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

The perpetual and vigorous nature of heart muscle work requires efficient myocardial energetics. This depends not only on adequate ATP production, but also on efficient delivery of ATP to muscle ATPases and rapid removal of ADP and other by-products of ATP hydrolysis. Indeed, recent evidence indicates that defects in communication between ATP-producing and ATP-consuming cellular sites are a major factor contributing to energetic deficiency in heart failure. In particular, the failing myocardium is characterized by reduced catalytic activity of creatine kinase, adenylate kinase, carbonic anhydrase, and glycolytic enzymes, which collectively facilitate ATP delivery and promote removal of ADP, Pi, and H+ from cellular ATPases. Although energy transfer through adenylate kinase and glycolytic enzymes has been recognized as an adaptive mechanism supporting compromised muscle energetics, in the failing myocardium the total compensatory potential of these systems is diminished. A gradual accumulation of defects at various steps in myocardial energetic signaling, along with compromised compensatory mechanisms, precipitates failure of the whole cardiac energetic system, ultimately contributing to myocardial dysfunction. These advances in our understanding of the molecular bioenergetics in heart failure provide a new perspective toward improving the energetic balance of the failing myocardium.
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PMID:Failing energetics in failing hearts. 1098 Aug 95

We have recently shown that mitochondrial function and energy metabolism are altered in the myocardium as well as in slow and fast locomotor muscles of rats subjected to prolonged congestive heart failure (CHF) suggesting a generalized metabolic myopathy in heart failure. Here, we investigate whether the diaphragm of CHF animals, which experiences both increased work and the general systemic influence of heart failure, will also be susceptible to altered energy metabolism. Biopsies were obtained from the costal diaphragm of failing rats 8 months after aortic banding. A marked increase in type I and type IIa myosin heavy chains at the expense of types IIx and IIb, suggests an adaptation towards a slower phenotype. Glycolytic enzymes decreased in CHF diaphragm with an increase in the H:M lactate dehydrogenase isoenzyme ratio. These results suggest a reorientation of the diaphragm muscle towards a slow, fatigue-resistant phenotype. However, maximal oxidative capacity assessed in saponin-permeabilized fibers in the presence of ADP was considerably reduced in CHF diaphragm (7.7+/-0.4 v 11.8+/-0.7 micromol O2/min/g dry weight in sham P<0.001), suggesting an alteration in oxidative phosphorylation. Furthermore, ADP sensitivity of CHF mitochondria was significantly increased (apparent Km for ADP 308+/-21 v 945+/-106 microM in sham P<0.001), whereas sensitivity to ADP in the presence of creatine was comparable (Km 79+/-12 v 90+/-11 microM in sham). In heart failure, therefore, the diaphragm muscle seems to adapt towards a more slow and economical contraction as a result of increased workload, but this adaptation is limited by the disease-induced altered mitochondrial function.
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PMID:Dual influence of disease and increased load on diaphragm muscle in heart failure. 1127 23

The use of angiotensin converting enzyme inhibitors (ACEIs), as well as of acetyl salicylic acid (ASA) in patients with hypertension, myocardial infarction or heart failure is recommended by the guidelines issued by several respected cardiological societies. However, some authors have argued that ASA may decrease the effectiveness of ACEIs by decreasing the release of prostagandins. Although such negative interaction is still not conclusively demonstrated, the merits of the use of this association should be judged in each individual patient with heart failure. It seems prudent to use low doses of ASA (< or = 250 mg/day) in these patients. ADP antagonists may constitute an alternative to ASA since they do not block prostaglandin synthesis.
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PMID:[Interaction between antiplatelet agents and angiotensin-converting enzyme inhibitors]. 1129 79

ATP and creatine phosphate (PCr) are prime myocardial high-energy phosphates. Their relative concentrations are conserved among mammalian species and across a range of physiologic cardiac workloads. The cardiac PCr/ATP ratio is decreased with several pathologic conditions, such as ischemia and heart failure, but there are no reports of an increase in the cardiac PCr/ATP ratio in any species or with interventions. We studied the in vivo energetics in transgenic mice lacking expression of the glucose transport protein GLUT4 (G4N) and observed a significant 60% increase in the myocardial PCr/ATP ratio in G4N that was confirmed in three different experimental settings including intact animals. The higher PCr/ATP in G4N is cardiac-specific and is due to higher total cardiac creatine (CR) concentrations in G4N than in wild-type (WT). However, [ATP], [ADP], and -DG(-ATP) did not differ between the strains. Expression of the creatine transport protein (CreaT) that is responsible for creatine uptake in myocytes was preserved in G4N cardiac tissue. These observations demonstrate, for the first time to our knowledge, that G4N manifest a unique increase in the cardiac PCr/ATP ratio, which suggests a novel genetic strategy for increasing myocardial creatine levels.
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PMID:An increase in the myocardial PCr/ATP ratio in GLUT4 null mice. 1191 71

1. The present review focuses on the adenine nucleotide translocator (ANT), which facilitates exchange of cytosolic ADP for mitochondrial ATP. This protein serves a central role in regulating cellular oxidative capacity. 2. The ANT, a nuclear-encoded mitochondrial protein, is developmentally regulated and, thus, accumulates within the mitochondrial membrane during maturation. 3. Accumulation of ANT parallels changes in kinetics of myocardial respiration determined from 31P magnetic resonance spectroscopy studies. 4. Thyroid hormone modulates developmental transitions in ANT content, as well as respiratory control patterns. These transitions are linked to quantitative ANT changes, not to alterations in functionality at individual exchanger sites. 5. Developmental programming for ANT and parallel alterations in oxidative phosphorylation kinetics are relevant to the heart, which exhibits remodelling in response to pathological processes. Maladaptive hearts exhibiting ANT deficits demonstrate ADP-dependent respiratory kinetics similar to the newborn heart. Thus, ANT deficits and alterations in mitochondrial respiratory function may contribute to the pathogenesis of myocardial remodelling and heart failure.
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PMID:The adenine nucleotide translocator: regulation and function during myocardial development and hypertrophy. 1198 46

1. This review is presented with the intent of illustrating the representative studies of functional and myocardial energetic consequences of hearts with postinfarction left ventricular (LV) remodelling or with concentric hypertrophy and diastolic LV dysfunction in porcine models. 2. Both eccentric and concentric cardiac hypertrophy are associated with the abnormal myocardial energetics that are most severe in hearts with congestive heart failure (CHF). Presently, these abnormalities cannot be satisfactorily explained to be the cause(s) of the dysfunction of failing hearts or cause the progress from compensated cardiac hypertrophy to CHF. 3. Mechanisms governing abnormal myocardial high-energy phosphate (HEP) metabolism in hearts with cardiac hypertrophy and CHF are unclear. Myocardial energy metabolism studies use both kinetic and thermodynamic models. The thermodynamic studies examine the myocardial steady state levels of high- and low-energy phosphate, which indicate myocardial energy state or phosphorylation potential that is defined by the ratio of [ATP]/([ADP][Pi]). The kinetics studies examine the reaction velocity that is regulated by: (i) quantity and activity of the key enzymes; (ii) the concentrations of all the substrates and products; and (iii) the Michaelis-Menten constants of each substrate of the reaction. 4. Significant alterations in myocardial concentrations of phosphocreatine (PCr), ATP and ADP, myocardial oxidative phosphorylation (OXPHOS) protein expression and substrate preference are found in hearts with postinfarction LV remodelling and CHF. However, to define a causal relationship is a different matter. 5. Future studies of animal models of LV hypertrophy or heart failure using gene manipulation may provide additional insights to answer the persisting question of whether limitations of ATP synthetic or transport capacities contribute to the pathogenesis of LV remodelling or failure.
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PMID:Myocardial energetics in cardiac hypertrophy. 1198 49

Cardiac G protein-coupled receptors that function through stimulatory G protein Galpha(s), such as beta(1)- and beta(2)-adrenergic receptors (beta(1)ARs and beta(2)ARs), play a key role in cardiac contractility. Recent data indicate that several Galpha(s)-coupled receptors in heart also activate Galpha(i), including beta(2)ARs (but not beta(1)ARs). Coupling of cardiac beta(2)ARs to Galpha(i) inhibits adenylyl cyclase and opposes beta(1)AR-mediated apoptosis. Dual coupling of beta(2)AR to both Galpha(s) and Galpha(i) is likely to alter beta(2)AR function in disease, such as congestive heart failure in which Galpha(i) levels are increased. Indeed, heart failure is characterized by reduced responsiveness of betaARs. Cardiac betaAR-responsiveness is also decreased with aging. However, whether age increases cardiac Galpha(i) has been controversial, with some studies reporting an increase and others reporting no change. The present study examines Galpha(i) in left ventricular membranes from young and old Fisher 344 rats by employing a comprehensive battery of biochemical assays. Immunoblotting reveals significant increases with age in left ventricular Galpha(i2), but no changes in Galpha(i3), Galpha(o), Galpha(s), Gbeta(1), or Gbeta(2). Aging also increases ADP-ribosylation of pertussis toxin-sensitive G proteins. Consistent with these results, basal as well as receptor-mediated incorporation of photoaffinity label [(32)P]azidoanilido-GTP indicates higher amounts of Galpha(i2) in older left ventricular membranes. Moreover, both basal and receptor-mediated adenylyl cyclase activities are lower in left ventricular membranes from older rats, and disabling of Galpha(i) with pertussis toxin increases both basal and receptor-stimulated adenylyl cyclase activity. Finally, age produces small but significant increases in muscarinic potency for the inhibition of both beta(1)AR- and beta(2)AR-stimulated adenylyl cyclase activity. The present study establishes that Galpha(i2) increases with age and provides data indicating that this increase dampens adenylyl cyclase activity.
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PMID:Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors. 1206 89

This review describes recent advances in cardiac magnetic resonance spectroscopy (MRS). MRS allows noninvasive characterization of the metabolic state of cardiac muscle, in both animal and human models. Recent experimental MRS studies have allowed new insights into the essential role of energetics in heart failure. Various new studies suggest a rapidly growing role of MRS for phenotyping new genetically modified mouse models, and recent methodologic advances include development of absolute quantification of high-energy phosphates, measurement of ATP turnover rates and thermodynamic parameters (such as free ADP and free energy change of ATP hydrolysis), and improved acquisition sequences. New patient studies demonstrate the potential value of MRS as a clinical diagnostic tool in patients with ischemic heart disease, heart failure, cardiac transplantation, valve disease, and genetic cardiomyopathy.
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PMID:Cardiac magnetic resonance spectroscopy. 1249 64

Increased generation of reactive oxygen species contribute to endothelial dysfunction in atherosclerosis, hypertension and heart failure. Recently, it was suggested that bursts of superoxide anions may inactivate endothelial surface-bound enzymes such as angiotensin converting enzyme (ACE). Here, we tested effects of xanthine/xanthine oxidase-derived superoxide anions on vascular responses and ACE activity in the isolated guinea pig heart. We analysed effects of intracoronary infusion of low concentration of xanthine oxidase (10 mU/ml) in the presence of xanthine (0,5 mM) (X/XO) on bradykinin, other endothelium-dependent and independent vasodilators (acetylcholine, ADP, SNAP), as well as vasoconstrictor responses to angiotensin I and angiotensin II. Surprisingly, X/XO significantly augmented coronary response to bradykinin without an effect on responses to ADP, acetylcholine, SNAP, angiotensin I and angiotensin II. In contrast, inhibition of ACE by perindoprilate (100 nM) resulted in augmentation of bradykinin-induced vasodilatation as well as diminution of angiotensin I-evoked vasoconstriction without an influence on other responses. In summary, in the isolated guinea pig heart, X/XO-derived free radicals selectively augmented coronary vasodilator response to bradykinin, which cannot be explained by X/XO-induced derangement of ACE. The mechanism of this paradoxical phenomenon, which might represent a defensive response of the coronary circulation to oxidative stress requires further investigations.
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PMID:Paradoxical augmentation of bradykinin-induced vasodilatation by xanthine/xanthine oxidase-derived free radicals in isolated guinea pig heart. 1251 3

Idiopathic dilated cardiomyopathy (DCM) is one of the leading causes of severe heart failure and the most common cause of heart transplantation due to its ventricular dilatations and contractile dysfuntions. Twenty percent of DCM is in the familiar form and the rest is sporadic. The clinical impact of DCM is far greater than its position in epidemiological terms. Despite recent improvements in therapy, both incidence and mortality are still very high. The main problem is its heterogeneous etiology. So far, three factors have been identified to be potentially important: enteroviral infection, immune mechanism and genetic factors. During the last 10 years there have been many investigations showing distinct autoantibodies or other immune factors in heterogeneous subsets of DCM which have contributed supportive and confounding evidence to the hypothesis that multiple autoimmune mechanisms are involved in DCM. Accumulated evidence hitherto demonstrated a variety of circulating autoantibodies in the sera of patients with DCM including antireceptor autoantibodies, myosin and ADP/ATP translocator protein, etc. Data available from both in-vitro and in-vivo studies of anti-receptor autoantibodies as well as from other autoantibodies and autoreactive lymphocytes demonstrated clearly that a subgroup of DCM is autoimmunity-mediated. This is understandable because DCM is heterogeneous, implying that different subgroups of DCM may have different pathogeneses. It may be practical in the future to separate "autoimmune cardiomyopathy" from other "idiopathic" DCM.
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PMID:Is cardiomyopathy an autoimmune disease? 1252 26


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