Pharmacological Cardioprotection against Ischemia Reperfusion Injury—The Search for a Clinical Effective Therapy

Abstract

Pharmacological conditioning aims to protect the heart from myocardial ischemia-reperfusion injury (IRI). Despite extensive research in this area, today, a significant gap remains between experimental findings and clinical practice. This review provides an update on recent developments in pharmacological conditioning in the experimental setting and summarizes the clinical evidence of these cardioprotective strategies in the perioperative setting. We start describing the crucial cellular processes during ischemia and reperfusion that drive acute IRI through changes in critical compounds (∆GATP, Na+, Ca2+, pH, glycogen, succinate, glucose-6-phosphate, mitoHKII, acylcarnitines, BH4, and NAD+). These compounds all precipitate common end-effector mechanisms of IRI, such as reactive oxygen species (ROS) generation, Ca2+ overload, and mitochondrial permeability transition pore opening (mPTP). We further discuss novel promising interventions targeting these processes, with emphasis on cardiomyocytes and the endothelium. The limited translatability from basic research to clinical practice is likely due to the lack of comorbidities, comedications, and peri-operative treatments in preclinical animal models, employing only monotherapy/monointervention, and the use of no-flow (always in preclinical models) versus low-flow ischemia (often in humans). Future research should focus on improved matching between preclinical models and clinical reality, and on aligning multitarget therapy with optimized dosing and timing towards the human condition.

Prolonged Door-to-Balloon time leads to glycocalyx damage and endothelial dysfunction in patients with ST-Elevation Myocardial Infarction and cardiogenic shock

“…The disruption in eGC integrity in cardiac IRI has been documented in the meantime 2 , but, to date, no satisfactory cardioprotective therapy against IRI is available for daily clinical practice 37 . Here, protecting the eGC in the case of STEMI and cardiogenic shock leads to less eGC damage, resulting in turn in less cardiac IRI, which has previously been demonstrated by using a recombinant syndecans-1 as an eGC recovering agent.…”

“…On the one hand, this is due to the complex and multi-layered cell biological background and mechanisms of eGC damage in cardiac IRI 3 , but, on the other, also to the limited translatability from basic research to clinical practice, both for diagnostic options and pharmacological approaches to managing IRI. 37 Our AFM-based methodology is time consuming and sophisticated, which precludes analyzing considerably larger, random sets of samples; however, there are approaches for meaningful analysis of the eGC status that can be probed in everyday clinical practice: For example, by visualizing the sublingual microcirculation the integrity of the glycocalyx could be assessed indirectly and could represent an important diagnostic tool to measure eGC integrity in the future and further predict the outcome of STEMI patients. 38 The association between sublingual microcirculation parameters and eGC dimensions has already been demonstrated for critically ill patients.…”

Prolonged Door-to-Balloon Time Leads to Endothelial Glycocalyx Damage and Endothelial Dysfunction in Patients with ST-Elevation Myocardial Infarction

“…The disruption to eGC integrity in cardiac IRI has been documented in the meantime [2], but, to date, no satisfactory cardioprotective therapy against IRI is available for daily clinical practice [40]. Here, protecting the eGC in the case of STEMI may result in less cardiac IRI.…”

Potential Role of Natural Antioxidants in Countering Reperfusion Injury in Acute Myocardial Infarction and Ischemic Stroke

“…Early after myocardial reperfusion, there is a burst of ROS generation [ 37 ], including hydrogen peroxide (H 2 O 2 ), superoxide radical anion (O 2 •−), hydroxyl radical (•OH), and peroxynitrite anion (ONOO−) [ 38 ]. In contrast, the most important ROS sources are NADPH oxidases (NOX), uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO) and the mitochondrion [ 31 ], the latter because of the oxidation of the ischemic accumulated succinate [ 39 , 40 ]. The mechanisms involved in IRI are summarized in Figure 1 .…”