Exercise Intolerance in Chronic Heart Failure

Circulation Journal REVIEW Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Exercise Intolerance in Chronic Heart Failure – Skeletal Muscle Dysfunction and Potential Therapies – Koichi Okita, MD, PhD; Shintaro Kinugawa, MD, PhD; Hiroyuki Tsutsui, MD, PhD

Chronic heart failure (CHF) is characterized as a clinical disorder displaying exercise intolerance; patients typically complain of early muscular fatigue. Previously, it was thought to be simply a failure of perfusion to the exercising musculature and consequent early onset of intramuscular acidosis in CHF. However, improved hemodynamics by cardiotonic agents did not lead to an increase in exercise tolerance. Later studies have shown that intrinsic skeletal muscle abnormalities exist in patients with CHF and could induce the early anaerobic metabolism that limits exercise tolerance. We review the clinical importance of skeletal muscle abnormalities in patients with CHF. Considering the significance of peripheral muscle abnormalities and their development might help physicians and researchers better understand the mechanisms of well-established exercise training and pharmacological therapies that have been shown to improve the prognosis for CHF, and thus develop potential novel therapies. (Circ J 2013; 77: 293 – 300)

Key Words: Exercise tolerance; Exercise training; Heart failure; Myopathy; Skeletal muscle

xercise intolerance is a major clinical manifestation in exercise with and without dobutamine infusion. Under infu- patients with chronic heart failure (CHF). It was orig- sion of dobutamine, both cardiac output and leg blood flow E inally considered to be the result of a failure of perfu- remarkably increased, whereas pulmonary pressure decreased sion to the exercising musculature and consequent early onset during rest and exercise. However, under such favorable he- of intramuscular acidosis. Under this theory, cardiotonic agents modynamic conditions, there was no significant improvement were administered to improve symptoms and exercise toler- in oxygen uptake and also no change in lactate production. ance in patients with CHF. However, the therapy had no effect Those results mean that the exercising muscle may not extract on exercise capacity despite hemodynamic improvement.1,2 oxygen even with its increased delivery. They also demon- Subsequently, the discrepancy between exercise tolerance and strated that intramuscular energetic metabolism in the leg mus- indices of left ventricular function has been reported.3,4 With cle showed no change despite the hemodynamic improvement this evidence, the study target shifted from central hemody- by dobutamine infusion in the same experimental setting. This namics to the peripheral circulation and skeletal muscle condi- evidence suggested that peripheral skeletal muscle abnormali- tion. The purpose of the present review is to summarize the ties might exist and influence exercise capacity in patients with widespread skeletal muscle abnormalities originating from re- CHF. A number of studies have demonstrated a significant duced perfusion and additive factors in patients with CHF, and relationship between exercise tolerance and skeletal muscle to discuss the mechanisms for such alterations and their rela- abnormalities.5–19 tion to established therapeutic tools, angiotensin-converting Subsequently, the discrepancy between exercise tolerance enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARB), and resting left ventricular ejection fraction in CHF has been β-blockers, and exercise training. shown.3,4 Why are resting indices of cardiac function not related to exercise tolerance? Skeletal muscle abnormalities might Exercise Intolerance and be initially caused by reduced peripheral blood flow followed by over-activation of neurohormonal factors (discussed later). Central Hemodynamic Function Additional undernutrition and physical deconditioning might In 1984, Wilson et al reported convincing evidence of the al- worsen this disorder. On the other hand, cardiovascular drugs ternative pathogenesis for CHF.2 They simultaneously measured could modify this pathophysiology. The original severity of central hemodynamics, leg blood flow, blood gas and lactate cardiac dysfunction should correlate with skeletal muscle dys- levels in patients with CHF by inserting catheters into the ra- function and exercise tolerance, but many other related factors dial artery, pulmonary artery and femoral vein, and perform- might contribute to their discordance. In addition, there is not ing respiratory gas analysis during graded bicycle ergometer a dependable parameter that accounts for cardiac functional

Received October 3, 2012; revised manuscript received December 22, 2012; accepted January 6, 2013; released online January 19, 2013 Department of Sport Education, Hokusho University, Ebetsu (K.O.); Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo (S.K., H.T.), Japan Mailing address: Koichi Okita, MD, PhD, Department of Sport Education, Hokusho University, 23 Bunkyodai, Ebetsu 069-8511, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-12-1235 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Circulation Journal Vol.77, February 2013 294 OKITA K et al.

Table. Skeletal Muscle Abnormalities in Chronic Heart Failure5–19 Morphology Histology Biochemistry Muscle wasting Type I fibers ↓ Oxidative enzymes ↓ Muscle fiber atrophy (IIb) ↓ ↔ Type II fibers ↑ Glycolytic enzymes ↑ ↔ Shift from type IIa to IIb Capillary density ↓ ↔ Shift from MHC1 to MHC2 Mitochondrial volume ↓ eNOS ↓ Apoptosis ↑ ↑, increased; ↓, decreased; ↔, unchanged; eNOS, endothelial nitric oxide synthase; MHC, myosin heavy chain. reserve. Resting cardiac function may not always reflect the Does Skeletal Muscle Metabolism Limit Exercise Capacity cardiac function during exercise. In fact, oxygen uptake and in CHF? cardiac output correlatively increase during incremental exer- Notably, in most studies demonstrating impaired muscle me- cise in patients with CHF.4 tabolism in CHF, only local muscle exercises such as calf plantar-flexion or forearm flection were used. With such local Morphological and Biochemical Abnormalities muscle exercises, regional blood flow to the exercising muscles is not reduced, even in CHF.5 Therefore, in those experi- in Skeletal Muscle (Table) mental settings, it could be concluded that skeletal muscle me- From the latter half of the 1980 s, there has been intensive re- tabolism might limit exercise capacity in CHF. However, would search of the peripheral muscles of CHF patients.5–15 Morpho- blood flow remain normal in systemic exercise with large mus- logical, histological, biochemical, metabolic and energetic cles? In fact, exercise intolerance is evaluated with systemic analyses were conducted by muscle biopsy, electromyography, exercises, in which the large muscles are recruited. In such near-infrared spectroscopy, and magnetic resonance technol- exercises, the blood flow to the exercising muscles is restrict- ogy. A common pathological condition in CHF is muscle ated according to cardiac pump function in CHF.1,2 rophy, often corresponding with cardiac cachexia and con- Jondeau et al20 performed a convincing study in patients tributing to exercise intolerance and poor prognosis.13,14 A with CHF using a leg bicycle ergometer, with the addition of widespread abnormality in skeletal muscle during the course an arm ergometer when the patient’s gas exchange ratio was of CHF is a change from IIa to IIb fibers.8,13,14,16–18 The type I >1.0 by respiratory gas analysis. They examined the gain of fibers decrease in number, while the type II fibers appeared to oxygen uptake by the addition of arm exercise to almost max- increase in number, but decrease in size. Alterations in the imal leg exercise in both CHF patients and normal controls. myosin heavy chain (MHC) composition appeared to mirror Although the normal controls showed no significant gain of these changes in fiber type.12,18 A shift from the slow oxidative oxygen uptake with additional arm exercise, oxygen uptake form (MHC1) to the fast form (MHC2a and MHC2b) has been was significantly increased in the patients with CHF. In other reported in patients with CHF and that change correlated with words, the cardiac pump capacity had not reached its limit exercise tolerance and the clinical severity of CHF.12,18 Mito- during usual maximal leg exercise. Moreover, the extent of the chondrial volume and the surface density of the cristae were increase in oxygen uptake significantly correlated with clinical reduced.9,13,14 Aerobic enzymes were reduced, while glycolytic severity, as indicated by peak oxygen uptake, in patients with enzymes tended to be increased.13,14,16 Those alterations indi- CHF. Thus, hemodynamic capacity is not the limiting factor cate a shift from aerobic to anaerobic metabolism, which re- in the systemic exercise capacity of CHF patients. sults in the early onset of fatigue and exercise intolerance.5–19 What factor actually limits exercise capacity in CHF? Be- In addition, impaired skeletal muscle metabolism and altered sides the metabolic and hemodynamic capacity, perception of ergoreflex are also demonstrated in CHF.13,18 effort by the central nervous system is an important factor that limits exercise.21 How can the skeletal muscle metabolism at peak exercise be characterized? To resolve this problem, we Skeletal Muscle Metabolism performed measurements of peak muscle metabolism in CHF Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) patients on an upright bicycle ergometer using 31P-MRS com- is a valuable method by which we can measure the intramus- bined with a metabolic freeze technique,15,22,23 which retained cular energetic metabolism and metabolic byproducts of exer- the metabolic byproducts and muscle pH for 6 min through an cising muscle. Using this technique, a number of studies have instantaneous circulatory occlusion to the muscle. At the end demonstrated that intramuscular metabolism is impaired dur- of the exercise, phosphocreatine was depleted in both CHF ing exercise in CHF.5–7,10,11,13,15 Patients show earlier muscular patients and normal controls; thus, the exercise limitation was acidosis and greater phosphocreatine depletion compared with consistent with the metabolic limitation in skeletal muscle. normal controls. We also reported that the impaired muscle Furthermore, the intramuscular pH was more severely lowered metabolism in CHF was still significant when exercise proto- in the CHF patients than in controls.15 Taken together with the cols were adjusted according to muscle volume or muscle findings from Jondeau et al20 and LeJemtel, skeletal muscle strength.7,15 The abnormal muscle metabolism was closely con- metabolism reaches its limit at the end of exercise, even with nected to the aforementioned intrinsic muscle abnormalities considerable cardiac reserve, in patients with CHF.15,20 Thus, and is the primary mechanism of the easy fatigability and ex- skeletal muscle metabolism limits the exercise capacity of CHF ercise intolerance in CHF patients. patients. On the other hand, the limitation of skeletal muscle metabolism might correspond with circulatory capacity in normal subjects (Figure 1). Skeletal muscle abnormalities accompanied by early anaero-

Circulation Journal Vol.77, February 2013 Exercise Intolerance in CHF 295

Figure 1. Muscle hypothesis in CHF. Skeletal muscle dysfunction rather than cardiac dysfunction limits exercise tolerance in most patients with CHF. CHF, chronic heart failure.

bic metabolism might lead to exercise limitation. In many Malnutrition patients with CHF, hemodynamic improvement is not acutely Patients with CHF sometimes have anorexia and malabsorp- translated into increased exercise tolerance because skeletal tion for psychological reason or because of the gastrointestinal muscle might limit their exercise capacity.1–4,13–15 These pa- congestion related to right heart failure.13 Previous studies ex- tients could effectively increase their exercise tolerance by amined the skeletal muscle abnormalities in patients with an- cardiac rehabilitation. On the other hand, in a subgroup of CHF orexia nervosa.16 In that disorder, there is type II dominant patients, anaerobic metabolism might be primarily mediated muscle wasting and reduction in metabolic enzyme levels. by impaired oxygen delivery to the skeletal muscle; thus, cardiac function might limit their exercise tolerance.4,24 Most of Hypoperfusion and Hypoxia these patients could not increase their exercise tolerance by It remains unclear whether hypoperfusion could directly medi- cardiac rehabilitation because of their low hemodynamic ca- ate skeletal muscle dysfunction. Peripheral blood flow is de- pacity and they might have poor prognosis.25,26 termined by cardiac function, capillary density and vasodilatory capacity. Information about capillary density in the skeletal Etiology of Skeletal Muscle muscles of CHF patients is inconsistent among studies, prob- ably because of different methodologies.13,14,17 Increased vas- Abnormalities (Figure 2) cular tonus and reduced vasodilatory capacity are peculiar to Deconditioning (Physical Inactivity) the patient’s condition.13,17 Physical deconditioning results in type I dominant muscle wast- Recently, a number of studies have reported skeletal mus- ing, alteration in muscle fiber numbers (type I are decreased cle dysfunction in chronic obstructive pulmonary disease or unchanged; type II are increased or unchanged), and meta- (COPD).16,29 Muscle wasting, the tendency of muscle fiber type bolic enzyme changes (aerobic increases or is unchanged; to shift from type I to type II and a reduction in aerobic en- glycolytic decreases or is unchanged).16 In CHF patients, phys- zymes are often observed in COPD. In the hypoxic condition, ical activity is often restricted, so deconditioning mediated muscle wasting and muscular dysfunction could occur because skeletal muscle alteration may also occur concomitantly with of a reduction in testosterone, increased inflammatory cyto- disease-based degradation. Some groups have emphasized the kines and enhanced oxidative stress.29 Interestingly, oxygen great contribution of deconditioning to skeletal muscle dys- supplementation partly improves the skeletal muscle dysfunc- function in CHF and it could be reversed by exercise train- tion in COPD patients.30 However, hypoperfusion in CHF ing.27 However, we could not normalize skeletal muscle dys- does not mean hypoxia. In fact, patients with CHF rarely show function even with intensive exercise training.28 Deconditioning peripheral hypoxia even during exercise.31 is a part of the mechanism of skeletal muscle abnormalities in CHF.

Circulation Journal Vol.77, February 2013 296 OKITA K et al.

Figure 2. Possible mechanisms for exercise intolerance in CHF from the very beginning of reduced peripheral blood flow modified by physical inactivity and undernutrition to skeletal muscle abnormalities and consequent exercise intolerance. The areas in which angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers and β-blockers could effect improvement are shown in the blue box (Left), whereas exercise training could be effective for all of the factors shown in the blue, violet (Middle) and green (Right) boxes. Dotted area shows therapeutic target of anabolic argents, such as testosterone. Cardiac resynchronization therapy could directly improve reduced peripheral blood flow. CHF, chronic heart failure; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; GH, growth hormone; IGF-1, insulin-like growth factor 1.

Growth Hormone (GH)/Insulin-Like Growth Factor 1 (IGF-1) CHF has not been clarified because of potential complications, Resistance such as acromegaly. Similar to patients with cancer or chronic inflammatory diseases, it has been reported that CHF patients show resistance Catabolic/Anabolic Imbalance to IGF-1 responsible for GH.14,32–38 Anker et al33 demonstrated Catabolic/anabolic imbalance, represented as aggravated cata- low or normal IGF-1 levels despite increased GH levels in CHF bolic and attenuated anabolic metabolism, is thought to be an patients with significant muscle wasting. They also showed important mechanism of skeletal muscle abnormality and that reduced local expression in IGF-1 and the blood IGF-1 other clinical orders in patients with CHF.18,33,37 Levels of level were related to decreased muscular volume and strength catabolic hormones, such as cortisol, catecholamines, and in CHF. GH/IGF-1 resistance in CHF might be partly explained angiotensin II, were significantly increased, whereas the levels by increased inflammatory cytokines.32–34 of anabolic hormones (testosterone, dehydroepiandrosterone In an animal model of CHF, increased expression of local sulfate [DHEAS]) and IGF-1 were decreased in patients with IGF-1 contributed to an improvement in muscle wasting, dys- CHF.38 These disorders were shown to relate to muscle wast- function, and overall survival rate.14,34 Clinical studies have ing, anemia, and the clinical severity and prognosis of CHF shown that treatment with GH increases left ventricular mass patients.32–39 Specifically, testosterone levels correlated with and improves both the hemodynamic and functional status exercise tolerance.39,40 Recently, a number of studies have ex- in patients with CHF because of dilated cardiomyopathy amined the usefulness of testosterone supplementation in pa- (DCM).14,35 In a double-blind, randomized, placebo-controlled tients with CHF.39–44 study of recombinant human GH in patients with DCM, there was a significant increase in the left ventricular mass of pa- Aggravated Muscle Protein Wastage tients given GH, but this was not accompanied by a change in Muscle protein degradation is regulated by lysosomal, Ca2+- clinical status.36 On the other hand, in CHF patients with GH dependent calpain and caspase and ATP-dependent ubiquitin- deficiency, GH replacement therapy increased exercise toler- proteasome systems.18,45–48 Muscle atrophy in diabetes melli- ance, flow-mediated vasodilation and left ventricular ejection tus, cancer, renal failure, starvation, and sepsis has been reported fraction, and reduced N-terminal pro-brain natriuretic peptide to be associated with enhanced activation of the ubiquitin- levels.37 However, the long-term outcome of GH therapy in proteasome system.49 That same system has been implicated

Circulation Journal Vol.77, February 2013 Exercise Intolerance in CHF 297

Figure 3. Therapeutic implications and potential therapeutic tools for exercise intolerance in chronic heart failure. CRT, cardiac resynchronization therapy; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker.

as an important contributor to the aggravated protein break- Oxidative Stress down and skeletal muscle atrophy in patients with CHF.45,50 It Over the past several decades, clinical and experimental stud- has been shown that increased IGF-1 reduces proteolysis and ies have provided substantial evidence that oxidative stress is atrophy.45,51,52 enhanced in CHF.66–72 The generation of reactive oxygen species (ROS) and the peroxidation of lipids are also enhanced in Apoptosis the skeletal muscle in CHF.67,69,71,72 Free radicals and ROS are TUNEL-positive nuclei have been detected more frequently produced via a mitochondrial respiratory chain, anaerobic me- in skeletal muscle cells from CHF patients than in normal tabolism (hypoxanthine degradation and acidosis), increased controls, suggesting accelerated apoptosis in CHF.18,19,45,50,53 sympathetic nerve activity, and increased proinflammatory cy- Furthermore, the incidence of apoptosis in skeletal muscle tokines in CHF.45,46 Mitochondria are the principal site of ROS cells related to both muscle wasting and exercise tolerance in production, so excessive ROS production may lead to mito- CHF18,53,54 and was associated with the circulating levels of chondrial damage and decreased oxidative capacity.67,69 Oxi- tumor necrosis factor-α (TNF-α).18,54,55 dative stress might also participate in accelerated apoptosis and atrophy of skeletal muscle fibers in CHF.14,19,32 Further- Inflammation more, oxidative stress is closely related to endothelial dys- CHF is associated with activation of the immune system and function by direct or indirect mechanisms,68,73 which also leads inflammation.56–58 Increased levels of TNF-α and interleukin- to exercise intolerance in CHF. 1β (IL-1β) are seen in patients with CHF.59–62 Inflammation aggravates skeletal muscle cell apoptosis and ubiquitin-depen- Neurohormonal Factors dent proteolysis.14,18,32,45 TNF-α directly induces skeletal mus- Over-activation of the renin-angiotensin system (RAS) is a cle protein loss and decreases contractile capacity, leading to landmark pathophysiologic change and an important factor in muscle wasting and dysfunction.17,32,63 IL-1β mediates muscle skeletal muscle abnormality in CHF.74 The RAS originally proteolysis by increased expression of atrogin-1 and induces plays a role in the growth of skeletal muscle and is related to the production of inducible nitric oxide synthase (iNOS), which exercise performance in humans, and the ACE gene is known might mediate oxidative stress.17,61,64 In addition, IL-1β de- as the athlete gene, based on the finding that athletes with the creases expression of genes regulating sarcoplasmic reticulum ACE genotype, representing lower activity of ACE, have high- Ca2+ ATPase (SERCA) and phospholamban, resulting in con- er endurance capacity.75,76 Elevated ACE activity is associated tractile dysfunction.17,65 Thus, the circulating levels of inflam- with increased levels of angiotensin II, which results in impaired matory cytokines correlate with deterioration in functional vasodilation and aggravates bradykinin degradation, leading capacity.56,60,62 The close linkage of inflammation with apop- to tissue hypoxia and reduced endurance capacity.13,19,74 In tosis and GH/IGF-1 resistance exacerbates muscle wasting addition, angiotensin II mediates muscle atrophy.77 and dysfunction.18,45,51 Increased sympathetic nerve activation (SNA), another important feature of CHF, contributes to peripheral vasoconstric- tion and limits skeletal muscle blood flow during rest and ex-

Circulation Journal Vol.77, February 2013 298 OKITA K et al. ercise, resulting in exercise intolerance.14,18 Inadequate perfusion the improvement in skeletal abnormalities with ACE inhibitor to exercising muscle is followed by increased ROS, triggering therapy have not been elucidated. muscle inflammation, and could contribute to the skeletal ab- Beta-blockers have been shown to improve symptoms, ex- normalities in CHF.14,18,19 The protective effect of β-blockers ercise capacity and mortality rates in patients with CHF.88–90 for skeletal muscle degeneration in CHF has been shown;14,18,19,78 In animal models of CHF, it has been demonstrated that β- however, it has not been clarified whether increased SNA con- blockers protect muscle protein oxidation.78 tributes directly to the skeletal muscle abnormalities in CHF. Another potential pharmacological strategy is the use of GH and/or IGF-1. In a subgroup of CHF patients with GH defi- Therapeutic Interventions for Skeletal Muscle ciency, GH replacement therapy improved clinical status and increased exercise tolerance.37 Because GH has potential side Dysfunction and Exercise Intolerance (Figure 3) effects, therapy specifically developed to increase local IGF-1 Exercise Training levels might be a novel way of improving the skeletal muscle Exercise training has novel pleiotropic effects and is now an abnormalities in CHF. In keeping with this concept, several established treatment for CHF, improving patients’ clinical out- studies have reported that testosterone supplementation im- comes and survival rates.79–81 There is no doubt that exercise proved exercise capacity, ventilatory efficiency, muscle training can effectively improve skeletal muscle abnormalities strength, and insulin sensitivity in patients with CHF without in CHF.14,17–19,27,28 We have also observed that exercise train- major side effects.39–44 Most recently, a meta-analysis con- ing improves skeletal muscle metabolism without improve- firmed the benefits of testosterone supplementation in CHF.91 ment of muscle blood flow.28 Notably, exercise training can be performed safely, because the exercise limitation in most CHF Cardiac Resynchronization Therapy (CRT) patients appears to be regulated by skeletal muscle metabo- CRT directly improves hemodynamics and slowly increases lism independent of cardiac reserve, as stated earlier.15 exercise capacity as a long-term treatment.92 The evidence also Aerobic training can increase mitochondrial and aerobic suggests the importance of skeletal muscle abnormalities in enzymes in skeletal muscle, leading to improvements in ener- the exercise intolerance of CHF patients. It is suggested that getic metabolism and exercise tolerance.14,17–19,27 Resistance CRT may gradually reverse many of the features of skeletal training can increase muscle bulk and also exercise toler- muscle abnormalities from upstream in the pathophysiologic ance.80,82 Levels of inflammatory cytokines, TNF-α and IL-1β, cascade, including SNA and inflammation Figure( 3).93 and of iNOS were reduced by exercise training, while expression of IGF-1 in skeletal muscle cell was increased, followed by inhibition of catabolic metabolism.17,18 It also increases Conclusions capillary density.17 Exercise-induced activation of Akt (serine/ We have summarized the clinical importance of skeletal mus- threonine kinase) and increased expression of endothelial (e) cle abnormalities in the exercise intolerance of patients with NOS and decreased expression of angiotensin I receptor and CHF. Therapeutic interventions affecting these abnormalities NAD(P)H oxidase can improve vasodilatory capacity and also seem to improve exercise intolerance and prognosis in CHF. decrease ROS production.73,83 These effects could be con- We hope that this review provides an opportunity for physi- nected with improved exercise tolerance, quality of life (QOL) cians and researchers to benefit from a global insight and meet and prognosis. the need for future therapeutic tools in the management of patients with CHF. Pharmacological Therapies Interventions that improve the hemodynamic incompetence Acknowledgments can alleviate symptoms, but cannot reduce the risk of disease This study was supported, in part, by Grant-in-Aid for Scientific Re- progression. In contrast, pharmacologic agents that block RAS search from Japan Society for the Promotion of Science, KAKENHI and SNA not only improve exercise tolerance and QOL, but (23500784). also reduce cardiovascular mortality.14,18,19,84 ACE inhibitors and ARB are established treatments for CHF, References 84 improving clinical symptoms and prognosis. Both of these 1. Maskin CS, Forman R, Sonnenblick EH, Frishman WH, LeJemtel vasodilators essentially inhibit RAS and angiotensin II, result- TH. Failure of dobutamine to increase exercise capacity despite he- ing in improvements in skeletal muscle dysfunction in humans modynamic improvement in severe chronic heart failure. Am J Car- and animal models of CHF.18,19 Researchers in a previous study diol 1983; 51: 177 – 182. performed muscle biopsies in patients with CHF to investigate 2. Wilson JR, Martin JL, Ferraro N. Impaired skeletal muscle nutritive flow during exercise in patients with congestive heart failure: Role the effects of RAS inhibition on skeletal muscle abnormali- of cardiac pump dysfunction as determined by the effect of dobuta- ties.85 After 6 months of treatment with either ACE inhibitors mine. Am J Cardiol 1984; 53: 1308 – 1315. or ARB, the slow oxidative form, MHC1, increased, and the 3. Rogers FJ. The muscle hypothesis: A model of chronic heart failure fast oxidative MHC2A and fast glycolytic MHC2b forms sig- appropriate for osteopathic medicine. J Am Osteopath Assoc 2001; 101: 576 – 583. nificantly decreased, and these changes were associated with 4. Nilsson KR, Duscha BD, Hranitzky PM, Kraus WE. Chronic heart increased exercise tolerance as reflected in increased peak failure and exercise intolerance: The hemodynamic paradox. Curr oxygen uptake in each group. It was also reported that ARB Cardiol Rev 2008; 4: 92 – 100. can prevent myocyte apoptosis, muscle atrophy, and changes 5. Wiener DH, Fink LI, Maris J, Jones RA, Chance B, Wilson JR. 86 Abnormal skeletal muscle bioenergetics during exercise in patients in MHC composition in an animal model of CHF. As men- with heart failure: Role of reduced muscle blood flow. Circulation tioned before, increased ACE activity may negatively affect 1986; 73: 1127 – 1136. skeletal muscle growth and endurance capacity,75 so its inhibi- 6. Mancini DM, Coyle E, Coggan A, Beltz J, Ferraro N, Montain S, et al. tion could contribute to improvement in oxidative capacity, Contribution of intrinsic skeletal muscle changes to 31P NMR skeletal muscle metabolic abnormalities in patients with chronic HF. including muscle fiber properties. In addition, ACE inhibitors Circulation 1989; 80: 1338 – 1346. might potentially inhibit angiotensin II-mediated downregula- 7. Nagai T, Okita K, Yonezawa K, Yamada Y, Hanada A, Ohtsubo M, tion of IGF-1.87 However, the precise mechanisms underlying et al. Comparisons of the skeletal muscle metabolic abnormalities in

Circulation Journal Vol.77, February 2013 Exercise Intolerance in CHF 299

the arm and leg muscles of patients with chronic heart failure. Circ J muscles in chronic hypoxemic patients: The effects of oxygen breath- 2004; 68: 573 – 579. ing. Muscle Nerve 1995; 18: 495 – 502. 8. Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and 31. Rubin SA, Brown HV, Swan HJ. Arterial oxygenation and arterial histology in ambulatory patients with long term heart failure. Circu- oxygen transport in chronic myocardial failure at rest, during exer- lation 1990; 81: 518 – 527. cise and after hydralazine treatment. Circulation 1982; 66: 143 – 148. 9. Drexler H, Riede U, Munzel T, Konig H, Funke E, Just H. Altera- 32. Strassburg S, Springer J, Anker SD. Muscle wasting in cardiac ca- tions of skeletal muscle in chronic HF. Circulation 1992; 85: 1751 – chexia. Int J Biochem Cell Biol 2005; 37: 1938 – 1947. 1759. 33. Anker SD, Volterrani M, Pflaum CD, Strasburger CJ, Osterziel KJ, 10. Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Doehner W, et al. Acquired growth hormone resistance in patients Mullen JL, et al. Contribution of skeletal muscle atrophy to exercise with chronic heart failure: Implications for therapy with growth hor- intolerance and altered muscle metabolism in HF. Circulation 1992; mone. J Am Coll Cardiol 2001; 38: 443 – 452. 85: 1364 – 1373. 34. Schulze PC, Späte U. Insulin-like growth factor-1 and muscle wast- 11. Massie BM, Simonini A, Sahgal P, Wells L, Dudley GA. Relation ing in chronic heart failure. Int J Biochem Cell Biol 2005; 37: 2023 – of systemic and local muscle exercise capacity to skeletal muscle 2035. characteristics in men with congestive HF. J Am Coll Cardiol 1996; 35. Acevedo M, Corbalán R, Chamorro G, Jalil J, Nazzal C, Campusano 27: 140 – 145. C, et al. Administration of growth hormone to patients with advanced 12. Vescovo G, Serafini F, Facchin L, Tenderini P, Carraro U, Dalla cardiac heart failure: Effects upon left ventricular function, exercise Libera L, et al. Specific changes in skeletal muscle myosin heavy capacity, and neurohormonal status. Int J Cardiol 2003; 87: 185 – chain composition in cardiac failure: Differences with disuse atrophy 191. as assessed on microbiopsies by a new electrophoretic micromethod. 36. Osterziel KJ, Strohm O, Schuler J, Friedrich M, Hänlein D, Heart 1996; 76: 337 – 343. Willenbrock R, et al. Randomised, double-blind, placebo-controlled 13. Clark AL, Poole-Wilson PA, Coats AJS. Exercise limitation in chron- trial of human recombinant growth hormone in patients with chronic heart failure: Central role of the periphery. J Am Coll Cardiol ic heart failure due to dilated cardiomyopathy. Lancet 1998; 351: 1996; 28: 1092 – 1102. 1233 – 1237. 14. Middlekauff HR. Making the case for skeletal myopathy as the major 37. Cittadini A, Saldamarco L, Marra AM, Arcopinto M, Carlomagno G, limitation of exercise capacity in heart failure. Circ Heart Fail 2010; Imbriaco M, et al. Growth hormone deficiency in patients with chron- 3: 537 – 546. ic heart failure and beneficial effects of its correction. J Clin Endo- 15. Okita K, Yonezawa K, Nishijima H, Hanada A, Ohtsubo M, Kohya T, crinol Metab 2009; 94: 3329 – 3336. et al. Skeletal muscle metabolism limits exercise capacity in patients 38. Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, with chronic heart failure. Circulation 1998; 98: 1886 – 1891. Medras M, et al. Anabolic deficiency in men with chronic heart fail- 16. Franssen FM, Wouters EF, Schols AM. The contribution of starva- ure: Prevalence and detrimental impact on survival. Circulation 2006; tion, deconditioning and ageing to the observed alterations in periph- 114: 1829 – 1837. eral skeletal muscle in chronic organ diseases. Clin Nutr 2002; 21: 39. Iellamo F, Rosano G, Volterrani M. Testosterone deficiency and 1 – 14. exercise intolerance in heart failure: Treatment implications. Curr 17. Duscha BD, Schulze PC, Robbins JL, Forman DE. Implications of Heart Fail Rep 2010; 7: 59 – 65. chronic heart failure on peripheral vasculature and skeletal muscle 40. Iellamo F, Volterrani M, Caminiti G, Karam R, Massaro R, Fini M, before and after exercise training. Heart Fail Rev 2008; 13: 21 – 37. et al. Testosterone therapy in women with chronic heart failure: A 18. Dalla Libera L, Vescovo G, Volterrani M. Physiological basis for pilot double-blind, randomized, placebo-controlled study. J Am Coll contractile dysfunction in heart failure. Curr Pharm Des 2008; 14: Cardiol 2010; 56: 1310 – 1316. 2572 – 2581. 41. Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone 19. Ventura-Clapier R, De Sousa E, Veksler V. Metabolic myopathy in treatment for men with chronic heart failure. Heart 2004; 90: 446 – heart failure. News Physiol Sci 2002; 17: 191 – 196. 447. 20. Jondeau G, Katz SD, Zohman L, Goldberger M, McCarthy M, 42. Malkin CJ, Pugh PJ, West JN, Van Beek EJR, Jones TH, Channer Bourdarias JP, et al. Active skeletal muscle mass and cardiopulmo- KS. Testosterone therapy in men with moderate severity heart fail- nary reserve: Failure to attain peak aerobic capacity during maximal ure: A double-blind randomized placebo controlled trial. Eur Heart bicycle exercise in patients with severe congestive heart failure. J 2006; 27: 57 – 64. Circulation 1992; 86: 1351 – 1356. 43. Malkin CJ, Jones TH, Channer KS. The effect of testosterone on 21. Kayser B. Exercise starts and ends in the brain. Eur J Appl Physiol insulin sensitivity in men with heart failure. Eur J Heart Fail 2007; 2003; 90: 411 – 419. 9: 44 – 50. 22. Harris RC, Edwards RH, Hultman E, Nordesjö LO, Nylind B, Sahlin 44. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli K. The time course of phosphorylcreatine resynthesis during recov- M, et al. Effect of long-acting testosterone treatment on functional ery of the quadriceps muscle in man. Pflügers Arch 1976; 367: 137 – exercise capacity, skeletal muscle performance, insulin resistance, 142. and baroreflex sensitivity in elderly patients with chronic heart fail- 23. Okita K, Nishijima H, Yonezawa K, Ohtsubo M, Hanada A, Kohya T, ure a double-blind, placebo-controlled, randomized study. J Am Coll et al. Skeletal muscle metabolism in maximal bicycle and treadmill Cardiol 2009; 54: 919 – 927. exercise distinguished by using in-vivo metabolic freeze method and 45. Dalla Libera L, Vescovo G. Muscle wastage in chronic heart failure, phosphorus-31 magnetic resonance spectroscopy in normal men. Am between apoptosis, catabolism and altered anabolism: A chimaeric J Cardiol 1998; 81: 106 – 109. view of inflammation? Curr Opin Clin Nutr Metab Care 2004; 7: 24. Wilson JR, Groves J, Rayos G. Circulatory status and response to 435 – 441. cardiac rehabilitation in patients with heart failure. Circulation 1996; 46. Attaix D, Ventadour S, Codran A, Béchet D, Taillandier D, Combaret 94: 1567 – 1572. L. The ubiquitin-proteasome system and skeletal muscle wasting. 25. Mancini D, Lietz K. Selection of cardiac transplantation candidates Essays Biochem 2005; 41: 173 – 186. in 2010. Circulation 2010; 122: 173 – 183. 47. Ventadour S, Attaix D. Mechanisms of skeletal muscle atrophy. Curr 26. Tabet JY, Meurin P, Beauvais F, Weber H, Renaud N, Thabut G, et al. Opin Rheumatol 2006; 18: 631 – 635. Absence of exercise capacity improvement after exercise training 48. McKinnell IW, Rudnicki MA. Molecular mechanisms of muscle at- program: A strong prognostic factor in patients with chronic heart rophy. Cell 2004; 119: 907 – 910. failure. Circ Heart Fail 2008; 1: 220 – 226. 49. Chamberlain JS. Cachexia in cancer zeroing in on myosin. N Engl J 27. Stratton JR, Dunn JF, Adamopoulos S, Kemp GJ, Coats AJ, Med 2004; 351: 2124 – 2125. Rajagopalan B. Training partially reverses skeletal muscle metabolic 50. Vescovo G, Dalla Libera L. Skeletal muscle apoptosis in experimen- abnormalities during exercise in heart failure. J Appl Physiol 1994; tal heart failure: The only link between inflammation and skeletal 76: 1575 – 1582. muscle wastage? Curr Opin Clin Nutr Metab Care 2006; 9: 416 – 28. Ohtsubo M, Yonezawa K, Nishijima H, Okita K, Hanada A, Kohya T, 422. et al. Metabolic abnormality of calf skeletal muscle is improved by 51. Dalla Libera L, Ravara B, Volterrani M, Gobbo V, Della Barbera M, localised muscle training without changes in blood flow in chronic Angelini A, et al. Beneficial effects of GH/IGF-1 on skeletal muscle heart failure. Heart 1997; 78: 437 – 443. atrophy and function in experimental heart failure. Am J Physiol Cell 29. Man WD, Kemp P, Moxham J, Polkey MI. Skeletal muscle dysfunc- Physiol 2004; 286: C138 – C144. tion in COPD: Clinical and laboratory observations. Clin Sci (Lond) 52. Schulze PC, Fang J, Kassik KA, Gannon J, Cupesi M, MacGillivray C, 2009; 117: 251 – 264. et al. Transgenic overexpression of locally acting insulin-like growth 30. Zattara-Hartmann MC, Badier M, Guillot C, Tomei C, Jammes Y. factor-1 inhibit ubiquitin-mediated muscle atrophy in chronic left- Maximal force and endurance to fatigue of respiratory and skeletal ventricular dysfunction. Circ Res 2005; 97: 418 – 426.

Circulation Journal Vol.77, February 2013 300 OKITA K et al.

53. Adams V, Jiang H, Yu J, Mobius-Winkler S, Fiehn E, Linke A, et al. 73. Kojda G, Hambrecht R. Molecular mechanisms of vascular adapta- Apoptosis in skeletal myocytes of patients with chronic HF is associ- tions to exercise: Physical activity as an effective antioxidant thera- ated with exercise intolerance. J Am Coll Cardiol 1999; 33: 959 – py? Cardiovasc Res 2005; 67: 187 – 197. 965. 74. Sonnenblick EH, LeJemtel TH. Pathophysiology of congestive heart 54. Vescovo G, Volterrani M, Zennaro R, Sandri M, Ceconi C, Lorusso R, failure: Role of angiotensin-converting enzyme inhibitors. Am J Med et al. Apoptosis in the skeletal muscle of patients with heart failure: 1989; 87: 88S – 91S. Investigation of clinical and biochemical changes. Heart 2000; 84: 75. Ostrander EA, Huson HJ, Ostrander GK. Genetics of athletic perfor- 431 – 437. mance. Annu Rev Genomics Hum Genet 2009; 10: 407 – 429. 55. Dalla Libera L, Sabbadini R, Renken C, Ravara B, Sandri M, Betto R, 76. Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P, et al. Apoptosis in the skeletal muscle of rats with heart failure is Dollery C, et al. Human gene for physical performance. Nature 1998; associated with increased serum levels of TNF-alpha and sphingo- 393: 221 – 222. sine. J Mol Cell Cardiol 2001; 33: 1871 – 1878. 77. Sukhanov S, Semprun-Prieto L, Yoshida T, Michael Tabony A, 56. Picano E, Morales MA, del Ry S, Sicari R. Innate inflammation in Higashi Y, Galvez S, et al. Angiotensin II, oxidative stress and skel- myocardial perfusion and its implication for heart failure. Ann NY etal muscle wasting. Am J Med Sci 2011; 342: 143 – 147. Acad Sci 2010; 1207: 107 – 115. 78. Dalla Libera L, Ravara B, Gobbo V, Danieli Betto D, Germinario E, 57. Yndestad A, Damås JK, Oie E, Ueland T, Gullestad L, Aukrust P. Angelini A, et al. Skeletal muscle myofibrillar protein oxidation in Systemic inflammation in heart failure: The whys and wherefores. heart failure and the protective effect of Carvedilol. J Mol Cell Car- Heart Fail Rev 2006; 11: 83 – 92. diol 2005; 38: 803 – 807. 58. Muller-Wedan U, Werdan K. Immune modulation by catecholamines: 79. Davies EJ, Moxham T, Rees K, Singh S, Coats AJ, Ebrahim S, et al. A potential mechanism of cytokine release in HF? Herz 2000; 25: Exercise training for systolic heart failure: Cochrane systematic re- 271 – 273. view and meta-analysis. Eur J Heart Fail 2010; 12: 706 – 715. 59. Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox 80. Piepoli MF, Conraads V, Corrà U, Dickstein K, Francis DP, Jaarsma WJ, et al. Hormonal changes and catabolic/anabolic imbalance in T, et al. Exercise training in heart failure: From theory to practice: chronic heart failure and their importance for cardiac cachexia. Cir- A consensus document of the Heart Failure Association and the culation 1997; 96: 526 – 534. European Association for Cardiovascular Prevention and Rehabilita- 60. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circu- tion. Eur J Heart Fail 2011; 13: 347 – 357. lating levels of tumor necrosis factor in severe chronic heart failure. 81. Nishi I, Noguchi T, Iwanaga Y, Furuichi S, Aihara N, Takaki H, et al. N Engl J Med 1990; 323: 236 – 241. Effects of exercise training in patients with chronic heart failure and 61. Adams V, Nehrhoff B, Spate U, Linke A, Schulze PC, Baur A, et al. advanced left ventricular systolic dysfunction receiving β-blockers. Induction of iNOS expression in skeletal muscle by IL-1beta and Circ J 2011; 75: 1649 – 1655. NFkappaB activation: An in vitro and in vivo study. Cardiovasc Res 82. Downing J, Balady GJ. The role of exercise training in heart failure. 2002; 54: 95 – 104. J Am Coll Cardiol 2011; 58: 561 – 569. 62. Anker SD, von Haehling S. Inflammatory mediators in chronic heart 83. Dimmeler S, Zeiher AM. Exercise and cardiovascular health: Get ac- failure: An overview. Heart 2004; 90: 464 – 470. tive to “AKTivate” your endothelial nitric oxide synthase. Circula- 63. Li YP, Schwartz RJ, Waddell ID, Holloway BR, Reid MB. Skeletal tion 2003; 107: 3118 – 3120. muscle myocytes undergo protein loss and reactive oxygen-mediated 84. Nair AP, Timoh T, Fuster V. Contemporary medical management of NF-kappaB activation in response to tumor necrosis factor alpha. systolic heart failure. Circ J 2012; 76: 268 – 277. FASEB J 1998; 12: 871 – 880. 85. Vescovo G, Dalla Libera L, Serafini F, Leprotti C, Facchin L, Volterrani 64. Spate U, Schulze PC. Proinflammatory cytokines and skeletal mus- M, et al. Improved exercise tolerance after losartan and enalapril in cle. Curr Opin Clin Nutr Metab Care 2004; 7: 265 – 269. heart failure: Correlation with changes in skeletal muscle myosin 65. Combes A, Frye CS, Lemster BH, Brooks SS, Watkins SC, Feldman heavy chain composition. Circulation 1998; 98: 1742 – 1749. AM, et al. Chronic exposure to interleukin 1beta induces a delayed 86. Dalla Libera L, Ravara B, Angelini A, Rossini K, Sandri M, Thiene G, and reversible alteration in excitation-contraction coupling of cul- et al. Beneficial effects on skeletal muscle of the angiotensin II type tured cardiomyocytes. Pflugers Arch 2002; 445: 246 – 256. 1 receptor blocker irbesartan in experimental heart failure. Circula- 66. Heistad DD, Wakisaka Y, Miller J, Chu Y, Pena-Silva R. Novel as- tion 2001; 103: 2195 – 2200. pects of oxidative stress in cardiovascular diseases. Circ J 2009; 73: 87. Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P. 201 – 207. Muscle-specific expression of IGF-1 blocks angiotensin II-induced 67. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and mito- skeletal muscle wasting. J Clin Invest 2005; 115: 451 – 458. chondrial DNA damage in heart failure. Circ J 2008; 72(Suppl A): 88. Bristow MR. Beta-adrenergic receptor blockade in chronic heart fail- A-31 – A-37. ure. Circulation 2000; 101: 558 – 569. 68. Higashi Y, Noma K, Yoshizumi M, Kihara Y. Endothelial function 89. Sabbah HN. Biologic rationale for the use of beta-blockers in the and oxidative stress in cardiovascular diseases. Circ J 2009; 73: 411 – treatment of heart failure. Heart Fail Rev 2004; 9: 91 – 97. 418. 90. Kubo T, Azevedo ER, Newton GE, Picton P, Parker JD, Floras JS. 69. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart Beta-blockade restores muscle sympathetic rhythmicity in human failure. Am J Physiol Heart Circ Physiol 2011; 301: H2181 – H2190. heart failure. Circ J 2011; 75: 1400 – 1408. 70. Fujita S, Ikeda Y, Miyata M, Shinsato T, Kubozono T, Kuwahata S, 91. Toma M, McAlister FA, Coglianese EE, Vidi V, Vasaiwala S, Bakal et al. Effect of Waon therapy on oxidative stress in chronic heart JA, et al. Testosterone supplementation in heart failure: A meta- failure. Circ J 2011; 75: 348 – 356. analysis. Circ Heart Fail 2012; 5: 315 – 321. 71. Kinugawa S, Tsutsui H, Hayashidani S, Ide T, Suematsu N, Satoh S, 92. Patwala AY, Woods PR, Sharp L, Goldspink DF, Tan LB, Wright et al. Treatment with dimethylthiourea prevents left ventricular re- DJ. Maximizing patient benefit from cardiac resynchronization ther- modeling and failure after experimental myocardial infarction in apy with the addition of structured exercise training: A randomized mice: Role of oxidative stress. Circ Res 2000; 87: 392 – 398. controlled study. J Am Coll Cardiol 2009; 53: 2332 – 2339. 72. Tsutsui H, Ide T, Hayashidani S, Suematsu N, Shiomi T, Wen J, et al. 93. Middlekauff HR. How does cardiac resynchronization therapy im- Enhanced generation of reactive oxygen species in the limb skeletal prove exercise capacity in chronic heart failure? J Card Fail 2005; muscles from a murine infarct model of heart failure. Circulation 11: 534 – 541. 2001; 104: 134 – 136.

Circulation Journal Vol.77, February 2013