Ph.D Thesis

Ph.D StudentHochberg Irit
SubjectA Molecular Basis for Inter-Individual Variability in
Development and Progression of Vascular Diseases
DepartmentDepartment of Medicine
Supervisors PROF. Andrew Peter Levy


Multiple factors affect the variable progression of vascular diseases in a given individual. Collateral blood vessels, which protect from ischemic tissue damage, are not found in all patients. There is a variability between diabetic patients in the development of microvascular and macrovascular complications.

Vascular endothelial growth factor (VEGF) is an endothelial specific mitogen, which plays a significant role in all angiogenic processes. Haptoglobin (Hp) is a plasma hemoglobin-binding protein, that is found in human subjects in one of three phenotypes.

We studied association of these factors with variability in vascular disease progression.

VEGF response to hypoxia in monocytes was correlated with the presence of coronary collaterals in patients with coronary stenosis and with presence of critical leg ischemia in patients with peripheral vascular disease. Hp phenotype was correlated with presence of diabetic retinopathy and diabetic nephropathy in diabetic subjects and with occurance of critical leg ischemia, restenosis and coronary collaterals in diabetic and non-diabetic subjects. Hp phenotype was correlated with cardiovascular end-points in a cohort of diabetic subjects from the Strong Heart Study.

We found a significant difference in the hypoxic induction of VEGF in patients with no coronary collaterals compared to patients with collaterals. This difference was not found between patients with and without critical leg ischemia. Diabetic subjects with Hp 1-1 have a significantly reduced risk of developing diabetic nephropathy and retinopathy, and both diabetic and non-diabetic subjects with Hp 1-1 had a significantly reduced risk for restenosis. Hp 2-1 was associated with more coronary collaterals and a reduced risk of restenosis compared to Hp 2-2. In the Strong heart study cohort, diabetic subjects with Hp 1-1 had a significantly reduced risk of cardiovascular end-points compared to subjects with Hp 2-1 and Hp 2-2. Subjects with Hp 2-1 had a significantly reduced risk of cardiovascuilar end-points compared to subjects with Hp 2-2.

We have discovered two factors significantly affecting inter-individual variability in development and progression of vascular diseases. This finding could have practical clinical applications  in risk assessment and care-planning for diabetic patients.