Insulin-Like Growth Factor 1 Receptor-Dependent Pathway Drives Epicardial Adipose Tissue Formation After Myocardial Injury.

BACKGROUND: Epicardial adipose tissue volume and coronary artery disease are strongly associated, even after accounting for overall body mass. Despite its pathophysiological significance, the origin and paracrine signaling pathways that regulate epicardial adipose tissue's formation and expansion are unclear. METHODS: We used a novel modified mRNA-based screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the adult heart. RESULTS: Using 2 independent lineage-tracing strategies in murine models, we show that cells originating from the Wt1+ mesothelial lineage, which includes epicardial cells, differentiate into epicardial adipose tissue after myocardial infarction. This differentiation process required Wt1 expression in this lineage and was stimulated by insulin-like growth factor 1 receptor (IGF1R) activation. IGF1R inhibition within this lineage significantly reduced its adipogenic differentiation in the context of exogenous, IGF1-modified mRNA stimulation. Moreover, IGF1R inhibition significantly reduced Wt1 lineage cell differentiation into adipocytes after myocardial infarction. CONCLUSIONS: Our results establish IGF1R signaling as a key pathway that governs epicardial adipose tissue formation in the context of myocardial injury by redirecting the fate of Wt1+ lineage cells. Our study also demonstrates the power of modified mRNA -based paracrine factor library screening to dissect signaling pathways that govern progenitor cell activity in homeostasis and disease.

Ischemic myocardial injuries after cardiac malformation repair in infants may be associated with oxidative stress mechanisms.

BACKGROUND: Despite advances in pediatric cardiac surgery, perioperative myocardial injury can be the major determinant of postoperative dysfunction after cardiac surgery. This study investigated the pathology-related differences in 29 infants with congenital heart disease that led to death. The infants were treated at the University Hospital of Ribeirão Preto, Brazil. METHODS: The patients were divided into four groups: Group 1, 16 infants who underwent operations for congenital heart disease on cardiopulmonary bypass; Group 2, four infants who underwent off-cardiopulmonary bypass operations for congenital heart disease; Group 3, nine infants who died from congenital heart disease prior to surgical treatment; and Group 4 (control group), five infants with no congenital heart disease and who died from other causes. The myocardial injuries and oxidative stress mechanisms were assessed by histopathology and immunohistochemistry and were quantified by morphometrical analyses. RESULTS: Contraction band necrosis and dystrophic calcification were found primarily in infants of Group 1. Coagulation necrosis and healing were prominent in Group 2, while infants without repair (Group 3) showed mainly colliquative myocytolysis. Apoptotic cells were more prominent in the operative groups. The control group showed no significant myocardial lesions. Lipid peroxidation was the principal mechanism of oxidative stress accounting for the myocardial lesions. CONCLUSION: The diversity of the lesions observed in these hearts seemed to indicate a large spectrum of cell damage due to inadequate myocardial perfusion, especially when these infants underwent surgery. Oxidative mechanisms could be a common mediator in the pathogenesis of myocardial injuries, mediated by peroxidation of the membrane phospholipids and resulting in changes in the permeability of the cell membrane, cell death, and intracellular calcium overload. Furthermore, an immature and often hypertrophied myocardium may promote unfavorable conditions, leading to heart failure and a lethal outcome.