Andreas Roessler

Coagulation Changes during Presyncope and Recovery

Orthostatic stress activates the coagulation system. The extent of coagulation activation with full orthostatic load leading to presyncope is unknown. We examined in 7 healthy males whether presyncope, using a combination of head up tilt (HUT) and lower body negative pressure (LBNP), leads to coagulation changes as well as in the return to baseline during recovery. Coagulation responses (whole blood thrombelastometry, whole blood platelet aggregation, endogenous thrombin potential, markers of endothelial activation and thrombin generation), blood cell counts and plasma mass density (for volume changes) were measured before, during, and 20 min after the orthostatic stress. Maximum orthostatic load led to a 25% plasma volume loss. Blood cell counts, prothrombin levels, thrombin peak, endogenous thrombin potential, and tissue factor pathway inhibitor levels increased during the protocol, commensurable with hemoconcentration. The markers of endothelial activation (tissue factor, tissue plasminogen activator), and thrombin generation (F1+2, prothrombin fragments 1 and 2, and TAT, thrombin-antithrombin complex) increased to an extent far beyond the hemoconcentration effect. During recovery, the markers of endothelial activation returned to initial supine values, but F1+2 and TAT remained elevated, suggestive of increased coagulability. Our findings of increased coagulability at 20 min of recovery from presyncope may have greater clinical significance than short-term procoagulant changes observed during standing. While our experiments were conducted in healthy subjects, the observed hypercoagulability during graded orthostatic challenge, at presyncope and in recovery may be an important risk factor particularly for patients already at high risk for thromboembolic events (e.g. those with coronary heart disease, atherosclerosis or hypertensives).

Time course of cardiovascular responses induced by mental and orthostatic challenges

Cardiovascular responses to single stressors diminish over time. Interaction of different stressors influencing hemodynamic variables, indicative of stress-induced reactivity and physiological responses are, however, poorly understood. We investigated time course of mental (using mental arithmetic, MA) and orthostatic (using head up tilt, HUT) challenges induced responses in 16 males. Three protocols were used: HUT, MA and MA+HUT, with sessions randomized and two weeks apart. Hemodynamic responses were compared for 30s epochs of stress application (stress(T1), stress(T2)...). Compared to baseline, HUT, HUT+MA and MA applications affected heart rate (HR) (+15.1+/-8.0 bpm, +20.0+/-9.2 bpm, +11.9+/-7.2 bpm, all ps<.001, respectively) and stroke volume (SV) (-22.3+/-8.1 ml, -22.0+/-10.4 ml, -7.6+/-8.7 ml, all ps<.001, respectively). HUT and MA+HUT induced HR increases were higher in stress(T2) compared to stress(T1) (p<.05) and reached maximum at stress(T2). HUT and MA+HUT further reduced SV in stress(T2) as compared to stress(T1) (p<.001); lowest SV was in stress(T2). Mean arterial pressure reached its minimum in stress(T1) during HUT and MA+HUT (-6.0+/-8.5mm Hg, p<.001, -4.4+/-9.7 mm Hg, p<.01, respectively) but increased in MA (+4.3+/-3.7 mm Hg, p<.01). Combination of MA+HUT resulted in different time courses of blood pressure responses as compared to HUT alone. We conclude that application of single or combined stress challenges lead to stressor- and time dependent-initial changes in cardiovascular responses. Our findings provide novel insights regarding the duration a stressor must be applied to elicit maximal cardiovascular responses.

Volume regulating hormone responses to repeated head-up tilt and lower body negative pressure

Eur J Clin Invest 2011; 41 (8): 863–869

Phase Synchronization of Hemodynamic Variables at Rest and after Deep Breathing Measured during the Course of Pregnancy

Background The autonomic nervous system plays a central role in the functioning of systems critical for the homeostasis maintenance. However, its role in the cardiovascular adaptation to pregnancy-related demands is poorly understood. We explored the maternal cardiovascular systems throughout pregnancy to quantify pregnancy-related autonomic nervous system adaptations. Methodology Continuous monitoring of heart rate (R-R interval; derived from the 3-lead electrocardiography), blood pressure, and thoracic impedance was carried out in thirty-six women at six time-points throughout pregnancy. In order to quantify in addition to the longitudinal effects on baseline levels throughout gestation the immediate adaptive heart rate and blood pressure changes at each time point, a simple reflex test, deep breathing, was applied. Consequently, heart rate variability and blood pressure variability in the low (LF) and high (HF) frequency range, respiration and baroreceptor sensitivity were analyzed in resting conditions and after deep breathing. The adjustment of the rhythms of the R-R interval, blood pressure and respiration partitioned for the sympathetic and the parasympathetic branch of the autonomic nervous system were quantified by the phase synchronization index γ, which has been adopted from the analysis of weakly coupled chaotic oscillators. Results Heart rate and LF/HF ratio increased throughout pregnancy and these effects were accompanied by a continuous loss of baroreceptor sensitivity. The increases in heart rate and LF/HF ratio levels were associated with an increasing decline in the ability to flexibly respond to additional demands (i.e., diminished adaptive responses to deep breathing). The phase synchronization index γ showed that the observed effects could be explained by a decreased coupling of respiration and the cardiovascular system (HF components of heart rate and blood pressure). Conclusions/Significance The findings suggest that during the course of pregnancy the individual systems become increasingly independent to meet the increasing demands placed on the maternal cardiovascular and respiratory system.

Effect of Orthostasis on Endothelial Function: A Gender Comparative Study

As the vascular endothelium has multiple functions, including regulation of vascular tone, it may play a role in the pathophysiology of orthostatic intolerance. We investigated the effect of orthostasis on endothelial function using EndoPAT®, a non-invasive and user-independent method, and across gender. As sex steroid hormones are known to affect endothelial function, this study examined the potential effect of these hormones on the endothelial response to orthostasis by including females at different phases of the menstrual cycle (follicular and luteal—where the hormone balance differs), and females taking an oral contraceptive. A total of 31 subjects took part in this study (11 males, 11 females having normal menstrual cycles and 9 females taking oral contraceptive). Each subject made two visits for testing; in the case of females having normal menstrual cycles the first session was conducted either 1–7 (follicular) or 14–21 days (luteal) after the start of menstruation, and the second session two weeks later, i.e., during the other phase, respectively. Endothelial function was assessed at baseline and following a 20-min orthostatic challenge (active standing). The EndoPAT® index increased from 1.71 ± 0.09 (mean ± SEM) at baseline to 2.07 ± 0.09 following orthostasis in females (p<0.001). In males, the index increased from 1.60 ± 0.08 to 1.94 ± 0.13 following orthostasis (p<0.001). There were no significant differences, however, in the endothelial response to orthostasis between females and males, menstrual cycle phases and the usage of oral contraceptive. Our results suggest an increased vasodilatatory endothelial response following orthostasis in both females and males. The effect of gender and sex hormones on the endothelial response to orthostasis appears limited. Further studies are needed to determine the potential role of this post orthostasis endothelial response in the pathophysiology of orthostatic intolerance.

Delaying orthostatic syncope with mental challenge: A pilot study

At orthostatic vasovagal syncope there appears to be a sudden decline of sympathetic activity. As mental challenge activates the sympathetic system, we hypothesized that doing mental arithmetic in volunteers driven to the end point of their cardiovascular stability may delay the onset of orthostatic syncope. We investigated this in healthy male subjects. Each subject underwent a head up tilt (HUT)+ graded lower body negative pressure (LBNP) up to presyncope session (control) to determine the orthostatic tolerance time, OTT (Time from HUT commencement to development of presyncopal symptoms/signs). Once the tolerance time was known, a randomized crossover protocol was used: either 1) Repeat HUT+LBNP to ensure reproducibility of repeated run or 2) HUT+LBNP run but with added mental challenge (2 min before the expected presyncope time). Test protocols were separated by 2 weeks. Our studies on five male test subjects indicate that mental challenge improves orthostatic tolerance significantly. Additional mental loading could be a useful countermeasure to alleviate the orthostatic responses of persons, particularly in those with histories of dizziness on standing up, or to alleviate hypotension that frequently occurs during hemodialysis or on return to earth from the spaceflight environment of microgravity.

Volume regulation and renal function at high altitude across gender.

Aims We investigated changes in volume regulating hormones and renal function at high altitudes and across gender. Methodology Included in this study were 28 subjects (n = 20 males; n = 8 females. ages: 19 – 65 yrs), who ascended to a height of 3440m (HA1), on the 3rd day and to 5050m (HA2), on the 14th day. Plasma and urinary creatinine and urinary osmolality as well as plasma levels of plasma renin activity (PRA), Aldosterone, antidiuretic hormone (ADH), and atrial natriuretic peptide (ANP) were measured. The plasma volume loss (PVL) was estimated from plasma density and hematocrit. Glomerular filtration rate (GFR) was measured based on nocturnal (9 hour) creatinine clearance; this was compared with various methods for estimation of GFR. Results The mean 24-hour urine production increased significantly in both sexes across the expedition. But PVL reached significance only in males. No changes in Na+ in plasma, urine or its fractional excretion were seen at both altitudes. Urinary osmolality decreased upon ascent to the higher altitudes. ADH and PRA decreased significantly at both altitudes in males but only at HA2 in females. However, no changes in aldosterone were seen across the sexes and at different altitudes. ANP increased significantly only in males during the expedition. GFR, derived from 9-h creatinine clearance (CreaCl), decreased in both sexes at HA1 but remained stable at HA2. Conventional Crea[p]-based GFR estimates (eGFR) showed only poor correlation to CreaCl. Conclusions We report details of changes in hormonal patterns across high altitude sojourn. To our knowledge we are not aware of any study that has examined these hormones in same subjects and across gender during high altitude sojourn. Our results also suggest that depending on the estimation formula used, eGFR underestimated the observed decrease in renal function measured by CreaCl, thus opening the debate regarding the use of estimated glomerular filtration rates at high altitudes.

Heart rate variability and baroreceptor reflex sensitivity in early- versus late-onset preeclampsia

Objective To determine whether there are differences in autonomic nervous system function in early- versus late-onset preeclampsia. Methods Matched case-control study. Cases were defined as singleton pregnancies with preeclampsia at < 34+0 weeks of gestation (early-onset preeclampsia) and ≥ 34+0 weeks of gestation (late-onset preeclampsia). For each case in each of the preeclampsia subgroups, three „control”uncomplicated singleton pregnancies were matched by maternal age, height, and week of gestation. Blood pressure and heart rate were measured continuously for 30 minutes in each participant. Baroreceptor reflex sensitivity (assessed using sequence technique), time and frequency domain heart rate variability measures, as SDNN, RMSSD, LFRRI, HFRRI and LF/HFRRI of R-R intervals, were compared between groups (p<0.05 significant). Results 24 women with preeclampsia (10 with early-onset and 14 with late-onset preeclampsia) and 72 controls were included in the study. SDNN, RMSSD and HFRRI were significantly higher in the late-onset preeclampsia group compared to gestational age matched controls (p = 0.033, p = 0.002 and p = 0.018, respectively). No significant differences in SDNN RMSSD and HFRRI between early-onset preeclampsia group and gestational age matched controls were observed (p = 0.304, p = 0.325 and p = 0.824, respectively). Similarly, baroreceptor reflex sensitivity was higher in late-onset preeclampsia compared to controls at ≥ 34 weeks (p = 0.037), but not different between early-onset preeclampsia compared to controls at < 34 weeks (p = 0.50). Conclusions Heart rate variability and baroreceptor reflex sensitivity are increased in late- but not early-onset preeclampsia compared to healthy pregnancies. This indicates a better autonomic nervous system mediated adaptation to preeclampsia related cardiovascular changes in late-onset disease.

Systemic vascular resistance and endogenous inhibitors of nitric oxide synthesis in early- compared to late-onset preeclampsia: preliminary findings

ABSTRACT Objective: To examine systemic vascular resistance index (SVRI), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) levels in preeclampsia at different gestations. Methods: Twenty-four preeclamptic patients (14 at ≥ 34 weeks’) and 72 matched healthy controls were included. SVRI was calculated from impedance cardiography measurements. ADMA and SDMA levels were determined using enzyme-linked immunosorbent assay. Results: SVRI and SDMA were higher in preeclampsia overall, in early onset and late onset compared to controls. SVRI was correlated with ADMA and SDMA, respectively. Conclusions: Early-onset and late-onset preeclampsia are both characterized by increased systemic vascular resistance and elevated levels of nitric oxide synthesis inhibitors.

Paradoxical clearance of hyaluronan fragments during haemodialysis and haemodiafiltration

BACKGROUND The physiological clearance of hyaluronic acid (HA), a mortality marker in end-stage kidney disease (ESKD) patients, occurs in the liver and in the kidneys and depends on its molecular mass. The aim of this study was to examine the effect of different modes of renal replacement therapy on levels of low- and high-molecular-mass HA (LMWHA and HMWHA, respectively). METHODS Levels of total plasma HA as well as LMWHA and HMWHA fractions were measured before and after haemodialysis (HD) and haemodiafliltration (HDF) treatments and compared with those in normal controls. Plasma β2-microglobulin was determined to be an independent inflammation marker. The isolated effect of the extracorporeal system on HMWHA fractions was investigated in a separate in vitro study. RESULTS In 150 ESKD patients, LMWHA (135 ng/mL) and HMWHA fractions (386 ng/mL) were elevated (P < 0.01), compared with those in 80 healthy persons. The LMWHA fraction remained unchanged both during HD and HDF, whereas the fraction of HMWHA, which is incapable of passing through dialysis membranes, decreased by about 40% (P < 0.05). The concentration of plasma β2-microglobulin correlated with the pro-inflammatory LMWHA (P < 0.0001; r = 0.67) but not with total HA. In vitro dialysis runs suggested that this decrease was not caused by degradation or adsorption of HMWHA fragments. CONCLUSIONS Our data suggest that the decrease in the high-mass HA level during HD and HDF mirrors a physiological clearance initiated by HD and HDF rather than by physical elimination in the extracorporeal circulation.