Metabolomics Mapping and Cardiac Resynchronization

项目总结/摘要 心力衰竭（HF）是一种流行病，影响570万美国成年人，预计其发病率将 到2030年增长46%。HF是一种从无症状（A期和B期）开始的连续沿着进行性疾病 症状（阶段C和D）。由于在无症状的患者中发生HF的风险很大， 左室收缩功能不全，在心力衰竭早期制定有效的干预措施势在必行。心脏 硬化治疗（CRT）是一种新型治疗方法，可降低HF住院率和死亡率， 改善LV收缩功能和HF症状。心脏再同步治疗对轻度左室收缩功能不全患者的疗效 功能障碍-EF为36%-50%，LBBB-尚未确定。目前尚不清楚早期是否 左室肥厚可防止LVEF恶化，逆转心室代谢重构。 心肌代谢的异质性、不同步性和心肌能量分布不足 和消耗是HF诱发心肌功能障碍的标志。然而，CRT对 心肌能量和底物代谢以及哪些代谢状态和途径促进心肌 恢复是未知的。此外，LBBB的代谢组学特征和受影响的代谢途径， 左心室侧壁的延迟传导面积尚未确定。此外，妇女可能受益 在改善生存率、HF事件和逆转LV重构方面，CRT的患者多于男性。然而 在女性中有利CRT结果的代谢机制尚未阐明。代谢组 对患者体液和心脏特异性冠状窦血液的监测对于精确性至关重要 它已被纳入NIH路线图。因此，通过分析严重和严重的代谢组学模式， 在CRT中，存在LBBB的轻度HF沿着性别和缺血-非缺血性HF差异 结果我们将发现有利于心脏功能恢复的代谢机制。本研究将 使用基于稳定同位素18 O的代谢组学技术和经心代谢图谱来了解 CRT如何改善心脏代谢并确定代谢途径和新的代谢组学生物标志物 这可能预测CRT后左室收缩功能的恢复。通过交叉研究设计，酰基- 肉毒碱，支链氨基酸和血液磷酸代谢物周转率将检查， 与LV功能障碍相关的生物标志物。这项研究将包括三个目标。 目的1：确定轻症患者代谢途径和代谢组学生物标志物的早期改变， HF和LBBB及其在早期CRT结局预测中的作用。目的2：表征代谢 严重缺血性和非缺血性心肌病的重塑途径，并确定机制 与CRT反应相关。目的3：研究心肌代谢组学特征及代谢产物的表达。 女性对CRT反应良好的机制。

PROJECT SUMMARY/ABSTRACT Heart failure (HF), an epidemic disease, affecting 5.7 million American adults, and the incidence is projected to increase by 46% by 2030. HF is a progressive disease along a continuum from asymptomatic (stage A and B) to symptomatic (stage C and D). Because of the substantial risk of incident HF in patients with asymptomatic LV systolic dysfunction, it is imperative to develop effective interventions at the early stage of HF. Cardiac resynchronization therapy (CRT) is a novel therapy that decreases HF hospitalization and mortality, and improves LV systolic function and HF symptoms. The effectiveness of CRT in patients with mild LV systolic dysfunction—EF of 36%-50% with LBBB—has not been determined. It is unknown whether early resynchronization will prevent LVEF deterioration and reverse ventricular metabolic remodeling. Heterogeneous nature of myocardial metabolism, dyssynchrony and deficient myocardial energy distribution and consumption are hallmarks of HF precipitating myocardial dysfunction. However, the effects of CRT on myocardial energy and substrate metabolism and which metabolic state and pathways facilitate myocardial recovery are unknown. Moreover, the metabolomics signatures of LBBB and metabolic pathways affected in delayed conduction area at the LV lateral wall have not been determined. Furthermore, women may benefit from CRT more than men in terms of improved survival, HF events, and reverse LV remodeling. Yet the metabolic mechanisms underlying favorable CRT outcomes in women have not been elucidated. Metabolomic monitoring of patient body fluids and cardiac-specific coronary sinus blood is of key importance for precision medicine and is included in NIH Roadmap. Accordingly, by analyzing metabolomics patterns in severe and mild HF in the presence of LBBB along with gender and ischemic-non-ischemic HF differences in CRT outcome we will discover metabolic mechanisms which favor the recovery of cardiac function. This study will use stable isotope 18O-based metabolomic technologies and transcardiac metabolic mapping to understand how CRT improves cardiac metabolism and to identify metabolic pathways and novel metabolomic biomarkers that may predict restoration of LV systolic function by CRT. With a cross-over study design, the role of acyl- carnitines, branched chain amino acids and blood phosphometabolite turnover rates will be examined as early biomarkers in relation to LV dysfunction. The study will include three aims. Aim 1: To determine early alteration in metabolic pathways and metabolomics biomarkers in patients with mild HF and LBBB, and their role in the prediction of outcomes of early CRT. Aim 2: To characterize metabolic remodeling pathways in severe ischemic and non-ischemic cardiomyopathy and to determine mechanistic associations with response to CRT. Aim 3: To determine the myocardial metabolomics traits and metabolic mechanisms that underlie a favorable response to CRT in women.