Mechanisms that Limit Regression of Myocardial Fibrosis Following Removal of Left Ventricular Pressure Overload

Am J Physiol Heart Circ Physiol. 2022 Jun 3. doi: 10.1152/ajpheart.00148.2022. Online ahead of print.

ABSTRACT

Left ventricular pressure overload (LVPO) can develop from antecedent diseases such as aortic valve stenosis and systemic hypertension and is characterized by accumulation of myocardial extracellular matrix (ECM). Evidence from patient and animal models support limited reductions in ECM following alleviation of PO, however, mechanisms that control the extent and timing of ECM regression are undefined. LVPO, induced by 4wks of transverse aortic constriction (TAC) in mice, was alleviated by removal of the band (unTAC). Cardiomyocyte cross-sectional area, collagen volume fraction (CVF), myocardial stiffness, and collagen degradation were assessed for: Control, 2wk TAC, 4wk TAC, 4wk TAC+2wk unTAC, 4wk TAC+4wk unTAC, and 4wk TAC+6wk unTAC. Compared with 4wk TAC, 2wk unTAC resulted in increased reactivity of collagen hybridizing peptide (CHP) (representing initiation of collagen degradation), increased levels of collagenases and gelatinases, decreased levels of collagen crosslinking enzymes, but no change in CVF. Compared to 2wk unTAC, 4wk unTAC demonstrated decreased CVF, which did not decline to control values. At 4wk and 6wk unTAC, CHP reactivity and mediators of ECM degradation were reduced versus 2wk unTAC, whereas levels of tissue inhibitor of metalloproteinase (TIMP)-1 increased. ECM homeostasis changed in a time dependent manner after removal of LVPO and is characterized by early increases in collagen degradation, followed by a later dampening of this process. Tempered ECM degradation with time is predicted to contribute to the finding that normalization of hemodynamic overload alone does not completely regress myocardial fibrosis.

PMID:35657618 | DOI:10.1152/ajpheart.00148.2022