Nitric oxide treatments as adjuncts to reperfusion in acute myocardial infarction: a systematic review of experimental and clinical studies

Abstract

Unmodified reperfusion therapy for acute myocardial infarction (AMI) is associated with irreversible myocardial injury beyond that sustained during ischemia. Studies in experimental models of ischemia/reperfusion and in humans undergoing reperfusion therapy for AMI have examined potential beneficial effects of nitric oxide (NO) supplemented at the time of reperfusion. Using a rigorous systematic search approach, we have identified and critically evaluated all the relevant experimental and clinical literature to assess whether exogenous NO given at reperfusion can limit infarct size. An inclusive search strategy was undertaken to identify all in vivo experimental animal and clinical human studies published in the period 1990–2014 where NO gas, nitrite, nitrate or NO donors were given to ameliorate reperfusion injury. Articles were screened at title and subsequently at abstract level, followed by objective full text analysis using a critical appraisal tool. In twenty-one animal studies, all NO treatments except nitroglycerin afforded protection against measures of reperfusion injury, including infarct size, creatinine kinase release, neutrophil accumulation and cardiac dysfunction. In three human AMI RCT’s, there was no consistent evidence of infarct limitation associated with NO treatment as an adjunct to reperfusion. Despite experimental evidence that most NO treatments can reduce infarct size when given as adjuncts to reperfusion, the value of these interventions in clinical AMI is unproven. Our study raises issues for the design of further clinical studies and emphasises the need for improved design of animal studies to reflect more accurately the comorbidities and other confounding factors seen in clinical AMI.

Nitroglycerin induces DNA damage and vascular cell death in the setting of nitrate tolerance

“…Interestingly, GTN treatment per se did not interfere with cardiac protection afforded by remote ischemic preconditioning in patients undergoing coronary surgery [30]. A critical evaluation of all the relevant experimental and clinical literature to assess whether exogenous NO (NO gas, nitrite, nitrate or NO donors) given at reperfusion can limit infarct size, revealed highly protective effects for most experimental studies whereas the benefit of these interventions in clinical myocardial infarction is unproven [3].…”

Effect of hypercholesterolaemia on myocardial function, ischaemia–reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

“…It is well established that hypercholesterolaemia is accompanied by a decrease in cardiac NO content and increased nitro‐oxidative stress; however, the role of NO donors in ischaemia/reperfusion injury with or without hypercholesterolaemia is not well established. Although NO treatment prior to or during the early reperfusion period can limit infarct size in preclinical studies, the excessive production of NO at the beginning of reperfusion reacts with ROS and forms peroxynitrite (see for reviews: Andreadou et al ., ; Bice et al ., ). The three clinical studies with NO donors that have been performed so far have revealed no evidence of infarct size reduction in patients treated with NO donors immediately prior to reperfusion.…”

“…Additionally, high concentrations of NO can promote cellular injury, a situation that is possible in patients being treated with several co‐medications including nitrates. Hence, cardioprotection by NO donors should be demonstrated in experimental models with co‐morbidities and relevant co‐medications prior to clinical translation (Ferdinandy et al , ; Andreadou et al , ; Bell et al ., ; Bice et al ., ).…”

Current Mechanistic Concepts in Ischemia and Reperfusion Injury

“…In a study by Lang et al [120], using NO inhalants after liver transplantation protected hepatocytes, promoted liver function recovery, and shortened the duration of hospital stay. In a meta-analysis by Bice et al [121], NO interventions also limited infarct size during the early reperfusion period. In myocardial injury, inhaled gaseous NO inhibited cardiomyocyte apoptosis and reduced infarct size [122-125].…”