Preventing Adverse Remodeling and Rupture During Healing After Myocardial Infarction in Mice and Humans

Adverse ventricular remodeling during the healing phase after acute myocardial infarction (MI) continues to be an important problem that impacts adult cardiology practice. Most clinicians and cardiovascular researchers recognize that significant left ventricular (LV) remodeling occurs during infarct healing, and optimal healing is critical for survival with a favorable outcome. Over the last 3 decades, several laboratories have been actively searching for specific molecular targets that may lead to the development of therapies and strategies to optimize postinfarct healing, prevent adverse remodeling, and improve clinical outcome. Others search for markers of adverse LV remodeling so as to identify high-risk patients for therapy. However, specific therapy to optimize healing and prevent adverse post-MI remodeling is currently lacking. Optimal medical therapy after MI may not be so optimal yet. Hearts continue to enlarge after MI, and heart failure is a growing burden.Article see p 145 Inflammation and extracellular matrix remodeling are 2 key components of healing and LV remodeling after MI.1,2 Several proinflammatory cytokines, including interleukin-6 (IL-6), are consistently upregulated in the infarct zone after experimental MI.2,3 The 3 members of the superfamily of IL-6 cytokines (IL-6, cardiotrophin-1, and leukemia inhibitory factor) share a common 130-kDa glycoprotein (gp130) receptor subunit for activation of their signaling pathways.4 All IL-6 cytokines are potent activators of signal transducer and activator of transcription 3 (STAT3). The IL-6 receptor binds the IL-6 ligand and the gp130 subunit, which in turn mediates signal transduction via 3 major downstream pathways (ie, Janus kinase/signal transducer and activator of transcription [JAK/STAT], Src-homology tyrosine phosphatase-signal transduction protein-extracellular signal-regulated kinase [SHP2-Ras-ERK], and phosphatidylinositol 3-kinase-dependent [P13/Akt]; Figure). After activation, negative-feedback mechanisms regulate gp130 signaling. IL-6 is produced by various cells, including cardiomyocytes, fibroblasts, and inflammatory cells, in the infarct border zone in animals and humans.3,4 It has been implicated …