Exercise training in heart failure

The reduction of exercise capacity with early occurrence of fatigue and dyspnea is a hallmark of heart failure syndrome. There are objective similarities between heart failure and muscular deconditioning. Deficiencies in peripheral blood flow and skeletal muscle function, morphology, metabolism, and function are present. The protective effects of physical activity have been elucidated in many recent studies: training improves ventilatory control, skeletal muscle metabolism, autonomic nervous system, central and peripheral circulation, and heart function. These provide the physiologic basis to explain the benefits in terms of survival and freedom from hospitalization demonstrated by physical training in heart failure.     

Exercise training in heart failure

The reduction of exercise capacity with early occurrence of fatigue and dyspnea is a hallmark of heart failure syndrome. There are objective similarities between heart failure and muscular deconditioning. Deficiencies in peripheral blood flow and skeletal muscle function, morphology, metabolism, and function are present. The protective effects of physical activity have been elucidated in many recent studies: training improves ventilatory control, skeletal muscle metabolism, autonomic nervous system, central and peripheral circulation, and heart function. These provide the physiologic basis to explain the benefits in terms of survival and freedom from hospitalization demonstrated by physical training also in heart failure.     

Skeletal Muscle Abnormalities in Chronic Heart Failure

Skeletal muscle abnormalities are well-established in patients with heart failure from an early stage in the progression of the disease and contribute to their symptoms and the limitation of physical activity. Heart failure–induced skeletal muscle pathology includes morphologic, histologic, and enzymatic changes along with derangements in skeletal muscle metabolism and autonomic function. These alterations influence both peripheral and ventilatory muscles, are present at rest, and deteriorate during exercise and their occurrence depends upon the severity and the duration of CHF syndrome. Future studies will be needed to elucidate the origin of skeletal “myopathy” and its reversibility, which is associated with improvement in exercise capacity, observed after physical training programs.     

Origins of Symptoms in Heart Failure

Chronic heart failure is accompanied by disabling symptoms, poor quality of life, and marked exercise limitation. Despite being initiated by a reduction in left ventricular pump function, the syndrome that develops in treated heart failure is one in which a vast array of noncardiac abnormalities develop, many of which may limit exercise in their own right, and some of which may lead to progressive deterioration in left ventricular performance and prognosis. The conventional explanations for the development of symptoms and exercise limitation in heart failure are now seen as being inadequate in many respects. Exercise is usually limited by either dyspnea or muscular fatigue, and it was originally thought the former reflected elevated pulmonary capillary wedge pressures producing pulmonary congestion and edema, whereas the latter was due to inadequate cardiac output, leading to poor muscular perfusion. Recent evidence has shown, however, that there is little correlation between left ventricular function and exercise limitation; that the limiting symptoms can be changed by relatively minor alterations in the exercise test procedure; and that the hemodynamic characteristics of patients do not predict whether fatigue or dyspnea is the predominant symptom. Abnormal peripheral blood flow, endothelial dysfunction, abnormal skeletal muscle structure and function, and skeletal muscle wasting all appear better correlated with symptom generation in heart failure than hemodynamic status. An early metabolic change in skeletal muscle, due in part to abnormal muscle metabolism, activates work-sensitive neural afferents (ergoreceptors) in the muscle, which reflexly increase sympathetic drive, ventilation, and generalized vasoconstriction as well as being prime candidates for carrying the fatigue signal to the cortical centers. Treatments that correct skeletal muscle abnormalities in chronic heart failure, such as ACE inhibitors and physical training, have been shown to improve exercise tolerance and to reduce both fatigue and dyspnea. In addition, such treatments, in particular exercise training of muscle, reduce the overactivity of the work-sensitive ergoreceptors, giving a possible mechanism for both the generation of symptoms and the beneficial response to treatments that improve either muscle blood flow or metabolism in heart failure. The importance of peripheral factors in chronic heart failure stresses the multiorgan nature of this syndrome.     

Impaired Exercise Tolerance in Heart Failure: Role of Skeletal Muscle Morphology and Function

Purpose of Review

To discuss the impact of deleterious changes in skeletal muscle morphology and function on exercise intolerance in patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), as well as the utility of exercise training and the potential of novel treatment strategies to preserve or improve skeletal muscle morphology and function.

Recent Findings

Both HFrEF and HFpEF patients exhibit a reduction in percent of type I (oxidative) muscle fibers and oxidative enzymes coupled with abnormal mitochondrial respiration. These skeletal muscle abnormalities contribute to impaired oxidative metabolism with an earlier shift towards glycolytic metabolism during exercise that is strongly associated with exercise intolerance. In both HFrEF and HFpEF patients, peripheral “non-cardiac” factors are important determinants of the improvement in exercise tolerance following aerobic exercise training. Adjunctive strategies that include nutritional supplementation with amino acids and/or anabolic drugs to stimulate anabolic molecular pathways in skeletal muscle show great promise for improving exercise tolerance and treating heart failure-associated sarcopenia, but these efforts remain early in their evolution, with no immediate clinical applications.

Summary

There is consistent evidence that heart failure is associated with multiple skeletal muscle abnormalities which impair oxygen uptake and utilization and contribute greatly to exercise intolerance. Exercise training induces favorable adaptations in skeletal muscle morphology and function that contribute to improvements in exercise tolerance in patients with HFrEF. The contribution of skeletal muscle adaptations to improved exercise tolerance following exercise training in HFpEF remains unknown and warrants further investigation.

     

Current concepts underlying benefits of exercise training in congestive heart failure patients

The pathophysiology of several conditions including heart failure is partly attributable to a failure of the cell energy metabolism. Studies have shown that exercise training (ET) improves quality of life (QOL) and is beneficial in terms of reduction of symptoms, mortality and duration of hospitalization. Increasingly, ET is now achieving acceptance as complimentary therapy in addition to routine clinical practice in patients with chronic heart failure (CHF). However, the mechanisms underlying the beneficial effects of ET are far less understood and need further evaluation. Evidence suggests that while CHF induces generalized metabolic energy depletion, ET largely enhances the overall function of the heart muscle. Hence, research efforts are now aiming to uncover why ET is beneficial as a complimentary treatment of CHF in the context of improving endothelial function and coronary perfusion, decreasing peripheral resistance, induction of cardiac and skeletal muscle cells remodeling, increasing oxygen uptake, substrate oxidation, and resistance to fatigue. Here we discuss the current evidence that suggest that there are beneficial effects of ET on cardiac and skeletal muscle cells oxidative metabolism and intracellular energy transfer in patients with CHF.     

Beneficial effects of endurance training on cardiac and skeletal muscle energy metabolism in heart failure

As endurance training improves symptoms and quality of life and decreases mortality rate and hospitalization, it is increasingly recognized as a beneficial practice for heart failure (HF) patients. However, the mechanisms involved in the beneficial effects of exercise training are far from being understood and need further evaluation. Independent of hemodynamics effects, exercise training participates in tissue remodeling. While heart failure induces a generalized metabolic myopathy, adaptation to endurance training mainly improves energetic aspects of muscle function. In the present review, after presenting the main characteristics of cardiac and skeletal muscle energy metabolism and the effects of exercise training, we will discuss the evidence for the beneficial effects of endurance training on cardiac and skeletal muscle oxidative metabolism and intracellular energy transfer in HF. These beneficial effects of exercise training seen in heart failure patients are also relevant to other chronic diseases (chronic obstructive pulmonary disease, diabetes, and obesity) and even for highly sedentary or elderly individuals [Booth F.W., Chakravathy M.V., Spangenburg E.E. Exercise and gene expression: physiological regulation of the human genome through physical activity. J Physiol (Lond) 2002;543:399-411]. Physical rehabilitation is thus a major health issue for populations in industrialized countries.     

Trainingstherapie bei kardiologischen Patienten (Sportkardiologie)

Clinical application of physical exercise has developed into an evidence-based therapeutic option for cardiovascular diseases, especially coronary artery disease (CAD) and chronic heart failure (CHF). In CAD regular physical exercise training partially corrects endothelial dysfunction and leads to an economization of left ventricular function. Meta-analyses have shown a reduction of angina pectoris symptoms and a decrease of total and cardiovascular mortality by regular aerobic exercise training. Endurance training for CHF reduces cardiac afterload by correcting peripheral endothelial dysfunction und leads to a better left ventricular function. In addition exercise training reduces the adrenergic tone and the stimulation of the renin-angiotensin-aldosterone system in CHF. Exercise training provides positive effects on the metabolism and function of skeletal muscle (e.g. reduced inflammation and oxidative stress). Supervised regular physical exercise training in CHF is safe and has improved the morbidity in clinical studies. Thus aerobic exercise training is an important component of therapeutic management of stable CAD and CHF with a class 1a recommendation in the current guidelines.     

Belastung und Belastbarkeit bei chronischer Herzinsuffizienz

BACKGROUND: Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF. During the last years several different peripheral factors as determinants of exercise intolerance have been defined, i.e. abnormalities in ventilation, reduced endothelium-dependent vasodilatation of peripheral conduit and resistance vessels, and altered skeletal muscle metabolism. Skeletal muscle alterations are characterized by a reduced oxidative capacity, a catabolic state with reduced local IGF-I expression and muscle atrophy, chronic inflammation with local expression of the inducible isoform of nitric oxide synthase (iNOS) and an accelerated rate of programmed cell death (apoptosis). EFFECTS OF PHYSICAL EXERCISE: Physical exercise training has evolved as an important therapeutic approach to influence these non-cardiac causes of exercise intolerance. After the first studies documenting the effect of aerobic training on the peripheral causes of exercise intolerance in CHF the question was asked: Should we treat the heart or the periphery to improve exercise intolerance in CHF? Today, we have come closer to the answer: It is now clear that these two systems are not mutually exclusive. Exercise training in CHF has been shown to improve skeletal muscle metabolism and function, to avert muscle catabolism, to reduce neurohumoral overactivation, to reverse endothelial dysfunction and to contribute to the prevention of pathologic left ventricular remodeling. After 6 months of regular exercise training oxidative capacity of the working skeletal muscle increases by approximately 40%. Regular exercise training leads to a significant improvement of endothelium-dependent vasodilatory capacity of peripheral resistance vessels, thereby reducting peripheral resistance in particular during exercise. These beneficial training effects result in a small, but significant improvement of stroke volume and reduction in cardiomegaly. CONCLUSION: Although several questions regarding patient selection, optimal training protocol and training intensity remain unanswered, exercise training can been seen as an established adjunct to pharmacotherapy in CHF. We may soon reach the conclusion that by treating the periphery with exercise programs we are in fact treating the heart, as well. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 ml/kg.min. For patients in stable CHF on optimal cardiac medication a combination of in-hospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potentials as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.     

Physical training as an adjunct therapy in patients with congestive heart failure: Patient selection, training protocols, results, and future directions

Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF: reduced endothelium-dependent vasodilation and altered skeletal muscle metabolism. Physical exercise training has evolved as an important therapeutic approach to influence these noncardiac causes of exercise intolerance. It has been shown to enhance the oxidative capacity of the working skeletal muscle, to attenuate ergoreflex activity, to correct endothelial dysfunction, and to improve ventilation. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 mL/kg.min^-1. Uncertainty remains concerning optimal patient selection, training protocol, and long-term effects on cardiac function. For patients experiencing stable CHF while on optimal cardiac medication, a combination of inhospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potential as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.     

Physical exercise in older patients with chronic heart failure

Maximal exercise capacity undergoes a steady decline after the age of 30 by approximately 10 % per decade. As a consequence of this development older people > 65 years of age suffer from the exercise limitation caused by age-associated cardiac, vascular and skeletal muscle changes. These physiologic alterations make older people especially vulnerable for the cardiovascular and peripheral alterations associated with chronic heart failure (CHF). These changes are not phenomenologically different from age-associated changes. Physical activity plays an important role for regaining a considerable part of vasomotor function, skeletal muscle contractility, and cardiac reserve. Up to now there are no prospective trials comparing the effects of physical training between older and younger patients with CHF. However, smaller observational studies indicate that elderly patients benefit equally well from training interventions with regard to functional improvements in proportion to their lower baseline values. In an aging population training aims at maintaining skeletal muscle force and muscle mass as well as locomotor coordination. Ultimately, the goal is to reduce the substantial morbidity among elderly CHF patients which constitute 79 % of all hospital admissions for heart failure.     

Stellenwert von trainingsbedingten Rückwirkungen am arteriellen Gef??system und der Skelettmuskulatur in der Therapie der Herzinsuffizienz NYHA II/III

Dynamic muscular exercise performed by healthy subjects leads to a rise in the left ventricular blood ejection with an acute increase in the local wall shear stress on the endothelium of the arterial vessels. These hemodynamic changes results in a release of endothelium-dependent relaxing factors, one of them concerns nitric oxide (NO). Therefore an arterial vasodilatation with an acute increase in the blood flow volume to the exercising muscle groups occurs. If more than 1/6 of the skeletal musculature is involved in exercise and if training duration exceeds 3-5 hours a week the chronically increased blood flow volume in the cardiovascular system triggers structural and functional changes of the heart and the arterial vessels. It develops a functional intact excentric hypertrophy of the myocardium; within the arterial vessels an increase in the diameter of the muscular arteries supplying the trained muscle groups occurs. These training-induced adaptations of the cardiovascular system are adjusted to improve the aerobic skeletal muscle metabolism. In congestive heart failure a pathological excentric myocardial hypertrophy is found. In this case the systolic myocardial function is impaired and the left ventricular ejection fraction is reduced already in early stages, so that the cardiac output can not be sufficiently increased during exercise. In addition a dysfunction of the endothelium of the arterial vessels occurs. As a consequence the endothelium-dependent arterial vasodilation is reduced, so that the peripheral arteries could not supply the muscle groups involved in exercise with enough blood flow volume. Therefore, the acute delivery of the working musculature with oxygen and energy substrates is insufficient, so that premature muscular fatigue occurs. The reduced exercise resistance of the patients leads chronically to a generalized skeletal muscle atrophy. Ultrastructural analysis revealed a decrease of oxidative type 1 muscle fibers with a relative increase of more glycolytic type 2 fibers. In addition, the volume density and the surface area of the cristae of mitochondria are reduced. All these changes results in a decrease of aerobic skeletal muscle metabolism independent of the blood flow volume, so that the physical fitness of the patients progressively decline. On the basis of the training-induced physiological adaptations of the cardiovascular system, a special exercise therapy supervised by a physician was developed for patients with congestive heart failure NYHA II/III. It have been shown that various exercise programs, which are adjusted to the degree of cardiac function impairment are suitable to restore the endothelial dysfunction of the arterial vessels as well as to cure the disturbed skeletal muscle metabolism in these patients independent of an improvement of cardiac function. Therefore in patients with congestive heart failure NYHA II/III who underwent regularly such an exercise therapy, the secondary impaired physical fitness could be rebuild without an excessive risk for an acute exercise-induced cardiovascular emergency.     

Exercise physiology in cardiovascular diseases

Exercise testing protocols and training regimens are well established for patients recovering from myocardial infarction or coronary artery bypass surgery. However, exercise rehabilitation programs for patients with peripheral arterial disease or left ventricular dysfunction with congestive heart failure have not been well developed. Several recent reports have established reproducible exercise testing protocols with objective measures of performance for patients with peripheral arterial disease and congestive heart failure. Using these testing methods to define changes in exercise capacity, exercise training programs have been shown to result in a significant increase in exercise performance and community-based quality of life. The mechanism of improvement appears to involve peripheral adaptations in skeletal muscle metabolism rather than increases in cardiac output or peripheral blood flow.     

Unraveling new mechanisms of exercise intolerance in chronic heart failure. Role of exercise training

Despite remarkable progress in the therapeutic approach of patients with chronic heart failure (CHF), exercise intolerance remains one of the hallmarks of the disease. During the past two decades, evidence has accumulated to underscore the key role of both endothelial dysfunction and skeletal muscle wasting in the process that gradually leads to physical incapacity. Whereas reverse ventricular remodeling has been attributed to aerobic exercise training, the vast majority of studies conducted in this specific patient population emphasize the reversal of peripheral abnormalities. In this review, we provide a general overview on underlying pathophysiological mechanisms. In addition, emphasis is put on recently identified pathways, which contribute to a deeper understanding of the main causes of exercise tolerance and the potential for reversal through exercise training. Recently, deficient bone marrow-related endothelial repair mechanisms have received considerable attention. Both acute exercise bouts, as well as exercise training, affect the mobilization of endothelial progenitor cells and their function. The observed changes following exercise training are believed to significantly contribute to improvement of peripheral endothelial function, as well as exercise capacity. With regard to skeletal muscle dysfunction and energy deprivation, adiponectin has been suggested to play a significant role. The demonstration of local skeletal muscle adiponectin resistance may provide an interesting and new link between the insulin resistant state and skeletal muscle wasting in CHF patients.     

Exercise training alters skeletal muscle mitochondrial morphometry in heart failure patients

BACKGROUND: Previous research has demonstrated that exercise intolerance in heart failure patients is associated with significant alterations in skeletal muscle ultrastructure and oxidative metabolism that may be more consequential than cardiac output. DESIGN: To examine the effect of exercise training on skeletal muscle mitochondrial size in chronic heart failure patients. METHODS: Six heart failure patients participated in 16-weeks of supervised upper and lower extremity exercise training. At the conclusion of training, percutaneous needle biopsies of the vastus lateralis were taken and electron microscopy was used to assess mitochondrial sizes. RESULTS: The exercise programme resulted in a significant increase in peak maximal oxygen consumption ( P< 0.05) and anaerobic threshold (P < 0.04). Knee extension muscle force increased following training ( P< 0.02). After exercise training, the average size of the mitochondria increased by 23.4% (0.036 to 0.046 mu(2), P< 0.015) and the average shape was unaltered. CONCLUSION: Exercise training with heart failure patients alters skeletal muscle morphology by increasing mitochondrial size, with no change in shape. This may enhance oxidative metabolism resulting in an increased exercise tolerance.     

Implications of chronic heart failure on peripheral vasculature and skeletal muscle before and after exercise training

The pathophysiology of chronic heart failure (CHF) is typically conceptualized in terms of cardiac dysfunction. However, alterations in peripheral blood flow and intrinsic skeletal muscle properties are also now recognized as mechanisms for exercise intolerance that can be modified by therapeutic exercise. This overview focuses on blood delivery, oxygen extraction and utilization that result from heart failure. Related features of inflammation, changes in skeletal muscle signaling pathways, and vulnerability to skeletal muscle atrophy are discussed. Specific focus is given to the ways in which perfusion and skeletal muscle properties affect exercise intolerance and how peripheral improvements following exercise training increase aerobic capacity. We also identify gaps in the literature that may constitute priorities for further investigation.     

Metabolic and structural impairment of skeletal muscle in heart failure

Physiologic endurance exercise performance is primarily limited by cardiac function. In patients with heart failure, there is dissociation between cardiac performance and exercise capacity, suggesting a distinct role of abnormal peripheral organ function, including skeletal muscle function. The impact of heart failure upon skeletal muscle and exercise performance will be discussed with a focus on molecular, structural, and functional derangements in skeletal muscle of patients with heart failure.     

Cardiac function and functional capacity: Implications for the failing heart

The exercise capacity of patients with congestive heart failure is determined by factors including the interaction of the right and left ventricles and their respective circulations, lung mechanics, skeletal muscle metabolism, and blood flow. Therapeutic efforts should be directed at all of the units in this complex process rather than the response of an individual system. Multiple therapeutic regimens such as nitrates and angiotensin converting enzyme inhibitors in combination with physical training and other therapies that improve pulmonary function produce optimal results. Using this holistic approach to therapy, the physician may have a beneficial impact on the exercise capacity of patients with congestive heart failure.     

Markedly improved skeletal muscle function with local muscle training in patients with chronic heart failure

Background: Reduced heart pump function and skeletal muscle abnormalities are considered important determinants for the low physical exercise capacity in chronic heart failure. Because of reduced ventricular function, traditional physical rehabilitation may cause underperfusion and low local work intensity, thereby producing suboptimal conditions for skeletal muscle training. Hypothesis: The study was undertaken to determine the effects of local exercise training, designed as one- or two-legged knee extensor training, on exercise capacity in patients with moderate chronic heart failure. Because such exercise models use only about one quarter to half the muscle mass used in cycle ergometer training, the influence of a restricted circulatory capacity should therefore be limited. Further, we aimed to determine whether or not chronic heart failure skeletal musculature abnormalities are counteracted with such training. Methods: Fourteen patients with chronic heart failure [age 58 ± 3 years, ejection fraction (EF) 28 ±4%] were randomized to two different training protocols three times a week for 8 weeks and compared with a nontraining control group (n = 7, age 62 ± 3, EF 27 ± 3%). Group 2L (n = 7) underwent simultaneous two-legged knee extensor training (about 4 kg working muscle) for 15 min at 65–75% of VO₂ max of the two-legged kick. Group 1L (n = 7) trained each leg at a time for 15 min of continuous one-legged dynamic knee extensor work with the same training load per muscle mass, that is, at 35% of VO₂ max of the two-legged kick (about 2 kg working muscle). Peak VO₂ of two-legged knee extensor exercise (1/min), two-legged endurance (W), and strength (Nm) were determined before and after the training period. The activity of citrate syn-thase (CS) was estimated in tissue samples from the quadriceps femoris muscle. Results: Peak VO₂ did not change with training. Two-legged knee extensor endurance exercise capacity increased by an average of 40–50% (p<0.01) in all training patients in both the 2L and 1L groups, while no change was observed in the control group. Depressed skeletal muscle CS activity increased by 25–35% in both training groups (p<0.01). Strength increased by 16% in the 2L group after training (p<0.05), while no change was seen in the 1L and control groups. Conclusions: Skeletal muscle changes in stable moderate chronic heart failure are not entirely irreversible. A major factor contributing to these changes and to exercise limitation is deconditioning. Local muscle training is efficient and can at least partially improve skeletal muscle function in these patients. Different degrees of local activation, that is, one- or two-legged knee extensor exercise, do not seem to differ in terms of their effect on exercise capacity. Depressed skeletal muscle oxidative capacity adapts to such physical training with increased activity to an extent not different from that for healthy volunteers.