Effect of non-hypotensive haemorrhage on plasma catecholamine levels and cardiovascular variability in man

Background: It is well known from animal research that non‐hypotensive haemorrhage produces sympathoexcitatory responses assessable by both the rise in plasma catecholamine levels and the shift of autonomic influences on the heart to more sympathetic and less parasympathetic control. Data in humans are restricted. Methods: Heart rate variability (HRV), systolic blood pressure (FINAPRES) variability (BPV), and catecholamine plasma levels were measured before and after haemorrhage in 30 healthy blood donors and compared with those from 10 control subjects without blood loss. Spectral power of HRV and BPV in very low (0·02–0·06 Hz), low (0·07–0·14 Hz), and high (0·15–0·40 Hz) frequency bands were calculated by Fourier analysis. Catecholamine plasma levels were assayed by dual column reverse‐phased high‐performance liquid chromatography (HPLC). Results: Haemorrhage of 5·6 ± 1·2 ml kg^?1 body weight increased plasma norepinephrine levels (215 ± 92 pg ml^?1 versus 254 ± 95 pg ml^?1; P = 0·002), increased BPV in the low frequency band (Mayer waves; 1·8 ± 1·0 ln [mmHg²] versus 2·0 ± 0·9 ln [mmHg²]; P = 0·021), and decreased the vagally transmitted high frequency HRV (6·9 ± 1·1 ln [MI²] versus 6·5±1·2 ln [MI²]; P<0·0001), but did not induce significant changes in heart rate (66 ± 11 bpm versus 67 ± 11 bpm; P = 0·79) and arterial blood pressure (mean values: 84 ± 13 mmHg versus 87 ± 13 mmHg; P = 0·12). Conclusions: As suggested by plasma norepinephrine levels, systolic BPV and HRV, non‐hypotensive haemorrhage produces sympathoexcitatory responses as well as vagal withdrawal of heart rate control in humans.     

Reduced cardiac sympathetic autonomic tone after long-term nasal continuous positive airway pressure in obstructive sleep apnoea syndrome

The increased sympathetic activation that occurs in obstructive sleep apnoea (OSA) may play an important role in associated morbidity. We investigated the effect of long-term (3 month) nasal continuous positive airway pressure (CPAP) on the autonomic nervous system assessed by heart rate variability (HRV). Fourteen patients (12 men), mean age 61·4 ± 8·1 years, with OSA underwent continuous synchronized electrocardiographic and polysomnographic monitoring. The apnoea/hypopnoea index (AHI) decreased from 50·6 ± 13·7 to 2·2 ± 2·5 events h^?1 after CPAP. HRV analysis showed significant decreases in low frequency (LF; from 7·12 ± 1·06 to 6·22 ± 1·18 ln ms² Hz^?1; P<0·001), high frequency (HF; from 5·91 ± 0·87 to 5·62 ± 0·92 ln ms² Hz^?1; P<0·05) and LF/HF (from 1·21 ± 0·12 to 1·11 ± 0·15 ln ms² Hz^?1; P<0·001) when the patients were asleep. The decrease in LF/HF was prolonged into the daytime (from 1·33 ± 0·22 to 1·24 ± 0·21 ln ms² Hz^?1; P<0·001). Treatment of OSA by CPAP significantly reduced the parameters of cardiac sympathetic tone, a favourable effect.     

Early activation of the coagulation system during lower body negative pressure

We considered that a moderate reduction of the central blood volume (CBV) may activate the coagulation system. Lower body negative pressure (LBNP) is a non‐invasive means of reducing CBV and, thereby, simulates haemorrhage. We tested the hypothesis that coagulation markers would increase following moderate hypovolemia by exposing 10 healthy male volunteers to 10 min of 30 mmHg LBNP. Thoracic electrical impedance increased during LBNP (by 2·6 ± 0·7 Ω, mean ± SD; P < 0·001), signifying a reduced CBV. Heart rate was unchanged during LBNP, while mean arterial pressure decreased (84 ± 5 to 80 ± 6 mmHg; P < 0·001) along with stroke volume (114 ± 22 to 96 ± 19 ml min^?1; P < 0·001) and cardiac output (6·4 ± 2·0 to 5·5 ± 1·7 l min^?1; P < 0·01). Plasma thrombin–antithrombin III complexes increased (TAT, 5 ± 6 to 19 ± 20 μg l^?1; P < 0·05), indicating that LBNP activated the thrombin generating part of the coagulation system, while plasma D‐dimer was unchanged, signifying that the increased thrombin generation did not cause further intravascular clot formation. The plasma pancreatic polypeptide level decreased (13 ± 11 to 6 ± 8 pmol l^?1; P < 0·05), reflecting reduced vagal activity. In conclusion, thrombin generation was activated by a modest decrease in CBV by LBNP in healthy humans independent of the vagal activity.     

Determination of baroreflex gain using auto-regressive moving-average analysis during spontaneous breathing

The heart rate component of the arterial baroreflex gain (BRG) was determined with auto-regressive moving-average (ARMA) analysis during each of spontaneous (SB) and random breathing (RB) protocols. Ten healthy subjects completed each breathing pattern on two different days in each of two different body positions, supine (SUP) and head-up tilt (HUT). The R–R interval, systolic arterial pressure (SAP) and instantaneous lung volume were recorded continuously. BRG was estimated from the ARMA impulse response relationship of R–R interval to SAP and from the spontaneous sequence method. The results indicated that both the ARMA and spontaneous sequence methods were reproducible (r=0·76 and r=0·85, respectively). As expected, BRG was significantly less in the HUT compared to SUP position for both ARMA (mean ± SEM; 3·5 ± 0·3 versus 11·2 ± 1·4 ms mmHg^–1; P<0·01) and spontaneous sequence analysis (10·3 ± 0·8 versus 31·5 ± 2·3 ms mmHg^–1; P<0·001). However, no significant difference was found between BRG during RB and SB protocols for either ARMA (7·9 ± 1·4 versus 6·7 ± 0·8 ms mmHg^–1; P=0·27) or spontaneous sequence methods (21·8 ± 2·7 versus 20·0 ± 2·1 ms mmHg^–1; P=0·24). BRG was correlated during RB and SB protocols (r=0·80; P<0·0001). ARMA and spontaneous BRG estimates were correlated (r=0·79; P<0·0001), with spontaneous sequence values being consistently larger (P<0·0001). In conclusion, we have shown that ARMA-derived BRG values are reproducible and that they can be determined during SB conditions, making the ARMA method appropriate for use in a wider range of patients.     

Impaired responses of plasma catecholamines to exercise in diabetic patients with abnormal heart rate reactions to tilt

Summary. The plasma catecholamine response to a standardized bicycle exercise test was evaluated in 24 insulin-dependent diabetic (IDDM) patients in whom the heart rate reactions to deep breathing (E/I ratio) and to tilt, the immediate acceleration and the transient deceleration (acceleration and brake indices), had been assessed as tests of autonomic neuropathy. Patients with an abnormal acceleration index (n= 8) showed, compared with non-diabetic (n= 18) controls who had participated in previous studies, an impaired increment in noradrenaline during exercise (80% of maximal working capacity) (MWC) (12·38 ± 1·46 nmol l^-1 vs. 18·74 ± 1·45 nmol I^-1; P<0·01) and adrenaline (50% of MWC: 0·25 ± 0·04 nmol I^-1 vs. 0·54 ± 0·08 nmol I^I–1; P<0·05). Similarly, patients with an isolated abnormal brake index (n= 6), i.e. with a normal acceleration index and a normal E/I ratio, showed compared with controls an impaired increment in noradrenaline (9·53 ± 1·66 nmol I^-1 vs. 18·74 ± 1·45 nmol I^-1; P<0·01) and adrenaline (1·41 ± 0·22 nmol I^-1 vs. 2·92 ± 0·51 nmol I^-1; P<0·05) during 80% of MWC. IDDM patients with abnormal heart rate reactions to tilt, an abnormal acceleration index or an abnormal brake index show impaired catecholamine responses to exercise, which can be demonstrated also in patients without signs of parasympathetic neuropathy.     

Influence of exercise training on heart rate variability in post-menopausal women with elevated arterial blood pressure

Low heart rate variability (HRV) has been reported to be an independent risk factor for the development of coronary heart disease in women and has recently been identified as a risk factor for cardiac sudden death and all-cause mortality. We have recently demonstrated that endurance-trained post-menopausal women demonstrate higher levels of HRV than sedentary control subjects. The purpose of the present study was to test the hypothesis that 12 weeks of regular aerobic exercise would increase HRV in sedentary post-menopausal women with elevated arterial blood pressure (BP) (i.e. either high normal BP or stage I hypertension). A secondary aim was to test the hypothesis that the increase in HRV with exercise training, if observed, would be associated with an increase in spontaneous cardiac baroreflex sensitivity (SBRS), an important physiological determinant of HRV. To accomplish these aims, we studied eight sedentary post-menopausal women (age=54·5±1·3 years) before and after 12 weeks of aerobic exercise training (3·3±0·3 days per week at 70%±2% of maximal heart rate for 43±3 min per day). Maximal oxygen uptake and body weight did not change (P>0·05) with training, but percentage fat (35·5±2·6% vs. 34·5±2·3%, P<0·05) decreased and treadmill time to exhaustion increased (9·8±0·5 vs. 11·3±0·5 min, P<0·05). Supine resting levels of heart rate, RR interval and the standard deviation of the RR interval (time domain measure of HRV) were unchanged (all P>0·05) from baseline levels after 12 weeks of aerobic training. Similarly, the high-frequency, low-frequency and total power of HRV (frequency domain measures) were also unchanged from baseline (all P>0·05). SBRS was also not different before and after aerobic exercise training (1062 vs. 1363 ms mmHg^?1 respectively, P>0·05). In contrast, systolic and diastolic BP were reduced approximately 8 and approximately 5 mmHg with training (both P<0·05) respectively. These results indicate that 12 weeks of moderate-intensity aerobic exercise training does not increase HRV or SBRS, despite producing a clinically significant reduction in BP at rest in post-menopausal women with elevated BP. Considered together with our previous findings in female master endurance athletes, these findings suggest that more intense and prolonged exercise training may be required to produce increases in HRV and SBRS in sedentary post-menopausal women.     

Blood volume distribution during head-up tilt induced central hypovolaemia in man

Summary. We evaluated regional electrical impedance (Z°) at 2.5 and 100 kHz to separate intra- and extracellular fluid changes and correlated Z° over the thorax (TI) to relative changes in the central blood volume (CBV) induced by head-up tilt. In nine experiments head-up tilt resulted in normotensive central hypovolaemia associated with a 3·7 & 0·4 Ohm (mean f SE) increase in TI_{100 kHz} after 60 min. In 24 experiments presyncopal symptoms were induced after 43±2 min, when TI_100kHz had increased 4·2 ± 0·2 Ohm. Head-up tilt instantly decreased the activity of technetium labelled erythrocytes (⁹⁹Tc^m) over the thorax by 24 ± 2%, and increased ⁹⁹Tc^m over the thigh by 68±10% (P< 0·01, n = 8) with no further changes during the sustained tilt. Haematocrite increased during head-up tilt from 43·1 ± 0·3 to 47·9 ± 0·6% (P<0·01, n= 8). Accordingly, the increase in TI (6·3 ± 0·6 vs. 4·5 0·4 Ohm, n= 6) and the decrease in Z° through one leg (7·2 ± 1·2 vs. 2·8 ± 0·5 Ohm, n= 6) at 2·5 kHz was more pronounced than at 100 kHz. Also the changes in TI were correlated to CBV as calculated from ⁹⁹T_c^m and haematocrite (r = 0.90, P < 0·01). The results suggest that: (1) Hypovolaemic shock is associated with a faster increase of TI than normotensive head-up tilt. (2) Head-up tilt is characterized by an initial decrease in CBV followed by a further decrease in plasma volume, which eventually leads to hypovolaemic shock. (3) Blood volume changes during head-up tilt are reflected in regional Z°.     

The exercise heart rate profile in master athletes compared to healthy controls

Endurance exercise protects the heart via effects on autonomic control of heart rate (HR); however, its effects on HR indices in healthy middle‐aged men are unclear. This study compared HR profiles, including resting HR, increase in HR during exercise and HR recovery after exercise, in middle‐aged athletes and controls. Fifty endurance‐trained athletes and 50 controls (all male; mean age, 48·7 ± 5·8 years) performed an incremental symptom‐limited exercise treadmill test. The electrocardiographic findings and HR profiles were evaluated. Maximal O₂ uptake (52·6 ± 7·0 versus 34·8 ± 4·5 ml kg^?1 min^?1; P<0·001) and the metabolic equivalent of task (15·4 ± 1·6 versus 12·2 ± 1·5; P<0·001) were significantly higher in athletes than in controls. Resting HR was significantly lower in athletes than in controls (62·8 ± 6·7 versus 74·0 ± 10·4 beats per minute (bpm), respectively; P<0·001). Athletes showed a greater increase in HR during exercise than controls (110·1 ± 11·0 versus 88·1 ± 15·4 bpm; P<0·001); however, there was no significant between‐group difference in HR recovery at 1 min after cessation of exercise (22·9 ± 5·6 versus 21·3 ± 6·7 bpm; P = 0·20). Additionally, athletes showed a lower incidence of premature ventricular contractions (PVCs) during exercise (0·0% versus 24·0%; P<0·001). Healthy middle‐aged men participating in regular endurance exercise showed more favourable exercise HR profiles and a lower incidence of PVCs during exercise than sedentary men. These results reflect the beneficial effect of endurance training on autonomic control of the heart.     

Autonomic nervous function at rest in aerobically trained and untrained oldermen

Therelationship between aerobictraining, vagal influence on the heart and ageing was examined by assessing aerobic fitness andresting heart rate variability in trained and untrained older men. Subjects were 11 trained cyclistsand runners (mean age=6±61·6 years) and 11 untrained, age-matchedmen (mean age=66±1·2 years). Heart rate variability testing involvedsubjects lying supine for 25 min during which subjects’ breathing was paced andmonitored (7·5 breaths min^?1). Heart rate variability was assessedthrough time series analysis (HRV_ts) of the interbeat interval. Results indicated thattrained older men (3·55±0·21 l min^?1) hadsignificantly (P<0·05) greater VO _2maxthan that of control subjects (2·35±0·15 l min^?1).Also, trained older men (52±1·8 beats min^?1) hadsignificantly (P<0·05) lower supine resting heart rate than that of controlsubjects (65±4·2 beats min^?1). HRV_ts at highfrequencies was greater for trained men (5·98±0·22) than for untrainedmen (5·23±0·32). These data suggest that regular aerobic exercise inolder men is associated with greater levels of HRV_ts at rest.     

High-density lipoprotein cholesterol, C-reactive protein, and prevalence and severity of coronary artery disease in 5641 consecutive patients undergoing coronary angiography

Background Although high‐density lipoprotein cholesterol (HDL‐C) and C‐reactive protein (CRP) are well‐established predictors for future cardiovascular events, little information is available regarding their correlation with the prevalence and severity of angiographically evaluated coronary artery disease (CAD). Material and methods Five thousand six hundred forty‐one consecutive patients undergoing coronary angiography for the evaluation of CAD were analysed. Cardiovascular risk factors were assessed by routine blood chemistry and questionnaire. CAD severity was graded by visual estimation of lumen diameter stenosis with significant stenoses defined as lumen diameter reduction of ≥ 70%. Coronary angiograms were graded as one‐, two‐ or three‐vessel disease, as nonsignificant CAD (lumen irregularities < 70%) or non‐CAD. Results HDL‐C (60·3 ± 18·5 vs. 51·9 ± 15·3 mg dL^?1; P < 0·001) was higher and CRP was lower (0·65 ± 1·68 vs. 1·02 ± 2·38 mg dL^?1; P < 0·001) in non‐CAD (n = 1517) compared to overall CAD patients (n = 4124). CAD patients were older (65·2 ± 10·5 years vs. 59·9 ± 11·4 years), more often diabetics (19·2% vs. 10·6%) and hypertensives (79·2% vs. 66·0%) and included more smokers (18·8% vs. 16·5%) (all P < 0·005). Low‐density lipoprotein cholesterol (124·5 ± 38·3 vs. 126·0 ± 36·3 mg dL^?1; P = NS) was similar in overall CAD and non‐CAD patients with more statin users (43·4% vs. 27·9%; P < 0·001) among CAD patients. Comparing non‐CAD with different CAD severities using analysis of variance, results did not change substantially. In a multivariate analysis, HDL‐C and CRP remained independently associated with the prevalence of CAD. In addition, HDL‐C is also a potent predictor for the severity of CAD. Conclusions In this large consecutive patient cohort, HDL‐C and CRP are independently associated with the prevalence of CAD. In this analysis, HDL‐C is an even stronger predictor for CAD than some other major classical risk factors.     

A comparison of two methods of heart rate variability assessment at high altitude

Heart rate variability (HRV) is a useful index of autonomic function and has been linked to the development of high altitude (HA) related illness. However, its assessment at HA has been undermined by the relative expense and limited portability of traditional HRV devices which have mandated at least a minute heart rate recording. In this study, the portable ithlete^? HRV system, which uses a 55 s recording, was compared with a reference method of HRV which utilizes a 5 min electrocardiograph recording (CheckMyHeart^?). The root mean squares of successive R‐R intervals (RMSSD) for each device was converted to a validated HRV score (lnRMSSD × 20) for comparison. Twelve healthy volunteers were assessed for HRV using the two devices across seven time points at HA over 10 days. There was no significant change in the HRV values with either the ithlete (P = 0·3) or the CheckMyHeart^? (P = 0·19) device over the seven altitudes. There was also a strong overall correlation between the ithlete^? and CheckMyHeart^? device (r = 0·86; 95% confidence interval: 0·79–0·91). The HRV was consistently, though non‐significantly higher with ithlete^? than with the CheckMyHeart^? device [mean difference (bias) 1·8 l; 95% CI ?12·3 to 8·5]. In summary, the ithlete^? and CheckMyHeart^? system provide relatively similar results with good overall agreement at HA.     

Restoration of peak vascular conductance after simulated microgravity by maximal exercise

We sought to determine if (i) peak vascular conductance of the calf was reduced following prolonged exposure to simulated microgravity, and (ii) if maximal cycle ergometry performed at the end of microgravity exposure stimulated a restoration of peak calf vascular conductance. To do this, peak vascular conductance of the calf was recorded following ischaemic plantar flexion exercise to fatigue in seven men after 16 days of head-down tilt (HDT) under two conditions: (i) after one bout of maximal supine cycle ergometry completed 24 h prior to performance of ischaemic plantar flexion exercise, and (ii) in a control (no cycle ergometry) condition. Following HDT, peak vascular conductance was reduced in the control condition (0·38 ± 0·02 to 0·24 ± 0·02 ml 100 ml^?1 min^?1 mmHg^?1; P = 0·04), but was restored when subjects performed cycle ergometry (0·33 ± 0·05 to 0·28 ± 0·04 ml 100 ml^?1 min^?1 mmHg^?1; P = 0·46). After HDT, time to fatigue during ischaemic plantar flexion exercise was not different from pre-HDT 24 h after performance of exhaustive cycle ergometry (120 ± 24 vs. 122 ± 19 s), but was decreased in the control condition (116 ± 11 vs. 95 ± 8 s; P = 0·07). These data suggest that a single bout of maximal exercise can provide a stimulus to restore peak vascular conductance and maintain time to fatigue during performance of ischaemic plantar flexion exercise.     

Endurance training,overtraining and baroreflex sensitivity in female athletes

We examined heavy training-induced changes in baroreflex sensitivity, plasma volume and resting heart rate and blood pressure variability in female endurance athletes. Nine athletes (experimental training group, ETG) increased intense training (70–90% VO _2max) volume by 130% and low-intensity training (<70% VO _2max) volume by 100% during 6–9 weeks, whereas the corresponding increases in six control athletes (CG) were 5% and 10% respectively. Maximal oxygen uptake (VO _2max) in the ETG and CG did not change, but in five ETG athletes VO _2max decreased from 53·0 ± 2·2 (mean ± SEM) (CI 46·8–59·2) ml kg^–1 min^–1 to 50·2 ± 2·3 (43·8–56·6) ml kg^–1 min^–1 (P<0·01), indicating overtraining. Baroreflex sensitivity (BRS) measured using the phenylephrine technique and blood pressure variability (BPV) did not change, but the low-frequency power of the R–R interval variability increased in the ETG (P<0·05). The relative change in plasma volume was 7% in the ETG and 3% in the CG. The changes in BRS did not correlate with the changes in plasma volume, heart rate variability and BPV. We conclude that heavy endurance training and overtraining did not change baroreflex sensitivity or BPV but significantly increased the low-frequency power of the R–R interval variability during supine rest in female athletes as a marker of increased cardiac sympathetic modulation.     

Mesenteric artery response to head-up tilt-induced centralhypovolaemia and hypotension

Superior mesenteric artery (SMA) blood flow and impedance were evaluated byduplex ultrasound during head-up tilt (HUT)-induced central hypovolaemia and hypotension ineight healthy volunteers. HUT induced a reduction in cardiac stroke volume from88·8±6·3 to 64·7±6·3 ml(mean±SEM; P<0·01) and an increase in thoracic electricimpedance from 38·6±2·1 to 42·6±2·1Ω (P<0·01) reflecting a reduced central blood volume. Maintainedtilt provoked a 30% reduction in mean arterial pressure (from 87·1±3·3to 63·4±3·6 mmHg; P<0·01) and the appearanceof presyncopal symptoms. During both the normotensive and the hypotensive phase of HUT, theSMA diameter (5·7±0·03 mm) and blood flow (514±75 ml min^?1) did not change significantly, although the end-diastolic velocity increasedfrom 9·7±4·8 to 39·7±4·0 cm s^?1 (P<0·01). The increase in diastolic velocity, despite amaintained or reduced arterial pressure, supports a reduction in the SMA impedance as it wasreproduced during a meal test when a moderate reduction in mean arterial pressure (87±4to 80±4 mmHg; P=0·04) was accompanied by a ninefoldincrease in the end-diastolic velocity (P<0·01). The results indicate areduction in the mesenteric vascular impedance to the extent that superior mesenteric artery bloodflow is maintained during HUT-induced central hypovolaemia and hypotension.     

Simultaneous quantification of myocardial perfusion,oxidative metabolism,cardiac efficiency and pump function at rest and during supine bicycle exercise using 1‐11C‐acetate PET – a pilot study

Background: PET using 1‐¹¹C‐acetate (ACE‐PET) applied at rest is used for measuring absolute myocardial blood flow (MBF) and oxidative metabolic rate (k_mono). We evaluated the feasibility of quantitative ACE‐PET during exercise. Methods: Five endurance athletes underwent dynamic PET scanning at rest and during supine bicycle stress. Exercise was maintained at a workload of 120 Watt for 17 min. The rate‐pressure product (RPP) was recorded repeatedly. MBF, k_mono in left (LV) and right (RV) ventricular wall, cardiac output (CO), cardiac efficiency and a lung uptake value reflecting left heart diastolic pressures were calculated from the PET data using previously validated models. Results: MBF increased from 0·71 ± 0·17 to 2·48 ± 0·25 ml min^?1 per ml, LV‐k_mono from 0·050 ± 0·005 to 0·146 ± 0·021 min^?1, RV‐k_mono from 0·023 + 0·006 to 0·087 + 0·014 min^‐1, RPP from 4·7 ± 0·8 to 13·2 ± 1·4 mmHg × min^?1 × 10³ and Cardiac Output from 5·2 ± 1·1 to 12·3 ± 1·2 l min ^?1 (all P < 0·001). Cardiac efficiency was unchanged (P = 0·99). Lung uptake decreased from 1·1 ± 0·2 to 0·6 ± 0·1 ml g^?1 (P < 0·001). Discussion: A number of important parameters related to cardiac function can be quantified non‐invasively and simultaneously with a short scanning protocol during steady state supine bicycling. This might open up new opportunities for studies of the integrated cardiac physiology in health and early asymptomatic disease.     

Ursodeoxycholic acid reduces lipid peroxidation and mucin secretagogue activity in gallbladder bile of patients with cholesterol gallstones

Background Recently it has been postulated that gallbladder mucin hypersecretion observed in the pathogenesis of cholesterol gallstone disease may be induced by biliary lipid peroxidation. Ursodeoxycholic acid treatment reduces mucin concentration and the formation of cholesterol crystals in the gallbladder bile of patients with cholesterol gallstones and this effect might be mediated by a decrease of biliary lipid peroxidation. Material and methods In a double‐blind, placebo‐controlled trial patients with symptomatic cholesterol gallstones received either ursodeoxycholic acid (750 mg daily) (n = 10) or placebo (n = 12) 10–12 days prior to cholecystectomy. As a marker for lipid peroxidation malondialdehyde was measured in bile together with mucin concentration. In addition, the mucin secretagogue activity of the individual bile samples was assessed in cultured dog gallbladder epithelial cells. Results Ursodeoxycholic acid therapy resulted in a significant reduction of lipid peroxidation in bile as determined by the biliary malondialdehyde concentration (1·36 ± 0·28 vs. 2·05 ± 0·38 µmol L^?1; P < 0·005) and the malondialdehyde (µmol L^?1)/total bile acid (mmol L^?1) ratio (0·02 ± 0·005 vs. 0·06 ± 0·01; P < 0·001). Furthermore, a decrease in mucin concentrations (0·7 ± 0·3 vs. 1·3 ± 0·5 mg mL^?1; P < 0·005) and of the mucin secretagogue activity of gallbladder bile (0·9 ± 0·2 vs. 2·2 ± 0·3 times control; P < 0·001) was observed. Conclusions The reduction of lipid peroxidation and mucin secretagogue activity of gallbladder bile induced by ursodeoxycholic acid treatment may contribute to the beneficial effects of this drug on gallbladder bile composition and symptoms in cholesterol gallstone patients.     

The pathophysiology of the insulin-like growth factor axis in fetal growth failure: a basis for programming by undernutrition?

Abstract. Recent evidence suggests that a number of adulthood conditions, including non-insulin dependent diabetes mellitus (NIDDM) and lipid and cardiovascular abnormalities are associated with intra-uterine growth retardation (IUGR). It is possible that this arises from programming of endocrine axes during development as a result of an adverse intra-uterine environment. Insulin-like growth factors (IGFs) are mitogenic polypeptides which stimulate cellular proliferation and differentiation and are important in human fetal development. The functions of IGFs are modulated by specific high affinity binding proteins (IGFBPs). IGFBP-1 is antagonistic to the insulin-like and growth promoting effects of IGF-I, and IGFBP-3 holds IGFs in the circulation by associating with IGFs and an acid labile subunit to form a ternary complex. Using specific radioimmunoassays and fetal serum obtained during diagnostic cordocentesis we have investigated the role of the IGF/IGFBP axis in human fetal development. In a study of 130 singleton pregnancies we have examined levels of immunoreactive IGFs and IGFBPs in normally grown fetuses (AGA), starved small fetuses affected by uteroplacental insufficiency (UPI), and non-starved small fetuses (SGA). IGF-1 was significantly lower in the UPI group (n= 14, 7·8±0·6 μg l^-1), than in either the SGA group (n= 22, 31·4±3·5 μg l^-1, P= 0·0001) or the AGA group (n= 94, 36·3±1·9 μg l^-1, P= 0·0001). IGFBP-3 showed similar changes (UPI: 682·6±50·0 μg l^-1; SGA: 831·9±55·5 μg l^-1; AGA: 847·7±19·8 μg l^-1). In contrast, IGFBP-1 levels were significantly higher in the UPI group (312·4±57·5 μg l^-1) than in either the SGA group (132·6±39·5 μg l^-1, P= 0·009) or the AGA group (116·9±25·4 μg l^-1, P= 0·003), and the normal inverse relationship between IGFBP-1 and insulin levels was lost in the UPI group. IGFBP-2 levels showed a similar pattern (UPI: 2510·3±178·0 μg l^-1; SGA: 878·5±80·3μg l^-1, P= 0·0001; AGA: 791·6±27·0 μg l^-1, P= 0·0001). Thus, there are clear differences between the two groups of SGA fetuses. It is possible that in utero‘programming’ of the IGF/IGFBP axis, as a result of fetal undernutrition, may be important in the pathogenesis of disease in adulthood.     

Dynamics of the heart rate variability and oxygen saturation response to acute normobaric hypoxia within the first 10 min of exposure

Although the heart rate variability (HRV) response to hypoxia has been studied, little is known about the dynamics of HRV after hypoxia exposure. The purpose of this study was to assess the HRV and oxygen saturation (SpO₂) responses to normobaric hypoxia (FiO₂ = 9·6%) comparing 1 min segments to baseline (normoxia). Electrocardiogram and SpO₂ were recorded during a 10‐min hypoxia exposure in 29 healthy male subjects aged 26·0 ± 4·9 years. Baseline HRV values were obtained from a 5‐min recording period prior to hypoxia. The hypoxia period was split into 10 non‐overlapping 1‐min segments and time domain HRV indexes (RMSSD and SDNN) were calculated for each segment. Differences (Δ) from baseline values were calculated and transformed using natural logarithm (Ln). This study revealed that the decrease in ΔSpO₂ became significant (P<0·001) in the first minute of hypoxia, the decrease in ΔLn RMSSD became significant (P = 0·002) in the second minute, and the decrease in ΔLn SDNN became significant (P = 0·001) in the third minute. Between the second and fifth minute of hypoxia, ΔSpO₂ correlated with ΔLn RMSSD (r = 0·57, P<0·001) and ΔLn SDNN (r = 0·44, P<0·001). Five min after the onset of hypoxia, ΔSpO₂ was significantly (P = 0·002) decreased but changes in ΔLn RMSSD (P = 0·344) and ΔLn SDNN (P = 0·558) were not significant. In conclusion, the decrease in HRV was proportional to desaturation but only during the first 5 min of hypoxia.     

Normovolemia defined according to cardiac stroke volume in healthy supine humans

Background: Both hypovolemia and a fluid overload are detrimental for outcome in surgical patients but the effort to establish normovolemia is hampered by the lack of an operational clinical definition. Manipulating the central blood volume on a tilt table demonstrates that the flat part of the Frank‐Starling curve is reached when subjects are supine and that finding may be applicable for a clinical definition of normovolemia. However, it is unknown whether stroke volume (SV) responds to an increase in preload induced by fluid administration. Methods: In 20 healthy subjects (23 ± 2 years, mean ± SD), SV was measured by esophageal Doppler before and after fluid administration to evaluate whether SV increases in healthy, non‐fasting, supine subjects. Two hundred millilitres of a synthetic colloid (hydroxyethyl starch, HES 130/0·4) was provided and repeated if a ≥10% increment in SV was obtained. Results: None of the subjects increased SV ≥10% following fluid administration but there was a minor increase in mean arterial pressure (92 ± 15 to 93 ± 12 mmHg, P = 0·01), while heart rate (HR) (66 ± 12 beats min^?1; P = 0·32), cardiac output (4·8 ± 1·1 l min^?1; P = 0·25) and the length of the systole corrected to a HR of 60 beats/min (corrected flow time; 344 ± 24 ms; P = 0·31) did not change. Conclusion: Supporting the proposed definition of normovolemia, non‐fasting, supine, healthy subjects are provided with a preload to the heart that does not limit SV suggesting that the upper flat part of the Frank‐Starling relationship is reached.     

Perfusion heterogeneity does not explain excess muscle oxygen uptake during variable intensity exercise

The association between muscle oxygen uptake (VO₂) and perfusion or perfusion heterogeneity (relative dispersion, RD) was studied in eight healthy male subjects during intermittent isometric (1 s on, 2 s off) one‐legged knee‐extension exercise at variable intensities using positron emission tomography and a‐v blood sampling. Resistance during the first 6 min of exercise was 50% of maximal isometric voluntary contraction force (MVC) (HI‐1), followed by 6 min at 10% MVC (LOW) and finishing with 6 min at 50% MVC (HI‐2). Muscle perfusion and O₂ delivery during HI‐1 (26 ± 5 and 5·4 ± 1·0 ml 100 g^?1 min^?1) and HI‐2 (28 ± 4 and 5·8 ± 0·7 ml 100 g^?1 min^?1) were similar, but both were higher (P<0·01) than during LOW (15 ± 3 and 3·0 ± 0·6 ml 100 g^?1 min^?1). Muscle VO₂ was also higher during both HI workloads (HI‐1 3·3 ± 0·4 and HI‐2 4·1 ± 0·6 ml 100 g^?1 min^?1) than LOW (1·4 ± 0·4 ml 100 g^?1 min^?1; P<0·01) and 25% higher during HI‐2 than HI‐1 (P<0·05). O₂ extraction was higher during HI workloads (HI‐1 62 ± 7 and HI‐2 70 ± 7%) than LOW (45 ± 8%; P<0·01). O₂ extraction tended to be higher (P = 0·08) during HI‐2 when compared to HI‐1. Perfusion was less heterogeneous (P<0·05) during HI workloads when compared to LOW with no difference between HI workloads. Thus, during one‐legged knee‐extension exercise at variable intensities, skeletal muscle perfusion and O₂ delivery are unchanged between high‐intensity workloads, whereas muscle VO₂ is increased during the second high‐intensity workload. Perfusion heterogeneity cannot explain this discrepancy between O₂ delivery and uptake. We propose that the excess muscle VO₂ during the second high‐intensity workload is derived from working muscle cells.