Studies on skeletal muscle and autonomic function in chronic heart failure

Human and animal studies on skeletal muscle and autonomic function in chronic heart failure, with particular emphasis on the role of exercise training, are discussed. Initially the complex syndrome of chronic heart failure is described including: definitions, epidemiology, aetiologies and pathophysiological characteristics focusing on both cardiac and non-cardiac changes. In particular, neuroendocrine excitation, characterised by activation of the sympathetic nervous system associated with a parasympathetic withdrawal, activation of the renin-angiotensin-aldosterone system, the arginine-vasopressin system, various endothelins as well as the counteracting atrial and brain natriuretic peptides, and musculoskeletal abnormalities involving structure, function and metabolism are reviewed. In additon, the effects of pharmacological and especially non- pharmacological (exercise training) interventions on autonomic balance and muscle metabolism in chronic heart failure are reported. Methodological aspects are subsequently discussed regarding assessment of sympatho- vagal balance and bioenergetic interpretation of the skeletal muscle metabolic changes during exercise in experimental and human chronic heart failure. Skeletal muscle metabolism is evaluated by using 3 phosphorus magnetic resonance spectroscopy, which provides the opportunity of a serial non-invasive assessment of inorganic phosphate, phosphocreatine, ATP levels and intracellular pH, all indices of glycolytic activity and mitochondrial oxidative capacity, both at rest and during exercise as well as during the recovery period. Sympatho-vagal balance is assessed by using heart rate variability measures and radiolabeled noradrenaline kinetics. Measures of heart rate variability in the time (standard deviation of R-R intervals) and frequency (power spectral analysis-derived low- and high-frequency components of heart rate variability) proved to be useful clinical tools for semi-quantitative assessment of sympatho-vagal balance and are widely used in our studies. Radiotracer kinetic techniques, using infusions of [3H] noradrenaline, enable us to estimate whole-body noradrenaline spillover to plasma (the overall rate at which noradrenaline released from nerve endings enters plasma) and whole-body noradrenaline plasma clearance simultaneously. Thus, we avoid the confounding influence of noradrenaline plasma clearance, which is reduced in severe chronic heart failure, when we simply measure plasma noradrenaline concentration as an index of sympathetic nervous activity. Phosphorus-31 magnetic resonance spectroscopy studies of skeletal muscle metabolism in heart failure have shown increased phosphocreatine breakdown and intracellular acidosis during exercise, both in human subjects as well as in rats following a large myocardial infarction. This increase in phosphocreatine breakdown and intracellular acidosis implies an increased glycolytic contribution to the required ATP synthesis, due either to an increase in the requirements for ATP (resulting perhaps from muscle atrophy or decrease in metabolic efficiency), to a defect in oxidative ATP synthesis, or to a primary alteration in the balance between glycogenolytic and oxidative ATP synthesis. Skeletal muscle metabolic changes were examined in the gastrocnemius muscle at rest and during exercise in patients with chronic heart failure and in healthy control subjects to look at the effects of physical training on skeletal muscle metabolism in heart failure, in the dominant forearm muscle at rest and during exercise in patients with extensive anterior myocardial infarction to describe the time course of skeletal muscle metabolism following first large anterior myocardial infarction and in the calf muscles during sciatic nerve stimulation at 2 Hz in a rat model with myocardial infarction to study the influence of exercise training and infarct size on muscle metabolism in experimental heart failure. Phosphocreatine recovery following exercise was also analysed, which has been proposed as a measure of muscle oxidative capacity that is independent of muscle mass, recruitment and workload. More specifically the end-exercise adenosine diphosphate concentration and initial phosphocreatine resynthesis rate were used to calculate the maximum rate of oxidative ATP synthesis, which is a quantitative measure of mitochondrial capacity (a function of mitochondrial content, mitochondrial activation state and blood flow). Another inverse measure of mitochondrial function, the half-time of phosphocreatine recovery, was calculated from the slope of a semilogarithmic plot. The sum of glycogenolytic ATP synthesis rate and the initial rate of phosphocreatine depletion was also used to estimate the initial rate of ATP turnover, which is equivalent, in practice, to the initial ATPase rate measured by the very early rate of phosphocreatine depletion. For a given initial power output, the initial rate of ATP turnover is inversely proportional to muscle mass and to metabolic efficiency, and for present purposes these parameters were taken together as the effective muscle mass. To quantify the reproducibility of heart rate variability measures, standard deviation of R-R intervals together with low- and high-frequency components of heart rate variability (by autoregressive spectral analysis) were calculated from short-term sampling periods. To this end 10 patients with chronic heart failure were evaluated during stable conditions and during two different sympathetic stimulations: inotrope (dobutamine) infusion and physical exercise. Our data indicate that the reproducibility of heart rate variability parameters is reasonable, although not particularly high at the higher levels of sympathetic stimulation. In an attempt to evaluate the ability of different methods to describe autonomic function in chronic heart failure 25 patients with moderate to severe chronic heart failure were studied before and after 8 weeks of physical training at home. Sympatho-vagal balance was assessed by 24-hour daytime and nocturnal heart rate, submaximal heart rate during bicycle exercise, heart rate variability in the time (standard deviation of R-R intervals) and frequency (low- and high-frequency components of heart rate variability) domain and radiolabeled noradrenaline spillover. Results show a lack of correlation between methods describing autonomic balance in chronic heart failure, indicating that a comprehensive description of the autonomic status may necessitate a panel of complementary methods. Human and animal studies examine the role of physical training programmes on skeletal muscle metabolism in experimental and human heart failure, evaluate the effects of physical training on autonomic balance (paying specific attention on the circadian pattern of heart rate variability before and after training) in stable chronic heart failure, assess the effects of inotrope 'training' (by pulsing jS-stimulant therapy) on exercise performance, J3- adrenoceptors density and chronotropic responsiveness in patients with chronic heart failure and finally describe the time course of central haemodynamics, autonomic function and skeletal muscle metabolism in patients following extensive anterior myocardial infarction: I. Firstly, studies on skeletal muscle and autonomic function in chronic heart failure describe the skeletal muscle metabolic abnormalities characterising the complex syndrome of chronic heart failure and examine the effects of exercise training programmes on skeletal muscle metabolism in experimental and human heart failure. Recent investigations have established the presence of intrinsic skeletal muscle metabolic abnormalities in chronic heart failure, thus explaining, at least partially, the lack of correlation between exercise performance and degree of left ventricular dysfunction. Muscle deconditioning is a possible mechanism underlying impaired skeletal muscle myopathy characterising patients with chronic heart failure. The influence of physical training on skeletal muscle metabolism was studied both after myocardial infarction in a rat model of the development of heart failure and in patients with moderate to severe chronic heart failure. Phosphorus-31 magnetic resonance spectroscopy and en2yme assays were performed in female wistar rats 12 weeks after coronary artery ligation and in a non-trained sham-operated control group. Infarcted rats were radomly allocated to either 6 weeks of training or non-training. Phosphorus-31 magnetic resonance spectroscopy was also used to study muscle metabolism during exercise in 12 patients with ischaemic chronic heart failure who underwent 8 weeks of home-based bicycle exercise training in a randomised crossover controlled trial. Phosphorus-31 spectra were collected from the calf muscles of both rats and patients (at rest, during sciatic nerve stimulation and during incremental- workload plantarflexion respectively, and during recovery from either stimulation or exercise) to evaluate changes in muscle pH and in the concentrations of phosphocreatine and adenosine diphosphate. In addition, fibre typing and enzymatic assays were performed on the calf muscles of the contralateral non-stimulated leg in rats to measure the mitochondrial oxidative enzymes citrate synthase and jS-hydroxyacyl CoA dehydrogenase and the mitochondrial-cytoplasmic enzyme glutamate pyruvate transferase. Evidence is presented that rats with congestive heart failure developed similar skeletal muscle metabolic changes in the handling of high energy phosphates to those described in humans with heart failure and that physical training programmes in rats and in patients with congestive heart failure can achieve a substantial correction of the impaired oxidative capacity of skeletal muscle. II. Secondly, studies on skeletal muscle and autonomic function in chronic heart failure throw light on the role of exercise training on the autonomic function in human chronic heart failure focusing, also, on the effects of training on the circadian pattern of heart rate variability parameters describing sympatho-vagal balance. Physical deconditioning may cause or perpetuate some of the secondary changes observed in chronic heart failure. These include excessive neurohormonal vasoconstrictor activity and alterations in autonomic control mechanisms (sympathetic predominance associated with parasympathetic withdrawal), which may exacerbate symptoms and effort intolerance. The effects of an exercise training programme on the autonomic function were studied in 25 patients with moderate to severe chronic heart failure (NYHA II-III), randomised to 8 weeks of home-based bicycle exercise (20 minutes per day, 5 days per week at 70-80% of their maximal heart rate) or avoidance of exercise in a crossover design. A well-defined diurnal pattern of dynamic changes in sympatho-vagal balance has been recently linked with the circadian variation of acute cardiovascular events. The effect of exercise training on the circadian pattern of heart rate variability, recorded over 24 hours in relation to both time and frequency, was studied in 12 patients with stable moderate to severe chronic heart failure, randomised in a crossover design to 8 weeks training or detraining, and compared with an age-sex matched control group of 12 normal subjects. The circadian pattern of heart rate variability was assessed by calculating low- and high- frequency power and their ratio for each hour. The possibility is discussed that the autonomic imbalance associated with chronic heart failure may in part be due to chronic physical deconditioning and may, at least partially, be reversible by exercise training programmes in carefully selected patients. Moreover, the circadian variations in autonomic parameters appeared to be preserved in chronic heart failure in both training and detraining conditions. III. Thirdly, studies on skeletal muscle and autonomic function in chronic heart failure attempt as closely as possible to imitate pharmacologically the stimulus to the –receptors of the cardiac myocyte produced by physical training. Physical training can improve symptoms, exercise performance, autonomic function and skeletal muscle metabolism in patients with chronic heart failure and the possibility has been discussed that pharmacological therapy may be able to simulate some of these benefits. Short (20-30 minutes) periods of high-level exercise were replaced with short bursts of pharmacological jS-adrenergic stimulation with dobutamine (sufficient to raise heart rate to 70-80% maximal and maintain the infusion for 30 minutes on 4 days per week) in an attempt to determine whether short duration pulsed inotropic therapy induces a pharmacological conditioning effect in 10 patients with stable moderate to severe chronic heart failure. Results were compared with a control group of 10 patients matched for age and severity where no dobutamine infusion was performed. Lymphocyte j3-receptor density, autonomic control (assessed by heart rate variability in the time and frequency domain and by noradrenaline plasma levels) and exercise tolerance were the major end points, which reevaluated immediately and 6 weeks after the completion of pulsed inotrope therapy and in the control group of patients. Results encourage us to reconsider the role of jS-receptor stimulants because short duration pulsed inotrope therapy induces pharmacological conditioning with improved symptoms and exercise tolerance associated with improved autonomic balance, j8-receptor up-regulation and enhanced chronotropic responsiveness in patients with chronic heart failure. Evidence is reported that these beneficial effects persist for at least 6 weeks after pulsed inotrope therapy. IV. Finally, studies on skeletal muscle and autonomic function in chronic heart failure enable us to obtain a better understanding of the genesis and prognostic significance of skeletal muscle and neurohormonal abnormalities in asymptomatic left ventricular dysfunction by studying their evolution sifter myocardial infarction. The time course of skeletal muscle metabolic changes and autonomic function following extensive anterior myocardial infarction was described in 10 patients, using 3 phosphorus magnetic resonance spectroscopy to study forearm metabolism, heart rate variability (in the time and frequency domain) and radiolabeled noradrenaline kinetics to assess sympatho- vagal balance and pulsed-wave Doppler to estimate cardiac output. Results were compared with 22 normal subjects and 22 patients with stable chronic heart failure. Studies were performed at 1-3 weeks ('early'), 6-8 weeks ('midj and 6-9 months ('late') following a first extensive anterior myocardial infarction. Data emerging from the study suggest that skeletal muscle metabolism and autonomic function become abnormal after an extensive myocardial infarction, although they do not follow similar patterns. Skeletal muscle metabolic abnormalities are slow to develop and unrelated to the degree of failure, whereas early excessive neurohormonal activation seem to characterise patients who subsequently develop chronic heart failure.Open Acces