devastating damage to human health. Nicotinamide ribose (NR), as one of the precursors of NAD synthesis, has been discovered...
Ischemic heart disease invariably leads to devastating damage to human health. Nicotinamide ribose (NR), as one of the precursors of NAD synthesis, has been discovered to exert a protective role in various neurological and cardiovascular disorders. Our findings demonstrated that pretreatment with 200 mg/kg NR for 3 h significantly reduced myocardial infarct area, decreased levels of CK-MB and LDH in serum, and improved cardiac function in the rats during myocardial ischemia-reperfusion (I/R) injury. Meanwhile, 0.5 mM NR also effectively increased the viability and decreased the LDH release of H9c2 cells during OGD/R. We had provided evidence that NR pretreatment could decrease mitochondrial reactive oxygen species (mtROS) production and MDA content, and enhance SOD activity, thereby mitigating mitochondrial damage and inhibiting apoptosis during myocardial I/R injury. Further investigations revealed that NR increased NAD content and upregulated SIRT3 protein expression in myocardium. Through using of SIRT3 small interfering RNA and the SIRT3 deacetylase activity inhibitor 3-TYP, we had confirmed that the cardioprotective effect of NR on cardiomyocytes was largely dependent on the inhibition of mitochondrial oxidative stress via SIRT3-SOD2 axis. Overall, our study suggested that exogenous supplementation with NR mitigated mitochondrial damage and inhibited apoptosis during myocardial I/R injury by reducing mitochondrial oxidative stress via SIRT3-SOD2-mtROS pathway.
Topics: Animals; Myocardial Reperfusion Injury; Sirtuin 3; Signal Transduction; Male; Niacinamide; Superoxide Dismutase; Rats, Sprague-Dawley; Rats; Apoptosis; Oxidative Stress; Pyridinium Compounds; Myocytes, Cardiac; Reactive Oxygen Species; Cell Line; Cardiotonic Agents; Sirtuins
PubMed: 38703508
DOI: 10.1016/j.biopha.2024.116689