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

Since mammalian cardiac myocytes essentially rely on aerobic energy metabolism, it has been assumed that cardiocytes die in a catastrophic breakdown of cellular homeostasis (i.e. necrosis), if oxygen supply remains below a critical limit. Recent observations, however, indicate that a process of gene-directed cellular suicide (i.e. apoptosis) is activated in terminally differentiated cardiocytes of the adult mammalian heart by ischemia and reperfusion, and by cardiac overload as well. Apoptosis or programmed cell death is an actively regulated process of cellular self destruction, which requires energy and de novo gene expression, and which is directed by an inborn genetic program. The final result of this program is the fragmentation of nuclear DNA into typical 'nucleosomal ladders', while the functional integrity of the cell membrane and of other cellular organelles is still maintained. The critical step in this regulated apoptotic DNA fragmentation is the proteolytic inactivation of poly-[ADP-ribose]-polymerase (PARP) by a group of cysteine proteases with some structural homologies to interleukin-1 beta-converting enzyme (ICE-related proteases [IRPs] such as apopain, yama and others). PARP catalyzes the ADP-ribosylation of nuclear proteins at the sites of spontaneous DNA strand breaks and thereby facilitates the repair of this DNA damage. IRP-mediated destruction of PARP, the 'supervisor of the genome', can be induced by activation of membrane receptors (e.g. FAS or APOI) and other signals, and is inhibited by activation of 'anti-death genes' (e.g. bcl-2). Overload-triggered myocyte apoptosis appears to contribute to the transition to cardiac failure, which can be prevented by therapeutic hemodynamic unloading. In myocardial ischemia, the activation of the apoptotic program in cardiocytes does not exclude their final destiny to catastrophic necrosis with release of cytosolic enzymes, but might be considered as an adaptive process in hypoperfused ventricular zones, sacrificing some jeopardized myocytes to regulated apoptosis, which may be less arrhythmogenic than necrosis with the primary disturbance of membrane function.
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PMID:Apoptosis in the heart: when and why? 897 66

The phosphodiesterase type III inhibitors piroximone (PIR) and enoximone (ENO) exert positive inotropic and vasodilating effects in patients with severe heart failure. PIR and ENO raise cyclic AMP levels in cardiac and vascular smooth muscle cells. Platelet activity is also regulated by intracellular levels of cyclic AMP. In this study we have investigated the effects of PIR and ENO on platelet activity in vivo and in vitro. PIR and ENO inhibited ADP induced platelet aggregation in a time- and concentration-dependent manner with IC50-values of 67 +/- 14 mumol/l and 129 +/- 6 mumol/l, respectively. Coincubation of PIR with the adenylate cyclase activator iloprost resulted in a synergistic potentiation of the platelet inhibitory effect. In anesthetized rats PIR and ENO (2 mg/kg bw) exerted an effective inhibition of collagen induced reduction in peripheral platelet count (vehicle 49 +/- 7%, PIR 22 +/- 8%, ENO 30 +/- 6%; P < 0.01). In washed human platelets incubation with PIR and ENO resulted in a time- and concentration-dependent increase of the intracellular second messenger cyclic AMP. In Fura-2 AM loaded platelets PIR and ENO diminished PAF induced Ca2+ mobilization concentration dependently. Thus, the observed antiplatelet effects following PIR and ENO might exert beneficial effects in patients with cardiovascular disease.
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PMID:Phosphodiesterase inhibitors piroximone and enoximone inhibit platelet aggregation in vivo and in vitro. 936 63

Our purpose was to determine whether hearts from mice bioengineered to lack either the M isoform of creatine kinase (MCK-/- mice) or both the M and mitochondrial isoforms (M/MtCK-/- mice) have deficits in cardiac contractile function and energetics, which have previously been reported in skeletal muscle from these mice. The phenotype of hearts with deleted creatine kinase (CK) genes is of clinical interest, since heart failure is associated with decreased total CK activity and changes in the relative amounts of the CK isoforms in the heart. We measured isovolumic contractile performance in isolated perfused hearts from wild-type, MCK-/-, and M/MtCK-/- mice simultaneously with cardiac energetics (31P-nuclear magnetic resonance spectroscopy) at baseline, during increased cardiac work, and during recovery. Hearts from wild-type, MCK-/-, and M/MtCK-/- mice had comparable baseline function and responded to 10 minutes of increased heart rate and perfusate Ca2+ with similar increases in rate-pressure product (48+/-5%, 42+/-6%, and 51+/-6%, respectively). Despite a similar contractile response, M/MtCK-/- hearts increased [ADP] by 95%, whereas wild-type and MCK-/- hearts maintained [ADP] at baseline levels. The free energy released from ATP hydrolysis decreased by 3.6 kJ/mol in M/MtCK-/- hearts during increased cardiac work but only slightly in wild-type (1.7 kJ/mol) and MCK-/- (1.5 kJ/mol) hearts. In contrast to what has been reported in skeletal muscle, M/MtCK-/- hearts were able to hydrolyze and resynthesize phosphocreatine. Taken together, our results demonstrate that when CK activity is lowered below a certain level, increases in cardiac work become more "energetically costly" in terms of high-energy phosphate use, accumulation of ADP, and decreases in free energy released from ATP hydrolysis, but not in terms of myocardial oxygen consumption.
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PMID:Impaired cardiac energetics in mice lacking muscle-specific isoenzymes of creatine kinase. 957 9

Stress alone is generally not sufficient to produce serious disease, but stress imposed upon pre-existing disease can contribute to disease progression. To explore this phenomenon, cold-immobilization stress was imposed on young 12.5 month, necrotic phase with small vessel coronary spasm) and older (5 month, quiescent phase, between necrosis and heart failure) cardiomyopathic hamsters. Our hypothesis was that changes in mitochondrial energy processes are involved in stress induced pathology. Polarographic and high performance liquid chromatography (HPLC) techniques were used to measure mitochondrial respiration and oxidative phosphorylation and concentrations of phosphocreatine and adenylates, respectively, in hearts from young and old cardiomyopathic hamsters (stressed and unstressed). No significant differences were found between the young (2.5 month) and old (5 month) age groups in unstressed and stressed healthy hamsters and between young (2.5 month) and old (5 month) unstressed cardiomyopathic hamsters with respect to different parameters of mitochondrial oxidative phosphorylation and with respect to concentration of bioenergetic metabolites, except that ADP concentration was higher in older cardiomyopathic hamsters. Application of stress uncovered differences between young and old cardiomyopathic hamsters: respiration control index was lower and State 4 respiration was higher in young compared to old cardiomyopathic hamsters; whereas the total concentration of ATP was decreased to the same level in both cardiomyopathic groups when compared to control. Mitochondrial oxidative phosphorylation in young cardiomyopathic hamsters was more sensitive to Ca2+, as evidenced by partial uncoupling of respiration and oxidative phosphorylation, than in older cardiomyopathic hamsters and controls. In conclusion, young cardiomyopathic hamsters, i.e. in the necrotic phase of disease, were more susceptible to stress induced changes in mitochondrial oxidative phosphorylation than older cardiomyopathic hamsters and controls.
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PMID:Mitochondrial oxidative phosphorylation in heart from stressed cardiomyopathic hamsters. 1019 86

Excessive right heart hypertrophy was investigated under additional acute hypoxic stress to find out a possible contribution of mitochondrial dysfunction to sudden heart failure. Severe right heart hypertrophy in rats was induced by exposure to hypobaric pressure (46,663 Pa) for 4 weeks. Heart rate, isovolumic pressure and coronary flow were determined in the Langendorff mode of perfusion. After normoxia, the hearts were subdued to acute hypoxia/reoxygenation. Mitochondrial membrane potential was measured at the heart surface by fluorometry using 2-(dimethylaminostyryl)-l-ethylpyridinium iodide (DASPEI). At the end of each experiment mitochondria were isolated and ATP synthesis, ATPase, as well as creatine kinase activity were determined. Compared to normal hearts the heart rate is decreased in the hypertrophied group whereas right ventricular systolic and (end)diastolic pressure (adjusted to isovolumetric maxima) are increased. Coronary flow is decreased. Cytosolic creatine phosphate ATP levels and ATP/ADP ratios are significantly (p < 0.01) decreased. Furthermore, ATP synthesis and creatine kinase activities are diminished. At high ADP, respiration is loosely coupled or partially uncoupled. Acute hypoxia is particularly deleterious to hypertrophied hearts: Mitochondrial membrane potential as measured by heart surface fluorometry decreases extensively and is only very incompletely restored during reoxygenation. Rate-pressure product decreases precipitously and is restored during reoxygenation only to a very low extent. The results indicate an insufficient energy metabolism of mitochondria during acute hypoxia/reoxygenation which adds to the earlier described shifted isozyme pattern of myosin and decreased activities of myosin and sarcoreticular Ca2+ ATPase, leading to myocardial failure in right heart hypertrophy.
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PMID:Hemodynamics and mitochondrial energy metabolism in right heart hypertrophy after acute hypoxic stress. 1021 64

We have tested the hypothesis that decreased functioning of creatine kinase (CK) at sites of energy production and utilization may contribute to alterations in energy fluxes and calcium homeostasis in congestive heart failure (CHF). Heart failure was induced by aortic banding in 3-week-old rats. Myofilaments, sarcoplasmic reticulum (SR), mitochondrial functions, and CK compartmentation were studied in situ using selective membrane permeabilization of left ventricular fibers with detergents (saponin for mitochondria and SR and Triton X-100 for myofibrils). Seven months after surgery, animals were in CHF. A decrease in total CK activity could be accounted for by a 4-fold decrease in activity and content (Western blots) of mitochondrial CK and a 30% decrease in M isoform of CK (MM-CK) activity. In myofibrils, maximal force, crossbridge kinetics, and alpha-myosin heavy-chain expression decreased, whereas calcium sensitivity of tension development remained unaltered. Myofibrillar CK efficacy was unchanged. Calcium uptake capacities of SR were estimated from the surface of caffeine-induced tension transient (SCa) after loading with different substrates. In CHF, SCa decreased by 23%, and phosphocreatine was 2 times less efficient in enhancing calcium uptake. Oxidative capacities of the failing myocardium measured as oxygen consumption per gram of fiber dry weight decreased by 28%. Moreover, the control of respiration by creatine, ADP, and AMP was severely impaired. Our observations provide evidence that alterations in CK compartmentation may contribute to alterations of energy fluxes and calcium homeostasis in CHF.
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PMID:Subcellular creatine kinase alterations. Implications in heart failure. 1040 Sep 12

Coupling of ATP-generating with ATP-consuming processes is an essential component in the cardiac bioenergetics responsible for optimal myocardial function. Although a number of enzymatic systems have been implicated in securing proper intracellular energy communication, their integrative response in a failing myocardium has not been determined so far. Therefore, we measured catalytic activities of enzymes responsible for the communication between ATP-generating and ATP-consuming processes in ventricular samples obtained from normal dogs and dogs with tachycardia-induced heart failure. In the failing myocardium, phosphotransfer activities of creatine kinase, adenylate kinase, 3-phosphoglycerate kinase and pyruvate kinase, which collectively deliver ATP and remove ADP from myofibrillar ATPases, were depressed by 30, 21, 44 and 20%, respectively, when compared to normal controls. The activity of hexokinase, an enzyme which directs phosphoryls into the glycolytic phosphotransfer pathway, was unchanged. Also, the activity of glyceraldehyde-3-phosphate dehydrogenase, which may shuttle inorganic phosphate between ATPases and ATP-synthases, was not affected by heart failure. However, the CO2-hydration activity of carbonic anhydrase, which together with creatine kinase, is presumed responsible for removal of protons from ATPases, was diminished by 21%. As these enzymatic systems are collectively required for adequate delivery of high-energy phosphoryl to, and removal of end-products from, cellular ATPases, the cumulative deficit in their flux capacities may provide a bioenergetic basis for impaired contraction-relaxation in the failing heart.
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PMID:Reduced activity of enzymes coupling ATP-generating with ATP-consuming processes in the failing myocardium. 1063 Jun 20

The small (21 kDa) guanine nucleotide-binding protein (small G protein) superfamily comprises 5 subfamilies (Ras, Rho, ADP ribosylation factors [ARFs], Rab, and Ran) that act as molecular switches to regulate numerous cellular responses. Cardiac myocyte hypertrophy is associated with cell growth and changes in the cytoskeleton and myofibrillar apparatus. In other cells, the Ras subfamily regulates cell growth whereas the Rho subfamily (RhoA, Rac1, and Cdc42) regulates cell morphology. Thus, the involvement of small G proteins in hypertrophy has become an area of significant interest. Hearts from transgenic mice expressing activated Ras develop features consistent with hypertrophy, whereas mice overexpressing RhoA develop lethal heart failure. In isolated neonatal rat cardiac myocytes, transfection or infection with activated Ras, RhoA, or Rac1 induces many of the features of hypertrophy. We discuss the mechanisms of activation of the small G proteins and the downstream signaling pathways involved. The latter may include protein kinases, particularly the mitogen-activated or Rho-activated protein kinases. We conclude that although there is significant evidence implicating Ras, RhoA, and Rac1 in hypertrophy, the mechanisms are not fully understood.
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PMID:Small guanine nucleotide-binding proteins and myocardial hypertrophy. 1082 30

The adenine nucleotide translocator (ANT), the only mitochondrial carrier for ADP and ATP, combines mitochondrial energy-producing and cytosolic energy-consuming processes. The ANT function was observed to be impaired in explanted heart tissue from patients with dilated cardiomyopathy (DCM). In order to clarify whether an altered ANT isoform composition might be responsible for the restricted ANT function, we analyzed the ANT isoform expression pattern in the myocardium of patients suffering from dilated cardiomyopathy. The ANT isoform mRNA pattern was analyzed in explanted hearts from patients with dilated cardiomyopathy (n = 29), ischemic (n = 22) and valvular cardiomyopathy (n = 7) using the polymerase chain reaction technique. Myocardium from 12 subjects without heart disease was used as control. In addition, right ventricular biopsies from 47 patients with dilated cardiomyopathy who underwent cardiac catheterization were tested. A shift in the ANT isoform transcription profile was found in heart tissue from patients with dilated cardiomyopathy, but not in those from patients with ischemic or valvular cardiomyopathy. The shift was characterized by an increase in the ANT1 mRNA percentage, a decrease in ANT2 and an unchanged ANT3 proportion. Both ventricles and the septum were affected by the shift. The alteration was also found in endomyocardial specimens taken from patients with ongoing dilated cardiomyopathy. An alteration in the ANT isoform pattern was found to be specific for dilated cardiomyopathy. It is not a general phenomenon of end-stage heart failure, but occurs already before the heart is finally damaged. Therefore, an altered ANT isoform expression appears to be a feature of a dilated cardiomyopathy-specific gene program.
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PMID:The myocardial expression of the adenine nucleotide translocator isoforms is specifically altered in dilated cardiomyopathy. 1090 36

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


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