Reversal of Heart Failure: Role of Vascular Recovery

项目总结 心力衰竭是全世界发病率和死亡率的主要原因，目前约有650万人受到影响 仅在美国，成年人就贡献了210亿美元的医疗费用。这项建议的目的是理解 心力衰竭恢复的机制。我们有临床证据表明心力衰竭的恢复包括 间质心肌纤维化减轻，微血管密度增加。我们的人类图书馆 左心室辅助装置(LVAD)植入/植入术的样本是一种方便的样本 来研究恢复的机制。在这些患者中，LVAD植入(和心脏卸载) 来自血液动力学的力量)促进了一些心功能的改善(通过评估 超声心动图)，这与间质纤维化减少和血管密度增加有关。基于 临床和临床前数据，我们假设从心力衰竭中恢复是(至少部分)血管 恢复。血管修复可能涉及间充质向内皮细胞的转化，即 心脏成纤维细胞(或其他间充质细胞)转分化为内皮细胞。此外，我们 有证据表明MEndoT可能需要糖酵解开关，直接影响DNA可及性和细胞 可塑性。在我们的第一个目标中，我们将描述心力衰竭的生理、细胞和分子特征。 在一个独特的小鼠模型中恢复。在第二个目标中，对分解的小鼠心脏的转录图谱如下 随着人类心脏组织在LVAD植入前后的获得，将与生物信息学相结合 分析预测心力衰竭恢复过程中的新基因。在我们的第三个目标中，我们将确认基因 在第一个目标中发现的决定因素是通过体外和体内功能获得或丧失研究发现的。此外, 我们将利用生物信息学探索糖酵解开关在细胞命运转换和血管恢复中的作用 对我们的RNAseq数据的分析，与特定细胞和有条件的功能增减研究证实 体外和体内的靶基因(如代谢途径)。这项提议的目的是产生 关于心力衰竭康复的基本见解，可能导致新的治疗策略。

PROJECT SUMMARY Heart failure is a major cause of morbidity and mortality worldwide, currently affecting an estimated 6.5 million adults in the US alone and contributing to $21 billion in health care costs. The aim of this proposal is to understand the mechanisms of heart failure recovery. We have clinical evidence that heart failure recovery involves a reduction in interstitial myocardial fibrosis and an increase in microvascular density. Our library of human samples from Left Ventricular Assist Device (LVAD) implantation/explantation represent a convenience sample to examine the mechanisms of recovery. In these patients, the LVAD implantation (and unloading of the heart from hemodynamic forces) promotes some improvement in ventricular function (as assessed by echocardiography) that is associated with decreased interstitial fibrosis and increased vascular density. Based on clinical and pre-clinical data, we hypothesize that recovery from heart failure is (at least in part) a vascular recovery. The vascular recovery may involve mesenchymal-to-endothelial transition (MEndoT), that is, the transdifferentiation of cardiac fibroblasts (or other mesenchymal cells) into endothelial cells. Furthermore, we have evidence that MEndoT may require a glycolytic switch that directly affects DNA accessibility and cellular plasticity. In our first aim, we will characterize the physiological, cellular, and molecular hallmarks of heart failure recovery in a unique mouse model. In the second aim, transcriptional profiling of disaggregated mouse hearts as well as human cardiac tissue obtained pre- and post-LVAD implantation will be combined with bioinformatics analyses to predict novel genes in heart failure recovery. In our third aim, we will confirm the genetic determinants discovered in the first aim using gain- or loss-of-function studies in vitro and in vivo. In addition, we will explore the role of the glycolytic switch in cell fate transitions and vascular recovery using bioinformatics analyses of our RNAseq data, confirmed with cell-specific and conditional gain- or loss-of-function studies of target genes (e.g. in metabolic pathways) in vitro and in vivo. The intent of this proposal is to generate fundamental insights regarding heart failure recovery that may lead to a new therapeutic strategy.