Michael J. Simmonds

Blood rheology and aging

The flow properties of blood play significant roles in tissue perfusion by contributing to hydrodynamic resistance in blood vessels. These properties are influenced by pathophysiological processes, thereby increasing the clinical relevance of blood rheology information. There is well-established clinical evidence for impaired blood fluidity in humans of advanced age, including enhanced plasma and whole blood viscosity, impaired red blood cell (RBC) deformability and enhanced RBC aggregation. Increased plasma fibrinogen concentration is a common finding in many studies owing to the pro-inflammatory condition of aged individuals; this finding of increased fibrinogen concentration explains the higher plasma viscosity and RBC aggregation in elderly subjects. Enhanced oxidant stress in advanced age is also known to contribute to altered blood fluidity, with RBC deformability being an important determinant of blood viscosity. Several studies have shown that physical activity may improve the hemorheological picture in elderly subjects, yet well-designed observational and mechanistic studies are required to determine the specific effects of regular exercise on hemorheological parameters in healthy and older individuals.

Exercise hemorheology: classical data, recent findings and unresolved issues.

The present review focuses on the past and recent knowledge in the field of exercise hemorheology and presents some unresolved issues for opening discussion. Acute exercise is associated with a rise in hematocrit which results in an increase in blood viscosity. Whereas increased blood viscosity was previously viewed as having negative consequences for cardiovascular function and aerobic performance, recent findings suggest dynamic changes in blood viscosity might be useful for vascular function during exercise by increasing nitric oxide production. Other determinants of blood viscosity are altered by exercise (e.g., decreased red blood cell deformability, increased red blood cell aggregation and plasma viscosity) and may, independent of the associated effect on blood viscosity, directly modulate aerobic capacity. However, the data published on the effects of exercise on the hemorheology are not consistent, with some studies showing decreased, unchanged, or increased red blood cell deformability/aggregation when compared with rest. These discrepancies seem to be related to the exercise protocol investigated, the population tested or the methodogy utilized for hemorheological measurements. Finally, this review focuses on the effects of exercise training (i.e. chronic physical activity) on the hemorheological profile of healthy individuals and patients with cardiovascular and metabolic disorders.

Nitric oxide, vasodilation and the red blood cell

Since the identification of the elusive endothelium-derived relaxing factor as nitric oxide (NO), much attention has been devoted to understanding its physiological effects. NO is a free radical with many roles, and owing to its neutral charge and high diffusion capacity, it appears NO is involved in every mammalian biological system. Most attention has been focused on the NO generating pathways within the endothelium; however, the recent discovery of a NO synthase (NOS)-like enzyme residing in red blood cells (RBC) has increased our understanding of the blood flow and oxygen delivery modulation by RBC. In the present review, pathways of NO generation are summarized, with attention to those residing within RBC. While the bioactivity of RBC-derived NO is still debated due to its generation within proximity of NO scavengers, current theories for NO export from RBC are explored, which are supported by recent findings demonstrating an extracellular response to RBC-derived NO. The importance of NO in the active regulation of RBC deformability is discussed in the context of the subsequent effects on blood fluidity, and the complex interplay between blood rheology and NO are summarized. This review provides a summary of recent advances in understanding the role played by RBC in NO equilibrium and vascular regulation.

Preliminary findings in the heart rate variability and haemorheology response to varied frequency and duration of walking in women 65–74 yr with type 2 diabetes

Heart rate variability (HRV) and haemorheology adaptations to 12 wk of varied-dose treadmill walking were investigated in women aged 65-74 yr with type 2 diabetes. Subjects were randomly allocated into two groups where exercise frequency and session duration were manipulated (Group 1: 2 × 60 min·wk(-1) or Group 2: 4 × 30 min·wk(-1)), but intensity and accumulated weekly duration of exercise were consistent between groups (100% gas-exchange threshold; 120 min·wk(-1)). Twelve weeks of exercise training significantly improved peak oxygen uptake, time to exhaustion, and gas-exchange threshold (p < 0.05), independent of exercise group. Exercise training did not significantly change glycaemic control or body mass. Red blood cell (RBC) aggregation and RBC deformability significantly decreased (p < 0.05) for both groups. No change in HRV was observed for Group 1, whereas several key indicators of HRV were significantly improved in Group 2 (p < 0.05). The present study was the first to report decreased RBC aggregation following an exercise-only intervention and that exercise training improved RBC aggregation without a concomitant improvement in glycaemic control. The accumulated weekly exercise duration may be the most important training component for the prescription of exercise in older women with type 2 diabetes.

Blood viscosity and hemodynamics during exercise

We tested the effects of submaximal exercise on blood viscosity (η(b)), nitric oxide production (NO) and hemodynamics. Relationships between the exercise-induced changes that occurred in these parameters were investigated. Nine subjects performed exercise for 15 min at 105% of the first ventilatory threshold. Mean arterial pressure (MAP) and cardiac output (Qc) were measured, allowing the determination of systemic vascular resistance (SVR). Blood was sampled at rest and at the end of exercise. The η(b) was determined at high shear rate and was used to calculate systemic vascular hindrance (VH). NO production was estimated by measuring plasma concentrations of NO stable end products (NOx). Qc, MAP, η(b) and NOx, increased with exercise, whereas SVR and VH decreased. The changes between rest and exercise were calculated and tested for correlations. We observed: 1) a positive correlation between the increase in η(b) and the increase in NOx; 2) a negative correlation between the increase in NOx and the decrease in VH; 3) a negative correlation between the increase in η(b) and the decrease in SVR. Although the increase in Qc and blood flow during exercise probably promoted NO production due to shear dependent stimulation of the endothelium, the present results also support that the rise in η(b) during exercise may be necessary for NO production and adequate vasodilation.

Exercise-induced blood lactate increase does not change red blood cell deformability in cyclists.

Background The effect of exercise-induced lactate production on red blood cell deformability and other blood rheological changes is controversial, given heavy-exercise induces biochemical processes (e.g., oxidative stress) known to perturb haemorheology. The aim of the present study was to examine the haemorheological response to a short-duration cycling protocol designed to increase blood lactate concentration, but of duration insufficient to induce significant oxidative stress. Methods Male cyclists and triathletes (n = 6; 27±7 yr; body mass index: 23.7±3.0 kg/m2; peak oxygen uptake 4.02±0.51 L/min) performed unloaded (0 W), moderate-intensity, and heavy-intensity cycling. Blood was sampled at rest and during the final minute of each cycling bout. Blood chemistry, blood viscosity, red blood cell aggregation and red blood cell deformability were measured. Results Blood lactate concentration increased significantly during heavy-intensity cycling, when compared with all other conditions. Methaemoglobin fraction did not change during any exercise bout when compared with rest. Blood viscosity at native haematocrit increased during heavy-intensity cycling at higher-shear rates when compared with rest, unloaded and moderate-intensity cycling. Heavy-intensity exercise increased the amplitude of red blood cell aggregation in native haematocrit samples when compared with all other conditions. Red blood cell deformability was not changed by exercise. Conclusion Acute exercise perturbs haemorheology in an intensity dose-response fashion; however, many of the haemorheological effects appear to be secondary to haemoconcentration, rather than increased lactate concentration.

Heart rate variability is related to impaired haemorheology in older women with type 2 diabetes

Impaired heart rate variability (HRV)and haemorheology are independently associated with cardiovascular disease and diabetic complications. The aim of the present study was to investigate the relationships between parameters of HRV,and red blood cell (RBC) aggregation and deformability, in older women with type 2 diabetes. Twenty women (age 69 ± 2 yr) with uncomplicated type 2 diabetes and twenty controls (age 69 ± 3 yr) participated in the study. Beat-to-beat cardiac (RR) intervals over 5 min were analysed for HRV parameters in the time and frequency domains. Blood was sampled for RBC deformability, as well as RBC aggregation in two suspending mediums: haematocrit adjusted plasma and 3% dextran 70. RBC aggregation was increased and HRV was impaired for those with type 2 diabetes when compared with control. RBC aggregation was negatively related to low frequency power of HRV, and was positively related to high frequency power of HRV, for subjects with type 2 diabetes. RBC deformability was positively related to HRV only for those with type 2 diabetes. Impaired haemorheology is associated with reduced HRV in older women with type 2 diabetes, suggesting changes in the microcirculation may result in impaired modulation of cardiac cycles.

A comparison of capillary and venous blood sampling methods for the use in haemorheology studies.

There is accumulating evidence that exercise may improve disturbed haemorheological parameters that are typically observed in various chronic diseases, thus there is a growing interest in exploring the influence of various exercise models for the improvement of haemorheology. Blood sampling using venipuncture, however, can be limiting during exercise and/or in field settings. The purpose of the present study was to investigate whether venous and capillary blood samples yield comparable red blood cell (RBC) deformability and aggregation indices. Twelve healthy volunteers (6 males and 6 females; age 30 ± 9 yrs; body mass index 24.9 ± 2.8 kg m(-2)) provided blood samples that were collected simultaneously from: i) a prominent forearm vein by venipuncture; ii) the earlobe using a lancet; iii) the middle finger using a lancet. Haematocrit, RBC deformability (Rheoscan-D, Sewon Meditech Inc., Korea) and RBC aggregation (Myrenne GmbH, Roetgen, Germany) were measured for each sample. Haematocrit and RBC deformability were not different between the three sampling sites, and the group averages of RBC aggregation parameters were not different between the three sampling methods. The time course of RBC aggregation was slower when using blood sampled from the earlobe, and there was stronger agreement between RBC aggregation parameters measured using venous and capillary finger samples compared with venous and earlobe. It is suggested that capillary blood sampling from the finger may provide a reliable alternative to venous blood sampling in clinical and field settings.

Cardiovascular dynamics during exercise are related to blood rheology

BACKGROUND The principal determinants of oxygen uptake (VO2) kinetics are controversial, with dynamic changes in central and peripheral factors mediating oxygen supply and utilisation suggested to be limiting. The aim of this study was to determine whether important parameters of blood rheology were related to the exercise-induced time-course changes in VO2 and cardiac output (Qc), or steady-state arteriovenous oxygen difference (a-vO2D) during submaximal cycling. METHODS AND RESULTS Blood was collected from ten healthy, recreationally active males and females (age: 21.7 ± 1.3 yr; body mass index: 22.7 ± 2.0 kg · m(-2)), before each subject cycled at 105% of the first ventilatory threshold. Red blood cell aggregation was negatively correlated with steady-state VO2 during exercise and the a-vO2D at rest (r = -0.73, p < 0.05), and positively correlated to Qc at rest (r = 0.71, p < 0.05). Blood viscosity at various shear rates was negatively correlated with the time constant of VO2 (all p < 0.01) on-transient kinetics. Red blood cell deformability at various shear stress was positively correlated to the time constant of VO2 (all p < 0.05) on-transient kinetics. CONCLUSIONS The findings of the present study suggest that the rheological properties of blood may modulate, at least in part, the rate of change in the uptake and/or utilisation of oxygen at the onset of exercise.

Oxidative Stress Increases Erythrocyte Sensitivity to Shear-Mediated Damage

Patients receiving mechanical circulatory support often present with heightened inflammation and free radical production associated with pre-existing conditions in addition to that which is due to blood interactions with nonbiological surfaces. The aim of this experimental laboratory study was to assess the deformability of red blood cells (RBC) previously exposed to oxygen free radicals and determine the susceptibility of these cells to mechanical forces. In the present study, RBC from 15 healthy donors were washed and incubated for 60 min at 37°C with 50 µM phenazine methosulfate (PMS; an agent that generates superoxide within RBC). Incubated RBC and negative controls were assessed for their deformability and susceptibility to mechanical damage (using ektacytometry) prior to the application of shear stress, and also following exposure to 25 different shear conditions of varied magnitudes (shear stress 1, 4, 16, 32, 64 Pa) and durations (1, 4, 16, 32, 64 s). The salient findings demonstrate that incubation with PMS impaired important indices of RBC deformability indicating altered cell mechanics by ∼19% in all conditions (pre- and postexposure to shear stress). The typical trends in shear-mediated changes in RBC susceptibility to mechanical damage, following conditioning shear stresses, were maintained for PMS incubated and control conditions. We demonstrated that free radicals hinder the ability of RBC to deform; however, RBC retained their typical mechanical response to shear stress, albeit at a decreased level compared with control following exposure to PMS. Our findings also indicate that low shear exposure may decrease cell sensitivity to mechanical damage upon subsequent shear stress exposures. As patients receiving mechanical circulatory support have elevated exposure to free radicals (which limits RBC deformability), concomitant exposure to high shear environments needs to be minimized.