Division of Cardiovascular Medicine, University of Utah Health, Salt Lake City, UT; Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah Health, Salt Lake City, UT.
Division of Cardiology, Washington University School of Medicine, St Louis, MO.
J Heart Lung Transplant. 2022 Oct;41(10):1309-1323. doi: 10.1016/j.healun.2022.07.007. Epub 2022 Jul 16.
Cardiac remodeling is an adaptive, compensatory biological process following an initial insult to the myocardium that gradually becomes maladaptive and causes clinical deterioration and chronic heart failure (HF). This biological process involves several pathophysiological adaptations at the genetic, molecular, cellular, and tissue levels. A growing body of clinical and translational investigations demonstrated that cardiac remodeling and chronic HF does not invariably result in a static, end-stage phenotype but can be at least partially reversed. One of the paradigms which shed some additional light on the breadth and limits of myocardial elasticity and plasticity is long term mechanical circulatory support (MCS) in advanced HF pediatric and adult patients. MCS by providing (a) ventricular mechanical unloading and (b) effective hemodynamic support to the periphery results in functional, structural, cellular and molecular changes, known as cardiac reverse remodeling. Herein, we analyze and synthesize the advances in our understanding of the biology of MCS-mediated reverse remodeling and myocardial recovery. The MCS investigational setting offers access to human tissue, providing an unparalleled opportunity in cardiovascular medicine to perform in-depth characterizations of myocardial biology and the associated molecular, cellular, and structural recovery signatures. These human tissue findings have triggered and effectively fueled a "bedside to bench and back" approach through a variety of knockout, inhibition or overexpression mechanistic investigations in vitro and in vivo using small animal models. These follow-up translational and basic science studies leveraging human tissue findings have unveiled mechanistic myocardial recovery pathways which are currently undergoing further testing for potential therapeutic drug development. Essentially, the field is advancing by extending the lessons learned from the MCS cardiac recovery investigational setting to develop therapies applicable to the greater, not end-stage, HF population. This review article focuses on the biological aspects of the MCS-mediated myocardial recovery and together with its companion review article, focused on the clinical aspects, they aim to provide a useful framework for clinicians and investigators.
心脏重构是心肌受到初始损伤后的一种适应性代偿生物学过程，它逐渐变得适应不良，导致临床恶化和慢性心力衰竭（HF）。这个生物学过程涉及到基因、分子、细胞和组织水平的几个病理生理适应。越来越多的临床和转化研究表明，心脏重构和慢性 HF 并不一定会导致一个静态的终末期表型，而是至少可以部分逆转。其中一个范例，为心肌弹性和可塑性的广度和限制提供了一些额外的启示，是长期机械循环支持（MCS）在先进的 HF 儿科和成人患者中的应用。MCS 通过提供（a）心室机械卸载和（b）对周围组织的有效血液动力学支持，导致功能、结构、细胞和分子变化，称为心脏逆重构。在此，我们分析和综合了我们对 MCS 介导的逆重构和心肌恢复生物学的理解进展。MCS 的研究环境可以获得人体组织，为心血管医学提供了一个无与伦比的机会，可以对心肌生物学和相关的分子、细胞和结构恢复特征进行深入的特征描述。这些人体组织发现引发了，并有效地推动了一种“从床边到实验室再回到床边”的方法，通过各种体外和体内的敲除、抑制或过表达机制研究，使用小动物模型。这些后续的转化和基础科学研究利用人体组织发现，揭示了心肌恢复的机制途径，目前正在进一步测试，以开发潜在的治疗药物。从本质上讲，该领域正在通过将从 MCS 心脏恢复研究环境中获得的经验教训扩展到开发适用于更大范围的 HF 人群的治疗方法来推进。这篇综述文章侧重于 MCS 介导的心肌恢复的生物学方面，与它的姊妹综述文章一起，旨在为临床医生和研究人员提供一个有用的框架。
