Deconditioning fails to explain peripheral skeletal muscle alterations in men with chronic heart failure

It remains controversial whether the skeletal muscle alterations in chronic heart failure (CHF) are due to disease pathophysiology or result from chronic deconditioning. The purpose of this study was to compare the skeletal muscle of CHF patients to peak oxygen consumption (peak VO(2)) matched sedentary controls.It has been established that skeletal muscle abnormalities are related to the exercise intolerance observed in patients with CHF.We studied the skeletal muscle of sedentary controls and patients with CHF matched for age, gender and peak VO(2).Hypothesis testing for the effects of group (CHF vs. normal), gender, and the interaction group x gender were performed. For capillary density only gender (p = 0.002) and the interaction of group x gender (p = 0.007) were significantly different. For 3-hydroxyl coenzyme A (CoA) dehydrogenase only group effect (p = 0.004) was significantly different. Mean values for capillary density were 1.46 +/- 0.28 for CHF men versus 1.87 +/- 0.32 for sedentary control men, 1.40 +/- 0.32 for CHF women versus 1.15 +/- 0.35 for sedentary control women. The activities for 3-hydroxyl CoA dehydrogenase were 3.09 +/- 0.88 for CHF men versus 4.05 +/- 0.42 for sedentary control men, 2.93 +/- 0.72 for CHF women versus 3.51 +/- 0.78 for sedentary control women.This study suggests that women and men adapt to CHF differently: men develop peripheral skeletal muscle abnormalities that are not attributable to deconditioning; women do not develop the same pathologic responses in skeletal muscle when compared with normal women matched for aerobic capacity.     

Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure

OBJECTIVES: The aim of this study was to assess the effects of regular physical exercise on local inflammatory parameters in the skeletal muscle of patients with chronic heart failure (CHF). BACKGROUND: Inflammatory activation with increased serum cytokine levels and expression of inducible nitric oxide synthase (iNOS) in the myocardium and peripheral skeletal muscles has been described in CHF. METHODS: Twenty male patients with stable CHF (left ventricular ejection fraction 25 +/- 2%; age 54 +/- 2 years) were randomized to a training group (n = 10) or a control group (n = 10). At baseline and after six months, serum samples and vastus lateralis muscle biopsies were obtained. Serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1-beta levels were measured by enzyme-linked immunosorbent assay, local cytokine, and iNOS expression by real-time polymerase chain reaction. RESULTS: Exercise training improved peak oxygen uptake by 29% in the training group (from 20.3 +/- 1.0 to 26.1 +/- 1.5 ml/kg. min; p < 0.001 vs. control group). While serum levels of TNF-alpha, IL-6, and IL-1-beta remained unaffected by training, local skeletal muscle TNF-alpha decreased from 1.9 +/- 0.4 to 1.2 +/- 0.3 relative U (p < 0.05 for change vs. control group), IL-6 from 71.3 +/- 16.5 to 41.3 +/- 8.8 relative U (p < 0.05 vs. begin), and IL-1-beta from 2.7 +/- 1.1 to 1.4 +/- 0.6 relative U (p = 0.02 vs. control group). Exercise training also reduced local iNOS expression by 52% (from 6.3 +/- 1.2 to 3.0 +/- 1.0 relative U; p = 0.007 vs. control group). CONCLUSIONS: Exercise training significantly reduced the local expression of TNF-alpha, IL-1-beta, IL-6, and iNOS in the skeletal muscle of CHF patients. These local anti-inflammatory effects of exercise may attenuate the catabolic wasting process associated with the progression of CHF.     

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.     

Differential effects of exercise training in men and women with chronic heart failure

Background

Abnormalities of myosin heavy chain (MHC) isoforms, enzyme activity, and capillarity contribute to the exercise intolerance that is characteristic of patients with heart failure. To what extent these changes can be reversed with exercise training and whether differences exist in the responses of men and women remains uncertain. We described and compared the effects of exercise training on exercise capacity and skeletal muscle histochemistry in men and women with chronic heart failure.

Methods

Fifteen patients (10 male) undergoing standard medical therapy completed a 14- to 24-week exercise training program. Peak oxygen consumption, MHC isoforms, capillary density, and selected metabolic enzymes were assessed before and after training.

Results

Peak oxygen consumption was improved 14% (P <.05); however, this increase was mostly because of the improvement observed in men versus women (+20% versus +2%, respectively, P < .01). At baseline, MHC I content was lower in men than in women (33% ± 3% vs 49.6% ± 5.5%, P < .05). MHC I improved with training in men, to 45.6% ± 4.5% (+38%, P < .05), versus women (−3%, P = .82), and the increase in men tended (P = .12) to be significant when compared with that in women. There were no significant changes in capillary density or muscle enzyme activity with training in the group as a whole or in men and women separately.

Conclusion

Among patients with chronic heart failure, improvements in peak exercise capacity may be more pronounced in men than in women. This difference in response of functional capacity to training paralleled differences observed between men and women for changes in MHC I isoforms.     

Exercise training in chronic heart failure: correlation between reduced local inflammation and improved oxidative capacity in the skeletal muscle.

BACKGROUND: Chronic heart failure (CHF) is accompanied by an inflammatory activation which occurs both systemically and in the skeletal muscle. Exercise training has been shown to reduce the local expression of cytokines and inducible nitric oxide synthase (iNOS) in muscle biopsies of CHF patients. INOS-derived NO can inhibit oxidative phosphorylation and contribute to skeletal muscle dysfunction in CHF. DESIGN: To investigate the correlation between changes in local iNOS expression associated with regular exercise and changes in aerobic enzyme activities in the skeletal muscle of patients with CHF. Twenty male CHF patients [ejection fraction 25% (SE 2), age 54 (SE 2) years] were randomized to a training (n=10) or a control group (C, n=10). METHODS: At baseline and after 6 months skeletal muscle iNOS expression was measured by real-time polymerase chain reaction. INOS protein and protein nitrosylation were assessed by immunohistochemistry. Cytochrome c oxidase (COX) activity was quantified electrochemically using the Clark oxygen electrode. RESULTS: Exercise training led to a 27% increase in cytochrome c oxidase activity [from 21.8 (SE 3.2) to 27.7 (SE 3.5) nmol O2/mg per min, P=0.02 versus baseline]. Changes in iNOS expression and iNOS protein content were inversely correlated with changes in COX-activity (r=-0.60, P=0.01; r=-0.71, P<0.001). CONCLUSIONS: The inverse correlation between iNOS expression/iNOS protein content and COX-activity indicates that local anti-inflammatory effects may contribute to improved muscular oxidative metabolism.     

Effects of exercise training on insulin-like growth factor-I expression in the skeletal muscle of non-cachectic patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with progressive muscle atrophy and reduced local expression of insulin-like growth factor I (IGF-I). DESIGN: The present study was designed to test the hypothesis that the local deficiency of IGF-I in the skeletal muscle of patients with CHF would respond to a 6-months aerobic training intervention. Therefore, 18 patients [mean age 52.4 (SD 4.8) years, left ventricular ejection function (LVEF) 27 (SD 6)%] were prospectively randomized to either 6 months of training or sedentary lifestyle. METHODS: Serum levels of growth hormone (GH) were measured by immunofluorometric assay, IGF-I by competitive solid phase immunoassay. IGF-I expression was assessed in vastus lateralis biopsies by real-time PCR. RESULTS: Exercise training led to a significant increase in peak oxygen uptake by 26% [from 20.3 (SD 3.3) ml/kg per min to 25.5 (SD 5.7) ml/kg per min, P=0.003 versus control]. Local expression of IGF-I increased significantly after exercise training by 81% [from 6.3 (SE 0.8) to 11.4 (SE 1.4) relative units, P=0.007 versus control] while IGF-I receptor expression was reduced by 33% [from 20.0 (SE 2.1) to 13.8 (SE 1.7) relative units, P=0.008 versus control]. Serum growth hormone (GH) rose modestly from 0.12 (SE 0.07) to 0.65 (SE 0.37) ng/ml in the training group (P=0.043 versus baseline), however, this change was not significant compared to the control group (P=0.848). IGF-I serum levels remained virtually unchanged. CONCLUSIONS: Exercise training improves local IGF-I expression without significant changes of systemic parameters of the GH/IGF-I axis. These findings indicate that exercise training has the therapeutic potential to attenuate peripheral skeletal muscle alterations in particular with respect to local IGF-I expression in patients with moderate CHF.     

The effect of moderate exercise training on skeletal muscle myosin heavy chain distribution in chronic heart failure

BACKGROUND: The myosin heavy chain (MHC) is altered in chronic heart failure (CHF), but the effect of exercise on MHC expression in CHF patients is not understood. The aim of the present study was to show the effect of aerobic exercise on MHC distribution in patients with CHF. METHODS: Patients (n=17) with stable NYHA class I-III CHF were randomised into training and control groups. For a period of three months, the training group cycled on an ergometric cycle 3 times a week for 30 min, the control group continued as they did previously. Both a baseline and a final 3 month graded maximal exercise test and exercise endurance test with constant submaximal work load were performed. Muscle samples, obtained from vastus lateralis muscle at baseline and after 3 months from the 8 patients in the training group and the 9 in the control group, were analysed for MHC distribution using SDS-polyacrylamide gel electrophoresis. RESULTS: Baseline MHC distributions were similar in both groups and training did not alter the MHC distribution. Exercise duration, at constant submaximal work load, improved from 14.9+/-7.1 to 26.9+/-9.6 min (p<0.01 for the change between the groups). Training did not improve peak oxygen consumption. CONCLUSION: No correlation between the change in exercise capacity and MHC distribution appeared despite the significant improvement of exercise duration.     

The effect of physical training on skeletal muscle in patients with chronic heart failure

BACKGROUND: The improvement of exercise capacity in patients with chronic heart failure (CHF) by physical training has been connected with reversal of the abnormalities in muscle fiber distribution and with the reduced activity of the enzymes of oxidative metabolism in skeletal muscle. However, the change in fiber type distribution induced by training is controversial and in previous studies the activities of the rate-limiting enzymes of the metabolic pathways have not been measured. AIMS: To examine the effect of dynamic training on percentage distribution of muscle fibers, on activities of the rate-limiting enzymes of the metabolic pathways and on electrophysiology in skeletal muscle. METHODS: A total of 27 patients with stable CHF (NYHA class II-III) were randomized to a training (N=12) or a control (N=15) group. The training group exercised on a bicycle ergometer for 30 min three times a week for 3 months using a load corresponding to 50-60% of their peak oxygen consumption. This was followed by a 3-month training period at home according to personal instructions. The control group did not change its physical activities. We studied muscle histology and measured the activities of the rate-limiting enzymes of anaerobic glycolysis (phosphofructokinase, PFK), glycogenolysis (phosphorylase), citric acid cycle (alpha-ketoglurate dehydrogenase, KGDH) and fatty acid oxidation (carnitinepalmitoyl transferase I and II, CPT I and II) from biopsies of the vastus lateralis muscle at baseline and after 3 and 6 months. Muscle strength and strength endurance with surface EMG and macro EMG of the right knee extensors were also determined. RESULTS: Exercise capacity, particularly submaximal, improved in the training group. The activity of PFK rose significantly but that of the other enzymes did not when compared with the change in the controls. Training had no effect on the percentage distribution of slow-twitch and fast-twitch muscle fibers or on capillary density around these fibers in skeletal muscle. Maximum voluntary force, strength endurance and the function of motor units remained unaffected. CONCLUSIONS: Dynamic training results in improved exercise endurance in CHF. In skeletal muscle, the capacity of anaerobic glycolysis is increased but that of the citric acid cycle and fatty acid oxidation is not. Furthermore, the improvement in exercise endurance seems to be independent of changes in the percentage distribution of muscle fibers, capillarity or electrophysiological factors.     

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.     

Chronic heart failure and skeletal muscle catabolism: effects of exercise training

Although the clinical picture of cardiac cachexia is well-known in patients with advanced chronic heart failure (CHF) the factors that determine who is at risk for this progressive catabolic syndrome and who is not remain unclear. Different endocrine systems have been accused of being involved in this process: an imbalance between catabolic and anabolic steroids with an elevated cortisol/dihydroepiandrosterone ratio, an increased resting metabolic rate due to high levels of circulating catecholamines, various cytokines are activated in CHF (i.e. TNF-alpha, IL-6, IL-1beta and others), and elevated levels of growth hormone (GH) with inappropriately normal or low serum levels of insulin-like growth factor-I (IGF-I) have been described in cardiac cachexia. These catabolic factors contribute to peripheral muscle atrophy, augment the expression of the inducible nitric oxide synthase (iNOS), which in turn inhibits the aerobic cellular metabolism. The present review examines whether the catabolic factors can be influenced by a classical anabolic intervention: regular physical exercise training. Long-term training programs increase skeletal muscle cytochrome c oxidase activity and are associated with reduced local expression of pro-inflammatory cytokines as well as iNOS, and augment local IGF-I production. In concert, these beneficial effects of exercise training may help to retard the catabolic process in CHF finally leading to cardiac cachexia and death.     

Effect of exercise training on chromogranin A and relationship to N-ANP and inflammatory cytokines in patients with chronic heart failure

Very little is known about the accuracy of intravenous myocardial contrast echocadiography (MCE) in the detection of myocardial hibernation. There are also currently no data on the comparison of MCE to late gadolinium-enhanced magnetic resonance (LGE-MR) in this clinical setting. The aim of this pilot study was to predict recovery of regional function in patients with ischemic LV dysfunction undergoing bypass surgery and to compare the accuracy of MCE with LGE-MR in this clinical setting. The sensitivity of preserved myocardial perfusion during MCE for segmental function recovery (hibernating myocardium) of akinetic segments was 78% and was similar to LGE-MR (87%, p—NS). Specificity of MCE was higher than for LGE-CMR (72%, and 52%, respectively; p < 0.01). This pilot study has showed good diagnostic accuracy of MCE for prediction of function recovery after bypass surgery, which is comparable to “gold standard” in assessing myocardial viability — LGE-MR.     

Effect of physical training on exercise capacity, gas exchange and N-terminal pro-brain natriuretic peptide levels in patients with chronic heart failure.

BACKGROUND: Decreased exercise capacity is the main factor restricting the daily life of patients with chronic heart failure. N-terminal pro-brain natriuretic peptide (NT pro-BNP) is strongly related to the severity of and is an independent predictor of outcome in chronic heart failure. DESIGN: The study aimed to evaluate the effect of exercise training on functional capacity and on changes in NT pro-BNP levels and to assess the effect of exercise training on quality of life. MATERIALS AND METHODS: Sixty patients (45 men/15 women, mean age 52.7 years; +/-5.3 SD), with stable heart failure (45 ischaemic/hypertensive and 15 idiopathic patients), in New York Heart Association (NYHA) functional class II (n=35) to III (n=25), with an ejection fraction less than 40%, were randomly assigned to a training (n=30) and a control group (n=30). The training group (30 patients) performed 3 months of supervised physical training programme using a bicycle ergometer for 30 min three times a week at a load corresponding to 60-70% of their oxygen consumption (VO2) peak. The control group did not change their previous physical activity. A graded maximal exercise test with respiratory gas analysis and an endurance test with constant workload corresponding to 85% of the peak oxygen load at the baseline and after 3 months were performed, and at the same times NT pro-BNP levels were measured. RESULTS: The exercise capacity increased from 15.8 (+/-2.3 SD) to 29.9 (+/-2.1 SD) min (P<0.0001) and the peak VO2 tended to improve from 14.5 (+/-1.4 SD) to 17.7 (+/-2.6 SD) ml/kg per min (P<0.0001) during the supervised training period. VO2 at the anaerobic threshold increased from 12.9 (+/-1.0 SD) to 15.5 (+/-1.7 SD) ml/kg per min (P<0.0001). NT pro-BNP levels decreased from 3376 (+/-3133 SD) to 1434 (+/-1673 SD) pg/ml (P=0.043). The positive training effects were associated with an improvement in the NYHA functional class. CONCLUSION: Physical training of moderate intensity significantly improves the exercise capacity and neurohormonal modulation in patients with chronic heart failure. This is associated with an alleviation of symptoms and improvement in quality of life.     

Ischaemic heart disease, skeletal muscle fibres and exercise capacity

Twenty-eight male patients with ischaemic heart disease (IHD)performed OBLA (onset of blood lactate accumulation) exercisestress tests and had muscle biopsies taken from their vastuslateralis muscle the day before coronary bypass grafting. All28 patients showed the same exercise performance pattern ascompared to healthy sedentary, age-matched, controls: a lowexercise intensity eliciting a blood lactate concentration of2.0 mmol x 1^–1 ( W_OBLA), W_OBLA corresponded to a highfraction (% W_OBLA) of W_SL (symptom limited or ‘maximal’capacity), and a low peak blood lactate concentration. The high% W_OBLA and low peak blood lactate indicated a reducedglycogenolyticcapacity (‘anaerobic’ performance). Muscle fibrecomposition disclosed a high mean value of fast twitch (FT),type II or ‘white’ muscle fibres, as compared tosedentary healthy controls. This indicated that this patientgroup constituted an extreme subgroup of the age-matched population.The distorted muscle fibre composition in IHD could refiectboth heredity as well as adaptation to physical inactivity,degenerative cytosolic properties, etc. Muscle and blood contentsof a mitochondrial electron trans-locator and nonspecific radicalscavenger, ubiquinone or coenzyme Q₁₀(CoQ₁₀), were low, whichcoincided with an elevated frequency of the fibre subgroup FT(c).The presence of the FT (c) fibre type is assumed to reflecthistological uma.     

Supervised exercise training improves aerobic capacity and muscle strength in older women with heart failure

BACKGROUND: The effect that supervised or unsupervised exercise training has on aerobic capacity (peak oxygen consumption [VO2peak]), muscle strength and quality of life in older women with heart failure remains unknown. OBJECTIVE: To examine the effect of six months (three months supervised followed by three months unsupervised) of aerobic training (AT) or combined aerobic and strength training (CAST) on VO2peak, muscle strength and quality of life in older women with heart failure. METHODS: Twenty older women (mean age +/- SD, 72+/-8 years) with clinically stable heart failure were randomly assigned to AT (n=10) or CAST (n=10). Supervised AT was performed two days per week at 60% to 70% heart rate reserve, whereas unsupervised training was performed two days per week at a rate of perceived exertion of 12 to 14 on the Borg scale. The CAST group also performed one to two sets of low-to-moderate intensity strength training two days per week. RESULTS: Supervised AT or CAST resulted in an increase in VO2peak (12%; P<0.05) and leg press strength (13%; P<0.05) that returned to baseline after unsupervised training. Vertical row strength was greater (+23%; P<0.05) after supervised CAST and remained unchanged after supervised or unsupervised AT. Supervised or unsupervised exercise training was not associated with a significant change in quality of life. CONCLUSIONS: Supervised AT or CAST are effective modes of exercise to improve VO2peak and muscle strength in older women with heart failure. However, the improvements in VO2peak and muscle strength are not maintained with unsupervised exercise training.