Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The history and findings at autopsy of a 9-year-old female with I-cell disease are reported. She manifested gargoyle face, progressive psychomotor retardation, and increased serum levels of lysosomal enzymes with decreased activities in peripheral blood lymphocytes. She received a bone marrow transplantation from her HLA-mismatched father when she was 8 years old. Rejection followed, and 9 months later, she died of cardiac failure secondary to aortic regurgitation. The characteristic inclusion bodies, ultrastructurally corresponding to double-membranous lamellar vacuoles and empty single membrane-bound vacuoles, were identified in dermal fibro blasts, macrophages, glomerular epithelial cells, cardiomyocytes and smooth muscle cells. Pale bodies, faintly eosinophilic cytoplasmic globular inclusions immunoreactive for plasma proteins, were observed in hepatocytes and renal collecting tubular epithelial cells. Enzyme histochemical analyses were performed for N-acetyl-beta-glucosaminidase, beta-glucuronidase, nonspecific esterase and acid phosphatase. Decreased activities of the acid hydrolases and their diffusion in the cytoplasm were seen in Kupffer's cells. Ultrastructural localization of acid phosphatase activity suggested the labilization of the lysosomal membrane. The abnormality in the intracellular transport of the acid hydrolases into the lysosomes in I-cell disease is briefly reviewed and discussed.
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PMID:I-cell disease: report of an autopsy case. 879 67

Epidemiologic studies suggest that daily ingestion of small amounts of alcohol may protect the heart, whereas higher intake may be detrimental. We studied: 1) cardiac performance, bioenergetics, and [Mg2+]i of isolated working rat hearts during perfusion with Krebs-Henseleit medium containing different concentrations of ethanol (EtOH), 2) mechanical responses. Ca2+ metabolism and Mg content of isolated coronary arteries obtained from dogs, sheep, and piglets subjected to varying concentrations of EtOH and [Mg2+]o and 3) intracellular free Ca2+ of isolated rat cardiac myocytes. In intact hearts, EtOH produced a biphasic hemodynamic change, depending upon concentration; 15 mM EtOH (0.07 g/dl) and 45 mM EtOH (0.21 g/dl) were stimulatory: 90 (0.42 g/dl), 135 (0.63 g/dl), and 170 mM (0.79 g/dl) EtOH were depressive. EtOH 15 and 45 mM increased coronary flow up to 150%, cardiac output up to 130%, stroke volume up to 135%, and oxygen consumption (VO2) up to 130%. However, 90 mM and higher EtOH depressed most hemodynamic parameters (except for heart rate) dose dependently. Lactic acid, lactic acid dehydrogenase, and creatine phosphokinase levels in the perfusate tended to be elevated progressively with increasing duration of EtOH perfusion and pH tended to be reduced (p < 0.05). [31P]NMR spectroscopy on hearts revealed that EtOH > or = 90 mM resulted in rises in Pi/ATP concentration ratio with no significant change in PCr/ATP ratio; [Mg2+]i levels fell and cytosolic pH tended to become slightly acidotic [19F]NMR spectroscopy of isolated myocytes revealed that [Ca2+]i rises at high concentrations of EtOH. With respect to coronary vascular muscle (CVM), low concentrations of EtOH resulted in a concentration-dependent reduction in contractions induced by K+, angiotensin II, and 5-HT; concentration-effect curves were shifted rightward to higher concentrations. Low [Mg2+]o potentiated contractions of CVM induced by EtOH. Low EtOH also resulted in reductions in exchangeable and membrane-bound 45Ca in CVM; medium to high concentrations of EtOH reduced Mg content in CVM and increased 45Ca. In the absence of [Ca2+]o, caffeine and EtOH induced similar, transient contractions followed by relaxation in K(+)-depolarized coronary arterial tissues. EtOH-induced contractions were completely abolished by pretreatment of tissues with caffeine. These results on isolated coronary vessels suggest that in addition to a need for [Ca2+]o, an intracellular release of Ca2+ is needed for EtOH to induce contractions. Overall, the data indicate that low concentrations of EtOH (15, 45 mM) are beneficial on cardiac performance, at least in the intact rat heart and coronary arteries: higher concentrations of EtOH (90, 135 mM) are detrimental. High concentrations of EtOH decrease coronary flow, lead to loss of cellular Mg2+, hypoxia, metabolic acidosis of the myocardium, cell membrane damage, and Ca2+ overload, which could result in cardiac failure. Cellular loss of Mg2+ appears to be causative in the detrimental actions of EtOH on the heart.
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PMID:Beneficial vs. detrimental actions of ethanol on heart and coronary vascular muscle: roles of Mg2+ and Ca2+. 888 48

Vascular tolerance develops rapidly in isolated vascular strips exposed to millimolar concentrations of nitroglycerin. Several mechanisms, including depletion of sulfhydryl groups, reduced biotransformation of nitrates to NO or nitrosothiols, oxygen free radical injury, and downregulation of a membrane-bound enzyme or a nitrate receptor, have been proposed, but the exact mechanism responsible for in-vitro tolerance remains unknown. In-vivo tolerance of the beneficial effects of nitrates on hemodynamics, myocardial ischemia, and exercise performance develops rapidly. It has been suggested, but remains to be proven, that development of venous tolerance and not arterial tolerance is responsible for the attenuation of nitrate effects during long-term nitrate therapy. Several mechanisms, including neurohormonal activation, depletion of sulfhdryl groups, and the shift of fluid from the extravascular to intravascular compartment have been implicated. However, the use of agents to counteract these mechanisms (ACE inhibitors, sulfhydryl donors, diuretics) has produced conflicting results. Thus, at present the mechanism responsible for in vivo tolerance to nitrates remains unknown. Both in vitro and in vivo vascular tolerance to nitrates can be prevented or minimized by providing nitrate-free or low-nitrate intervals. However, during nitrate-free periods, rebound phenomena (rest angina in patients with ischemic heart disease or a deterioration in exercise performance prior to the renewal of the morning dose in patients with stable angina) remain a clinical concern. When treating patients with stable angina pectoris, it must be recognized that none of the nitrate preparations or formulations can provide round-the-clock antianginal or antiischemic prophylaxis. In these patients, beneficial antianginal and antiischemic effects of nitrates for 10-14 hours during the daytime can be maintained by using formulations and dosing regimens that avoid or minimize the development of tolerance (standard formulation of isosorbide-5-mononitrate, 20 mg in the morning and 7 hours later; slow-release formulation of isosorbide-5-mononitrate, 120-240 mg once a day; or nitroglycerin patch delivering 0.6 nitroglycerin per hour for 10-12 hours each day). Only the patch on and off treatment is associated with nitrate rebound. Although intermittent nitrate therapy is not associated with the development of tolerance, this strategy cannot be recommended for treating unstable angina because rebound angina during nitrate-free periods complicates clinical decision making. In the acute phase of unstable angina, continuous treatment with intravenous nitroglycerin is recommended because it permits rapid up- or down-titration. Tolerance towards antianginal and antiischemic effects does develop in a substantial number of patients with 24 hours, but this can be overridden by dose escalation and restoration of the therapeutic effectiveness of nitroglycerin. Tolerance towards the beneficial effects of nitrates on hemodynamics and on exercise performance also develops rapidly during continuous or long-term nitrate therapy, and for these reasons nitrates are not used as first-line therapy to treat chronic heart failure. In combination with hydralazine, high-dose isosorbide dinitrate (30-40 mg four times a day) improves survival, but this combination therapy is inferior to ACE inhibitors.
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PMID:Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure. 911 Jan 17

Apoptosis is an organized, energy dependent process, which leads to cell death. Its definition is based on distinct morphological features [10] and demonstration of internucleosomal DNA degradation [27], executed by selectively activated DNAses [4, 22]. The morphologic hallmarks of apoptosis include chromatic margination, nuclear condensation and fragmentation, and condensation of the cell with preservation of organelles. The process is followed by fragmentation of the cell into membrane-bound apoptotic bodies, which undergo phagocytosis by nearby cells without associated inflammation [10, 11]. Apoptosis characteristically occurs in insolated single cells. The duration of apoptosis is estimated to be from 12 to 24 hours, but in cell culture visible morphologic changes are accomplished in less than two hours [10, 16]. Non-apoptotic cell death, a prototype of which is cell death due to ischemia (oncosis), is characterized by depletion of intracellular ATP stores, swelling of the cell with disruption of organelles and rupture of the plasma membrane [15]. Groups of necrotic cells and inflammation are found in tissues [10, 15]. The significance of apoptosis has mostly been studied using the TUNEL assay that detects DNA strand breaks in tissue sections and allows quantification of apoptotic cells by light microscopy [6]. Common experience seems to be that the TUNEL assay is prone to false positive or negative findings. This has been explained by the dependence of the staining kinetics on the reagent concentration [17], fixation of the tissue [2] and the extent of proteolysis [17]. Active RNA synthesis [12] and DNA damage in necrotic cells [17, 19] may cause non-specific staining. To obtain reliable and reproducible results, TUNEL assay should be carefully standardized by using tissue sections treated with DNAse (positive control of apoptosis). Quantification of apoptosis should include enough microscopic fields and identification of the cell type undergoing apoptosis. The specificity of the results can be substantiated by combining other methods with TUNEL, such as assessment of the pattern of DNA fragmentation or evaluation of the morphological features. Even though there is high variation in the results obtained in consecutive studies under the same circumstances, increasing evidence shows that TUNEL-positive cardiomyocytes and internucleosomal DNA fragmentation are associated with various cardiac diseases, including acute myocardial infarction and heart failure [reviewed in 5, 9]. Some morphological features of apoptosis have been observed in TUNEL-positive cardiomyocytes using light microscopy (Figure 1) or confocal microscopy [20]. Electron microscopic evidence of apoptosis has been found in the degenerating conduction system [7], in experimental heart failure [23], and in human hibernating myocardium [3]. In acutely ischemic myocardium the interpretation of the findings remains controversial, since only non-apoptotic cell morphology has been found in electron microscopy [8, 19]. One explanation might be abortion of the apoptotic program due to the lack of ATP before the morphologic features are fully evident [14]. Another explanation is the possibility that non-apoptotic cell death and apoptosis share common mechanisms in the early phases of the processes [14, 19]. The exact mechanisms of ischemic cell death remain to be clarified and the classification between apoptosis and non-apoptosis cell death to be specified. Recently, caspase activation has emerged as the central molecular event leading to apoptosis, preceding DNA degradation and the development of apoptotic morphology [22, 25]. New methods have been developed to demonstrate caspase activation [1, 13]. Inhibition of caspase may be an efficient way to prevent apoptotic cardiomyocyte death as well as to define and specifically probe the significance of apoptotic cell death in cardiac diseases.
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PMID:Morphologic criteria and detection of apoptosis. 1041 42

The heart is often refereed to as an "beta-adrenergic organ" because beta-adrenergic agonists are powerful stimulants of cardiac contractility. Catecholamines acting through beta-adrenoceptors produce both positive inotropic and chronotropic effects in human heart. It is now generally accepted that in human heart both beta 1- and beta 2-adrenoceptors coexist. beta-Adrenergic transduction system consist of membrane-bound beta-receptors, the effector enzyme adenylyl cyclase and guanine nucleotide-binding transduction (G) proteins. Repeated long-lasting agonist stimulus evokes homologous or heterologous desensitization of transduction system. Chronic heart failure accompanies with decreased responsiveness to beta-adrenoceptor agonists and is thought to exacerbate the loss of cardiac contractility. Depending on the etiology of heart failure abnormalities of the beta-receptor-G protein-adenylyl cyclase system result from a reduced of beta 1-receptors, uncoupling of beta 1- or beta 2-receptors, alteration of G-protein function, or decreased catalytic subunit activity of adenylyl cyclase and enhanced expression of beta-adrenoceptor kinase. The model most widely used is that of circulating lymphocytes that contain a homogeneous population of beta 2-adrenoceptors. The biochemical and pharmacological properties of human lymphocyte beta 2-adrenoceptors are quite comparable to those of heart beta 2-receptors. The analysis of lymphocyte beta 2-adrenoceptor-adenylyl cyclase system can be used as a model for long-term regulation of human cardiac beta 1- and beta 2-adrenoceptors only if serial changes in response to administration of non-selective beta-adrenergic agonists or antagonists are being investigated. This review concentrates on beta-adrenoceptors in human healthy heart and in heart failure and also on lymphocyte beta 2-adrenoceptors and on the changes of these receptors properties under the influence of some cardiotropic drugs.
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PMID:[Beta-adrenergic receptors of the normal heart and in heart failure]. 1082 33

Cardiovascular disease is a leading cause of death worldwide. In recent years it has emerged that loss of myocardial cells may be a major pathogenic factor. Cell death can occur in a destructive, uncontrolled manner via necrosis or by a highly regulated programmed cell suicide mechanism termed apoptosis. As cell death in conditions such as heart failure and myocardial infarction does not always follow a typically apoptotic pathway, it remains to be established whether it occurs by apoptosis, necrosis, or a novel uncharacterized mechanism combining aspects of both types of cell death. Apoptotic pathways have been well studied in nonmyocytes and it is thought that similar pathways exist in cardiomyocytes. These pathways include death initiated by ligation of membrane-bound death receptors or death initiated by release of cytochrome c from mitochondria. Increasing evidence supports the existence of these pathways and their regulators in the heart. These regulators include inhibitors of caspases, which are the key enzymes of apoptosis, the Bcl-2 family of proteins, growth factors, stress proteins, calcium, and oxidants. It is hoped that a better understanding of the pathways of apoptosis and their regulation may yield novel therapeutic targets for cardiovascular disease.
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PMID:Losing heart: the role of apoptosis in heart disease--a novel therapeutic target? 1181 61

The natriuretic peptide and renin-angiotensin systems are physiological counterparts with opposite roles in the regulation of electrolyte balance and blood pressure. In both systems, membrane-bound, zinc-dependent peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II, and neutral endopeptidase (NEP) degrades the natriuretic peptides. Simultaneous inhibition NEP and ACE by a single molecule (a vasopeptidase inhibitor) is a new therapeutic approach in hypertension. Wider applications for vasopeptidase inhibitors being studied include their role as cardioprotective agents in heart failure, as renoprotective agents in chronic renal failure and diabetic nephropathy, and as vasculoprotective agents in endothelial dysfunction and athersclerosis.
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PMID:Inhibition of peptidases in the control of blood pressure. 1246 66

Omapatrilat belongs to the vasopeptidase inhibitors, ie, drugs that possess the ability to inhibit simultaneously the membrane-bound zinc metalloproteases, angiotensin-converting enzyme (ACE), and the neutral endopeptidase EC 3.4.24.11 (NEP). Omapatrilat was targeted to treat patients with hypertension and congestive heart failure. The preclinical and early clinical studies conducted with omapatrilat were very promising. Indeed, omapatrilat appeared to be a very potent antihypertensive agent with very favorable effects on cardiac function in heart failure patients. In contrast to these early studies, the large clinical trials were more disappointing. The results of the OCTAVE trial confirmed the antihypertensive efficacy of omapatrilat, but at the price of an angioedema rate more than threefold higher than that of an ACE inhibitor in the overall population (2.17% vs 0.68%), and close to fourfold higher in the black population. In OVERTURE, a large randomized control trial in heart failure, angioedema was also more common with omapatrilat, but the incidence was much lower (0.8% with omapatrilat vs 0.5% with enalapril). However, omapatrilat was not convincingly superior to the ACE inhibitor. Because angioedema is probably a class side effect of vasopeptidase inhibitors, the higher incidence of this potentially life-threatening complication with omapatrilat has likely stopped the development of this new class of agents. The future of vasopeptidase inhibitors will depend on the ability to improve the risk/benefit ratio either by developing agents that produce less angioedema, or by defining more precisely a high-risk population that could take advantage of dual ACE/NEP inhibition.
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PMID:Recent clinical trials with omapatrilat: new developments. 1284 71

The removal of damaged, superfluous or energy-starved cells is essential for biological homeostasis, and occurs in every tissue type. Programmed cell death occurs through several closely regulated signal pathways, including apoptosis, in which cell components are broken down and packaged into small membrane-bound fragments that are then removed by neighbouring cells or phagocytes. This process is activated in the cardiac myocyte in response to a variety of stresses, including oxidative and nitrosative stress, and involves mitochondria-derived signals. Loss of cardiac myocytes through apoptosis has been shown to induce cardiomyopathy in a variety of gene-targeted animal models. Because cardiac myocytes have strictly limited ability to regenerate, sustained programmed cell death is likely to contribute to the development and progression of heart failure in a variety of myocardial diseases. At the same time, the cardiac myocyte possesses a number of mechanisms for defence against short-term haemodynamic and oxidative stresses. Our laboratory has recently examined the role of nitric oxide (NO) as a regulator of the programmed death of cardiac myocytes, and the potential contribution of NO and NO-dependent signalling to the loss of myocytes in heart failure. We will review the role of c-Jun N-terminal kinase in response to oxidative and nitrosative stress, and summarise evidence for its role as a cytoprotective mechanism. We will also review evidence implicating NO in the pathophysiology of heart failure, in the context of the extensive and sometimes contradictory body of research on NO and cell survival.
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PMID:Nitric oxide and promotion of cardiac myocyte apoptosis. 1552 66

The renin-angiotensin system (RAS) plays an important role in regulating arterial pressure, blood volume, thirst, cardiac function, and cellular growth. Both a circulating and multiple tissue-localized systems have been identified, and are generally portrayed as a series of reactions that occur sequentially with a single outcome: angiotensinogen is cleaved by renin to form angiotensin I, which in turn is processed by angiotensin-converting enzyme (ACE) to angiotensin II, which then activates either the AT1 or the AT2 plasma membrane receptor. Evidence has emerged, however, showing that some RAS components play important roles outside of this canonical scheme. This article provides an overview of some recently identified extra-system functions. In addition to forming angiotensin II, ACE is a multifunctional enzyme equally important in the metabolism of vasodilator and antifibrotic peptides. As the membrane-bound form, ACE functions as a "receptor" that initiates intracellular signaling leading to gene expression. Both angiotensin I and II may lead to actions that are independent of, or even oppose, those of the RAS via their metabolism by the novel ACE-homologue ACE2. The two angiotensin II receptor types have ligand-independent roles that influence cellular signaling and growth, some of which may result from the ability to form hetero-dimers with other 7-transmembrane receptors. Finally, intracellular angiotensin II has been demonstrated to have actions on cell-communication, gene expression, and cellular growth, through both receptor-dependent and independent means. A greater understanding of these extra-system functions of the RAS components may aid in the development of novel treatments for hypertension, myocardial ischemia, and heart failure.
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PMID:Working outside the system: an update on the unconventional behavior of the renin-angiotensin system components. 1583 68


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