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 re- lated 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 mus- cles 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 at- ed 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