Intrinsic skeletal muscle alterations in chronic heart failure patients: a ...

Heart Fail Rev (2012) 17:421–436 DOI 10.1007/s10741-011-9289-4

Intrinsic skeletal muscle alterations in chronic heart failure patients: a disease-specific myopathy or a result of deconditioning? T. A. Rehn • M. Munkvik • P. K. Lunde I. Sjaastad • O. M. Sejersted

•

Published online: 14 October 2011 Ó Springer Science+Business Media, LLC 2011

Abstract Chronic heart failure (CHF) patients frequently experience impaired exercise tolerance due to skeletal muscle fatigue. Studies suggest that this in part is due to intrinsic alterations in skeletal muscle of CHF patients, often interpreted as a disease-specific myopathy. Knowledge about the mechanisms underlying these skeletal muscle alterations is of importance for the pathophysiological understanding of CHF, therapeutic approach and rehabilitation strategies. We here critically review the evidence for skeletal muscle alterations in CHF, the underlying mechanisms of such alterations and how skeletal muscle responds to training in this patient group. Skeletal muscle characteristics in CHF patients are very similar to what is reported in response to chronic obstructive pulmonary disease (COPD), detraining and deconditioning. Furthermore, skeletal muscle alterations observed in CHF patients are reversible by training, and skeletal muscle of CHF patients seems to be at least as trainable as that of matched controls. We argue that deconditioning is a major contributor to the skeletal muscle dysfunction in CHF patients and that further research is needed to determine whether, and to what extent, the T. A. Rehn (&) M. Munkvik P. K. Lunde I. Sjaastad O. M. Sejersted Institute for Experimental Medical Research, Oslo University Hospital, Ullevaal, 0407 Oslo, Norway e-mail: [email protected] T. A. Rehn M. Munkvik P. K. Lunde I. Sjaastad O. M. Sejersted Center for Heart Failure Research, University of Oslo, Oslo, Norway I. Sjaastad Department of Cardiology, Oslo University Hospital, Ullevaal, Oslo, Norway

intrinsic skeletal muscle alterations in CHF represent an integral part of the pathophysiology in this disease. Keywords Congestive heart failure Deconditioning Skeletal muscle Inflammation Exercise Training

Introduction Patients suffering from chronic heart failure (CHF) frequently experience impaired exercise tolerance due to skeletal muscle fatigue. Studies suggest that this in part is due to intrinsic alterations in skeletal muscle of CHF patients, and current literature presents these alterations as an integral part of the pathophysiology of heart failure. Understanding the underlying mechanisms for the increased skeletal muscle fatigue in CHF will influence the therapeutic approach to both skeletal muscle and the heart [1]. In the present article, we critically review the evidence for skeletal muscle alterations in heart failure, plausible underlying mechanisms and how these are influenced by training. The role of deconditioning is emphasized, as we believe that skeletal muscle alterations secondary to deconditioning are of greater importance in evaluating and interpreting intrinsic skeletal muscle properties in CHF patients than what is presently acknowledged. Only controlled studies are included in this review and animal studies only in areas where clinical studies are lacking or considered insufficient.

Intrinsic skeletal muscle alterations in CHF CHF patients have reduced peak exercise capacity as measured by maximal oxygen uptake (VO2max) that

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correlates well with NYHA classifications [2, 3] and seems to be the best predictor of mortality in CHF [4] together with the minute ventilation/carbon dioxide production (VE/ VCO2) slope, which can be considered an indirect measure of anaerobic threshold [5, 6]. One obvious explanation for reduced exercise capacity and increased skeletal muscle fatigue is restricted perfusion of the exercising muscles due to reduced cardiac output (CO). This may especially hold true when engaging a large muscle mass. However, there is poor correlation between resting hemodynamic indices of cardiac function and exercise intolerance in these patients [7–12]. Furthermore, interventions that improve central hemodynamics, such as dobutamine infusion, have no effect on exercise duration, oxygen extraction or pH in the exercising muscle [13–15]. Collectively, this leads to the assumption that peripheral adaptations to CHF, particularly intrinsic skeletal muscle alterations, may in part be responsible for the observed reduction in exercise tolerance. Endothelial dysfunction [16] and altered microcirculation [17, 18] probably also play a role in this respect. This is however beyond the scope of this review.

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extensor protocol that enabled direct assessment of fatigue demonstrated that resistance to fatigue (measured as fall in peak torque during repeated maximal isokinetic contractions) was lower in the CHF group than in controls [24]. Several similar studies, mostly performed on knee extensors, have confirmed this finding in both dynamic [25–28] and isometric [25, 27, 29–32] exercise protocols (Table 1). Importantly, there seems to be no difference in muscle mass-specific blood flow between CHF patients and healthy subjects during one-legged knee extension [33]. Additionally, neurophysiological assessment indicates that the cause of fatigue lies within the skeletal muscle itself, as enhanced muscle fatigue is not caused by impaired central motor drive or by abnormalities in the neuromuscular junction [27, 28].

Possible mechanisms for increased fatigability of skeletal muscle in CHF Current consensus is that CHF patients exhibit a myopathy that directly affects functional capacity, and various mechanisms have been suggested.

Isolated skeletal muscle fatigability Metabolic and morphological changes The concept of fatigue refers to a subjective feeling of increasing effort to maintain desired work rate or an urge to reduce work intensity. Objectively, it can for instance be measured as reduced maximal force development [19] or reduced muscle shortening [20] during exercise. Increased skeletal muscle fatigability is reported in CHF patients when exercising even a small muscle mass, where muscle perfusion is not limited by the pumping capacity of the heart (Table 1). In order to directly assess skeletal muscle fatigability, study design must ensure that blood supply to the tested muscles is not limited by the pumping capacity of the failing heart. Optimally, blood flow to the muscle under study should be monitored during the experiment. Alternatively, muscles with a mass that clearly does not challenge cardiac capacity, such as hand- or finger-muscles, should be studied. We here only refer to controlled studies complying with this criterion. Massie et al. demonstrated that CHF patients exhibited elevated levels of inorganic phosphate (Pi) at rest, as well as an increased phosphocreatin (PCr) utilisation and a more rapid decrease in muscular pH during finger flexor exercise as compared to controls [21]. They later found that this was unrelated to blood flow [22], and that the more symptomatic patients and those with the most limited exercise tolerance also had the largest drop in pH [23]. Although these findings indicate a reduced oxidative capacity in skeletal muscle, they do not include distinct parameters of fatigue. A follow-up study by the same group using a dynamic knee

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Studies report reduced oxidative capacity in the skeletal muscle of CHF patients as compared to controls [23, 34–36]. Increased atrophy [37, 38], increased apoptosis [39–42] and a fiber-type switch toward a less fatigue-resistant phenotype [35, 36, 43] have also been described in clinical studies. A reduced number of capillaries per muscle fiber are frequently reported in CHF patients [26, 34–36, 43–45]. However, studies estimating the ratio of capillaries to cross-sectional fiber area, a more physiologically relevant measure, could not detect any difference between CHF patients and healthy subjects [35, 43, 46, 47], although reduced [34] as well as increased [48] ratios have been reported. Recently, Esposito et al. reported normal basal level of VEGF mRNA, an appropriate upregulation in response to acute exercise as well as normal vasculature in skeletal muscle of CHF patients [49], indicating that reduced capillarity is unlikely to be responsible for the reduced exercise capacity associated with CHF. Altered Ca2? handling Animal studies report a delayed rise and decline as well as reduced amplitude of Ca2? transients in single muscle fibers of CHF rats compared to controls [50–52]. Both altered release rate through the ryanodine receptor and altered uptake rate by the sarcoplasmatic reticulum Ca2? ATPase (SERCA) in the sarcoplasmatic reticulum (SR)

Muscle studied (unilaterally)

Knee extensors

Knee extensors

Knee extensors Plantar flexors

Knee extensors

Plantar flexors Knee extensors

Knee extensors

Knee extensors

Foot dorsiflexors

References

Brassard et al. [29]

Schulze et al. [32]

Sunnerhagen et al. [25]

Massie et al. [24]

Harridge et al. [28]

Magnusson et al. [26]

Yamani et al. [30]

Minotti et al. [27]

Standing heel rise test

CHF etiology: Not specified

1. Time to reach 60% of MVC during a sustained voluntary maximal isometric contraction 2. Number of contractions to reach 60% of MVC during intermittent isometric contractions

N: 9/8

2. The number of isokinetic contractions required for peak torque to decline to 60% of its initial value

1. Time to reach 60% of MVC during a sustained voluntary maximal isometric contraction

Fatigue index = Peak torque from the 3 best of the first 5/peak torque from the 3 best of the last 5 of 50 consecutive maximal concentric contractions

CHF etiology: IHD, CM NYHA: I(1), II(3), III(5)

N: 11/10

NYHA: I–IV

CHF etiology: IHD, CM

N: 11/11

NYHA: II(8), III(3)

Electrical stimulation for 2 min (300 ms/s at 20 Hz). Fall in peak torque from the first 3 to the last 3 isometric contractions

Plantar flexors –

Increased fatigability both during sustained isometric contractions and during intermittent isometric contractions

2. Increased fatigability in the CHF group during isokinetic work

1. Reduced isometric endurance in the CHF group

Increased fatigability during dynamic work

No difference

Plantar flexors –


Fatigue index = Peak torque from the 3 best of the first 5/peak torque from the 3 best of the last 5 of 50 consecutive maximal concentric contractions

N: 6/6

Knee extensors –

Knee extensors –


NYHA: II(5), III(1)*

Reduction in peak torque from the first 3 to the last 3 of 15 maximal isokinetic knee extensions


N: 18/8

NYHA: I(2), II(7), III(7), IV(2)



Plantar flexors –

Isokinetic endurance; Fall in peak torque from the first to the last 3 of 50 maximal contractions

N: 16/112 Plantar flexors –

Knee extensors – Increased isometric and isokinetic fatigability

Knee extensors – Isometric endurance; time to hold 40% of MVC

Increased fatigability of maximal isometric contractility

Reduced isometric endurance

Time to exhaustion during isometric contraction at 60% of MVC Decrease of force during 20 s maximal isometric contraction

Main findings in CHF patients

Fatigue parameter

CHF etiology: IHD, ICM, VHD NYHA: II(10), III(6)

N: 17/12

NYHA: II(1), III(10), IV(6)


N: 25/18

NYHA: II or higher

CHF etiology: IHD, ICM

Intervention groups N: CHF/controls

Table 1 Controlled studies directly assessing fatigue in small muscle groups of CHF patients

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No differences between groups, with or without circulatory occlusion Decline in isometric force during repetitive supramaximal titanic ulnar nerve stimulation, both with and without circulatory occlusion

CM cardiomyopathy, ICM idiopathic cardiomyopathy, IHD ischemic heart disease, VHD valvular heart disease, NYHA New York Heart Association classification of clinical signs of CHF

Adductor pollicis – Adductor pollicis -

Adductor pollicis

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N: 10/5

Increased isometric fatigability in a subpopulation of CHF patients (severe heart failure) MVC after 20 min of intermittent isometric contractions as a percentage of the initial MVC NYHA: Not specified

Knee extensors Buller et al. [31]

Mild/moderate (5), severe (5)

Knee extensors Knee extensors CHF etiology: IHD

Muscle studied (unilaterally) References

Table 1 continued

Intervention groupsN: CHF/ controls

Main findings in CHF patients

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Fatigue parameter

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may be responsible for these functional changes [51, 53– 55]. Increased SERCA activity was found in type II fibers of CHF patients compared to controls [56]. In line with this, Harridge et al. found reduced time to peak tension in the plantar flexors as well as significantly faster relaxation in the knee extensors of CHF patients during electrical stimulation of the muscle [28]. Besides increased SERCA activity, this finding may also be due to an altered fibertype composition within the muscle with a higher proportion of type IIa or IIx fibers. A recent study indicates that Ca2? handling-related protein expression is decreased in a sympathetic hyperactivity-induced CHF mouse model and that exercise training improves skeletal muscle function associated with favorable changes in the net balance of skeletal muscle Ca2? handling proteins [57]. The experimental findings of a possible alteration of intracellular Ca2? handling in CHF have to our knowledge only been pursued in two clinical studies. The first of these found an increased SR ATPase activity in CHF patients as indicated by a quantitative histochemical method [58]. Notably, the CHF and the control group in this study were not age matched, mean age being 64 and 51 years, respectively. Recently, Munkvik et al. concluded that apart from a lower Ca2? leak from SR, Ca2? handling in skeletal muscle from CHF patients was not different from that of healthy, agematched control subjects [59]. Thus, the role of Ca2? kinetics in skeletal muscle fatigue in CHF patients remains to be further elucidated. Whether altered myofibrillar Ca2? sensitivity may contribute to increased fatigability in CHF is not known, but a recent study indicates that this could be of importance [60]. Altered cytokine production in skeletal muscle CHF is reported to be associated with elevated plasma levels of pro-inflammatory cytokines [61–63], although it seems that the plasma levels of cytokines are dependant on the etiology of heart failure [64, 65]. Furthermore, plasma levels of pro-inflammatory cytokines seem to increase with disease severity and have predictive prognostic value [61, 66–69]. Whether systemic inflammation is an integral part of the pathophysiology of CHF or whether it represents an epiphenomenon is not clear. Cardiomyocytes [70, 71], immune cells [72], liver [73, 74], gut [75] and skeletal muscle cells [76] represent putative sources of the increased cytokine levels reported in CHF. However, it is not known to what extent different cell types contribute to the increased systemic cytokine concentrations. Interleukin (IL)-6 and IL-8 are produced in skeletal muscle of healthy young men and released into the systemic circulation during exercise [77]. Tumor necrosis factor (TNF)-a has also been reported to be produced in skeletal muscle fibers of healthy, young men [76], although its release to the

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systemic circulation has not been documented. Moreover, studies indicate that elevated plasma levels of IL-6 and TNF-a might have deleterious effects on heart function [71, 78]. The fact that skeletal muscle produces cytokines [42, 76] and can act as an endocrine organ [77] could be of therapeutic interest in CHF and should therefore be investigated further. There are reports of increased skeletal muscle expression of IL-1b and TNF-a in a CHF rat model [79] as well as in CHF patients [42]. Also, Tsutamoto et al. demonstrated a higher IL-6 concentration in the femoral vein than in the femoral artery in a study including 80 patients with CHF of various etiology and an average NYHA class of 2.4 [80]. Whether skeletal muscle is a contributor to the systemic low-grade inflammation associated with CHF is however not clear. Theoretically, such a skeletal muscle cytokine production might have negative impact on the skeletal muscle itself [79, 81–84] and on the heart [71, 78, 85–87], thereby possibly creating a vicious cycle. Although cytokines produced in skeletal muscle probably influence systemic cytokine levels, there seems to be a large difference in the concentration of several cytokines between blood and skeletal muscle [88]. As recently reviewed, the anti-inflammatory effect of whole-body training in CHF patients, as reflected by decreased levels of pro-inflammatory cytokines in plasma, seems well documented [89]. Exercise training also reduces the local inflammation in skeletal muscle [82]. Possibly, some of the beneficial effects of exercise training in this patient group might be mediated by reduced systemic inflammation secondary to decreased skeletal muscle production, and release, of pro-inflammatory cytokines. A possible role for extracellular matrix (ECM) Research on muscular fatigue in CHF has focused on the skeletal muscle fiber itself, while possible alterations of the adjacent extracellular matrix (ECM) and its components have apparently not been explored in detail. Force transmission from the myocytes to the bone is dependent on the structural integrity between individual muscle fibers and the ECM [90]. The connective tissue, dominated by collagen, is of particular importance for this force transmission as it interacts closely with the contractile elements of the muscle [91]. Furthermore, proteoglycans are of importance in linking together the fibrous structures of the ECM [92, 93]. Alterations in ECM components can therefore contribute to decreased resistance to fatigue. Interestingly, biomarkers of ECM remodeling and collagen turnover were recently demonstrated to be positively correlated to both mortality and morbidity in CHF patients [94]. Matrix metalloproteinases (MMPs) are important modulators of ECM, and increased activity of these

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proteins has been reported in skeletal muscle of CHF rats at about 3 and 6 weeks after induction of heart failure [95, 96]. A follow-up study found that increased MMP activity and collagen content in skeletal muscle at 6 weeks post-infarction were accompanied by increased fatigability of the isolated soleus muscle in these animals [88]. Interestingly, at 18 weeks post-infarction, all parameters had returned to Sham level. Hence, alterations within the ECM and the accompanying skeletal muscle fatigue seem to be temporary phenomenon. Although one study has reported increased fibrosis in skeletal muscle of cachectic CHF patients [39], the role of skeletal muscle ECM in CHF patients remains to be explored in clinical studies.

Myopathy versus deconditioning Experimental studies that control for deconditioning As presented, many studies suggest that CHF induces intrinsic alterations in skeletal muscle. However, we do not know whether these changes truly reflect pathophysiological mechanisms of the disease or whether they are mainly related to decreased activity in CHF patients compared their age-matched, healthy peers [97]. Possibly, there could be a combination of these two alternative explanations. To our knowledge, two animal studies have included monitoring of spontaneous activity level in the investigation of skeletal muscle properties in confirmed CHF, both in a rat post-infarction CHF model. Simonini et al. demonstrated a fiber-type shift toward a less fatigue-resistant phenotype, as well as decreased oxidative capacity in the skeletal muscle of CHF rats compared to Sham [98]. In their experiments, activity level was similar in the two groups 8 weeks after induction of heart failure [98]. Similarly, Lunde et al. later reported equal activity levels in CHF and Sham rats at 6 weeks post-infarction [52], at which time they found a marked reduction in the rate of Ca2? removal from the cytosol and a marked slowing of relaxation of the soleus muscle in the CHF group during a fatigue protocol. A third study found reduced PCr resynthesis rate and a downregulation of b-adrenoceptor density in skeletal muscle of rats with myocardial infarction despite a spontaneous activity level equal to that of control animals [99]. However, in this study, objective criteria for CHF, like edema or hemodynamic deteriorations, were not measured. Nevertheless, these three studies indicate that skeletal muscle alterations can take place independently of deconditioning in CHF rats. The relevance of these experimental studies is however largely dependent on CHF rats displaying increased skeletal muscle fatigue analogous to what is reported in patients. All experimental studies that suggest altered

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contractile function and increased skeletal muscle fatigue in post-infarction CHF rats compared to Sham operated rats performed their contractile experiments about 6 weeks after induction of heart failure [50, 52, 60, 100, 101]. Whether these findings can be reproduced at later time points, or whether they represent temporary, more acute phenomenon, is not known. The first experimental study to include an isotonic fatigue protocol, thus allowing the muscle to shorten during stimulation, has recently been published [102]. This study could not reproduce previous findings from isometric fatigue protocols of increased skeletal muscle fatigability in CHF rats. Importantly, results from animal studies are not necessarily relevant for heart failure patients. Additionally, the relatively acute effects reported in animal models of heart failure are probably most relevant to the acute stage of human heart failure and less relevant to the chronic heart failure condition [65]. Therefore, animal studies should focus on more long-term effects in order to be relevant for the setting of human chronic heart failure. Clinical studies that control for deconditioning In 1996, Vescovo and colleagues concluded that CHF is accompanied by a disease-specific myopathy that is not related to reduced activity level, i.e., deconditioning [103]. This conclusion was based on the comparison of skeletal muscle atrophy and fiber-type changes in the gastrocnemius muscle of CHF patients with five patients restricted to bed for over 1 year due to stroke. They found that the CHF patients had a fiber-type switch toward a faster phenotype, whereas the bed-restricted stroke patients displayed a fibertype switch toward a slower phenotype. On this basis, they concluded that these two processes represent separate mechanisms and that the fiber-type redistribution in CHF patients is probably not related to deconditioning. Whether stroke patients restricted to bed for over 1 year represent an adequate control group if one wants to investigate skeletal muscle adaptations to deconditioning relevant for CHF patients is questionable. Previous studies have actually demonstrated that inactivity encompasses a switch toward a faster phenotype [104–106], in accordance with what is found in CHF patients. Two of the 5 stroke patients had 100% type I muscle fibers, indicative of a process of more pathological character, possibly involving a selective apoptosis of type II fibers. Another study compared skeletal muscle properties in CHF patients with healthy controls with matching VO2peak and concluded that the skeletal muscle abnormalities seen in CHF could not be due to deconditioning alone [45]. Again, one can discuss whether controls matched for VO2peak is a valid control group as such a poor exercise capacity, despite normal heart function, implies either an

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extreme degree of deconditioning, beyond what can be attributed to the CHF group, or other concurrent condition limiting exercise capacity. In the literature, these two clinical studies are interpreted as ‘‘proof of principle’’ to the statement that deconditioning is not the primary cause of altered skeletal muscle properties in CHF patients. Interestingly, Miller et al. recently reported that CHF patients, when controlled for activity level, had an altered quantity and functionality of the myosin molecule in skeletal muscle, accompanied by a reduced maximal Ca2?activated tension development MHC I muscle fibers [107]. Additionally, CHF patients had decreased cross-bridge kinetics and an increased myosin attachment time, possibly as a compensatory mechanism for a myosin protein loss [108]. This finding represents a potential mechanism for the increased skeletal muscle fatigue in CHF patients and deserves further investigation. A recent study showed that intracellular signaling pathways might be altered in CHF patients to promote skeletal muscle atrophy and dysfunction through modulation of myofilament protein metabolism [109]. The same research group also demonstrated reduced knee extensor function in CHF patients compared to controls. Importantly, both these studies thoroughly controlled for activity level between CHF patients and healthy subjects [110].

Similar findings in CHF, deconditioning and chronic obstructive pulmonary disease (COPD) The above-mentioned skeletal muscle alterations reported in human studies are compatible with deconditioning (Table 2). Furthermore, detraining, defined by cessation or a marked reduction in training, seems to encompass the same muscular adaptations as deconditioning. Studies have demonstrated a reduction in the activity of oxidative enzymes [104, 105, 111–117] as well as ATP production [115], muscle atrophy [106, 116, 118–120] and a fiber-type switch toward a faster phenotype [104–106] in response to training cessation. Similarly to what is reported in CHF and deconditioning, the results regarding capillarisation are less clear [105, 112, 113]. Although experimental studies have found increased apoptosis in response to muscle unloading [121, 122] and that apoptosis can be reduced by training the muscle [123], clinical studies to confirm these findings have to our knowledge not been performed. Skeletal muscle characteristics in CHF patients and chronic obstructive pulmonary disease (COPD) patients are also strikingly similar, as both patient groups display muscle characteristics similar to what is reported in deconditioning/ detraining (Table 2). Given that CHF and COPD represent two distinct different pathophysiological processes, it is reasonable to assume that a common denominator, like

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Table 2 A comparison of skeletal muscle properties reported in the state of CHF, COPD and deconditioning in clinical studies. Only controlled studies are included Relevant parameter

CHF References

COPD :/;/l

References

Deconditioning/detraining :/;/l

:/;/l

References

Oxidative capacity

[23, 34–36]

;

[163–168]

;

[105, 169–171]

;

Atrophy

[37, 38]

:

[167, 172, 173]

:

[105, 169, 174–180]

: :

Apoptosis

[39–42]

:

[181]

:

[181]

Altered fiber-type distribution

[35, 36, 43]

:

[163, 168, 172, 182–184]

:

[105, 106, 180, 185]

:

Altered intracellular Ca2? handling

[58, 59]

l

[183, 186]

l

[187]

:

Inflammation

[42, 81]

:

[184, 188–192]

l

Capillarisation

[26, 34–36, 43–46, 48]

l

[172, 183, 184, 193, 194]

l

[105, 169, 175]

l

Isolated skeletal muscle fatigability

[24–32]

:

[168, 195–197]

:

[198–200]

:

References in parenthesis. CHF congestive heart failure, COPD chronic obstructive pulmonary disease, : increase, ; decrease, l studies are conflicting and conclusion cannot be made

reduced activity level, might be responsible for the altered skeletal muscle properties in these two patient groups. Importantly, studies using activity monitors have demonstrated that both CHF and COPD patients are markedly inactive in daily life compared to age-matched healthy controls [124, 125]. Similar findings have been reported using questionnaires adapted to assess physical activity in the elderly [126, 127]. As previously reviewed [128], aging is known to bring along many of the same skeletal muscle adaptations as seen in CHF, COPD and deconditioning. However, the effects of aging when comparing these different states are controlled for given that the compared groups are age matched.

Can exercise training reverse skeletal muscle alterations in heart failure? Studies from the late 1970s and the early 1980s [129, 130] suggested a role of exercise training in the rehabilitation of CHF patients. Subsequent studies demonstrate that exercise intervention increases VO2peak [131–134], improves quality of life [131–135] and reduces mortality [131, 136, 137] in these patients. Exercise training also increases peak cardiac output in CHF patients, either through increased stroke volume, increased heart rate (HR) or an increase in the product of stroke volume x HR [132, 138–143]. It should be noted that not all studies report such an effect [143–145]. Although the muscle of CHF patients seems to be abnormal at baseline, exercise intervention studies find these abnormalities to be reversible (Table 3). The effect of local exercise training of a small muscle group, thus avoiding restricted blood flow to the muscle due to reduced cardiac function, has been investigated in five studies [146–150] (Table 3). This type of training increases peak work load [148] and endurance [149, 150]. Oxidative capacity of the

muscle is also improved as reflected either by increased activity of key aerobic enzymes [146, 148, 149] or by an increase of intracellular pH and PCr levels both at rest and during work [147, 150]. Magnusson et al. also reported increased capillary to fiber ratio as well as increased peak work rate during one-legged knee extension [148]. Systemic exercise training, like cycling, stair climbing or bilateral knee extensor training, consistently leads to a higher VO2peak and improved exercise tolerance in CHF patients [82, 145, 151, 152]. Several factors may account for this improvement, and improved oxidative capacity is a candidate factor [82, 132, 140, 153, 154]. This type of training also reduces oxidative stress and the level of inflammatory cytokines in skeletal muscle [42, 155] and results in skeletal muscle hypertrophy [145, 156] as well as reduced apoptosis [42]. Interestingly, the transforming growth factor-b-related cytokine myostatin was recently identified as an important mediator of cardiac-induced skeletal muscle wasting and cachexia in animal studies [157]. Clinical studies should be performed to see whether myostatin represents the link between cardiac failure and skeletal muscle wasting in the clinical setting of CHF. Training has been reported to induce a fiber-type shift toward a more fatigue-resistant phenotype [158], but this failed to be confirmed in later studies [146, 156, 159, 160]. The same controversy is true for capillarisation, as one study reported increased capillary to fiber ratio after training [152], whereas others did not [145, 160, 161]. In order to directly compare training effects on skeletal muscle properties of CHF patients to that of the healthy, age-matched population, studies that train both groups would be of interest. To date, only two such studies exist to our knowledge. These show that skeletal muscle of CHF patients is at least as trainable as that of controls and that pre-training alterations in skeletal muscle normalizes compared to controls after few weeks of training [59, 162].

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Table 3 Effects of exercise training on intrinsic properties of skeletal muscle in CHF patients References

Patient characteristics

Endpoints to evaluate

Effect of training

CHF etiology: IHD

Peak power

NYHA: 2.4 (mean)

Ca2? handling

Increase in peak power similar to controls after 6 weeks of training No effect on Ca2? release rate or leak in the CHF group

Fiber-type distribution

Unaltered fiber-type distribution

Oxidative capacity VEGF

Increased CS activity. Anaerobic enzymes unaltered mRNA and protein level of VEGF increased

Oxidative capacity

Increase in intracellular pH and PCr level without changes in blood flow


Oxidative capacity

Increased activity of CS and HAD. PFK unaltered

NYHA: II(5), III(5), IV(1)

Capillarisation

Increased VO2max and peak work load during onelegged exercise

Local exercise training N: CHF(/healthy controls for baseline comparison) Munkvik et al. [59]

N: 11 Gustafsson et al. [146]

CHF etiology: IHD, ICM, HT NYHA: II(4), III(4) N: 8

Ohtsubo et al. [147]

CHF etiology: ICM NYHA: II(6), III(1) N: 7/7

Magnusson et al. [148]

N: 11 Gordon et al. [149]

CHF etiology: IHD, ICM, HT

Oxidative capacity

Increased capillary/fiber ratio Increased CS activity; PFK unaltered

NYHA: II(8), III(8) N: 16 Stratton et al. [150]

CHF etiology: IHD, ICM, VHD

Oxidative capacity

Increased intracellular pH, both during rest and work Reduced PCr utilization during exercise

NYHA: I(2), II(7), III(1)

Increased PCr resynthesis rate

N: 10

Increased exercise duration

Systemic exercise training Wisloff et al. [132]

CHF etiology: IHD

PGC-1a

Increased PGC-1a in response to interval training

NYHA: 2.5 (mean)

Ca2? handling

Increased rate of Ca2? reuptake in response to interval training


Not altered by training

N: 27, of which 9 served as controls Harjola et al. [159]

CHF etiology: IHD, ICM NYHA: I(2), II(7), III(5) N: 17, of which 9 served as controls

Gielen et al. [82]


Systemic aerobic capacity

Increased VO2max

NYHA: II(18), III(2)

Oxidative capacity

Reduced iNOS and nitrotyrosine content paralleled by an increased

N: 20, of which 10 served as controls Hambrecht et al. [151]

Cytochrome c oxidase activity



Increased VO2max


IGF-1

Increased IGF-1 and reduced IGF-1 receptor levels

N: 18, of which 9 served as controls Linke et al. [42]



Increased VO2max


Local inflammation

Reduced oxidative stress and apoptosis

N: 23, of which 11 served as controls/12 Keteyian et al. [161]

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Reduced expression of TNFa and IL1b



Increased VO2max in men but not in women

NYHA: II–III

Capillarisation

No change in endothelial cell/muscle fiber ratio

N: 15

Oxidative capacity

Unaltered enzyme activity


Increased MHC1 in men, but not in women

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429

Table 3 continued References

Patient characteristics

Endpoints to evaluate

Effect of training

Gielen et al. [155]



Increased VO2max


Local inflammation

Reduced mRNA level of TNF-a, IL-1b and IL-6

N: 20, of which 10 served as controls/10 Larsen et al. [201]


Reduced iNOS expression both in mRNA and protein level Fiber-type size, area and distribution

Trend toward increased thickness for all fiber types.

Antioxidant enzyme-related genes

Upregulation of genes encoding copper zinc superoxide dismutase and gluthatione peroxidase

Rate limiting metabolic enzymes

PFK activity increased; Key aerobic enzymes unaltered

N: 27, of which 15 served as controls CHF etiology: IHD, ICM


Unaltered capillary/fiber ratio

Capillarisation Systemic aerobic capacity

Increased VO2max and exercise tolerance

NYHA: II(5), III(4)

Capillarisation

Increased capillary/fiber ratio



No effect on fiber-type distribution

NYHA: II(9), III(7)

Fiber size

Increased cross-sectional area of all fiber types



Increase in type I fibers; Decrease in type II fibers


Mitochondrial ultrastructure

Increased surface density of cytochrome c oxidasepositive mitochondria, inner mitochondrial membrane and mitochondrial cristae

NYHA: II-III N: 15/15 Ennezat et al. [202]

CHF etiology: IHD, ‘‘nonischemic’’ heart disease

Trend toward an increase in type IIb and decrease in type I fiber area

NYHA: III(14) N: 14, of which 4 served as controls Kiilavuori et al. [160]

CHF etiology: IHD, ICM NYHA: II(15), III(12)

Scarpelli et al. [152]

No change in fiber-type distribution

N: 9 Tyni-Lenne et al. [156]

N: 16, of which 8 served as controls Hambrecht et al. [158]

N: 18, of which 9 served as controls Tyni-Lenne et al. [153]


Oxidative capacity

NYHA: II(9), III(7)

Increased activity of CS and LDH Increased VO2max during bilateral knee extension

N: 16, of which 8 served as controls Belardinelli et al. [145]

Hambrecht et al. [140]



Increased VO2max despite unaltered peak cardiac output


Capillarisation

Unaltered capillary/fiber ratio

N: 27, of which 9 served as controls

Fiber size

Hypertrophy of type I and type II fibers



Increased VO2max


Oxidative capacity

Increased volume density of mitochondria

N: 22, of which 10 served as controls Adamopoulos et al. [154]

CHF etiology: IHD

Increased cytochrome c oxidase-positive mitochondria Increased maximal leg oxygen consumption Oxidative capacity

Reduced PCr depletion during exercise

NYHA: II(7), III(5)

Reduced PCr recovery half-time

N: 12/15

Decreased ADP during exercise Increased exercise tolerance

CM cardiomyopathy, HT hypertension, ICM idiopathic cardiomyopathy, IHD ischemic heart disease, NYHA New York Heart Association classification of clinical signs of CHF, VHD valvular heart disease

Conclusion Skeletal muscle alterations in CHF patients are similar to what is found in deconditioning/detraining and COPD and

are normalized in response to training. Few studies have thoroughly controlled for the effect of deconditioning when describing skeletal muscle properties in CHF patients. Interestingly, the training intervention studies to include a

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control group beyond baseline characteristics indicate that skeletal muscle of CHF patients adapts similarly to training as that of their age-matched, healthy peers. Whether this is the case irrespective of disease severity or degree of cachexia is not known. It is likely that the intrinsic alterations of skeletal muscle in CHF patients are largely due to deconditioning, but the possible contribution of a diseasespecific myopathy should be pursued in future clinical studies that thoroughly control for the effect of deconditioning.

Future perspectives Future animal studies should include assessment of skeletal muscle function and characteristics at later time points after induction of CHF than what has previously been done. Possibly, the relative acute experimental models of heart failure are most relevant to the acute stage of human heart failure and less appropriate to investigate skeletal muscle properties in chronic heart failure patients. Such studies should therefore focus on more long-term effects of in order to be relevant for the setting of human chronic heart failure. Combining atherosclerotic animals with the postinfarction CHF rat model should be considered. To control for the impact of activity level when investigating skeletal muscle properties in CHF patients, future clinical studies should include meticulous monitoring of activity level, e.g., by the use of pedometers, accelerometers or more sophisticated activity monitoring systems [124] where the time spent in different activities and positions can be accurately measured. More training intervention studies should include controls groups in the training regimen so that training effects in CHF patients could be directly compared to controls. It seems that skeletal muscle of CHF patients and healthy subjects responds similarly to training when the pumping capacity of the heart is not a limiting factor. Whether the muscular adaptations to whole-body training are different between these two groups remains to be answered. Future studies to directly compare the skeletal muscle effects of such training regimens are therefore of interest. Studies should differentiate between subpopulations in this patient group, particularly with regard to gender, clinical severity and etiology, as these factors could influence skeletal muscle properties in different ways. The possible role of myostatin as a link between the failing heart and skeletal muscle cachexia is interesting and merits further investigation in clinical studies. Whether CHF patients with substantially elevated systemic cytokine levels respond similarly to training as patients with close to normal cytokine levels should be investigated.

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Heart Fail Rev (2012) 17:421–436 Conflict of interest Drs Rehn, Munkvik, Lunde, Sjaastad and Sejersted have no conflicts of interests or financial ties to disclose.

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