UMLS:C0018801 - FACTA Search

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

Cardiac hypertrophy is an adaptive response that normalizes wall stress and compensates for increased workload. It is accompanied by distinct qualitative and quantitative changes in the expression of protein isoforms concerning contractility, intracellular Ca(2+)-homeostasis and metabolism. Changes in the myosin subunit isoform expression improves contractility by an increase in force generation at a given Ca(2+)-concentration (increased Ca(2+)-sensitivity) and by improving the economy of the chemo-mechanical transduction process per amount of utilised ATP (increased duty ratio). In the human atrium this is achieved by partial replacement of the endogenous fast myosin by the ventricular slow-type heavy and light chains. In the hypertrophic human ventricle the slow-type beta-myosin heavy chains remain unchanged, but the ectopic expression of the atrial myosin essential light chain (ALC1) partially replaces the endogenous ventricular isoform (VLC1). The ventricular contractile apparatus with myosin containing ALC1 is characterised by faster cross-bridge kinetics, a higher Ca(2+)-sensitivity of force generation and an increased duty ratio. The mechanism for cross-bridge modulation relies on the extended Ala-Pro-rich N-terminus of the essential light chains of which the first eleven residues interact with the C-terminus of actin. A change in charge in this region between ALC1 and VLC1 explains their functional difference. The intracellular Ca(2+)-handling may be impaired in heart failure, resulting in either higher or lower cytosolic Ca(2+)-levels. Thus the state of the cardiomyocyte determines whether this hypertrophic adaptation remains beneficial or becomes detrimental during failure. Also discussed are the effects on contractility of long-term changes in isoform expression of other sarcomeric proteins. Positive and negative modulation of contractility by short-term phosphorylation reactions at multiple sites in the myosin regulatory light chain, troponin-I, troponin-T, alpha-tropomyosin and myosin binding protein-C are considered in detail.
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PMID:Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms. 961 95

Annexins are characterized by Ca2+-dependent binding to phospholipids. Annexin II mainly participates in cell-cell adhesion and signal transduction, whereas annexins V and VI also seem to regulate intracellular calcium cycling. Their abundance and localization were determined in left ventricle (LV) and right ventricle (RV) from hypertensive guinea pigs, during the transition from compensatory hypertrophy to heart failure. Immunoblot analysis of annexins II, V, and VI revealed an increased accumulation (2.6-, 1.45-, and 2.3-fold, respectively) in LV from hypertensive guinea pigs and no modification in RV. Immunofluorescent labeling of annexins II, V, and VI; of Na+-K+-ATPase; and of sarcomeric alpha-actinin showed that in control LV and RV, 1) annexin II is present in nonmuscle cells; 2) annexins V and VI are mainly observed in the sarcolemma and intercalated disks of myocytes; 3) annexins II, V, and VI strongly label endothelial cells and adventitia of coronary arteries; and 4) annexin VI is present in the media. At the onset of heart failure, the most striking changes are the increased protein accumulation in LV and the very strong labeling of annexins II, V, and VI in interstitial tissue, suggesting a role in fibrosis development and cardiac remodeling.
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PMID:Localization and quantitation of cardiac annexins II, V, and VI in hypertensive guinea pigs. 1019 38

Low plasma levels of taurine are associated with losses of cardiac sarcomeric proteins, leading to heart failure in mammals. Recently, it was proposed that cardiac taurine depletion serves to defend the heart against injury caused by regional ischemia in mammals. The role of taurine has not been well documented in broilers, particularly in relation to pulmonary hypertension syndrome (PHS; ascites). Three independent experiments evaluated plasma taurine in male broilers by utilizing the following treatments: unoperated controls (CONTROL; n = 10 in each experiment); sham operated (SHAM; n = 11, 12, and 10); or, unilaterally pulmonary artery clamped (PAC; n = 18, 29, and 24) that did (PAC-ascites) or did not (PAC-normal) develop ascites within 12 d postsurgery. Plasma samples were collected 9 and 11 d postsurgery in Experiments 1 and 2, respectively, and 2 d before and 4, 8, and 12 d after surgery in Experiment 3. Plasma taurine was analyzed by HPLC. Twelve days postsurgery, the birds were euthanatized, and ventricles were weighed for calculating the right:total ventricular weight ratio (RV:TV). The RV:TV of PAC birds (>0.35) consistently was higher (P < 0.01) than that of CONTROL and SHAM birds (<0.27 and 0.25, respectively). In Experiments 1 and 2, plasma taurine was higher (P < 0.05) in PAC-ascites (380 and 370 nmol/mL) than in SHAM broilers (183 and 186 nmol/mL), whereas CONTROL (262 and 278 nmol/mL) and PAC-normal (362 and 300 nmol/mL) broilers tended to have intermediate plasma taurine levels. In Experiment 3, PAC birds had higher (P < 0.05) plasma taurine at 8 and 12 d postsurgery when compared with presurgery levels, whereas plasma taurine was unchanged over time in CONTROL and SHAM birds. These results suggest cardiac taurine may be released into the plasma as a protective mechanism in response to the induction of pulmonary hypertension, hypoxemia, and right-side heart failure, similar to the mechanism reported for protecting cardiac muscle from ischemia in mammals.
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PMID:Plasma taurine levels in broilers with pulmonary hypertension syndrome induced by unilateral pulmonary artery occlusion. 1056 Aug 39

The cytoskeleton of cardiac myocytes consists of actin, the intermediate filament desmin and of alpha- and beta-tubulin that form the microtubules by polymerization. Vinculin, talin, dystrophin and spectrin represent a separate group of membrane-associated proteins. In numerous experimental studies, the role of cytoskeletal alterations especially of microtubules and desmin, in cardiac hypertrophy and failure (CHF) has been described. Microtubules were found to be accumulated thereby posing an increased load on myocytes which impedes sarcomere motion and promotes cardiac dysfunction. Other groups were unable to confirm microtubular densification. The possibility exists that these changes are species, load and chamber dependent. Recently, damage of the dystrophin molecule and MLP (muscle LIM protein) were identified as possible causes of CHF. Our own studies in human hearts with chronic CHF due to dilated cardiomyopathy (DCM) showed that a morphological basis of reduced contractile function exists: the cytoskeletal and membrane-associated proteins are disorganized and increased in amount confirming experimental reports. In contrast, the contractile myofilaments and the proteins of the sarcomeric skeleton including titin, alpha-actinin, and myomesin are significantly decreased. These changes can be assumed to occur in stages and are here presented as a testable hypothesis: (1) The early and reversible stage as present in animal experiments is characterized by accumulation of cytoskeletal proteins to counteract an increased strain without loss of contractile material. (2) Further accumulation of microtubules and desmin to compensate for the increasing loss of myofilaments and titin represents the late clinical and irreversible state. We suggest, based on a structural basis for heart failure, an integrative view which closes the gap between changes within cardiac myocytes and the involvement of the extracellular matrix, including the development of fibrosis. These factors contribute significantly to structural ventricular remodeling and dilatation finally resulting in reduced cardiac function.
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PMID:The role of the cytoskeleton in heart failure. 1072 47

Experimental studies have shown that in hypertrophy and heart failure, accumulation of microtubules occurs that impedes sarcomere motion and contributes to decreased ventricular compliance. We tested the hypothesis that these changes are present in the failing human heart and that an entire complex of structural components, including cytoskeletal, linkage, and extracellular proteins, are involved in causing functional deterioration. In explanted human hearts failing because of dilated cardiomyopathy (ejection fraction </=20%), expression of alpha- and beta-tubulin, desmin, vinculin, fibronectin, and vimentin was determined by Northern and Western blot analysis and compared with normal myocardium from explants not used for transplantation. The mRNA for alpha- and beta-tubulin was increased to 2.4-fold (P<0.01) and 1.25-fold (NS), respectively; for desmin, 1.2-fold (P<0.05); for fibronectin, 5-fold (P<0.001); and for vimentin, 1.7-fold (P<0.05). Protein levels for alpha-tubulin increased 2.6-fold (P<0.02); for beta-tubulin, 1.2-fold (P<0.005); for desmin, 2.1-fold (P<0.001); for vinculin, 1.2-fold (P<0.005); for fibronectin, 2.9-fold (P<0.001); and for vimentin, 1.5-fold (P<0. 005). Confocal microscopy showed augmentation and disorganization of all proteins studied. In combination with the loss of myofilaments and sarcomeric skeleton previously reported, these changes suggest cardiomyocyte remodeling. Increased fibronectin and elevated interstitial cellularity (vimentin labeling) indicate progressive fibrosis. The present results suggest a causative role of cytoskeletal abnormalities and myofilament loss for intrinsic contractile and diastolic dysfunction in failing hearts.
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PMID:Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. 1078 6

Mutations causing hypertrophic cardiomyopathy have been described in nine genes encoding sarcomeric proteins. We report a new mutation in three families, with a C-->G transversion in nucleotide 12 307 of the beta-myosin heavy chain gene, located at the essential light chain interacting region, resulting in the replacement of arginine by glycine at amino acid residue 723. PCR amplification of the selected regions followed by single strand conformation polymorphism analysis, DNA sequencing of the polymorphic patterns and restriction analysis were used to detect the mutation. A total of 23 individuals were diagnosed as carriers, and seven were obligate carriers or had been clinically diagnosed. The Arg723Gly mutation was associated with a malignant phenotype. Ten out of 30 affected members died suddenly or needed an implantable cardioverter-defibrillator at a mean age of 42, and seven members developed progressive heart failure, leading to death or heart transplant in five, at a mean age of 50 years. Echocardiography showed non-obstructive left ventricular hypertrophy in affected members older than 20 (sensitivity 68%). Mean survival of affected members was 51 years. In conclusion, a new mutation Arg723Gly in beta-myosin heavy chain gene is reported which shortens life expectancy because of sudden death and end-stage heart failure.
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PMID:Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in beta-myosin heavy chain gene. 1111 6

Heart failure is a major health problem and is associated with a high mortality and morbidity. Recently, the role of the genetic background in the onset and development of the disease has been evidenced in both heart failure with and without systolic dysfunction, and in familial and non-familial forms of this condition. Familial forms of dilated cardiomyopathy are more frequent than previously thought. Various modes of inheritance and phenotypes have been reported and this condition appears genetically highly heterogenous. Five genes (dystrophin, cardiac actin, desmin, lamin A/C and delta-sarcoglycan), and additional loci, have been identified in families in which dilated cardiomyopathy is isolated or associated with other cardiac or non-cardiac symptoms. It has been postulated that the molecular defect involved could lead to abnormal interactions between cytoskeletal proteins, responsible either for defect in force transmission or for membrane disruption. More recently, the identification of mutations in genes encoding sarcomeric proteins has led to a second hypothesis in which the disease might also result from a force generation defect. In non-monogenic dilated cardiomyopathy, susceptibility genes (role in the development of the disease) and modifier genes (role in the evolution/prognosis of the disease) have so far been identified. Some data suggest that the efficacy of angiotensin converting enzyme inhibitors, and side-effects, might be related to some genetic polymorphisms, such as the I/D polymorphism of the angiotensin converting enzyme gene. Although preliminary, these data are promising and might be the first step towards application of phamacogenetics in heart failure. This is of paramount importance as the medical treatment of heart failure is characterized by the need for polypharmacy. One of the major challenges of the next millenium, therefore, will be to identify genetic factors which might help define responders to major treatment classes, including angiotensin converting enzyme inhibitors, beta-adrenoreceptor antagonists, angiotensin AT1 receptor antagonists, spironolactone, vasopeptidase inhibitors and endothelin receptor antagonists.
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PMID:Are we ready for pharmacogenomics in heart failure? 1130 Oct 53

Heart-specific inhibition of survival pathway gp130 was recently shown to sensitize transgenic mice towards stress stimuli, resulting in rapid onset of cardiac dilatation and heart failure. In order to identify further survival pathways we evaluated the role of transcription factor nuclear factor-kappa B (NF-kappa B) in tumour necrosis factor-alpha (TNF-alpha)-induced apoptosis of cardiomyocytes. TNF-alpha stimulation (10 ng/ml) of both H9c2 cells and primary cardiomyocytes isolated from neonatal Wistar rats resulted in rapid nuclear translocation of NF-kappa B complexes. The NF-kappa B complexes consisted of rel-proteins p50 and p65, as revealed by supershift analysis. Addition of proteasome inhibitor MG132 or adenoviral expression of a truncated I kappa B alpha (I kappa B Delta N) inhibited TNF-alpha-induced NF-kappa B nuclear translocation in a dose-dependent manner. Both neonatal cardiomyocytes and H9c2 cells were resistant to TNF-induced apoptosis. However, specific inhibition of NF-kappa B activation by Ad5-I kappa B alpha Delta N (MOI=50) or MG132 (5 microm) increased apoptosis as measured by subG1-assay (H9c2 cells) and annexin V binding/propidium iodide (neonatal cardiomyocytes, FACS-analysis: 7+/-2% to 26+/-5% annexin V positive/PI negative), respectively. TUNEL-assay double-stained with anti-alpha-sarcomeric actin confirmed apoptosis of neonatal cardiomyocytes. Furthermore, caspase-3 activation was increased by 52+/-7% in neonatal cardiomyocytes after TNF alpha+Ad5-I kappa B alpha Delta N compared to TNF alpha+Ad5-control treatment. Protein levels of hiAP1, hiAP2, x-iAP, bcl-2 and bcl-x(L) were neither downregulated by NF-kappa B inhibition nor upregulated by TNF-alpha stimulation. In summary, cardiomyocytes utilize transcription factor NF-kappa B to activate survival factors in the context of TNF-alpha stimulation. As locally increased levels of TNF-alpha have been detected in heart failure, NF-kappa B activity is essential for cellular homeostasis in the heart.
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PMID:Effect of NF-kappa B Inhibition on TNF-alpha-induced apoptosis and downstream pathways in cardiomyocytes. 1144 25

Short duration exposure to cellular stresses have been shown to activate p38 mitogen-activated protein kinase (MAPK) in cultured rat ventricular cardiomyocytes and isolated perfused hearts; however, effects of chronic stress on p38 MAPK are not well understood. This study determined whether alterations in the p38 MAPK pathway occurred prior to end-stage human heart failure. The p38 MAPK alpha isoform was detectable in human cardiac tissue. However, carefully controlled analysis of protein and message in this study demonstrated an absence of the p38 MAPK beta -isoform. Low levels of message for the non-SB203580 sensitive p38 MAPK gamma and delta isoforms were also detected in both normal and failing human myocardium. Ischemic and idiopathic end-stage failing human hearts were compared to non-failing hearts for both p38 alpha MAPK protein level and total p38 MAPK activity. Western blotting techniques demonstrated no significant changes in total p38 alpha MAPK content. However, approximately 75% decreases in active/phosphorylated p38 MAPK (P<0.005) were observed in both ischemic and idiopathic failing hearts compared to non-failing hearts. In-gel kinase assays confirmed that activated p38 MAPK, detected by Western blotting, phosphorylated its potential downstream targets. When compared to non-failing hearts, approximately 46% decreases in p38 MAPK phosphorylation of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK-2) were observed in ischemic and idiopathic failing hearts (P=0.03 and P=0.04 respectively). Active p38 MAPK was localized to sarcomeric structures in the cytosol of myocytes by confocal immunofluorescence microscopy. The correlation between decreased MAPKAPK-2 phosphorylation and loss of active p38 MAPK in failing human myocytes suggests that decreases in the activation of p38 MAPK alpha, the predominant cardiac isoform, occur prior to end-stage heart failure.
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PMID:Decreased p38 MAPK activity in end-stage failing human myocardium: p38 MAPK alpha is the predominant isoform expressed in human heart. 1144 40

Cardiomyopathies are defined as diseases of the myocardium associated with cardiac dysfunction ranging from lifelong symptomless forms to major health problems such as progressive heart failure, arrhythmia, thromboembolism, and sudden cardiac death. They are classified by morphological characteristics as hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), and restrictive cardiomyopathy (RCM). A familial cause has been shown in 50% of patients with HCM, 35% with DCM, and 30% with ARVC. In HCM, nine genetic loci and more than 130 mutations in ten different sarcomeric genes and in the gamma 2 subunit of AMP-activated protein kinase (AMPK) have been identified, suggesting impaired force production associated with inefficient use of ATP as the crucial disease mechanism. In DCM, 16 chromosomal loci with defects of several proteins also involved in the development of skeletal myopathies have been detected. These mutated cytoskeletal and nuclear transporter proteins may alter force transmission or disrupt nuclear function, resulting in cell death. Further DCM mutations have also been identified in sarcomeric genes, which indicates that different defects of the same protein can result in either HCM or DCM. In ARVC, six genetic loci and mutations in the cardiac ryanodine receptor, which controls electromechanical coupling, and in plakoglobin and desmoglobin (molecules involved in desmosomal cell-junction integrity), have been identified. Yet, no genetic linkage has been shown in RCM. Apart from disease-causing mutations, other factors, such as environment, genetic background, and the recently identified modifier genes of the renin-angiotensin, adrenergic, and endothelin systems are likely to result in the wide variety of RCM clinical presentations. Treatment options are symptomatic and are mainly focused on treatment of heart failure and prevention of thromboembolism and sudden death. Identification of patients with high risk for major arrhythmic events is important because implantable cardioverter defibrillators can prevent sudden death. Clinical and genetic risk stratification may lead to prospective trials of primary implantation of cardioverter defibrillators in people with hereditary cardiomyopathy.
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PMID:Cardiomyopathies: from genetics to the prospect of treatment. 1171 9

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