We studied the effect of regular physical activity on cardiac and vascular autonomic modulation during a 5-yr controlled randomized training intervention in a representative sample of older Finnish men. Heart rate variability (HRV) and blood pressure variability (BPV) are markers of cardiac and vascular health, reflecting cardiac and vascular autonomic modulation. One hundred and forty randomly selected 53- to 63-yr-old men were randomized into two identical groups: an intervention (EX) group and a reference (CO) group, of which 89 men remained until the final analysis (EX: n = 47; CO: n = 42). The EX group trained for 30–60 min three to five times a week with an intensity of 40–60% of maximal oxygen consumption. The mean weekly energy expenditure of the training program for the 5-yr training period was 3.80 MJ, and 71% of the EX group exceeded the mean. The EX group had a significantly (P < 0.01) higher oxygen consumption at ventilatory aerobic threshold (V̇o2VT) than the CO group at the 5-yr time point. V̇o2VT had a tendency to increase in the EX group and decrease in the CO group (interaction P < 0.001) from the baseline to the 5-yr time point. Peak performance did not change. Low-frequency power of R-R interval variability decreased in the EX group (P < 0.01, by 6%) from the baseline to the 5-yr time point. BPV did not change. In conclusion, low-intensity regular exercise training did not prevent HRV from decreasing or change BPV in 5 yr in older Finnish men.
- autonomic nervous system function
- oxygen consumption
heart rate (HR) variability (HRV) means the oscillations between consecutive instantaneous R-R intervals (RRI) (36). Blood pressure (BP) can be evaluated in each RRI, after which short-term BP variability (BPV) can be calculated. Reduced HRV, a marker of cardiac autonomic modulation, has been shown to be an independent predictor of overall mortality in old people (37), precede ischemic events (18), and be associated with an increased risk for sudden cardiac death (12, 17). Even healthy aging is related to a decrease in HRV (2) [e.g., decreases the low-frequency power (LFP) of RRI variability by 13% per 10 yr]. HRV has been shown to be related to cardiorespiratory fitness (8a, 11, 39), although some studies do not agree with that (8). Furthermore, in some longitudinal exercise training studies lasting up to 12 mo with young (21, 38) and old subjects (21, 31, 35) and with healthy subjects (21, 31, 38) and cardiac patients (35), HRV has been reported to increase. However, some studies have not found any significant effect of exercise training on HRV in old subjects (25, 34, 40).
BPV is much less studied. Laitinen et al. (20) have shown BPV to be negatively associated with age, body mass index (BMI), and baroreflex sensitivity and positively associated with BP level. The clinical relevance of beat-to-beat BPV at the population level has not been investigated. In the Ohasama study, high systolic BPV obtained every 30 min has been shown to be an independent predictor of cardiovascular mortality (16), and Sega et al. (33) reported independent relationships between the left ventricular mass index determined in echocardiography and 24-h BP level and BPV.
Controlled randomized long-term trials of the effect of regular physical activity on HRV and BPV are missing. The goal of the present randomized controlled 5-yr exercise training intervention was to evaluate the effect of regular exercise training on HRV and BPV, i.e., cardiac and vascular autonomic modulation. We hypothesized that during the first training year, HRV and BPV would increase, but after reaching steady state in the training load it would no more increase but could also decrease. In the reference (CO) group, we supposed HRV and BPV to decrease to the 5-yr time point. The basis of the hypothesis was an interaction of aging and increased training load in the intervention (EX) group, i.e., in the EX group the positive effect of the increasing exercise training stimulus on HRV would be stronger than the effect of aging during the first training year. After a higher level of HRV was reached with the increasing training stimulus as a consequence of increased vagal cardiac modulation and decreased sympathetic cardiac modulation, HRV could decrease because of an impairing effect of aging on the receptor level (9) and an effect on overall autonomic activity (32). In the CO group, the only remarkably influencing factor would be the effect of aging on cardiac autonomic function.
Subjects. A randomly selected sample of middle-aged (range: 53–63 yr) men was obtained from the Finnish population registry. They signed an informed consent form for participation. After a recruitment period (30), 140 men were randomized to either the CO (n = 70) or EX (n = 70) groups. During the 5-yr intervention, 20 subjects were lost: 6 due to death (2 in the EX group and 4 in the CO group), 9 due to loss of motivation (5 in the EX group and 4 in the CO group), 3 due to a malignant disease (in the CO group), 1 due to lack of time (in the EX group), and 1 due to moving elsewhere (in the EX group). Thirty-one men were lost from the final analysis because of missing data in at least one of the time points. In 15 of them, HRV analyses could not be done because of extrasystolias or atrial fibrillation. The characteristics of the 89 men in the final analysis are presented in Table 1. Forty-four of the men were healthy (had only minor musculoskeletal disorders or allergies), and 45 men (25 in the EX group and 20 in the CO group) had cardiovascular, metabolic, pulmonary, or psychiatric diseases/disorders and used regular medication (Table 1). According to a 7-day recall, the groups were equal in their activity level at the baseline. However, individual differences in both groups concerning activity level were wide.
Exercise training program. The progressive training program consisted of walking, jogging, cross-country skiing, swimming, and cycling. During the first 3 mo, the men were advised to exercise three times a week for 30–45 min at an intensity corresponding to brisk walking. Thereafter, the duration was increased to 45–60 min/session, and the frequency was increased to five times a week. Exercise intensity was determined individually and modified annually when indicated to correspond to the ventilatory aerobic threshold, i.e., 40–60% of maximal oxygen consumption (V̇o2). The program was planned to correspond to an energy expenditure of 6.28 MJ/wk. The men in the EX group kept an exercise training logbook, and they were provided with personal HR monitors (Polar Edge, Polar Electro) to monitor the intensity of exercises. The men in the CO group kept their exercise training logbook once a year for 6 wk. According to the regulations of the Ethics Committee, the men in the CO group were advised to make a personal choice on whether or not to engage in physical exercise. The method for coding and counting training activity of the logbooks has been previously published (1). The outcome was mean exercise energy expenditure for the training years. The assessment of the physical activity level was done by the 7-day physical activity recall method (6, 29) at the baseline and once a year during the intervention.
Experimental protocol. The study protocol was approved by the Ethics Committee of the University of Kuopio. Measurements were done before the exercise training intervention (baseline) and at 1- and 5-yr time points. Anthropometry and a maximal cardiorespiratory test with a bicycle ergometer (Ergo-line 900), including breathing gas analyses (Sensormedics 2900z, Sensormedics; Yorba Linda, CA), were performed on the same day. HRV and BPV measurements were in most cases performed between 1 to 4 wk before or after the maximal test.
Anthropometry. Body weight was measured with a digital scale in light clothing without shoes. Waist circumference was measured from midway between the lower rib margin and the iliac crest. Hip circumference was measured at the level of trochanter major, and the waist-to-hip ratio was calculated. The measurements were carried out between 9 AM and 2 PM at about the same time in each follow-up measurement for each subject.
Cardiorespiratory fitness. Cardiorespiratory fitness was evaluated with a maximal incremental (20 W/min) bicycle ergometer exercise test until subjective and objective (increased V̇o2 of <150 ml/min despite an increase in work load) maximum. In some cases, the maximum could not be reached because of the symptoms of the subjects (e.g., pain, breathlessness, dizziness) or ventricular extrasystolias (over 10 per min). The ECG (Case 12, Marquette Electronics; Milwaukee, WI) was continuously monitored during the test. Lung ventilation (VE), V̇o2, and carbon dioxide (CO2) production were measured using mixing chamber respiratory gas analyses with a sampling interval of 20 s. A gas analyzer was connected online to a computer and calibrated before and after each test. Maximal V̇o2 was determined as the highest V̇o2 of all measured 20-s intervals at the end of the exercise load (28). The criteria for ventilatory aerobic threshold (VT) were as follows: the first nonlinear increase of ventilation and the lowest value of ventilation equivalent for oxygen before starting to increase. The criteria for respiratory compensation threshold, i.e., anaerobic threshold (AnT) were as follows: the time point when the respiratory exchange ratio (V̇co2/V̇o2) was ∼1.00 with a simultaneous, second nonlinear increase in ventilation.
HRV and BPV at supine rest. The men entered the laboratory room at 8–12 AM after at least 2 h of fasting. Breakfast was instructed to be light. The men had not consumed coffee, cola beverages, tea, or chocolate for 12 h. Smoking was forbidden for 12 h and alcoholic beverages for 48 h before the measurements. The men were instructed to sleep enough during the previous night and to avoid exercise and strenuous physical loads for 24 h before the measurements. The patients had taken their normal medication. The room was silent with dimmed lights, and the room temperature was 20–22° C. After a 10-min supine rest, theECG (Rigel MultiCare 302, Rigel Research; Surrey, UK) and continuous arterial blood pressure from the middle finger (Ohmeda; Englewood, CO) were registered for 5 min at supine rest. They were simultaneously analog to digital converted (200 Hz, 12 bits) and saved on the hard disk of an IBM personal computer/AT-compatible microcomputer for subsequent off-line analysis. During the registration, the finger with the cuff was kept at heart level. A software package (CAFTS, Medikro; Kuopio, Finland) was used for evaluating HRV and BPV in time and frequency domains. RRI, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), LFP (0.04–0.15 Hz), and high-frequency power (HFP; 0.15–0.40 Hz) of RRI, SAP, and DAP variabilities were calculated.
QRS detection was completed with numerical derivation of the ECG signal, followed by thresholding. In the last phase of the QRS detection, the temporal resolution of the R peaks and RRIs was increased with a second-order polynomial fit interpolation of each R wave. Spectral analysis of HRV was performed using a modified covariance autoregressive model with a fixed model order of 14. The regions of interest were selected by excluding ectopic beats and by visual judgement of stationarity.
Statistics. Skewed distributions of HRV variables were normalized by natural logarithmic transformation (ln). The data was analyzed by two-way ANOVA for repeated measurements with smoking habit (no = 1, yes = 2) and health status (healthy = 1, patients = 2) as covariates. Student's t-tests for nonpaired and paired samples were used as post hoc tests. SPSS for Windows release 10.0.7 (SPSS; Chicago, IL) was used in statistical analyses. The results are expressed as means ± SE (95% confidence intervals for mean) if not otherwise noted. A P value of 0.05 was used as a critical level of significance.
In addition to the reported analyses, we divided the EX group to three equal subgroups according to their change in maximal oxygen uptake at the 5-yr time point compared with the baseline and analyzed the HRV and BPV changes in these three subgroups. No significant changes were found in any of the subgroups. This has not been reported widely because it did not bring anything new to the result.
Compliance. Calculated from the exercise training logbooks, the mean exercise energy expenditure for the EX group was 3.80 MJ/wk for the 5 yr. The compliance for the mean exercise energy expenditure was 71%, but it was just 39% for the planned energy expenditure of 6.28 MJ/wk. In the 7-day physical activity recalls, mean weekly energy expenditure for moderate intensity exercise (equal and over 6 metabolic equivalents) increased from baseline to intervention from 4.0 ± 6.3 to 8.3 ± 5.9 (means ± SD) MJ/wk in the EX group, but it also increased in the CO group from 4.5 ± 8.5 to 7.5 ± 8.1 MJ/wk. On the other hand, for light activities (equal and over 4 metabolic equivalents), energy expenditure decreased in both groups from 12.5 ± 9.9 to 7.7 ± 3.6 MJ/wk in the EX group and from 10.2 ± 10.6 to 7.7 ± 5.0 MJ/wk in the CO group.
Anthropometry. There were no significant changes in BMI (EX: from 26.8 ± 0.3 to 26.9 ± 0.4 kg/m2; CO: from 26.9 ± 0.5 to 27.4 ± 0.5 kg/m2) or waist/hip circumference (EX: stayed at the level of 0.98 ± 0.01; CO: stayed at the level of 0.97 ± 0.01) from the baseline to the 5-year time point.
Cardiorespiratory fitness. V̇o2, VE, and HR at VT were significantly higher at the 5-year time point in the EX group than in the CO group. They had a tendency to increase in the EX group and decrease in the CO group to the 5-year time point (significant interaction). V̇o2 at AnT increased at the 1-yr time point in the EX group but decreased to the baseline level at the 5-year time point. In the CO group, V̇o2 at AnT also decreased from the 1- to 5-yr time point (significant interaction). Maximal aerobic capacity did not change (Table 2).
HRV and BPV. HRV behavior was similar in the EX and CO groups. The only significant change in HRV was the decrease in RRI LFP in the EX group from the 1- to 5-yr time point. BPV did not show significant changes (Table 3).
Our 5-yr exercise training intervention did not show any significant positive effect on HRV and BPV. On the contrary, LFP RRI even decreased in the EX group. Aging has been shown to reduce HRV by about as much in 5 yr as the men demonstrated here (2). According to our study, it would seem that regular low-intensity physical activity has no or a very weak long-term effect on HRV and BPV, which may be covered under the effect of aging. Short-term training interventions by Loimaala et al. (23), Perini et al. (25), and Stein et al. (34) support the finding of the ineffectiveness of aerobic training on resting cardiac autonomic modulation in older people. The finding of Iwasaki et al. (14) supports our hypothesis of an acute positive effect of exercise training on HRV showing its increase at 3- and 6-mo time points of regular training with even decrease at the 9- and 12-mo time points. Our first time point to measure HRV changes was 1 yr, and according to Iwasaki et al. (14) at that time point the best effect of the training program would have been over. In addition, the following points should be taken into consideration when interpreting the present results. First, even if the present level of physical activity (low intensity, low quantity) did not influence cardiac and vascular autonomic modulation at rest in short-term recordings in older people, that does not rule out its effectiveness to change cardiac autonomic modulation during some activities or interventions or the reactivity of the autonomic nervous system. Second, the compliance of the present training program has possibly been too low to get any increase in HRV. Finally, confounding factors, e.g., medication, diseases, and smoking, could have a strong effect on HRV and BPV, which could cover the effect of physical activity. In addition, members of the present population-based sample were nonhomogeneous in their former activity levels. This, together with the fact that the effect of physical activity is heterogeneous and much genetically determined, may slightly influence the results.
Previous cross-sectional HRV studies have found [11, 39 (during exercise)] or have not found [8 (supine, sitting, standing), 39 (supine rest)] a significant effect of physical activity on HRV. However, the studies are not fully comparable with each other because of the different methods and HRV variables used. Goldsmith et al. (11) measured 24-h recordings, whereas the others measured short recordings of some minutes. The value of HRV in predictive use has been recognized particularly with 24-h Holter recordings (36). In addition, some previous randomized longitudinal exercise training studies have used 24-h HRV (23, 31, 35, 38). To our knowledge, only two previous randomized exercise training interventions using short-term HRV recordings at rest have been reported (7, 40). Of the previous randomized longitudinal studies (7, 23, 31, 35, 38, 40) a positive effect of aerobic training on daytime HRV has been found in three studies (31, 35, 38), all using 24-h recordings. In the other randomized studies, significant effects have not been found, even with a significant increase in maximal aerobic capacity. In addition, none of the randomized longitudinal studies found a significant effect on nighttime HRV. Of the other but nonrandomized studies using short-term recordings of HRV, some have found a positive effect of exercise training on HRV (14, 21) and some have not (25).
Considering the previous studies and the result of the present study, any specific explaining factor for the different results is difficult to find. However, there seems to be a trend toward more positive findings in 24-h recordings (11, 31, 35, 38) and recordings done during or after some intervention or activity (31, 35, 39; during exercise, 38) than in short-term recordings (14, 21, 40) and during supine rest (14, 40). The explanation of better response on daytime HRV to exercise training might be the better and faster recovery of HRV (13) after physical activity and, on the other hand, smaller decrease of HRV during physical activity (21) in exercise-trained subjects compared with sedentary subjects. These changes cannot be seen during resting recordings, which can make them less sensitive to training-induced changes. On the other hand, 24-h recordings are difficult to control. However, both reproducibility of the short-term 10-min HRV recordings and 24-h recordings analyzed in the frequency domain seem to be satisfactory for repeated measurements (19, 43).
Changes in BPV were not found in the present study. Previous studies of BPV and exercise training are scarce. Radaelli et al. (27) found an increase in sympathetic modulation of pheripheral vessels (increase in both LFP SAP and DAP) with aerobic training in chronic heart failure patients but not in healthy controls. Similarly, moderate exercise training increased LFP SAP in sedentary healthy subjects, but more intensive training seemed to decrease LFP SAP to the baseline level (14). Concordant to this, heavy training in healthy athletes did not change BPV (41). Long-term randomized training studies of BPV are missing. In our previous 1-yr low-intensity training study in older men, we did not find any changes in BPV (40). Therefore, it has been hypothesized that BPV changes with exercise training could rather result in vascular remodeling through adaptation of endothelium and smooth muscle (14) than changes in vascular vasomotor activity.
When evaluating the effect of training on HRV and BPV in the present study, we must look at the effect on aerobic capacity, which could be an indirect indicator of compliance as well. In that context, the response to the present training program was slight. However, there was still a significant differing effect on VT. We want to emphasize the value of this finding. In the older age group, the main long-term effect (such as a 5-yr period in the present study) of regular physical activity might be not to increase maximal and submaximal aerobic capacity but to prevent its decrease. The present training program, even with low intensity and quantity, had that kind of effect, which was best seen at VT. Furthermore, even if V̇o2 at the maximal level has usually been used as the “golden standard” of increased aerobic capacity, low-intensity aerobic training may not have increased maximal aerobic capacity, but it may have affected the submaximal capacity in the older age group (8b). Recently, Gitt et al. (10) reported a low anaerobic threshold (corresponding with VT here) to predict early death in chronic heart failure patients even better than maximal V̇o2. Naturally, our results are not fully comparable with the Gitt et al. (10) results because one-half of our subjects were healthy. However, valid measurements of maximal aerobic capacity in healthy old people, but especially chronically ill people, can sometimes be difficult because of loss of motivation, musculoskeletal limitations, peripheral arterial disease, or indications to stop the exercise by the physician (e.g., ventricular ectopies), leading to premature cessation of the test.
Compliance of the present study was moderate, which could have been predicted by to the previous studies. The longer the intervention, the worse the adherence and compliance has been shown to be (42). As an example, in the home-based exercise training study in sedentary subjects of Preisinger et al. (26), compliance for the exercise training program at the 3.0 ± 1.3 yr follow-up was just 48%. In the longer trial, it has been shown to be even lower (15).
The present study has some limitations. The breathing frequency was not measured. However, we know that breathing frequency affects frequency-domain components. The usual breathing frequency of adults can be assumed to be ∼12–15 breaths/min, which is in the high frequency field of RRI variability, and, therefore, the modulating effect of respiration can be seen as a peak in the high-frequency field of power spectral analysis. The limit between high- and low-frequency fields of RRI variability in the power spectral analysis has been set (36) so that only a breathing frequency of <9 breaths/min gives a respiratory peak to the low-frequency field. Therefore, it is unlikely that the present training program could have decreased the breathing frequency enough to bias the results, even if exercise training is believed to decrease breathing frequency.
The subjects of the previous randomized studies have been sedentary healthy men (7, 23), both healthy men and women (33), or patients recovering from an acute coronary event (35). The population of the present study included both healthy men and patients because the goal of the study was to observe the effect of exercise training on a general population sample of older Finnish men. The patients used medication, especially β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and Ca2+ antagonists (Table 1), of which β-blockers increase HRV (3, 4), but there is no real evidence of the effect of ACE inhibitors and Ca2+ antagonists on HRV (22). At the individual level, there were no obvious systematic effects of any of the medications. There were also some smokers in both groups. However, the smokers did not change their habit during the 5 yr. Therefore, the effect of smoking on the results was obviously minimal. Furthermore, smoking was forbidden for 12 h before the test.
In conclusion, the present randomized study, which is unique in its length, did not show significant changes in cardiac and vascular autonomic regulation with regular exercise training. Just moderate compliance for the present 5-yr exercise training trial makes evaluation of the effect of training more challenging.
We thank Helena Antikainen for the help with HRV and BPV measurements and Tuula Tiihonen for the help with spiroergometric and anthropometric measurements.
This study was supported by grants from the Finnish Ministry of Education and the Medical Research Fund of Kuopio University Hospital.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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