“…Ischemic preconditioning is considered the gold standard of cardioprotection ( Basalay et al, 2020 ). In remote preconditioning, brief episodes of I/R are administered to organs or tissues other than the heart and can be easily applied in a non-invasive way, e.g., using a blood pressure cuff on an arm or a leg ( Lang and Kim, 2022 ; Penna et al, 2022 ; Comità et al, 2023 ; Ferdinandy et al, 2023 ; Zhao et al, 2023 ). Another way to protect the heart against the consequences of I/R injury is pharmacological conditioning (i.e., volatile anesthetics, opioids or α 2 -adrenoceptor agonists), a concept that is based on the administration of specific drugs mimicking the effect of ischemic preconditioning ( Roth et al, 2021 ; Penna et al, 2022 ; Ferdinandy et al, 2023 ).…”
Section: Cardioprotective Role Of Endocannabinoids During Preconditio...mentioning
confidence: 99%
“…Controlled occlusions or pharmacological interventions activate a molecular self-defense program which delays the progression of infarction. The subsequent activation of multiple endogenous cardioprotective mechanisms including adenosine, protein kinase, calcium signalling, nitric oxide release, reduction in ROS but also the involvement of autacoids, hormones, neurotransmitters and cytokines lead to cardioprotection and reduce infarct size ( Penna et al, 2022 ; Heusch, 2023 ).…”
Section: Cardioprotective Role Of Endocannabinoids During Preconditio...mentioning
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 CB2 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 CB2 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.
“…Ischemic preconditioning is considered the gold standard of cardioprotection ( Basalay et al, 2020 ). In remote preconditioning, brief episodes of I/R are administered to organs or tissues other than the heart and can be easily applied in a non-invasive way, e.g., using a blood pressure cuff on an arm or a leg ( Lang and Kim, 2022 ; Penna et al, 2022 ; Comità et al, 2023 ; Ferdinandy et al, 2023 ; Zhao et al, 2023 ). Another way to protect the heart against the consequences of I/R injury is pharmacological conditioning (i.e., volatile anesthetics, opioids or α 2 -adrenoceptor agonists), a concept that is based on the administration of specific drugs mimicking the effect of ischemic preconditioning ( Roth et al, 2021 ; Penna et al, 2022 ; Ferdinandy et al, 2023 ).…”
Section: Cardioprotective Role Of Endocannabinoids During Preconditio...mentioning
confidence: 99%
“…Controlled occlusions or pharmacological interventions activate a molecular self-defense program which delays the progression of infarction. The subsequent activation of multiple endogenous cardioprotective mechanisms including adenosine, protein kinase, calcium signalling, nitric oxide release, reduction in ROS but also the involvement of autacoids, hormones, neurotransmitters and cytokines lead to cardioprotection and reduce infarct size ( Penna et al, 2022 ; Heusch, 2023 ).…”
Section: Cardioprotective Role Of Endocannabinoids During Preconditio...mentioning
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 CB2 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 CB2 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.
“…All of these pathways converge to the mitochondria, acting through the opening of the mitochondrial ATP-sensitive potassium channel (mKATP) and the mitochondrial permeability transition pore (mPTP). Reviewed below are important molecules involved in cardioprotection [ 3 – 5 ]. Fig.…”
Section: Molecular Mechanisms Of Cardioprotectionmentioning
confidence: 99%
“…However, reduced infarct size and improved cardiac function have been observed after inhibition or deficiency of one of the components of the NLRP3 inflammasome or using several NLRP3 inhibitors and gene silencing [ 46 – 49 ]. Interestingly, the fact that ischemic preconditioning (IPreC) was ineffective in NLRP3-deficient mice suggests that NLRP3 may play a double role in the ischemia–reperfusion heart, being able to trigger protective signaling and participating in IPreC, but also able to concur with the progression of cardiac injury and promoting cardiomyocyte loss after ischemia–reperfusion [ 50 ]. Furthermore, more about the inflammasome-independent role of NLRP3 and inflammasome protective signaling in AMI is described in detail in another review article [ 51 , 52 ].…”
Section: Molecular Mechanisms Of Cardioprotectionmentioning
Acute myocardial infarction (AMI) is associated with high morbidity and mortality worldwide. Although early reperfusion is the most effective strategy to salvage ischemic myocardium, reperfusion injury can develop with the restoration of blood flow. Therefore, it is important to identify protection mechanisms and strategies for the heart after myocardial infarction. Recent studies have shown that multiple intracellular molecules and signaling pathways are involved in cardioprotection. Meanwhile, device-based cardioprotective modalities such as cardiac left ventricular unloading, hypothermia, coronary sinus intervention, supersaturated oxygen (SSO
2
), and remote ischemic conditioning (RIC) have become important areas of research. Herein, we review the molecular mechanisms of cardioprotection and cardioprotective modalities after ischemia–reperfusion injury (IRI) to identify potential approaches to reduce mortality and improve prognosis in patients with AMI.
“…To solve the contradiction between the significant cardioprotective effect obtained by a single cardioprotective strategy in animal experiments and the failure of clinical translation is the original intention of the multi-target strategy. One of the common denominators of the shortcomings of multiple translational trials is that patients have other specific comorbidities in addition to the application of PCI (1,3,22,45,59,71,(78)(79)(80). Consequently, we hypothesize that the multi-target strategy for protecting myocardial IRI in the animal testing stage may be applied to specific comorbidities, exert a more substantial cardioprotective effect, and better guide clinical trials (81).…”
Section: Multi-target Strategies For Myocardial Ischemia-reperfusion ...mentioning
Despite promising breakthroughs in diagnosing and treating acute coronary syndromes, cardiovascular disease’s high global mortality rate remains indisputable. Nearly half of these patients died of ischemic heart disease. Primary percutaneous coronary intervention (PCI) and coronary artery bypass grafting can rapidly restore interrupted blood flow and become the most effective method for salvaging viable myocardium. However, restoring blood flow could increase the risk of other complications and myocardial cell death attributed to myocardial ischemia-reperfusion injury (IRI). How to reduce the damage of blood reperfusion to ischemic myocardium has become an urgent problem to be solved. In preclinical experiments, many treatments have substantial cardioprotective effects against myocardial IRI. However, the transition from these cardioprotective therapies to clinically beneficial therapies for patients with acute myocardial infarction remains elusive. The reasons for the failure of the clinical translation may be multi-faceted, and three points are summarized here: (1) Our understanding of the complex pathophysiological mechanisms of myocardial IRI is far from enough, and the classification of specific therapeutic targets is not rigorous, and not clear enough; (2) Most of the clinical patients have comorbidities, and single cardioprotective strategies including ischemia regulation strategies cannot exert their due cardioprotective effects under conditions of hyperglycemia, hypertension, hyperlipidemia, and aging; (3) Most preclinical experimental results are based on adult, healthy animal models. However, most clinical patients had comorbidities and received multiple drug treatments before reperfusion therapy. In 2019, COST Action proposed a multi-target drug combination initiative for prospective myocardial IRI; the optimal cardioprotective strategy may be a combination of additive or synergistic multi-target therapy, which we support. By establishing more reasonable preclinical models, screening multi-target drug combinations more in line with clinical practice will benefit the translation of clinical treatment strategies.
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