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European Journal of Heart Failure 2007 9(6-7):630-636; doi:10.1016/j.ejheart.2007.03.003
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© 2007 European Society of Cardiology

Exercise training reduces sympathetic nerve activity in heart failure patients treated with carvedilol

Raffael Fragaa, Fábio G. Francoa, Fabiana Roveda, Luciana N.J. de Matosa, Ana M.F.W. Bragaa, Maria U.P.B. Rondona, Daniel R. Rottaa, Patricia C. Brumb, Antonio C.P. Barrettoa, Holly R. Middlekauffc and Carlos E. Negrãoa,b,*

a Heart Institute (InCor), University of São Paulo, Medical School, São Paulo, Brazil
b School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
c University of California, Los Angeles, Medical School, Department of Cardiology, USA

* Corresponding author. Instituto do Coração - (InCor), Unidade de Reabilitação Cardiovascular e Fisiologia do Exercício, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo, SP, CEP 05403-000, Brazil. Tel: +55 11 3069 5699; fax: +55 11 3069 5043. E-mail address: cndnegrao{at}incor.usp.br


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Evidence suggests that carvedilol decreases muscle sympathetic nerve activity (MSNA) in patients with heart failure (HF) but carvedilol fails to improve forearm vascular resistance and overall functional capacity. Exercise training in HF reduces MSNA and improves forearm vascular resistance and functional capacity.

Aims: To investigate whether the beneficial effects exercise training on MSNA are maintained in the presence of carvedilol.

Methods and results: Twenty seven HF patients, NYHA Class II–III, EF <35%, peak VO2 <20 ml/kg/min, treated with carvedilol were randomly divided into two groups: exercise training (n=15) and untrained (n=12). MSNA was recorded by microneurography. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. The four-month training program consisted of three 60-min exercise/week on a cycloergometer. Baseline parameters were similar between groups. Exercise training reduced MSNA (–14±3.3 bursts/100 HB, p=0.001) and increased forearm blood flow (0.6±0.1 mL/min/100 g.p p>0.001) in HF patients on carvedilol. In addition, exercise training improved peak VO2 in HF patients (20±6%, p=0.002). MSNA, FBF and peak VO2 were unchanged in untrained HF patients on carvedilol.

Conclusion: Exercise training reduces MSNA in heart failure patients treated with carvedilol. In addition, the beneficial effects of exercise training on muscle blood flow and functional capacity are still realized in patients on carvedilol.

Key Words: Heart failure • Exercise • Autonomic control • Carvedilol

Received October 24, 2006; Revised February 1, 2007; Accepted March 7, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Although treatment with the beta-blocker carvedilol improves patient outcome and reduces mortality in heart failure [1-3], the mechanisms of this benefit are not fully understood. Carvedilol has (competitive) alpha and beta blocking effects, and anti-oxidant effects, but fails to improve muscle blood flow and functional capacity. In a randomized controlled trial, 6 months of carvedilol therapy did not change forearm vascular resistance compared with placebo [4]. In some [4], but not all [5] studies, carvedilol decreases muscle sympathetic nerve activity (MSNA).

Studies conducted in the last 15 years have repeatedly demonstrated that exercise training is safe and beneficial to patients with heart failure [6-8]. Exercise training improves functional capacity and quality of life in humans with heart failure [7,8]. Additionally, we found that, in a randomized controlled trial, 4 months of exercise training compared with a sedentary life style, dramatically reduced MSNA in patients with HF [9]. Likewise other investigators have found that exercise training reduces whole body norepinephrine levels and improves heart rate variability in heart failure patients [6,10,11]. However, all these previous studies were carried out at a time when β-blockers were not standard therapy for heart failure patients [6,9,11]. In the era of β-blocker therapy for heart failure, we have no information regarding the effects of exercise training on sympathetic nerve activity in patients treated with carvedilol. One of the few studies available showed that exercise training increased limb peak hyperemic blood flow and functional capacity in heart failure patients under carvedilol treatment [12]. This amelioration in muscle blood flow may be caused by a reduction in sympathetic nerve activity.

In the present study, we describe the effects of exercise training on MSNA, muscle vascular resistance and functional capacity in chronic heart failure patients under carvedilol therapy. Our hypothesis was that exercise training would reduce MSNA in chronic heart failure patients who were already receiving carvedilol treatment. In addition, exercise training would improve muscle vascular resistance and functional capacity in these patients.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
All subjects gave written informed consent for this study, which was approved by the Human Subject Protection Committee of the Heart Institute (InCor) and Clinical Hospital, University of São Paulo Medical School. Twenty seven chronic heart failure patients, age range 35-75 years, New York Heart Association Functional Class II-III, ejection fraction <35%, peak VO2 <20 ml/kg/min, β-blocker therapy with carvedilol, and stable medical therapy were randomly divided into an untrained group (n=12) and exercise-trained group (n=15). All subjects underwent heart rate and blood pressure measurements, echocardiography, cardiopulmonary exercise test, and neurovascular study (microneurography and venous occlusion plethysmography) before and after the exercise training program or untrained period, within 4 months of enrolment in the study. The physical activity in the untrained group was closely controlled every week by interview to make sure that the untrained status was unchanged throughout the study.

2.2. Measurements and procedures
2.2.1. Exercise training program
Subjects underwent 4 months of exercise training, which consisted of three 60-min exercise sessions/week under supervision at the Heart Institute. 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 (sit-ups, push-ups, and pull-ups), and 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, the bicycle workload was slightly increased. Heart rate reduction was rarely used to adjust the bicycle workload, since the patients were under β-blocker treatment. Aerobic exercise training duration increased progressively, so that, all patients could perform 40 min of bicycle exercise at the established intensity.

2.2.2. Muscle sympathetic nerve activity
MSNA was recorded directly from the peroneal nerve using the technique of microneurography [13,14]. 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 bandpassed filtered (700 to 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 [9]. Muscle sympathetic bursts were identified by visual inspection by a single investigator (C.E.N.) blinded to the study protocol, and were expressed as burst frequency (bursts per min), and bursts per 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 [15].

2.2.3. Forearm blood flow
Forearm blood flow 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 plethysmograph device (Hokanson, Bellevue, Washington). Sphygmomanometer cuffs were placed around the wrist and upper arm. At 15-s intervals, the upper cuff was inflated above venous pressure for 7 to 8 s. Forearm blood flow (mL/min/100 mL) was determined on the basis of a minimum of four separate readings. Forearm vascular resistance was calculated by dividing mean arterial pressure by forearm blood flow. The reproducibility of forearm blood flow measured at different time intervals in the same individual expressed as mL/min/100 mL in our laboratory is r=0.93.

2.2.4. Cardiopulmonary exercise test
Maximal exercise capacity was determined by means of a maximal progressive exercise test on an electromagnetically braked cycle ergometer (Medifit 400L, Medical Fitness Equipment, Maarn, Netherlands), with work rate increments of 5 W and 10 W every 1 min at 60 rpm 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, Vmax 229 model, Buena Vista, California). 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 rpm. This method is considered the gold standard for assessing patients' exercise capacity [16]. Anaerobic threshold was determined to occur at the breakpoint between the increase in the carbon dioxide production and VO2 (V-slope) [17] 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 [18]. Respiratory compensation was determined to occur at the point at which 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 [19]. 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 non-linear part of the data after the onset of ventilatory compensation for metabolic acidosis excluded [20].

Heart rate (EKG) was continuously monitored during exercise test and for 6 min during the recovery period. Blood pressure (auscultatory method) levels were measured every minute during the exercise test and for 6 min during the recovery period.

2.2.5. Other measurements
Arterial pressure was monitored non-invasively. Heart rate was monitored continuously through lead II of the electrocardiogram. Echocardiographic techniques and calculations of different cardiac dimensions were performed in accordance with the recommendations of The American Society of Echocardiography Committee [21,22]. Left ventricular ejection fraction was evaluated by Simpson's biplane method [23].

2.3. Statistical analysis
The data are presented as mean±SEM. The initial differences and delta changes between groups were tested by unpaired Student T-test. Paired Student T-test was used to compare the changes within group (pre vs. post). A p value of ≤0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Baseline characteristics
Baseline characteristics are displayed in Table 1. Baseline parameters were all similar between exercise-trained heart failure patients treated with carvedilol and untrained heart failure patients treated with carvedilol. All patients were taking angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and carvedilol. In addition, some were taken digoxin, diuretics and spironolactone. The mean dose of carvedilol was 38±4 mg/day in the exercise training group and 34±6 mg/day in the untrained group (p=NS). The mean time that patients were on their maximal dose of carvedilol was 8±2 months in exercise-trained group and 7±2 months in untrained group (p=NS).


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  		Table 1 Baseline measurements

 
3.2. Effects of exercise training
Exercise training caused no significant change in resting heart rate, left ventricular ejection fraction, left ventricular end diastolic volume and blood pressure in heart failure patients treated with carvedilol (Table 2). However, exercise training significantly reduced MSNA burst frequency and burst incidence in heart failure patients treated with carvedilol (p=0.001 and p=0.001, Fig. 1A and B, respectively). In addition, exercise training significantly reduced forearm vascular resistance and significantly increased forearm blood flow in heart failure patients treated with carvedilol (both p<0.001). Exercise training caused a significant increase in peak VO2 in heart failure patients treated with carvedilol (p=0.001). VE/VCO2 slope decreased significantly after exercise training (Table 2, p<0.05). Exercise training significantly improved heart rate recovery as defined by the reduction in heart rate levels from the peak of exercise and the first minute of recovery (16±3 vs. 22±3 bpm, p=0.02). No significant changes in heart rate, mean blood pressure, left ventricular ejection fraction, MSNA burst frequency and burst incidence, peak VO2, heart rate recovery and VE/VCO2 slope were observed in untrained heart failure patients treated with carvedilol.


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  		Table 2 Parameters pre and post-exercise training or untraining period

 


Figure 01
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  		Fig. 1 MSNA burst frequency (panel A) and burst incidence (panel B) in chronic exercise-trained heart failure patients treated with carvedilol and chronic untrained patients treated with carvedilol. Note that exercise training significantly reduced MSNA burst frequency and burst incidence in chronic heart failure patients.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The novel finding of the present study is that exercise training reduces MSNA in heart failure patients treated with carvedilol. Carvedilol does not blunt the beneficial effects of exercise on MSNA, nor negate the improvements in muscle blood flow and functional capacity previously reported with carvedilol therapy. In addition, our findings suggest an association between the reduction in MSNA and the decrease in muscular vascular resistance after training in heart failure patients.

The reduction in MSNA in exercise-trained heart failure patients has clinical implications, because sympathetic activation is associated with poor prognosis in heart failure [24]. Moreover, a recent study has demonstrated that MSNA is an independent predictor of mortality in patients with heart failure [25]. Although our study is insufficient to conclude that exercise training improves prognosis in heart failure, it suggests that the improvement in patient outcome after exercise training is, at least in part, associated with a reduction in central sympathetic outflow. A more definite conclusion regarding the effects of exercise training on mortality rate in heart failure patients will be available soon in the HF-ACTION trial [26].

Although the precise mechanisms underlying the reduction in sympathetic nerve activity after exercise training in heart failure are not fully understood, previous studies in animal models provide some insights into the reduction in central sympathetic outflow in humans with heart failure. Liu et al. [27] described that an exercise training regimen restores arterial baroreflex control of heart rate and renal sympathetic nerve activity in pacing-induced heart failure rabbits. The same group of investigators reported that exercise training enhanced cardiopulmonary reflex sensitivity in rabbits with heart failure [28]. In addition, they reported that exercise training normalizes plasma and central angiotensin II, and central AT1 receptor messenger RNA [29]. Other investigators found that exercise training improved muscle ergoreflex control in heart failure patients [6]. Taken together, these findings suggest that increases in inhibitory influences on MSNA, and modulation of excitatory influence, are both likely involved in the reduction of central sympathetic outflow after exercise training in humans with heart failure [30].

Our study demonstrates that moderate exercise training significantly increases forearm blood flow in patients treated with carvedilol. Why is this finding so important? It is consistent with the notion that exercise training reduces peripheral vascular resistance, a primary target for many of the therapies in heart failure. At baseline, carvedilol, a third-generation β-blocker agent with relatively non-selective β1- versus β2-receptor properties [31,32] and vasodilator properties that blocks {alpha}1-adrenergic receptors [33,34], was not associated with reduced muscle vascular resistance in patients with heart failure [4]. Similarly, Vanhees et al. failed to show improvement in systemic and brachial artery vascular resistance after short-term administration of atenolol in healthy humans [35]. The effects of exercise training on muscle blood flow have also been reported by other investigators. Vanhees et al., did not report an increase in brachial artery blood flow after exercise training in healthy sedentary volunteers using a randomized cross-over study [36]. Thus, the effects of exercise training on muscular blood flow in heart failure patients differ from those obtained in healthy humans. In an elegant study, Demopoulos et al. [12] observed a significant improvement in calf blood flow, but not in forearm blood flow, after bicycle ergometer training in heart failure patients treated with carvedilol. These findings are consistent with the notion that the effects of exercise training on peripheral blood flow in heart failure patients are not systemic, but specific to the musculature involved in the exercise training. However, Linke and colleagues reported reversal of radial artery endothelial dysfunction in patients with heart failure following a lower-limb exercise training program [37]. In the present study, and in our previous report in a different group of heart failure patients [9], we also found improvement in forearm blood flow after leg exercise training in heart failure patients. Heterogeneity of study populations and differences in exercise regimens may explain the difference between Demopoulos' study, and the others [9,37].

The mechanisms involved in the increase of muscle blood flow after exercise training in patients treated with β-blocker is beyond the scope of our study. However, it is conceivable that exercise training changes the balance between vasodilator and vasoconstrictor forces that modulates muscle blood flow. Our findings clearly show that exercise training dramatically reduces MSNA. Previous studies have consistently demonstrated that exercise training improves endothelial function in patients with heart failure [37-40].

The effects of β-blocker agents on exercise training adaptations in healthy humans have been studied previously. Beta-blocker agents, especially non-selective β-adrenergic blockers, have been shown to attenuate the increase in peak VO2 in healthy individuals [41-43], although in these studies the training period was never longer than 13 weeks. In contrast to healthy individuals, β-adrenergic blockade does not preclude the beneficial effects of exercise training on functional capacity in heart failure patients [12]. The differences between the effects of β-adrenergic blockade on peak VO2 in exercise-trained healthy individuals and exercise-trained heart failure patients may be explained by the level at which the exercise training adaptation takes place. While in healthy individuals exercise conditioning seems to depend largely on cardiac adaptations [43], in heart failure patients, it depends primarily on skeletal muscle adaptations [44,45]. Since β-adrenergic blockade does not impact on the exercise-induced classical skeletal muscle adaptations [43], heart failure patients, in contrast to healthy individuals, will be less susceptible to the negative influence of β-adrenergic blockade on the increase of peak VO2 with training. Our study confirms that exercise training, in the presence of carvedilol therapy, still improves functional capacity in patients with heart failure [12]. Moreover, it suggests that the augmented peak VO2 after our exercise paradigm is consistent with the increase in muscle blood flow as a consequence of MSNA reduction caused by exercise training and carvedilol treatment. It may also reflect the reduction in pro-inflammatory agents and reactive oxygen species, which, in turn, increase oxidative capacity in the skeletal muscle [45,46]. These findings reinforce the importance of prescribing both exercise training and pharmacological therapy with carvedilol in heart failure patients.

Medications, especially ACE inhibitors, have been associated with the increase in peak VO2 in heart failure patients as a phenomenon called drug-induced physical conditioning that results in a spontaneous increase in patient activity as symptoms decrease [47,48]. However, long-term β-blocker treatment seems to prevent the drug-induced physical conditioning by blunting heart rate response to exercise [43] and limiting the reversal of the peripheral abnormalities that are primarily responsible for the increase in peak aerobic capacity in heart failure patients [49]. How do our results fit in this knowledge? Four months of carvedilol treatment did not change peak VO2 in untrained heart failure patients. Thus, the present study confirms that carvedilol does not improve functional capacity in heart failure patients [4,12] and that the improvement in peak VO2 in exercise-trained patients treated with carvedilol was, in fact, due to the exercise training.

In heart failure patients, ventilation inefficiency, as indicated by increased VE/VCO2 slope, contains prognostic information that extends beyond that provided by maximal oxygen uptake [50]. In the present study, we found a significant reduction in VE/VCO2 slope after exercise training in heart failure patients under carvedilol treatment. These findings have clinical implications and may be involved in the heart failure patient outcome. The mechanisms involved in such amelioration of ventilatory responses are unknown. However, it is possible that the improvement in lung diffusion and ventilation/perfusion ratio delay muscle acidosis and, in consequence, ergoreflex activation [20,51]. These changes result in lower ventilatory drive during exercise, and hence, the decrease in VE/VCO2 slope after training in heart failure patients treated with β-blockers.

Resting bradycardia is an important marker of exercise training effects in humans [52]. Moreover, this training adaptation has been also reported in heart failure patients [9]. In the present study, however, we found no reduction in resting heart rate in exercise-trained heart failure patients. This finding is likely due to the use of β-adrenergic blockade. Similar observations were reported by other investigators in heart failure patients treated with carvedilol [12]. Interesting was the fact that the rate of heart rate recovery was significantly improved by exercise training. This finding is particularly important because previous studies have shown that an attenuated heart rate recovery immediately after exercise is a strong predictor of mortality in heart failure patients [53,54].

4.1. Limitation
The dose of carvedilol was not standardized in this study, but was decided by the treating physician. Although the carvedilol dose was not standardized, this study may more accurately reflect the effects of an exercise program on a background of carvedilol as it is actually prescribed in the community.

4.2. Perspectives
Our study provides important information in regard to the treatment of heart failure patients. It shows that a non-pharmacological therapy based on exercise training reduces central sympathetic outflow and muscle vascular resistance and improves functional capacity in patients with heart failure already on carvedilol therapy. Despite the vasodilator properties of carvedilol, this medication does not improve muscle blood flow and peak VO2 in heart failure patients [4]. Thus our study emphasizes that exercise training should be strongly recommended for the treatment of heart failure patients even in the presence of carvedilol therapy.


   Acknowledgements
 
We want to express our gratitude to the Fundação de Amparo à Pesquisa do Estado de São Paulo, São Paulo - SP (FAPESP # 2005/59740-7), and to Fundação Zerbini, São Paulo - SP for granting our study and Conselho Nacional de Pesquisa for supporting Carlos E Negrão (CNPq # 304304/2004-2), and Maria Urbana P. B. Rondon (CNPq # 305159/2005-4).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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