Tachycardia-induced Metabolic Remodeling Drives Cardiac Dysfunction

心动过速，或异常快的心率，是心血管疾病发病率和死亡率的重要风险因素。 众所周知，长时间的心动过速会导致既往没有结构性心脏病的患者发生心肌病。 此外，心力衰竭患者中常见的一过性心动过速会加剧心血管疾病。 结果。然而，目前对心动过速诱发心脏疾病的分子驱动因素知之甚少。 功能障碍。我们知识上的这种差距阻碍了更有效的心力衰竭治疗的发展， 尤其是对于难以控制的心动过速患者。这份K99/R00提案将利用最近在 诱导多能干细胞(IPSC)、组织工程和多组学技术来揭示分子 信号通路在心动过速相关心脏病的病理中起关键作用。申请者是Dr。 屠成义，已经建立并验证了一个使用工程心脏组织(EHT)的体外心动过速平台。 在目标1中，屠呦呦博士将在有或没有心动过速的情况下对EHTS进行代谢学和转录组分析。至 验证EHT模型、心动过速所致心力衰竭犬样本的生理学相关性 也将被剖析。来自EHTS和犬类样本的初步数据一致地表明 糖酵解动态平衡的破坏可能是心动过速对心功能的损害。 代谢组学分析表明，在EHTS中快速收缩导致糖酵解的选择性积聚 中间体，如3-磷酸甘油醛(GA3P)和3-磷酸甘油酸酯(3PG)。有趣的是， 促进脂肪酸代谢加速了心动过速EHTS患者心肌收缩能力的恢复。基座 根据这些新的结果，目标2将专注于阐明不同的糖酵解中间代谢物如何影响 心肌细胞的功能，这还有待系统地研究。最后，目标3(R00阶段)将 使用最先进的质谱学工作流程筛选糖酵解的新结合靶点 心肌细胞中的中间体，并检验操纵这些靶点的潜在治疗益处。这 K99/R00提案将由一个具有不同专业知识的优秀指导团队指导，其中包括导师Dr。 Joseph Wu(IPSC和心脏生物学)，共同导师Sanjiv Narayan博士(心律失常)，顾问Michael博士 斯奈德(遗传学和多组学)、戴玉琴博士(代谢组学)、斯坦利·齐博士(CRISPR干扰)和Dr。 贝丝·普鲁特(生物工程)，以及合作者法比奥·雷奇亚博士(犬类模型)和唐纳德·贝斯博士 (心脏生理学)。总括而言，拟议研究的完成将大大提高我们的机构性 了解心动过速如何对心脏产生不利影响，从而为治疗创造新的机会 干预措施。拟议中的培训将显著加强和扩大屠呦呦博士的研究专长， 为他向独立的心血管研究人员过渡提供了实质性的动力。

Tachycardia, or abnormally fast heart rate, is an important risk factor for cardiovascular morbidity and mortality. Prolonged tachycardia is known to induce cardiomyopathy in patients who have no prior structural heart diseases. Moreover, transient tachycardia, frequently observed in heart failure patients, can exacerbate the cardiovascular outcome. However, very little is known about the molecular drivers underlying tachycardia-induced cardiac dysfunction. This gap in our knowledge hinders the development of more effective heart failure treatment, especially for patients with hard-to-control tachycardia. This K99/R00 proposal will leverage recent advances in induced pluripotent stem cell (iPSC), tissue engineering, and multiomics technologies to uncover the molecular signaling pathways critically involved in the pathology of tachycardia-related heart disease. The applicant, Dr. Chengyi Tu, has established and validated an in vitro tachycardia platform using engineered heart tissue (EHT). In Aim 1, Dr. Tu will perform metabolomic and transcriptomic profiling of EHTs with or without tachypacing. To validate the physiological relevance of the EHT model, canine samples from tachypacing-induced heart failure will also be profiled. Preliminary data from the EHTs and the canine samples coherently indicate that the disruption of glycolysis homeostasis may underly the impairment of cardiac function by tachycardia. Metabolomics analysis shows that tachypacing in EHTs resulted in a selective accumulation of glycolysis intermediates such as glyceraldehyde 3-phosphate (GA3P) and 3-phosphoglycerate (3PG). Interestingly, promotion of fatty acid metabolism accelerated the recovery of cardiac contractility in tachypaced EHTs. Based on these novel results, Aim 2 will focus on elucidating how different glycolysis intermediate metabolites affect the function of cardiomyocytes, which has yet to be systematically examined. Lastly, Aim 3 (R00 phase) will employ state-of-the-art mass spectrometry workflow to screen for novel binding targets of glycolysis intermediates in cardiac cells, and examine the potential therapeutic benefits of manipulating these targets. This K99/R00 proposal will be guided by an excellent mentoring team with diverse expertise, including mentor Dr. Joseph Wu (iPSCs and cardiac biology), co-mentor Dr. Sanjiv Narayan (arrhythmia), advisors Dr. Michael Snyder (genetics and multi-omics), Dr. Yuqin Dai (metabolomics), Dr. Stanley Qi (CRISPR interference) and Dr. Beth Pruitt (bioengineering), as well as collaborators Dr. Fabio Recchia (canine model) and Dr. Donald Bers (cardiac physiology). To sum up, the completion of the proposed study will significantly advance our mechanistic understanding of how tachycardia adversely affects the heart, thereby creating new opportunities for therapeutic interventions. The proposed training will significantly strengthen and expand Dr. Tu’s research expertise, providing substantial momentum to his transition toward an independent cardiovascular researcher.