Dadson Keith, Kovacevic Vera, Rengasamy Palanivel, Kim Grace Ha Eun, Boo Stellar, Li Ren-Ke, George Isaac, Schulze P Christian, Hinz Boris, Sweeney Gary
Department of Biology, York University, Toronto, Canada.
Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Canada.
Int J Cardiol. 2016 Aug 1;216:32-42. doi: 10.1016/j.ijcard.2016.03.240. Epub 2016 Apr 23.
The cardiac remodelling process in advanced heart failure due to pressure overload has not been clearly defined but likely involves mechanisms of cardiac fibrosis and cardiomyocyte hypertrophy. The aim of this study was to examine pressure overload (PO)-induced cardiac remodelling processes and their reversibility after unloading in both humans with heart failure and a mouse model of PO induced by aortic constriction.
METHODS & RESULTS: Speckle tracking echocardiography showed PO-induced cardiac dysfunction in mice was reversible after removal of aortic constriction to unload. Masson's Trichrome staining suggested that PO-induced myocardial fibrosis was reversible, however detailed analysis of 3-dimensional collagen architecture by scanning electron microscopy demonstrated that matrix remodelling was not completely normalised as a disorganised network of thin collagen fibres was evident. Analysis of human left ventricular biopsy samples from HF patients revealed increased presence of large collagen fibres which were greatly reduced in paired samples from the same individuals after unloading by left ventricular assist device implantation. Again, an extensive network of small collagen fibres was still clearly seen to closely surround cardiomyocytes after unloading. Other features of PO-induced remodelling including increased myofibroblast content, cardiomyocyte disarray and hypertrophy were largely reversed upon unloading in both humans and mouse model. Previous work in humans demonstrated that receptors for adiponectin, an important mediator of cardiac fibrosis and hypertrophy, decreased in heart failure patients and returned to normal after unloading. Here we provide novel data showing a similar trend for adiponectin receptor adaptor protein APPL1, but not APPL2 isoform.
LV unloading diminishes PO-induced cardiac remodelling and improves function. These findings add new insights into the cardiac remodelling process, and provide novel targets for future pharmacologic therapies.
压力超负荷导致的晚期心力衰竭中的心脏重塑过程尚未明确界定，但可能涉及心脏纤维化和心肌细胞肥大机制。本研究的目的是在心力衰竭患者和主动脉缩窄诱导的压力超负荷小鼠模型中，研究压力超负荷（PO）诱导的心脏重塑过程及其卸载后的可逆性。
斑点追踪超声心动图显示，在去除主动脉缩窄以减轻负荷后，小鼠中PO诱导的心脏功能障碍是可逆的。Masson三色染色表明，PO诱导的心肌纤维化是可逆的，然而，通过扫描电子显微镜对三维胶原结构的详细分析表明，基质重塑并未完全恢复正常，因为明显可见薄胶原纤维的无序网络。对心力衰竭患者的人左心室活检样本分析显示，大胶原纤维的存在增加，在通过植入左心室辅助装置卸载后，来自同一患者的配对样本中其数量大幅减少。同样，卸载后仍清晰可见广泛的小胶原纤维网络紧密围绕心肌细胞。PO诱导的重塑的其他特征，包括肌成纤维细胞含量增加、心肌细胞排列紊乱和肥大，在人和小鼠模型中卸载后大多得到逆转。先前在人体中的研究表明，脂联素（心脏纤维化和肥大的重要介质）的受体在心力衰竭患者中减少，并在卸载后恢复正常。在这里，我们提供了新的数据，显示脂联素受体衔接蛋白APPL1有类似趋势，但APPL2亚型没有。
左心室卸载可减轻PO诱导的心脏重塑并改善功能。这些发现为心脏重塑过程提供了新的见解，并为未来的药物治疗提供了新的靶点。
