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JACC. Heart Failure Jun 2024As a result of the widespread use of reperfusion therapies and secondary prevention over the last 30 years, there has been a dramatic reduction in the risk of mortality... (Review)
Review
As a result of the widespread use of reperfusion therapies and secondary prevention over the last 30 years, there has been a dramatic reduction in the risk of mortality and development of heart failure (HF) following acute myocardial infarction (MI). Despite this, the development of chronic HF remains a common occurrence in the days, months, and years following MI. Neurohormonal inhibition remains the mainstay of pharmacologic prevention of HF following MI, with recent trials showing an additive benefit of a neprilysin inhibitor or a sodium glucose co-transporter 2 inhibitor in reducing the risk of development of HF but no significant effect on mortality. Novel imaging tools may help refine risk stratification in high-risk patients and allow greater targeting of preventative therapies in patients most likely to benefit. Research is ongoing into novel therapies aiming to minimize the degree of myocardial damage and prevention of progressive adverse remodeling following MI.
PubMed: 38878010
DOI: 10.1016/j.jchf.2024.04.025 -
Frontiers in Pharmacology 2024Ischemic heart disease, associated with high morbidity and mortality, represents a major challenge for the development of drug-based strategies to improve its prognosis.... (Review)
Review
Re-evaluation of the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria.
Ischemic heart disease, associated with high morbidity and mortality, represents a major challenge for the development of drug-based strategies to improve its prognosis. Results of pre-clinical studies suggest that agonists of cannabinoid CB receptors and multitarget cannabidiol might be potential cardioprotective strategies against ischemia-reperfusion injury. The aim of our study was to re-evaluate the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria published recently by the European Union (EU) CARDIOPROTECTION COST ACTION. To meet the minimum criteria of those guidelines, experiments should be performed (i) on healthy small animals subjected to ischemia with reperfusion lasting for at least 2 hours and (ii) confirmed in small animals with comorbidities and co-medications and (iii) in large animals. Our analysis revealed that the publications regarding cardioprotective effects of CB receptor agonists and cannabidiol did not meet all three strict steps of IMPACT. Thus, additional experiments are needed to confirm the cardioprotective activities of (endo)cannabinoids mainly on small animals with comorbidities and on large animals. Moreover, our publication underlines the significance of the IMPACT criteria for a proper planning of preclinical experiments regarding cardiac ischemia-reperfusion injury.
PubMed: 38873412
DOI: 10.3389/fphar.2024.1382995 -
Biomedicine & Pharmacotherapy =... Jul 2024Echinops plants have received great attention for the treatment of many diseases due to pharmacological properties such as their antidiabetic, antioxidant, and...
Cardioprotective effects of the aqueous extract of Echinops cephalotes on myocardial ischemia-reperfusion in rats by modulation of MMP-2, MMP-9, TIMP, and oxidative stress.
Echinops plants have received great attention for the treatment of many diseases due to pharmacological properties such as their antidiabetic, antioxidant, and anti-inflammatory characteristics. The major purpose of the present study was to investigate the cardioprotective benefits of Echinops cephalotes (Ech) against myocardial ischemia-reperfusion (MI/R) injury. Male Wistar rats were randomly allocated to three groups: sham, MI, and MI + Ech. The left coronary artery (LAD) was blocked for 30 minutes to induce MI. In the treatment group, rats were given 150 mg/kg/day of Ech extract for 28 days. Aqueous extracts were made from Echinops plants. To study heart function, fibrosis, cardiac damage indicators, and oxidative stress factors, echocardiography, Masson's trichrome staining, and biochemical tests were used. The expression of matrix metalloproteinase 2 and 9 (MMP2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP) was determined using Western blotting. Tissue damage was assessed using hematoxylin and eosin staining. MI group exhibited significantly reduced ejection fraction (EF) and fractional shortening (FS), enhanced levels of lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), cardiac Troponin I (cTnI), and malondialdehyde (MDA), as well as a decrease in the Glutathione (GSH) tissue content, reduced activity of superoxide dismutase (SOD), increasing fibrosis, upregulations of MMP-2 and MMP-9, and reduction of TIMP compared to the sham group. The findings suggest that Ech in particular, could be a promising therapeutic agent to reduce the damage in MI by targeting oxidative stress and modulating the activities of matrix metalloproteinases and their tissue inhibitors.
Topics: Animals; Male; Oxidative Stress; Rats, Wistar; Matrix Metalloproteinase 2; Plant Extracts; Matrix Metalloproteinase 9; Myocardial Reperfusion Injury; Cardiotonic Agents; Rats; Myocardium; Tissue Inhibitor of Metalloproteinases; Fibrosis; Water; Antioxidants
PubMed: 38870633
DOI: 10.1016/j.biopha.2024.116927 -
Cardiovascular Drugs and Therapy Jun 2024Cardiovascular disease remains the leading cause of death worldwide. Dexmedetomidine is a highly selective α2 adrenergic receptor agonist with sedative, analgesic,... (Review)
Review
PURPOSE
Cardiovascular disease remains the leading cause of death worldwide. Dexmedetomidine is a highly selective α2 adrenergic receptor agonist with sedative, analgesic, anxiolytic, and sympatholytic properties, and several studies have shown its possible protective effects in cardiac injury. The aim of this review is to further elucidate the underlying cardioprotective mechanisms of dexmedetomidine, thus suggesting its potential in the clinical management of cardiac injury.
RESULTS AND CONCLUSION
Our review summarizes the findings related to the involvement of dexmedetomidine in cardiac injury and discusses the results in the light of different mechanisms. We found that numerous mechanisms may contribute to the cardioprotective effects of dexmedetomidine, including the regulation of programmed cell death, autophagy and fibrosis, alleviation of inflammatory response, endothelial dysfunction and microcirculatory derangements, improvement of mitochondrial dysregulation, hemodynamics, and arrhythmias. Dexmedetomidine may play a promising and beneficial role in the treatment of cardiovascular disease.
PubMed: 38869744
DOI: 10.1007/s10557-024-07579-9 -
Cureus May 2024Left ventricular thrombus is a major complication following myocardial infarction, particularly in patients with anterior myocardial infarction or dilated...
Left ventricular thrombus is a major complication following myocardial infarction, particularly in patients with anterior myocardial infarction or dilated cardiomyopathies regardless of coronary reperfusion therapy. Embolization of mural thrombus is one of the major causes of large vessel occlusion ischemic stroke. A combination therapy of antiplatelet (single or dual antiplatelet) and anticoagulant is mandatory in the management of myocardial infarction and left ventricular thrombus with or without stroke. To our knowledge, there are no guidelines on the optimal regimen (dual or triple therapies) and timing of administration in cases of cardio-cerebral infarction. It is difficult for clinicians to balance the risks of intracranial hemorrhage and coronary stent thrombosis. Here, we describe the case of a gentleman who had recently undergone coronary intervention and presented with ischemic stroke and left ventricular thrombus, along with the management challenges in this scenario.
PubMed: 38868266
DOI: 10.7759/cureus.60196 -
Cardiovascular Diabetology Jun 2024The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune...
Y4 RNA fragments from cardiosphere-derived cells ameliorate diabetic myocardial ischemia‒reperfusion injury by inhibiting protein kinase C β-mediated macrophage polarization.
The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune and inflammatory cells, potentially driven by abnormalities in their number and function due to diabetes, may play a significant role. In the present investigation, we simulated myocardial I/R injury by inducing ischemia through ligation of the left anterior descending coronary artery in mice for 40 min, followed by reperfusion for 24 h. Previous studies have indicated that protein kinase Cβ (PKCβ) is upregulated under hyperglycemic conditions and is implicated in the development of various diabetic complications. The Y4 RNA fragment is identified as the predominant small RNA component present in the extracellular vesicles of cardio sphere-derived cells (CDCs), exhibiting notable anti-inflammatory properties in the contexts of myocardial infarction and cardiac hypertrophy. Our investigation revealed that the administration of Y4 RNA into the ventricular cavity of db/db mice following myocardial I/R injury markedly enhanced cardiac function. Furthermore, Y4 RNA was observed to facilitate M2 macrophage polarization and interleukin-10 secretion through the suppression of PKCβ activation. The mechanism by which Y4 RNA affects PKCβ by regulating macrophage activation within the inflammatory environment involves the inhibition of ERK1/2 phosphorylation In our study, the role of PKCβ in regulating macrophage polarization during myocardial I/R injury was investigated through the use of PKCβ knockout mice. Our findings indicate that PKCβ plays a crucial role in modulating the inflammatory response associated with macrophage activation in db/db mice experiencing myocardial I/R, with a notable exacerbation of this response observed upon significant upregulation of PKCβ expression. In vitro studies further elucidated the protective mechanism by which Y4 RNA modulates the PKCβ/ERK1/2 signaling pathway to induce M2 macrophage activation. Overall, our findings suggest that Y4 RNA plays an anti-inflammatory role in diabetic I/R injury, suggesting a novel therapeutic approach for managing myocardial I/R injury in diabetic individuals.
Topics: Animals; Protein Kinase C beta; Myocardial Reperfusion Injury; Macrophages; Disease Models, Animal; Male; Mice, Inbred C57BL; Signal Transduction; Interleukin-10; Mice; Diabetic Cardiomyopathies; Cells, Cultured; Phenotype; Myocytes, Cardiac; Mitogen-Activated Protein Kinase 3; Macrophage Activation; Mitogen-Activated Protein Kinase 1; Ventricular Function, Left; Phosphorylation
PubMed: 38867293
DOI: 10.1186/s12933-024-02247-6 -
Cardiovascular Drugs and Therapy Jun 2024Coronary artery bypass grafting (CABG) on cardiopulmonary bypass (CPB) is associated with myocardial ischemia-reperfusion injury (IRI), which may limit the benefit of...
PURPOSE
Coronary artery bypass grafting (CABG) on cardiopulmonary bypass (CPB) is associated with myocardial ischemia-reperfusion injury (IRI), which may limit the benefit of the surgery. Both experimental and clinical studies suggest that Intralipid, a lipid emulsion commonly used for parenteral nutrition, can limit myocardial IRI. We therefore aimed to investigate whether Intralipid administered at reperfusion can reduce myocardial IRI in patients undergoing CABG on CPB.
METHODS
We conducted a randomized, double-blind, pilot trial in which 29 adult patients scheduled for CABG were randomly assigned (on a 1:1 basis) to receive either 1.5 ml/kg Intralipid 20% or Ringer's Lactate 3 min before aortic cross unclamping. The primary endpoint was the 72-h area under the curve (AUC) for troponin I.
RESULTS
Of the 29 patients randomized, 26 were included in the study (two withdrew consent and one was excluded before surgery). The 72-h AUC for troponin I did not significantly differ between the control and Intralipid group (546437 ± 205518 versus 487561 ± 115724 arbitrary units, respectively; P = 0.804). Other outcomes (including 72-h AUC for CK-MB, C-reactive protein, need for defibrillation, time to extubation, length of ICU and hospital stay, and serious adverse events) were similar between the two groups.
CONCLUSION
In patients undergoing CABG on CPB, Intralipid did not limit myocardial IRI compared to placebo.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02807727 (registration date: 16 June 2016).
PubMed: 38864969
DOI: 10.1007/s10557-024-07594-w -
Basic Research in Cardiology Jun 2024The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH)...
The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson's trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.
PubMed: 38864895
DOI: 10.1007/s00395-024-01063-z -
Molecular Medicine (Cambridge, Mass.) Jun 2024Programmed cell death is an important mechanism for the development of hepatic ischemia and reperfusion (IR) injury, and multiple novel forms of programmed cell death...
BACKGROUND
Programmed cell death is an important mechanism for the development of hepatic ischemia and reperfusion (IR) injury, and multiple novel forms of programmed cell death are involved in the pathological process of hepatic IR. ERRFI1 is involved in the regulation of cell apoptosis in myocardial IR. However, the function of ERRFI1 in hepatic IR injury and its modulation of programmed cell death remain largely unknown.
METHODS
Here, we performed functional and molecular mechanism studies in hepatocyte-specific knockout mice and ERRFI1-silenced hepatocytes to investigate the significance of ERRFI1 in hepatic IR injury. The histological severity of livers, enzyme activities, hepatocyte apoptosis and ferroptosis were determined.
RESULTS
ERRFI1 expression increased in liver tissues from mice with IR injury and hepatocytes under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Hepatocyte-specific ERRFI1 knockout alleviated IR-induced liver injury in mice by reducing cell apoptosis and ferroptosis. ERRFI1 knockdown reduced apoptotic and ferroptotic hepatocytes induced by OGD/R. Mechanistically, ERRFI1 interacted with GRB2 to maintain its stability by hindering its proteasomal degradation. Overexpression of GRB2 abrogated the effects of ERRFI1 silencing on hepatocyte apoptosis and ferroptosis.
CONCLUSIONS
Our results revealed that the ERRFI1-GRB2 interaction and GRB2 stability are essential for ERRFI1-regulated hepatic IR injury, indicating that inhibition of ERRFI1 or blockade of the ERRFI1-GRB2 interaction may be potential therapeutic strategies in response to hepatic IR injury.
Topics: Animals; Humans; Male; Mice; Apoptosis; Disease Models, Animal; Ferroptosis; GRB2 Adaptor Protein; Hepatocytes; Liver; Mice, Knockout; Reperfusion Injury
PubMed: 38862918
DOI: 10.1186/s10020-024-00837-4 -
Basic Research in Cardiology Jun 2024Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping... (Review)
Review
Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.
PubMed: 38856733
DOI: 10.1007/s00395-024-01062-0