Effect of chronic left ventricular unloading on myocardial remodeling: Multimodal assessment of two heterotopic heart transplantation techniques

Abstract

Cardiac recovery is possible by means of mechanical unloading yet remains rare. Excessive unloading-associated myocardial atrophy and fibrosis may adversely affect the process of reverse remodeling. In this study, we sought to evaluate the effect of different intensities of chronic left ventricular (LV) unloading on myocardial remodeling. Twenty-five isogenic Lewis rats underwent complete LV unloading (CU, n = 15) induced by heterotopic heart transplantation or partial LV unloading (PU, n = 10) by heterotopic heart-lung transplantation. Information obtained from serial echocardiography, 2-deoxy-2[(18)F]fluoro-d-glucose ((18)F-FDG)-positron emission tomography, and an LV pressure-volume catheter were used to evaluate the morphology, glucose metabolism, and hemodynamic performance of the orthotopic hearts and heterotopic transplants over 4 weeks. Cell size, collagen content, tissue cytokines (interleukin [IL]-1α, IL-2, IL-6, IL-10, tumor necrosis factor-α, and vascular endothelial growth factor), and matrix metalloproteinase-2 and -9 were also determined. The recorded parameters included LV end-systolic dimension, LV end-diastolic dimension, posterior wall thickness, diastolic interventricular septum thickness, LV fractional shortening, and LV ejection fraction. We demonstrated an LV load-dependent relationship using echo-based structural (left posterior wall thickness, diastolic interventricular septum thickness, and left ventricular end-diastolic dimension) and functional (LV fractional shortening and LV ejection fraction) parameters, as well as an (18)F-FDG uptake (all p < 0.05). This load-dependent relationship was also evidenced in measurements from the pressure-volume conductance catheter (stroke volume, stroke work, cardiac output, dP/dTmax, and -dP/dTmin; all p < 0.05). Significant myocardial atrophy and fibrosis were observed in unloaded hearts, whereas concentrations of cytokines and matrix metalloproteinases were comparable in both unloading conditions. Partial and complete unloading affected the remodeling of non-failing hearts in a rodent model to different extents on myocardial atrophy, fibrosis, glucose metabolism, and mechanical work. Cardiac atrophy is the prominent change after mechanical unloading, which exaggerates the proportion of total collagen that is responsible for diastolic dysfunction.