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We compared the effects of exercise training on neurovascular control and functional capacity in men and women with chronic heart failure (HF).
Forty consecutive HF outpatients from the Heart Institute, University of Sao Paulo, Brazil were divided into the following four groups matched by age: men exercise-trained (n = 12), men untrained (n = 10), women exercise-trained (n = 9), women untrained (n = 9). Maximal exercise capacity was determined from a maximal progressive exercise test on a cycle ergometer. Forearm blood flow was measured by venous occlusion plethysmography. Muscle sympathetic nerve activity (MSNA) was recorded directly using the technique of microneurography. There were no differences between groups in any baseline parameters. Exercise training produced a similar reduction in resting MSNA (P = 0.000002) and forearm vascular resistance (P = 0.0003), in men and women with HF. Peak VO2 was similarly increased in men and women with HF (P = 0.0003) and VE/VCO2 slope was significantly decreased in men and women with HF (P = 0.0007). There were no significant changes in left-ventricular ejection fraction in men and women with HF.
The benefits of exercise training on neurovascular control and functional capacity in patients with HF are independent of gender.
Heart failure (HF) is a major health problem worldwide. The incidence and prevalence of HF is increasing and this trend will likely increase as the population ages. Statistics show that the overall prevalence of HF is essentially equal between men and women.1 Pharmacologic therapy has been shown to be effective in modifying the natural history of the disease and reducing mortality in HF patients.2 However, despite advances in treatment, chronic HF remains highly lethal. A cohort study conducted between 1996 and 2000 showed that the mortality rate was 50% in men and 46% in women, at 5 years following the diagnosis of HF.3 Moreover, the median survival among patients with reduced left-ventricular systolic function is 3.9 years.4
Dyspnoea and exercise intolerance are the hallmarks of HF, appearing in the earliest stages of HF and progressing with the severity of cardiac dysfunction.5 However, the mechanisms underlying exercise intolerance in HF are complex; exercise intolerance can be attributed to (i) cardiac dysfunction, (ii) sympathetic hyperactivity, (iii) endothelial dysfunction, (iv) decreased peripheral blood flow, and (v) skeletal muscle abnormalities.6 Several studies have shown that exercise training is an effective, non-pharmacological strategy for the treatment of HF patients. Exercise training has been shown to improve cardiac output,7 peripheral blood flow,8,9 and skeletal muscle abnormalities,10,11 leading to an improvement in functional capacity12 and quality of life in patients suffering from HF.13 However, most of these studies were conducted largely in men with HF. Although healthy women tend to respond to exercise training in the same way as men, it remains unknown if exercise training is similarly beneficial in men and women with HF. In one of the few studies conducted in men and women with HF, exercise training caused a similar increase in skeletal muscle strength and oxidative capacity and a similar reduction in blood lactate and plasma norepinephrine in both genders.13 However, some methodological limitations in the study rendered the interpretation of the actual effects of exercise training in men and women with HF uncertain.
In the present study, we investigated whether the benefits of exercise training on sympathetic nerve activity, vascular resistance, and functional capacity were similar in men and women with chronic HF.
Patients with clinically stable HF, aged between 40 to 70 years, in New York Heart Association functional class II to III and with an ejection fraction ≤40% were eligible to participate in the study. Patients with unstable angina, recent myocardial infarction (less than 3 months), severe chronic obstructive pulmonary disease, uncontrolled systemic arterial hypertension, and/or neurological or orthopaedic disabilities were excluded.
Forty consecutive outpatients from the Heart Institute, Clinical Hospital, Medical School, University of Sao Paulo, Brazil were divided into the following four groups matched by age: men exercise-trained (n = 12), men untrained (n = 10), women exercise-trained (n = 9), women untrained (n = 9). The study was conducted in accordance with the Declaration of Helsinki. All subjects gave written informed consent for this study, which was approved by the Human Subject Protection Committee of the Heart Institute (InCor) and the Ethics Committee of Clinical Hospital, University of São Paulo Medical School.
The training programme was based on several published protocols that have demonstrated a conditioning effect.14 Subjects underwent exercise training under supervision at the Heart Institute. The 4 month training programme consisted of three 60 min exercise sessions/week. Each exercise session consisted of 5 min stretching exercises, 25 min of cycling on an ergometer bicycle in the first month and up to 40 min in the last 3 months, 10 min of local strengthening exercises, 5 min of cool down with stretching exercises. The exercise intensity was established by heart rate levels that corresponded to anaerobic threshold up to 10% below the respiratory compensation point obtained in the cardiopulmonary exercise test. When a training effect was observed, as indicated by the patients using a Borg Perceived Exertion Scale or heart rate reduction of 8–10%, the bicycle work rate was increased by 0.25 or 0.5 kpm to return to the target heart rate levels. Aerobic exercise training duration increased progressively so that all patients could perform 40 min of bicycle exercise at the established intensity. The control patients were instructed to avoid any regular exercise programme or any non-supervised exercise programme during the study.
Forearm blood flow (FBF) was measured by venous occlusion plethysmography. The non-dominant arm was elevated above heart level to ensure adequate venous drainage. A mercury-filled silastic tube attached to a low-pressure transducer was placed around the forearm and connected to a plethysmography device (Hokanson, Bellevue, WA). Sphygmomanometer cuffs were placed around the wrist and upper arm. At 15 s intervals, the upper cuff was inflated above venous pressure for 7–8 s. Forearm vascular resistance (FVR) was calculated by dividing mean arterial blood pressure by FBF. The reproducibility of FBF measured at different time intervals in the same individual expressed as mL/min/100 ml in our laboratory is r = 0.93.
Muscle sympathetic nerve activity (MSNA) was recorded directly from the peroneal nerve using the technique of microneurography.15,16 Multiunit post-ganglionic muscle sympathetic nerve recordings were made using a tungsten microelectrode. Signals were amplified by a factor of 50 000 to 100 000 and band-pass filtered (700–2000 Hz). Nerve activity was rectified and integrated (time constant 0.1 s) to obtain a mean voltage display of sympathetic nerve activity that was recorded on paper. All recordings of MSNA met previously established and described criteria. Muscle sympathetic bursts were identified by visual inspection, and were expressed as burst frequency (bursts/min), and burst incidence (bursts/100 heart beats). The reproducibility of MSNA measured at different time intervals in the same individual expressed as bursts/min is r = 0.88, and expressed as bursts/100 heart beats is r = 0.91.17
Maximal exercise capacity was determined by means of a maximal progressive exercise test on an electromagnetically braked cycle ergometer (Medifit 400 L, Medical Fitness Equipment, Maarn, The Netherlands), using a ramp protocol with work rate increments of 5–10 W every minute until exhaustion. Oxygen uptake (VO2) and carbon dioxide production were determined by means of gas exchange on a breath-by-breath basis in a computerized system (SensorMedics, Model Vmax 229, Buena Vista, CA, USA). Peak VO2 was defined as the maximum attained VO2 at the end of the exercise period in which the subject could no longer maintain the cycle ergometer velocity at 60 r.p.m. This method is considered the gold standard for assessing a patients exercise capacity.18 Anaerobic threshold was determined to occur at the breakpoint between the increase in the carbon dioxide output and VO2 (V-slope)19 or the point at which the ventilatory equivalent for oxygen and end-tidal oxygen partial pressure curves reached their respective minimum values and began to rise.20 Respiratory compensation was determined to occur at the point at which the ventilatory equivalent for carbon dioxide was lowest before a systematic increase and when end-tidal carbon dioxide partial pressure reaches a maximum and begins to decrease.21 The reproducibility of the peak VO2 measured at a different time interval in the same individual expressed as mL/kg/min in our laboratory is r = 0.95. The VE/VCO2 slope was measured by linear regression, with the nonlinear part of the data after the onset of ventilatory compensation for metabolic acidosis excluded.22
Blood pressure was monitored non-invasively and intermittently using automatic and oscillometric cuffs (Dixtal, DX 2710, Brazil, Manaus). The cuff inflated every minute. Heart rate was monitored continuously through lead II of the electrocardiogram. Ejection fraction was determined by two-dimensional echocardiography.
The experimental protocol was performed between 8:00 and 9:00 AM at a constant room temperature of 21°C. The subject was positioned and electrocardiogram leads were placed on the chest. Then the leg was positioned for microneurography and an adequate nerve recording site was obtained. Cuffs for FBF measurements were placed on the non-dominant arm. Finally, the cuff for blood pressure measurement was placed on the left leg. The subjects then rested for 15 min. Muscle sympathetic nerve activity, FBF, arterial pressure, and heart rate were recorded for 5 min. This experimental protocol was performed before and after 4 months of exercise training or clinical follow-up in the untrained group.
The cardiopulmonary exercise testing was performed 3–5 days before the experimental protocol and was repeated after 4 months of exercise training or clinical follow-up in the untrained group.
The data are presented as mean ± SEM. Baseline differences between groups were evaluated by one-way analysis of variance. Paired Student's t-test was used to evaluate the effects of exercise training or clinical follow-up within each group. Two-way analysis of variance was used to determine if the changes caused by exercise training or clinical follow-up (untrained groups) (delta change) were different between the groups (exercise training effect, gender effect, and interaction). In the case of significance, Scheffé's post hoc comparison was used to determine differences between groups. Pearson's correlation coefficient was used to investigate if changes in neurovascular function after exercise training correlated with changes in functional capacity and respiratory pattern. A P-value of ≤0.05 was considered statistically significant.
Baseline characteristics of patients are displayed in Table 1. There were no differences between groups in any of the variables measured.
Compliance with exercise training was very good, with 85–100% of the sessions attended for both women and men with HF. The effects of 4 months of exercise training or clinical follow-up (untrained) are shown in Table 2. The comparison within each group by means of Student's t-test showed that exercise training or clinical follow-up caused no changes in resting ejection fraction, heart rate, or mean blood pressure in men and women with HF. In contrast, exercise training significantly reduced muscle sympathetic burst frequency in men (Figure 1A) and women (Figure 1A). Similarly, exercise training significantly reduced muscle sympathetic burst incidence in men (Figure 1B) and women (Figure 1B). No significant changes in muscle sympathetic burst frequency and muscle sympathetic burst incidence were found in untrained men and women. Further analysis to compare the changes provoked by exercise training or clinical follow-up in MSNA by means of two-way analysis of variance showed that exercise training significantly and similarly reduced muscle sympathetic nerve frequency (exercise training effect, P = 0.000002; gender effect, P = 0.41) and incidence (exercise training effect, P = 0.000005; gender effect, P = 0.46) in men and women. In terms of muscle blood flow, the comparisons within each group showed that exercise training significantly increased FBF in men (Figure 2A) and women (Figure 2A) and significantly reduced FVR in men (Figure 2B) and women (Figure 2B). No significant changes in FBF and FVR were found in untrained men and women. The comparisons between groups showed that the changes provoked by exercise training on muscle blood flow were similar in men and women. Exercise training significantly and similarly increased FBF in men and women (exercise training effect, P = 0.001; gender effect, P = 0.52) and significantly and similarly reduced FVR (exercise training effect, P = 0.0003; gender effect, P = 0.13) in men and women. Exercise training significantly increased peak VO2 in men (Figure 3) and women (Figure 3). No significant changes in peak VO2 were found in untrained men and women. The comparisons between groups showed that exercise training significantly and similarly increased peak VO2 in men and women (exercise training effect, P = 0.0003; gender effect, P = 0.32). Exercise training significantly decreased VE/VCO2 slope in men (P = 0.01) and women (P = 0.04). No significant changes in VE/VCO2 slope were found in untrained men and women. The comparisons between groups showed that exercise training significantly and similarly decreased VE/VCO2 slope in men and women (exercise training effect, P = 0.0007; gender effect, P = 0.66). Exercise training significantly decreased New York Heart Association functional class in men (P = 0.002) and women (P = 0.0007). No significant changes were observed in untrained men and women. The comparisons between groups showed that the decrease in New York Heart Association functional class was similar in men and women (exercise training effect, P = 0.000001; gender effect, P = 0.95).
Further analysis showed significant correlation between changes in MSNA and changes in peak VO2 in exercised-trained women (P = 0.03; r = −0.71), but not in exercised-trained men (P = 0.85; r = −0.06). No significant correlation was found between changes in FBF and changes in peak VO2. In addition, we found no significant correlation between changes in MSNA and FBF and changes in VE/VO2 in men and women.
Previous studies have shown that exercise training significantly reduces MSNA and muscle vascular resistance in patients with chronic HF.9,14,23 The present study extends the knowledge that the reduction in MSNA and muscle vasoconstriction caused by exercise training occurs in both men and women with chronic HF. In addition, our study demonstrates that the improvement in functional capacity, expressed by peak VO2, is similar in exercise-trained men and exercise-trained women with chronic HF. Exercise intolerance in HF patients has been attributed to skeletal myopathy. In addition, several lines of evidence suggest that exaggerated sympathetic nerve activity plays a role in skeletal myopathy in patients with chronic HF.24 Muscle ischaemia provoked by increased sympathetic nerve activity causes oxidative stress and inflammation. Oxidative stress activates nuclear factor-kappaB, which is a necessary transcription factor for cytokine gene expression.25 Tumour necrosis factor-alpha and interleukin-6 have been associated with increased skeletal muscle catabolism and apoptosis.26–28 Thus, interventions that reduce sympathetic nerve activity represent potential strategies in the treatment of the exercise dysfunction related to the skeletal myopathy of HF. The present study provides convincing evidence that exercise training significantly reduces MSNA and muscle vasoconstriction in men and women with chronic HF. Moreover, it suggests an association between the improvement in neurovascular control and functional capacity in these patients. In fact we found significant correlation between MSNA and peak VO2, although this finding was only statistically significant in exercise-trained women.
The effects of exercise training on functional capacity in men and women with HF have been a matter of previous investigations. Tyni-Lenné et al.13 found that exercise training increased peak VO2 in men and women with HF. More recently, Keteyian et al.29 observed a 20% increase in peak VO2 in men with HF and a 2% increase in women with HF, suggesting that the trainability of women with HF is much more modest than in men with HF. However, these studies did not include an untrained control groups for either men or women. In addition, the number of women in one of the studies was small. The present study shows that 4 months of exercise training significantly increased peak VO2 in both men and women with chronic HF, and that this increase was similar between the genders. During the same period no changes in peak VO2 were observed in either of the control groups. Thus, we believe that our study provides convincing evidence that exercise training improves functional capacity in men and women with chronic HF.
The present study was not designed to investigate the mechanisms involved in the reduction of MSNA caused by exercise training in patients with HF. However, previous findings in animal models link the improvement in arterial baroreflex and chemoreflex control and cardiopulmonary control with the reduction in sympathetic nerve activity in HF.30 Moreover, the reduction in the expression of the angiotensin II type I receptors in the paraventricular nucleus of the hypothalamus and in the rostral ventrolateral medulla and nucleus tractus solitarius31 in exercise-trained HF animals suggests that central nervous system alteration counteracts the sympathetic overactivity in HF.
In healthy subjects, aerobic capacity is known to be 15–30% lower in women than men.32–34 This gender-based difference is well established and is thought to be attributable to smaller heart size, lower haemoglobin levels, and smaller muscle mass in women.33,34 In a larger sample, other investigators found lower aerobic capacity in women with HF when compared with men with HF, despite the lower risk of death for any given VO2 value in women.35,36 The present findings show that peak VO2 is not different between men and women with HF, which is consistent with the similarity of increased MSNA and vasoconstriction between genders. The mechanisms involved in the improvement in peak VO2 in men and women with HF are beyond the scope of the present study. However, our findings are suggestive of an improvement in skeletal muscle, since several lines of evidence point to the fact that exercise intolerance in HF is due to skeletal myopathy.24 Although previous study has shown that women are more dependent on peripheral adaptations (maximal arterio-venous O2 difference) than men,37 it seems unlikely that this is the case in our study for the following reasons. First, left-ventricular ejection fraction before and after training was not different between women and men with HF. Secondly, we were dealing HF patients, whereas other investigators studied elderly individuals in good health.
VE/VCO2 slope contains prognostic information in HF patients.38 In the present study, we found that exercise training significantly reduced VE/VCO2 slope regardless of gender. Thus, this finding has clinical implications in the treatment of women and men with HF.
The present study extends the knowledge that moderate intensity exercise training does not change resting left-ventricular ejection fraction in patients with chronic HF. However, it does not answer the question of whether more intense exercise or interval training has a differential effect on left-ventricular ejection fraction in men and women with HF. This is an interesting topic for future investigations.
We recognize limitations in our study. We did not control menopausal status or hormone replacement therapy in our study. However, there were only a few women under the age of 50 years, the average age of menopause, included in our study. The majority of women were post-menopausal. In addition, in a previous study we found that oestrogen therapy did not change the cardiopulmonary responses during submaximal and maximal exercise in post-menopausal women.39 Thus it is unlikely that menopausal status or hormone replacement therapy is a confounding variable in our study. Another concern could be that the distribution of HF aetiologies was different between genders. We have recently reported that the levels of MSNA and FBF in patients with HF were independent of HF aetiology,40 thus it is unlikely that differing HF aetiology distribution influenced our interpretation in the present study. Our exercise paradigm included mostly leg exercise. Thus the effects of exercise training on muscle blood flow could be even greater if we had measured calf blood flow. The 4 month training programme consisted of three 60 min exercise-training sessions in a week, which may be less than the exercise requirement specified in the 2007 AHA/ACC guidelines.41 It is possible that a more prolonged exercise-training programme would have induced greater improvements in neurovascular control and functional capacity in men and women with HF. In addition, it is possible that the number of patients included in our study was too small to draw the conclusion that the effects of exercise training on neurovascular control and functional capacity in women and men with HF are similar. Although we cannot rule out this possibility, the uniformity of the individual data regarding MSNA and peak VO2 considerably strengthens the present findings.
The present findings have some potential clinical implications for the treatment of humans with HF. The benefits induced by exercise training on autonomic control, vasoconstriction, and functional capacity in both genders suggest that men as well as women with chronic HF should be referred to a cardiac rehabilitation programme. In addition, since MSNA and FBF are independent predictors of mortality in patients with chronic HF,42 the reduction in MSNA and the increase in FBF in exercise-trained men and women with chronic HF are suggestive of an improvement in prognosis in patients with HF regardless of gender.
In conclusion, the benefits of exercise training on the reduction in sympathetic nerve activity and vasoconstriction, and the increase in functional capacity in advanced HF are independent of gender.
This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2005/59740-7) and, in part, by Fundação Zerbini. C.E.N., M.U.P.B.R., P.C.B., L.M.A.-C., T.S.N. were supported by Conselho Nacional de Pesquisa (CNPq #302146/2007-5, #303518/2008-1, #301519/2008-0, #142366/2009-9, #142367/2009-5, respectively). H.R.M. is supported by NIH RO1-HL084525.
Conflict of interest: none declared.