INTRODUCTION — The hallmark of heart failure (HF) is exercise intolerance due to dyspnea and fatigue. These symptoms were, in the past, thought to result entirely from central hemodynamic derangements, which might be reversed by inotropic agents and/or vasodilators. (See "Inotropic agents in heart failure with reduced ejection fraction".)
However, it is now clear that significant skeletal muscular pathology is also present in HF and may contribute to the associated symptoms [1]. The evidence associating skeletal muscular abnormalities and exercise intolerance, and the beneficial effects of cardiac rehabilitation for patients with HF will be reviewed here. An overview of normal exercise physiology, the use of measurement of peak oxygen consumption (peak VO2) to assess exercise capacity and prognosis, and the ability of cardiac rehabilitation to improve exercise capacity in patients with mild to moderate HF are discussed separately. (See "Exercise physiology" and "Exercise capacity and VO2 in heart failure" and "Cardiac rehabilitation in patients with heart failure".)
IMPACT OF MEDICAL THERAPY ON EXERCISE TOLERANCE — Exercise capacity is reduced even in mild HF. Exercise intolerance and fatigue may be the result of a reduction in cardiac output, which is due primarily to impaired myocardial function, and may be exaggerated by decreased plasma and blood volumes caused by excessive diuresis [2]. Although the cardiac output may be relatively normal at rest, it is usually unable to increase adequately with even mild exertion [3]. As in normal subjects, peak VO2 in patients with HF is directly related to peak exercise cardiac output and muscle blood flow (figure 1). However, the inability to appropriately increase cardiac output in HF results in an insufficient increase in perfusion to exercising muscle, which can cause early anaerobic metabolism, an inadequate increase in muscle strength, and muscle fatigue [4].
With the success of medical therapy for HF in the early 1980s, several investigators evaluated the acute impact of inotropic agents and vasodilators on exercise capacity in patients with HF. As an example, one study evaluated 11 patients with New York Heart Association (NYHA) class III HF and a mean left ventricular ejection fraction (LVEF) of 20 percent who underwent exercise on a bicycle ergometer before and during infusion of dobutamine [5]. Although dobutamine improved peak exercise cardiac output (6.5 versus 7.4 L/min, p<0.01) and reduced pulmonary capillary wedge pressure (PCWP), it failed to significantly increase exercise duration (5.5 versus 5.8 minutes).
Another study investigated the effect of the potent vasodilator hydralazine on blood flow to exercising skeletal muscle and exercise capacity in 10 patients with NYHA class III HF and a mean LVEF of 19 percent [6]. Hydralazine, administered intravenously, substantially increased peak cardiac output during exercise on a bicycle ergometer (5.6 versus 6.7 L/min, p<0.01) and improved femoral venous flow, indicating improved femoral arterial flow and delivery of oxygen to the exercising skeletal muscle. However, maximum oxygen consumption (VO2max) was unaffected because of a reduction in systemic and leg oxygen extraction after hydralazine administration.
A similar lack of improvement in exercise capacity, despite hemodynamic improvement, has also been noted after the acute administration of other vasodilators including angiotensin converting enzyme (ACE) inhibitors [7,8], isosorbide dinitrate [9], and prazosin [10]. The inability of inotropic and vasodilator therapies that acutely improve hemodynamic function to increase exercise capacity has suggested that exercise impairment in HF may reflect additional factors such as intrinsic skeletal muscular defect in oxygen utilization.
In contrast, chronic therapy with ACE inhibitors does improve exercise capacity and symptoms. It is uncertain if these beneficial effects of ACE inhibitors are the result of improved cardiac output or are related to skeletal muscle factors. One study obtained muscle biopsies from patients with HF prior to and after therapy with enalapril and compared them to those obtained from normals [11]. Enalapril had no effect on skeletal muscle metabolism or on the number of capillaries per muscle fiber, both of which were reduced in HF. There was an increase in muscle fiber area but this was probably due to increased physical activity. In another study, treatment with either enalapril or losartan for six months improved exercise capacity in association with a shift in leg muscle contractile protein composition toward more fatigue-resistant fibers [12]. How these changes might occur is not understood.
In a study of mice with HF induced by myocardial infarction, treatment with a sodium-glucose co-transporter 2 (SGLT2) inhibitor improved skeletal muscle dysfunction by increasing fatty acid oxidation [13].
SKELETAL MUSCLE DYSFUNCTION — Skeletal muscle dysfunction occurs in all patients with HF, regardless of the ejection fraction, but is best described in patients with systolic HF [14,15]. The inability of an acute increase in cardiac output to improve exercise tolerance in patients with HF suggests that factors in addition to the low muscle blood flow during exercise may be involved [1,16]. One such factor is skeletal muscle dysfunction induced by chronic hypoperfusion, which can lead to muscle wasting, interference with oxygen utilization, and delayed recovery of muscle and total body oxygenation after submaximal exercise (figure 2) [4,16,17]. Physical deconditioning appears to play a contributory role [18]. In support of this view, many of the observed abnormalities in skeletal muscle structure and function observed in patients with HF are seen in normal controls with a similar level of inactivity [19]. However, a specific effect of HF, per se, is suggested by the failure of skeletal muscle to respond normally to exercise training in patients with HF [20].
Apoptosis — Myocyte apoptosis is seen in the skeletal muscles of patients with chronic HF and its magnitude is associated with the severity of exercise capacity limitation and the degree of muscle atrophy [21].
Capillary density — Capillary density strongly correlates with human skeletal muscle oxidative capacity and may play a role in determining exercise capacity in patients with HF. In one study of 22 males with HF and 10 normal controls, those with HF had a significant reduction in microvascular density in the absence of other major peripheral skeletal muscle alterations [22]. There was an inverse relationship between capillary density and maximal oxygen consumption and total exercise time, suggesting that a reduction in capillary density within skeletal muscle may precede biochemical and functional alterations.
Oxidative stress — Oxidative stress and the generation of reactive oxygen species (ROS) play an important role in the development of HF. Oxidative stress may also be related to exercise intolerance in these patients. As an example, one animal model of HF found an increase in the generation of ROS within skeletal muscle; this was associated with ROS-mediated lipid peroxidation [23]. Oxidative stress is a cause of mitochondrial dysfunction that can lead to both apoptosis of muscle cells and decreased production of adenosine triphosphate (ATP).
Biochemical abnormalities — The normal muscle fibers of each motor unit are homogeneous and may be either twitch type I (also called red or slow fibers) or twitch type II (also called white or fast fibers) based upon their myoglobin content and time-to-peak tension (table 1) [24,25].
●Type I fibers have a high oxidative capacity, are fatigue-resistant, and are recruited for low-level endurance exercise.
●Type II fibers have a high glycolytic capacity and are recruited for short bursts of rapid, heavy work. There are two subtypes of type II fibers: type IIa are slow twitch, while type IIb are fast twitch.
A number of biochemical abnormalities in skeletal muscle have been identified in patients with HF [1]. In one study, for example, skeletal muscle biopsy revealed atrophy of both type IIa and IIb fibers, an increased percentage of the fast twitch, easily fatigable type IIb fibers, and preservation of type I fiber size [25]. There was a significant inverse correlation between the percentage of type IIb fibers and VO2max, suggesting that an increase in this fiber type may be in part responsible for the observed exercise intolerance (figure 3). There was also a significant positive correlation between the percentage of the slow twitch "endurance" type I fibers and peak VO2. In addition, there is increased synthesis of fast, more fatiguable myosin heavy chain isoforms that have higher oxygen and ATP consumption and reach anaerobic threshold earlier [21]. Despite the shift in fiber type, myofibrillar contractile capacity, and calcium sensitivity are not altered; however, there are alterations in mitochondrial function, suggesting that the myopathy in HF is metabolic in origin [26].
Energetic dysfunction — To further delineate skeletal muscle metabolism in patients with HF, magnetic resonance spectroscopy has been utilized to evaluate high-energy phosphate fluxes during exercise [25,27]. The energy supply for skeletal muscle contraction comes from the breakdown of ATP to adenosine diphosphate (ADP) and inorganic phosphate (Pi). Phosphocreatine (PCr) serves as the high energy phosphate store in skeletal muscle, and donates its phosphate group to ADP to regenerate ATP and creatine (Cr). When energy is available from nutrient metabolism, Pi is added to Cr to regenerate PCr. (See "Energy metabolism in muscle".) These reactions can be summarized by the following three equations:
ATP --> ADP + Pi
PCr + ADP --> ATP + Cr
Pi + Cr --> PCr
Magnetic resonance (MR) spectroscopy can detect the phosphorus-31 radioisotope of each of the three phosphate peaks of ATP as well as the PCr and Pi peaks (figure 4). The ratio of the areas under the Pi and PCr peaks provides an estimation of the high energy phosphate supply available for utilization. An increase in the Pi/PCr ratio suggests a reduction in energy supply and is a useful indicator of the rate of energy utilization during exercise. On the other hand, the normalized PCr ratio (PCr / [PCr + Pi]) increases as the supply of high energy phosphate increases.
One study compared exercise MR spectroscopy data from the flexor digitorum superficialis muscle during finger flexion exercise in 22 men with HF and 11 age and size-matched normal volunteers [27]. The following findings were noted in the patients with HF:
●A significantly lower intracellular pH at each workload, suggesting lactic acid accumulation due to anaerobic metabolism.
●A significantly lower normalized PCr ratio at each workload, indicating more rapid depletion, which may reflect decreased production of ATP and/or less efficient utilization of high energy phosphates during exercise.
●No difference in forearm venous blood flow during exercise utilizing plethysmographic measurements, indicating that the metabolic abnormalities were not due to vascular insufficiency.
A later study noted similar findings, with PCr depletion occurring at a much lower peak VO2 in patients with HF compared to normal controls [28]. In addition, muscle metabolic capacity was correlated with peak VO2 during maximal exercise.
Other changes that have been described in patients with HF include fewer capillaries surrounding each muscle fiber, higher lactate dehydrogenase activity, and reduced succinate dehydrogenase activity [29,30]. These findings suggest a reduction in effective mitochondrial number and/or function.
In summary, patients with HF have skeletal muscle atrophy, an increased percentage of type IIb fibers, and intrinsic skeletal muscular metabolic defects, leading to less efficient use of high energy phosphates and more rapid accumulation of lactic acid.
Functional abnormalities — In addition to these structural and biochemical defects, a number of functional abnormalities have been identified in patients with HF [1].
●Skeletal muscle ergoreceptors or metaboreceptors are enhanced in HF, possibly resulting in an increase in the ventilatory response to exercise and the sensation of dyspnea [16,31]. Continuous inspired oxygen may reduce ventilation at rest and with exercise, and increase exercise duration, suggesting that suppression of peripheral chemoreceptors may improve exercise capacity [31].
●The inadequate forward output leads to increased sympathetic tone, peripheral vasoconstriction, and reductions in renal blood flow and urinary sodium and water excretion [32]. This response to exertion explains in part the tendency for patients to retain sodium and water during the day when they are more active.
●Increased levels of inducible nitric oxide synthase and nitric oxide within skeletal muscles may contribute to reduced muscle contractile performance and muscle wasting [33]. In one report, for example, the relative amount of mitochondrial creatine kinase, a key enzyme for rapid energy transfer from mitochondria to cytosol, was significantly reduced in patients with HF compared to controls; the amount of mitochondrial creatine kinase was inversely correlated with inducible nitric oxide synthase expression [34].
Involvement of the respiratory muscles — Skeletal muscle dysfunction can involve the respiratory muscles as part of the generalized skeletal myopathy in HF [35]. This abnormality may contribute to dyspnea on exertion and may help identify patients with a worse prognosis, particularly those with an intermediate VO2max (10 to 20 mL/mg/kg) [36].
The diaphragm shows a different adaptation from skeletal and respiratory muscle. There is a shift from fast to slow fibers with an increase in oxidative capacity and a decrease in glycolytic capacity [37]. These changes are similar to those seen in the limb muscles that occur with endurance training, suggesting that they result from the increased work of breathing.
There are also changes in pulmonary function in HF. Even in the absence of pulmonary congestion, HF is associated with an exaggerated increase in minute ventilation in response to exercise that is out of proportion to the increase in carbon dioxide production [38,39]. Hyperventilation is primarily due to ventilation/perfusion mismatching, the severity of which is related to the severity of the HF [39]. The combination of increased ventilation and normal gas exchange (unless limited by pulmonary congestion) means that arterial hypoxia does not generally occur during exercise.
SUMMARY
●Exercise intolerance in patients with heart failure (HF), regardless of the ejection fraction, is caused by hemodynamic derangements as well as by skeletal muscle dysfunction. (See 'Skeletal muscle dysfunction' above.)
●Exercise capacity improves with chronic angiotensin converting enzyme (ACE) inhibitor therapy, although it does not improve after acute administration of drugs such as ACE inhibitor, hydralazine, or isosorbide dinitrate. (See 'Impact of medical therapy on exercise tolerance' above.)
●Chronic hypoperfusion and physical deconditioning may contribute to the structural and functional abnormalities in skeletal muscle seen in patients with HF. (See 'Skeletal muscle dysfunction' above.)
●Oxidative stress caused by excessive oxygen free radicals and/or high levels of inducible nitric oxide may lead to skeletal muscle cell apoptosis and impaired generation of adenosine triphosphate (ATP) by mitochondria.
●Patients with HF have skeletal muscle atrophy, an increased percentage of type IIb fibers, and intrinsic skeletal muscular metabolic defects, leading to less efficient production and/or use of high energy phosphates and more rapid accumulation of lactic acid. (See 'Biochemical abnormalities' above.)
●Skeletal muscle dysfunction involving the respiratory muscles may contribute to dyspnea in patients with HF. (See 'Involvement of the respiratory muscles' above.)
