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
