Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
The Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina.
Am J Physiol Heart Circ Physiol. 2022 Jul 1;323(1):H165-H175. doi: 10.1152/ajpheart.00148.2022. Epub 2022 Jun 3.
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 supports limited reductions in ECM following alleviation of PO, however, mechanisms that control the extent and timing of ECM regression are undefined. LVPO, induced by 4 wk 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, 2-wk TAC, 4-wk TAC, 4-wk TAC + 2-wk unTAC, 4-wk TAC + 4-wk unTAC, and 4-wk TAC + 6-wk unTAC. When compared with 4-wk TAC, 2-wk 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 cross-linking enzymes, but no change in CVF. When compared with 2-wk unTAC, 4-wk unTAC demonstrated decreased CVF, which did not decline to control values. At 4-wk and 6-wk unTAC, CHP reactivity and mediators of ECM degradation were reduced versus 2-wk 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. In this study, a murine model demonstrated persistent interstitial fibrosis and myocardial stiffness following alleviation of pressure overload.
左心室压力超负荷（LVPO）可由主动脉瓣狭窄和系统性高血压等前驱疾病发展而来，其特征是心肌细胞外基质（ECM）的积累。来自患者和动物模型的证据支持在缓解 PO 后 ECM 的减少程度有限，但是控制 ECM 消退程度和时间的机制尚不清楚。在小鼠中，通过 4 周的横主动脉缩窄（TAC）诱导 LVPO，并通过去除带（unTAC）来缓解。评估了心肌细胞横截面积、胶原容积分数（CVF）、心肌僵硬度和胶原降解：对照、2 周 TAC、4 周 TAC、4 周 TAC+2 周 unTAC、4 周 TAC+4 周 unTAC 和 4 周 TAC+6 周 unTAC。与 4 周 TAC 相比，2 周 unTAC 导致胶原杂交肽（CHP）的反应性增加（代表胶原降解的开始）、胶原酶和明胶酶水平增加、胶原交联酶水平降低，但 CVF 没有变化。与 2 周 unTAC 相比，4 周 unTAC 显示 CVF 降低，但未降至对照值。在 4 周和 6 周 unTAC 时，CHP 反应性和 ECM 降解的介质与 2 周 unTAC 相比降低，而金属蛋白酶组织抑制剂（TIMP）-1 的水平增加。LVPO 去除后，ECM 平衡以时间依赖的方式发生变化，其特征是胶原降解早期增加，随后该过程减弱。随着时间的推移，温和的 ECM 降解预计有助于解释仅使血流动力学超负荷正常化并不能完全使心肌纤维化消退的发现。在这项研究中，一种鼠模型在缓解压力超负荷后表现出持续的间质纤维化和心肌僵硬度。
