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

Molecular signaling that induces cardiac hypertrophy and dilated cardiomyopathy and the transition to decompensation is complex and poorly understood. Extrinsic hemodynamic stresses such as hypertension as well as intrinsic stresses such as genetic defects in sarcomeric proteins and cytoskeletal proteins trigger the process. Both stresses lead to similar outcomes of altered contractility and eventually heart failure. Activation of G-protein coupled receptors initiates cascades of signaling pathways, which promote cardiac hypertrophy by phosphorylation of transcriptional factors and changes in gene expression. Stimulation of these signaling molecules also activates a variety of kinases and phosphatases that induce altered phosphorylation of myofilament proteins. In this review, we focused on these functional effects of small G-protein, Ras and Rho, signaling pathways that reside within the cytoplasm downstream of membrane receptors and upstream of the transcriptional factors. It has been demonstrated that phosphorylation of myofilament proteins alter mechano-energetics of myofilament and contractile function of the heart. Therefore, understanding the role of low molecular weight G-proteins in both cardiac and vascular biology has become particularly important in view of the development of specific inhibitors of effectors of small G-proteins such as p38 MAP kinase and Rho-dependent kinase.
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PMID:Cardiac sarcomeric function, small G-protein signaling, and heart failure. 1646 22

The mechanical stress imposed by hemodynamic overload on heart walls is a primary event in triggering the cardiac hypertrophic response. Integrins, a class of membrane receptors, are major players in transmitting the mechanical force across the plasma membrane and sensing the mechanical load in cardiomyocytes. In fact, integrins, together with a number of associated cytoskeletal proteins, connect the sarcomeric contractile apparatus to the extracellular matrix across the plasma membrane and trigger intracellular signaling pathways activating the cardiomyocyte hypertrophy program. In this review, we will discuss the role of the muscle-specific integrin isoform beta1D and of associated proteins such as FAK, melusin, vinculin, zyxin, VASP, and migfilin that are the most upstream elements ("initiators") activated by mechanical strain. These molecules trigger a coordinated downstream signaling cascade involving proteins such as AKT, RAS, and MAPKs that execute the biochemical program leading to cardiomyocyte hypertrophy. Better understanding of the functional role of the initiator elements is of key importance to developing novel strategies to control cardiac hypertrophy and prevent heart failure.
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PMID:Integrin signalling: the tug-of-war in heart hypertrophy. 1646 4

In the setting of chronic heart failure (HF), progressive left ventricular (LV) dysfunction and chamber remodeling may be due, in part, to altered expression and disorganization of cytoskeletal, linkage and extracellular proteins. This brief review describes changes in expression of cytoskeletal, linkage and extracellular protein using LV tissue obtained from dogs with progressive HF produced by multiple sequential intracoronary microembolizations. LV tissue samples from 6 untreated HF dogs (LV ejection fraction 20% to 25%) and 3 normal dogs were used. Sections from freshly frozen tissue were prepared, immunostained for specific proteins and studies by confocal microscopy. In failing hearts, confocal microscopy showed disorganization of key cytoskeletal proteins that, when combined with the loss of myofilaments and sarcomeric skeleton, suggest substantial cardiomyocyte remodeling. Cardiomyocytes in areas bordering old infarcts invariably exhibited disorganization of alpha-actinin. The cytoskeleton protein desmin showed increased expression in areas of extensive fibrosis. Staining for pancadherin showed interruptions of intercalated disks in areas of intensive interstitial fibrosis. Observation of increased fibronectin and increased interstitial cellularity based on vimentin labeling is suggestive of ongoing fibrosis. Based on these findings, we conclude that the structural changes observed in failing LV myocardium of dogs with intracoronary microembolizations-induced HF are extensive and typical of those seen and previously described in LV myocardium of explanted failed human hearts. The observed structural changes in this experimental model of HF also support the notion that these cytoskeletal, linkage and extracellular disorganization of structural proteins may be important maladaptations that contribute, albeit in part, to the progression of LV dysfunction and remodeling characteristic of the HF state.
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PMID:Expression of cytoskeletal, linkage and extracellular proteins in failing dog myocardium. 1658 78

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20-48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant.
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PMID:Cardiomyopathy, familial dilated. 1683 24

The vertebrate heart possesses autoregulatory mechanisms enabling it first to sense and then to adapt its force of contraction to continually changing demands. The molecular components of the cardiac mechanical stretch sensor are mostly unknown but of immense medical importance, since dysfunction of this sensing machinery is suspected to be responsible for a significant proportion of human heart failure. In the hearts of the ethylnitros-urea (ENU)-induced, recessive embryonic lethal zebrafish heart failure mutant main squeeze (msq), we find stretch-responsive genes such as atrial natriuretic factor (anf) and vascular endothelial growth factor (vegf) severely down-regulated. We demonstrate through positional cloning that heart failure in msq mutants is due to a mutation in the integrin-linked kinase (ilk) gene. ILK specifically localizes to costameres and sarcomeric Z-discs. The msq mutation (L308P) reduces ILK kinase activity and disrupts binding of ILK to the Z-disc adaptor protein beta-parvin (Affixin). Accordingly, in msq mutant embryos, heart failure can be suppressed by expression of ILK, and also of a constitutively active form of Protein Kinase B (PKB), and VEGF. Furthermore, antisense-mediated abrogation of zebrafish beta-parvin phenocopies the msq phenotype. Thus, we provide evidence that the heart uses the Integrin-ILK-beta-parvin network to sense mechanical stretch and respond with increased expression of ANF and VEGF, the latter of which was recently shown to augment cardiac force by increasing the heart's calcium transients.
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PMID:Integrin-linked kinase, a novel component of the cardiac mechanical stretch sensor, controls contractility in the zebrafish heart. 1695 Dec 48

Cytokine systems are activated in heart failure, and it is believed that interaction between such systems may be important during progression of this disorder. We have previously shown that failing hearts have increased levels of the interleukin-6 related cytokine leukemia inhibitory factor (LIF) and activin A, a member of the transforming growth factor-beta family. The aim of this study was to examine the effects of activin A on cardiomyocytes and a potential interaction with LIF-mediated changes in cell signaling and growth. Cardiomyocytes were isolated from 1- to 3-day-old Wistar rats, and the cells were treated with LIF, activin A or a combination thereof. Our main findings were: (i) activin A treatment reduced the LIF-mediated increase in cardiomyocyte length, perimeter and sarcomeric organization and was accompanied by a substantially decreased alpha-skeletal actin gene expression. (ii) The activin A-mediated phosphorylation of Smad2 was markedly enhanced by LIF. (iii) Activin A markedly induced SOCS3 gene expression, while LIF potently increased the expression of Smad7 mRNA, representing inhibitors of LIF and activin A signaling pathways, respectively. (iv) Inhibiting activation of the Smad2/3 pathway abolished the effects of activin A on LIF-induced changes in cell length, perimeter and sarcomeric organization. In conclusion, activin A markedly attenuates LIF-induced changes in cardiomyocytes, reflecting a potentially important role for both activin A and the Smad2/3 pathway in regulation of myocardial remodeling.
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PMID:Activin A inhibits organization of sarcomeric proteins in cardiomyocytes induced by leukemia inhibitory factor. 1692 21

Studies in the field of microarray technology have exploded onto the scene to delve into the unknown underlying mechanisms and pathways in molecular disease. Diseases of the cardiovascular system, particularly those with unexplained molecular etiologies, such as heart failure, have more recently been investigated using array technology. Our laboratory has sought to examine gene expression profiles of human heart failure using a 10,000+ element cardiovascular-based complementary DNA microarray constructed in-house, termed the "CardioChip." Our studies have identified panels of genes, such as those encoding sarcomeric and cytoskeletal proteins, stress proteins, and Ca2+ regulators, that are differentially expressed in disease conditions as compared with samples from nonfailing hearts. Microarrays are effective tools for examining molecular portraits of the cardiovascular disease condition.
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PMID:"Chip"ping away at heart failure. 1693 11

Increased relative expression of the slow molecular motor of the heart (beta-myosin heavy chain [MyHC]) is well known to occur in many rodent models of cardiovascular disease and in human heart failure. The direct effect of increased relative beta-MyHC expression on intact cardiac myocyte contractility, however, is unclear. To determine the direct effects of increased relative beta-MyHC expression on cardiac contractility, we used acute genetic engineering with a recombinant adenoviral vector (AdMYH7) to genetically titrate beta-MyHC protein expression in isolated rodent ventricular cardiac myocytes that predominantly expressed alpha-MyHC (fast molecular motor). AdMYH7-directed beta-MyHC protein expression and sarcomeric incorporation was observed as soon as 1 day after gene transfer. Effects of beta-MyHC expression on myocyte contractility were determined in electrically paced single myocytes (0.2 Hz, 37 degrees C) by measuring sarcomere shortening and intracellular calcium cycling. Gene transfer-based replacement of alpha-MyHC with beta-MyHC attenuated contractility in a dose-dependent manner, whereas calcium transients were unaffected. For example, when beta-MyHC expression accounted for approximately 18% of the total sarcomeric myosin, the amplitude of sarcomere-length shortening (nanometers, nm) was depressed by 42% (151.0+/-10.7 [control] versus 87.0+/-5.4 nm [AdMYH7 transduced]); and genetic titration of beta-MyHC, leading to 38% beta-MyHC content, attenuated shortening by 57% (138.9+/-13.0 versus 59.7+/-7.1 nm). Maximal isometric cross-bridge cycling rate was also slower in AdMYH7-transduced myocytes. Results indicate that small increases of beta-MyHC expression (18%) have Ca2+ transient-independent physiologically relevant effects to decrease intact cardiac myocyte function. We conclude that beta-MyHC is a negative inotrope among the cardiac myofilament proteins.
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PMID:Calcium-independent negative inotropy by beta-myosin heavy chain gene transfer in cardiac myocytes. 1736 98

Myosin motors are central to diverse cellular processes in eukaryotes. Homologues of the myosin chaperone UNC-45 have been implicated in the assembly and function of myosin-containing structures in organisms from fungi to humans. In muscle, the assembly of sarcomeric myosin is regulated to produce stable, uniform thick filaments. Loss-of-function mutations in Caenorhabditis elegans UNC-45 lead to decreased muscle myosin accumulation and defective thick filament assembly, resulting in paralyzed animals. We report that transgenic worms overexpressing UNC-45 also display defects in myosin assembly, with decreased myosin content and a mild paralysis phenotype. We find that the reduced myosin accumulation is the result of degradation through the ubiquitin/proteasome system. Partial proteasome inhibition is able to restore myosin protein and worm motility to nearly wild-type levels. These findings suggest a mechanism in which UNC-45-related proteins may contribute to the degradation of myosin in conditions such as heart failure and muscle wasting.
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PMID:The UNC-45 chaperone mediates sarcomere assembly through myosin degradation in Caenorhabditis elegans. 1743 72

Hypertrophic cardiomyopathies have an estimated prevalence of 1/500. The analysis of the genes coding for the 10 most commonly involved sarcomeric proteins, fails to detect a mutation in about one third of cases. In some of these cases, cardiomyopathy can be attributed to a genetics storage disease with enlarged glycogen vacuolss (PRKAG2 deficiency, Danon disease, Pompe disease) and/or lysosomol vacuoles (Donon disease, Pompe disease, Fabry disease). These diseases all have in common a short PR interval. PRKAG2 deficiency is due to a dominant mutation of the gamma2 subunit of the cardiac AMP kinose. It leads to a storage cardiomyopathy which may be associated with sudden death in 10% of cases, due to ventricular arrhythmia or auriculoventricular blocks. Danon disease is an X-linked dominant inherited disease characterized by cardiomyopathy, squeletal myopathy and mental retardation. Cardiac transplantation is indicated in both affected men and women. In the infantile form of Pompe disease, enzyme replacement therapy with olglucosidase alpha shows efficacy on cardiac failure with a significant regression of ventricular hypertrophy on ECG, echocardiography and radiography
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PMID:[Inherited metabolic cardiomyopathies]. 1754 68


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