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Rheology, Cardiovascular Risk Factors and Silent Atherosclerosis

Jaime Levenson, M.D.

 Centre de Médecine Préventive Cardiovasculaire, INSERM CRI
Hôpital Broussais – Paris - France
E-Mail : levenso@worldnet.fr

Arterial wall rigidity

Blood and plasma viscosity

Blood cells, endothelial cells and shear stress

References

Rheology of the circulation can be regarded as a branch of biomechanics related with vessel wall deformation and blood dynamics under mechanical stresses. The role of these forces in diffuse arterial rigidity, localized atherosclerotic plaque and thrombogenesis raise increasing interest in clinical research.

The mechanical stress related to intravascular pressure induces changes in the physical properties of the arterial wall (ie. arterial compliance, wall viscosity) which may contribute to the degenerative process of the arteries. The stress related to blood flow dynamics, or wall shear stress, which depends on blood viscosity and the velocity gradient at the arterial wall play an important role on the thickening and localization of arterial plaques in the vascular tree.

Arterial wall rigidity

Diffuse arterial rigidity, related to the sclerotic component of atherosclerosis, is detectable by the measurement of pulse-wave velocity (1), evaluated by simultaneously recording two arterial pulses (pressure or velocity by mecanography or Doppler ultrasound) at two different peripheral sites. Local arterial rigidity can be measured by recording the motion of the walls of the peripheral arteries (carotid or femoral) using an echotracking system (2). With aging, arteries progressively stiffen, dilate, and lenghten, and the arterial wall thickens. Chronic hypertension increased both diffuse and local arterial rigidity, but the arterial rigidity did not homogeneously affect the arterial tree (2). In diabetes mellitus with chronic elevation of blood glucose, arterial distensibility is decreased. It is likely that glycosylation (which is proportional to ambient glucose level) may reduce the elasticity of connective tissue in blood vessels. Smoking also has been demonstrated to increase aortic pulse wave velocity both in normotensive and hypertensive subjects independently of pressure and aging effects (1). The effect of smoking and hypertension on aortic rigidity were shown to be cumulative (1) (Figure 1).

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Figure 1: Pulse wave velocity in normotensive and hypertensive nonsmokers and smokers. From Levenson et al (1) with permission.

The lack of relationship between aortic pulse wave velocity and total serum cholesterol has been reported in women as well as in men (3). Conflicting results have been reported concerning the arterial wall stiffness in atherosclerosis. Comparison of arterial pulse wave velocity in Chinese subjects with low incidence of atherosclerotic disease against values obtained in several Western populations with a higher incidence of atherosclerosis, showed a higher rather than lower pulse wave velocity in the Chinese population and a greater increase with increasing age (3). Diffuse vascular sclerosis might contribute to left ventricular hypertrophy by increasing pulsatile workload, and accelerate the degenerative processes in arterial walls submitted to higher pulsatile cyclic stress.

Blood cells, endothelial cells and shear stress

The stress generated by blood flow can functionally or structurally modulate the circulating blood cells as well as the endothelial cells and participate in the genesis and development of arterial wall pathophysiology.

In endothelial cells, flow-induced shear stress stimulate numerous responses including, increased release of the vasoactive compounds prostacyclin, nitric oxide, endothelin-1 that regulate vessel tone, the production of the second messenger cAMP, cGMP, inositol triphosphate, the secretion of tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1), the expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1); and the gene expression of c-foss, c-jun and c-myc (4).

The most relevant and well known effect of shear stress on exposed circulating cells is represented by erythrocyte and platelet aggregation.

The aggregation and disaggregation of red blood cells (RBC) play an important role in the pathophysiological behavior of the blood circulation. The aggregation of RBC is a reversible phenomenon that occurs with macromolecules bridging the membranes of adjacent cells, and it is influenced by the shearing force of blood, the properties of erythrocytes (concentration, deformability, surface charge, and shape) and the bridging force of high molecular weight plasma proteins (5).

An increase in erythrocyte aggregation induces an increase in blood viscosity and affects the capillary flow by forming the "sludge". Erythrocyte hyperaggregability is observed in subjects with cardiovascular risk factors like hypertension, hyperlipoproteinemia and smoking and in such clinical situations as myocardial ischemia thromboembolic states and retinal venous occlusion. In hypertension (5) and in hypercholesterolemia (6), fibrinogen plays a major role in the increase of erythrocyte aggregation. In addition, in hypercholesterolemia, increase of fibrinogen, total plasma proteins, apolipoprotein (Apo) B, and lipoprotein (Lp)AI: AII could partially explain the enhanced parameters of erythrocyte aggregation. In contrast increase of high density lipoprotein (HDL-C), particularly HDL2-C subfraction and Lp A1, may counteract this action (6). The decrease of negative cell surface charge mainly originating from sialic acid present in the sugar moiety of membrane-bound glycoproteins, results in a increase in erythrocyte aggregation. The aggregation properties of erythrocytes, independent of plasma environment using dextran as a bridging macromolecule, showed an enhanced disaggregation shear rate threshold and an inverse relationship with erythrocyte sialic acid content. Thus the decreased erythrocyte sialic acid content may intensify the effect of fibrinogen on aggregation and disaggregation of erythrocytes and participate in the development of atherothrombotic complications (7).

Human platelets perceive in the circulation identical mechanical fluid forces than other blood cells. Under controlled conditions of high shear which mimics the rheological situation existing in certain districts of the arterial circulation, in vitro studies have shown that shear forces activate platelets and facilitate spontaneous or agonist-induced platelets aggregation (8). Under physiological condition of vascular blood flow, shear forces also exert indirect effects on platelets by modulating the synthesis and/or the release by endothelial cells of various vasoactive and antithrombotic factors (9). Among these substances are prostacyclin (PGI 2), endothelium-derived relaxing factor identified as nitric oxide (NO) and endothelins (Ets). The double influence of the direct and indirect actions of shear forces on platelet reactivity is thus essential and the study of their role in the control of platelet metabolism should consider these two types of effects (10).

Blood and plasma viscosity

The measurement of shear stress in humans requires the simultaneous determination of blood viscosity and shear rate which are generally restricted to ex vivo models. Blood viscosity and its determinants (hematocrit, fibrinogen, plasma viscosity, red cell deformability, red cell aggregation) were largely evaluated in the last years, showing that most of these parameters were related to several well established cardiovascular risk factors.

Plasma viscosity is a simple hemorheological parameter with a puissant capability to predict primary and secondary cardiovascular risk disease. In a previous longitudinal study we demonstrated that changes in plasma viscosity were independent determinants in smoking status, systolic blood pressure, gamma glutamyl transferase, total cholesterol, fibrinogen and hemoglobine in men, and changes in fibrinogen and Apo B in women (11). In addition, different prospective studies demonstrated that plasma viscosity was associated with the incidence of CHD events in middle-aged men (12) with the incidence of CHD and stroke in older men and women (13), with the recurrence of stroke and with a first major incident CHD event in men in the Monica study (14). Plasma viscosity is largely determined by fibrinogen levels considered as an independent predictor of coronary heart disease and stroke. Several studies showed association between plasma fibrinogen and a number of the major cardiovascular risk factors, including age, smoking, cholesterol, triglycerides, blood pressure, diabetes and lower socioeconomic status. We observed that fibrinogen concentration is frequently elevated in subjects with carotid, femoral, and aortic arterial plaques and coronary atherosclerosis (15-16) and particularly in those subjects with several diseased arterial sites. The hyperviscosity induced by increased fibrinogen may be one of the mechanisms linking cardiovascular risk factors to the atherothrombotic process.

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Figure 2: Mean values (± SEM) of fibrinogen according to the number of atherosclerotic plaques at different sites (carotid, aorta, femoral and coronary). Number inside bars are number in each group and percentage of total subjects. Comparisons are versus 0 diseased sites. From Levenson et al (16) with permission.

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References

  1. LEVENSON J, SIMON A, CAMBIEN F, BERETTI C : Cigarettes smoking and hypertension. Factors independently associated with blood hyperviscosity and arterial rigidity. Arteriosclerosis. 7 : 572-578, 1987.
  2. SIMON ACh, O'ROURKE MF, LEVENSON J : Arterial distensibility and its effect on wave reflection and cardiac loading in cardiovascular disease. Coronary Artery disease. 2 : 1111-1120, 1991.
  3. AVOLIO AP, CHIEN SG, WANG RP, ZHANG CL, LI MF and O’ROURKE MF. Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation. 68: 50, 1983.
  4. DAVIS PF, TRIPATHI SC. Mechanical stress mechanisms and the cell: an endothelial paradigm. Circulation Research. 72: 239-245, 1993.
  5. RAZAVIAN M, DEL PINO M, SIMON A, LEVENSON J : Increase in erythrocyte disaggregation shear stress in hypertension. Hypertension. 20 : 247-252, 1992.
  6. RAZAVIAN SM, ATGER V, GIRAL Ph, CAMBILLAU M, DEL PINO M, SIMON A, MOATTI N, LEVENSON J, the P.C.V.METRA. Influence of HDL subfractions on erythrocyte aggregation in hypercholesterolemic men. Arterioscler Thromb. 14 : 361-366, 1994.
  7. HADENGUE A, RAZAVIAN SM, DEL PINO M, SIMON A, LEVENSON J. Influence of sialic acid on erythrocyte aggregation in hypercholesterolemia. Thromb Haem. 76: 944-949, 1996.
  8. KROLL MH, HELLUMS JD, MCINTRE LV, SCHAFER AI, MOAKE JL. Platelets and shear stress. Blood. 88: 1525-1541, 1996.
  9. MAZEAUD M, LEVENSON J, LE QUAN SANG H, SIMON A, DEVYNCK MA : Platelet aggregation and in vivo shear forces. Thrombosis and Haemostasis. 71 : 26-31, 1994.
  10. GAGNET C, DEVYNCK MA, SIMON A, LEVENSON J. Influence of hypercholesterolemia and endothelin-3 pre-treatment on the effects of shear forces on platelet aggregation and cyclic GMP content. Atherosclerosis. 143 : 91-97, 1999.
  11. BONITHON-KOPP C, LEVENSON J, SCARABIN PY, GUILLANEUF MT, KIRZIN JM, MALMEJAC A, GUIZE L. Longitudinal associations between plasma viscosity and cardiovascular risk factors in a middle-aged french population. Atherosclerosis. 104: 173-182, 1993.
  12. YARNELL JWG, BAKER IA, SWEETNAM PM, BAINTON D, O’BRINE JR, WHITEHEAD PJ, ELWOOD PC. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease : the Caerphilly and Speedwell Collaborative Heart Disease Studies. Circulation. 83:836-844, 1991.
  13. LOWEE GDO, LEE AJ, RUMLEY A, PRICE JF, FOWKES FGR. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol. 96: 198-173, 1997.
  14. KOEING W, SUND M, FILIPIAK B, DORING A, LOWEL H, ERNST E. Plasma viscosity and the risk of coronary heart disease. Results from the MONICA-Augsburg Cohort Study 1984 to 1992. Arterioscler Thromb Vasc Biol. 1998; 18: 768-772.
  15. LEVENSON J, GIRAL P, RAZAVIAN M, GARIEPY J, SIMON A. Fibrinogen and silent atherosclerosis in subjects with cardiovascular risk factors. Arterioscl Thromb Vasc Biol. 15: 1263-1268, 1995.
  16. LEVENSON J, GIRAL P, MEGNIEN JL, GARIEPY J, PLAINFOSSE MC, SIMON A. Fibrinogen and its relations to subclinical extracoronary and coronary atherosclerosis in hypercholesterolemic men. Arterioscler Thromb Vasc Biol, 17: 45-50, 1997.

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Correspondence:
Jaime LEVENSON MD
INSERM CRI
Centre de Médecine Préventive Cardiovasculaire
Hôpital Broussais
96 rue Didot
75674 Paris Cedex 14
Tel : 33 .1. 43.95.93.92 Fax : 33.1.45.39.11.93
E-Mail : levenso@worldnet.fr


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Bioengineering

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Update
10/03/99