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期疾病发展而来,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PO缓解后ECM的有限减少,然而,控制ECM回归的程度和时间的机制是不确定的。LVPO,在小鼠中通过4周的横向主动脉缩窄(TAC)诱导,通过去除频带(unTAC)来缓解。心肌细胞横截面积,胶原蛋白体积分数(CVF),心肌僵硬度,和胶原蛋白降解进行了评估: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导致胶原蛋白杂交肽(CHP)的反应性增加(代表胶原蛋白降解的开始),胶原酶和明胶酶的水平增加,胶原蛋白交联酶的水平降低,但CVF没有变化。与2周unTAC相比,4周unTAC显示CVF降低,没有下降到控制值。在4周和6周unTAC,与2周unTAC相比,CHP反应性和ECM降解介质降低,而金属蛋白酶组织抑制剂(TIMP)-1水平升高。去除LVPO后,ECM稳态以时间依赖性方式变化,其特征是胶原蛋白降解的早期增加,随后是这个过程的后期抑制。预测随时间的回火ECM降解有助于发现仅血流动力学超负荷的正常化不会完全消退心肌纤维化。在这项研究中,小鼠模型显示压力超负荷缓解后持续的间质纤维化和心肌僵硬度.
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.NEW & NOTEWORTHY In this study, a murine model demonstrated persistent interstitial fibrosis and myocardial stiffness following alleviation of pressure overload.