From in vitro blood rheology to useful bedside instrumentation for cardiovascular diseases: history and challenges.

I present an historical overview beginning with Prof. Harry L. Goldsmith, my first summer research supervisor in 1963 in microrheology, evolving years later to introduction into my laboratories at McGill University of the coaxial cylinder couette flow device for dynamic, real-time measurements of platelet aggregation in platelet suspensions sheared up to 8000/s, analyzed with a flow cytometer, and finally to a technology transfer of this rheological approach toward the marketplace. I and collaborators observed the shear-dependent roles of different adhesive receptors in mediating human platelet aggregation, and the importance of shear in evaluating efficacy of antiplatelet drugs, in contrast to studies with a classical aggregometer. I outline the well-published rationale for using flow devices, such as the coaxial cylinder couette, to assist clinicians and health managers assess the drug and clinical outcome efficacy of antithrombotic drugs in cardiovascular diseases, as well as their future applications.

Platelet adhesion and aggregation and fibrin formation in flowing blood: a historical contribution by Giulio Bizzozero.

At the occasion of the first centennial of Giulio Bizzozero's death, the modern readers' attention is addressed to some ingenious experiments Bizzozero performed in Turin, Italy, around 1880. He discovered and carefully described blood platelet function in flowing conditions and the relationship between platelet adhesion to an artificial surface, aggregation and subsequent fibrin formation and deposition on activated platelet membrane. Bizzozero challenged contemporary concepts involving leukocytes in blood coagulation, but concluded that participation of blood platelets and white cells in fibrin formation was conceivable.

The current state of extracorporeal haemorheotherapy: from haemodilution via cascadefiltration to rheohaemapheresis.

Rheological therapy aims at an improvement of organ perfusion however, it has to be stressed that the tonus of the blood vessels also plays an important role for both the blood distribution and the rheology in the micro- and the macrocirculation. Conventional rheotherapy consists of attempts to influence nutrition and life style, to apply drugs such as purin derivatives, vasodilatating or defibrinising substances and hypervolaemic (using infusion therapy), hypovolaemic, e.g., blood letting, erythrocytapheresis and--the most widely distributed- -isovolaemic haemodilution. With the introduction of centrifugal devices, and approximately 10 years later with the introduction of hollow fibre and flat sheet membrane techniques, a considerable increase of therapeutical efficacy was achieved. These technologies were successfully applied for the treatment of cellular and plasmatic hyperviscosity syndromes. The treatment of less severe diseases of the micro- and macrocirculation, vessel stenosis, vessel wall sclerosis, malformation of the blood vessel architecture, pathological clinical-chemical blood parameters and maldistribution have hardly been taken into consideration. Our group at Köln investigated different plasma differential separation techniques and demonstrated, that adsorption as well as filtration could be applied. These different techniques being 6-10 times more effective as conventional haemodilution techniques have in common high molecular weight proteins determining the viscosity of plasma and thus whole blood viscosity is removed, however differences among the different elimination techniques do exist. The rheological and clinical importance of such differences has to be determined. Applying filtration techniques for both primary and secondary separations, the concept of Rheohaemapheresis was developed. A corresponding quality program was also introduced into our clinical routine. Rheohaemapheresis is supported from the currently introduced concept of the synergetic consideration of the microcirculation. Age related macular degeneration, so far without generally accepted therapy, is a most advanced indication based on several pilot studies and a prospective, randomised controlled trial. Other diseases of the microcirculation have also successfully been treated.

Indicator dilution methods for measuring blood flow, volume, and other properties of biological systems: a brief history and memoir.

In 1824 Hering introduced an indicator-dilution method for measuring blood velocity. Not until 1897 was the method extended by Stewart to measure blood (volume) flow. For more than two decades, beginning in 1928, Hamilton and colleagues measured blood flow, including cardiac output. They proposed that the first-passsage indicator concentration-time curve could be recovered from observed curves that included recirculation by semilogarithmic extrapolation of the early downslope. Others followed with attempts to fit the complete first-passage curve by various forms, such as by the sum of three exponential terms (three well-stirred compartments in series). Stephenson (1948) thought of looking at indicator-dilution curves as convolutions of indicator input with a probability density function of traversal times through the system. Meier and I reached a similar conclusion, and extended it. The fundamental notion is that there exists a probability density function of transit times, h(t), through the system. We proved that mean transit time t= V/F, where V is volume in which the indicator is distributed. Thus, V, F, and t might all be calculated, or r alone might suffice if one wanted only to know relative blood flow. I extended the analysis to include residue detection of indicator remaining in the system, so that V, F, and could be calculated by external monitoring. Chinard demonstrated the value of simultaneous multiple indicator-dilution curves with various volumes of distribution. Goresky extended the technique to study cell uptake and metabolism. He also found a transform of indicator-dilution output curves (equivalent to multiplying the ordinate by tand dividing the time by t) which made congruent the family of unalike curves obtained by simultaneous injection of indicators with different volumes of distribution. Bassingthwaighte showed the same congruency with the transform of outputs of a single indicator introduced into a system with experimentally varied blood flows. We showed the same congruency for the pulmonary circulation, adding a correction for delays. Success of these transforms suggests that the architecture of the vascular network is a major determinant of the shape of density functions of transit times through the system, and that there is in this architecture, a high degree of self-similarity, implying that the fractal power function is a component in shaping the observed density of transit times. I proposed that the distribution of capillary critical opening pressures, which describes recruitment of vascular paths, may be important in shaping indicator-dilution curves, and that h(t) may be derived from flow-pressure and volume-pressure curves under some circumstances.