Aging-Related Defects Are Associated With Adverse Cardiac Remodeling in a Mouse Model of Reperfused Myocardial Infarction

Mortality due to coronary artery disease is known to increase progressively with age. Older age was associated with a higher risk of in-hospital and post-discharge mortality in the GISSI-2 (Gruppo Italiano per lo Studio della Sopravivenza nell’Infarcto Miocardico 2) trial (1) and was a predictor of death and left ventricular dilation in patients with acute myocardial infarction (MI) enrolled in the SAVE (Survival and Ventricular Enlargement) trial (2). The exponential age-related increase in infarction-related mortality rates was not explained by larger infarcts (1). Although both clinical and experimental studies have demonstrated the adverse effects of senescence on cardiac function and remodeling after MI (2,3), the mechanisms responsible for these effects remain poorly understood. Post-infarction remodeling is closely intertwined with an inflammatory reaction that ultimately results in fibrous tissue deposition and formation of a scar. Inflammatory mediators regulate key cellular interactions in the infarct, modulating deposition and metabolism of extracellular matrix proteins in the wound. These actions have profound effects on the reparative response and ultimately determine the geometric characteristics of the infarcted ventricle by affecting the tensile strength of the scar (4–6). Both clinical studies and experimental investigations demonstrated aging-associated defects in inflammation and tissue repair. Cutaneous wounds heal more slowly in elderly patients as compared with younger patients (7,8) and show diminished expression of endothelial adhesion molecules (9). Furthermore, healing wounds in aged animals demonstrate a defective response to exogenously administered growth factors (10). We hypothesized that aging-associated alterations in inflammatory mediator expression and impaired responsiveness of senescent cells to growth factors might be important mechanisms responsible for defective infarct healing and adverse remodeling in elderly patients. With a mouse model of reperfused infarction, we compared the inflammatory and fibrotic response between young and old animals. Aging was associated with an attenuated post-infarction inflammatory response, delayed phagocytosis of dead cardiomyocytes, and markedly decreased collagen deposition in the infarct. These defects resulted in increased ventricular dilation and hypertrophy. Fibroblasts isolated from senescent animals exhibited a blunted response to transforming growth factor (TGF)-β stimulation, suggesting that impaired responsiveness to growth factors might mediate defective healing in senescent mouse infarcts.