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Hypertension. 2005;45:391-398
Published online before print February 7, 2005, doi: 10.1161/01.HYP.0000156540.25707.af
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(Hypertension. 2005;45:391.)
© 2005 American Heart Association, Inc.

Original Articles

Endurance Exercise Training in Orthostatic Intolerance

A Randomized, Controlled Trial

Robert Winker; Alfred Barth; Daniela Bidmon; Ivo Ponocny; Michael Weber; Otmar Mayr; David Robertson; André Diedrich; Richard Maier; Alex Pilger; Paul Haber; Hugo W. Rüdiger

From the Division of Occupational Medicine (R.W., A.B., D.B., I.P., M.W., R.M., A.P., H.W.R.), Medical University of Vienna, Austria; Unit of Sports and Performance Medicine (P.H.), Medical University of Vienna, Austria; the Autonomic Dysfunction Center (D.R., A.D., P.H.), Vanderbilt University, Nashville, Tenn; and the Military Hospital Vienna-Stammersdorf (O.M.), Austria.

Correspondence to Robert Winker, MD, Division of Occupational Medicine, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail robert.winker{at}meduniwien.ac.at

Abstract

Orthostatic intolerance is a syndrome characterized by chronic orthostatic symptoms of light-headedness, fatigue, nausea, orthostatic tachycardia, and aggravated norepinephrine levels while standing. The aim of this study was to assess the protective effect of exercise endurance training on orthostatic symptoms and to examine its usefulness in the treatment of orthostatic intolerance. 2768 military recruits were screened for orthostatic intolerance by questionnaire. Tilt-table testing identified 36 cases of orthostatic intolerance out of the 2768 soldiers. Subsequently, 31 of these subjects with orthostatic intolerance entered a randomized, controlled trial. The patients were allocated randomly to either a "training" (3 months jogging) or a "control" group. The influence of exercise training on orthostatic intolerance was assessed by determination of questionnaire scores and tilt-table testing before and after intervention. After training, only 6 individuals of 16 still had orthostatic intolerance compared with 10 of 11 in the control group. The Fisher exact test showed a highly significant difference in diagnosis between the 2 groups (P=0.008) at the end of the study. Analysis of the questionnaire-score showed significant interaction between time and group (P=0.001). The trained subjects showed an improvement in the average symptom score from 1.79±0.4 to 1.04±0.4, whereas the control subjects showed no significant change in average symptom score (2.09±0.6 and 2.14±0.5, respectively). Our data demonstrate that endurance exercise training leads to an improvement of symptoms in the majority of patients with orthostatic intolerance. Therefore, we suggest that endurance training should be considered in the treatment of orthostatic intolerance patients.


Key Words: autonomic nervous system • catecholamines • exercise training

Abnormalities of orthostatic tolerance can occur as a consequence of neurological diseases, internal diseases, or impairment of blood volume, and can be explained by well-defined autonomic neuropathic and pathophysiological states. The mechanism of idiopathic orthostatic intolerance (OI) is still unclear and is often difficult to treat.

Idiopathic orthostatic intolerance is a syndrome characterized by adrenergic symptoms that occur when upright posture is assumed.1,2 The typical symptoms that are relieved by lying down or sitting are lightheadedness, nausea, headache, and palpitation.3 Patients with OI show a pronounced increase in heart rate of at least 30 beats per minute without orthostatic hypotension,4 accompanied by elevated plasma norepinephrine concentrations (>600 pg/mL).5

Management of patients with OI is difficult. An increase in blood volume by higher intake of fluid and salt,4 as well as the use of ß-blockers6 and yohimbine,7 have been suggested.

It is well-known that exercise training increases plasma volume and the tonus of striated muscles.8 Because some patients with OI showed a tendency to lower blood volume,9 endurance training might be beneficial to improve orthostatic symptoms in these patients. Another indication for a positive impact of exercise training on OI is its described ß-blocker-like hemodynamic effect.10

However, there have been no systematic studies on the effect of endurance exercise training in OI. There is controversy in the literature as to whether endurance training has a positive or a negative effect on orthostatic tolerance. Some studies suggest that training can reduce orthostatic tolerance. Greenleaf et al even stated that "trained men can run, but they cannot stand."11 Another report indicates that chronic endurance training causes orthostatic hypotension.12 Smith and Raven suggested that the negative effect of training on orthostatic tolerance was caused by long training periods (>6 months) at very high levels.13 In contrast other studies report an improvement of orthostatic tolerance after training.14–16 Most studies are performed in healthy subjects. Thus, the effect of endurance training in patients with idiopathic orthostatic is unknown.

The aim of the present study was to examine whether endurance training leads to improvement in symptoms in OI patients and therefore proves useful in their management.

Methods

Study Design and Randomization
A prospective, randomized, 2-tailed controlled pilot trial was performed to compare the mitigation of symptoms in a training group (endurance training) with a control group (spontaneous remission). A total of 2768 military recruits from the Austrian Army between April 2002 and December 2002 were screened by 10-item questionnaire as previously described.1 All subjects had undergone an extensive medical evaluation when entering the army several months before the study and had been found healthy. The subjects did not exhibit symptoms of a systemic illness that might affect the autonomic nervous system and did not take medications. Of the 2768, 161 subjects were enrolled because of a conspicuous symptom score in the screening test, but 8 of the 161 subjects refused further participation in the study. The remaining 153 subjects were examined by tilt-table test, and according to its outcome 36 had an idiopathic OI. Because of internal military shifts, only 31 of them were randomly allocated to either a "training" group (n1=16) or a "control: group (n2=15). The second survey was 3 months after the intervention of jogging in the "training group" and after 3 months without intervention in the "control group." Four subjects in the "control" group were lost in the follow-up because of internal military shifting (Figure). During the intervention, meals were provided by the military service. Therefore, dietary intake of sodium was considered to be equal in both groups. The study was approved by the ethics committee of the medical faculty of the University of Vienna. All subjects gave written informed consent before entering the study. Procedures followed were in accordance with institutional guidelines.



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  		Flow chart showing the enrollment and status of patients.

Inclusion Criteria
Inclusion criteria for OI were an increase of at least 30 beats per minute in heart rate after the tilt test and plasma norepinephrine concentrations >600 pg/mL after 30 minutes upright during the tilt-table examination.

Primary and Secondary Outcome Measures
The primary outcome measure for assessing the effectiveness of the therapy was defined prospectively as the number of subjects who had OI cured 3 months after the training compared with the control group. As secondary outcome measures, the change in questionnaire scores and in some physiological characteristics (hemodynamic and autonomic variables) were compared between the 2 groups.

Tilt-Table Investigation
One hundred fifty-three subjects underwent a tilt-table test. All examinations occurred between 8:00 AM and 10:00 AM in a quiet, dimly lit room at a comfortable constant ambient temperature (22°C, 50% to 55% humidity). A digital plethysmograph (Task Force Monitor; CNSystems Medizintechnik17) was installed around the second phalanx of the middle finger of the right hand to provide a continuous noninvasive measurement of arterial blood pressure. The right arm was supported so that the finger cuff remained constantly at heart level. In addition to the beat-by-beat recording, blood pressure and heart rate were measured every 2 minutes by sphygmomanometer on the left arm during 30 minutes of lying horizontally and during 30 minutes in a 75° upright position on the tilt-table test. Subjects were supported by belts at the level of the hips and by a footrest. Plasma catecholamine levels were determined by high-performance liquid chromatography, as previously described.1,18

Questionnaire
All subjects were interviewed by a questionnaire previously demonstrated to be highly valid and reliable.1 Cronbach {alpha} was 0.888, and the questionnaire showed high validity by means of a logistic regression, in which 129 of 138 subjects could be classified correctly (P=0.0001). The subjects specified the presence and frequency of nausea, tremor in hands, dizziness, palpitation, headache, profuse perspiration, blurred vision, chest discomfort, lightheadedness, and concentration difficulties. The total symptom score was calculated by summing up the singular item scores, taking into account the frequency of typical orthostatic symptoms (score 0 to 4). For sake of conciseness, an average symptom score for all 10 symptoms will be used for further analysis, which aggregates the global symptom strain.

DNA Sequencing
All patients with OI underwent direct DNA sequencing of exon 9 of the norepinephrine transporter gene to look for a mutation that has been related to the presence of OI.19 Guanine is replaced by cytosine at position 237 (G237C), resulting in a change from alanine to proline (Ala457Pro) within a highly conserved region of the transmembrane domain. DNA sequencing was performed as previously described.20

Total Circulating Blood Volume
The total circulating blood volume was measured by pulse dye densitometry (LiMON; PULSION Medical Systems AG) in every subject of the "training group" before and after exercise endurance training. Pulse dye densitometry detects the concentration of indocyanine green dye (ICG-PULSION; PULSION Medical Systems AG) in the blood by using different wavelengths.

Total circulating blood volume is calculated by the injected amount of indocyanine green dye related to the indocyanine green dye concentration at time point zero, using the formula:


{18MM1}

Indocyanine green dye (0.5 mg/kg body weight) was injected into an antecubital vein within 5 seconds. Light is transmitted through a fingertip to a sensor positioned on the other side. The relative concentration of indocyanine green dye in the arterial blood is determined from the ratio of the relations of the pulsatile and the nonpulsatile signal of each of the 2 selected wavelengths (805 and 905 nm). This relative concentration is calibrated by the input of the current cardiac output to derive the absolute concentration in mg/L blood and to calculate the total circulating blood volume with the formula mentioned.

Impedance Cardiography and Heart Rate Variability
We used the Task Force Monitor (CNSystems Medizintechnik17), which includes electrocardiogram, impedance cardiography, beat-to-beat blood pressure by the vascular unloading technique, and oscillometric blood pressure recording for additional hemodynamic measurements. Stroke volume and cardiac output were estimated using impedance cardiography as previously described.21 Briefly, a constant sinusoidal alternating current I0 of 400 µA and 40 kHz was passed through the thorax between short-band electrodes placed on the neck and on the lower thorax aperture (both sides the xiphoid). The indocyanine green dye signals dZ/dt(t) and Z0(t) are used for the estimation of stroke volume by an improved Kubicek method.22,23 Autonomic parameters are obtained by analysis of heart rate variability derived from detected R-R intervals in the ECG.22,24 An adaptive autoregressive model, as proposed by Bianchi et al,25 based on an recursive least-squares algorithm to estimate power spectral density was used.24 Time-variant autoregressive coefficients are determined by adaptive parametric identification, which obtains weighted values of a sliding exponential window with a history of {approx}60 beats. Absolute power in the low-frequency (LF) band (LF: 0.03 to 0.4 Hz), high frequency (HF) bands (HF: 0.4 to 0.15 Hz), and the ratio between of the power in LF and HF bands were calculated according to the Task Force recommendations.26

Ergometry and Training Protocol
The individual working capacity was calculated as a percentage of the predicted (100% workload) Watt value (derived from the tabulation and standardized for sex, age, and body surface27). Briefly, the workload was increased every 2 minutes in steps of 25 W, beginning with 25 W and going until the point of exhaustion (Ergoline, Ergometrics 900). The individual physical working capacity (PWC)ind was expressed as the individual maximal power (Watt)max in percent of a reference value (Wattref): PWCind=100xWattmax/Wattref.27

An individual pulse-oriented training program for endurance was designed for every subject. All subjects of the "training group" exercised according to their individual training heart rate, at 60% of the maximum performance capacity, according to the following formula: training heart rate=resting heart rate+(heart rate max –resting heart rate) x0.6±5 bpm. The training heart rate was monitored by a heart rate monitor (Polar pacer). The training program consisted of 3 training cycles, each for a duration of 4 weeks.

First training cycle: 4 weeks (3x30 minutes jogging/week)

Second training cycle: 4 weeks (3x40 minutes jogging/week)

Third training cycle: 4 weeks (3x50 minutes jogging/week) A sports medicine scientist supervised the duration of the training units. At the end of the training period, the following variables were determined: (1) changes in physical working capacity, assessed by an additional ergometry; (2) any improvement in the OI symptoms, as quantified by questionnaire scores; and (3) changes in heart rate and the increment in norepinephrine levels when standing upright, determined at a further tilt-table examination.

Statistical Analysis
The significance of the difference in the number of subjects with OI between groups at time point 2 was evaluated by a Fisher exact test (primary end point). Effects of group and time on the total symptom score of the questionnaire were analyzed using an ANOVA model. Differences with respect to the baselines were, for each symptom, analyzed separately by 2-tailed t tests, or, if the dependent parameters were not distributed normally or because of heterogeneous variances, by Mann-Whitney-tests. The effects of the training on the symptoms assessed by the questionnaire were investigated by 1-sided paired t tests or Wilcoxon tests, respectively. Change in physical capacity, blood volume, stroke index, cardiac index, and heart rate variability of both groups were analyzed by 1-sided paired t tests. To control type I error inflation. the Bonferroni-Holm procedure was applied in case of multiple comparisons. All data were analyzed using SPSS 11.0 for Windows (SPSS Inc., Chicago, Ill; 1989 to 1999); P≤0.05 was considered significant in all analyses.

Results

Basic Characteristics and Baseline Hemodynamic Variables
No significant differences between the 2 groups were found for age (P=0.089), height (P=0.671), weight (P=0.215), and the body mass index (P=0.317) or hemodynamic variables (Table 1); Differences in the following hemodynamic variables occurred only during the second survey: upright heart rate, upright heart rate change, upright plasma norepinephrine concentration, and supine blood pressure (Table 2). Effects of training on hemodynamic variables are presented in Table 3.


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  		TABLE 1. Characteristics of Study Population and Baseline Hemodynamic Variables at First Survey


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  		TABLE 2. Baseline Hemodynamic Variables at the Second Survey


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  		TABLE 3. Effects of Training on Hemodynamic Variables

Primary Outcome Measure
We identified 10 subjects of the training group who recovered from OI using the inclusion criteria for OI (see Methods section), whereas only 1 individual of the control group recovered from OI by the second survey. This represents a training-related improvement of 62.5% in the group undergoing study, but a spontaneous remission rate of only 9%, which is clearly significant (Fisher exact: P=0.008, 2-sided). In a posteriori power analysis with the final sample size obtained from the soldier population, and for an assumed spontaneous remission rate of 10% and a healing rate of {approx}60%, test power would have been exactly 80% (2-sided).

Secondary Outcome Measures
The effects of the training were also investigated by analyzing the mean rating of symptoms of the questionnaire by means of an ANOVA model for repeated measurements, whereby, naturally, the focus of interest does not lie on the main effects of time and group (both would result in P<0.001) but rather on the interaction between group and time point (effect of time is different for treatment and control group). The interaction between time point and group was highly significant (P<0.001). In multiple univariate analyses, the following symptoms significantly improved with respect to the trained group: dizziness, headache, blurred vision, lightheadedness, tremor in hands, and concentration difficulties. In the control group, there was no significant improvement of any symptom (Table 4). After controlling type I error inflation by the Bonferoni-Holm procedure, the effects on concentration difficulties, dizziness, and tremor in hands were significant also on the single-symptom level. The changes in the average symptom score were –0.75 (score at survey 1: 1.79±0.4; at survey 2: 1.04±0.4; improvement of symptoms) for the training group, and 0.05 (score at survey 1: 2.09±0.6; at survey 2: 2.14±0.5; impairment of symptoms) for the control group, which is highly significant (P<0.001).


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  		TABLE 4. Symptoms of Trained Subjects and Controls at First and Second Survey

Impedance Cardiography and Ergometry
Physical capacity and blood volume increased significantly after training (P=0.001). Significance is maintained even when type I error inflation is taken into account. To ensure that post-training increases in work capacity were not partially caused by greater effort, peak heart rates of ergometry from both surveys were compared (peak heart rat: 197±6 [survey 1] and 198±6 [survey 2]; 2-tailed P=0.43). In the trained subjects, the stroke index in the tilt phase and the cardiac output index in supine and tilt phase increased only descriptively (Table 5), whereas the stroke index during the lying phase showed a statistical significant improvement (P=0.048). In contrast, no significant differences were found for stroke index and cardiac index in the supine and tilt phases in the control group (Table 5).


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  		TABLE 5. Physical Capacity, Blood Volume, Stroke Index, and Cardiac Index of Subjects at First and Second Survey

Autonomic Measurements
Autonomic variables in the 2 subject groups at both surveys are given in Table 6. Exercise increased the HF power, expressed in normalized units, in both the supine (P=0.015) and tilt phases (P=0.019). However, when analyzing LF/HF ratio, a significant decrease was observed during tilt (P=0.005; this significance also holds after applying Bonferroni-Holm procedure). No significant differences were found in controls between survey 1 and survey 2.


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  		TABLE 6. Autonomic Variables in Trained Subjects and Controls at the First and Second Surveys

DNA Sequencing
The specific A457P mutation of the norepinephrine transporter was not detected in any of the 31 OI patients.

Discussion

The objective of this study was to determine whether endurance training has an effect on OI. Previous studies on the influence of exercise training on orthostatic tolerance reported controversial results,11–14,16,28 which may be related to different inclusion criteria, training regimes, methods used for assessment of changes, and a different pathophysiological mechanism, depending on physical capacity: In untrained subjects, symptoms of OI has been related to hypovolemia and a possible cardiac atrophy.29 In contrast in highly fit subjects, symptoms of OI might be caused by attenuated carotid baroreflex responsiveness and a larger compliance of the heart.30

To our knowledge, this is the first study with well-defined inclusion criteria to assess subjects with OI. In addition, our training regime was adapted to the training capacities of the individual subjects (Table 5). The tilt-table test method used with a long duration of supine resting31 and of tilting phase32 is the gold standard for measurement of response to postural change,33 and it is therefore considered to be an optimal instrument for the diagnosis of OI.

Two main observations were made in our study. First, we found a mitigation of symptoms in subjects after training. Second, we demonstrated an influence of training on the outcome of tilt-table testing. The improvement of OI is considered to be related to the observed increases in plasma and blood volumes. A similar effect has been reported previously in patients after salt loading.34

However, significant increases in plasma volume also occurred in subjects who still had OI after the training regime. In addition, we could not find any difference in the other registered variables between subjects who improved and subjects who still had OI after training (including size, weight, blood volume, maximal individual capacity, stroke index, cardiac index, peripheral resistance, and heart rate variability). The mechanism of OI might be different between the training "responders" and "nonresponders."

Increases in stroke index and cardiac index after training was higher in the supine as in upright position. Significance was only reached for the increase of stroke index after training in the supine position and a tendency of bigger increase for cardiac index after training in the supine position (P=0.06). This observation suggests that this specific improvement becomes more evident during relatively more parasympathetic-predominant supine position than the relatively more sympathetic-predominant upright position, although an improvement was registered in all variables. The rather high (40%) reduction in stroke index from lying to standing position indicates increased venous pooling. This is in good agreement with previously reported data.35

Decrease of heart rate, increase of stroke volume, increase of normalized HF during tilt, and decrease of the ratio of LF-to-HF power of heart rate variability point to an enhanced parasympathetic tone after training, which could be responsible for the relief of symptoms of OI. The absolute HF power of heart rate variability is mainly determined by vagal tone36,37 and can be interpreted as an enhanced parasympathetic control of heart rate. In contrast, the LF power is influenced by both the sympathetic and the vagal activity.38 Therefore, the use of LF-to-HF ratio as an index of sympathovagal balance has been discussed controversially.39 However, in context with our other results of decreased heart rate and increased stroke volume, we conclude that the effect of training on the symptoms of OI is mainly caused by a shift of the sympathovagal balance toward the vagal enhancement. Furlan et al found higher LF/HF ratios in OI patients compared with controls in supine phase and during tilt, suggesting a hyperadrenergic state.40 Also, our observed LF/HF ratios at first survey before training were notably higher in both positions compared with known normal values26,41 and compared to controls42 (average LF/HF ratio supine of the present study cohort [n=27] versus controls without OI [n=60]: 2.1±0.9 versus 1.4±0.8, P=0.003; average LF/HF ratio tilt of present study cohort versus controls: 16.5±8.4 versus 11.9±3.1, P=0.001). In addition, we noted a reduction of total peripheral resistance after training (Table 5), which suggests a decrease of sympathetic activity. This shift from sympathetic to vagal predominance after training might be beneficial for OI subjects.

Our data showed that endurance training has a beneficial effect on heart pump performance. First, it might have an direct effect on the myocardium by increasing its contractility.43 Second, it strengthens muscles of abdominal area and legs, which are potential muscle pumps improving venous return to the heart.44 Last, exercise reduces vasomotor tonus, which is visible in a decreased total peripheral resistance.45 Improved contractiliy, increased preload, and reduced afterload improve the heart pumping function. Exercise itself might have also a direct effect on the autonomic system. Reduction of sympathetic activity46 and increased vagal activity46,47 have been described after exercise. A decrease of sympathetic innervation leads to less vasoconstriction and consequently to a reduction of peripheral resistance. Decreased sympathetic and increased vagal activity reduced heart rate. Our data showed that exercise reduced heart rate and absolute power in HF of heart rate variability indicating an increased vagus tone. Reduced peripheral resistance (Table 5) and decreased LF oscillation of blood pressure (data not shown) indicate a reduced sympathetic control. The described effects can be beneficial for our subjects with OI. Endurance training resets the relationship between autonomic control and heart function to lower sympathetic and higher vagal input. That means during orthostatic stress, same heart pump performance can be achieved by less sympathetic activation and vagal withdraw. In our subjects, it is reflected in reduced orthostatic heart rate and catecholamine levels during standing after exercise.

We showed that endurance training has a direct effect on the heart pump function and autonomic control. A possible explanation for the nonresponders might relate to the heterogeneity of OI. Assuming the same compliance, the nonresponder could have a nonreversible atrophy of the myocard, or partial peripheral dysautonomia, or another genetic cause of OI, which cannot be affected by exercise. Some pathophysiologic forms of OI might be more amenable to exercise intervention than others.48 Because autonomic control of the circulation is influenced by genetic factors,49,50 it is possible that OI is at least partly genetically determined51–53 and that the variable response to exercise may mirror a genetic variability of OI. The genetic form of OI caused by the A457 mutation was not seen in our subjects.19 The 1 subject belonging to the control group, who had an improvement, may represent a spontaneous improvement, which may occur.48,54

Our study has 4 limitations. It was limited to young, healthy men. Thus, extrapolation of the results to other groups such as young women or elderly patients is not possible. Second, 4 subjects of the control group were lost to follow-up because of internal military shift reasons. However, the group sizes in this randomized trial were still sufficient to reveal a statistically significant effect of exercise training on OI. Third, blood volume and physical working capacity was only determined in trained subjects. However, we did not expect changes in these variables in the control group with no training. Fourth, salt intake is an important factor for OI that should be controlled. Trained and controlled subject have been selected randomly and given the same standardized meal. They have been instructed to follow the diet. We assume a good compliance of our subjects but we cannot exclude violations. In addition to changes in plasma volume, we found changes in peripheral resistance and autonomic control, which indicate a primary effect of training.

In conclusion, our data provide evidence that young patients with OI may benefit from endurance training of moderate intensity for a long period of time. Increase of physical capacity, however, was not a predictor of improvement in orthostatic tolerance. Nevertheless, the majority of patients, 62.5%, responded to endurance exercise training. This response to treatment is similar to the response to salt supplementation (63%) and even greater than the response to ß-blockers (40%) found in another study.54 There is less evidence about other medications, because there have been no controlled studies to evaluate the effectiveness of any other intervention on OI. Therefore, we suggest that endurance exercise training is a useful instrument in the management of patients with OI.

OI is of great relevance for occupational medicine, first because it implies a substantial impairment of work performance, and second because it represents a major safety risk for particular professions.1 In a follow-up study, 90% of the OI patients were able to resume their occupations54 after treatment with salt supplementation, ß-blockers, fludrocortisone, yohimbine, or midodrine. In the minority of patients not responding to exercise training (in our sample, 37.5% of the subjects), other treatments (eg, ß-blocker, clonidine, midodrine, and administration of mineralocorticoids) should be considered. Although the majority of patients will benefit from therapy, the symptoms may persist in individual cases. In such instances, the only solution is to retrain the patient for a job in a sitting position to avoid orthostatic stress.

Acknowledgments

We are indebted to Walter Habenbacher, CN-Systems (technical assistance), for his contributions to this study. This study was supported by a grant from the Jubiläumsfonds of the National Bank of Austria (OENB-Grant Project number 9724), and by National Institutes of Health grants MO1 RR00095 and 5P01 HL56693. Supported by Austrian National Bank project number 9724 and by National Institutes of Health grants MO1 RR00095 and 5P01 HL56693.

Received October 4, 2004; first decision October 27, 2004; accepted January 10, 2005.

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