Massé Danielle D, Shar Jason A, Brown Kathleen N, Keswani Sundeep G, Grande-Allen K Jane, Sucosky Philippe
Department of Mechanical and Materials Engineering, Wright State University, Dayton, OH, United States.
Department of Bioengineering, Rice University, Houston, TX, United States.
Front Cardiovasc Med. 2018 Sep 13;5:122. doi: 10.3389/fcvm.2018.00122. eCollection 2018.
Discrete subaortic stenosis (DSS) is a congenital heart disease that results in the formation of a fibro-membranous tissue, causing an increased pressure gradient in the left ventricular outflow tract (LVOT). While surgical resection of the membrane has shown some success in eliminating the obstruction, it poses significant risks associated with anesthesia, sternotomy, and heart bypass, and it remains associated with a high rate of recurrence. Although a genetic etiology had been initially proposed, the association between DSS and left ventricle (LV) geometrical abnormalities has provided more support to a hemodynamic etiology by which congenital or post-surgical LVOT geometric derangements could generate abnormal shear forces on the septal wall, triggering in turn a fibrotic response. Validating this hypothetical etiology and understanding the mechanobiological processes by which altered shear forces induce fibrosis in the LVOT are major knowledge gaps. This perspective paper describes the current state of knowledge of DSS, articulates the research needs to yield mechanistic insights into a significant pathologic process that is poorly understood, and proposes several strategies aimed at elucidating the potential mechanobiological synergies responsible for DSS pathogenesis. The proposed roadmap has the potential to improve DSS management by identifying early targets for prevention of the fibrotic lesion, and may also prove beneficial in other fibrotic cardiovascular diseases associated with altered flow.
离散性主动脉瓣下狭窄（DSS）是一种先天性心脏病，会导致纤维膜组织形成，从而使左心室流出道（LVOT）的压力梯度增加。虽然手术切除隔膜在消除梗阻方面已取得一些成功，但它带来了与麻醉、胸骨切开术和心脏搭桥相关的重大风险，并且复发率仍然很高。尽管最初有人提出遗传病因，但DSS与左心室（LV）几何形态异常之间的关联为血液动力学病因提供了更多支持，即先天性或手术后的LVOT几何排列紊乱可在间隔壁上产生异常剪切力，进而引发纤维化反应。验证这一假设病因并了解剪切力改变在LVOT中诱导纤维化的机械生物学过程是主要的知识空白。这篇观点论文描述了DSS的当前知识状态，阐明了对一个了解甚少的重要病理过程获得机制性见解所需的研究，提出了几种旨在阐明导致DSS发病机制的潜在机械生物学协同作用的策略。所提出的路线图有可能通过确定预防纤维化病变的早期靶点来改善DSS的管理，并且在与血流改变相关的其他纤维化心血管疾病中可能也被证明是有益的。
