The role of inflammatory and fibrogenic pathways in heart failure associated with aging

Abstract

Heart failure is strongly associated with aging. Elderly patients with heart failure often have preserved systolic function exhibiting left ventricular hypertrophy accompanied by a decline in diastolic function. Experimental studies have demonstrated that age-related cardiac fibrosis plays an important role in the pathogenesis of diastolic heart failure in senescent hearts. Reactive oxygen species and angiotensin II are critically involved in fibrotic remodeling of the aging ventricle; their fibrogenic actions may be mediated, at least in part, through transforming growth factor (TGF)-beta. The increased prevalence of heart failure in the elderly is also due to impaired responses of the senescent heart to cardiac injury. Aging is associated with suppressed inflammation, delayed phagocytosis of dead cardiomyocytes, and markedly diminished collagen deposition following myocardial infarction, due to a blunted response of fibroblasts to fibrogenic growth factors. Thus, in addition to a baseline activation of fibrogenic pathways, senescent hearts exhibit an impaired reparative reserve due to decreased responses of mesenchymal cells to stimulatory signals. Impaired scar formation in senescent hearts is associated with accentuated dilative remodeling and worse systolic dysfunction. Understanding the pathogenesis of interstitial fibrosis in the aging heart and dissecting the mechanisms responsible for age-associated healing defects following cardiac injury are critical in order to design new strategies for prevention of adverse remodeling and heart failure in elderly patients.

Fig. 1

Pathways involved in the pathogenesis of cardiac fibrosis in the senescent heart. Reactive oxygen species (ROS) and angiotensin II signaling appear to play an important role in mediating fibrotic remodeling of the aging heart. Both ROS and angiotensin II activate transforming growth factor (TGF)-β/Smad2/3 signaling pathways, but also induce pro-inflammatory mediator expression. Inflammatory cytokines may induce and activate matrix metalloproteinases (MMPs) enhancing matrix degradation, whereas activation of TGF-β/Smad2/3 signaling may promote myofibroblast transdifferentiation and collagen deposition. Interstitial fibrosis in senescent hearts is associated with cardiomyocyte loss due to apoptosis and necrosis. Symbols: M, mononuclear cell; E, endothelial cell; Fi, fibroblast; CM, cardiomyocyte; α-SMA, α-smooth muscle actin; VCAM-1, vascular cell adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1

Fig. 2

Age-related defects in the inflammatory and reparative response lead to enhanced adverse remodeling following myocardial infarction. Although aging is associated with enhanced baseline inflammation and fibrosis, acute infarction results in suppressed but prolonged inflammatory reaction, impaired cardiomyocyte phagocytosis, and markedly diminished collagen deposition in the scar. Evolving evidence suggests that the alterations in post-infarction cardiac repair may be due to impaired responsiveness of senescent fibroblasts to growth factors, such as TGF-β. Whether this is due to an aging-related reduction of TGF-β receptor (TGF-βR) expression by fibroblasts, or reflects impaired TGF-β/Smad2/3 signaling in senescent cells, remains unknown. Diminished collagen deposition may lead to a marked reduction in tensile strength of the scar, resulting in accentuated dilation of the infarcted ventricle. Symbols: Ma, macrophage, Fi, fibroblast. Histopathological images show Sirius red–stained sections from young (Y) and senescent (S) mouse infarcts after 7 days of reperfusion identifying the collagen network