Abstract
L1 ESCHM Plenary Lecture
Philippe Connes
Laboratoire LIBM EA7424, Equipe “Biologie Vasculaire et du Globule Rouge”, Université Claude Bernard Lyon 1, France
Blood rheological responses to exercise in the sickle cell disease patient are reviewed in light of the exercise response of normal hemoglobin subjects, and those with heterozygous and homozygous forms of the disorder:
(1) Exercise and blood rheology: Blood viscosity increases during exercise. This increase would be the consequences of the rise in hematocrit, plasma viscosity and red blood cell (RBC) aggregation, and the decrease of RBC deformability. The decrease of RBC deformability has been attributed to lactic acidosis and oxidative stress. However, we and others reported that RBC deformability can also increase during exercise in highly trained individuals, and this increase would be the consequence of a greater production of nitric oxide (NO) into the RBC.
(2) Sickle cell trait (SCT): SCT is the heterozygous form of sickle cell disease (SCD) and is usually considered to be a benign condition. However, large epidemiological studies demonstrated a higher risk for SCT individuals to collapse during exercise. At rest, blood viscosity and arterial rigidity are higher in SCT compared to control individuals. During exercise, blood viscosity of SCT carriers reaches very high values but adequate hydration has been demonstrated to offset this increase.
(3) SCD: SCD patients have abnormal hemoglobin (HbS), which polymerizes under de-oxygenation and causes the sickling of RBC. Sickle RBC are fragile and poorly deformable. Patients with the lowest RBC deformability are at higher risk to develop leg ulcers, glomerulopathy and priapism while those with the highest deformability have frequent vaso-occlusive crises (VOC). Any rise in blood viscosity increases the risk for VOC because vascular reactivity is blunted in SCD. Hemolysis, increased oxidative stress and the high amount of circulating microvesicles are involved in the development of vasculopathy in SCD. Enhanced eryptosis caused by oxidative stress would be the cause of RBC-microparticles genesis in SCD.
L2 ISB Poiseuille Medal Award
Axel R. Pries
Charité Universitätsmedizin Berlin
Rheological properties of newtonian fluids are fixed material properties and don’t change with shear rate or shear stress. However, it is well known, that blood being a complex fluid exhibits a deviation from that behavior with increasing apparent viscosity at decreasing shear rate. This results from a change in the interaction between the different components of the blood, water and small solutes, macromolecules and blood cells. Such a pseudoplastic behavior can still be seen as a material property of the blood, which is not the case for phenomena reported for the perfusion of blood through narrow bore glass tubes, microvessels or microvascular networks. In these conditions, the observed hemodynamic behavior is dictated by the interacting properties of the blood and the structures it is flowing through – i.e. the systems properties.
These properties deviate from those obtained with a newtonian homogenous fluid perfused through the same structures in several aspects which result from the interactions between the flowing components and the external structure. The presence of a confined space with a (cross-sectional) dimension comparable to that of blood cells causes increasing influence of the tube or vessel wall with the cells for decreasing diameter. This leads to an accumulation of cells in the axial flow regions and to a decrease of viscous cell to cell interactions. The former is the basis of the Fahraeus-Effect, the reduction of hematocrit in small tubes or vessels (volume fraction) relative to the hematocrit of the blood perfused to them (flow fraction). The Fahraeus-Effect together with the latter leads to the surprising and strong reduction of effective viscosity during flow in small tubes or vessels, the Fahraeus-Lindquist-Effect. In microvessels the vessel wall is not a rigid surface but rather a gel with complex mechanical and biological properties, the so called endothelial surface layer or glycocalyx which further modifies the hemodynamic properties of the system. The next level of interactions is seen at microvascular bifurcations where red cells and blood plasma usually exhibit unequal distribution to the daughter vessels (phase separation effect). In microvascular networks the different properties of arterio-veneous flow pathways consisting of the increasingly smaller vessels of the arterial trees, the capillaries and venules with increasing diameter in the veneious vessel trees and the successive microvascular bifurcations lead to additional effects on hematocrit and flow (Network-Fahraeus-Effect and Pathway-Effect).
L3 ISB Plenary Lecture
Frank J.Gijsen
Department of Biomedical Engineering, Erasmus Medical Center Rotterdam, The Netherlands
The role of low and oscillating shear stress as a key factor for localizing early atherosclerotic plaques is generally accepted. Once more advanced plaques protrude into the lumen, the shear stress they are exposed to changes. The influence of shear stress on plaque composition in advanced atherosclerosis is not fully understood. In this review, we discuss our recent studies on the relationship between shear stress, plaque composition and the location of plaque rupture in human coronary arteries. We have shown that elevated shear stress levels can be found over plaques that are not subjected to treatment. Regional exposure of certain plaque regions to high shear stress is therefore a condition that will pertain for a prolonged period of time. We have also shown that in more advanced atherosclerosis the necrotic core experiences higher shear stress. Low shear stress plaque regions can be found downstream of the plaque and are stiffer. High shear stress plaque regions can be found either at the upstream, shoulder or cap region of the plaque, and are softer. The plaque regions exposed to the highest shear stress are the softest and are the ones exposed to the highest shear stresses. The high shear stress plaque regions are the only regions that get softer over time. Finally, high shear stress is also associated with the location of plaque rupture in non-culprit lesion in human coronary arteries. Combining our findings with data from literature, we can conclude that advanced coronary plaques grow in the distal regions. The distal plaque regions are exposed to low shear stress, are stiffer and have a stable plaque phenotype. The regions exposed to high shear stress are softer, and are associated with vulnerable plaque features.
L4 ISCH Medal Award
Brian M. Cooke
Biomedicine Discovery Institute and Department of Microbiology, Monash University, Victoria 3800, Australia
The pathogenesis of falciparum malaria and bovine babesiosis are remarkably similar. In both, parasite-infected red blood cells (RBCs) accumulate in the microvasculature causing vaso-occlusive clinical syndromes. Whilst the cellular and molecular mechanisms underpinning the pathogenesis of malaria have been intensely scrutinised, babesiosis has been relatively ignored; despite the fact that babesia parasites offer considerable experimental advantages to relate the function of specific parasite genes to pathological sequelae. In the Cooke Laboratory, we characterise the rheological properties of bovine RBCs infected by B. bovis (BbRBCs) and compare them with human RBCs infected with P. falciparum (PfRBCs). Like PfRBCs, flowing BbRBCs adhere to vascular endothelial cells and form stable interactions that correlate with microvascular sequestration. Intriguingly however, high resolution imaging of BbRBCs reveals structures on their surface (that mediate adhesion) that were morphologically very different to the knob-like structures on the surface of PfRBCs that mediate their adhesion. Using multiple experimental approaches, we have now identified numerous novel proteins at the membrane skeleton of BbRBCs which we believe will be directly involved in the formation of these unique ‘ridge-like’ structures and hence in pathogenesis and virulence. Linking these novel proteins with physiologically-relevant functions in BbRBCs will also identify future therapeutic strategies to combat both babesia and malaria infections.
L5 ISCH Plenary Lecture
Sehyun Shin
Department of Mechanical Engineering, Korea University, Seoul, Korea
Engineering Research Center for Biofluid Biopsy, Korea University, Seoul, Korea
There have been many quantitative studies of platelet aggregation and thrombosis, but clinical applications have been poor due to various reasons. For the unmet clinical needs, it is desirable to develop an innovative technology with understanding the basic biology of platelet and utilizing microfluidic technology. Thus, this presentation provides an overview of commercial point of care devices for platelet testing and recent microfluidic studies with a description of their innovative techniques. Furthermore, we have demonstrated the characteristics of our microfluidic device to test platelet function as well as antiplatelet response. In this presentation, major advantages of microfluidics for testing platelets are assessed via mimicking the pathophysiological environment of blood vessels, including hemodynamics as well as injured blood vessels. An analysis is presented of unsolved issues in platelet function tests using microfluidics.
L6 ESCHM Fåhraeus Award
Carlota Saldanha
Instituto de Medicina Molecular, Instituto de Bioquimica, Faculdade de Medicina, Universidade de Lisboa
Anucleated, erythrocytes or red blood cells (RBCs) may be considered a simple and easily obtained “ex vivo” experimental model that could provide a means to study what occurs in nucleated cells, in terms of metabolism, ion transport, membrane fluidity and exovesicles among other properties. However RBCs are unique in their oxygen transport function in addition to their role in nitric oxide (NO) availability. The biochemical and the biophysical properties of RBCs allow them to be sensors and active partners in hemorheology and in inflammatory conditions. RBCs are more than a hemoglobin container; they are an indispensable player. The aim of this Fahraeus lecture is to summarize the key points obtained from studies centered on the erythrocyte and its multiple functions. The characterization of the RBC’s biophysical and rheological properties and its association with inflammatory biomarkers, both in macro and microcirculation, and interactions with white blood cells are highlighted. The RBC’s biomolecular behavior, as therapeutic targets and as biomarkers are identified.
Numerous features of RBC function relevant to microvascular function are reviewed, such as: the ability to release exovesicles; receptor function of the erythrocyte membrane enzyme acetylcholinesterase; the identification of the signal transduction for the scavenging and delivery of NO and internal mobilization of NO derivatives; the identification of CD47 as the RBC membrane receptor for soluble fibrinogen (Fib); the influence of Fib on RBC NO efflux; the association between RBC NO efflux and several parameters of inflammatory vascular disease; the interrelationship between erythrocyte deformability and NO and its dependence on internal and external biomolecules; and the role of erythrocyte deformability in affecting microvascular leukocyte margination in inflammatory diseases.
L7 Plenary lectures in tribute to Prof. Oguz Baskurt
Ozlem Yalcin
Department of Physiology, School of Medicine, Koc University, Istanbul, Turkey
It has been previously demonstrated that the effects of blood rheological alterations are less pronounced in vivo compared to in vitro. The first big group of the determinants of the results of experiments on in vivo flow dynamics is the experimental model and the methods used. The properties of the organ or tissue under investigation significantly affects the influence of hemorheological alterations on pressure-flow relationship in vivo. The methods used in in vivo studies also influence the results of the experiments. Another important factor that determines the results of in vivo hemorheology studies is the nature of hemorheological alterations. The results of the experiments investigating the influence of hemorheological alterations on pressure-flow relationship in vivo are also determined by the methods used to modify hemorheological properties of blood. The results of in vivo experiments are also affected by interfering physiological factors directly related to the living organism, organ or tissue. An alteration in hemorheology may result in a decreased blood flow in a vascular segment. This will be followed by decreased oxygen supply to the tissue, which will trigger a vasodilatory response, or metabolic autoregulation, restoring normal blood flow and tissue oxygen supply. Hemorheological extra load can easily be compensated by decreased vascular hindrance, resulting from metabolic autoregulation. However, this can only work if there is enough autoregulatory reserve. In conclusion, the relation between the hemodynamics and hemorheological alteration is extremely complex but with the systematic analysis of the related data, it is possible to provide better clinical explanations for the pathophysiological processes in which hemorheological factors are involved.