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

Oral feeding with the creatine analogue beta-guanidinopropionate (beta-GP) reduces myocardial phosphocreatine and creatine concentrations by about 80%in vitro, this is accompanied by reduced contractile performance. We hypothesized, thus, that beta-GP feeding leads to hemodynamic changes in vivo characteristic of heart failure. beta-GP was fed to Wistar rats for up to 8 weeks. In isolated hearts, function was measured isovolumically, myocardial energetics were followed with (31)P-NMR spectroscopy. In vivo hemodynamics were measured with Millar-Tip-catheters and an electromagnetic flow probe. Beta-GP feeding did not alter heart weight. In vitro, diastolic pressure-volume curves indicated structural left ventricular dilatation, and a 36% reduction of left ventricular developed pressure was found; phosphocreatine was reduced by approximately 80%, ATP unchanged and creatine kinase reaction velocity ((31)P-MR saturation transfer) decreased by approximately 90%. The total creatine pool (high-pressure liquid chromatography) was reduced by up to approximately 70%. In contrast to in vitro findings, in vivo cardiac hemodynamics (including left ventricular developed pressure, d P/d t(max), cardiac output and peripheral vascular resistance) at rest and during acute volume loading showed no alterations after beta-GP feeding. The only functional impairment observed in vivo was a 14% reduction of maximum left ventricular developed pressure during brief aortic occlusion. In the intact rat, cardiac and/or humoral compensatory mechanisms are sufficient to maintain normal hemodynamics in spite of a 90% reduction of creatine kinase reaction velocity. However, chronic beta-GP feeding leads to structural left ventricular dilatation.
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PMID:Functional and energetic consequences of chronic myocardial creatine depletion by beta-guanidinopropionate in perfused hearts and in intact rats. 1052 22

We investigated the time course of genesis of skeletal muscle dysfunction and sympatho-vagal imbalance after myocardial infarction. We studied 22 normal controls, 22 patients with >6 months stable chronic heart failure and 10 patients after a first massive myocardial infarction at 1-3 weeks (the "early" period), 6-8 weeks ("mid") and 6-9 months ("late") following their infarct. Four patients developed overt heart failure. Forearm muscle metabolism was studied using (31)P magnetic resonance spectroscopy (MRS). Sympatho-vagal balance was assessed by heart rate variability and radiolabelled norepinephrine kinetics. Increased norepinephrine spillover (0.55+/-0.02 v 0.27+/-0.04 mg/min/m(2); P<0.01) and decreased heart rate variability were confined to those post-myocardial infarction patients who subsequently developed heart failure. Resting cardiac output was normal in all the post-myocardial infarction patients, although the response of cardiac output to supine bicycle exercise at the "mid" study point was less in the group who subsequently developed heart failure (9+/-1 v 41+/-8 %; P<0.005). In the MRS studies, there were no detectable differences between those who did or did not develop heart failure. The initial rate of ATP turnover, calculated from initial-exercise changes in pH and phosphocreatine (PCr), was increased in established chronic heart failure, but in the post-myocardial infarction patients a numerically similar increase reached statistical significance only in the early group (19+/-3 v 11+/-1 mM/min; P<0.005). The apparent maximum rate of oxidative ATP synthesis, calculated from post-exercise PCr recovery kinetics, was lower than control in the late post-myocardial infarction and established chronic heart failure groups 34+/-5 v 55+/-4 mM/min; P<0.03 and 38+/-3 v 55+/-4 mM/min; P<0.003, respectively). Skeletal muscle metabolism and autonomic function become abnormal after an extensive myocardial infarction. While skeletal muscle abnormalities are relatively slow to develop and unrelated to the degree of failure, excessive neurohormonal activation and impaired cardiac output response to exercise seem from an early stage to characterize patients who subsequently develop chronic heart failure.
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PMID:The time course of haemodynamic, autonomic and skeletal muscle metabolic abnormalities following first extensive myocardial infarction in man. 1052 28

Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing beta(2)ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of beta(2)AR overexpression during ischemia, perfused hearts from TG4 and wild-type mice were subjected to 20-minute ischemia and 40-minute reperfusion. During ischemia, ATP and pH fell lower in TG4 hearts than wild type. Ischemic injury was greater in TG4 hearts, as indicated by lower postischemic recoveries of contractile function, ATP, and phosphocreatine. Because beta(2)ARs, unlike beta(1)ARs, couple to G(i) as well as G(s), we pretreated mice with the G(i) inhibitor pertussis toxin (PTX). PTX treatment increased basal contractility in TG4 hearts and abolished the contractile resistance to isoproterenol. During ischemia, ATP fell lower in TG4+PTX than in TG4 hearts. Recoveries of contractile function and ATP were lower in TG4+PTX than in TG4 hearts. We also studied mice that overexpressed either betaARK1 (TGbetaARK1) or a betaARK1 inhibitor (TGbetaARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGbetaARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGbetaARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, beta(2)AR overexpression increased ischemic injury, whereas betaARK1 overexpression was protective. Ischemic injury in the beta(2)AR overexpressors was exacerbated by PTX treatment, implying that it was G(s) not G(i) activity that enhanced injury. Unlike beta(2)AR overexpression, basal contractility was increased by betaARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.
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PMID:Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury. 1057 39

Chronic treatment with beta-receptor blockers or angiotensin-converting enzyme (ACE) inhibitors in heart failure can reduce mortality and improve left ventricular function, but the mechanisms involved in their beneficial action remain to be fully defined. Our hypothesis was that these agents prevent the derangement of cardiac energy metabolism. Rats were subjected to myocardial infarction (MI) or sham operation. Thereafter, animals were treated with bisoprolol, captopril, or remained untreated. Two months later, cardiac function was measured in the isolated heart by a left ventricular balloon (pressure-volume curves), and energy metabolism of residual intact myocardium was analyzed in terms of total and isoenzyme creatine kinase (CK) activity, steady-state levels (ATP, phosphocreatine), and turnover rates (CK reaction velocity) of high-energy phosphates (31P nuclear magnetic resonance) and total creatine content (HPLC). Bisoprolol and partially captopril prevented post-MI hypertrophy and partially prevented left ventricular contractile dysfunction. Residual intact failing myocardium in untreated, infarcted hearts showed a 25% decrease of the total, a 26% decrease of MM-, and a 37% decrease of the mitochondrial CK activity. Total creatine was reduced by 15%, phosphocreatine by 21%, and CK reaction velocity by 41%. Treatment with bisoprolol or captopril largely prevented all of these changes in infarcted hearts. Thus the favorable functional effects of beta-receptor blockers and ACE inhibitors post-MI are accompanied by substantial beneficial effects on cardiac energy metabolism.
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PMID:Effects of ACE inhibition and beta-receptor blockade on energy metabolism in rats postmyocardial infarction. 1060 Aug 34

31p nuclear magnetic resonance (NMR) spectroscopy represents a unique instrument to noninvasively monitor myocardial metabolism in humans. The technique has been used to study the metabolism in myocardial hypertrophy in humans with hypertension, aortic stenosis, aortic incompetence, mitral regurgitation, and hypertrophic cardiomyopathy, as well as after maintenance dialysis or long-term physical exercise in elite cyclists. A primary aim is the determination of the phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, which reflects the energetic state of the myocardium. Recent investigations take advantage of proton decoupling in 31p NMR spectroscopy, which, besides the PCr/ATP ratio, also allows the determination of the inorganic phosphate/ PCr and the phosphomonoester/PCr ratios as additional indicators for alterations in myocardial metabolism. Abnormal myocardial metabolism was found in humans with aortic stenosis, mitral regurgitation, hypertrophic cardiomyopathy, and in patients who undergo maintenance dialysis. A trend toward a lower PCr/ATP ratio was reported in hypertension and aortic incompetence patients. Several studies have revealed a dependence of the metabolic abnormalities on the degree of heart failure, and one study claimed that a correlation with the extent of hypertrophy exists. No metabolic abnormalities were found in elite cyclists.
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PMID:31P nuclear magnetic resonance spectroscopy: a noninvasive tool to monitor metabolic abnormalities in left ventricular hypertrophy in human. 1075 May 82

MR spectroscopy is the only method that allows for the noninvasive study of cardiac metabolism in the human heart without the use of external radioactive tracers. 31P-spectroscopy allows to examine the high-energy phosphates ATP and phosphocreatine. Clinical studies with 31P-spectroscopy have focused on three areas: heart failure, valve disease and coronary artery disease. Whether MR spectroscopy will become a routine diagnostic tool in the future remains to be determined.
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PMID:[Clinical relevance of MR spectroscopy of the heart]. 1090 4

MR spectroscopy is the only method for non-invasive detection of various aspects of cardiac metabolism in humans. While the 1H nucleus of water and fat molecules is the signal source for MR imaging, the MR spectroscopic technique allows for the study of a number of other nuclei, such as 13C, 19F, 23Na, 31P, 39K and 87Rb. Clinical applications presently are confined to the 31P nucleus. 31P-MR spectroscopy allows the non-invasive study of cardiac high-energy phosphate metabolites ATP and phosphocreatine. The phosphocreatine/ATP ratio is considered an index of the energetic state of the heart. Possible clinical indications include heart failure, valve disease and coronary artery disease. In heart failure, the phosphocreatine/ATP ratio is reduced and correlates with clinical severity, ejection fraction and prognosis. In mitral and aortic valve disease, a reduced phosphocreatine/ATP ratio may indicate the optimum timing for valve replacement. In coronary artery disease, a regional decrease of phosphocreatine during stress ("biochemical ergometry") may indicate local ischemia. Furthermore, absolute quantification of high-energy phosphates may allow diagnosis of myocardial viability. Major technical developments, leading to improved spatial and temporal resolution will be necessary to establish MR spectroscopy as a routine clinical tool.
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PMID:Cardiac magnetic resonance spectroscopy: potential clinical applications. 1094 81

The intracellular mechanisms of regulation of energy fluxes and respiration in contracting heart cells were studied. For this, we investigated the workload dependencies of the rate of oxygen consumption and metabolic parameters in Langendorff-perfused isolated rat hearts.(31)P NMR spectroscopy was used to study the metabolic changes during transition from perfusion with glucose to that with pyruvate with and without active creatine kinase system. The experimental results showed that transition from perfusion with glucose to that with pyruvate increased the phosphocreatine content and stability of its level at increased workloads. Inhibition of creatine kinase reaction by 15-min infusion of iodoacetamide decreased the maximal developed tension and respiration rates by a factor of two.(31)P NMR data were analyzed by a mathematical model of compartmentalized energy transfer, which is independent from the restrictions of the classical concept of creatine kinase equilibrium. The analysis of experimental data by this model shows that metabolic stability-constant levels of phosphocreatine, ATP and inorganic phosphate-at increased energy fluxes is an inherent property of the compartmentalized system. This explains the observed substrate specificity by changes in mitochondrial membrane potential. The decreased maximal respiration rate and maximal work output of the heart with inhibited creatine kinase is well explained by the rise in myoplasmic ADP concentration. This activates the adenylate kinase reaction in the myofibrillar space and in the mitochondria to fulfil the energy transfer and signal transmission functions, usually performed by creatine kinase. The activity of this system, however, is not sufficient to maintain high enough energy fluxes. Therefore, there is a kinetic explanation for the decreased maximal respiration rate of the heart with inhibited creatine kinase: i.e. a kinetically induced switch from an efficient energy transfer pathway (PCr-CK system) to a non-efficient one (myokinase pathway) within the energy transfer network of the cell under conditions of low apparent affinity of mitochondria to ADP in vivo. This may result in a significant decrease in the thermodynamic affinity of compartmentalized ATPase systems and finally in heart failure.
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PMID:Metabolic control of contractile performance in isolated perfused rat heart. Analysis of experimental data by reaction:diffusion mathematical model. 1096 33

Spectroscopy is close to becoming an integral part of the clinical MR examination to achieve a complete morphological, functional, and metabolic evaluation of the human heart. 31P-NMR spectroscopy is used to noninvasively assess human myocardial energy metabolism. Abnormalities in the phosphocreatine (PCr) to ATP ratio are observed in ischemic heart disease, heart failure, transplanted hearts, and hypertrophic cardiomyopathy. NMR spectroscopy 31P spectra obtained at rest, during exercise or pharmacological stress allow the observation of the earliest metabolic responses of myocardial ischemia. 1 spectroscopy can evaluate the concentration of intracellular creatine and myocardial lipids as a means of evaluating myocardial viability. The increase in total 23Na in ischemic tissue provides information about the extent and location of viable tissue. Higher magnetic fields, gradient strength, and technological advances in pulse sequence and localization will result in better spatial and temporal resolution improving the clinical utility of the technique.
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PMID:Cardiac MR spectroscopy in the new millennium. 1147 51

Nitric oxide (NO), a potent regulator of myocardial contractility, has been implicated in the development of heart failure; however, no study exists describing the relation between expression of inducible nitric oxide synthase (iNOS), formation of NO in vivo, and cardiac contractility. We have therefore generated transgenic (TG) mice overexpressing iNOS under the cardiospecific alpha-myosin heavy chain (alpha-MHC) promoter. In vitro, iNOS activity in hearts of two transgenic lines was 260- to 400-fold above controls (wild type [WT]), but TG mice were viable and appeared normal. Ventricular mass/body weight ratio did not differ; heart rate and cardiac output as well as mean arterial blood pressure were decreased by 10%. NO(x) levels of hearts and blood of TG mice were 2.5- and 2-fold above WT controls, respectively. In the isolated heart, release of the NO oxidation products nitrate and nitrite, an index of in vivo NOS activity, was 40-fold over WT. However, cardiac hemodynamics and levels of ATP and phosphocreatine were unaltered. The high iNOS activity was associated with reduced cardiac L-arginine in TG hearts to only 15% of the WT, indicating limited substrate availability, whereas L-citrulline was 20-fold elevated. Our findings demonstrate that the heart can tolerate high levels of iNOS activity without detrimental functional consequences. The concept that iNOS-derived NO is the triggering factor in the pathomechanism leading to heart failure therefore needs to be reevaluated.
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PMID:Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. 1452 22


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