Ph.D Thesis

Ph.D StudentAlgranati Dotan
SubjectPhysical Determinants of Normal and Obstructed Coronary Flow
DepartmentDepartment of Biomedical Engineering
Supervisor PROFESSOR EMERITUS Yoram Lanir
Full Thesis textFull thesis text - English Version


Ischemic heart diseases, stemming mainly from coronary obstruction (stenosis), are a major cause of morbidity and mortality worldwide. Intriguingly, ischemia onset is transmurally heterogeneous, the deeper (subendocardial) layers being more vulnerable than more superficial (subepicardial) ones. This experimental observation is especially puzzling in light of the fact that atherosclerosis-induced stenoses are observed exclusively in epicardial coronary arteries, whereas intramural arteries are practically athero-protected. Initiation of both ischemia and atherosclerosis highly depend on flow conditions. Hence, investigation of the determinants of both pathologies requires comprehension of the local coronary flow conditions. These are presently unknown, mainly due to the excessive difficulties associated with flow measurements in the beating heart, difficulties that turn computerized simulation into an attractive alternative.

Hereinafter, local coronary flow conditions were investigated in order to address open research and clinical questions using a unique computational framework that consists of several sub-models relating to the coronary anatomy, the vessel in-situ mechanics, the dynamic network flow, and the myocardium/vessel interaction.

 Being a pivotal key for realistic flow analysis and the subject of long-standing ongoing dispute, the physical determinants of myocardium/vessel interaction have been investigated first. The results imply that only an extravascular loading that stems from both the left-ventricle cavity pressure and the contraction-induced intra-myocyte pressure can account for published data on coronary flow. The data includes total and regional coronary flow under different heart loadings (e.g. heart rate changes), as well as patterns and magnitude of dynamic intravascular flow, pressure and diameter changes where these can be measured.

The validated computational platform was next applied to explore the origins of subendocardial vulnerability to ischemia. Subendocardial vulnerability was found to result from a higher compliance of subendocardial vasculature, which is due to both the non-linear vessel pressure-diameter relationship and the in-homogeneity in the extra-vascular loading across the wall. Importantly, this elucidation of the origins of vulnerability provides mechanistic insight into the therapeutic effects of different types of clinical procedures of the coronary patient.

Finally, the computational framework was applied to evaluate indices presently used in the clinic to describe the severity of a coronary stenosis. These indices determine the appropriate type of treatment modality to be adopted. The results here indicate that while none of the indices is reliable under all possible changes in physiological conditions, the pressure-based fractional flow reserve (FFR) is more reliable in representing the stenosis severity than the commonly used index of degree of lumen obstruction.