Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754633
Title: Studies on skeletal muscle and autonomic function in chronic heart failure
Author: Adamopoulos, Stamatis
Awarding Body: University of London
Current Institution: Imperial College London
Date of Award: 2001
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Abstract:
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.
Supervisor: Coats, Andrew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.754633  DOI: Not available
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