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Query: UMLS:C0015672 (fatigue)
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Chronic heart failure is a well-recognized syndrome in which left ventricular impairment produces a constellation of secondary changes in other organ symptoms leading to symptoms such as muscular fatigue and dyspnoea and objective limitation to exercise tolerance. With modern drug therapy of diuretics and ACE inhibitors, the majority of patients have minimal if any signs of congestion, and yet severe symptomatic limitation remains. This limitation bears little relationship to conventional measures of either left ventricular function or the haemodynamic profile of the patient. The symptoms limiting exercise are predominantly fatigue or dyspnoea, and yet the classical pathophysiological explanations for their genesis now seem inadequate. Recent investigations, as demonstrated, in part, by the research presented in this symposium, attest to the importance of abnormalities in peripheral blood flow and in skeletal muscle in producing both objective limitation to exercise and in explaining the generation of the exercise-limiting symptoms of the syndrome of stable optimally treated chronic heart failure. In addition it is now evident that these muscle changes may in addition have pathophysiological significance for the maintenance of sympatho-excitation during exercise and potentially therefore in the progression of left ventricular remodelling and in the susceptibility to ventricular arrhythmias. This paper presents some of the background evidence which leads to the hypothesis that a feedback loop links changes in skeletal muscle to abnormal reflex cardiopulmonary control which may both limit exercise and be harmful in the progression of the syndrome.
J Mol Cell Cardiol 1996 Nov
PMID:The "muscle hypothesis" of chronic heart failure. 893 79

Exertional fatigue is a major limiting symptom in patients with heart failure. Nevertheless, the mechanism responsible for this fatigue remains unclear. Reduced skeletal muscle blood flow, altered muscle oxidative enzymes, decreased muscle mass and altered muscle contractility have all been implicated but the precise contribution of these factors remains to be determined. Clinically, the severity of muscle fatigue is usually determined from the patient history. This approach is unreliable since symptoms reported during normal daily activities correlate poorly with objective measures of exercise performance. The degree of perceived fatigue noted during formal exercise testing also correlates poorly with objective measures of muscle behavior, such as blood lactate levels. Cardiopulmonary exercise testing can be used to identify the onset of lactate release, or the anaerobic threshold, and therefore provides more objective information about muscle behavior. However, an increase in blood lactate does not necessarily indicate muscle fatigue. Surface recordings of muscle electromyograms during exercise permits detection of increasing EMG signal, an indicator of fatigue. This technique is potentially valuable but is technically challenging. Finally, muscle fatigue can be assessed by monitoring developed tension during repetitive contractions of the quadriceps muscle. This index of muscle fatigability correlates relatively closely with maximal exercise performance and provides the best index of fatigue currently available. However, further studies are needed to document the clinical utility of this methodology.
J Mol Cell Cardiol 1996 Nov
PMID:Evaluation of skeletal muscle fatigue in patients with heart failure. 893 82

The arterio-venous concentrations of oxygen, glucose and lactate, as well as blood flow and muscle levels of lactate, glucose, hexose-phosphates and glycogen of rat hind leg muscle were determined under basal conditions and under mild and intense exercise, as well as during post-exercise recovery. During intense exercise and fatigue glycogen is practically exhausted, providing glycosyl residues to the hexose-phosphates pool in addition to increased glucose uptake from the blood. The result is the production of huge amounts of lactate, which accumulates in muscle and the skin, and buildup the arterial concentrations. During recovery lactate is slowly disposed of, and the muscle takes up large amounts of glucose which is stored into glycogen, with fully reinstated glucose oxidation. The data shown suggest that the shift from oxidative to mainly anaerobic utilization of glucose is not as streamlined as is usually assumed, since the results found here hint at the wasteful utilization of glycogen-derived hexose skeletons for other synthetic pathways. Glucose, nevertheless, is of paramount importance as energy staple to sustain untrained intense exercise in the rat.
Biochem Mol Biol Int 1997 Apr
PMID:Carbohydrate handling in the hind leg muscle of exercising rats. 911 35

Hypertrophic cardiomyopathy (HCM) is manifested by severe thickening of the left ventricle with significant diastolic dysfunction. Previous observations on the improvement in diastolic function and left ventricular wall thickness through the therapeutic administration of coenzyme Q10 (CoQ10) in patients with hypertensive heart disease prompted the investigation of its utility in HCM. Seven patients with HCM, six non-obstructive and one obstructive, were treated with an average of 200 mg/day of CoQ10 with mean treatment whole blood CoQ10 level of 2.9 micrograms/ml. Echocardiograms were obtained in all seven patients at baseline and again 3 or more months post-treatment. All patients noted improvement in symptoms of fatigue and dyspnea with no side effects noted. The mean interventricular septal thickness improved significantly from 1.51 +/- 0.17 cm to 1.14 +/- 0.13 cm, a 24% reduction (P < 0.002). The mean posterior wall thickness improved significantly from 1.37 +/- 0.13 cm to 1.01 +/- 0.15 cm, a 26% reduction (P < 0.005). Mitral valve inflow slope by pulsed wave Doppler (EF slope) showed a non-significant trend towards improvement, 1.55 +/- 0.49 m/sec2 to 2.58 +/- 1.18 m/sec2 (P < 0.08). The one patient with subaortic obstruction showed an improvement in resting pressure gradient after CoQ10 treatment (70 mmHg to 30 mmHg).
Mol Aspects Med 1997
PMID:Treatment of hypertrophic cardiomyopathy with coenzyme Q10. 926 16

1. Magnocellular neurosecretory cells (MNCs) in the rat hypothalamus adopt a phasic pattern of spike discharge under conditions demanding enhanced vasopressin release, such as during dehydration or hemorrhage. The emergence of phasic firing minimizes the occurrence of secretory fatigue from the axon terminals of MNCs, thereby maximizing vasopressin release from the neurohypophysis. 2. Intracellular and whole-cell recordings from hypothalamic slices or explants in vitro have shown that phasic firing is supported by the presence of a plateau potential which arises from the summation of spike depolarizing afterpotentials (DAPs). Modulatory actions of neurotransmitters on the amplitude of the DAP, therefore, represent possible mechanisms by which the expression of phasic firing may be regulated in vivo. 3. Here we review the basis for phasic firing in MNCs of the rat supraoptic nucleus and present recent findings concerning the direct and indirect mechanisms through which selected neurotransmitters have been found to regulate the amplitude of DAPs.
Cell Mol Neurobiol 1998 Feb
PMID:Extrinsic modulation of spike afterpotentials in rat hypothalamoneurohypophysial neurons. 952 26

Limb muscles can be injured during and after vigourous contractions. However, this injury is most evident under specific conditions. The strength and type of muscle contraction as well as the contractile status of the muscle are important determinants of injury. The initiating event leading to muscle injury is not clearly understood but there are several leading theories. The respiratory muscles are of obvious importance to survival, and fatigue or injury to them has been hypothesized to be prevented by various mechanisms. One such mechanism is reduced activation by the central nervous system. In this review information on the neural activation of the breathing muscles during inspiratory loading is discussed and reveals that neural activation to the diaphragm, the main inspiratory muscle, is high. Previous studies investigating the presence of muscle fatigue immediately after such inspiratory loading have shown little evidence of it. However, based on information from limb muscles, delayed or secondary muscle injury might occur and could produce deleterious effects on respiratory muscle function. Recent evidence shows that chronic low intensity inspiratory loading can produce diaphragmatic injury (Reid et al.) and secondary or delayed muscle injury can occur three days after an acute period of high intensity inspiratory loading. The results reviewed in this article suggest that the respiratory muscles, specifically the diaphragm, are not spared from injury or the results of muscle injury. Diaphragmatic function during the period of secondary muscle injury is markedly impaired and thus respiratory muscle injury is a phenomenon that warrants further investigation.
Mol Cell Biochem 1998 Feb
PMID:Determinants of diaphragmatic injury. 954 51

The interaction between a patient and a ventilator is the major determinant of the amount of respiratory muscle rest achieved by the machine. We are beginning to acquire a better understanding of the mechanisms that underlie this complex interaction, but this information has yet to be integrated into the routine clinical management of ventilator-supported patients. To achieve that goal, we need better techniques of detecting and monitoring patient-ventilation asynchrony, and the development of simple algorithms that can minimize its occurrence. Finally, research is needed to determine the occurrence and importance of respiratory muscle fatigue during failed weaning attempts so as to better guide the timing and pace of the weaning process in problematic patients.
Mol Cell Biochem 1998 Feb
PMID:Respiratory muscle dysfunction in mechanically-ventilated patients. 954 52

It is now recognized that respiratory muscle fatigue contributes to the development of respiratory failure in some patients with lung disease. This observation has prompted an examination into the mechanisms of development of muscle fatigue, with the understanding that an elucidation of these processes may lead to new therapeutic approaches to the treatment of these patients. A series of recent studies examining this issue have, moreover, discovered that oxygen-derived free radicals generated during strenuous contraction may modulate respiratory muscle contractile function and contribute to the development of muscle fatigue. The data supporting this concept include: (a) direct (e.g. EPR, ESR studies) and indirect (evidence of lipid peroxidation, protein carbonyl formation, glutathione oxidation) evidence that there is heightened free radical production in contracting muscle, (b) evidence that pharmacologic depletion of muscle antioxidant stores increases degree of muscle fatigue present after a period of exercise, and (c) evidence that administration of agents that act as free radical scavengers retard the development muscle fatigue. Free radicals may produce these changes in muscle force generating capacity by interacting with and altering the function of a number of intracellular-biophysical processes (i.e. sarcolemmal action potential propagation, sarcoplasmic reticulum calcium handling, mitochondrial function, contractile protein interactions).
Mol Cell Biochem 1998 Feb
PMID:Free radical induced respiratory muscle dysfunction. 954 53

The myosin heavy chain (MHC) exists as multiple isoforms that are encoded for by a family of genes. The respiratory musculature demonstrates muscle-specific and temporally-dependent changes in MHC isoform expression during maturation. Developmental expression of MHC isoforms correlate well with postnatal changes in actomyosin ATPase activity, specific force generation (P0/CSA), maximum unloaded velocity of shortening (V0) and and fatigue resistance. More specifically, as the expression of MHCneonatal declines and MHC2A, MHC2X, and MHC2B increase, actomyosin ATPase activity, P0/CSA, V0, and muscle fatigability increase. The increase in actomyosin ATPase activity with maturation is partially offset by a postnatal increase in oxidative capacity; however, as fatigue resistance declines with development it is apparent that the energy costs of contraction are not fully matched by an increase in energy production. Developmental transitions in smooth muscle MHC phenotype also occur although their functional importance remains unclear.
Comp Biochem Physiol B Biochem Mol Biol 1998 Mar
PMID:Myosin heavy chain transitions during development. Functional implications for the respiratory musculature. 973 30

Hereditary primary adrenal insufficiency syndromes due to ACTH resistance include hereditary glucocorticoid deficiency (HGD) and Allgrove's syndrome (AS). Patients with both conditions present in childhood with failure to thrive, weakness, and fatigue or adrenal crisis; patients with AS in addition have alacrima and achalasia (triple A syndrome). We studied four kindreds with HGD and four kindreds with AS for abnormalities of the ACTH receptor (ACTHR) gene. The ACTHR coding sequence in all AS kindreds and two HGD kindreds was normal. Analysis of the ACTHR gene of the proband in one of the HGD kindreds showed him to be homozygous for the previously described G221T transition causing a Ser74Ile substitution of the protein, which has been shown to inactivate the ACTHR in signal transduction. The proband in another HGD kindred was found to be a compound heterozygote with the G221T transition in one allele and a novel C818A transition in the other allele of ACTHR. The C818A transition caused the substitution of the highly conserved Pro273 by His in the receptor protein. In vitro expression of the mutated ACTHR in mouse melanoma M3 cells showed that at a medium ACTH concentration of 3 nM, cells transfected with the wild-type ACTHR produced twofold and threefold, respectively, of the amount of intracellular cAMP when compared to cells transfected with the ACTHR carrying the Pro273His and the Ser74Ile mutation, respectively, confirming that HGD in this kindred is caused by loss-of-function mutations of the ACTHR. These results showed that the genetic cause of the ACTH-resistant syndromes is heterogeneous.
Mol Genet Metab 1998 Aug
PMID:Genetic heterogeneity of adrenocorticotropin (ACTH) resistance syndromes: identification of a novel mutation of the ACTH receptor gene in hereditary glucocorticoid deficiency. 975 16


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