Carol Act Supplement to Data-driven optimization of therapy for heart failure

摘要 本提案是对NOT-HL-23-078《鼓励研究的行政补充文件》的回应 并为HL163977寻求12个月的额外支持，数据驱动的优化 治疗心力衰竭。父R01在2026年前处于活动状态。 HL163977的首要目标是开发一种可用于测试心脏的计算机模型 心力衰竭患者的治疗策略和优化治疗。目标1开发了一个系统 称为MyoVent，作为实现压力感受器反射控制和心肌生长的试验台。目标2和目标3使用 使用MyoVent开发的技术，并将它们部署在名为MyoFE的更复杂的3D框架中 创建特定于患者的个性化模型。 该团队取得了快速进展，目标1现已基本完成。这一突破是通过以下方式实现的 开发调节同心(壁厚/变薄)和偏心(腔扩张/)的算法 收缩)对生理信号作出反应的生长。具体地说，该模型假设心脏生长 向心稳定细胞内ATP浓度而偏心生长对被动敏感 肌动蛋白细丝感受到的细胞内应力。这些生长规律再现了心脏生长的模式。 在临床相关情况下观察，包括高血压、运动和肌球蛋白不稳定 超级放松的状态。 这一补充将把模拟扩展到瓣膜心脏病。目标是有重点的。团队将会 检验生长规律是否能预测临床观察到的偏心性和向心性生长模式 二尖瓣关闭不全(包括二尖瓣脱垂)和狭窄，以及主动脉瓣关闭不全和 狭窄。这将在一年内由一名高度合格和经验丰富的博士后完成，他将在 在联系PI的监督下。

ABSTRACT This proposal is submitted in response to NOT-HL-23-078 “Administrative supplements to encourage research in valvular heart disease” and seeks 12 months of additional support for HL163977, Data-driven optimization of therapy for heart failure. The parent R01 is active until 2026. The overarching goal of HL163977 is to develop a computer model of the heart that can be used to test therapeutic strategies and optimize treatments for patients who have heart failure. Aim 1 develops a system called MyoVent as a test-bed for implementing baroreflex control and myocardial growth. Aims 2 and 3 use the techniques developed with MyoVent and deploy them in a more sophisticated 3D framework called MyoFE to create patient-specific personalized models. The team has made rapid progress and Aim 1 is now mostly complete. The breakthrough was accomplished by developing algorithms that modulate concentric (wall thickening / thinning) and eccentric (chamber dilation / constriction) growth in response to physiologic signals. Specifically, the model assumes that hearts grow concentrically to stabilize the intracellular ATP concentration while eccentric growth is sensitive to the passive intracellular stress sensed by titin filaments. These growth laws reproduce the patterns of cardiac growth observed in clinically-relevant conditions including hypertension, exercise, and destabilization of the myosin super-relaxed state. This supplement will extend the simulations to valvular heart disease. The objective is focused. The team will test whether the growth laws predict the patterns of eccentric and concentric growth observed clinically in patients with mitral valve insufficiency (including mitral valve prolapse) and stenosis, and aortic valve insufficiency and stenosis. This will be accomplished in a single year by a highly-qualified and experienced post-doc who will work under the supervision of the contact PI.