Mechanics and matrix: positive feedback loops between fibroblasts and ECM drive interstitial cardiac fibrosis

Interstitial cardiac fibrosis arises due to deposition and accumulation of extracellular matrix (ECM) and occurs in hearts subject to increases in mechanical load. Cardiac fibroblasts sense changes in mechanical load through several mechanosensors including integrin ECM receptors and stretch activated ion channels, which signal to induce ECM protein production through various pathways. Over time, processes intrinsic to fibroblasts and to the ECM occur to progress and sustain fibrosis through reciprocal, positive feedback loops. Changes in ECM include nascent collagen production, changes in ECM composition, and differential modification of collagen in fibers. Persistently fibrotic ECM contributes to a stiffer myocardium which can lead to the development of cardiomyopathies and heart failure.