Abstract
Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality in modern medicine. Early reperfusion accomplished by primary percutaneous coronary intervention is pivotal for reducing myocardial damage in ST elevation AMI. However, restoration of coronary blood flow may paradoxically trigger cardiomyocyte death secondary to a reperfusion-induced inflammatory process, which may account for a significant proportion of the final infarct size. Unfortunately, recent human trials targeting myocardial ischemia/reperfusion (I/R) injury have yielded disappointing results. In experimental models of myocardial I/R injury, the complement system, and in particular the lectin pathway, have been identified as major contributors. In line with this, C1 esterase inhibitor (C1INH), the natural inhibitor of the lectin pathway, was shown to significantly ameliorate myocardial I/R injury. However, the hypothesis of a considerable augmentation of myocardial I/R injury by activation of the lectin pathway has not yet been confirmed in humans, which questions the efficacy of a therapeutic strategy solely aimed at the inhibition of the lectin pathway after human AMI. Thus, as C1INH is a multiple-action inhibitor targeting several pathways and mediators simultaneously in addition to the lectin pathway, such as the contact and coagulation system and tissue leukocyte infiltration, this may be considered as being advantageous over exclusive inhibition of the lectin pathway. In this review, we summarize current concepts and evidence addressing the role of the lectin pathway as a potent mediator/modulator of myocardial I/R injury in animal models and in patients. In addition, we focus on the evidence and the potential advantages of using the natural inhibitor of the lectin pathway, C1INH, as a future therapeutic approach in AMI given its ability to interfere with several plasmatic cascades. Ameliorating myocardial I/R injury by targeting the complement system and other plasmatic cascades remains a valid option for future therapeutic interventions.
Highlights
Ischemic heart disease is still a major cause of morbidity and mortality worldwide
This review focuses on the role of the lectin pathway in myocardial I/R injury and the potential benefit of therapeutic application of its natural inhibitor, C1 esterase inhibitor (C1INH)
We have summarized current concepts and evidence addressing the role of the lectin pathway as a potent regulator of myocardial I/R injury in murine models and the human setting
Summary
Ischemic heart disease is still a major cause of morbidity and mortality worldwide. In the United States, more than 700,000 episodes of acute myocardial infarctions (AMIs) are diagnosed annually [1]. Regarding inflammation as one mediator of I/R injury, experimental and clinical studies have shown that reperfusion after transient ischemia results in activation of endothelial cells, the contact and the complement system and attraction of neutrophils to the site of infarction [9, 10]. Three pathways can activate the complement cascade: the classical, the alternative, and the lectin pathway After initiation, these three pathways converge at the level of cleavage and activation of complement component C3, which subsequently leads to the generation of the anaphylatoxins (C3a, C5a) and the membrane attack complex (MAC; C5b-9). In the context of AMI, activation of the lectin pathway of complement after AMI may impact on I/R injury through activation of the complement cascade and via promotion of clot formation (coagulation and fibrinolytic system) and of inflammation (kallikrein-kinin cascade, activation of endothelial cells, and attraction of neutrophils). Inhibition of the lectin pathway, at the level of MASP-1/-2 seems to be advantageous over downstream inhibition of the complement
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