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

摘要 冠状动脉血流在正常心脏中存在显著的空间不均一性，其在 冠心病(CHD)。尽管缺血在冠心病中具有重要的临床相关性，但物理和 健康和疾病中冠脉血流空间异质性的生物学决定因素仍不确定。 因此，一些治疗的机制，如冠状静脉窦(CS)闭塞，搏动性间歇 冠状静脉窦(CS)闭塞(PICSO)和选择性自体逆流(SARP)也不是很清楚。 高性能计算的进步现在使尝试解剖逼真的分布式成为可能 数学模型，其中冠状动脉血管系统的形态细节被认为是真正的 阐明流动的空间异质性。因此，我们在此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上精确的3D数据的自动调节冠状动脉循环的完整模型 关于跳动的心脏；它整合了心肌-血管相互作用(MVI)和血管反应性，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干预的理论基础。 经过验证的模型将阐明冠脉血流重新分布的临床重要机制。 以及CS干预的作用机制。我们的中心假设是 心肌氧(O2)需求导致冠脉血流的空间异质性，而缺血增加了冠脉血流 通过折衷MVI和自动调节实现异构性。由于与以下方面相关的固有困难 活体心内膜下测量：冠脉循环缺乏有效的生物物理模型 一直是取得进展的关键障碍。我们的建议解决了这一障碍，并具有推进的潜力 多尺度、多物理建模方面的科学知识，并最终掌握诊断和治疗方面的临床实践 冠心病的治疗。因此，三个具体目标是：1)开发一种经过实验验证的物理学-- 基于自动调节冠脉循环与心脏力学相结合的计算框架。2) 阐明心内膜下对缺血易损性的力学机制。3)确定机械 CSO、PICSO和SARP的作用机理及其影响因素。这项建议 采用综合方法(理论、计算模型和实验)来阐明两者之间的关系 血流灌注的空间异质性与心脏机械功、自动调节和耗氧量之间的关系 在病理和治疗条件下。拟议的工作将产生一种新的计算框架 这将被用来阐明控制缺血时心内膜下脆弱性的关键因素以及 CSO、PICSO和SARP的作用机制。生物物理建模框架还将作为 基于标准医学影像辅助诊断构建特定患者心脏模型的基础 和冠心病的治疗

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