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)

Rho, a Ser-Thr kinase identified as a member of the RAS GTPase super family, is highly expressed in the heart, and has been implicated in the development of heart failure. GTPase Rho is located downstream of Gq, and Rho and the associated kinase (Rho kinase) regulate myofibril organization, apoptosis, and myofibrillar sensitivity to calcium. Myocardial injury and dysfunction occur after major burn injury, and this phenomenon has been linked to cardiac myocyte synthesis and the secretion of proinflammatory cytokines. Whether Rho-associated kinase modulates any aspect of cardiomyocyte synthesis of inflammatory mediators, contributing to myocardial dysfunction, has not been studied and was the focus of this study. Hearts were collected at several times postburn to determine if an acute injury such as thermal trauma altered myocardial Rho kinase expression. In addition, cardiomyocytes were isolated (collagenase digestion) from adult control Sprague Dawley rats, plated (5 x 10 cells/microtiter well), incubated with medium alone or in the presence of burn serum (collected 24 h after burn over 40% total body surface area in rats) in a CO2 incubator at 37 degrees C in the presence/absence of specific Rho-kinase inhibitors (HA1077, 10 microM or Y27632, 10 microM). After 18 h, supernatants were collected to measure secreted cytokines (enzyme-linked immunoabsorbant assay), cells were loaded with Fura-2AM (2 microg) or sodium-binding benzofuran isophthalate (2 microg) for 45 min at 37 degrees C, and fluorescence was measured with an InCyt IM2 fluorescence imaging system to measure myocyte calcium and sodium. In parallel studies, cells were examined to determine if burn serum challenge increased Rho kinase in this cell population. In vivo burn injury or in vitro burn serum challenge of isolated myocytes increased Rho-kinase expression and promoted cardiomyocyte secretion of tumor necrosis factor-alpha, interleukin 1beta, and interleukin 6, and increased cardiomyocyte calcium and sodium levels compared with values measured when myocytes were incubated in medium alone (P < 0.05). Pretreating cardiomyocytes with Rho-kinase inhibitor (HA1077 or Y27632) prevented burn serum-related upregulation of Rho-kinase and attenuated the associated inflammatory cytokine responses, and attenuated myocyte calcium and sodium loading. Our data suggest that the Rho-kinase pathway is one potential upstream regulator of cardiac inflammatory response to burn injury.
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PMID:Rho-associated kinase modulates myocardial inflammatory cytokine responses. 1598 21

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

The aim of this study was to investigate the effects of aging on the profile of myocardial substrate utilization and cardiac function using a physiological profile of substrates. Hearts from 6-, 15- and 24-month male Wistar rats were perfused in the isovolumic Langendorff mode, with physiological concentrations of 13C labeled palmitate, and either 13C labeled lactate or 13C glucose. 13C-NMR glutamate isotopomer analysis was performed to determine the contribution of the different substrates to oxidative metabolism. Palmitate oxidation was significantly increased and lactate oxidation depressed in the 24-month old, senescent hearts compared to the mature 6-month hearts. This metabolic remodeling was paralleled with a marked decline in cardiac function and efficiency. These results highlight that adaptations in substrate utilization occur during senescence and may contribute to the age-related increase in the incidence of heart failure.
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PMID:Metabolic remodeling in the aging heart. 1632 10

An in situ versus in vitro comparison of relative dose-dependent effects of halothane on cardiac performance was investigated, including ventricular systolic/diastolic function. Such comparative studies may be of interest to individuals working on heart failure models, cardiac device testing, or xenotransplantation. Normal swine (n=9) received halothane at levels of 0.25, 0.5 and 1 MAC (minimum alveolar concentration) for 30 min each. Parameters assessed included: 1) heart rate; 2) arterial blood pressure; 3) pulmonary artery, central venous, left and right ventricular pressures; 4) cardiac output; 5) end-expiratory CO(2) and halothane levels; 6) cardiac temperature; and 7) arterial blood gases. Hearts were removed using standard cardioplegic procedures and reperfused in four-chamber working mode (n=8); again the effects of increasing halothane concentrations on cardiac performance were analyzed. When comparing biventricular depressive effects (negative inotropic, negative lusitropic) of halothane in vivo and in vitro, there were distinct quantitative differences. The negative lusitropic effects were less pronounced in vitro; this was especially true for the right ventricle. Yet, in vitro, halothane at all doses induced more pronounced decreases in left heart output compared to the right. The large mammalian isolated four-chamber working heart model allows for novel assessment of pharmacodynamics and/or evaluation of cardiac devices under a range of hemodynamic performances. Halothane, a cardiodepressive agent, induced direct myocardial depressive effects in vitro similar to those recorded in vivo; hence additional systemic effects are considered to play a minor role in ultimate performances, e.g., compensatory responses due to autonomic controls.
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PMID:In vivo versus in vitro comparison of swine cardiac performance: induction of cardiodepression with halothane. 1684 74

Aging is associated with left ventricular hypertrophy, dilatation, and fibrosis of the heart. The Fischer 344/Brown Norway F1 (F344/BNF1) rat is recommended for age-related studies by the National Institutes on Aging because this hybrid rat lives longer and has a lower rate of pathological conditions than inbred rats. However, little is known about age-associated changes in cardiac and aortic function and structure in this model. This study evaluated age-related cardiac changes in male F344/BNF1 rats using ECHO, gross, and microscopic examinations. Rats aged 6-, 30-, and 36-mo were anesthetized and two-dimensional ECHO measurements, two-dimensional guided M-mode, Doppler M-mode, and other recordings from parasternal long- and short-axis views were obtained using a Phillips 5500 ECHO system with a 12 megahertz transducer. Hearts and aortas from sacrificed rats were evaluated grossly and microscopically. The ECHO studies revealed persistent cardiac arrhythmias (chiefly PVCs) in 72% (13/18) of 36-mo rats, 10% (1/10) of 30-mo rats, and none in 6-mo rats (0/16). Gross and microscopic studies showed left ventricular (LV) dilatation, borderline to mild hypertrophy, and areas of fibrosis that were common in 36-mo rats, less evident in 30-mo rats, and absent in 6-mo rats. Aging was associated with mild to moderate decreases of LV diastolic and systolic function. Thus, male F344/BN F1 rats demonstrated progressive age-related (a) decline in cardiac function (diastolic and systolic indices), (b) LV structural changes (chamber dimensions, volumes, and wall thicknesses), and (c) persistent arrhythmias. These changes are consistent with those in humans. The noninvasive ECHO technique offers a means to monitor serial age-related cardiac failure and therapeutic responses in the same rats over designated time intervals.
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PMID:Age-associated changes in hearts of male Fischer 344/Brown Norway F1 rats. 1712 29

Chronic Chagas' disease represents the result of the interaction between the host and the parasite, producing different clinical features: from a mild disease to a severe heart failure. In the present investigation, we analyzed whether Trypanosoma cruzi strain and/or reinfections in the acute stage, determine changes in the chronic phase (135 days postinfection, d.p.i) that could explain the diverse evolution of cardiac lesions. After infection of albino Swiss mice (n = 170) with 50 blood trypomastigote of the T. cruzi, strain Tulahuen (n = 80) and the isolate SGO-Z12 (n = 90), respectively, and reinfections at 10 and 20 d.p.i. Parasitemia, survival, electrocardiography, affinity and density of cardiac beta-receptors and histopathology of the heart were studied. Parasitemias in reinfected mice were significantly higher than those in single-infected mice. Survival of SGO-Z12-infected group was significantly higher than the other groups (p < 0.01). All Tulahuen-reinfected mice and 55-67% of the infected and SGO-Z12-reinfected groups presented some electrocardiographic abnormality (p < 0.01). Hearts from single-infected mice presented fibber disorganization and necrosis; reinfected groups also exhibited fibber fragmentation and a diminished affinity and a higher beta-adrenergic receptors' density than the other groups (p < 0.05). Therefore, parasite strain and reinfections determine different cardiac damage, and either (or both) of these factors are involved in the severity of the clinical picture and the prognosis of the chronic cardiac disease.
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PMID:Reinfections and Trypanosoma cruzi strains can determine the prognosis of the chronic chagasic cardiopathy in mice. 1737 64

Epsilon protein kinase C (epsilonPKC) plays pivotal roles in myocardial infarction and in heart failure. Although cardiac transplantation is a well-established therapy for severe heart failure, allograft rejection and host inflammatory responses limit graft function and reduce life expectancy. Here we determined whether sustained epsilonPKC inhibition beginning 3 days after transplantation suppress allograft rejection and improve cardiac transplantation using a murine heterotopic transplantation model. Hearts of FVB mice (H-2(q)) were transplanted into C57BL/6 mice (H-2(b)). Delivery of the epsilonPKC inhibitor, TAT(47-57)-epsilonV1-2 (epsilonV1-2, n=9, 20 mg/kg/day), or the carrier control peptide, TAT(47-57) (TAT, n=8), by osmotic pump began 3 days after transplantation and continued for the remaining 4 weeks. epsilonV1-2 treatment significantly improved the beating score throughout the treatment. Infiltration of macrophages and T cells into the cardiac grafts was significantly reduced and parenchymal fibrosis was decreased in animals treated with epsilonV1-2 as compared with control treatment. Finally, the rise in pro-fibrotic cytokine, TGF-beta and monocyte recruiting chemokine MCP-1 levels was almost abolished by epsilonV1-2 treatment, whereas the rise in PDGF-BB level was unaffected. These data suggest that epsilonPKC activity contributes to the chronic immune response in cardiac allograft and that an epsilonPKC-selective inhibitor, such as epsilonV1-2, could augment current therapeutic strategies to suppress inflammation and prolong graft survival in humans.
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PMID:Pharmacological inhibition of epsilon PKC suppresses chronic inflammation in murine cardiac transplantation model. 1770 96

The heart adapts to changes in nutritional status and energy demands by adjusting its relative metabolism of carbohydrates and fatty acids. Loss of this metabolic flexibility such as occurs in diabetes mellitus is associated with cardiovascular disease and heart failure. To study the long-term consequences of impaired metabolic flexibility, we have generated mice that overexpress pyruvate dehydrogenase kinase (PDK)4 selectively in the heart. Hearts from PDK4 transgenic mice have a marked decrease in glucose oxidation and a corresponding increase in fatty acid catabolism. Although no overt cardiomyopathy was observed in the PDK4 transgenic mice, introduction of the PDK4 transgene into mice expressing a constitutively active form of the phosphatase calcineurin, which causes cardiac hypertrophy, caused cardiomyocyte fibrosis and a striking increase in mortality. These results demonstrate that cardiac-specific overexpression of PDK4 is sufficient to cause a loss of metabolic flexibility that exacerbates cardiomyopathy caused by the calcineurin stress-activated pathway.
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PMID:Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. 1808 2

We report here that interleukin (IL)-13 protects BALB/c mice from myocarditis, whether induced by peptide immunization or by viral infection. In contrast to mild disease in IL-4 knockout (KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirus B3 (CVB3)-induced autoimmune myocarditis and myocarditogenic peptide-induced experimental autoimmune myocarditis. Such severe disease was characterized by increased cardiac inflammation, increased total intracardiac CD45(+) leukocytes, elevated anti-cardiac myosin autoantibodies, and increased cardiac fibrosis. Echocardiography revealed that IL-13 KO mice developed severe dilated cardiomyopathy with impaired cardiac function and heart failure. Hearts of IL-13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL-1beta, IL-18, interferon-gamma, transforming growth factor-beta1, and IL-4 as well as histamine. The hallmark of the disease in IL-13 KO mice was the up-regulation of T-cell responses. CD4(+) T cells were increased in IL-13 KO hearts both proportionally and in absolute number. Splenic T cells from IL-13 KO mice were highly activated, and myosin stimulation additionally increased T-cell proliferation. CD4(+)CD25(+)Foxp3(+) regulatory T-cell numbers were decreased in the spleens of IL-13 KO mice. IL-13 deficiency led to decreased levels of alternatively activated CD206(+) and CD204(+) macrophages and increased levels of classically activated macrophages. IL-13 KO mice had increased caspase-1 activation, leading to increased production of both IL-1beta and IL-18. Therefore, IL-13 protects against myocarditis by modulating monocyte/macrophage populations and by regulating their function.
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PMID:Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation. 1840 98

TNFalpha is a cytokine wit pleiotropic functions in many organs. In the heart increased TNFalpha levels are not only associated with heart failure, but also, paradoxically, with protection from ischemic damage. To test whether the protective role of TNFalpha in the heart is concentration-dependent, we studied two mouse heart models with low (two- to threefold) over-expression of endogenous TNFalpha: mice deficient in a translational repressor of TNFalpha mRNA, TIA-1(-/-), and mice over-expressing human TNFalpha. Hearts lacking TIA-1 were characterized for their endogenous TNFalpha over-expression during normal Langendorff perfusion. To define which TNFalpha receptor mediates cardiac protection, we also used mice lacking the TNFR1 receptor. Contractile function was assessed in isolated hearts perfused in the isovolumic Langendorff mode during and following global no-flow ischemic stress and in response to varying extracellular [Ca(2+)] to determine their contractile response and Ca(2+) sensitivity. All hearts with low over-expression of TNFalpha, independent of human or murine origin, have improved contractile performance and increased Ca(2+) sensitivity (by 0.2-0.26 pCa). Hearts lacking TNFR1 have contractile performance equal to wild type hearts. Recovery from ischemia was greater in TIA-1(-/-) and was diminished in TNFR1(-/-). Better contractile function in TNFalpha over-expressing hearts is not due to improved cardiac energetics assessed as [ATP] and glucose uptake or to differences in expression of SERCA2a or calmodulin. We suggest that low levels of TNFalpha increase the Ca(2+) sensitivity of the heart via a TNFR1-mediated mechanism.
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PMID:Low over-expression of TNFalpha in the mouse heart increases contractile performance via TNFR1. 1845 58


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