New aspects for the role of physical training in the management of patients with chronic heart failure

International Journal of Cardiology 90 (2003) 1–14 www.elsevier.com / locate / ijcard

Review

New aspects for the role of physical training in the management of patients with chronic heart failure Stamatis Adamopoulos*, John T. Parissis, Dimitrios Th. Kremastinos Second Department of Cardiovascular Medicine, Onassis Cardiac Surgery Center, Athens, Greece Received 23 May 2002; received in revised form 5 August 2002; accepted 2 September 2002

Abstract Recent experimental and clinical data have shown that physical training is an important therapeutic intervention in the management of patients with chronic heart failure (CHF), improving central hemodynamics and attenuating peripheral abnormalities (endothelial dysfunction and skeletal myopathy) characterizing the progression of the syndrome. Additionally, physical training seems to beneficially modulate peripheral immune responses of CHF expressed by elevated circulating proinflammatory cytokines, soluble cellular adhesion molecules and soluble apoptosis signaling molecules, resulting in improvement in exercise capacity of CHF patients. This article summarizes current knowledge about the beneficial role of physical training in CHF, as well as about traditional and novel mechanisms contributing to the physical training-induced improvement in clinical performance of CHF patients.  2002 Elsevier Ireland Ltd. All rights reserved. Keywords: Physical training; Endothelial dysfunction; Skeletal muscle; Inflammation; Cytokines; Chronic heart failure

1. Introduction Chronic heart failure (CHF) is a complex syndrome characterized by signs and symptoms related to inadequate tissue perfusion, fluid retention, neurohormonal reactions and abnormal central and peripheral immune responses [1].There are many similarities between the abnormalities associated with CHF and those seen in physical deconditioning. In both conditions there is exercise intolerance, sympathetic hyperactivation [2–4], increased resting heart rate, reduced heart rate variability (HRV) [5,6], wasted skeletal muscle [7,8] and depleted skeletal muscle oxidative enzymes [9–11]. Physical deconditioning in CHF may, therefore, contribute to some of *Corresponding author. Zinonos 9, 15234 Halandri, Athens, Greece. Tel.: 13-010-684-8463; fax: 13-010-949-3373. E-mail address: [email protected] (S. Adamopoulos).

the secondary abnormalities seen in CHF such as changes in the neurohormonal axis, skeletal muscle metabolism and the autonomic control of the cardiovascular system [12,13]. During the last decade, investigations have established that physical training has beneficial effects in compensated heart failure on exercise tolerance, central and peripheral hemodynamics, ventilation, symptomatic status and metabolic responses [14–17]. At the same period, Coats et al. demonstrated significant improvements in the autonomic control of heart rate and HRV as well as in norepinephrine kinetics after physical training [18]. Furthermore, there is growing evidence supported by experimental and clinical data that exercise training programmes can produce an improvement in skeletal muscle performance of CHF patients [11,19,20], as well as a correction in abnormal endothelial function observed in the syndrome of CHF [20,21]. Finally, recent studies underline the immunomodulatory role

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of physical training in patients with CHF, as shown by the reduction of circulating proinflammatory and chemotactic cytokines, soluble apoptosis mediators, soluble cellular adhesion molecules and other markers of monocyte / macrophage–endothelial cell adhesive interaction [22,23]. The present review describes novel aspects about the potential mechanisms involved to the beneficial effects of physical training in CHF.

2. Physical training modulates autonomic function in chronic heart failure Regular physical training has been shown to improve exercise tolerance in normal subjects and in patients with ischemic heart disease [24], prevent the changes in body composition and fuel metabolism associated with ageing [25], improve blood lipid profile, reduce susceptibility to ventricular arrhythmias and modify psychological status [26–28], all of which would be of considerable clinical and prognostic benefit in patients with CHF. Moreover, physical training results in diminished sympathetic responses for a given level of exercise, as indicated by the substantial reduction in blood catecholamine levels (by as much as 90% at heavy work rates), heart rate and systolic blood pressure in normal individuals [29–31]. This hormonal component of the training adaptation occurs very early in the course of a vigorous endurance training programme [30]. The observation of a strong link between sympathetic response and exercise requirements implies that sympathetic tone during work is subjected to precise control mechanisms [32]. Although the forwarded hypothesis that these control mechanisms originate in cardiovascular or muscular chemoreceptors or from the motor cortex deserves further investigation, there is growing evidence that muscle ergoreflex contributes significantly to the hemodynamic, autonomic and ventilatory responses to exercise in men [33]. Finally, endurance training enhances baroreflex sensitivity and HRV in normal subjects [34], borderline hypertensives [35] and established hypertensives [5]. The benefits of localized conditioning [36] or systemic exercise training [15] on skeletal muscle morphologic, histochemical and biochemical characteristics as well as functional and blood flow abnor-

malities in patients with CHF have been well documented. Although a subgroup of these patients showed improved central hemodynamics after training, the increases in systemic exercise performance have been primarily attributed to improvements in the peripheral mechanisms. Little, however, is known regarding the effects of exercise training programmes on autonomic control of the cardiovascular system in heart failure. On the other hand, patients with CHF are characterized by a marked activation of various neurohormonal mechanisms, including enhancement of renin activity and elevation of circulating catecholamines, natriuretic peptides and arginine–vasopressin [12,37]. These autonomic changes increase peripheral vascular resistance and reduce blood flow to various organs (especially during exercise), including skeletal muscles. Moreover, the degree of elevation of norepinephrine and natriuretic peptides [38,39] or decrease in vagal tone, HRV and baroreflex sensitivity [4,40– 42] has been shown to be independent risk factors for death. Physical training has been demonstrated to decrease rest plasma catecholamine levels in patients with ischemic heart disease [2], enhance HRV and improve baroreceptor sensitivity in hypertensives, reflecting an increase in vagal tone [5]. Exercise conditioning increased the ventricular fibrillation threshold through a shift in sympatho-vagal balance towards vagal predominance in dogs with experimentally induced myocardial infarction [43]. An insight into the mechanisms underlying the beneficial effects of training is gained in an experimental model of acute myocardial ischemia where 6 weeks of physical training produced a concomitant increase in baroreflex sensitivity, HRV and repetitive extrasystole threshold and protected all animals from recurrence of ventricular fibrillation during treadmill [44]. A training-induced reduction in adrenergic tone and increase in vagal tone has been associated with higher ventricular fibrillation threshold in trained dogs with a healed myocardial infarction [45]. Recent meta-analysis of randomized trials of cardiac rehabilitation with exercise [46,47] indicate a moderate reduction in total and cardiovascular mortalities persisting throughout the follow-up of patients after myocardial infarction. The correct identification of patients who might benefit most from an exercise training programme is still a subject of controversy. Exercise training may, however, prolong survival in post-myocardial infarction patients with depressed

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left ventricular function [48]. Although this study does not elucidate the mechanism whereby training may prolong survival, a beneficial effect by inducing a change in the autonomic balance of the heart is strongly suggested. This speculation is based on the (a) strong evidence linking the autonomic nervous system to cardiovascular mortality after myocardial infarction [49], (b) impairment of autonomic innervation to and from the heart induced by myocardial ischemia and infarction, thus modulating the development of malignant arrhythmias and predisposing the occurrence of sudden death [50,51], (c) deterioration of cardiac function by worsening the process of ventricular remodeling as a result of elevated sympathetic activity causing an increase in wall stress and loading condition [52] and (d) modification of sympatho-vagal balance toward a condition of parasympathetic dominance in normal subjects after physical training [34,35]. This autonomic hypothesis is further supported by a recent study [53] where exercise training, performed 8 weeks after a myocardial infarction, modifies the sympatho-vagal control of HRV (both in the time and frequency domain) toward a persistent enhancement in parasympathetic tone, known to be associated with a better prognosis. Besides preventing life-threatening arrhythmias in high risk patients, training-induced increase in markers of vagal activity [44] may limit the deleterious effects of sympathetic hyperactivity on left ventricular performance, particularly in patients with low ejection fractions. A clinical report demonstrates an improvement in the harmful process of left ventricular remodeling in post-infarction patients with left ventricular dysfunction by participation in a structured exercise rehabilitation programme, possibly due to a chronic reduction in sympathetic tone [54]. The duration of the training period seems to be a crucial factor when the main goal is modulation of autonomic control of the cardiovascular system, both in its tonic and phasic components. Thus, training affected only the reflex activity of the autonomic nervous system in patients underwent 4 weeks of rehabilitation after a first myocardial infarction [55], whereas up to 6 months of regular physical exercise were required to obtain a significant increase in 24-h parasympathetic tone in patients with left ventricular dysfunction and low HRV after infarction [56]. A moderate long period of endurance training can,

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therefore, modulate the cardiovascular autonomic control of heart rate in a manner similar to that obtained with b-blockers [57] or with muscarinic receptor stimulation [58], which has been associated with favorable prognosis. Rest had traditionally been recommended for all patients with CHF until the late 1980s [59]. Several investigators demonstrated that patients with impaired left ventricular function could obtain some benefit from cardiac rehabilitation programmes without any detectable deterioration in left ventricular ejection fraction [37,60] or additional negative effect on infarct expansion [61]. It was not until the end of the 1980s that the first uncontrolled reports were published of patients with CHF achieving increases in exercise performance after physical training [15,16]. Although this has now been confirmed in controlled trials in heart failure [17], very few controlled studies have been conducted to look at the effects of physical training programmes on the autonomic regulation of the cardiovascular function in this category of patients. Perhaps, the most important attempt to describe the effects of physical training on autonomic balance has been provided by the Oxford group in a randomized controlled trial of 8 weeks home-based exercise training in patients with moderate to severe CHF [18]. Physical training produced significant, and perhaps important, reductions in 24-h heart rate, day and night heart rate, submaximal workload exercise heart rate, enhancement in chronotropic responsiveness, markedly increased heart rate variability in the time domain in both waking and sleep states (expressed by standard deviation of normal morphology R–R intervals), significant improvement in heart rate variability in the frequency domain (using power spectral analysis of the resting ECG) consisted of reduction in the low-frequency component and increase in the high-frequency component and significant reduction in whole-body radiolabeled norepinephrine spillover (Fig. 1). These measurements all showed an important shift away from sympathetic towards increased vagal activity after training and may reflect beneficial changes in the baroreceptor sensitivity and skeletal muscle ergoreflex. Abnormalities of muscle afferents are hypothesized to underlie the neurohormonal activation in heart failure and physical training not only improved the exercise capacity of the trained forearm but also partially reversed the abnormal sympathetic, vasoconstrictor

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Fig. 1. Graphs showing effects of physical training on heart rate variability, expressed as standard deviation of the R–R intervals, of 640 consecutive beats (upper panel) and whole-body norepinephrine spillover (lower panel). Note the training-induced increase in heart rate variability and decrease in whole-body norepinephrine spillover (adapted from Ref. [18]).

and ventilatory responses to exercise via a reduction of the muscle ergoreflex excitation [62]. The same investigators [63] extended their autonomic studies by looking also on the circadian variation of HRV in both normal controls and patients with CHF before and after physical training. The circadian variations of the low- and high-frequency components of HRV throughout the day are similar in normal subjects and in patients in both training and detraining conditions, indicating that the training-induced improvement in time and frequency domain measures of HRV is an

inherent phenomenon rather than due to increased physical activity after training and that the syndrome of heart failure is characterized by a resetting of autonomic balance rather than autonomic neuropathy. More recently, reversal of autonomic derangements, by increasing the parasympathetically mediated component of HRV, has been shown with physical training in patients with CHF [64]. Even more recently, the European Heart Failure Training Group [65] reviewed the progress of 134 stable heart failure patients, studied in randomized controlled trials of physical training, and reported a good correlation between training-induced beneficial changes in autonomic parameters (chronotropic responsiveness, norepinephrine at peak exercise and standard deviation of HRV) and improvement in exercise performance. These correlations might be reflecting the close relationship of increased fitness to reduced heart rate and norepinephrine spillover and increased HRV. Thus, there may be a beneficial feedback between improvement in cardiovascular function and shifts in autonomic balance from sympathetic to vagal predominance. Physical training may improve not only physical fitness but also prognosis, as has been suggested in patients with ischemic heart disease without heart failure, perhaps by partially correcting abnormalities associated with increased mortality [66–68], such as reducing norepinephrine spillover and improving exercise tolerance and HRV measures in the time and frequency domain. Reduction in the adrenergic and increase in the vagal tone have been recently proposed as the main mechanism underlying the favorable outcome in the only, so far, study translating a sustained improvement in functional capacity and quality of life into a better clinical outcome after long-term moderate exercise training [69].

3. Physical training and skeletal muscle function in chronic heart failure Physical inactivity results in decreased mitochondrial enzyme activity and physical training has been shown to increase b-hydroxyacyl CoA dehydrogenase and citrate synthase activity [7] in normal subjects. Training is also known to induce an increase of the level of glutamate pyruvate transferase, a mitochondrial-cytoplasmic enzyme, which permits the

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generation of alanine and ketoglutarate from pyruvate and glutamate, thus reducing the formation of lactate during exercise and increasing the pH, providing at the same time more oxaloacetate to the first step of the Krebs cycle [7,70]. More recently in normal subjects, training has been associated with improved skeletal muscle oxidative capacity, as assessed by 31 P magnetic resonance spectroscopy (MRS) studies. Thus, forearm training led to a higher pH at submaximal workloads [71]. A reduction in inorganic phosphate / phosphocreatine (Pi / PCr) ratio at submaximal workloads and an increase in PCr recovery rates have also been found with training, indicative of an improvement in oxidative metabolism [72,73]. Recent investigations have established the beneficial role of exercise training on skeletal muscle function and metabolism in patients with CHF. Although it remains controversial whether the morphological, histochemical and biochemical alterations as well as functional abnormalities in skeletal muscle represent disuse or specific characteristics associated with CHF, the benefits of training have been well documented. Thus, Sullivan et al. [15] were able to demonstrate significant improvement in exercise capacity, expressed by peak oxygen consumption, in response to 4–6 months of systemic exercise training in patients with stable CHF. The same investigators showed lessening of the metabolic abnormalities observed before training, expressed by a reduction in both arterial and venous lactate levels. Since the conditioning stimulus was systemic, it is unclear whether the measured changes in the exercising limb, suggesting an improved skeletal muscle response to exercise, are attributable solely to peripheral adaptations. Employing localized (wrist flexor) conditioning in patients with CHF, Minotti et al. [74] demonstrated improvement in muscle bioenergetics, as assessed by the slope of the regression line relating Pi / PCr to submaximal workloads, and increase in forearm endurance by 260%, effects which are independent of muscle mass, limb blood flow, plasma catecholamines or a central cardiovascular response. Coats et al. [17] confirmed the benefits of training on exercise tolerance and symptoms in patients with moderate to severe CHF by using, for the first time, a randomized, controlled design and home-based exercise regimen. A more recent study demonstrates that the metabolic abnormalities seen in exercising skeletal muscle in patients with CHF can be reversed, at least partially,

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by local muscle training either during incremental or during endurance exercise [75]. The effects of exercise training on skeletal muscle metabolic abnormalities, characterizing the complex syndrome of chronic heart failure, were examined by the Oxford group in both experimental and human heart failure through a more generalized training programme (treadmill in rats and upright bicycle exercise in humans). Initially the influence of physical training on skeletal muscle metabolism after myocardial infarction was studied in a rat model of the development of heart failure [76]. Rats with congestive heart failure developed similar skeletal muscle metabolic changes in the handling of high energy phosphates to those described in heart failure in humans. More important was the training-induced normalization of skeletal muscle metabolism, as reflected by the lower PCr and pH during sciatic nerve stimulation and by the longer PCr and adenosine diphosphate recovery half-times only in the nontrained group of animals with congestive heart failure. This normalization, including correction of the lower citrate synthase activity seen also only in the non-trained rats with CHF, was achieved without any change in calf muscle mass or individual fibre size between trained and non-trained animals, making, therefore, atrophy unlikely to be the sole cause of the muscle metabolic changes characterizing heart failure. Subsequently, the effects of physical training on skeletal muscle metabolism in patients with chronic heart failure were investigated by using 31 P MRS [77]. Physical training in humans produced a significant reduction in PCr depletion, an attenuation of acidification and a blunted rise of adenosine diphosphate concentration during exercise as well as an enhanced rate of PCr resynthesis during recovery (an index of mitochondrial oxidative capacity, which is independent of muscle mass). The reduction in acidification and PCr utilization during exercise as well as the increases in maximal rate of mitochondrial ATP synthesis (Q max ) and PCr resynthesis rate during recovery, after either localized or more systemic training programs, indicate an increased capacity for oxidative metabolism (due to an increase in either mitochondrial content or functional capacity of the existing mitochondria) and a decreased dependence on glycolysis in the trained skeletal muscles. Regular (even low intensity) physical training not

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only increases exercise tolerance and delays anerobic metabolism during submaximal exercise in patients with CHF but, also, improves oxidative capacity of the exercising muscle by increasing the total volume density of mitochondria and the volume density of cytochrome c oxidase-positive mitochondria [78,79]. This significant increase in oxidative capacity of skeletal muscle (vastus lateralis) after endurance training is significantly correlated with the improvement in functional capacity and peak oxygen uptake; patients with severe exercise intolerance and / or severe ventricular dysfunction exhibit the most impressive training-induced changes in oxidative capacity of skeletal muscle and in peak oxygen consumption. In addition, change in oxygen consumption at ventilatory threshold is significantly correlated with change in volume density of cytochrome c oxidase-positive mitochondria in skeletal muscle, suggesting that the improved oxidative capacity of the mitochondria may account for the delayed onset of ventilatory threshold after exercise training. Apart from muscle conditioning in the training programmes, what are the other possible explanations of the training-induced improvement in skeletal muscle oxidative capacity? The MRS changes observed in patients with CHF after training, could simply have resulted from performing the same work with more muscle induced by training. Although the possibility of reversing wasting of skeletal muscles by training cannot be excluded, it has been shown that localized skeletal muscle training can produce beneficial 31 P MRS responses at submaximal workloads without any associated change in muscle mass [80]. Moreover, the same investigators and more recently Stratton et al. [75] by using recovery characteristics showed significant training-induced improvement in PCr resynthesis rate and in mitochondrial Q max , indices independent of muscle mass. In addition, ambulatory physical training programmes improve ultrastructural morphology and oxidative capacity of skeletal muscle determined semiquantitatively by cytochemistry, a method well correlated with biochemical determination of oxidative enzymes and largely independent of muscle mass [79,81]. Muscle blood flow during exercise may be reduced in patients with CHF as a result of diminished cardiac output and impaired vasodilatory reserve [82–84] and

blood flow alterations resulting from an enhancement in capillary density have been observed after physical training [85]. The training induced biochemical improvements could, therefore, be explained by a reduced peripheral resistance with concomitant increase in peak blood flow to the exercising leg and markedly reduced arterial and venous lactate levels that have been reported by Sullivan et al. [15]. The same investigators, however, provide evidence that after training the lactate production was delayed at submaximal exercise independent of leg blood flow and O 2 delivery, in keeping with the findings of a more recent controlled and prospectively randomized study, which showed decreased submaximal blood lactate levels after regular exercise, despite an unchanged leg blood flow at submaximal workloads, indicating, also, a delay in onset of leg anerobic lactate production [79]. It has also recently been noted that reduced skeletal muscle endurance in patients with CHF, is, in part, independent of limb blood flow [80]. Again Minotti et al. [74,81], in their localized forearm exercise training study in CHF patients, showed improvement in muscle bioenergetics independently of changes in limb blood flow or in the underlying cardiac dysfunction. In patients with peripheral vascular disease, exercise training has been shown to lead to improvements in functional and metabolic parameters, even without demonstrable improvements in blood flow [86]. These human data confirm previous experimental findings where no difference in blood flow was found between trained and sedentary infarcted rats with left ventricular dysfunction [87]. However, despite these findings, redistribution of blood flow within the leg to more effectively perfuse the exercising muscles cannot be excluded [88]. In addition, although exercise of small muscle groups may not be limited by blood flow, exercise of large muscle groups, which may be more responsible for exercise intolerance in CHF, may be limited by blood flow. Finally, the corrections of muscle metabolic changes after training could also be explained by the differences in blood flow distribution towards glycolytic muscles prior to training [89] and towards oxidative muscles after training [90]. Although training-induced improvements in metabolic responses to exercise are compatible with the hypothesis that deconditioning can cause part of the skeletal muscle metabolic defect in CHF, one cannot exclude the possibility that patients may continue to

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have a primary defect due to oxygen delivery and utilization and the training effect was non-specific. Improvements in oxidative metabolism with exercise training could be due to an increase in mitochondrial number or an increase in the oxidative capacity of existing mitochondria, in keeping with animal and human data in normal subjects [7,91,92], suggesting increase in mitochondrial content and oxidative enzymes with endurance training. Recent studies have focused on the effects of training programmes on skeletal muscle oxidative capacity in patients with moderate to severe CHF and found significant increases in the total volume density of mitochondria and volume density of cytochrome c oxidase-positive mitochondria independently from muscle mass or peripheral blood flow [79]. Even more recently, evidence is provided that regular physical exercise improves both basal endothelial nitric oxide (NO) formation and agonist-mediated endothelium-dependent vasodilation of the skeletal muscle microvasculature in patients with CHF by increasing expression of endothelial NO synthase and preventing the production of vasoconstrictor prostanoids and free radicals [93]. Training-induced improvement in endothelium dysfunction is associated with a significant increase in exercise performance [21,94]. Restoration, at least partially, of endothelial function with physical training may contribute to the redistribution of skeletal muscle blood flow with a preferential supply to oxidative muscles during submaximal exercise, thus explaining the increase in oxidative enzyme capacity of the working skeletal muscle observed in patients with CHF, which is closely related to the improved exercise tolerance after physical training [79,95]. The contribution of peripheral neural adjustments to the decreased PCr depletion during exercise and improved oxidative ATP synthesis (expressed by Q max ) after training cannot be excluded. These may be related to either alterations in recruitment of motorneurons with endurance training or increased sensitivity of b 2 muscle metabolic receptors compatible with the reduced sympathetic activity found with training [17]. Whatever the potential mediator of the positive effects of exercise training on the exercising muscle, the resolution of skeletal muscle abnormalities may be responsible for the reduced activity of the exaggerated muscle ergoreflex, thereby improving the abnor-

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mal responses to exercise (heightened sympathetic, vasoconstrictor and ventilatory drives) characteristic of heart failure [62].

4. Physical training as immunomodulatory treatment in chronic heart failure The overactivation of several neurohormonal systems and overproduction of biologically active peptides such as norepinephrine, angiotensin II, aldosterone, endothelin-1 and proinflammatory cytokines are important pathophysiological parameters that contribute to disease progression in the failing heart [1]. Especially, the existence of an abnormal inflammatory response, mediated mainly by proinflammatory cytokines and other cytokine-related factors, is responsible for some aspects of the syndrome phenotype, such as the adverse left ventricular remodeling, endothelial dysfunction and peripheral myopathy [96–98]. Deleterious effects of inflammatory cytokine cascade on the cardiovascular system of patients with CHF are summarized in Table 1. Proinflammatory cytokines (i.e. TNF-a, IL-1 and IL-6) which are elevated into circulation of CHF patients, cause myocardial and endothelial dysfunction in CHF, either by increasing the production of oxygen free radicals and expression of inducible Table 1 Adverse biological effects of inflammatory cytokine cascade in chronic heart failure I. Cardiac Promotion of left ventricular remodeling Depression of cardiac contractility Cardiomyocyte hypertrophy Cardiomyocyte apoptosis Cardiac fibrosis II. Vascular Progression of atherosclerosis Oxidative stress NO impairment Vasoconstriction Endothelial cell apoptosis Adverse vascular remodeling III. Skeletal muscular Reduction of skeletal muscle blood flow Anabolic / catabolic imbalance Inhibition of proteinosynthesis Skeletal muscle cell apoptosis Cachexia

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nitric oxide synthase (iNOS) or by triggering apoptosis in myocardial and endothelial cells through oxidative stress [97–99]. Interleukin-6 (IL-6) and related cytokines have also been implicated in the development of cardiac hypertrophy, through stimulation of their common receptor gp130 expressed in cardiac myocytes [100]. Proinflammatory cytokine hyperactivation is also associated with increased gene expression of iNOS and decreased gene expression of anabolic peptide insulin-like growth factor-1 (IGF-1) in the skeletal muscle of patients with CHF, leading to attenuation of mitochondrial energy transfer (and, thus, attenuation of skeletal muscle contractile performance) and / or skeletal myocyte apoptosis [101–103]. These deleterious, central and peripheral effects may be important pathophysiologic events associated with the impaired exercise capacity of patients with heart failure [1,96,97,101–103]. Furthermore, increased circulating levels of chemotactic cytokines (C–C chemokines), such as macrophage chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1a (MIP-1a), have been recently found in CHF [104]. These molecules are potent chemoattractants of monocytes and lymphocytes, with particularly high concentrations in those with the most severe heart failure [104,105]. Chemotactic cytokines may represent not only a ‘new’ parameter of enhanced immune activation in CHF but may also reflect an important pathogenic mechanism in the development of this syndrome. Increased MCP-1 secretion from endothelial and smooth muscle cells may lead to infiltration of monocytes into the arterial wall and generation of reactive oxygen species in monocytes, which may be involved in the pathogenesis of atherosclerosis and increased apoptosis of cardiomyocytes and endothelial cells observed in patients with CHF [104–106]. On the other hand, human monocyte–endothelial cell interaction induces synthesis of inflammatory cell colony-stimulating factors, such as macrophage colony-stimulating factor (M-CSF) and granulocyte– macrophage colony-stimulating factor (GM-CSF), which play an important role in the pathogenesis of atherosclerosis and inflammation by stimulating a range of functional activities of mature neutrophils, monocytes and eosinophils including regulation of leukocyte adhesion, augmentation of surface antigen expression, superoxide anion generation and enhance-

ment of cytokine production [107]. In the case of GM-CSF, we have also demonstrated elevated levels of this inflammatory factor in CHF, which are associated with the hemodynamic deterioration and neurohormonal activation characterizing this syndrome [108]. Finally, cytokines and oxygen free radicals induce the expression of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). These adhesion molecules are cleaved into the circulation by activated endothelial cells and can be measured as ‘soluble adhesion molecules’ (sICAM-1 and sVCAM-1). There is growing evidence that CHF is associated with elevated soluble adhesion molecules which may represent a marker of endothelial activation or damage [109,110]. On the other hand, it is known that an intense physical exercise induces an inflammatory reaction as demonstrated by the delayed increase in blood of acute phase proteins and among them of C-reactive protein [111]. There is also evidence for a diminished acute phase reaction due to regular exercise suggesting a suppression of this inflammatory response through exercise training [111]. Larsen et al. [112] have also reported that there is a modest negative correlation between IL-6 plasma levels and skeletal muscle fiber thickness at baseline, suggesting that proinflammatory cytokines may be involved in the pathogenesis of the CHF-related skeletal myopathy. The same group [113] showed that 12-week aerobic exercise training causes a significant reduction of TNF-a plasma levels and a notable increase of skeletal muscle capillary density, permitting better flow reserve of exercising muscles in patients with moderate CHF. These training-induced beneficial changes were associated with the increase in the 6-min walk test (as a marker of exercise capacity) and the improvement of functional status of CHF patients. Furthermore, programmes of physical training by causing sustained, pulsatile increases in peripheral blood flow, affect the release of prostaglandins in the skeletal muscle microvasculature [114], induce the expression of constitutive NOS (cNOS) and cytosolic superoxide dismutase [115], a free radical scavenger, and enhance Ca 21 influx in endothelial cells, which is necessary for both NO and prostaglandin synthesis [116,117]. Additionally, our group’s studies [22,118] have shown that an exercise training programme intervenes in the various stages

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of inflammatory and apoptotic processes in patients with CHF, by reducing not only the major proinflammatory cytokines TNF-a (Fig. 2) and IL-6, which enhance the cytokine cascade and are potent inducers of apoptosis, but also the soluble receptors of TNF-a and IL-6, which are products of a monocyte– myocyte / endothelial cell interaction and biological modulators of circulating cytokine actions. In the same patient population [22], the 12-week home-

Fig. 2. Effects of physical training on circulating proinflammatory cytokine tumor necrosis factor (TNF)-alpha (top) and apoptosis inducer sFas ligand (bottom). Note the decrease in these inflammatory variables with training in patients with chronic heart failure (adapted from Ref. [22]).

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based exercise training programme also causes a significant reduction of representative plasma apoptotic markers such as soluble Fas (sFas) receptor (sFas: soluble form of apoptosis receptor Fas which may block the action of apoptosis inducer Fas ligand into circulation, may play an important role in the regulation of peripheral immune responses in various autoimmune diseases, and may be related with clinical deterioration and worsening prognosis of patients with CHF [119]) and soluble apoptosis inducer Fas ligand (sFasL) (sFasL: a TNF-a related cytokine which is synthesized as a membrane-bound protein that can be converted by proteolytic cleavage into a

Fig. 3. Correlations between training-induced changes in peak oxygen consumption (VO 2 max ) and reductions in tumor necrosis factor (TNF)alpha (top) and soluble Fas (sFas) ligand (bottom) levels in patients with chronic heart failure (adapted from Ref. [22]).

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Fig. 4. Effects of physical training on inflammatory markers granulocyte–macrophage colony-stimulating factor (GM-CSF) and macrophage chemoattractant protein-1 (MCP-1) as well as on soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1). Note the significant reduction of GM-CSF (a, upper left panel), MCP-1 (b, lower left panel), sICAM-1 (a, upper right panel) and sVCAM-1 (b, lower right panel) (adapted from Ref. [23]).

Table 2 Immunomodulatory effects of physical training in chronic heart failure II. Inhibition of cytokine–chemokine production III. Reduction of acute phase reactant proteins IV. Regulation of monocyte activation and adhesion V. Inhibition of inflammatory cell-growth signals and growth factor production VI. Reduction of soluble apoptosis signalling molecules VII. Reduction of free radical generation VIII. Attenuation of monocyte–endothelial cell adhesive interaction

soluble form, promotes intercellular Ca 21 homeostasis alterations, caspase activation, apoptotic gene transcription and apoptotic cell death after crosslinking with receptor Fas, and, finally, has been correlated with the severity of symptoms and functional status of CHF patients [120]) (Fig. 2). In CHF patients, significant correlations were found between physical training programme-induced improvement in patient exercise capacity and the respective reductions in TNF-a and sFasL plasma levels (Fig. 3) [22,118]. These observations suggest that exercise training may exert its beneficial effects on functional status of CHF patients, at least partially, by suppressing the proinflammatory cytokine activation characterizing the progress and clinical deterioration of CHF. Furthermore, we have recently reported [23,121] that exercise training programmes reduce peripheral inflammatory factors (i.e. inflammatory cell growth factor GM-CSF; chemotactic cytokine MCP-1; soluble cellular adhesion molecules sICAM-1 and sVCAM-1), which are representative markers of macrophage–endothelial cell adhesive interaction and basal parts of complex inflammatory cytokine network in CHF (Fig. 4). Training-induced changes in soluble cellular adhesion molecules were also significantly correlated with the respective improvement in endothelial function and clinical performance of CHF patients (Fig. 5) [121]. This indicates that peripheral inflammation may underlie the impaired exercise capacity seen in CHF and that traininginduced improvement in exercise tolerance may be attributed to the attenuation of the peripheral inflammatory process, possibly via reversing the deleterious effects of endothelial dysfunction. Physical training therefore, by virtue of its anti-inflammatory and anti-apoptotic effects, seems to beneficially regulate peripheral immune responses, resulting in improvement in exercise capacity of CHF patients. Table 2 describes the main immunomodulatory effects of physical training in CHF. In conclusion, increasing evidence shows that modulation of immunological variables is emerging as a major therapeutic goal in the treatment of patients with CHF and that physical training may represent an important immunomodulatory option that may possibly intervene in the progression of the syndrome.

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Fig. 5. Correlations between training-induced changes in VO 2 max and reduction in sVCAM-1 (top) levels, as well as between training-induced increase in peripheral blood flow (improvement of endothelial function) and the respective reduction of sVCAM-1 (bottom) levels in patients with chronic heart failure [121].

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