IJCS | Volume 31, Nº4, July / August 2018

435 Borges et al. Oncocardiology and the symptom fatigue Int J Cardiovasc Sci. 2018;31(4)433-442 Review Article during exercises influencing the production of force is the depletion of energy substrate required for ATP synthesis and the variation in intracellular concentration of Ca++, H+, lactate, phosphate, and ADP. A failure of the muscle in maintaining homeostasis (depending on variations in Ca++ and H+ levels, for example) compromises force production at the cross-bridge level, resulting in the development of fatigue. Another mechanism that contributes to muscle fatigue is the production of free radicals. Current evidence suggests that free radicals can damage the contractile proteins myosin and troponin and decrease the number of cross- bridges, compromising muscle strength. The increased production of free radicals can also compromise the function of the sodium/potassium pump in the skeletal muscle and cause muscle fatigue. 17 Skeletal muscle contraction is a complex process that involves a certain number of cellular proteins and the energy production system, with the interaction of the contractile proteins actin and myosin in the presence of intracellular ATP and Ca++. The process of muscle contraction begins with the arrival of a nerve impulse in the neuromuscular junction. The action potential of the motor neuron causes the release of acetylcholine in the synaptic cleft, which in turn leads to depolarization of the muscle cell. When it reaches the sarcoplasmic reticulum, the action potential promotes the release of Ca++, which binds to troponin and causes a change in the position of tropomyosin. The active sites in actin are then exposed, allowing an “energized” myosin cross- bridge to bind to the actin molecule. When the neural activity ceases at the level of the neuromuscular junction, Ca++ is removed from the sarcoplasm and actively pumped into the sarcoplasmic reticulum by the Ca++ pump, breaking the cycle of muscle contraction. The term “excitation-contraction coupling” is defined as the sequence of events inwhich the nerve impulse reaches the muscle membrane and causes shortening of the muscle via cross-bridge activity. 18 Fatigue in chronic diseases Clinical fatigue is often found in chronic diseases like HF and cancer. Several metabolic, neurological, and myofibrillar adaptations are involved in these conditions and implicated in the onset of fatigue. 19 Ewans &Lambert 4 have pointed out that cachexia and deconditioning are probably involved in the persistence of fatigue at the end of treatment and after resolution of the disease. Fatigue in heart failure Fatigue and dyspnea are cardinal symptoms of HF. Fatigue is triggered by inadequate blood perfusion affecting the respiratory and peripheral muscles and leads to reduced oxidative capacity. Dyspnea, in turn, is caused by an excessive ventilatory demand or a ventilatory disorder arising from sensory systems involved in breathing. The symptom fatigue can be caused by cardiac cachexia and malnutrition that accompany the severe metabolic stage of the disease. 8 Patients with advanced HF may develop sarcopenia associated with aging and physical inactivity, resulting in worsening of fatigue. The symptom fatigue connected to HF is also related to anemia, sleep apnea, electrolyte disturbance, use of beta-blockers and diuretics, in addition to depression. 20 Theexercise intolerancepresent inHFmaybeassociated with central (chronotropic response and reduced ejection fraction) or peripheral (endothelial dysfunction with decreased release of nitric oxide, increased total peripheral resistance and lower vasodilatory response) limitations. The ventilatory muscle weakness present in HF, in turn, is also a limitation that may reflect a greater increase in the work of the diaphragm, triggering a sensation of dyspnea. 21 Another adaptation found in HF that can contribute to aggravate fatigue is the decrease in contractile function. The myopathy observed in HF clearly reflects the reduction in oxidative phosphorylation with increased type IIb fibers and decreased type I fibers, which are regarded as determinants in the reduction of functional capacity. The administration of drugs used in HF, such as losartan and enalapril, improves exercise tolerance with normalization of the composition of the muscle fibers (i.e., reduction in glycolytic fibers [type IIb] and increase in aerobic fibers [type 1]), in addition to improving the maximum energy expenditure (VO 2 ). 22 Similar results have been obtained with exercise training in patients with HF, which resulted in improved endurance, physical activity, and oxidative phosphorylation of the skeletal muscle. 23 The muscle weakness eventually observed in patients with HF can be attributed to changes in function and amount of proteins in the myofilaments and not only to muscle atrophy. These changes are probably secondary and apparent in relation to the deconditioning and/or disuse resulting from the disease and allow the definition of the muscle phenotype in patients with HF. 24,25