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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myocardial cells are able to adapt the cardiac pump function rapidly and widely to the changing requirements of vital organs through intrinsic and extrinsic regulatory mechanisms. This regulation is achieved by alteration of [Ca2+]i mobilization, Ca2+ sensitivity of myofibrils or both. Frank-Starling's mechanism achieved by alteration of Ca2+ sensitivity and force-frequency relation, primarily due to modulation of [Ca2+]i mobilization, are important intrinsic mechanisms. As extrinsic mechanisms, catecholamines play a crucial role by activation of both beta- and alpha 1-adrenoceptors through cyclic AMP, and products of phosphoinositide hydrolysis, as messengers, respectively. Adenosine and ACh act via similar transduction processes, including Gi or Gk proteins coupled to inhibition of adenylate cyclase, or activation of K+ channels. Most of these regulations are modulated and constitute crucial pathophysiological mechanisms in chronic heart failure.
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PMID:[Signal transduction in regulation of myocardial contractility]. 839 32

An impaired function of the myocardial beta-adrenergic receptor system has been reported in patients with end-stage heart failure and this impairment has been postulated to be a factor in further deterioration of cardiac contractile function. As ventricular dysfunction is often associated with prolonged alcohol abuse, we investigated whether or not chronic administration of ethanol could induce alterations in the beta-adrenergic receptor adenylate-cyclase system in rats. Male Wistar rats of 8 weeks of age received 33% ethanol in drinking water for 3 months. As compared with control rats drinking water, the ethanol-treated rats showed weight loss and an increase in the heart/body weight ratio. Chronic ethanol increased myocardial contents of norepinephrine and epinephrine, possibly resulting from sympathoadrenal activation. The beta-adrenergic receptor density (Bmax) of the myocardial membrane was significantly decreased in the ethanol-treated rats (27.7 +/- 9.9 vs 39.0 +/- 6.0 fmol/mg protein, p < 0.01), while the affinity (Kd) did not differ between the two groups. The myocardial content of cyclic-AMP was also reduced in the ethanol rats (865 +/- 59 vs 1055 +/- 83 pmol/g w.w., p < 0.01). These observations indicate that chronic ethanol administration depresses the function of the beta-adrenergic receptor adenylate-cyclase system. The decreased beta-adrenergic receptor density was partly attributed to down-regulation due to increased sympathetic stimulation. This impaired function may contribute to the cardiac contractile dysfunction observed in chronic alcoholics.
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PMID:Alterations in beta-adrenergic receptor density and cyclic-AMP level in the myocardium of rats chronically treated with alcohol. 839 53

Chronic activation of the sympathetic nervous system in human heart failure is believed to cause cardiac beta-adrenoceptor desensitisation. We have investigated the relationship between beta-adrenoceptor desensitisation and cyclic AMP levels in cardiac myocytes isolated from the ventricle of guinea-pigs chronically infused with noradrenaline hydrochloride for 7 days. Functional beta-adrenoceptor desensitisation was confirmed by a significant decrease in the maximum isoprenaline-stimulated contraction amplitude and an increased EC50 for isoprenaline. In the absence of beta-adrenoceptor stimulation, basal cyclic AMP levels were significantly depressed in populations of myocytes from noradrenaline-treated animals compared to sham-operated controls, and this was not accounted for by myocyte hypertrophy or necrosis. Similarly, there was a significant decrease in cyclic AMP levels at maximally inotropic isoprenaline concentrations. Threshold and maximum inotropic concentrations of the phosphodiesterase inhibitor, 3-isobutyl-l-methylxanthine (IBMX), restored isoprenaline-stimulated cyclic AMP levels in noradrenaline-treated guinea-pig cardiac myocytes, although we have previously reported no increase in maximum inotropic effect of isoprenaline with these compounds.
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PMID:Cyclic AMP levels in ventricular myocytes from noradrenaline-treated guinea-pigs. 888 22

To better characterize the role of skeletal muscle in chronic heart failure we studied energetic charge, metabolites and enzyme activity in the energy production pathway. We selected 15 males with severe chronic heart failure (NYHA class III, stable clinical conditions and in normal nutritional status) and seven controls. Controls and patients were submitted to biopsy of the vastus lateralis muscle in resting and fasting conditions. Hormone profiles were also evaluated. Our results showed near normal ATP, ADP and AMP concentrations, but there were substantially more reductions in glycogen (46 +/- 5 vs 77 +/- 6 mumoles glycosidic units.g-1 fresh tissue) and creatine phosphate (5 +/- 1 vs 13 +/- 1 mumoles.g-1 fresh tissue) in patients than in controls. We also found a reduction in glycolytic activity (pyruvate kinase 1009 +/- 79 vs 1625 +/- 26 nmoles. min-1.mg protein-1), despite normal tricarboxylic acid cycle velocity, an increase in alanine amino-transferase (964 +/- 79 vs 425 +/- 34 nmoles. min-1.mg protein-1) and in aspartate aminotransferase (515 +/- 44 vs 291 +/- 56 nmoles.min-1.mg protein-1). An increase was also observed in total NADH cytochrome c reductase (128 +/- 14 vs 68 +/- 5 nmoles.min-1.mg protein-1), while cytochrome oxidase activity was normal. The cortisol/insulin ratio was slightly elevated (77 +/- 4 vs 32 +/- 12). In conclusion, normonutritive patients with severe heart failure show an imbalance in the energy production/utilization ratio. The impairment is probably due both to a decrease in production and an increase in consumption of energy owing to greater cellular workload and/or a hypercatabolic state.
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PMID:Biochemical analysis of muscle biopsy in overnight fasting patients with severe chronic heart failure. 892 17

We studied peripheral skeletal muscle metabolism in monocrotaline-treated rats. Two distinct groups emerged: a percentage of the animals developed ventricular hypertrophy, with no signs of heart failure (compensated group), whilst others, besides ventricular hypertrophy, developed the syndrome of congestive heart failure (CFH group). Oxidative metabolism and redox cellular state were expressed in terms of creatine phosphate, purine (ATP, ADP and AMP) and pyridine (NAD and NADH) nucleotides tissue content. Skeletal muscles with different metabolism were studied: (a) Soleus (oxidative), (b) extensor digitorium longus (glycolytic) and tibialis anterior (oxidative and glycolytic). The results showed that in CFH animals a decreased high-energy phosphates content occurs in the soleus and extensor digitorum longus, but not in the tibialis anterior. In the soleus. ATP declined from 20.31 +/- 2.5 of control group to 9.55 +/- 0.61 mumol/g dry wt. while in the extensor digitorum longus ATP declined from 30.92 +/- 2.68 to 22.7 +/- 1.54 mumol/g dry wt. In both these muscles, a shift of NAD/NADH couple towards oxidation was also observed (from 26.58 +/- 3.34 to 6.95 +/- 0.97 and from 18.88 +/- 3.43 to 10.57 +/- 1.61, respectively). These alterations were more evident in the aerobic soleus muscle. On the contrary, no major changes occurred in skeletal muscle metabolism of compensated animals. The results show that: (1) a decrease in muscle high-energy phosphates occurs in CFH; (2) this is accompanied by a decrease of NAD/NADH couple suggesting an impairment in oxygen utilization or availability.
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PMID:Skeletal muscle metabolism in experimental heart failure. 893 80

Deficient myocardial cyclic AMP concentrations contribute to abnormal Ca2+ handling and systolic and diastolic dysfunction in chronic heart failure (CHF). We tested the hypothesis that decreased cyclic AMP in skeletal muscle of animals with failure may contribute to the weakness and easy fatiguability also common in patients with CHF. We compared intracellular Ca2+ signaling and contractility in skeletal muscle preparations from rats 6 weeks after myocardial infarction-induced CHF versus sham-operated controls. Bundles of 100 to 200 cells were dissected from the extensor digitorum longus (EDL) muscle of control and CHF rats. Muscles from CHF rats exhibited depressed tension development compared with control muscles during twitches. Treatment with 2mM dibutyryl cyclic AMP returned tension and Ca2+ towards normal levels. There was no evidence of cellular atrophy in the CHF rats. In conclusion, EDL skeletal muscle from rats with CHF had intrinsic abnormalities in excitation-contraction coupling that could be reversed with cyclic AMP supplementation as previously reported for the heart. This suggests that deficient cyclic AMP levels may contribute to both cardiac and skeletal muscle dysfunction in CHF.
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PMID:Deficient cellular cyclic AMP may cause both cardiac and skeletal muscle dysfunction in heart failure. 895 67

In the human heart the beta-adrenergic receptor-G-protein-adenylyl cyclase system is the most powerful physiologic mechanism to acutely increase contractility and/or heart rate. In the failing human myocardium beta 1-adrenergic receptor number is decreased, and this is accompanied by a reduced beta 1-adrenergic receptor mediated positive inotropic effect. Cardiac beta 2-adrenergic receptor number may or may not decrease; however, beta 2- adrenergic receptor mediated positive inotropic effects are also reduced, possibly because the functional activity of myocardial Gi is increased, thereby inhibiting cyclic AMP formation. The aging human heart shows some similarities with the failing human heart: in both settings, of chronic heart failure and age, beta-adrenergic receptor mediated effects and all other cyclic AMP dependent effects are depressed and Gi-protein is increased.
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PMID:Beta-adrenergic receptors in failing human myocardium. 895 42

Depression of myocardial contractility plays an important role in the development of heart failure; therefore, intensive interest and passion have been generated to develop cardiotonic agents to improve the contractile function of the failing heart. Inotropic agents that increase cyclic AMP, either by increasing its synthesis or reducing its degradation, exert dramatic short-term hemodynamic benefits, but these acute effects cannot be extrapolated into long-term improvement of the clinical outcome in patients with advanced heart failure. Administration of these agents to an energy-starved failing heart would be expected to increase myocardial energy use and could accelerate disease progression. The role of digitalis in the management of heart failure has been controversial, but ironically the drug has now been proved to favorably affect the neurohormonal disorders and its reevaluation is now being intensively investigated. More recently, attention has been focused on other inotropic agents that have a complex and diversified mechanism. Recent clinical studies have demonstrated that they are potentially useful in the long-term treatment of heart failure patients. These agents have some phosphodiesterase-inhibitory action but also possess additional effects, including acting as cytokine inhibitors, immunomodulators, or calcium sensitizers. However, their therapeutic ratio is narrow and further studies are warranted to establish their optimal doses and their eventual status in the treatment of heart failure.
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PMID:Inotropic agents in the treatment of heart failure: despair or hope? 911 Jan 13

Early heart failure is characterized by elevated plasma atrial natriuretic peptide (ANP) levels, but little is known about the direct effects of ANP on cardiac myocytes. In neonatal rat cardiac myocytes, ANP induced apoptosis in a dose-dependent and cell type-specific manner. Maximum effects occurred at 1 microM ANP, with a 4-5-fold increase in apoptotic cells, reaching a maximum apoptotic index of 19%. In contrast, the maximum apoptotic index of ANP-treated non-myocytes was 1.1 +/- 0.2%, equivalent to control cultures. ANP treatment also sharply reduced levels of Mcl-1 mRNA, a Bcl-2 homologue, coincident with the increase in the incidence of apoptosis. ANP induction of apoptosis was receptor-dependent and mediated by cyclic GMP: the effect was mimicked by 8-bromo-cGMP, a membrane-permeable analog, and by sodium nitroprusside, an activator of soluble guanylyl cyclase, and was potentiated by a cGMP-specific phosphodiesterase inhibitor, zaprinast. Interestingly, norepinephrine, a myocyte growth factor, inhibited ANP-induced apoptosis via activation of the beta-adrenergic receptor and elevation of cyclic AMP. These results show that ANP is a specific effector of cardiac myocyte apoptosis in culture via receptor-mediated elevation of cGMP. Furthermore, at least in this model, ANP and norepinephrine may have opposing roles in the modulation of cardiac myocyte growth and survival.
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PMID:Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. 916 55

Coronary artery disease and ischemic myocardial damage form the most common cause of failure of the heart to pump enough blood for oxygenation of the body at a healthy blood pressure and at a low pressure in the veins. This paper gives an overview of the mechanisms involved in excitation-contraction coupling which are important to control of the force of the heartbeat. The inability of the heart in failure to eject a sufficient amount of blood in order to meet the needs of the body is thought to result from molecular changes in cardiac cells causing decreased active (systolic) force and impaired (diastolic) relaxation together with a greater stiffness of the remodelled ventricular wall. The failure to generate a forceful contraction is in part a consequence of derailment of the processes in the failing cardiac cells to manipulate calcium ions, despite the increased stimulus from nervous and hormone systems to enhance cardiac performance. By lack of adequate release and uptake of calcium ions, the amount of mechanical work that can be put out by the heart muscle is diminished and the heart may fail. Uptake of calcium ions by the intracellular store-the sarcoplasmic reticulum-is impaired in congestive heart failure probably as result of inadequate gene expression. In consequence, the amount of calcium that is released during each heartbeat is less than normal, thus force is reduced; in addition, the positive response of force to increased heart rate is lost. In normal heart muscle, the response of the contractile filaments to calcium ions depends strongly on sarcomere length thus explaining Starling's Law of the heart. Recent evidence suggests that this sensitivity is largely lost in congestive heart failure thereby reducing the effectiveness of stretch of cardiac cells on the mechanical output. The reduction of the maximal velocity of shortening of the cardiac sarcomere in heart failure is not well understood, but may in part be related to changes in the internal load as a result of changes in visco-elastic components of the myocardium Lastly, the effect of longstanding sympathetic drive to the heart during the development of heart failure induces a loss of sensitivity of the myocardium to catecholamines by loss of beta 1 receptors and partial uncoupling of the beta receptors from production of cyclic AMP; hence the effect of sympathetic activation is diminished and the heart has to rely more on Starling's Law. Increase of the filling pressure of the left ventricle may in part accommodate the ongoing demands of the body. However, in the case of a stenosed coronary arterial system, the increased end-diastolic pressure carries the substantial risk of aggravating pre-existent myocardial ischemia.
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PMID:Heart failure and Starling's Law of the heart. 919 98


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