Orthostatic Intolerance Is Independent of the Degree of Autonomic Cardiovascular Adaptation after 60 Days of Head-Down Bed Rest.

Spaceflight and head-down bed rest (HDBR) can induce the orthostatic intolerance (OI); the mechanisms remain to be clarified. The aim of this study was to determine whether or not OI after HDBR relates to the degree of autonomic cardiovascular adaptation. Fourteen volunteers were enrolled for 60 days of HDBR. A head-up tilt test (HUTT) was performed before and after HDBR. Our data revealed that, in all nonfainters, there was a progressive increase in heart rate over the course of HDBR, which remained higher until 12 days of recovery. The mean arterial pressure gradually increased until day 56 of HDBR and returned to baseline after 12 days of recovery. Respiratory sinus arrhythmia and baroreflex sensitivity decreased during HDBR and remained suppressed until 12 days of recovery. Low-frequency power of systolic arterial pressure increased during HDBR and remained elevated during recovery. Three subjects fainted during the HUTT after HDBR, in which systemic vascular resistance did not increase and remained lower until syncope. None of the circulatory patterns significantly differed between the fainters and the nonfainters at any time point. In conclusion, our data indicate that the impaired orthostatic tolerance after HDBR could not be distinguished by estimation of normal hemodynamic and/or neurocardiac data.

Is autonomic modulation different between European and Chinese astronauts?

PURPOSE: The objective was to investigate autonomic control in groups of European and Chinese astronauts and to identify similarities and differences. METHODS: Beat-to-beat heart rate and finger blood pressure, brachial blood pressure, and respiratory frequency were measured from 10 astronauts (five European taking part in three different space missions and five Chinese astronauts taking part in two different space missions). Data recording was performed in the supine and standing positions at least 10 days before launch, and 1, 3, and 10 days after return. Cross-correlation analysis of heart rate and systolic pressure was used to assess cardiac baroreflex modulation. A fixed breathing protocol was performed to measure respiratory sinus arrhythmia and low-frequency power of systolic blood pressure variability. RESULTS: Although baseline cardiovascular parameters before spaceflight were similar in all astronauts in the supine position, a significant increase in sympathetic activity and a decrease in vagal modulation occurred in the European astronauts when standing; spaceflight resulted in a remarkable vagal decrease in European astronauts only. Similar baseline supine and standing values for heart rate, mean arterial pressure, and respiratory frequency were shown in both groups. Standing autonomic control was based on a balance of higher vagal and sympathetic modulation in European astronauts. CONCLUSION: Post-spaceflight orthostatic tachycardia was observed in all European astronauts, whereas post-spaceflight orthostatic tachycardia was significantly reduced in Chinese astronauts. The basis for orthostatic intolerance is not apparent; however, many possibilities can be considered and need to be further investigated, such as genetic diversities between races, astronaut selection, training, and nutrition, etc.

The slope of the segmental stretch-strain relationship as a noninvasive index of LV inotropy.

OBJECTIVES: The aim of this study was to test the hypothesis that the noninvasively constructed slope of the relationship between left ventricular (LV) regional systolic strain and stretch during atrial contraction represents LV inotropic state. BACKGROUND: LV systolic response to a changing preload depends on its inotropic state. Changing the preload has allowed constructing the slope of the end-systolic pressure-volume relationship that is used as an invasive measurement of LV inotropy. We assumed that the slope of the relationship between regional systolic LV strain (total_S) and stretch during atrial contraction (preS) depends on the LV inotropic state as well and can thus be used as a LV inotropy index. METHODS: Strain curves (tissue Doppler) were extracted from 27 healthy individuals to determine the normal stretch-strain relationship at rest, during a low-dose dobutamine (LD) challenge and during passive leg-lift (LL). The method was also applied in 7 patients with breast cancer before and after chemotherapy with anthracyclines. RESULTS: PreS and total_S correlated closely in all subjects (r = 0.82). Total_S values increased (p < 0.05) with LD (-20.44 ± 3.89% vs. -24.24 ± 5.55%) and LL (-19.65 ± 3.77% vs. -24.05 ± 3.67%), whereas preS increased only with LL (5.96 ± 1.72% vs. 8.61 ± 2.18%), but not with LD (6.83 ± 2.34% vs. 7.29 ± 2.24%). No changes of total_S or preS were observed after the exposure to chemotherapy (-21.23 ± 2.93% vs. -21.49 ± 2.89% and 8.11 ± 1.03% vs. 8.59 ± 1.73%, respectively). The slope of stretch-strain relationship got steeper with LD (-1.47 ± 0.36 vs. -2.34 ± 0.36, p < 0.05), declined after the chemotherapy (-1.68 ± 0.15 to -0.86 ± 0.23, p < 0.05) and did not change with LL (-1.39 ± 0.57 vs. -1.51 ± 0.38, p = NS). CONCLUSIONS: The slope of the regional stretch-strain relationship can be regarded as a noninvasive index of myocardial inotropic state. It gets steeper with increasing inotropy, does not change with preload induced changes of LV systolic function, and flattens after the exposure to a cardiotoxic drug.

Cardiac output and sympathetic vasoconstrictor responses during upright tilt to presyncope in healthy humans.

Syncope is a common clinical condition occurring even in healthy people without manifest cardiovascular disease. The purpose of this study was to determine the role of cardiac output and sympathetic vasoconstriction in neurally mediated (pre)syncope. Twenty-five subjects (age 15­51) with no history of recurrent syncope but who had presyncope during 60 deg upright tilt were studied; 10 matched controls who completed 45 min tilting were analysed retrospectively. Beat-to-beat haemodynamics (Modelflow), muscle sympathetic nerve activity (MSNA) and sympathetic baroreflex sensitivity (MSNA­diastolic pressure relation) were measured. MSNA, haemodynamic responses and baroreflex sensitivity during early tilting were not different between presyncopal subjects and controls. Hypotension was mediated by a drop in cardiac output in all presyncopal subjects, accompanied by a decrease in total peripheral resistance in 16 of them (64%, group A). In the other 9 subjects, total peripheral resistance was well maintained even at presyncope (36%, group B). Cardiac output was smaller (3.26 ± 0.34 (SEM) vs. 5.02 ± 0.40 l min(−1), P = 0.01), while total peripheral resistance was greater (1327 ± 117 vs. 903 ± 80 dyn s cm(−5), P < 0.01) in group B than group A at presyncope. The steeper fall in cardiac output in group B was due to a drop in heart rate. MSNA decreased rapidly at presyncope after the onset of hypotension. Thus, a moderate fall in cardiac output with coincident vasodilatation or a marked fall in cardiac output with no changes in peripheral vascular resistance may contribute to (pre)syncope. However, an intrinsic impairment of vasomotor responsiveness and sympathetic baroreflex function is not the cause of neurally mediated (pre)syncope in this population.

Haemodynamic adaptation during sudden gravity transitions.

Haemodynamic responses during parabolic flight were studied. The hypothesis that haemodynamic changes may be counteracted by a transient vagal reflex during acute gravity transitions was tested. ECG, arterial pressure and respiration were recorded continuously in seven male subjects during parabolic flight. Beat-to-beat haemodynamic parameters were estimated. In the supine position no significant differences were shown among the different gravity phases. In the upright position, significant within-group differences were observed across gravity phases for all parameters. Postural differences in haemodynamic data disappeared during the microgravity phase and were enlarged during hypergravity phases. Detailed temporal analysis of cardiac time series in standing subjects confirmed the hypothesized biphasic response of initial parasympathetic modulation: a sharp increase of RRI within 3-5 s followed by a 10% decrease in the remaining period of microgravity (p < 0.001); a sharp increase in SAP within 2-4 s followed by a slow decrease of 25%. Significant within-group differences were observed in the standing position for mean RRI (836 ± 170 ms, p = 0.003), DAP (66 ± 8 mmHg, p < 0.001), MAP (139 ± 12 mmHg, p = 0.001), RRI HF amplitude (17.6 ± 7.5 ms, p < 0.001), SV (146 ± 5%, p < 0.001) and SVR (73 ± 10%, p = 0.020). In standing subjects, the initial baroreflex-mediated vagal heart rate response is limited to a transition period at early microgravity lasting about 3-5 s, followed by a gradual heart rate recovery during the remaining 15-17 s due to a parasympathetic withdrawal. The resultant increase in cardiac output induces a baroreflex-mediated systemic vasodilatation, which may be the driving force for a decreased arterial pressure in weightlessness.

The most likely time and place of introduction of BTV8 into Belgian ruminants.

BACKGROUND: In northern Europe, bluetongue (BT) caused by the BT virus (BTV), serotype 8, was first notified in August 2006 and numerous ruminant herds were affected in 2007 and 2008. However, the origin and the time and place of the original introduction have not yet been determined. METHODS AND PRINCIPAL FINDINGS: Four retrospective epidemiological surveys have been performed to enable determination of the initial spatiotemporal occurrence of this emerging disease in southern Belgium: investigations of the first recorded outbreaks near to the disease epicenter; a large anonymous, random postal survey of cattle herds and sheep flocks; a random historical milk tank survey of samples tested with an indirect ELISA and a follow-up survey of non-specific health indicators. The original introduction of BTV into the region probably occurred during spring 2006 near to the National Park of Hautes Fagnes and Eifel when Culicoides become active. CONCLUSIONS/SIGNIFICANCE: The determination of the most likely time and place of introduction of BTV8 into a country is of paramount importance to enhance awareness and understanding and, to improve modeling of vector-borne emerging infectious diseases.

Effects of mental stress on autonomic cardiac modulation during weightlessness.

Sustained weightlessness affects all body functions, among these also cardiac autonomic control mechanisms. How this may influence neural response to central stimulation by a mental arithmetic task remains an open question. The hypothesis was tested that microgravity alters cardiovascular neural response to standardized cognitive load stimuli. Beat-to-beat heart rate, brachial blood pressure, and respiratory frequency were collected in five astronauts, taking part in three different short-duration (10 to 11 days) space missions to the International Space Station. Data recording was performed in supine position 1 mo before launch; at days 5 or 8 in space; and on days 1, 4, and 25 after landing. Heart rate variability (HRV) parameters were obtained in the frequency domain. Measurements were performed in the control condition for 10 min and during a 5-min mental arithmetic stress task, consisting of deducting 17 from a four-digit number, read by a colleague, and orally announcing the result. Our results show that over all sessions (pre-, in-, and postflight), mental stress induced an average increase in mean heart rate (Delta7 +/- 1 beats/min; P = 0.03) and mean arterial pressure (Delta7 +/- 1 mmHg; P = 0.006). A sympathetic excitation during mental stress was shown from HRV parameters: increase of low frequency expressed in normalized units (Delta8.3 +/- 1.4; P = 0.004) and low frequency/high frequency (Delta1.6 +/- 0.3; P = 0.001) and decrease of high frequency expressed in normalized units (Delta8.9 +/- 1.4; P = 0.004). The total power was not influenced by mental stress. No effect of spaceflight was found on baseline heart rate, mean arterial pressure, and HRV parameters. No differences in response to mental stress were found between pre-, in-, and postflight. Our findings confirm that a mental arithmetic task in astronauts elicits sympathovagal shifts toward enhanced sympathetic modulation and reduced vagal modulation. However, these responses are not changed in space during microgravity or after spaceflight.

Adaptation of heart rate and blood pressure to short and long duration space missions.

To what extent does going to space affect cardiovascular function? Although many studies have addressed this question, the answer remains controversial. Even for such primary parameters as heart rate (HR) and blood pressure (BP) contradictory results have been presented. The purpose of this investigation was to evaluate HR and arterial BP in 11 male astronauts who each took part in nine different space missions aboard the International Space Station (ISS), for up to 6 months. Pre-flight HR and BP readings were obtained in both the standing and supine positions on Earth and were taken as reference values. Our results show that HR and arterial BP in space equal pre-flight supine values. In all subjects, HR and mean arterial BP (MAP) were lower in space compared with pre-flight standing (both p<0.05). HR in space was well maintained at pre-flight supine level for up to 6 months in all astronauts while MAP tended to adapt to a level in between the ground-based standing and supine positions. Also pulse pressure (PP) decreased over the course of long duration spaceflight. In conclusion, our data indicate that weightlessness relaxes the circulation in humans for an extended duration of up to 6 months in space.

Cardiac autonomic regulation under hypnosis assessed by heart rate variability: spectral analysis and fractal complexity.

OBJECTIVE: This study examined the effects of hypnosis on autonomic cardiac control. We hypothesized a modification of autonomic modulation of the heart rate with an enhanced vagal tone during hypnosis compared to baseline. METHODS: In 12 healthy subjects (6 men and 6 women, 22.2 +/- 1.0 years of age) ECG was recorded at baseline and during hypnosis. Heart rate variability parameters were obtained in the frequency domain (LFnu: low frequency normalized units, and HFnu: high frequency normalized units) and from nonlinear analysis methods (detrended fluctuation analysis, DFA). RESULTS: Compared to the control condition, hypnosis showed a significantly decreased LFnu, a significantly increased HFnu, and a significantly decreased LF/HF. DFA showed a significantly decreased short-range similarity. Heart rate remained unchanged. CONCLUSION: Autonomic cardiac tone is significantly modified during hypnosis by shifting the balance of the sympathovagal interaction toward an enhanced parasympathetic modulation, accompanied by a reduction of the sympathetic tone and a decreased short-range similarity but without a concomitant change in heart rate. Central and secondary autonomous nervous system changes induced by hypnosis are a possible explanation for our results. Another highly probable explanation is given by a variation in the depth of respiration. Hypnosis appears to prevent the autonomic responses expected during neutral stimulation.

Complexity of cardiovascular regulation in small animals.

Oscillations of heart rate and blood pressure are related to the activity of the underlying control mechanism. They have been investigated mostly with linear methods in the time and frequency domains. Also, in recent years, many different nonlinear analysis methods have been applied for the evaluation of cardiovascular variability. This review presents the most commonly used nonlinear methods. Physiological understanding is obtained from various results from small animals.

Steep fall in cardiac output is main determinant of hypotension during drug-free and nitroglycerine-induced orthostatic vasovagal syncope.

BACKGROUND: How much of the hypotension occurring during postural syncope is cardiac output-mediated and how much can be ascribed to a fall in systemic vascular resistance are unknown. The contribution of both determinants may be influenced by the use of vasoactive drugs. OBJECTIVE: The purpose of this study was to assess the determinants of hypotension during drug-free and nitroglycerine (NTG)-induced vasovagal presyncope in routine tilt table testing. METHODS: In this retrospective study, a total of 56 patients (37 female; age 36 +/- 19 years) with suspected vasovagal syncope and a positive tilt test at two clinical centers were selected. In 29 patients, presyncope was provoked by 0.4 mg sublingual NTG, administered in the 60 degrees head-up tilt position. In the other 27 patients, presyncope was provoked by passive tilt alone. Finger arterial pressure was monitored continuously, and left ventricular stroke volume was computed from pressure pulsations. RESULTS: After NTG administration, heart rate rose, and peak heart rate was similar in all patients. Use of NTG did not affect circulatory patterns precipitating a vasovagal response. On average in all patients, marked hypotension was mediated by an approximately 50% fall in cardiac output, whereas systemic vascular resistance was well maintained until presyncope. CONCLUSION: Hypotension during routine tilt testing is cardiac output-mediated, and the mechanism appears independent of the use of 0.4 mg sublingual NTG. The study data challenge the conventional idea of systemic vasodilation as the overriding cause of hypotension during postural syncope.

Tilt training increases the vasoconstrictor reserve in patients with neurally mediated syncope evoked by head-up tilt testing.

AIMS: Tilt training is a useful therapeutic option in neurally mediated syncope (NMS). We tested the hypothesis that tilt training will restore orthostatic tolerance by increasing the degree of vasomotor reserve during sustained orthostatic stress. METHODS AND RESULTS In this follow-up study we enrolled 17 patients (age 31 +/- 22 years, 11 females) with a clinical diagnosis of NMS and two consecutive positive tilt tests. The head-up tilt test was repeated day after day: one session per day. All patients were instructed to continue a programme of daily standing training at home. Follow-up tilt testing was performed after a period of 6 weeks in 14 patients. ECG and finger arterial blood pressure (Portapres) were recorded during subsequent tilt testing. Left ventricular stroke volume (SV), cardiac output, and systemic vascular resistance were computed from the pressure pulsations (Modelflow). Spontaneous cardiac baroreflex sensitivity was estimated by cross-spectral analysis of heart rate (HR) and systolic blood pressure. In all patients, orthostatic tolerance was restored after 4.1 +/- 0.9 tilt sessions, median 4. The follow-up tilt test was also negative in all patients. This was accompanied by a significant rise in systemic vascular resistance to compensate for a postural reduction in SV in the sustained head-up tilt position. No evidence could be provided of altered baroreflex control of HR after tilt training. CONCLUSION: Tilt training restores orthostatic tolerance at least in part by increasing the amount of vasoconstriction that can ultimately be made available during sustained orthostatic stress. The increased vasoconstrictor reserve is preserved after 6 weeks of continued standing training at home.

Evaluation of antibody-ELISA and real-time RT-PCR for the diagnosis and profiling of bluetongue virus serotype 8 during the epidemic in Belgium in 2006.

In 2006 bluetongue (BT) emerged for the first time in North-Western Europe. Reliable diagnostic tools are essential in controlling BT but data on the diagnostic sensitivity (Se) and specificity (Sp) are often missing. This paper aims to describe and analyse the results obtained with the diagnostics used in Belgium during the 2006 BT crisis. The diagnosis was based on a combination of antibody detection (competitive ELISA, cELISA) and viral RNA detection by real-time RT-PCR (RT-qPCR). The performance of the cELISA as a diagnostic tool was assessed on field results obtained during the epidemic and previous surveillance campaigns. As the infectious status of the animals is unknown during an epidemic, a Bayesian analysis was performed. Both assays were found to be equally specific (RT-qPCR: 98.5%; cELISA: 98.2%) while the diagnostic sensitivity of the RT-qPCR (99.5%) was superior to that of the cELISA (87.8%). The assumption of RT-qPCR as standard of comparison during the bluetongue virus (BTV) epidemic proved valid based on the results of the Bayesian analysis. A ROC analysis of the cELISA, using RT-qPCR as standard of comparison, showed that the cut-off point with the highest accuracy occurred at a percentage negativity of 66, which is markedly higher than the cut-off proposed by the manufacturer. The analysis of the results was further extended to serological and molecular profiling and the possible use of profiling as a rapid epidemiological marker of the BTV in-field situation was assessed. A comparison of the serological profiles obtained before, during and at the end of the Belgian epidemic clearly showed the existence of an intermediate zone which appears soon after BTV (re)enters the population. The appearance or disappearance of this intermediate zone is correlated with virus circulation and provides valuable information, which would be entirely overlooked if only positive and negative results were considered.

Impact of age on the vasovagal response provoked by sublingual nitroglycerine in routine tilt testing.

NTG (nitroglycerine) is used in routine tilt testing to elicit a vasovagal response. In the present study we hypothesized that with increasing age NTG triggers a more gradual BP (blood pressure) decline due to a diminished baroreflex-buffering capacity. The purpose of the present study was to examine the effect of NTG on baroreflex control of BP in patients with distinct age-related vasovagal collapse patterns. The study groups consisted of 29 patients (16-71 years old, 17 females) with clinically suspected VVS (vasovagal syncope) and a positive tilt test. Mean FAP (finger arterial pressure) was monitored continuously (Finapres). Left ventricular SV (stroke volume), CO (cardiac output) and SVR (systemic vascular resistance) were computed from the pressure pulsations (Modelflow). BRS (baroreflex sensitivity) was estimated in the time domain. In the first 3 min after NTG administration, BP was well-maintained in all patients. This implied an adequate arterial resistance response to compensate for steeper reductions in SV and CO with increasing age. HR (heart rate) increased and the BRS decreased after NTG administration. The rate of mean FAP fall leading to presyncope was inversely related to age (r=0.51, P=0.005). Accordingly, patients with a mean FAP fall >1.44 mmHg/s (median) were generally younger compared with patients with a slower mean FAP-fall (30+/-10 years compared with 51+/-17 years; P=0.001). The main determinant of the rate of BP fall on approach of presyncope was the rate of fall in HR (r=0.75, P<0.001). It was concluded that, in older patients, sublingual NTG provokes a more gradual BP decline compared with younger patients. This gradual decline cannot be ascribed to failure of the baroreflex-buffering capacity with increasing age. Age-related differences in the laboratory presentation of a vasovagal episode depend on the magnitude of the underlying bradycardic response.

Low-dose exercise training does not influence cardiac autonomic control in healthy sedentary men aged 55-75 years.

The purpose of this study was to evaluate the effects of a realistic, feasible, and commonly used fitness training programme on cardiac autonomic control in 14 sedentary men aged 62.0 +/- 6.1 years (mean +/- s). All participants performed a one-year fitness training programme in which training intensity and frequency were specifically chosen to be compliant for the majority of the participants (2-3 sessions per week at moderate intensity). At the same time, a reference group consisting of 15 sedentary age-matched men (age 64.2 +/- 6.5 years) did not change their habitual physical activity. Measurements were performed before and after the training intervention. Cardiac autonomic control was inferred from resting values (supine and standing) of heart rate variability (HRV) computed in the frequency domain over 10-min intervals. Endurance capacity was evaluated during a maximal incremental bicycle ergometer test. In spite of an increase in peak oxygen consumption (VO2peak) by 6.4% after training, heart rate in the training group remained unchanged at rest and at the same metabolic demand. No changes in resting parameters of HRV were shown for either groups or positions. Results from this study provide no evidence of a clinically meaningful increase in the vagal modulation to the sinus node at rest after one year of low-volume and moderate-intensity fitness training in men aged 55-75 years.

Fractal dimension in health and heart failure.

BACKGROUND: Non-linear analysis of heart rate variability (HRV) can give additional information about autonomic control of the heart rate. This study applied the fractal dimension (FD) in a congestive heart failure (CHF) population. METHODS: FD and HRV were evaluated in a healthy population (n=21) and an end-stage heart failure population (n=21) using 1-h segments during the day and night from Holter recordings. RESULTS: CHF patients presented a loss of circadian variation in both FD and conventional time- and frequency-domain HRV indices. FD was higher in the CHF population both during the day and night. In the CHF population the correlation between FD and high-frequency power of HRV was lost. CONCLUSION: Day-night variations of heart rate fluctuations are lost in heart failure. Changes in FD reflecting physiological and pathophysiological changes were observed.

Effects of autonomic blockade on non-linear cardiovascular variability indices in rats.

1. The present study assesses the effects of autonomic blockade (alpha- and beta-adrenoceptor and cholinergic) on cardiovascular function studied by heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity in rats using non-linear dynamics. Little is known about the influence of pharmacological autonomic nervous system interventions on non-linear cardiovascular regulatory indices. 2. In 13 conscious rats, heart rate and aortic blood pressure were measured continuously before, during and after autonomic blockade with atropine, phentolamine and propranolol. Non-linear scaling properties were studied using 1/f slope, fractal dimension and long- and short-term correlation. Non-linear complexity was described with correlation dimension, Lyapunov exponent and approximate entropy. Non-linear indices were compared with linear time and frequency domain indices. 3. Beta-adrenoceptor blockade did not alter the non-linear characteristics of HRV and BPV, although low-frequency power of HRV was depressed. Alpha-adrenoceptor blockade decreased the scaling behaviour of HRV, whereas cholinergic blockade decreased the complexity of the non-linear system of HRV. For BPV, the scaling behaviour was increased during alpha-adrenoceptor blockade and the complexity was increased during cholinergic blockade. The linear indices of HRV and BPV were decreased. 4. The present results indicate that the beta-adrenoceptor system has little involvement in the generation of non-linear HRV and BPV in rats. 5. Alpha-adrenoceptor blockade mostly influenced the scaling properties of the time series, whereas cholinergic blockade induced changes in the complexity measures. 6. The absence of the baroreflex mechanism can trigger a compensatory feed-forward system increasing the complexity of BPV.

Aging and nonlinear heart rate control in a healthy population.

In recent years more studies are using nonlinear dynamics to describe cardiovascular control. Because of the large dispersion of physiological data, it is important to have large studies with both male and female participants to establish a range of physiological healthy values. This study investigated the effect of gender and age on nonlinear indexes. Nonlinear scaling properties were studied by using 1/f slope (where f is frequency), fractal dimension, and detrended fluctuation analysis short- and long-term correlations (DFAalpha(1) and DFAalpha(2), respectively). Nonlinear complexity was described with correlation dimension (CD), Lyapunov exponent (LE), and approximate entropy (ApEn). The population consisted of 135 women and 141 men (age, 18-71 yr). Twenty-four hour ECG recordings were obtained by using Holter monitoring. The recordings were split into daytime (8 AM-9 PM) and nighttime (11 PM-6 AM). A day-night variation was present in all nonlinear heart rate variability (HRV) indexes, except for the CD in the female population. During the night the percentage of CD values of surrogate data files differing from the CD value of the original data increased. All nonlinear indexes were significantly correlated with age. Deeper analysis per age category of 10 yr showed a stabilization in the age decline of the fractal dimension and ApEn at the age of > or =40 yr. The vagal pathways seemed to be more involved in the generation of nonlinear fluctuations. Higher nonlinear behavior was evident during the night. No clear difference between men and women was found in the nonlinear indexes. Nonlinear indexes decline with age. This can be related to the concept of decreasing autonomic modulation with advancing age.