Novel Role of Platelets in Mediating Inflammatory Responses and Ventricular Rupture or Remodeling Following Myocardial Infarction

Abstract

Objective-The goal of this study was to investigate the role of platelets in systemic and cardiac inflammatory responses and the development of postinfarct ventricular complications, as well as the efficacy of antiplatelet interventions. Methods and Results-Using a mouse myocardial infarction (MI) model, we determined platelet accumulation and severity of inflammation within the infarcted myocardium by immunohistochemistry and biochemical assays, analyzed peripheral blood platelet-leukocyte conjugation using flow cytometry, and tested antiplatelet interventions, including thienopyridines and platelet depletion. Platelets accumulated within the infarcted region early post-MI and colocalized with inflammatory cells. MI evoked early increase in circulating platelet-leukocyte conjugation mediated by P-selectin/P-selectin glycoprotein ligand-1. Antiplatelet interventions inhibited platelet-leukocyte conjugation in peripheral blood, inflammatory infiltration, content of matrix metalloproteinases or plasminogen activation, and expression of inflammatory mediators in the infarcted myocardium (all PϽ0.05) and lowered rupture incidence (PϽ0.01). Clopidogrel therapy alleviated the extent of chronic ventricular dilatation by serial echocardiography. Key Words: ischemic heart disease Ⅲ leukocytes Ⅲ platelets Ⅲ thienopyridines Ⅲ inflammation Ⅲ myocardial infarction Ⅲ ventricular rupture T he role of platelets in atherosclerotic lesions and acute coronary syndrome has been well documented. The proinflammatory actions of platelets have received increasing attention. 1,2 Platelets contribute to inflammatory responses through release of inflammatory mediators and plateletleukocyte interactions by which platelets mediate leukocyte activation and infiltration into inflamed tissues. 1,2 There are several reports of an elevated proportion of platelet-leukocyte aggregates tested ex vivo in blood samples from patients with acute coronary syndromes. [3][4][5] The current rationale for routine use of the platelet P2Y 12 receptor inhibitors thienopyridines (clopidogrel and prasugrel) is to prevent arterial thrombosis following coronary intervention. 6 Thienopyridine treatment is known to inhibit platelet-leukocyte interactions in the peripheral blood of patients with peripheral atherosclerotic vascular disease, coronary artery disease, or renal transplantation. 5,6 Myocardial infarction (MI) evokes intense inflammatory responses both systemically and within the infarcted myocardium, with adverse consequences. 7 The potential contribution of platelets to postinfarct cardiac inflammation remains unexplored. Relevant to this is the question of whether thienopyridines exert cardiac protection through inhibition of platelet's inflammatory action in the infarcted myocardium, independent of vascular thrombosis. Conclusion-PlateletsVentricular wall rupture is a fatal complication of acute MI, with a death rate of 70% to 90%. 8,9 Recent experimental studies, including ours, have provided strong evidence that wall rupture is the consequence o...

Prasugrel Metabolites Inhibit Neutrophil Functions

“…In contrast, two recent studies suggested that clopidogrel enhances inflammatory responses in rodent models of rheumatoid arthritis (Boilard et al, 2010;Garcia et al, 2011). The reasons for the proinflammatory effects of clopidogrel in this animal model compared with others is not known, although the use of exposed collagen in generating rheumatoid arthritis may activate unique inflammatory pathways that are regulated differently than those observed in other models of inflammation (Diehl et al, 2010;Hagiwara et al, 2011;Liu et al, 2011). Interestingly, previous studies suggest that the P2Y 12 receptor may be expressed in cell types other than platelets, such as lymphocytes (Wang et al, 2004;Diehl et al, 2010), monocytes (Wang et al, 2004), and dendritic cells (Ben Addi et al, 2010), indicating that P2Y 12 antagonists might also target the nonplatelet P2Y 12 receptor.…”

“…2009; Bhavaraju et al, 2010;Boilard et al, 2010;Garcia et al, 2011;Liu et al, 2011;Winning et al, 2011). However, despite the important role of neutrophils in inflammation (Nathan, 2006), these drugs have not been evaluated for their effect on neutrophil functions.…”

“…Treatment with the P2Y 12 receptor antagonist clopidogrel significantly attenuated lipopolysaccharide (LPS)-induced inflammatory responses and lung injury (Hagiwara et al, 2011). In addition, this drug also alleviated the severity of cardiac inflammation and post-myocardial infarction in a mouse myocardial infarction model (Liu et al, 2011). In contrast, two recent studies suggested that clopidogrel enhances inflammatory responses in rodent models of rheumatoid arthritis (Boilard et al, 2010;Garcia et al, 2011).…”

Dual-Contrast Molecular Imaging Allows Noninvasive Characterization of Myocardial Ischemia/Reperfusion Injury After Coronary Vessel Occlusion in Mice by Magnetic Resonance Imaging

“…This may reflect the inflammatory reaction of ischemia/reperfusion injury, which is in accordance with recent findings that platelets play a pathogenic role in this pathological process and are a therapeutic target and that their involvement determines the rate of complications in mice such as ventricular rupture. 6,36 Overall, the combined LIBS-MPIO/LGE imaging could provide important clinical information delineating the area at risk and inflammation, in addition to the area of necrosis as determined by LGE imaging. Whether the combination of these 2 imaging methods allows a clinically relevant risk prediction of adverse cardiovascular events in patients after MI remains to be determined.…”

“…4,5 In addition, the amount of platelets in the ischemic/reperfused myocardium has an important prognostic value. 6 Studies have shown that a high degree of microvascular obstruction that involves platelet microthrombi results in a poor outcome. 7,8 In addition, the extent of myocardial necrosis is widely accepted to be an important prognostic factor, 9,10 and cardiac magnetic resonance imaging (MRI) can be used to characterize wall motion and myocardial necrosis (late gadolinium enhancement [LGE]) after AMI.…”