Mechanical Unloading During Left Ventricular Assist Device Support Increases Left Ventricular Collagen Cross-Linking and Myocardial Stiffness

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Abstract
Background— Left ventricular assist devices (LVADs) induce reverse remodeling of the failing heart except for the extracellular matrix, which exhibits additional pathophysiological changes, although their mechanisms and functional consequences are unknown. Methods and Results— Hearts were obtained at transplant from patients with idiopathic dilated cardiomyopathy (DCM) not requiring LVAD support (n=30), patients requiring LVAD support (n=16; LVAD duration, 145±33 days), and 5 nonfailing hearts. Left (LV) and right ventricular (RV) ex vivo pressure-volume relationships were measured, and chamber and myocardial stiffness constants were determined. Myocardial tissue content of total and cross-linked collagen, collagen types I and III, MMP-1, MMP-9, TIMP-1, and angiotensin (Ang) I and II were measured. LV size, mass, and myocyte diameter decreased after LVAD compared with DCM without LVAD (P<0.05). Total and cross-linked collagen and ratio of type I to III collagen increased in DCM compared with nonfailing he...