IN the 19th century there were two major hypotheses to explain the pathogenesis of atherosclerosis: the "incrustation" hypothesis and the "lipid" hypothesis. The incrustation hypothesis of von Rokitansky,1 proposed in 1852 and modified by Duguid,2 suggested that intimal thickening resulted from fibrin deposition, with subsequent organization by fibroblasts and secondary lipid accumulation. The lipid hypothesis, proposed by Virchow3 in 1856, suggested that lipid in the arterial wall represented a transduction of blood lipid, which subsequently formed complexes with acid mucopolysaccharides; lipid accumulated in arterial walls because mechanisms of lipid deposition predominated over those of removal. The two hypotheses are now . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199201233260406?articleTools=true

The pathogenesis of coronary artery disease and the acute coronary syndromes (1).

The boundary layer equations for plane, incompressible, and steady flow are 

$$\matrix{ {u{{\partial u} \over {\partial x}} + v{{\partial u} \over {\partial y}} = - {1 \over \varrho }{{\partial p} \over {\partial x}} + v{{{\partial ^2}u} \over {\partial {y^2}}},} \cr {0 = {{\partial p} \over {\partial y}},} \cr {{{\partial u} \over {\partial x}} + {{\partial v} \over {\partial y}} = 0.} \cr }$$

Boundary Layer Theory

Dynamic strength of molecular adhesion bonds.

Leukocytes roll on a selectin at physiologic flow rates: Distinction from and prerequisite for adhesion through integrins

Vascular endothelial cells (ECs) are exposed to hemodynamic forces, which modulate EC functions and vascular biology/pathobiology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. These findings have led to the concept that the disturbed flow pattern in branch points and curvatures causes the preferential localization of atherosclerotic lesions. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to pathophysiology of clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. In the venous system, disturbed flow resulting from reflux, outflow obstruction, and/or stasis leads to venous inflammation and thrombosis, and hence the development of chronic venous diseases. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in pathogenesis of vascular diseases and can help to elucidate the phenotypic and functional differences between quiescent (nonatherogenic/nonthrombogenic) and activated (atherogenic/thrombogenic) ECs. This review summarizes the current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.

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Effects of Disturbed Flow on Vascular Endothelium: Pathophysiological Basis and Clinical Perspectives

Margination of leukocytes in blood flow through small tubes

The behaviour of individual human red cells and rouleaux were studied under the microscope in suspensions of 0.1 N m$^{-2}$, especially in viscous isotonic Dextran solutions, the cells oriented themselves at a constant angle to the flow and their membrane appeared to rotate about the interior. Although this behaviour was analogous to that of liquid drops, the concavity was still present in the deformed erythrocytes, whose mean major diameters in plasma increased by 1.05 $\mu $m as the shear stress increased from 0 to 0.4 N m$^{-2}$. Deformation, through bending, was also observed with linear rouleaux of > 6 cells, here, at even the lowest shear stresses. By contrast, glutaraldehyde hardened cells and rouleaux rotated, without deforming, as rigid disks and rods respectively.

Flow Behaviour of Erythrocytes. I. Rotation and Deformation in Dilute Suspensions

Red cell motions and wall interactions in tube flow.

Adhesion of human platelets to collagen on the walls distal to a tubular expansion

Disturbed flows associated with the particular geometry of vessels are considered not only to play an important role in the focal deposition of platelets and white cells on artificial surfaces and the localization of thrombosis and atherosclerosis in vivo, but also to exert some detrimental effects on both the circulating blood cells and the vessel wall, resulting in hemolysis of red cells, activation and aggregation of platelets and white cells, and formation of aneurysms and dilatation of the vessel wall in regions of disturbed flow. Ideally, therefore, it is desirable to avoid creating any flow disturbance, but if this is inevitable, to minimize the size and intensity of the disturbed flows that may form in living vessels as the result of vascular surgery or in channels of artificial organs and vascular prostheses. Except for the case of very high flow rates (or high Reynolds numbers well over 2000), turbulent flow either in the straight parts of arteries in vivo, or in any artificial conduit having a circular cross section, is not likely to be seen. Therefore, in the context of the present paper, we will limit our description and discussion only to the phenomena that occur at Reynolds numbers smaller than 2000 and in steady flow. During the past 10 years or so we have been carrying on a series of investigations on the role of fluid mechanical factors in the localization of thrombosis and atherosclerosis in man, and studying the flow patterns in various vessels of simple and complex geometries by means of flow visualization and cinemicrographic techniques. In this paper we will summarize our findings on the detailed three-dimensional structures of disturbed flows formed in glass models of stenoses and T-junctions, compare them with those observed in isolated transparent natural arteries and veins prepared from dogs and humans postmortem, and then identify the differences in geometrical structures and flow patterns between the artificial vessels and the natural blood vessels in order to find out the optimum conditions to eliminate or minimize the region of disturbed flow that may form in vivo as well as in any channel of artificial vessels.

Harry L. Goldsmith

Papers

Margination of leukocytes in blood flow through small tubes

Flow Behaviour of Erythrocytes. I. Rotation and Deformation in Dilute Suspensions

Red cell motions and wall interactions in tube flow.

Adhesion of human platelets to collagen on the walls distal to a tubular expansion

Flow patterns in vessels of simple and complex geometries.