Metabolomics Mapping and Cardiac Resynchronization

代谢组学绘图和心脏再同步

• 批准号: 10326338
• 负责人: Yong-Mei Cha
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-08 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326338
• 关键词: Adult; Affect; American; Area; Biological Markers; Blood; Body Fluids; Branched-Chain Amino Acids; Bundle-Branch Block; Cardiac; Cardiomyopathies; Carnitine; Cell physiology; Clinical; Clinical Trials; Consumption; Control Groups; Coronary sinus structure; Critical Pathways; Cross-Over Studies; Crossover Design; Data; Defibrillators; Deterioration; Devices; Disease; Disease Progression; EFRAC; Effectiveness; Enrollment; Epidemic; Event; Functional disorder; Gender; Healthcare; Heart; Heart failure; Heterogeneity; Hospitalization; Impairment; Incidence; Intervention; Knowledge; Label; Lateral; Left; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Left Ventricular Remodeling; Metabolic; Metabolic Pathway; Metabolism; Myocardial; Myocardial dysfunction; Nature; Outcome; Pacemakers; Pathway interactions; Patient Monitoring; Patient Selection; Patients; Pattern; Persons; Prevention; Process; Progressive Disease; Prospective Studies; Randomized; Recovery; Research Design; Risk; Role; Symptoms; Technology; Testing; United States National Institutes of Health; Ventricular; Whole Blood; Woman; acylcarnitine; base; cardiac resynchronization therapy; community burden; early detection biomarkers; effective intervention; follow-up; health care delivery; heart damage; heart function; heart metabolism; improved; men; metabolic profile; metabolomics; mortality; novel; novel therapeutics; outcome prediction; precision medicine; predicting response; prevent; response; restoration; stable isotope; therapy outcome; trait; translational approach; treatment group; treatment guidelines; treatment response

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.

项目摘要/摘要 心力衰竭（HF），一种流行病，影响了570万美国成年人，该事件预计将是 到2030 有症状（C阶段和D）。由于无症状患者发生出现HF的大量风险 LV收缩功能障碍，必须在HF的早期制定有效的干预措施。心脏 重新同步疗法（CRT）是一种新型疗法，可降低HF住院和死亡率，并且 改善LV收缩功能和HF症状。 CRT在轻度LV收缩期患者中的有效性 功能障碍 - 尚未确定LBBB的36％-50％-50％。尚不清楚早期 重新同步将防止LVEF定义并反向心室代谢重塑。 心肌代谢，异同步和心肌分布不足的异质性质 消耗是HF沉淀心肌功能障碍的标志。但是，CRT对 心肌能量和底物代谢，以及代谢状态和途径促进心肌 恢复未知。此外，LBBB和代谢途径的代谢组学特征受到影响 尚未确定LV侧壁的延迟传导区域。此外，妇女可能会受益 在改善生存，HF事件和反向LV重塑方面，CRT比男性多。但是 尚未阐明女性有利CRT结局的代谢机制。代谢组 监测患者体液和心脏特异性冠状动脉血液对精度至关重要 药物，包括在NIH路线图中。彼此之间，通过分析严重和 在LBBB存在的情况下，轻度的HF以及CRT中的性别和缺血性 - 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。这项研究会 使用稳定的同位素基于18O的代谢组学技术和跨心脏代谢映射来理解 CRT如何改善心脏代谢途径并识别代谢途径和新型代谢生物​​标志物 这可以预测CRT通过CRT恢复LV收缩功能。随着跨界研究设计，酰基的作用 肉碱，支链氨基酸和血液磷酸盐代谢物的周转率将在早期进行检查 与LV功能障碍有关的生物标志物。该研究将包括三个目标。 目的1：确定中等中期患者的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结果预测中的作用。目标2：代谢特征 严重缺血和非缺血性心肌病的重塑途径，并确定机械 与对CRT的响应的关联。目标3：确定心肌代谢组学特征和代谢 对女性CRT的有利反应的机制。

项目成果

Cardiac Resynchronization Therapy Modulates Peripheral Sympathetic Activity.

• DOI: 10.1016/j.hrthm.2020.02.022
• 发表时间: 2020-02
• 期刊: Heart rhythm
• 影响因子: 5.5
• 作者: P. Xiao;Cheng Cai;Pei Zhang;C. DeSimone;Dereen Ernst;Y. Yin;Peng-Sheng Chen;Y. Cha