The convective supply of oxygen through the microcirculation to the tissues is the product of blood flow and oxygen content of the blood and depends on red blood cells (RBCs) in two ways. The RBCs contain the oxygen-binding protein haemoglobin so that the oxygen content is proportional to the concentration of RBCs or haematocrit (Hct). Thus increasing Hct leads to an increase in the capacity for the blood to carry oxygen. However, the rheological properties of the blood depend critically on Hct and the viscosity of the blood increases exponentially with Hct. Since blood flow depends inversely on viscosity, increasing Hct leads to a reduction in blood flow. The balance between these two opposing effects of Hct on oxygen supply leads to the concept of optimal haematocrit at which oxygen supply is maximum, usually near a Hct of about 50% (Birchard, 1997). What happens when systemic Hct rises substantially above the optimal level? Elevated Hct or polycythaemia results as an adaptive physiological response to sojourn at high altitude. A pathological condition known as polycythaemia vera results from an unwanted overproduction of RBCs and is associated with increased cardiovascular risk. Because of the obvious link between elevated Hct and increased blood viscosity, it is generally thought that the increased cardiovascular risk is due to pathological changes in haemodynamics, often resulting in peripheral ischaemia, which lead to increased total peripheral resistance and arterial blood pressure. In an article in a recent issue of The Journal of Physiology, Richter et al. (2011) suggest that the origin of cardiovascular problems associated with chronically elevated Hct lies rather with interactions between the RBCs and the glycocalyx or endothelial surface layer (ESL). The animal model used in the study of Richter et al. (2011) was that of a transgenic mouse (tg6) line which overexpressed human erythropoietin (Vogel & Gassmann, 2011). The systemic Hct of the tg6 mice was 85% compared with 46% for the control mice. Interestingly, mean arterial pressure was not significantly different between the two groups, being 77 ± 5 mmHg for the tg6 group and 69 ± 2 mmHg for the control group. However, there is a dramatic difference in average lifespan between the two groups: the tg6 mice live an average of 7.4 months compared with 26.7 months for the control mice. This study emphasized microcirculatory measurements, carried out on venules of the cremaster muscle. The endothelial surface layer or glycocalyx represents the interface between the flowing blood and the endothelial surface. Under normal conditions the thickness of this gel-like structure varies between 0.4 and 1.2 μm depending on several factors. The thickness of this layer has been quantified by several different approaches, and in the study of Richter et al. (2011), the microviscometric method developed by Damiano et al. (2004) was employed to analyse velocity profile data collected using the μ-PIV technique. In the μ-PIV method, the cross-sectional velocity distribution of 0.5 μm diameter fluorescent microspheres was measured and interpreted by the microviscometric method, which provided calculated data on a variety of key microhaemodynamic variables. The results of the study of Richter et al. (2011) in regard to the ESL were that the thickness of the ESL in tg6 mice was 0.13 μm compared with the more usual value of 0.52 μm for the control mice. Thus, the substantially elevated Hct found for the tg6 mice was associated with a significantly thinner ESL. There are several consequences of this thinner ESL. Haemodynamically, the calibre of the microvessel lumen will be increased by about twice the difference in ESL thickness or about 0.8 μm, leading to a smaller contribution to vascular resistance to blood flow. Results of a flow simulation model are presented by Richter et al. (2011) which show the incremental contributions of Hct and ESL thickness to vascular resistance. A thinner ESL barrier in the tg6 mice also means that platelets and leukocytes could come closer to the endothelial surface, making it a more prothrombogenic surface than in control mice. The question arises as to whether the high Hct chronically degrades the ESL or whether another mechanism associated with high Hct might be responsible for the much lower ESL thickness. The authors investigated this issue by reducing Hct in both the tg6 and control mice using isovolaemic haemodilution. When the tg6 mice were haemodiluted to the same Hct as the control mice, there was no significant difference in ESL thickness, indicating that the thin ESL in tg6 mice could result from a readily reversible, compressive mechanical effect of RBCs on the ESL. The involvement of alterations in endothelial glycocalyx or ESL (e.g. from damage or degradation) has been invoked to account, at least in part, for a number of pathological conditions and the article by Richter et al. (2011) provides a novel addition to this growing list.
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Aug 20, 2012
Kimberly D Arnott + 2
Open Access