Department of Medicine, Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY, USA.
Eur J Clin Invest. 2013 Sep;43(9):986-95. doi: 10.1111/eci.12118. Epub 2013 Jun 17.
Acute cardiomyocyte necrosis in the infarcted heart generates damage-associated molecular patterns (DAMPs), activating complement and Toll-Like Receptor (TLR)/Interleukin (IL)-1 signalling and triggering an intense inflammatory reaction. Infiltrating leucocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels, the geometric, functional and molecular alterations associated with postinfarction remodelling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the postinfarction inflammatory reaction may be crucial to protect the myocardium from dilative remodelling and progressive dysfunction. Inhibition and resolution of postinfarction inflammation involve mobilization of inhibitory mononuclear cell subsets and require activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the postinfarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti-integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischaemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodelling. Given the pathophysiologic complexity of postinfarction remodelling, personalized biomarker-based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro-inflammatory signals (such as IL-1 and monocyte chemoattractant protein-1) may be effective in patients with defective resolution of postinfarction inflammation who exhibit progressive dilative remodelling. In contrast, patients with predominant hypertrophic/fibrotic responses may benefit from anti-TGF strategies.
急性心肌细胞坏死在梗死的心脏产生损伤相关的分子模式(DAMPs)，激活补体和 Toll 样受体(TLR)/白细胞介素(IL)-1 信号通路，并触发强烈的炎症反应。浸润的白细胞清除梗死区域的死细胞，同时激活修复途径，导致瘢痕形成。随着梗死的愈合，心室重塑，与梗死后重塑相关的几何、功能和分子改变是由炎症级联驱动的，并参与心力衰竭的发展。由于梗死心脏中不受控制的炎症会诱导基质降解和心肌细胞凋亡，因此及时抑制梗死后炎症反应对于保护心肌免受扩张性重塑和进行性功能障碍可能至关重要。梗死后炎症的抑制和消退涉及抑制性单核细胞亚群的动员，并需要激活内源性停止信号。我们的论文讨论了梗死后炎症反应启动、激活和消退所涉及的基本细胞和分子事件，重点是确定治疗靶点。抗整合素方法在心肌梗死患者中的失败和越来越多的实验证据表明，炎症可能不会增加缺血性心肌细胞死亡，而是加重基质降解导致扩张性重塑。鉴于梗死后重塑的病理生理复杂性，需要基于生物标志物的个体化方法来针对炎症和修复反应失调的患者亚群。抑制促炎信号（如白细胞介素-1 和单核细胞趋化蛋白-1）可能对那些表现出进行性扩张性重塑的梗死后炎症消退有缺陷的患者有效。相比之下，主要表现为肥厚/纤维化反应的患者可能受益于抗转化生长因子(TGF)策略。
