Optical Tools to Assess the Role of Hemodynamics in the Development of Congenital Heart Defects

评估血流动力学在先天性心脏缺陷发展中的作用的光学工具

• 批准号: 8985102
• 负责人: MICHAEL W. JENKINS
• 金额: $ 61.27万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985102
• 关键词: 3-Dimensional; Ablation; Affect; Alcohols; Algorithmic Software; Algorithms; American; Biological Assay; Blood flow; Cardiac; Cardiac Output; Cardiac development; Cardiovascular system; Chemical Exposure; Complex; Congenital Abnormality; Congenital Heart Defects; Defect; Development; Double Outlet Right Ventricle; Early Diagnosis; Embryo; Embryonic Development; Embryonic Heart; Etiology; Experimental Models; Feedback; Genetic; Heart; Heart Rate; Hypoxia; Image; Knowledge; Lasers; Lead; Light; Link; Location; Measurement; Measures; Methods; Modification; Molecular; Monitor; Morphology; Nerve; Neural Crest Cell; Neurons; Normalcy; Optical Coherence Tomography; Optics; Pathway interactions; Pattern; Penetration; Phenotype; Physiologic pulse; Play; Protocols documentation; Research Personnel; Role; Side; Speed; Spottings; Staging; Stroke Volume; Structural defect; Structure; System; Techniques; Technology; Testing; Time; United States; blood flow measurement; cardiogenesis; clinically relevant; computerized data processing; design; design and construction; developmental cardiology; genetic manipulation; hemodynamics; in vivo; public health relevance; reconstruction; shear stress; tool

 DESCRIPTION (provided by applicant): Congenital heart defects (CHDs) are one of the most common and devastating birth defects, afflicting 32,000 babies born in the United States each year, and over 1 million Americans alive today. Altered hemodynamics during development has been shown to be a contributing factor to CHDs, regardless of whether the initial trigger is environmental or genetic. However, there is currently a lack of appropriate tools for studying the effects of clinically relevant hemodynamic perturbations on the development of later defects. The objective of this project is to design, construct, and apply the tools necessary to measure and precisely perturb hemodynamics in early embryonic development and then detect and quantify the resultant CHDs that develop. We propose to use optical techniques for both measurement and perturbation. We have previously demonstrated that optical coherence tomography (OCT) can measure many hemodynamic parameters, including heart rate, cardiac output, stroke volume, shear stress, and regurgitation. For this project, we will construct an ultrahigh-speed OCT system using new hardware and software algorithms to acquire hemodynamic parameters in real-time. We will build the system to be able to conduct longitudinal imaging studies of multiple embryos in parallel. New optical control (OC) technology has been developed for stimulating and inhibiting nerves and neurons, using pulsed infrared light to induce thermal effects. We have recently adapted this technology to stimulate embryonic hearts both in vivo and ex vivo and have a proof-of-concept demonstration for inhibiting cardiac activity. OC enables precise control of heart rate and development of advanced OC protocols will enable complex alteration of the heart's beat patterns (e.g. altered atrioventricular delay). We will perform further optimization of OC parameters and integrate OC into our ultrahigh-speed OCT system. This will enable the development of a closed-loop control system utilizing real-time OCT parameters as feedback to maintain hemodynamic parameters at desired values for long periods of time, even as the embryo grows and develops. We will also construct a double-sided Bessel-beam OCT system to obtain, in conjunction with optical clearing techniques, sufficient depth penetration to acquire structural images of later stage 4-chambered embryonic hearts. Finally, after validating these systems, we will apply this technology to test the hypothesis that altered regurgitation and shear stress on the developing cardiac cushions (valve precursors) will lead to valve defects. We will also explore whether compromised cardiac cushions also lead to misalignment of the great vessels (e.g. double outlet right ventricle). Upon completion, we will have developed tools and gathered significantly more information on when, how, and to what degree the developing cardiovascular system is most vulnerable to abnormal hemodynamics. With this knowledge, we will be better equipped to determine which molecular pathways are most influenced by altered hemodynamics, to develop earlier detection strategies, and potentially to treat CHDs more effectively.

 描述（由申请人提供）：先天性心脏病 (CHD) 是最常见和最具破坏性的出生缺陷之一，每年影响美国出生的 32,000 名婴儿，目前有超过 100 万美国人在发育过程中血流动力学发生改变。无论最初的触发因素是环境还是遗传，它都是导致冠心病的一个因素。然而，目前有一些适当的工具可用于研究临床相关血流动力学的影响。该项目的目标是设计、构建和应用必要的工具来测量和精确扰动早期胚胎发育中的血流动力学，然后检测和量化所产生的先心病。我们之前已经证明光学相干断层扫描 (OCT) 可以测量许多血流动力学参数，包括心率、心输出量、每搏输出量、剪切应力和反流。将使用新的硬件和软件算法构建超高速 OCT 系统来实时获取血流动力学参数，我们将构建能够并行进行多个胚胎纵向成像研究的系统。已开发用于刺激和抑制神经和神经元，使用脉冲红外光诱导热效应，我们最近采用该技术来刺激体内和离体胚胎心脏，并进行了抑制心脏活动的概念验证演示。 OC 可实现精确控制心率和先进 OC 协议的开发将实现心脏跳动模式的复杂改变（例如改变房室延迟），我们将进一步优化 OC 参数并将 OC 集成到我们的超高速 OCT 系统中。利用实时 OCT 参数作为反馈的闭环控制系统，即使在胚胎生长和发育时，也能长时间将血流动力学参数维持在所需值。 OCT系统与光学透明技术相结合，获得足够的深度穿透，以获取后期四腔胚胎心脏的结构图像。最后，在验证这些系统后，我们将应用该技术来检验反流和剪切应力对心脏的影响的假设。开发心脏垫（瓣膜前体）将导致瓣膜缺陷，我们还将探讨受损的心脏垫是否也会导致大血管错位（例如双出口右心室）。工具并收集了关于发育中的心血管系统何时、如何以及在何种程度上最容易受到血流动力学异常影响的更重要的信息，有了这些知识，我们将能够更好地确定哪些分子途径最受血流动力学影响，从而进行早期检测。策略，并有可能更有效地治疗先心病。