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)

Heart failure (HF) is a progressive degenerative and malignant syndrome with a large number of aetiologies including coronary artery disease, chronic hypertension, exposure to toxins, bacteria and viruses and in a significant percentage of HF patients, the causal mechanism is unclear. The HF trail of morbidity and mortality is well documented and is characterised by step-like periods of relative symptomatic stability, compensation, separated by decompensatory episodes. The homeostatic response to the decline in cardiac function is diverse and involves most organs. There is an increase in resting rate, intra-cardiac hormone production (catecholamines, aldosterone, etc.) and in particular structural changes occur with increased mass and dilatation (dilated cardiomyopathy, DCM). DCM is associated with decreased cardiac output, contractility and energy efficiency and an increase in pro-arrhythmia and conduction defects. Kass et al. (Circulation 91(9) (1995) 2314) first demonstrated in patients who had undergone a dynamic cardio-myoplasty procedure, that, preventing further dilatation in DCM was beneficial and that the improved cardiovascular status was largely independent of muscle stimulation. We hypothesised that this outcome could be achieved by implanting a fabric cardiac support device around both ventricles to the AV junction. Subsequently, it was shown by us and others (Kass et al., 1995) (Cardiovasc. Res. 44(3) (1999) 549); (Ann. Thorac. Surg. 70(4) (2000) 1275) (in different animal models of DCM) that passive ventricular constraint prevented further dilatation, initiated left ventricular volume reduction and reversed the decline in ejection fraction, mitral valve integrity and left ventricular contractility, when compared with untreated controls. Subsequent European and North American clinical trials in patients with DCM of varying aetiologies have shown equal promise and an absence of device related complications (Circulation 104(12 Suppl. 1) (2001) I270); (Ann. Thorac. Cardiovasc. Surg. 7(5) (2001) 278). The mechanisms behind this improvement have yet to be fully clarified however the support generated by the device upon the right and ventricular freewall would lower wall tension. Not only is passive ventricular constraint a very promising treatment modality for heart failure and DCM it should provide a useful research tool for the study of the role of ventricular dilatation in the progression of heart failure.
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PMID:Passive ventricular constraint. 1273 79

Beta-adrenoceptor/cAMP-dependent Ser16-phosphorylation as well as Ca(2+)-dependent Thr17-phosphorylation of phospholamban (PLB) influences SERCA 2a activity and thus myocardial contractility. To determine the cross-signaling between Ca2+ and cAMP pathways, the phosphorylation of Ser16-PLB and Thr17-PLB was studied at increasing stimulation frequencies as well as in the presence of beta-adrenergic stimulation in isolated ventricular trabeculae from failing (dilative cardiomyopathy, DCM, heart transplants, n=9) and non-failing human myocardium (donor hearts, NF, n=9). In addition, we measured the intracellular Ca(2+)-transient (fura-2) at increasing stimulation frequencies (0.5-3.0 Hz). Protein expression of SERCA 2a and phospholamban was similar in DCM and NF. In DCM, diastolic [Ca2+]i was increased and systolic [Ca2+]i as well as Ser16 PLB-phosphorylation were decreased as compared to NF at 0.5 Hz. The positive force-frequency relationship in human non-failing myocardium was accompanied by a frequency-dependent increase in Ser16-PLB, but not Thr17-PLB phosphorylation. In DCM, Ser16-PLB as well as Thr17-PLB phosphorylation were not altered at higher stimulation frequencies. After application of isoprenaline (1 microM), a profound increase in Ser16-PLB phosphorylation was accompanied by a small increase in Thr17-PLB phosphorylation, only in NF. The frequency-dependent phosphorylation of Ser16-PLB may favor an increase in Ca2+ transient and force generation in humans. Cross talk signaling of Ser16/Thr17-PLB phosphorylation after beta-adrenergic stimulation exists in non-failing, but not in failing human myocardium. The Ca(2+)-dependent CaM-kinase activity may be altered in human heart failure.
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PMID:Ser16-, but not Thr17-phosphorylation of phospholamban influences frequency-dependent force generation in human myocardium. 1453 Sep 77

Randomized aldactone evolution study (RALES) and eplerenone post-AMI heart failure efficacy and survival study (EPHESUS) had shown that aldosterone blockade (AB) with standard therapy resulted in a reduction in mortality in patients with congestive heart failure (CHF) and acute myocardial infarction (AMI). However, the mechanism for the beneficial effect of AB remains unknown. To evaluate the effect of spironolactone (Spi) on left ventricular (LV) remodeling, 34 CHF patients with DCM were randomly divided into the Spi (+) or Spi (-) groups. Four months of treatment with Spi improved the LV volume and mass. To evaluate the effect of Spi on post-infarct LV remodeling, 134 patients with first anterior AMI were randomly divided into the Spi (+) or Spi (-) groups after revascularization. LV ejection fraction was significantly improved after 1 month in the Spi (+) group compared with that in the Spi (-) group. LV end-diastolic volume index was significantly suppressed in the Spi (+) group compared with that in the Spi (-) group. Transcardiac extraction of aldosterone through the heart was significantly suppressed in the Spi (+) group and was significant lower in the Spi (+) group compared with the Spi (-) group. These findings indicate that AB combined with standard therapy can prevent LV remodeling in patients with CHF and AMI, suggesting that the failing heart is the target organ of the aldosterone.
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PMID:Mineralocorticoid receptor antagonist spironolactone improves left ventricular remodeling in patients with congestive heart failure and acute myocardial infarction. 1527 27

Mutations in sarcomeric proteins can lead to either hypertrophic or dilated cardiomyopathy depending on their effects on the structural and functional properties of the contractile unit of the heart. Mutations in cardiac troponin T, which binds the calcium-responsive troponin complex to alpha-tropomyosin, have been shown to result in cardiac hypertrophy or cardiac dilatation and heart failure, depending on the nature of the specific mutation. In this study, we report the identification of a novel cardiac troponin T mutation (A171S) leading to dilated cardiomyopathy and sudden cardiac death. In contrast to prior described mutations, the A171S mutation results in a significant gender difference in the severity of the observed phenotype with adult males (over 20 years of age) demonstrating more severe ventricular dilatation [left ventricular end diastolic dimension (LVEDD) 7.1 vs. 5.1cm; P=0.01, t test] and left ventricular dysfunction [left ventricular shortening fraction (LVSF) 21 vs. 34%; P=0.04, t test] than adult females. The described mutation substitutes a hydrophilic amino acid for a hydrophobic one in a highly conserved domain involved in the interaction between troponin T and alpha-tropomyosin. Interestingly, four previously described mutations within 12 amino acids of A171 lead to a hypertrophic phenotype, suggesting that further characterization of the functional consequences of the A171S mutation may lead to a better understanding of the pathophysiology of DCM and of the functional differences between HCM- and DCM-causing mutations in cardiac troponin T.
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PMID:Novel troponin T mutation in familial dilated cardiomyopathy with gender-dependant severity. 1546 34

Familial cardiomyopathies represent a substantial portion of idiopathic dilated cardiomyopathy in clinical practice. Diversity of clinical presentations and variability in penetrance lead to under-recognition of this disease entity as an inherited disorder. The mechanisms by which mutations in different genes perturb cardiac function and lead to pathologic remodeling help us understand the molecular pathways in disease pathogenesis and define the potential targets for therapeutic interventions. Appreciating when DCM is inherited might spare unnecessary diagnostic efforts and, instead, help give appropriate attention to the timely detection of subclinically affected family members. Establishing preventive therapy in asymptomatic family members showing early signs of cardiac dysfunction might prevent death and slow down progression to end-stage heart failure.
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PMID:Genetic ideology of dilated cardiompathy. 1598 85

Cardiomyopathies are heart muscle diseases, which have been defined by their central hemodynamics and macropathology and divided in five major forms: dilated (DCM), hypertrophic (HCM), restrictive (RCM), right ventricular (RVCM), and nonclassifiable cardiomyopathies (NCCM). Furthermore, the most recent WHO/WHF definition also comprises, among the specific cardiomyopathies, inflammatory cardiomyopathy as a distinct entity, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy has been defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm(2)), the term viral cardiomyopathy or viral persistence in DCM should be applied according to the WHF Task Force recommendations. Within the German heart failure net it is the authors' working hypothesis, that DCM shares genetic risk factors with other diseases of presumed autoimmune etiology and, therefore, the same multiple genes in combination with environmental factors lead to numerous different autoimmune diseases including DCM. Therefore, the authors' primary goal is to acquire epidemiologic data of patients with DCM regarding an infectious and inflammatory etiology of the disease. Circumstantial evidence points to a major role of viral myocarditis in the etiology of DCM. The common presence of viral genetic material in the myocardium of patients with DCM provides the most compelling evidence, but proof of causality is still lacking. In addition, autoimmune reactions have been described in many studies, indicating them as an important etiologic factor. Nevertheless, data on the proportion of patients, in whom both mechanisms play a role are still missing.A pivotal role for autoimmunity in a substantial proportion of patients with DCM is supported by the presence of organ-specific autoantibodies, inflammatory infiltrates and pro-inflammatory cytotoxic cytokines. Furthermore, familial occurrence of DCM has been described in about 20-30% of cases, with the presence of autoantibodies and abnormal cytokine profiles in first-degree relatives with asymptomatic left ventricular enlargement. This suggests the involvement of a disrupted humoral and cellular immunity early in the development of the disease. A similar pattern of humoral and cellular immune dysregulation has been described in other autoimmune diseases. There is considerable evidence that genetic factors play an important role in the pathogenesis of DCM, either as contributors to the susceptibility to environmental factors or as determinants of functional and structural changes that characterize the phenotypic expression of the disease.Yet, it is not known whether the susceptibility to immunologically mediated myocardial damage reflects the presence of genetic risk factors shared by other autoimmune diseases. Preliminary investigations suggest, that this is the case, because the frequency of autoimmune disorders other than DCM was higher in first-degree relatives of the subjects with DCM including juvenile diabetes, rheumatoid arthritis, thyroiditis, psoriasis, and asthma. The nature of the genetic risk is undetermined and probably involves genes in the major histocompatibility (MHC) locus as well as other susceptibility loci. Therefore, the authors started their investigation with the search for MHC class 2 DQ polymorphisms in the peripheral blood of patients with DCM in parallel to the search for new interesting susceptibility loci by the use of the microarray analysis regarding genes responsible for inflammatory and autoimmune diseases. By this approach a new insight in the familial clustering of other autoimmune diseases in patients with DCM and in genetic predisposition can be expected.
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PMID:Inflammatory dilated cardiomyopathy (DCMI). 1617 Jun 86

Bone marrow-derived stem cells may contribute to the regeneration of non-haematopoietic organs. In order to test whether an increase in circulating stem cell numbers improves impaired myocardial function we treated 16 male patients with chronic heart failure due to dilated (DCM; n = 7) or ischaemic cardiomyopathy (ICM; n = 9) with the stem cell mobilising cytokine granulocyte colony-stimulating factor (G-CSF; four 10-day treatment periods interrupted by treatment-free intervals of equal length). Safety and efficacy analyses were performed at regular intervals. Peak CD34+ cell counts remained constant from cycle to cycle. Cardiac side effects in ICM patients included occasional episodes of dyspnea or angina and one episode of fatal ventricular fibrillation. Nine (4 DCM, 5 ICM) of 12 patients receiving four full G-CSF cycles experienced an improvement by one New York Heart Association (NYHA) class and a statistically significant increase in six-minute walking distance. By contrast, none of 8 ICM historical controls had a change in NYHA class during a similar time period. Statistically significant changes in echocardiographic parameters were not recorded. Sequential administration of G-CSF is feasible and possibly effective in improving physical performance in patients with chronic heart failure. Patients with ICM may be at risk of increased angina and arrhythmias.
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PMID:Granulocyte colony-stimulating factor-induced blood stem cell mobilisation in patients with chronic heart failure--Feasibility, safety and effects on exercise tolerance and cardiac function. 1623 6

Cardiomyopathies are responsible for a high proportion of cases of congestive heart failure and sudden death, as well as for the need for transplantation. Understanding of the causes of these disorders has been sought in earnest over the past decade. We hypothesized that DCM is a disease of the cytoskeleton/sarcolemma, which affects the sarcomere. Evaluation of the sarcolemma in DCM and other forms of systolic heart failure demonstrates membrane disruption; and, secondarily, the extracellular matrix architecture is also affected. Disruption of the links from the sarcolemma to ECM at the dystrophin C-terminus and those to the sarcomere and nucleus via N-terminal dystrophin interactions could lead to a "domino effect" disruption of systolic function and development of arrhythmias. We also have suggested that dystrophin mutations play a role in idiopathic DCM in males. The T-cap/MLP/alpha-actinin/titin complex appears to stabilize Z-disc function via mechanical stretch sensing. Loss of elasticity results in the primary defect in the endogenous cardiac muscle stretch sensor machinery. The over-stretching of individual myocytes leads to activation of cell death pathways, at a time when stretch-regulated survival cues are diminished due to defective stretch sensing, leading to progression of heart failure. Genetic DCM and the acquired disorder viral myocarditis have the same clinical features including heart failure, arrhythmias, and conduction block, and also similar mechanisms of disease based on the proteins targeted. In dilated cardiomyopathy, the process of progressive ventricular dilation and changes of the shape of the ventricle to a more spherical shape, associated with changes in ventricular function and/or hypertrophy, occurs without known initiating disturbance. In those cases in which resolution of cardiac dysfunction does not occur, chronic DCM results. It has been unclear what the underlying etiology of this long-term sequela could be, but viral persistence and autoimmunity have been widely speculated.
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PMID:Inflammatory cardiomyopathy: there is a specific matrix destruction in the course of the disease. 1632 65

Titin is a giant protein that constitutes the third myofilament of the sarcomere. Single titin molecules anchor in the Z-disk and extend all the way to the M-line region of the sarcomere. Successive titin molecules are arranged head-to-head and tail-to-tail, providing a continuous filament along the full length of the myofibril. The majority of titin's I-band region is extensible and functions as a molecular spring that when extended develops passive force. We will discuss mechanisms for adjusting titin-based force, including alternative splicing and posttranslational modifications. Multiple biological functions can be assigned to different regions of the titin molecule. In addition to titin's role in determining passive muscle stiffness, recent evidence suggests a role in protein metabolism, compartmentalization of metabolic enzymes, binding of chaperones, and positioning of the membrane systems of the T-tubules and sarcoplasmic reticulum. We will also discuss titin-based force adjustments that occur in various muscle diseases and several disease-causing titin mutations that have been discovered. We will focus on the role of titin in heart failure patients that was recently investigated in patients with end-stage heart failure due to non-ischemic dilated cardiomyopathy. In end-stage failing hearts, compliant titin isoforms comprise a greater percentage of titin and changes in titin isoform expression in heart failure patients with DCM significantly impact diastolic filling by lowering myocardial stiffness.
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PMID:Titin: physiological function and role in cardiomyopathy and failure. 1641 44

Clinical and animal studies suggest that estrogen receptors are involved in the development of myocardial hypertrophy and heart failure. In this study, we investigated whether human myocardial estrogen receptor alpha (ERalpha) expression, localization, and association with structural proteins was altered in end stage-failing hearts. We found a 1.8-fold increase in ERalpha mRNA and protein in end-stage human dilated cardiomyopathy (DCM, n=41), as compared with controls (n=25). ERalpha was visualized by confocal immunofluorescence microscopy and localized to the cytoplasm, sarcolemma, intercalated discs and nuclei of cardiomyocytes. Immunofluorescence studies demonstrated colocalization of ERalpha with beta-catenin at the intercalated disc in control hearts and immunoprecipitation studies confirmed complex formation of both proteins. Interestingly, the ERalpha/beta-catenin colocalization was lost at the intercalated disc in DCM hearts. Thus, the ERalpha/beta-catenin colocalization in the intercalated disc may be of functional relevance and a loss of this association may play a role in the progression of heart failure. The increase of total ERalpha expression may represent a compensatory process to contribute to the stability of cardiac intercalated discs.
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PMID:Estrogen receptor alpha up-regulation and redistribution in human heart failure. 1667 50

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