Abstract P471: Mechanisms Controlling Regression Of Cardiac Fibrosis By Removal Of Pressure Overload

Antecedent conditions, like aortic stenosis, can induce left ventricular pressure overload (LVPO), that can lead to Heart Failure with Preserved Ejection Fraction (HFpEF). Myocardial fibrosis and stiffness are key characteristics of HFpEF. Cardiac fibroblasts are the primary cell type regulating ECM production and deposition. In previous studies, biopsies isolated at the time of SAVR surgery, to correct stenosis, and then at 1-year and 5-years post-SAVR showed reductions in hypertrophy and fibrosis demonstrating these processes can regress. However, cellular mechanisms, including fibroblast activity, are poorly defined. Define mechanisms that contribute to remodeling of ECM before and after LVPO. LVPO was induced using transverse aortic constriction (TAC). LVPO was relieved by removal of the band (unTAC) at 4 wks. Cardiomyocyte cross-sectional area (CSA), collagen volume fraction (CVF), and protein production was measured by histology and immunoblot for five time points: nonTAC, 2wk TAC, 4wk TAC, 4wk TAC+2wk unTAC, and 4wk TAC+4wk unTAC. In response to LVPO, myocyte CSA increased by 23% at 2wk TAC and by 47% at 4wk. CVF increased by 64% and 204% at 2wk and 4wk TAC, respectively, versus nonTAC. In 2wk TAC hearts, SMA, a marker of fibroblast activation was increased as was production of two collagen cross-linking enzymes, lysyl oxidase (LOX) and LOXL2, in the absence of significant increases in markers of ECM degradation. After unloading, myocyte CSA decreased by 20% in 2wk unTAC versus 4wk TAC and CVF decreased by 38% in 4wk unTAC versus 4wk TAC. Coincident with decreases in CVF, levels of pro-MMP2 increased at 2wk unTAC as did levels of degraded collagen measured by collagen hybridizing peptide reactivity. Whereas markers of ECM deposition, LOX and LOXL2, were not increased in unTAC myocardium, a resurgence of SMA production occurred in 2wk unTAC. In LVPO hearts, hypertrophy was characterized by increases in myocyte CSA, greater CVF, and fibroblast activation with increased production of pro-fibrotic ECM. After unloading, hypertrophy and fibrosis significantly decreased accompanied by increases in ECM degrading activity and reductions in proteins that contribute to collagen assembly.

Duke Scholars

Author Gary Michael Felker Medicine, Cardiology