Wednesday, July 20, 2011

Hemodynamic shear stress, calcification and atherosclerosis

Atherosclerosis calcification occurs at sites of atherosclerotic plaques, where there is a combination of cellular necrosis, inflammation and cholesterol deposition.
Ectopic vascular calcification was viewed until recently as a passive consequence of aging. Although it is recognized that ectopic vascular calcification is a consequence of a dysregulated process, the specific molecular etiology remains unclear. There are conflicting ideas regarding the mechanisms underlying cardiovascular calcification, and the pathological and prognostic importance of vascular calcification still a matter of debate (1).
Osteoporosis, that is associated with calcium deficiency, has been also associated with atherosclerosis in many studies, with findings that bone mineral density declined while atherosclerotic plaque increased. We have discussed about this subject during the last year advocating acidosis as the link between these two diseases (2).
Coronary artery calcification measured by computed tomography (CT scans) is considered a radiographic confirmation of atherosclerosis, predicting cardiovascular events, and has been evaluated as a surrogate measure in randomized trials. However, in a study published in 2009 the annual rate of CAC increase was measured in 10 trials having observed a rate of 17% which was seen as moderately higher for patients with chronic kidney disease and those receiving dialysis. The study observed no consistent or reproducible treatment effect of any therapy on this outcome. These data have suggested to the authors that CAC may not be a suitable surrogate target for treatment trials in patients with cardiovascular or renal disease when measured after 12 months or reported on an annualized basis (3)
Nevertheless a very recently study from MESA (Multi Ethnic Study of Atherosclerosis) has shown that even healthy patients with low-density lipoprotein cholesterol (LDL-C) are associated with adverse coronary heart disease events if their CT scans demonstrate calcium buildup in their coronary arteries. Of 5,627 participants who were not receiving any baseline lipid-lowering therapies 3,714 (66%) had LDL-C 130mg/dl. Among the persons with low LDC-C, older age, male sex, hypertension, diabetes and low HDL-C were associated with adverse events (4).
It is interesting to notice that increased calcium content in diets supplemented with cholesterol has been show to decrease atherosclerosis in rabbits. Also, some epidemiological studies suggested that high levels of calcium in drinking water may decrease atherosclerosis (5).
Hemodynamic shear stress and calcification
A recent study developed in Switzerland, aimed to investigate regional plaque morphology and using intravascular ultrasound and virtual histology in coronary artery bifurcations, found that segments on the contralateral wall of the bifurcation which have previously identified as regions with low shear stress not only exhibited a higher plaque burden but also a higher degree of calcification (6). An analogous relationship was suggested by previous studies indicating that mechanical forces play a role in aortic valve calcification. Since calcium deposits occur almost exclusively on the aortic surfaces of AV leaflets it has been hypothesized that adverse pattern of fluid shear stress on the aortic surface of AV leaflets promotes calcification (7,8,9)
In the acidity theory of atherosclerosis the hemodynamic shear stress is an important step in the process leading to atherogenesis (10).
Carlos Monteiro
1. Johnson RC, Leopold JA and Loscalzo J. Vascular calcification: Pathological mechanisms and clinical implications. Circulation Research 2006; 99: 1044 -1059. Full free text at
2. Acidity: The link between atherosclerosis and osteoporosis, January 5, 2010 at
3. McCullow PA and Chinnayan KM. Annual progression of coronary calcification in trials of preventive therapies: A systematic review. Arch Intern Med 2009, 169 (22):2064-70. Full free text at
4. Blankstein R, Budoff MJ, Shaw LJ et al. Predictors of coronary heart disease events among asymptomatic persons with low low-density lipoprotein cholesterol. J Am Coll Cardiol, 2011;58:364-374
5. HSU HH and Culley NC. Effects of dietary calcium on atherosclerosis, aortic calcification, and icterus in rabbits fed a supplemental cholesterol diet. Lipids in Health and Disease 2006, 5.16. Full free text
6. Toggweiler S, Urbanek N, Schoenenberger AW, Erne P. Atherosclerosis, 2010 Oct;212(2):524-7
7. Hoehn D, Sun L and Sucosky P. Role of pathologic shear stress alterations in aortic valve endothelial activation. Cardiovascular Engineering and Technology 2010, V1;N2: 165-178. Full free text at
8. Ge L, Sotiropoulos F. Direction and magnitude of blood flow shear stresses on the leaflets of aortic valves: is there a link with valve calcification? J Biomech Eng 2010 Jan;132(1): 014505
9. Yap CH, Saikrishnan N, Tamilselvan G and Yoganathan AP. Experimental measurement of dynamic fluid shear stress on the aortic surface of the aortic valve of the aortic valve leaflet. Biomech Model Mechanobiol, 2011 Mar 18
10. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at