Mechanisms of coronary flow heterogeneity: Implications for coronary sinus occlusion therapy

冠状动脉血流异质性的机制：对冠状窦封堵治疗的影响

基本信息

批准号：
10645096
负责人：
GHASSAN S KASSAB
金额：
$ 68.11万
依托单位：
CALIFORNIA MEDICAL INNOVATIONS INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645096
关键词：
3-Dimensional Acute Address Affect Anatomy Animals Balloon Occlusion Biological Blood Vessels Blood capillaries Blood flow Cardiac Chronic Clinical Research Computer Models Consumption Coronary Coronary Arteriosclerosis Coronary Circulation Coronary Stenosis Coronary heart disease Coronary sinus structure Coupling Data Diagnosis Diffuse Disease Effectiveness Family suidae Foundations Genes Health Heart Heterogeneity High Performance Computing Homeostasis Intervention Ischemia Knowledge Length Liquid substance Measurement Mechanics Medical Imaging Metabolic Modeling Morphology Myocardial Myocardium Nature Organ Outcome Oxygen Oxygen Consumption Pathologic Patient Selection Patients Percutaneous Transluminal Coronary Angioplasty Perfusion Physics Property Refractory Regional Blood Flow Risk Role Scientific Advances and Accomplishments Societies Solid Therapeutic Time Tissues Translating Treatment Effectiveness Trees Vascular System Vascular blood supply Venous Work ameroid animal data biophysical model clinical practice clinically relevant clinically significant computer framework coronary vasculature effective therapy experimental study in vivo mathematical model novel porcine model pressure regional difference restraint theories treatment optimization

项目摘要

ABSTRACT Significant spatial heterogeneity of coronary blood flow exists in the normal heart and it is exaggerated in coronary heart disease (CHD). Despite the significant clinical relevance of ischemia in CHD, the physical and biological determinants of spatial heterogeneity of coronary blood flow in health and disease remain uncertain. As a result, the mechanisms of some treatments, such as coronary sinus (CS) occlusion, pulsatile intermittent coronary sinus (CS) occlusion (PICSO) and selective auto-retroperfusion (SARP), are also not well understood. Advances in high-performance computing now make it possible to attempt anatomically realistic distributive mathematical models, where morphological details of the coronary vascular system are considered to truly elucidate the spatial heterogeneity of flow. Hence, our general objective in this proposal is to develop a validated full model of an autoregulated coronary circulation based on anatomically accurate 3D data in a dynamic model of the beating heart; one that integrates myocardium-vessel interaction (MVI) and vasoreactivity, can explain the spatial heterogeneity of coronary blood flow in ischemia, and elucidate the rationale for these CS interventions. The validated model will illuminate clinically significant mechanisms underlying the redistribution of coronary flow in ischemia and the mechanisms of CS interventions. Our central hypothesis is that regional differences in myocardial oxygen (O2) demand produce spatial heterogeneity in coronary flow and that ischemia increases flow heterogeneity by compromising MVI and autoregulation. Due to inherent difficulties associated with subendocardial measurements in vivo, the absence of a validated biophysical model of the coronary circulation has been a critical barrier to progress. Our proposal addresses this barrier and has the potential to advance scientific knowledge in multi-scale, multi-physics modeling and, ultimately, clinical practice in diagnosis and treatment of CHD. Accordingly, the three Specific Aims are to: 1) Develop an experimentally validated, physics- based computational framework coupling autoregulated coronary circulation with cardiac mechanics. 2) Elucidate the mechanical mechanisms of subendocardial vulnerability to ischemia. 3) Determine the mechanical mechanism of action of CSO, PICSO and SARP as well as factors affecting these treatments. This proposal takes an integrated approach (theory, computational models, and experiments) to elucidate the relationship between spatial heterogeneity of perfusion and cardiac mechanical work, autoregulation, and O2 consumption under pathological and treatment conditions. The proposed work will produce a novel computational framework that will be used to elucidate the key factors controlling subendocardial vulnerability in ischemia and the mechanism of actions of CSO, PICSO and SARP. The biophysical modeling framework will also serve as a foundation for constructing patient-specific heart model based on standard medical imaging to assist in diagnosis and treatment of CHD

抽象的正常心脏中冠状动脉血流存在显着的空间异质性，而在正常心脏中这种异质性被夸大了。冠心病（CHD）。尽管缺血与冠心病具有显着的临床相关性，但身体和健康和疾病中冠状动脉血流空间异质性的生物决定因素仍然不确定。因此，一些治疗的机制，如冠状窦 (CS) 闭塞、脉动间歇性治疗冠状窦 (CS) 闭塞 (PICSO) 和选择性自动逆灌注 (SARP) 也尚未得到充分了解。高性能计算的进步现在使得尝试解剖学上现实的分布成为可能数学模型，其中冠状血管系统的形态细节被认为是真实的阐明流动的空间异质性。因此，我们在本提案中的总体目标是开发一个经过验证的基于动态模型中解剖学精确 3D 数据的自动调节冠脉循环的完整模型跳动的心脏；一种整合了心肌-血管相互作用（MVI）和血管反应性的方法，可以解释缺血时冠状动脉血流的空间异质性，并阐明这些 CS 干预措施的基本原理。经过验证的模型将阐明冠状动脉血流重新分布的临床重要机制缺血和 CS 干预机制。我们的中心假设是，地区差异心肌氧 (O2) 需求会产生冠状动脉血流的空间异质性，并且缺血会增加血流通过损害 MVI 和自动调节来实现异质性。由于固有的困难体内心内膜下测量，缺乏经过验证的冠状循环生物物理模型一直是进步的关键障碍。我们的提案解决了这一障碍并有潜力推进多尺度、多物理建模的科学知识，以及最终的诊断和临床实践治疗冠心病。因此，三个具体目标是： 1) 开发一种经过实验验证的物理- 基于计算框架耦合自动调节冠状动脉循环与心脏力学。 2）阐明心内膜下易受缺血影响的机械机制。 3）确定机械 CSO、PICSO 和 SARP 的作用机制以及影响这些治疗的因素。这个提议采用综合方法（理论、计算模型和实验）来阐明这种关系灌注的空间异质性与心脏机械功、自动调节和 O2 消耗之间在病理和治疗条件下。拟议的工作将产生一个新颖的计算框架这将用于阐明控制缺血和心内膜下脆弱性的关键因素 CSO、PICSO 和 SARP 的行动机制。生物物理建模框架也将作为为基于标准医学影像构建患者特异性心脏模型辅助诊断奠定基础和冠心病的治疗