Rehabilitation of decreased motor performance in patients with chronic fatigue syndrome: should we treat low effort capacity or reduced effort tolerance?

AIM: The aetiology, pathophysiology, diagnostic delineation and treatment of chronic fatigue syndrome (CFS) remain a matter of debate. Here some aspects of the debate are elucidated, with a particular focus on the patients' decreased motor performance. HYPOTHESIS: The pathophysiological basis of decreased motor performance in CFS may, theoretically, involve three components: (1) a peripheral energetic deficit (impaired oxidative metabolism and/or physical deconditioning); (2) a central perceptual disturbance (higher effort sense or increased 'interoception'); and (3) a fundamental failure of the neurobiological stress system, leading to an abnormal 'sickness response'. It is proposed that the first two components may lead to low effort capacity, while the third component may lead to reduced effort tolerance. Although there is evidence for low effort capacity influencing symptoms and functional limitations in CFS, it is assumed that reduced effort tolerance might be the primary disturbance in CFS. DIAGNOSTIC IMPLICATIONS: Distinguishing low effort capacity and reduced effort tolerance may contribute to a refinement of current diagnostic criteria of CFS and the identification of subgroups. THERAPEUTIC IMPLICATIONS: The above-mentioned distinction may make it possible to formulate a rationale for an effective implementation and adequate outcome evaluation of rehabilitation strategies in CFS. RESEARCH IMPLICATIONS: This new heuristic framework may inform future research aimed at disentangling the complex determination of impaired motor performance in CFS, as well as studies aimed at customizing treatment to different subtypes of patients.

How relevant are exercise capacity measures for evaluating treatment effects in chronic fatigue syndrome? Results from a prospective, multidisciplinary outcome study.

OBJECTIVE: To evaluate the outcome of a multidisciplinary treatment programme for patients with chronic fatigue syndrome, including health-related quality of life (HRQoL) and psychosocial variables, and exercise capacity measures. DESIGN: A six-month prospective outcome study. SETTING: University outpatient rehabilitation clinic; group setting. SUBJECTS: One hundred and sixteen women fulfilling chronic fatigue syndrome criteria. INTERVENTIONS: Cognitive behaviourally and graded exercise-based strategies; emphasis on adaptive lifestyle changes. MEASURES: Short Form General Health Survey (SF-36); Symptom Checklist (SCL-90); Causal Attribution List (CAL); Self-Efficacy Scale (SE); maximum progressive bicycle ergometer test with respiratory gas analysis; and isokinetic leg strength test, before and after treatment. RESULTS: The total group significantly improved on nearly all reported HRQoL/psychosocial variables. Changes in exercise capacity measures were rather modest and did not correlate or only weakly correlated with HRQoL/psychosocial variables. Subgroup analyses indicated that less fit patients improved significantly more on exercise capacity measures than their more fit counterparts. Patients who were fitter at baseline scored better on pretreatment HRQoL/psychosocial variables, but both subgroups improved similarly on these variables. CONCLUSIONS: Health-related quality of life and psychosocial functioning in patients with chronic fatigue syndrome improves after a six-month cognitive behaviourally and graded exercise-based multidisciplinary treatment programme. Increase in exercise capacity measures is not a necessary condition for reported improvements, except for less fit patients.

The pulse pressure-to-stroke index ratio predicts cardiovascular events and death in uncomplicated hypertension.

OBJECTIVES: The goal of this study was to assess the prognostic power of the pulse pressure-to-stroke index (PP-to-SVi) ratio for cardiovascular events and mortality in patients with uncomplicated hypertension. BACKGROUND: The prognostic significance of pulse pressure (PP) has been studied repeatedly, but few data are available on the PP-to-SVi ratio. METHODS: Invasive hemodynamic measurements, including brachial intra-arterial pressure and stroke index by the direct oxygen Fick method, were performed in the period 1972 to 1982 in 192 patients with uncomplicated hypertension; their outcome was ascertained in 1994. RESULTS: Age at baseline averaged 37 +/- 12 years; brachial artery pressure was 165 mm Hg +/- 30/89 +/- 17 mm Hg; PP averaged 76 mm Hg +/- 18 mm Hg, and the PP-to-SVi ratio was 1.67 mm Hg/(ml/m2) +/- 0.73 mm Hg/(ml/m2). During 3,057 patient years of follow-up, 19 patients died, and 44 experienced at least one fatal or nonfatal cardiovascular event. Cox regression analysis revealed that the PP-to-SVi ratio was a significant predictor of fatal and nonfatal cardiovascular events and of all-cause mortality after control for age and gender (p < 0.01). Its predictive power persisted after additional adjustment for mean arterial pressure and heart rate. Each 0.75-mm Hg/(ml/m2) increase in the PP-to-SVi ratio was independently associated with a 79% increase in the risk of a cardiovascular event (p = 0.01) and a 2.05-fold greater risk of all-cause mortality (p = 0.01). CONCLUSIONS: The PP-to-SVi ratio is a significant and independent predictor of cardiovascular events and mortality in selected patients with uncomplicated hypertension.

Left ventricular diastolic function predicts outcome in uncomplicated hypertension.

Whereas left ventricular systolic function has been shown to predict outcome in hypertensive patients without clinical evidence of heart failure, the prognostic power of diastolic function has not been examined. We assessed the relation of mean pulmonary capillary wedge pressure as an index of left ventricular diastolic function to mortality and the incidence of cardiovascular events in patients with uncomplicated hypertension at baseline. Invasive hemodynamic measurements were performed in the period 1972 to 1982 in 172 hypertensive patients without evidence of cardiovascular disease, cardiomegaly or heart failure, and their outcome was ascertained in 1994. Age at baseline averaged 37 +/- 12 years, brachial artery pressure was 162 +/- 30/88 +/- 18 mm Hg, and mean pulmonary wedge pressure 6.3 +/- 3.0 mm Hg. During 2675 patient-years of follow-up, 15 patients died and 34 suffered at least one fatal or nonfatal cardiovascular event. Cox regression analysis showed that pulmonary wedge pressure was a significant predictor of total mortality and of cardiovascular events, after control for age and gender (P < .05). Each 1 mm Hg increase in wedge pressure was associated with a 23% increase in the risk of all-cause mortality and a 13% increase in the risk of a cardiovascular event. The prognostic power was independent of mean brachial artery pressure, body mass index, serum cholesterol, electrocardiographic left ventricular hypertrophy, and smoking at baseline. We conclude that mean pulmonary wedge pressure, which is likely to reflect left ventricular diastolic function in the selected patients of the current study, is a significant and independent predictor of mortality and of cardiovascular events in uncomplicated hypertension.

Relationships of heart rate and heart rate variability with conventional and ambulatory blood pressure in the population.

BACKGROUND: Most studies on relationships between blood pressure and autonomic nervous function, assessed by power spectral analysis of heart rate variability, have used conventional or clinic blood pressure measurements in selected subjects, which may have influenced the results. OBJECTIVE: We aimed to investigate, in a population-based approach, associations of heart rate and heart rate variability, assessed in basal resting conditions and in response to standing, with conventional blood pressure measured by an investigator, and with ambulatory blood pressure monitored outside the laboratory. METHODS: RR interval and respiration were registered in 614 men and women, ages 25-89 years. After exclusion of subjects with myocardial infarction or diabetes and elimination of unsatisfactory recordings, 549 subjects remained for analyses at supine rest and 515 of these to assess the orthostatic responses. Hypertension was present in 39% of the subjects. The low-frequency (LF) and high-frequency (HF) components of heart rate variability were quantified by use of autoregressive modelling and expressed in absolute and normalized units. RESULTS: At supine rest, indices of heart rate variability were not independently related to 24 h systolic blood pressure, whereas some indices showed weak associations with diastolic 24 h pressure; the relationships were in general stronger for conventional blood pressure. For example, partial correlation coefficients of the relationships of the LF: HF ratio with systolic pressure were 0.12 (P < or = 0.01) for conventional pressure and 0.02 (NS) for 24 h pressure; these coefficients amounted to 0.20 (P < or = 0.001) and 0.11 (P < or = 0.01) for the diastolic pressures. The decrease of HF power and the increase of the LF:HF ratio on standing were significantly blunted at higher blood pressure, both when measured conventionally and by ambulatory monitoring (P < or = 0.001 for the LF: HF ratio). CONCLUSIONS: Relationships between autonomic nervous function at rest, assessed by use of power spectral analysis of heart rate variability, and conventional blood pressure, can at least partly be ascribed to the influence of the measurement conditions, whereas the orthostatic autonomic responses appear to be influenced by blood pressure per se.

A randomised, placebo-controlled, double-blind, crossover study of losartan and enalapril in patients with essential hypertension.

The primary objective of this randomised, placebo- controlled, double-blind, crossover study, was to evaluate and compare the longer term effects of the angiotensin II type 1 receptor antagonist losartan and the converting enzyme inhibitor enalapril on 24-h ambulatory blood pressure (BP). After a 4-week placebo run-in period, nine patients with essential hypertension entered the double-blind phase of the study, which consisted of three 6-week periods during which patients were treated with placebo, enalapril 20 mg o.d. or losartan 50 mg o.d. Losartan and enalapril, taken between 07.00 and 08.00, reduced ambulatory BP throughout the 24-h period. Average night time BP was reduced from 133/85 mm Hg on placebo to 124/78 mm Hg on enalapril and to 126/77 mm Hg on losartan. Daytime BP averaged 157/101 mm Hg on placebo, and was significantly lower during enalapril (142/91 mm Hg) than during losartan treatment (147/95 mm Hg). Clinic BP, measured 2 to 4 hours after drug intake, was reduced to the same extent by both drugs. The losartan-induced BP changes were significantly related to those obtained with enalapril (0.63 < r < 0.93). Ambulatory BP monitoring was repeated after 4 weeks of combined therapy in six patients. The BP lowering effect of the combination was not significantly better than that achieved with enalapril alone. In conclusion, losartan 50 mg o.d. and enalapril 20 mg o.d. lower BP to approximately the same extent, except for a more pronounced effect of enalapril on daytime ambulatory BP. The current study does not provide convincing evidence that addition of losartan to enalapril in the doses used further reduces BP.

Peak oxygen uptake better predicts outcome than submaximal respiratory data in heart transplant candidates.

BACKGROUND: Many studies have focused on the prognostic power of peak oxygen uptake VO(2) in patients with chronic heart failure, but maximal exercise testing is not without risk. The purpose of the present study was, therefore, to assess the prognostic significance of the steepness of changes in ventilation and carbon dioxide output VO(2) during submaximal exercise in comparison with VO(2). METHODS AND RESULTS: The study population consisted of 284 adult heart transplant candidates who performed a graded maximal bicycle ergometer test with respiratory gas analysis. Using the respiratory data up to a gas exchange ratio of 1.0, 3 submaximal slopes were calculated in each patient. During follow-up (median, 1.33 years), 57 patients died and 149 had >/=1 cardiovascular event. When using Cox proportional hazards analysis, both peak VO(2) and submaximal respiratory slopes predicted outcome before and after accounting for age, sex, and body mass index. However, whereas the prognostic power of peak VO(2) was independent of submaximal respiratory data, the prognostic significance of the slopes was lost after controlling for peak VO(2). Stepwise regression analysis even selected peak VO(2) as an independent prognostic index among the following factors: cause of heart failure, ejection fraction, pulmonary vascular resistance, natremia, and the forced expiratory volume in 1 s. CONCLUSIONS: Respiratory data during submaximal exercise are significant predictors of outcome in patients with chronic heart failure, but their prognostic power is inferior to that of peak VO(2). However, these data may be useful when maximal exercise is contraindicated or not achievable.

Influence of demographic, anthropometric and lifestyle characteristics on heart rate and its variability in the population.

OBJECTIVE: The purpose of this investigation was to assess the effects of age, gender, posture and their interactions, and of body mass index and lifestyle factors, on heart rate, its total variance and its variability in the frequency domain in a population-based sample of healthy subjects. METHODS: RR interval and respiration were registered in the supine and in the standing position in 302 men and 312 women, aged 25-89 years; 424 subjects were healthy and had recordings suitable for analysis. Power spectral analysis was performed by use of autoregressive modelling and by fast Fourier transform, and the low-frequency (LF) and high-frequency (HF) components were expressed in both absolute (ms2) and normalized units RESULTS: In the supine position, heart rate was higher in women than in men (P<0.001) and was not affected by age. Total variance and absolute LF and HF power markedly declined with age in each gender (P<0.001). Men had higher absolute LF power than women (P<0.001), whereas HF power was similar by gender; the age-related decline of HF power tended to be steeper in women (P = 0.06). The normalized LF and HF powers also decreased with age (P<0.01), except for the LF component in women; young men had higher LF power and lower HF power than young women, but the gender difference disappeared in the sixth decade of life. The LF: HF ratio was not influenced by age in supine men; the ratio was lower in women at young age, but increased to the level of men at greater age. Heart rate increased on standing, whereas its total variance was reduced; HF power declined, irrespective of the units, normalized LF power and the LF: HF ratio increased, whereas absolute LF power decreased (P<0.001). The postural changes of heart rate and of the frequency components did not differ by gender, but were attenuated with increasing age (P<0.05). Alcohol consumption did not influence heart rate and its variability, whereas independent effects of habitual physical activity, smoking habits and body mass index explained no more than 4% of the variance of some measures of heart rate variability. CONCLUSIONS: Age, gender and/or some lifestyle factors significantly affect heart rate and various components of its variability in the supine position and in response to standing. The results are similar for autoregressive modelling and fast Fourier transform, but may differ according to the units in which the spectral components are expressed.

Prediction of peak exercise oxygen uptake by cardiopulmonary measurements at rest in heart transplant candidates.

OBJECTIVE: Peak oxygen uptake (VO2) is a powerful prognostic index, but maximal exercise testing in heart transplant candidates has a number of disadvantages. It is unknown whether it is possible to predict peak VO2 from a comprehensive dataset with parameters of heart and lung function at rest. METHODS: One hundred adult patients in sinus rhythm and with either idiopathic or ischaemic heart failure performed a graded cycle ergometer test until volitional fatigue and underwent radionuclide ventriculography, heart catheterization, and lung function measurements at rest. RESULTS: Weight, height, age, gender and aetiology of heart failure explained 48% of the variance of peak VO2. On top of these anthropometric, demographic and clinical patient characteristics, 12% of the variance of peak VO2 was additionally explained by all resting measurements combined, i.e. radionuclide left ventricular ejection fraction, peak ejection rate, peak filling rate, cardiac frequency, mean right atrial pressure, pulmonary capillary wedge pressure, pulmonary artery pressures, cardiac output, forced vital capacity, forced expiratory volume in one second, and pulmonary diffusing capacity (cumulative R2 = 0.60); among these, pulmonary vascular resistance was the most important predictor (+6%; P < 0.001). Analyses in a subset of 43 male patients pointed out that systemic pressures and vascular resistance were not related to peak VO2. CONCLUSION: On the basis of resting left ventricular function, haemodynamics, and routine pulmonary measurements, it is unlikely to accurately predict exercise tolerance in the majority of heart transplant candidates, i.e. patients with either idiopathic or ischaemic heart failure and able to exercise until exhaustion.

Prognostic significance of exercise versus resting blood pressure in patients with chronic heart failure.

BACKGROUND: Results on the prognostic value of exercise blood pressure differ among studies; this may be related to the characteristics of the studied population. OBJECTIVE: To assess the prognostic significance of blood pressure measured during exercise in patients with chronic heart failure being considered for heart transplantation. DESIGN AND METHODS: Symptom-limited bicycle exercise testing with measurement of blood pressure and respiratory gas analysis was performed in 274 potential candidates for heart transplantation. They were then followed up for mortality and cardiovascular events. RESULTS: Results are given as the mean +/- SD. The age of the patients was 51.5+/-11.0 years, the resting blood pressure was 114+/-20/75+/-12 mmHg, the peak work load was 91+/-33 W and the peak oxygen uptake was 15.1+/-5.0 ml/min per kg. The systolic blood pressure increased to 128+/-21 mmHg at 30 W and to 133+/-23 mmHg at 50% of the peak work load. During the total follow-up time of 513 years, 55 patients died and 145 suffered at least one cardiovascular event. After controlling for age, gender and body mass index, mortality and incidence of events were inversely related to the systolic pressure at 30 W or at 50% of the peak work load, or to both (P < 0.05). The inverse associations of outcome with the systolic pressure at 50% of the peak work load persisted after additional adjustment for resting pressure and for peak oxygen uptake. CONCLUSION: The data indicate that a lower exercise systolic pressure, particularly at 50% of the peak work load, is associated with a higher mortality and a greater incidence of cardiovascular events.

Power spectral analysis of heart rate variability by autoregressive modelling and fast Fourier transform: a comparative study.

OBJECTIVE: To compare the results from autoregressive modelling (ARM) and from fast Fourier transform (FFT), the most commonly used methods for the analysis of short-term heart rate variability in the frequency domain. METHODS & RESULTS: RR interval and respiratory activity were recorded in the supine and standing positions under standardized laboratory conditions in a population-based sample of 614 subjects. The low-(LF) and high-frequency (HF) components of heart rate variability were identified by power spectral analysis, by use of FFT, with application of two sets of frequency ranges, and by ARM; LF and HF power were expressed in both normalized (%) and absolute units (ms2). The RR interval, its variance and the HF power decreased from the supine to the standing position (P < 0.001). The LF power increased on standing when expressed in normalized units, but decreased in absolute units, whereas the LF-to-HF ratio increased (P < 0.001). On the low side of the spectrum, FFT slightly overestimated the LF component obtained with ARM, when the predefined frequency range was 0.05-0.15 Hz (P < 0.001); the underestimation of LF in the frequency range 0.07-0.14 Hz was more pronounced, particularly in the erect position (P < 0.001). Both FFT methods overestimated (P < 0.001) the ARM HF component, more so for the 0.15-0.50 Hz range than for the 0.14-0.35 Hz range. Finally, we observed considerable within-subject differences between methods, which were estimated by calculation of the limits of agreement. CONCLUSIONS: Different methods for spectral decomposition of short-term heart rate variability yield similar qualitative results, but the quantitative results differ between ARM and FFT, and within the FFT method according to the selected frequency range.

Impact of age and gender on peak oxygen uptake in chronic heart failure.

Anthropometric and demographic characteristics are important determinants of exercise performance in healthy subjects, but their influence has not yet been studied in severe chronic heart failure, although peak oxygen uptake is frequently assessed in such patients for prognostic purposes. The aim of the present analysis was to examine the association between peak oxygen uptake and age, gender, and measures of body size in patients with severe chronic heart failure. We selected 122 (99 male) adult heart transplant candidates who were able to perform a bicycle ergometer test with respiratory gas analysis until voluntary fatigue. Peak oxygen uptake was higher in male than in female patients, both before and after adjustment for weight. In single regression analysis on the total study population, peak oxygen uptake was positively related to weight and to height, but inversely to age (r = 0.59 (P < 0.001), 0.42 (P < 0.001), and -0.33 (P < 0.001), respectively). Multiple stepwise regression analysis identified weight (P < 0.001), age (P < 0.001), and gender (P < 0.01) as independent determinants of peak oxygen uptake (cumulative R2 = 0.45). Similar to the findings in healthy subjects, peak oxygen uptake of patients with severe chronic heart failure is influenced by anthropometric and demographic characteristics.

Atrial fibrillation is associated with a lower exercise capacity in male chronic heart failure patients.

OBJECTIVE: To study the influence of atrial fibrillation on peak oxygen uptake (peak VO2) in chronic heart failure. An unfavourable effect of atrial fibrillation has been shown in several patient populations, but the results have not been consistent in chronic heart failure. METHODS: Data were analysed from male heart transplant candidates who were able to perform graded bicycle ergometry until exhaustion with respiratory gas analysis and measurement of heart rate. Patients in atrial fibrillation (n = 18) were compared with patients in sinus rhythm (n = 93). RESULTS: Age, weight, height, and aetiology of chronic heart failure did not differ significantly between the two groups. Cardiac catheterisation at supine rest showed that heart rate was comparable, but that stroke volume and cardiac output were lower (p < 0.05) in atrial fibrillation. Systolic and diastolic left ventricular function, assessed by radionuclide angiography at rest, were not significantly different. Peak VO2 (mean (SD): 13.8 (3.6) v 17.1 (5.6) ml/kg/min; p < 0.01) and peak work load (78 (27) v 98 (36) W; p < 0.05) were lower in the patients with atrial fibrillation, though respiratory gas exchange ratio and Borg score were similar in the two groups. Patients with atrial fibrillation had a higher heart rate sitting at rest before exercise (93 (16) v 84 (16) beats/min) and at peak effort (156 (23) v 140 (25) beats/min) (p < 0.05). CONCLUSIONS: Atrial fibrillation is associated with a 20% lower peak VO2 in patients with chronic heart failure, suggesting that preserved atrial contraction or a regular rhythm, or both, are critical to maintain cardiac output and exercise performance.

Life style as a blood pressure determinant.

In Belgium, an affluent Western European country, participation in sports, alcohol intake, and living in a working class area were identified as the life style factors with the closest associations with the blood pressure level. Obesity was another important blood pressure correlate. Sodium intake, determined from the 24 h urinary output, and smoking were not associated with blood pressure. Controlled intervention studies have proven that weight reduction, endurance training and alcohol abstinence effectively reduce blood pressure. In the light of these intervention studies, the Belgian findings and the published work highlight the potential of preventive strategies aimed at these major life style factors.

Prognostic value of invasive hemodynamic measurements at rest and during exercise in hypertensive men.

In 1994, we ascertained the outcome of 143 hypertensive men in whom invasive hemodynamic measurements were performed at rest and during graded bicycle exercise during the period 1972-1982 to assess (1) which of the hemodynamic components of blood pressure is associated with the incidence of cardiovascular events and total mortality, and (2) whether the hemodynamic response to dynamic exercise adds prognostic precision to the data at rest. During 2186 patient years of follow-up, 38 patients suffered at least one fatal or nonfatal cardiovascular event and 17 patients died. Cox regression analysis showed that systolic pressure and systemic vascular resistance measured at rest, during submaximal exercise (50 W), and at peak effort were significant (P < .01) predictors of the age-adjusted incidence of cardiovascular events and total mortality. However, exercise blood pressure did not significantly predict the incidence of cardiovascular events over and above pressure at rest; by contrast, exercise systemic vascular resistance added prognostic precision to vascular resistance at rest (P < .01). As for total mortality, systolic pressure and systemic vascular resistance at peak exercise carried prognostic information that was independent of the results at rest (P < .05); this was not the case for measurements during submaximal exercise. We conclude that the prognostic importance of blood pressure is related to systemic vascular resistance. The prognostic precision of exercise pressure, on top of pressure at rest, is limited. Exercise systemic vascular resistance, however, provides prognostic information beyond that available from measurements at rest, particularly for the incidence of cardiovascular events.

Prognostic significance of peak oxygen uptake in hypertension.

The aim of this study was to investigate the prognostic value of cardiopulmonary fitness in hypertension. From 1972 to 1982 oxygen uptake and heart rate were recorded during an exercise test to exhaustion in 216 patients (143 men). Their outcome was ascertained in 1994. During 3,411 patient years of follow-up, 53 patients suffered at least one fatal or nonfatal cardiovascular event and 25 patients died. After adjustment for age, gender, and weight, the relative hazard rates (RHR; Cox regression) of peak oxygen uptake (l.min-1) amounted to 0.44 (P = 0.01) for the first occurring cardiovascular events and 0.35 (P = 0.05) for all-cause mortality. These RHR remained significant after additional adjustment for traditional cardiovascular risk factors (RHR = 0.45 and 0.28, respectively; P < 0.05). Heart rate at 50 W did not predict outcome after adjustment for age and gender (P = 0.94 and 0.14, respectively), nor after additional adjustment for heart rate at rest (P = 0.86 and 0.61, respectively). In conclusion, a lower peak oxygen uptake, but not a higher submaximal heart rate, is significantly and independently associated with a higher incidence of cardiovascular events and a higher total mortality in hypertensive patients.