Drag-Reducing Polymers Improve Vascular Hemodynamics and Tissue Oxygen Supply in Mouse Model of Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic metabolic disease characterised by hyperglycaemia and glucose intolerance caused by impaired insulin action and/or defective insulin secretion. Long-term hyperglycaemia leads to various structural and functional microvascular changes within multiple tissues, including the brain, which involves blood-brain barrier alteration, inflammation and neuronal dysfunction. We have shown previously that drag-reducing polymers (DRP) improve microcirculation and tissue oxygen supply, thereby reducing neurologic impairment in different rat models of brain injury. We hypothesised that DRP could improve cerebral and skin microcirculation in the situation of progressive microangiopathies associated with diabetes using a mouse model of diabetes mellitus. Diabetes was induced in C57BL/6 J mice with five daily consecutive intraperitoneal injections of streptozotocin (50 mg/kg/day). Animals with plasma glucose concentrations greater than 250 mg/dL were considered diabetic and were used in the study following four months of diabetes. DRP (2 ppm) was injected biweekly during the last two weeks of the experiment. Cortical and skin (ear) microvascular cerebral blood flow (mCBF) and tissue oxygen supply (NADH) were measured by two-photon laser scanning microscopy (2PLSM). Cerebrovascular reactivity (CVR) was evaluated by measuring changes in arteriolar diameters and NADH (tissue oxygen supply) during the hypercapnia test. Transient hypercapnia was induced by a 60-second increase of CO2 concentration in the inhalation mixture from 0% to 10%. Compared to non-diabetic animals, diabetic mice had a significant reduction in the density of functioning capillaries per mm3 (787 ± 52 vs. 449 ± 25), the linear velocity of blood flow (1.2 ± 0.31 vs. 0.54 ± 0.21 mm/sec), and the tissue oxygen supply (p < 0.05) in both brain and skin. DRP treatment was associated with a 50% increase in all three parameters (p < 0.05). According to the hypercapnia test, CVR was impaired in both diabetic groups but more preserved in DRP mice (p < 0.05). Our study in a diabetic mouse model has demonstrated the efficacy of hemorheological modulation of blood flow by DRP to achieve increased microcirculatory flows and tissue oxygen supply.

Haemorheologic Enhancement of Cerebral Perfusion Improves Oxygen Supply and Reduces Aß Plaques Deposition in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a consequence of complex interactions of age-related neurodegeneration and vascular-associated pathologies, affecting more than 44 million people worldwide. For the last decade, it has been suggested that chronic brain hypoperfusion and consequent hypoxia play a direct role in the pathogenesis of AD. However, current treatments of AD have not focused on restoring or improving microvascular perfusion. In a previous study, we showed that drag reducing polymers (DRP) enhance cerebral blood flow and tissue oxygenation. We hypothesised that haemorheologic enhancement of cerebral perfusion by DRP would be useful for treating Alzheimer's disease. We used double transgenic B6C3-Tg(APPswe, PSEN1dE9) 85Dbo/Mmjax AD mice. DRP or vehicle (saline) was i.v. injected every week starting at four months of age till 12 months of age (10 mice/group). In-vivo 2-photon laser scanning microscopy was used to evaluate amyloid plaques development, cerebral microcirculation, and tissue oxygen supply/metabolic status (NADH autofluorescence). The imaging sessions were repeated once a month till 12 months of age. Statistical analyses were done by independent Student's t-test or Kolmogorov-Smirnov tests where appropriate. Differences between groups and time were determined using a two-way repeated measures ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. In the vehicle group, numerous plaques completely formed in the cortex by nine months of age. The development of plaques accumulation was accompanied by cerebral microcirculation disturbances, reduction in tissue oxygen supply and metabolic impairment (NADH increase). DRP mitigated microcirculation and tissue oxygen supply reduction - microvascular perfusion was 29.5 ± 5%, and tissue oxygen supply was 22 ± 4% higher than in the vehicle group (p < 0.05). In the DRP group, amyloid plaques deposition was substantially less than in the vehicle group (p < 0.05). Thus, rheological enhancement of blood flow by DRP is associated with reduced rate of beta amyloid plaques deposition in AD mice.

Resuscitation Fluid with Drag Reducing Polymer Enhances Cerebral Microcirculation and Tissue Oxygenation After Traumatic Brain Injury Complicated by Hemorrhagic Shock.

Traumatic brain injury (TBI) is frequently accompanied by hemorrhagic shock (HS) which significantly worsens morbidity and mortality. Existing resuscitation fluids (RF) for volume expansion inadequately mitigate impaired microvascular cerebral blood flow (mvCBF) and hypoxia after TBI/HS. We hypothesized that nanomolar quantities of drag reducing polymers in resuscitation fluid (DRP-RF), would improve mvCBF by rheological modulation of hemodynamics. METHODS: TBI was induced in rats by fluid percussion (1.5 atm, 50 ms) followed by controlled hemorrhage to a mean arterial pressure (MAP) = 40 mmHg. DRP-RF or lactated Ringer (LR-RF) was infused to MAP of 60 mmHg for 1 h (pre-hospital), followed by blood re-infusion to a MAP = 70 mmHg (hospital). Temperature, MAP, blood gases and electrolytes were monitored. In vivo 2-photon laser scanning microscopy was used to monitor microvascular blood flow, hypoxia (NADH) and necrosis (i.v. propidium iodide) for 5 h after TBI/HS followed by MRI for CBF and lesion volume. RESULTS: TBI/HS compromised brain microvascular flow leading to capillary microthrombosis, tissue hypoxia and neuronal necrosis. DRP-RF compared to LR-RF reduced microthrombosis, restored collapsed capillary flow and improved mvCBF (82 ± 9.7% vs. 62 ± 9.7%, respectively, p < 0.05, n = 10). DRP-RF vs LR-RF decreased tissue hypoxia (77 ± 8.2% vs. 60 ± 10.5%, p < 0.05), and neuronal necrosis (21 ± 7.2% vs. 36 ± 7.3%, respectively, p < 0.05). MRI showed reduced lesion volumes with DRP-RF. CONCLUSIONS: DRP-RF effectively restores mvCBF, reduces hypoxia and protects neurons compared to conventional volume expansion with LR-RF after TBI/HS.

Improvement of Impaired Cerebral Microcirculation Using Rheological Modulation by Drag-Reducing Polymers.

Nanomolar intravascular concentrations of drag-reducing polymers (DRP) have been shown to improve hemodynamics and survival in animal models of ischemic myocardium and limb, but the effects of DRP on the cerebral microcirculation have not yet been studied. We recently demonstrated that DRP enhance microvascular flow in normal rat brain and hypothesized that it would restore impaired microvascular perfusion and improve outcomes after focal ischemia and traumatic brain injury (TBI). We studied the effects of DRP (high molecular weight polyethylene oxide, 4000 kDa, i.v. at 2 µg/mL of blood) on microcirculation of the rat brain: (1) after permanent middle cerebral artery occlusion (pMCAO); and (2) after TBI induced by fluid percussion. Using in vivo two-photon laser scanning microscopy (2PLSM) over the parietal cortex of anesthetized rats we showed that both pMCAO and TBI resulted in progressive decrease in microvascular circulation, leading to tissue hypoxia (NADH increase) and increased blood brain barrier (BBB) degradation. DRP, injected post insult, increased blood volume flow in arterioles and red blood cell (RBC) flow velocity in capillaries mitigating capillary stasis, tissue hypoxia and BBB degradation, which improved neuronal survival (Fluoro-Jade B, 24 h) and neurologic outcome (Rotarod, 1 week). Improved microvascular perfusion by DRP may be effective in the treatment of ischemic stroke and TBI.

Menopausal status affects the susceptibility of stored RBCs to mechanical stress.

The mechanical fragility index (MFI) is an in vitro measure of sublethal injury to RBCs. In our previous experiments, we demonstrated that an increase in sublethal injury (increasing MFI) was a component of the RBC storage lesion, and that the MFI was significantly higher amongst the RBC units from male donors compared to pre-menopausal female donors during storage. It was hypothesized that hormonal or menstrual factors contributed to this difference. In this study, we found that RBC units donated by post-menopausal women demonstrated an MFI that was significantly higher than those donated by pre-menopausal women throughout storage.

Drag-reducing polymers diminish near-wall concentration of platelets in microchannel blood flow.

The accumulation of platelets near the blood vessel wall or artificial surface is an important factor in the cascade of events responsible for coagulation and/or thrombosis. In small blood vessels and flow channels this phenomenon has been attributed to the blood phase separation that creates a red blood cell (RBC)-poor layer near the wall. We hypothesized that blood soluble drag-reducing polymers (DRP), which were previously shown to lessen the near-wall RBC depletion layer in small channels, may consequently reduce the near-wall platelet excess. This study investigated the effects of DRP on the lateral distribution of platelet-sized fluorescent particles (diam. = 2 µm, 2.5 × 108/ml) in a glass square microchannel (width and depth = 100 µm). RBC suspensions in PBS were mixed with particles and driven through the microchannel at flow rates of 6-18 ml/h with and without added DRP (10 ppm of PEO, MW = 4500 kDa). Microscopic flow visualization revealed an elevated concentration of particles in the near-wall region for the control samples at all tested flow rates (between 2.4 ± 0.8 times at 6 ml/h and 3.3 ± 0.3 times at 18 ml/h). The addition of a minute concentration of DRP virtually eliminated the near-wall particle excess, effectively resulting in their even distribution across the channel, suggesting a potentially significant role of DRP in managing and mitigating thrombosis.

The use of the mechanical fragility test in evaluating sublethal RBC injury during storage.

BACKGROUND: The mechanical fragility index (MFI) is an in vitro measurement of the extent of RBC sublethal injury. Sublethal injury might constitute a component of the RBC storage lesion, thus the MFI was determined serially during routine RBC storage. METHODS: Leucoreduced AS-5- and SAGM-preserved RBCs were stored under routine blood bank conditions. The mechanical fragility (MF) of each unit was serially measured during storage. RESULTS: For both AS-5 and SAGM units, male and female RBCs demonstrated statistically significant increases in the MFI during storage. The MFI was significantly lower in AS-5 units compared to SAGM units throughout storage. Female RBCs had significantly lower MFI vs. male RBCs in both AS-5 and SAGM units at all times. No significant differences in MFI were observed between ABO groups for both genders for AS-5 RBCs. CONCLUSIONS: The MF of RBCs increases during storage. Both gender and preservation solution influenced the MFI; however, the male:female MFI ratios were similar at all time-points and remained stable, suggesting that gender-based biological differences exist independent of storage solution. The MF could be a useful test for evaluating the effect of novel interventions intended to mitigate the susceptibility of RBCs to sublethal injury during storage.

Drag reducing polymers improve tissue perfusion via modification of the RBC traffic in microvessels.

This paper reports a novel, physiologically significant, microfluidic phenomenon generated by nanomolar concentrations of drag-reducing polymers (DRP) dissolved in flowing blood, which may explain previously demonstrated beneficial effects of DRP on tissue perfusion. In microfluidic systems used in this study, DRP additives were found to significantly modify traffic of red blood cells (RBC) into microchannel branches as well as reduce the near-wall cell-free layer, which normally is found in microvessels with a diameter smaller than 0.3 mm. The reduction in plasma layer size led to attenuation of the so-called "plasma skimming" effect at microchannel bifurcations, increasing the number of RBC entering branches. In vivo, these changes in RBC traffic may facilitate gas transport by increasing the near vessel wall concentration of RBC and capillary hematocrit. In addition, an increase in near-wall viscosity due to the redirection of RBC in this region may potentially decrease vascular resistance as a result of increased wall shear stress, which promotes endothelium mediated vasodilation. These microcirculatory phenomena can explain the previously reported beneficial effects of DRP on hemodynamics in vivo observed in many animal studies. We also report here our finding that DRP additives reduce flow separations at microchannel expansions, deflecting RBC closer to the wall and eliminating the plasma recirculation zone. Although the exact mechanism of the DRP effects on RBC traffic in microchannels is yet to be elucidated, these findings may further DRP progress toward clinical use.

Microhaemodynamics within the blade tip clearance of a centrifugal turbodynamic blood pump.

A persistent challenge facing the quantitative design of turbodynamic blood pumps is the great disparity of spatial scales between the primary and auxiliary flow paths. Fluid passages within journals and adjacent to the blade tips are often on the scale of several blood cells, confounding the application of macroscopic continuum models. Yet, precisely in these regions there exists the highest shear stress, which is most likely to cause cellular trauma. This disparity has motivated these microscopic studies to visualize the kinematics of the blood cells within the small clearances of a miniature turbodynamic blood pump. A transparent model of a miniature centrifugal pump having an adjustable tip clearance (50-200 microm) was prepared for direct optical visualization of the region between the impeller blade tip and the stationary housing. Synchronized images of the blood cells were obtained by a microscopic visualization system, consisting of an inverted microscope fitted with long-working-distance objective lens (40x), mercury lamp, and high-resolution charge-coupled device camera electronically triggered by the rotation of the impeller. Experiments with 7 microm fluorescent particles revealed the influence of the gap dimension on the trajectory across the blade thickness. The lateral component of velocity (perpendicular to the blade) was dramatically enhanced in the 50 microm gap compared with the 200 microm gap, thereby reducing the exposure time. Studies with diluted bovine blood (Ht = 0.5 per cent) showed that the concentration of cells traversing the gap is also reduced dramatically (30 per cent) as the blade tip clearance is reduced from 200 microm to 50 microm. These results motivate further investigation into the microfluidic phenomena responsible for cellular trauma within turbodynamic blood pumps.

I.V. infusion of a drag-reducing polymer extracted from aloe vera prolonged survival time in a rat model of acute myocardial ischaemia.

BACKGROUND: I.V. infusion of drag-reducing polymers (DRPs) has been shown to improve survival time in animals subjected to haemorrhagic shock. We hypothesized that DRPs might prolong survival time in rats following acute myocardial ischaemia (AMI). METHODS: Sixteen adult male rats were anaesthetized and mechanically ventilated. An i.v. infusion of either Dextran-40 2.5% (Control, n=8) or Dextran-40 2.5% containing 50 microg ml(-1) of an aloe vera-based DRP (DRP, n=8) was initiated at 3.5 ml h(-1). The left anterior descending coronary artery was ligated. Blood pressure, skin-tissue perfusion, and heart rate were monitored and arterial blood samples were analysed. RESULTS: The mortality at 60 min following coronary ligation was 0% in the DRP group vs 50% in the control group (P=0.025). DRP-treated animals maintained higher mean arterial pressure [60.9 (5.1) vs 47.5 (5.1) mm Hg, P=0.004] and tissue perfusion [4.2 (3.4) vs 1.2 (0.5) TPU, P=0.029]. The DRP group trended towards better acid-base status with base excess [-5.0 (1.7) vs -8.1 (5.1) mmol litre(-1), P=0.083] and pH [7.42 (0.07) vs 7.35 (0.02), P=0.03]. CONCLUSIONS: Administration of nanomolar concentrations of aloe vera-based DRP prolonged survival time in animals with AMI. DRPs may offer a novel method to treat organ/tissue hypoperfusion.

The role of diastolic pump flow in centrifugal blood pump hemodynamics.

We tried to verify the hypothesis that increases in pump flow during diastole are matched by decreases in left ventricular (LV) output during systole. A calf (80 kg) was implanted with an implantable centrifugal blood pump (EVAHEART, SunMedical Technology Research Corp., Nagano, Japan) with left ventricle to aorta (LV-Ao) bypass, and parameters were recorded at different pump speeds under general anesthesia. Pump inflow and outflow pressure, arterial pressure, systemic and pulmonary blood flow, and electrocardiogram (ECG) were recorded on the computer every 5 ms. All parameters were separated into systolic and diastolic components and analyzed. The pulmonary flow was the same as the systemic flow during the study (p > 0.1). Systemic flow consisted of pump flow and LV output through the aortic valve. The ratio of systolic pump flow to pulmonary flow (51.3%) did not change significantly at variable pump speeds (p > 0.1). The other portions of the systemic flow were shared by the left ventricular output and the pump flow during diastole. When pump flow increased during diastole, there was a corresponding decrease in the LV output (Y = -1.068X + 51.462; R(insert)(2) = 0.9501). These show that pump diastolic flow may regulate expansion of the left ventricle in diastole.

Relationship of blood pressure and pump flow in an implantable centrifugal blood pump during hypertension.

The purpose of this study was to evaluate the real time relationship between pump flow and pump differential pressure (D-P) during experimentally induced hypertension (HT). Two calves (80 and 68 kg) were implanted with the EVA-HEART centrifugal blood pump (SunMedical Technology Research Corp., Nagano, Japan) under general anesthesia. Blood pressure (BP) in diastole was increased to 100 mm Hg by norepinephrine to simulate HT. Pump flow, D-P, ECG, and BP were measured at pump speeds of 1,800, 2,100, and 2,300 rpm. All data were separated into systole and diastole, and pump flow during HT was compared with normotensive (NT) conditions at respective pump speeds. Diastolic BP was increased to 99.3+/-4.1 mm Hg from 66.5+/-4.4 mm Hg (p<0.01). D-P in systole was under 40 mm Hg (range of change was 10 to 40 mm Hg) even during HT. During NT, the average systolic pump flow volume was 60% of the total pump flow. However, during HT, the average systolic pump flow was 100% of total pump flow volume, although the pump flow volume in systole during HT decreased (33.1+/-5.7 vs. 25.9+/-4.0 ml/systole, p<0.01). In diastole, the average flow volume through the pump was 19.6+/-6.9 ml/diastole during NT and -2.2+/-11.1 ml/diastole during HT (p<0.01). The change in pump flow volume due to HT, in diastole, was greater than the change in pump flow in systole at each pump speed (p<0.001). This study suggests that the decrease of mean pump flow during HT is mainly due to the decrease of the diastolic pump flow and, to a much lesser degree, systolic pump flow.

Continuously maintaining positive flow avoids endocardial suction of a rotary blood pump with left ventricular bypass.

This study showed the usefulness of maintaining positive pump flow to avoid endocardial suction and as an assist bypass. Three calves were implanted with centrifugal pumps. Hemodynamics and pump parameters were measured at varying pump speeds (from 1,100 to 2,300 rpm). In each test pump, speed was adjusted to create 3 hemodynamic states: both positive and negative flow (PNF), positive and zero flow (PZF), and continuously positive flow (CPF). The pump flow volume was determined during systole (Vs) and diastole (Vd). Vs in PNF was 29.6 ml and was not significantly different from Vs in PZF (p > 0.15). Vd in PNF was significantly different from Vd in PZF (p < 0.05). All bypass rates of PNF were over 30% of pulmonary flow. All PZF bypass rates were between the PNF rate and the CPF rate. These data showed that PZF satisfied the minimum requirement of assist flow and was under 100% bypass. Thus, PZF may avoid endocardial suction.

Assessing acute platelet adhesion on opaque metallic and polymeric biomaterials with fiber optic microscopy.

The degree of platelet adhesion and subsequent thrombus formation is an important measure of biocompatibility for cardiovascular biomaterials. Traditional methods of quantifying platelet adhesion often are limited by the need for direct optical access, limited spatial resolution, or the lack of temporal resolution. We have developed a new imaging system that utilizes fiber optics and fluorescence microscopy for the quantification of platelet adhesion. This fiber optic remote microscope is capable of imaging individual fluorescently labeled platelets in whole blood on opaque surfaces. Using this method, platelet adhesion was quantified on a series of metallic [low-temperature isotropic carbon (LTIC); titanium alloy (Ti); diamond-like carbon (DLC); oxidized titanium alloy (TiO); and polycrystalline diamond (PCD)] and polymeric [woven Dacron (WD)] collagen-impregnated Dacron (HEM), expanded polytetrafluoroethylene (ePTFE), and denucleated ePTFE (dePTFE)] biomaterials designed for use in cardiovascular applications. These materials were perfused with heparinized whole human blood in an in vitro parallel plate flow chamber. Platelet adhesion after 5 min of perfusion ranged from 3.7 +/- 1.0 (dePTFE) to 16.8 +/- 1.5 (WD) platelets/1000 micrometer. The temporal information revealed by these studies provides a comparative measure of the acute thrombogenicity of these materials as well as some insight into their long-term hemocompatibilities. Also studied here were the effects of wall shear rate and axial position on platelet adhesion. A predicted increase in platelet adhesion with increased wall shear rate and a trend toward a decrease in platelet adhesion with increased axial distance was observed with the fiber optic microscope. Future applications for this imaging technique may include the long-term evaluation of thrombosis in blood-contacting devices in vitro and, in animal models, in vivo.

Rotary blood pump flow spontaneously increases during exercise under constant pump speed: results of a chronic study.

Many types of rotary blood pumps and pump control methods have recently been developed with the goal of clinical use. From experiments, we know that pump flow spontaneously increases during exercise without changing pump control parameters. The purpose of this study was to determine the hemodynamics associated with the long-term observation of calves implanted with centrifugal blood pumps (EVAHEART, Sun Medical Technology Research Corporation, Nagano, Japan). Two healthy female Jersey calves were implanted with devices in the left thoracic cavity. A total of 22 treadmill exercise tests were performed after the 50th postoperative day. During exercise, the following parameters were compared with conditions at rest: heart rate, blood pressure, central venous oxygen saturation (SvO2), pump speed, and pump flow. The pump flow in a cardiac cycle was analyzed by separating the systole and diastole. Compared to the base data, statistically significant differences were found in the following interrelated parameters: the heart rate (66.8 +/- 5.2 vs. 106 +/- 9.7 bpm), mean pump flow (4.8 +/- 0.2 vs. 7.0 +/- 0.3 L/min), and volume of pump flow in diastole (26.0 +/- 1.8 vs. 13.5 +/- 2.5 ml). During exercise, the volume of pump flow in systole was 3 times larger than that measured in diastole. Blood pressure, SvO2, and pump speed did not change significantly from rest to exercise. These results suggested that the mean pump flow depends on the systolic pump flow. Therefore, the increase in the mean pump flow during exercise under constant pump speed was caused by an increase in the heart rate.

Decrease in red blood cell deformability caused by hypothermia, hemodilution, and mechanical stress: factors related to cardiopulmonary bypass.

During extracorporeal circulation in cardiopulmonary bypass (CPB) surgery, blood is exposed to anomalous mechanical and environmental factors, such as high shear stress, turbulence, decreased oncotic pressure caused by dilution of plasma, and moderate and especially deep hypothermia widely applied during CPB in infants. These factors cause damage to the red blood cells (RBCs), which is manifest by immediate and delayed hemolysis and by changes in the mechanical properties of RBCs. These changes include, in particular, decrease in RBC deformability impeding the passage of RBCs through the microvessels and may contribute to the complications associated with CPB surgery. We investigated in vitro the independent and combined effects of hypothermia, plasma dilution, and mechanical stress on deformability of bovine RBCs. Our studies showed each of these factors to cause a significant decrease in the deformability of RBCs, especially acting synergistically. The impairment of RBC deformability caused by hypothermia was found to be more pronounced for RBCs suspended in phosphate buffered saline (PBS) than for RBCs suspended in plasma. The decrease in RBC deformability caused by mechanical stress was significantly exacerbated by dilution of plasma with PBS. In summary, results of our in vitro study strongly point to a possible detrimental consequence of conventional CPB arising from increased RBC rigidity, which may lead to impaired microcirculation and tissue oxygen supply.

Chronic animal health assessment during axial ventricular assistance: importance of hemorheologic parameters.

Chronic testing of the Nimbus/UOP Axial Flow Pump was performed on 22 calves for periods of implantation ranging from 27 to 226 days (average, 74 days). The following parameters were measured: plasma free hemoglobin, blood and plasma viscosity, erythrocyte deformability and mechanical fragility, oxygen delivery index (ODI), blood cell counts, hematocrit, hemoglobin, blood urea nitrogen, creatinine, bilirubin, total protein, fibrinogen, and plasma osmolality. Most of the above parameters were stable during the full course of support. Compared with baseline, statistically significant differences during the entire period of implantation were only found in: hematocrit (p<0.001), hemoglobin (p<0.005), red blood cell (RBC) count (p<0.001), and whole blood viscosity (p<0.01). Plasma viscosity and ODI were mostly stable during the period of implantation. In some animals, an acute increase in fibrinogen concentration, plasma and blood viscosity, and a decrease in ODI were found to be early signs of the onset of infection. A small (10%) decrease in deformability of RBCs was found during the first 2 weeks after implantation. This alteration in RBC deformability was highly correlated (r = 0.793) with changes in total plasma protein concentration that fell more than 15% (p<0.001) during the same period. Mechanical fragility of RBCs was found to be slightly increased after implantation. Plasma free hemoglobin remained close to baseline level (p>0.2). After the first 2 weeks of the postoperative period, pump performing parameters for all animals were consistent and stable. In general, the Nimbus/UOP Axial Flow Pump demonstrated basic reliability and biocompatibility and did not produce significant alterations in the mechanical properties of blood or animal health status. The pump provided adequate hemodynamics and was well tolerated by the experimental animal for periods as long as 7.5 months. Monitoring rheologic parameters of blood is very helpful for evaluation of health during heart-assist device application.

Gender difference in rheologic properties of blood and risk of cardiovascular diseases.

According to official statistical data there is a significant difference between pre-menopausal women and age-matched men in morbidity and mortality from cardiac diseases and especially from myocardial infarction. There are several speculations regarding the nature of this phenomenon which have both supporting and refuting evidence. Our hypothesis was that due to regular physiologic bleeding, rheological properties of blood of pre-menopausal women are superior to those of men, and place such women at a lower risk of cardiovascular diseases than men in any age group. We believe that this difference in hemorheological properties is due to the reduced concentration of red blood cells (RBCs) and due to greater population of younger and less population of older RBCs in female blood. We studied mechanical properties of blood from 47 pre-menopausal women and 50 age-matched men. Compared to female blood, male blood had higher viscosity and RBC aggregation and lower RBC deformability. Oxygen Delivery Index, calculated as a ratio of hematocrit to blood viscosity, was found to be significantly lower in male blood. Decreased oxygen delivery along with increased RBC aggregation and decreased RBC deformability may contribute to the higher risk for the development of cardiovascular diseases. Regular blood donation may reduce hematocrit and blood viscosity, improve rheological properties of blood, and increase oxygen delivery in men.

Progress on development of the Nimbus-University of Pittsburgh axial flow left ventricular assist system.

Nimbus Inc. (Rancho Cordova, CA) and the University of Pittsburgh have completed the second year of development of a totally implanted axial flow blood pump under the National Institutes of Health Innovative Ventricular Assist System Program. The focus this year has been on completing pump hydraulic development and addressing the development of the other key system components. Having demonstrated satisfactory pump hydraulic and biocompatibility performance, pump development has focused on design features that improve pump manufacturability. A controller featuring full redundancy has been designed and is in the breadboard test phase. Initial printed circuit layout of this circuit has shown it to be appropriately sized at 5 x 6 cm to be compatible with implantation. A completely implantable system requires the use of a transcutaneous energy transformer system (TETS) and a diagnostic telemetry system. The TETS power circuitry has been redesigned incorporating an improved, more reliable operating topography. A telemetry circuit is undergoing characterization testing. Closed loop speed control algorithms are being tested in vitro and in vivo with good success. Eleven in vivo tests were conducted with durations from 1 to 195 days. Endurance pumps have passed the 6 month interval with minimal bearing wear. All aspects of the program continue to function under formal quality assurance.

Assessment of bovine platelet life span with biotinylation and flow cytometry.

Reduced platelet life span is associated with the implantation of a variety of cardiovascular devices and may be used as a gauge of device biocompatibility. In the bovine model, platelet life span has previously been assessed with radioisotope labeling of removed platelets followed by reinjection and periodic gamma counting of blood samples. We report here the use of protein-reactive biotin (sulfo-N-hydroxysuccinimido [NHS]-biotin) as an alternative to radioisotope techniques whereby reinjected biotinylated platelets are subsequently detected in blood samples using phycoerythrin-streptavidin and flow cytometric techniques. Platelet life span was quantified in a normal calf (4.9 days) and in a calf prior to (6.1 days) and following (3.1 days) implantation of a Nimbus Axial Flow Pump ventricular assist device. The assessment of bovine platelet life span with biotinylation and flow cytometry avoids the technical, regulatory, and safety considerations associated with radioisotope usage and appears readily amenable to application in cardiovascular device testing.