“Vulnerable plaques”:  inflammation, blood viscosity and risk of cardiovascular events

Vascular lesions in atherosclerosis have different risk of leading to a major event, which is most often (athero-)thrombotic. Not the degree of stenosis determines highest risk, but the presence of inflammatory activity and a large soft central lipid core covered with a thin fibrous cap. (1) These lesions are considered to be “vulnerable plaques” (Figure 1) which are prone to rupture, leading to an atherothrombotic cascade, often culminating in a complete obstruction of the vessel or incomplete obstruction with spread of  microembolism form the ruptured plaque, both resulting in subsequent tissue necrosis in the vessel-related area. Extensive efforts are going on to detect these “vulnerable plaques” by intravascular ultrasound, thermal detection, spectroscopy, etc. (2) Instead of seeking for the often multiple “vulnerable plaques” our goal is to reduce the imminent thread of rupture by reducing the mechanical stress on these endovascular sites. While vascular lesions in atherosclerosis usually occur at sites of low shear, high shear conditions finally determine whether these lesions destabilize into rupture-prone “vulnerable plaques”. (3)

Figure 1: Vulnerable plaque (from: Texas Heart Institute)

Figure 2: Inflammation is the “secret killer” in cardiovascular disease

At similar flow rates blood viscosity determines the level of mechanical shear on the lesion, because viscosity=shear stress/shear rate (4) . Blood viscosity increases when the inflammation level in blood rises (5), reason why increased inflammation parameters are more and more considered to be harbingers of major cardiovascular events in atherosclerosis. (6) The most well-known inflammation parameter is CRP and the risk of cardiovascular events increases linearly with the rise of CRP, independent from the usual Framingham risk factors (Figure 3). (7) The recent Jupiter trial showed 50% reduction of vascular events in apparently healthy  persons with normal cholesterol but only slightly increased CRP level, when inflammation was reduced by potent statin therapy.(8)

Microcirculation, increased aggregation and blood viscosity

Blood viscosity plays also a key role in the microcirculation. (9,10) Reaching the arterioles RBC aggregates normally disperse due to increased shear, after which RBCs flow as individual cells through the capillaries. After capillary passage they again form aggregates within the collecting venules. This implies that flow resistance in the capillary system is especially influenced when the entering blood cells are stuck together. Factors that increase aggregation, such as fibrinogen, CRP or other ‘acute-phase’ proteins (5), increase flow resistance in the post-capillary venules and cause “sludging” of the blood; this “sludging” is expression of increased blood viscosity. Although arteriovenous fistulas often exist in the microcirculatory bed to bypass the encountered resistance, tissue extraction of oxygen will nevertheless be impaired. (11)

Atrial fibrillation, blood viscosity and atrial stretch

Elevated levels of inflammation in blood as expressed by high CRP levels have shown to increase the recurrence rate of paroxystic atrial fibrillation (AF). (12). Similarly, blood transfusion, which rises blood viscosity by increasing hematocrit, has found to be related with the occurrence of AF, when given in the post surgery period.(13)  Reduction of CRP levels by intensive statin therapy has shown to reduce the risk of AF substantially within weeks. (14)  A clear explanation has not yet been found, but a preliminary study demonstrated that atrial stretch as expressed by BNP-levels is immediately reduced by 40% if blood viscosity is decreased by 20%. (15) The reduced atrial stretch by less blood viscosity can be explained by Poisseuille’s law: Q= ΔP π.r4/8l.η, in which Q= total flow, ΔP=pressure gradient, r=vessel radius, l= tube length and η= blood viscosity.

Preliminary clinical experiences with HemoCard Vision central venous catheter and ultimate vision

Preliminary clinical experiences with the Hemocard Vision central venous catheter have shown, that on-line detection of blood viscosity correlates with increased inflammatory activity, as expressed by elevated CRP levels. Therefore, monitoring blood viscosity on-line in patients with high inflammation level, as usually occurs in Intensive Care patients, not only gives rapid and continuous insight in the level of inflammation as a more sophisticated medical thermometer (16), but will also draw attention to the clinician to take appropriate preventive measures before vascular events occur.(11) At the same time tissue perfusion may be optimized, because an optimum of blood viscosity exists at each level of inflammation. (17) This rheological optimum in chronic inflammatory disease is realized by the occurrence of anemia (18) and “normalization” of the hematocrit by EPO has already shown to be contraproductive, leading to worse cardiovascular outcome. (19,20) Monitoring the level of blood viscosity in Intensive Care patients prone to AF may also determine those patients at highest risk for AF and may help the clinician to decide if increasing blood viscosity by blood transfusion is acceptable and/or preventive antiarrhythmic therapy should be installed in those highest risk patients.

Finally, not the CRP as such seems to be the primary cause of all cardiovascular damage, but recent genetic/epidemiological studies have shown that the main cause is the inflammatory process of which CRP in most cases is the expression. (21,22) Our concept is that the increased viscosity of blood by inflammation is the major cause of detrimental cardiovascular events in the micro- as well as in the macro-circulation. This concept continues to drive our efforts to develop an on-line blood viscosity monitoring tool.

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