Andreas Rössler

Orthostatic Stimuli Rapidly Change Plasma Adrenomedullin in Humans

The aim of this study was to evaluate the effect of orthostasis on the time course of plasma adrenomedullin concentration. On 5 different days, normotensive subjects were randomized to undergo for 30 minutes either 12 degrees, 30 degrees, 53 degrees, or 70 degrees passive head-up tilt or to remain supine. Venous blood was collected from each subject in the supine position before tilting, at 3 and 27 minutes during tilting, and at 2 and 50 minutes after orthostasis. Plasma adrenomedullin increased significantly with tilt of >/=30 degrees in a stimulus-dependent manner. Approximately half of the increase seen at 27 minutes occurred during the first 2 minutes of upright positioning; the maximum effect with 70 degrees tilt was +70%. Elevations in norepinephrine, epinephrine, aldosterone, plasma renin activity, vasopressin, heart rate, and mean arterial pressure were also significant. Hematocrit, blood density, plasma density, and plasma volume loss rose (P<0.05) at 53 degrees and 70 degrees tilt. Our results indicate that adrenomedullin may play an important role in stabilization of hemodynamics during passive orthostasis. In conclusion, plasma adrenomedullin rapidly increases with orthostatic challenge in a stimulus-dependent manner and also swiftly returns to baseline levels after the subject resumes the supine position.

Reactive hyperemia in the human liver

We tested whether hepatic blood flow is altered following central hypovolemia caused by simulated orthostatic stress. After 30 min of supine rest, hemodynamic, plasma density, and indocyanine green (ICG) clearance responses were determined during and after release of a 15-min 40 mmHg lower body negative pressure (LBNP) stimulus. Plasma density shifts and the time course of plasma ICG concentration were used to assess intravascular volume and hepatic perfusion changes. Plasma volume decreased during LBNP (-10%) as did cardiac output (-15%), whereas heart rate (+14%) and peripheral resistance (+17%) increased, as expected. On the basis of ICG elimination, hepatic perfusion decreased from 1.67 +/- 0.32 (pre-LBNP control) to 1.29 +/- 0.26 l/min (-22%) during LBNP. Immediately after LBNP release, we found hepatic perfusion 25% above control levels (to 2.08 +/- 0.48 l/min, P = 0.0001). Hepatic vascular conductance after LBNP was also significantly higher than during pre-LBNP control (21.4 +/- 5.4 vs. 17.1 +/- 3.1 ml.min(-1).mmHg(-1), P < 0.0001). This indicates autoregulatory vasodilatation in response to relative ischemia during a stimulus that has cardiovascular effects similar to normal orthostasis. We present evidence for physiological post-LBNP reactive hyperemia in the human liver. Further studies are needed to quantify the intensity of this response in relation to stimulus duration and magnitude, and clarify its mechanism.

Plasma hyaluronan concentration: no circadian rhythm but large effect of food intake in humans

Abstract This study was designed to determine if a circadian rhythm in plasma hyaluronan concentration [HA] exists in the absence of physical activity, and if plasma [HA] is associated with feeding in human subjects. Five persons were studied under standardized conditions, blood samples being taken between 0600 and 2200 hours at 30-min intervals. Any orthostatic challenge and muscle activity was abolished by immobilization by a 6° head-down bed-rest, and the effect of a quasi-continuous ingestion of energy compared a normal, three-portion diet of equivalent energy content or to fasting. Reproducibility of HA profiles on two consecutive half-days was also studied. A highly sensitive immunoassay was used to determine plasma [HA]. The data indicated that without physical activity and without food ingestion, [HA] was unchanged and displayed no diurnal rhythm. In addition, we observed that [HA] increased after the first food intake, peaking after 60 min, and concluded from our results that without ingestion of a larger meal, and sessions of postural or muscle activity, no circadian plasma [HA] rhythm exists.

Hormonal and plasma volume changes after presyncope

Eur J Clin Invest 2011; 41 (11): 1180–1185

An ultrasensitive, nonisotopic immunoassay for hyaluronan using the streptavidin–biotin system

A time-resolved fluoroimmunoassay for measuring hyaluronan concentrations in plasma and several biological fluids is described. The solid-phase immunoassay is based on the competition between aggregation of hyaluronan with the cartilage proteoglycan monomer, followed by binding of a monoclonal antibody to keratan sulfate of the proteoglycan and a biotinylated anti-mouse IgG. Fluorescence can be measured by a time-resolved fluorometer after binding of Eu(3+)-labelled streptavidin to the biotinylated IgG. The assay is precise and correlates well (r = 0.986) with the only established radioimmunoassay known. The results show that it is essential to perform a blank run without addition of proteoglycan, as endogenous proteoglycan disturbs the measurement and causes underestimation of plasma hyaluronan. The distinguishing feature of this assay is its extreme sensitivity (< 0.24 microgram/l of plasma). The mean analytical recovery after serial dilutions and addition was 100.3 and 101.3%, the within-assay and between-assay coefficients of variation were 3.67% and 7.02%, respectively.

Effect of postural changes on cardiovascular parameters across gender

Introduction: We investigated the effect of postural changes on various cardiovascular parameters across gender. Twenty-eight healthy subjects (16 male, 12 female) were observed at rest (supine) and subjected to 3 interventions; head-down tilt (HDT), HDT with lower body negative pressure (HDT+ LBNP at −30 mm Hg), and head-up tilt (HUT), each for 10 minutes separated by a 10 minutes recovery period. Methods: Measurements were recorded for heart rate (HR), standard deviation of the normal-to-normal intervals, root mean square of successive differences between the normal-to-normal intervals, heart rate variability-low frequency (LFRRI), heart rate variability-high frequency (HFRRI), low frequency/high frequency ratio (LFRRI/HFRRI), systolic blood pressure (SBP), mean arterial pressure (MAP), diastolic blood pressure (DBP), total peripheral resistance index (TPRI), stroke index (SI), cardiac index (CI), index of contractility (IC), left ventricular work index, and left ventricular ejection time. Results: Across all cardiovascular parameters, there was a significant main effect of the intervention applied but there was no significant main effect of gender across all parameters. Conclusions: The results suggest that there are no specific gender differences in regards to the measured variables under the conditions of this study. Furthermore, these results suggest that in healthy subjects, there appears to be evidence that LBNP partially elicits similar cardiovascular responses to HUT, which supports the use of LBNP as an intervention to counteract the effects of central hypovolemia.

Influence of bed rest on plasma galanin and adrenomedullin at presyncope

The role of hormones in reduced orthostatic tolerance following long‐term immobilization remains uncertain. We have previously shown that plasma concentrations of adrenomedullin and galanin, two peptides with vasodepressor properties, rise significantly during orthostatic challenge. We tested the hypothesis that bedrest immobilization increases the rise in adrenomedullin and galanin during orthostatic challenge leading to presyncope.

Poststroke alterations in heart rate variability during orthostatic challenge.

Abstract Older adults following recovery from ischemic stroke have a higher incidence of orthostatic hypotension, syncope, and fall risk, which may be related to impaired autonomic responses limiting the ability to maintain cerebral blood flow. Thus, we investigated cerebrovascular and cardiovascular regulation in 23 adults ≥55 years of age, 10 diagnosed with ischemic stroke, and 13 age-matched healthy controls when sitting at rest and upon standing to compare differences of autonomic variables at ∼7 months (218 ± 41 days) poststroke. Arterial blood pressure via finger plethysmography, muscle-pump baroreflex via electromyography, heart rate variability via 3-lead ECG, and cerebral blood flow velocity via transcranial Doppler were analyzed while sitting for 5 minutes and then during quiet standing for 5 minutes. From the seated to standing position, the stroke group had significantly greater decline in the low frequency component of heart rate variability (164 [79] vs 25 [162] ms2; P = 0.043). All other cardiovascular parameters and assessments of autonomic function were not significantly different between the two groups. Our findings support the hypothesis of continued autonomic dysfunction after recovery from ischemic stroke, with potential attenuation of the cardiovascular response to standing. However, further investigation is required to determine the mechanisms underlying the increased risk of orthostatic hypotension, syncope, and falls poststroke.

effect of computerized cognitive training with virtual spatial navigation task during bed rest immobilization and recovery on vascular function: A pilot study

We investigated the effects of bed rest (BR) immobilization, with and without computerized cognitive training with virtual spatial navigation task (CCT), on vascular endothelium on older subjects. The effects of 14-day BR immobilization in healthy older males (n=16) of ages 53–65 years on endothelial function were studied using EndoPAT®, a noninvasive and user-independent method. From the group of 16 older men, 8 randomly received CCT during the BR, using virtual navigation tasks in a virtual environment with joystick device. In all the cases, EndoPAT assessments were done at pre- and post-BR immobilization as well as following 28 days of ambulatory recovery. The EndoPAT index increased from 1.53±0.09 (mean ± standard error of the mean) at baseline to 1.61±0.16 following immobilization (P=0.62) in the group with CCT. The EndoPAT index decreased from 2.06±0.13 (mean ± standard error of the mean) at baseline to 1.70±0.09 at the last day of BR study, day 14 (BR14) (P=0.09) in the control group. Additionally, there were no statistically significant differences between BR14 and at 28 days of follow-up (rehabilitation program) (R28). Our results show a trend of immobilization in older persons affecting the vasoconstrictory endothelial response. As the control subjects had a greater increase in EndoPAT index after R28 (+0.018) compared to subjects who had cognitive training (+0.11) (calculated from the first day of BR study), it is possible that cognitive training during BR does not improve endothelial function but rather contributes to slowing down the impairment of endothelial function. Finally, our results also show that EndoPAT may be a useful noninvasive tool to assess the vascular reactivity.

Modeling of hyaluronan clearance with application to estimation of lymph flow

One of the important factors in blood pressure regulation is the maintenance of the level of blood volume, which depends on several factors including the rate of lymph flow. Lymph flow can be measured directly using cannulation of lymphatic vessels, which is not clinically feasible, or indirectly by the tracer appearance rate, which is the rate at which macromolecules appear into the blood from the peritoneal cavity. However, indirect lymph flow measurements do not always provide consistent results. Through its contribution to osmotic pressure and resistance to flow, the macromolecule hyaluronan takes part in the regulation of tissue hydration and the maintenance of water and protein homeostasis. It arrives in blood plasma through lymph flow. Lymphatic hyaluronic acid (HA, hyaluronan) concentration is several times higher than that in plasma, suggesting that the lymphatic route may account for the majority of HA found in plasma. Furthermore, circulating levels of HA reflect the dynamic state between delivery to-and removal from-the bloodstream. To develop an accurate estimation of the fluid volume distribution and dynamics, the rate of lymph flow needs to be taken into account and hyaluronan could be used as a marker in estimating this flow. To examine the HA distribution and system fluid dynamics, a six-compartment model, which could reflect both the steady-state relationships and qualitative characteristics of the dynamics, was developed. This was then applied to estimate fluid shifts from the interstitial space via the lymphatic system to the plasma during different physiological stresses (orthostatic stress and the stress of ultrafiltration during dialysis). Sensitivity analysis shows that during ultrafiltration, lymph flow is a key parameter influencing the total HA level, thus suggesting that the model may find applications in addressing the problem of estimating lymph flow. Since the fluid balance between interstitium and plasma is maintained by lymph flow and microvasculature filtration, our novel method of flow estimation may provide an important tool for understanding fluid dynamics during perturbations of the cardiovascular system. Since the fluid balance between interstitium and plasma is maintained by lymph flow and microvasculature filtration, our novel method of flow estimation may provide an important tool for understanding fluid dynamics during perturbations of the cardiovascular system.