Effect of atherosclerosis on transmural convection and arterial ultrastructure - Implications for local intravascular drug delivery

Local infusion of agents through perforated catheters may reduce neointimal formation following vascular angioplasty. Such treatment will succeed only if the drug is retained within the arterial intima long enough to promote repair. Drugs will be dispersed throughout the wall predominantly by transmural convection instead of diffusion if the Peclet number, Pe=J(1-sigma(f))/P, is greater than unity, where J is the transmural fluid flow per unit surface area and sigma(f) and P are the reflection and permeability coefficients to the drug, respectively. Although the targets of local drug delivery will be atherosclerotic vessels, little is known about the transport properties of these vessels. Accordingly, we evaluated the effects of hypercholesterolemia and atherosclerosis on J per unit pressure (hydraulic conductance, L-p) and on ultrastructure in femoral arteries. Measurements were made at 30, 60, and 90 mm Hg in anesthetized New Zealand white rabbits fed a normal diet (n=6) and after 3 weeks of lipid feeding (n=19). Atherosclerosis was induced in six lipid-fed animals by air desiccation of a femoral artery. Hydraulic conductance was significantly greater in vessels from hypercholesterolemic than from normal animals and decreased with pressure only in hypercholesterolemic arteries. Atherosclerosis did not augment hydraulic conductance compared with hypercholesterolemia alone. Electron microscopic examination demonstrated damaged endothelium in hypercholesterolemic arteries and both altered endothelium and less tightly packed medial tissue, compared with controls, in atherosclerotic vessels, at least at lower pressures. Peclet numbers for macromolecules exceeded unity for all three groups of arteries and reached 0.3 to 0.4 for molecules as small as heparin. Thus, convection plays a dominant role in the distribution of macromolecular agents following local delivery and may result in their rapid transport to the adventitia in the femoral artery.