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)

Gap junction channels form the basis of intercellular communication in the heart. In the working myocardium, the connexin43 (Cx43) is most abundantly found, whereas connexin40 (Cx40) is expressed in the atria and in the conduction system [together with low levels of connexin45 (Cx45)]. However, little is known about the differential regulation of the connexins by pathophysiologically stimuli such as tumor necrosis factor alpha (TNFalpha). Inasmuch as TNFalpha may play a contributory role in the concert of factors involved in the pathophysiology of heart failure and because this cardiac disease often leads to ventricular reentrant arrhythmia, the goal of our study was to find out whether TNFalpha may influence the expression of the cardiac connexins connexin43, connexin40, and connexin45. Neonatal rat cardiomyocytes were exposed to TNFalpha (10, 40, 100, 400, and 1000 pg/ml) for 24 h with or without additional treatment with the mitogenic-activated protein kinase (MAP-kinase) inhibitors SB203580 [4-(4-fluorophenyl)-2-(4-methyl-sulfinylphenyl)-5-(4-pyridyl)-1H-imidazole; 10(-5) M, protein38 mitogenic-activated protein kinase (p38 MAP kinase) inhibitor] or the MEK1 (mitogenic-activated protein kinase/extracellular signal-regulated kinase kinase) inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 10(-5) M]. Connexin43, connexin40, and connexin45 expressions were analysed using Western blot analysis, immunohistology, and polymerase chain reaction (PCR) studies (connexin43 and connexin40). TNFalpha induced a concentration-dependent increase in connexin43 (by 2.9+/-0.6, P<0.05, n=5) but not in connexin40 or connexin45 expressions. Both connexins (40 and 45) showed a very low expression near the detection limit. The increases in connexin43 expression could be completely suppressed by SB203580 (0.9+/-0.4, P<0.05, n=5) but not by PD98059. In absence of a stimulating drug, these inhibitors (SB203580 or PD98059) did not affect connexin43 content. Additional PCR experiments revealed increases in connexin43 mRNA under the influence of 100 pg/ml TNFalpha (211+/-38%, P<0.05, n=5), which could be completely suppressed by SB203580. In contrast, the connexin40 expression remained unchanged. From these results, we conclude that TNFalpha can differentially regulate cardiac connexin expression via p38 MAP kinase pathway and thus may alter intercellular communication. This may contribute to the changes observed in heart failure with regard to the formation of an arrhythmogenic substrate.
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PMID:Chronic regulation of the expression of gap junction proteins connexin40, connexin43, and connexin45 in neonatal rat cardiomyocytes. 1549 89

Electrophysiological remodeling involving gap junctions has been demonstrated in failing hearts and may contribute to intercellular uncoupling, delayed conduction, enhanced arrhythmias, and vulnerability to sudden death in patients with heart failure. Recently, we showed that failing human hearts exhibit marked increases in connexin45 (Cx45) expression in addition to previously documented decreases in connexin43 (Cx43) expression. Each of these changes results in reduced gap junction coupling. The objective of the present study was to examine functional consequences of increased Cx45 in cardiac gap junctions. Transgenic mice with cardiac-selective overexpression of the developmentally downregulated cardiac connexin, connexin45 (Cx45OE mice) were subjected to in vivo electrophysiology studies in which an intracardiac catheter was used to induce ventricular arrhythmias in anesthetized mice, and in which ambulatory ECG monitoring was used to detect spontaneous arrhythmias in unanesthetized mice. Hearts were analyzed by TaqMan RT-PCR, immunostaining, immunoblotting, and echocardiography. Lucifer yellow and neurobiotin dye transfer was used to assess coupling in transgenic and control myocyte cultures. Cx45 mRNA was two orders of magnitude greater in Cx45OE mice. Cx45-immunoreactive signal at gap junctions increased twofold and total Cx45 protein by immunoblotting increased 25% in Cx45OE mice compared with nontransgenic littermate controls. Functionally, Cx45OE mice exhibited more inducible ventricular tachycardia than controls but did not exhibit any other functional or structural derangements as assessed by echocardiography. Ventricular myocytes isolated from Cx45OE mice exhibited diminished intercellular transfer of Lucifer yellow dye and increased transfer of neurobiotin, consistent with altered cell-to-cell communication. Thus increased myocardial expression of Cx45 results in remodeling of intercellular coupling and greater susceptibility to ventricular arrhythmias in vivo.
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PMID:Overexpression of cardiac connexin45 increases susceptibility to ventricular tachyarrhythmias in vivo. 1612 8

In addition to functional alterations, heart failure has a structural basis as well. This concerns all components of the cardiac myocytes as well as the extracellular space. Proteins of the cardiomyocyte can be subdivided in 5 different categories: 1) Contractile proteins including myosin, actin, tropomyosin and the troponins. 2) Sarcomeric skeleton: titin, myosin binding protein C, alpha-actinin, myomesin, and M-protein. 3) True 'cytoskeletal' proteins: tubulin, desmin and actin. 4) Membrane-associated proteins: dystrophin, spectrin, talin, vinculin, ankyrin and others. 5) Proteins of the intercalated disc: desmosomes consisting of desmoplakin, desmocollin, desmoglein and desmin; adherens junctions with N-cadherin, the catenins and vinculin, and gap junctions with connexin. Failing myocardium obtained from patients undergoing cardiac transplantation exhibits ultrastuctural degeneration and an altered nucleus/cytoplasm relationship. The contractile proteins and those of the sarcomeric skeleton, especially titin, are downregulated, the cytoskeletal proteins desmin and tubulin and membrane-associated proteins such as vinculin and dystrophin are upregulated and those of the intercalated disc are irregularly arranged. Elevation of cytoskeletal proteins correlates well with diastolic and contractile dysfunction in these patients. The enlarged interstitial space contains fibrosis, i.e. accumulations of fibroblasts and extracellular matrix components, in addition to macrophages and microvascular elements. Loss of the contractile machinery and related proteins such as titin and alpha-actinin may be the first and decisive event initiating an adaptive increase in cytoskeleton and membrane associated components. Fibrosis may be stimulated by subcellular degeneration. The hypothesis is put forward that all proteins of the different myocardial compartments contribute to the deterioration of cardiac function in heart failure.
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PMID:The cytoskeleton and related proteins in the human failing heart. 1622 10

Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with arrhythmogenesis and sudden cardiac death (SCD). Hcy decreases constitutive neuronal and endothelial nitric oxide (NO), and cardiac diastolic relaxation. Hcy increases the iNOS/NO, peroxynitrite, mitochondrial NADPH oxidase, and suppresses superoxide dismutase (SOD) and redoxins. Hcy activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) disrupt the normal pattern of cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling, leading to a pro-arrhythmic environment. The goal of this review is to elaborate the mechanism of Hcy-mediated iNOS/NO in E-M uncoupling and SCD. It is known that Hcy creates arrhythmogenic substrates (i.e. increase in collagen/elastin ratio and disruption in connexin-43) and exacerbates heart failure during chronic volume overload. Also, Hcy behaves as an agonist to N-methyl-D-aspartate (NMDA, an excitatory neurotransmitter) receptor-1, and blockade of NMDA-R1 reduces the increase in heart rate-evoked by NMDA-analog and reduces SCD. This review suggest that Hcy increases iNOS/NO, superoxide, metalloproteinase activity, and disrupts connexin-43, exacerbates endothelial-myocyte uncoupling and cardiac failure secondary to inducing NMDA-R1.
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PMID:Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia. 1717 94

Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na(+) channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca(2+) channel, Kv4.2 K(+) channel alpha-subunit, and Cx45 mRNA abundances and the peak ventricular Na(+) current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure.
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PMID:Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation. 1733 99

Electrical activation of the myocardium to produce effective pumping of blood depends on the orderly coordinated spatial and temporal transfer of current from one cell to another via gap junctions. Normal ventricular myocytes are extensively coupled by gap junctions and have the capacity to rapidly increase the amount of connexin within gap junction plaques to meet physiological demands for enhanced cell-cell communication. However, myocytes can also rapidly uncouple in response to injury or disease. In general, both acute and chronic forms of heart disease caused by diverse etiologies are associated with changes in the expression of connexins and remodeling of gap junctions. Such remodeling may have both adaptive and maladaptive consequences and contribute to major clinical processes such as heart failure and sudden cardiac death. Our laboratory has investigated mechanisms regulating cell-cell electrical coupling in the heart under physiological and pathophysiological conditions. This review is focused on selected aspects of this work pertaining to changes in coupling in response to acute and chronic ischemic heart disease and in familial cardiomyopathies caused by mutations in genes encoding desmosomal proteins.
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PMID:Remodeling of gap junctions in ischemic and nonischemic forms of heart disease. 1758 61

Biventricular pacing (cardiac resynchronization therapy ) has been shown to be a very effective therapy for patients with heart failure and dyssynchrony, with improved survival now shown in a recent trial. Electrical dyssynchrony, usually quantified by the duration of the QRS complex, is distinct from mechanical dyssynchrony. Intraventricular mechanical dyssynchrony is most commonly manifest by decreased septal work with concomitant early lateral wall prestretch and subsequent inefficient late contraction. Intraventricular dyssynchrony appears to be more predictive of response to CRT than interventricular dyssynchrony. Mechanical left ventricular dyssynchrony also is associated with regional molecular derangements in connexin-43, stress response kinases, and tumor necrosis factor-alpha. These molecular derangements may lead to abnormalities in conduction velocity and action potential duration, which may predispose to ventricular arrhythmia. Biventricular pacing corrects abnormal regional wall stresses and results in electrical, mechanical, and molecular left ventricular remodeling.
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PMID:Physiology of biventricular pacing. 1787 30

Our previous study reveals that connexin (Cx) 43 is targeted by ACh to prevent lethal arrhythmia. Granulocyte colony-stimulating factor (G-CSF), used against ischemic heart failure, may be another candidate, however, with unknown mechanisms. Therefore, we investigated the cellular effects of G-CSF. G-CSF activated the Wnt and Jak2 signals in cardiomyocytes, and up-regulated Cx43 protein and phosphorylation levels. In addition, G-CSF enhanced the localization of Cx43, beta-catenin and cadherin on the plasma membrane. G-CSF inhibited the reduction of Cx43 by enhancing Cx43 anchoring and sustained the cell-cell communication during hypoxia. Consequently, G-CSF suppressed ventricular arrhythmia induced by myocardial infarction. As a result, G-CSF could be used as a therapeutic tool for arrhythmia.
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PMID:Granulocyte colony-stimulating factor activates Wnt signal to sustain gap junction function through recruitment of beta-catenin and cadherin. 1788 12

Although cardiac synchronization is important in maintaining myocardial performance, the mechanism of dys-synchronization in ailing to failing myocardium is unclear. It is known that the cardiac myocyte contracts and relaxes individually; however, it synchronizes only when connected to one another by low resistance communications called gap junction protein (connexins) and extra cellular matrix (ECM). Therefore, the remodeling of connexins and ECM in heart failure plays an important role in cardiac conduction, synchronization and arrhythmias. This review for the first time addresses the role of systemic accumulation of homocysteine (Hcy) in vasospasm, pressure and volume overload heart failure, hypertension and cardiac arrhythmias. The attenuation of calcium-dependent mitochondrial (mt), endothelial and neuronal nitric oxide synthase (mtNOS, eNOS and nNOS) by Hcy plays a significant role in cardiac arrhythmias. The signal transduction mechanisms in Hcy-induced matrix metalloproteinase (MMP) activation in cardiac connexin remodeling are discussed.
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PMID:Cardiac dys-synchronization and arrhythmia in hyperhomocysteinemia. 1804 55

Therapeutic strategies to protect the ischemic myocardium have been studied extensively. Reperfusion is the definitive treatment for acute coronary syndromes, especially acute myocardial infarction; however, reperfusion has the potential to exacerbate lethal tissue injury, a process termed "reperfusion injury." Ischemia/reperfusion injury may lead to myocardial infarction, cardiac arrhythmias, and contractile dysfunction. Ischemic preconditioning of myocardium is a well described adaptive response in which brief exposure to ischemia/reperfusion before sustained ischemia markedly enhances the ability of the heart to withstand a subsequent ischemic insult. Additionally, the application of brief repetitive episodes of ischemia/reperfusion at the immediate onset of reperfusion, which has been termed "postconditioning," reduces the extent of reperfusion injury. Ischemic pre- and postconditioning share some but not all parts of the proposed signal transduction cascade, including the activation of survival protein kinase pathways. Most experimental studies on cardioprotection have been undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of other disease processes. However, ischemic heart disease in humans is a complex disorder caused by or associated with known cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, insulin resistance, atherosclerosis, and heart failure; additionally, aging is an important modifying condition. In these diseases and aging, the pathological processes are associated with fundamental molecular alterations that can potentially affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Among many other possible mechanisms, for example, in hyperlipidemia and diabetes, the pathological increase in reactive oxygen and nitrogen species and the use of the ATP-sensitive potassium channel inhibitor insulin secretagogue antidiabetic drugs and, in aging, the reduced expression of connexin-43 and signal transducer and activator of transcription 3 may disrupt major cytoprotective signaling pathways thereby significantly interfering with the cardioprotective effect of pre- and postconditioning. The aim of this review is to show the potential for developing cardioprotective drugs on the basis of endogenous cardioprotection by pre- and postconditioning (i.e., drug applied as trigger or to activate signaling pathways associated with endogenous cardioprotection) and to review the evidence that comorbidities and aging accompanying coronary disease modify responses to ischemia/reperfusion and the cardioprotection conferred by preconditioning and postconditioning. We emphasize the critical need for more detailed and mechanistic preclinical studies that examine car-dioprotection specifically in relation to complicating disease states. These are now essential to maximize the likelihood of successful development of rational approaches to therapeutic protection for the majority of patients with ischemic heart disease who are aged and/or have modifying comorbid conditions.
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PMID:Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. 1804 61

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