Wednesday, May 14, 2025
5/14/2025
Mechanisms of coronary flow heterogeneity: Implications for coronary sinus occlusion therapy - 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
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