RESUMO
Cardiac lymphatic vessel growth (lymphangiogenesis) and integrity play an essential role in maintaining tissue fluid balance. Inhibition of lymphatic lymphangiogenesis is involved in cardiac edema and cardiac remodeling after ischemic injury or pressure overload. However, whether lymphatic vessel integrity is disrupted during angiotensin II- (Ang II-) induced cardiac remodeling remains to be investigated. In this study, cardiac remodeling models were established by Ang II (1000 ng/kg/min) in VEGFR-3 knockdown (Lyve-1Cre VEGFR-3f/-) and wild-type (VEGFR-3f/f) littermates. Our results indicated that Ang II infusion not only induced cardiac lymphangiogenesis and upregulation of VEGF-C and VEGFR-3 expression in the time-dependent manner but also enhanced proteasome activity, MKP5 and VE-cadherin degradation, p38 MAPK activation, and lymphatic vessel hyperpermeability. Moreover, VEGFR-3 knockdown significantly inhibited cardiac lymphangiogenesis in mice, resulting in exacerbation of tissue edema, hypertrophy, fibrosis superoxide production, inflammation, and heart failure (HF). Conversely, administration of epoxomicin (a selective proteasome inhibitor) markedly mitigated Ang II-induced cardiac edema, remodeling, and dysfunction; upregulated MKP5 and VE-cadherin expression; inactivated p38 MAPK; and reduced lymphatic vessel hyperpermeability in WT mice, indicating that inhibition of proteasome activity is required to maintain lymphatic endothelial cell (LEC) integrity. Our results show that both cardiac lymphangiogenesis and lymphatic barrier hyperpermeability are implicated in Ang II-induced adaptive hypertrophic remodeling and dysfunction. Proteasome-mediated hyperpermeability of LEC junctions plays a predominant role in the development of cardiac remodeling. Selective stimulation of lymphangiogenesis or inhibition of proteasome activity may be a potential therapeutic option for treating hypertension-induced cardiac remodeling.
Assuntos
Angiotensina II/metabolismo , Cardiomegalia/metabolismo , Edema Cardíaco/metabolismo , Vasos Linfáticos/metabolismo , Angiotensina II/administração & dosagem , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Edema Cardíaco/tratamento farmacológico , Edema Cardíaco/patologia , Edema Cardíaco/fisiopatologia , Células Endoteliais/metabolismo , Linfangiogênese/efeitos dos fármacos , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Permeabilidade/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Doxorubicin (Dox), an effective antineoplastic drug, was limited use for cardiotoxicity. Xinshuitong Capsule (XST), a patented herbal formula, showed desirable beneficial effects in the treatment of chronic heart failure (CHF) patients. However, the drug on Dox-induced cardiotoxicity remains unclear. Ninety male Sprague-Dawley rats were randomized into two groups: 15 rats were selected as the normal group and 75 rats were injected intraperitoneally with Dox to establish CHF rat models, the success ones were randomly divided into five groups: low XST (LXST), medium XST (MXST) or high XST (HXST) (4.9, 9.8, or 19.6 g/kg d) administrated intragastrically twice a day for 4 weeks, with the captopril-treated group and the model group as comparison. The model group showed the cardiac functions generally impaired, and CHF mortality rate higher (47%) than those in the XST-treated groups (averaged 24%, P < 0.05). Compared with XST-treated groups, myocardial remodeling, inflammation and desarcomerization, and higher water content more severe in the cardiac tissue in the model group (P < 0.05), which was associated with higher expressions of mRNA or protein levels of AQP1, 4 and 7. Dox-impaired cardiac functions, cardiac remodeling and myocardial edema could be dose-dependently reverted by XST treatment. XST could inhibit AQP1, 4 and 7 at mRNA levels or at protein levels, which was associated with the attenuation of myocardial edema and cardiac remodeling, decreasing the ventricular stiffness and improving the cardiac functions and rats' survival. AQPs is involved in cardiac edema composed one of the mechanisms of Dox-induced cardiotoxicity, XSTvia inhibition of AQPs relieved the Dox-induced side effects.
Assuntos
Aquaporinas/antagonistas & inibidores , Medicamentos de Ervas Chinesas/farmacologia , Edema Cardíaco/prevenção & controle , Insuficiência Cardíaca/prevenção & controle , Miocárdio/metabolismo , Administração Oral , Animais , Aquaporina 1/antagonistas & inibidores , Aquaporina 1/genética , Aquaporina 1/metabolismo , Aquaporina 4/antagonistas & inibidores , Aquaporina 4/genética , Aquaporina 4/metabolismo , Aquaporinas/genética , Aquaporinas/metabolismo , Água Corporal/metabolismo , Cápsulas , Cardiotoxicidade , Doença Crônica , Modelos Animais de Doenças , Doxorrubicina , Medicamentos de Ervas Chinesas/administração & dosagem , Edema Cardíaco/induzido quimicamente , Edema Cardíaco/metabolismo , Edema Cardíaco/patologia , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Masculino , Miocárdio/patologia , Ratos Sprague-Dawley , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the long-QT syndrome type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. LQT3 was induced with sea anemone toxin (ATXII) in Langendorff-perfused guinea pig hearts (n = 34). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel ß1-subunit adhesion domain antagonist (ßadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and ßadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, to our knowledge, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by means of managing sodium levels and preventing cardiac edema in patients.NEW & NOTEWORTHY This is the first study to demonstrate that the long-QT syndrome type 3 (LQT3) phenotype can be exacerbated or concealed by regulating extracellular sodium concentrations and/or the intercalated disc separation. The animal experiments and computational modeling in the current study reveal a critically important clinical implication: sodium dysregulation in the presence of edema within the intercalated disc can markedly increase the risk of arrhythmia in LQT3. These findings strongly suggest that maintaining extracellular sodium within normal physiological limits may be an effective and inexpensive therapeutic option for patients with congenital or acquired sodium channel gain-of-function diseases.
Assuntos
Potenciais de Ação , Edema Cardíaco/complicações , Edema Cardíaco/metabolismo , Frequência Cardíaca , Hipernatremia/sangue , Hipernatremia/complicações , Síndrome do QT Longo/metabolismo , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Sódio/sangue , Animais , Venenos de Cnidários , Simulação por Computador , Modelos Animais de Doenças , Edema Cardíaco/patologia , Edema Cardíaco/fisiopatologia , Cobaias , Hipernatremia/fisiopatologia , Preparação de Coração Isolado , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/fisiopatologia , Masculino , Modelos Cardiovasculares , Miócitos Cardíacos/patologiaRESUMO
We reported the involvement of oxidative stress and prostaglandins including thromboxane and prostacyclin in pre-cardiac edema (early edema) caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While the involvement of oxidative stress in TCDD-induced toxicity has been frequently reported, the mechanism of its action is still unclear. In the present study, oxidative stress inducers including paraquat, hydrogen peroxide (H2O2) and rotenone augmented early edema (edema) induced by a low concentration of TCDD (0.1 ppb) at 55 hr post fertilization (hpf), while each of them alone did not cause edema. Edema caused by TCDD plus oxidative stress inducers was almost abolished by antioxidants, an antagonist for thromboxane receptor (ICI-192,605) and an agonist for prostacyclin receptor (beraprost), suggesting that the site of action of these inducers was in the regular signaling pathway after activation of aryl hydrocarbon receptor type 2 (AHR2) by TCDD. Oxidative stress inducers also enhanced edema caused by an agonist for the thromboxane receptor (U46619), and the enhancement was also inhibited by antioxidants. Sulforaphane and auranofin, activators of Nrf2 that is a master regulator of anti-oxidative response, did not affect U46619-evoked edema but almost abolished TCDD-induced edema and potentiation by paraquat in both TCDD- and U46619-induced edema. Taken together, the results suggest that oxidative stress augments pre-cardiac edema caused by TCDD via activation of thromboxane receptor-mediated signaling in developing zebrafish. As paraquat and other oxidative stress inducers used also are environmental pollutants, interaction between dioxin-like compounds and exogenous source of oxidative stress should also be considered.
Assuntos
Dibenzodioxinas Policloradas , Peixe-Zebra , Animais , Edema Cardíaco/metabolismo , Edema Cardíaco/veterinária , Embrião não Mamífero/metabolismo , Peróxido de Hidrogênio/metabolismo , Larva/metabolismo , Estresse Oxidativo , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Proteínas de Peixe-Zebra/metabolismoRESUMO
Stress cardiomyopathy (SC) is an increasingly recognized form of acute heart failure, which has been linked to a wide variety of emotional and physical triggers. The pathophysiological mechanisms of the disease remain incompletely understood, however, inflammation has been recently shown to play a pivotal role. This review summarizes the most notable findings of myocardial inflammation, demonstrated from biopsies and cardiac magnetic resonance imaging in humans. In the acute stage macrophage infiltration appears to represent the substrate for myocardial edema, together defining the local myocardial inflammation. This appears to evolve into a low grade systemic chronic inflammation which could explain the protracted clinical course of these patients and raises hope for finding a specific SC cardiac biomarker as well as a therapeutic breakthrough. As a parallel to the human findings the review covers some of the emerging mechanistic insights from experimental models, which, albeit not proven in the human condition, highlight the possible importance in pursuing distinct paths of investigation such as the beta-receptor signaling, aberrations of nitric oxide generation and signaling and the contribution of the vascular endothelium/permeability to edema and inflammation during the acute stage.
Assuntos
Edema Cardíaco , Miocardite , Cardiomiopatia de Takotsubo , Animais , Biópsia , Edema Cardíaco/diagnóstico por imagem , Edema Cardíaco/metabolismo , Edema Cardíaco/patologia , Edema Cardíaco/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Imageamento por Ressonância Magnética , Miocardite/diagnóstico por imagem , Miocardite/metabolismo , Miocardite/patologia , Miocardite/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Transdução de Sinais , Cardiomiopatia de Takotsubo/diagnóstico por imagem , Cardiomiopatia de Takotsubo/metabolismo , Cardiomiopatia de Takotsubo/patologia , Cardiomiopatia de Takotsubo/fisiopatologiaRESUMO
Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and hypertension. The aim of this study was to establish a murine model of myocardial edema and elucidate the response of cardiac lymphatics and the myocardium. Myocardial edema without infarction was induced in mice by cauterizing the coronary sinus, increasing pressure in the coronary venous system, and inducing myocardial edema. In male mice, there was rapid development of edema 3 h following coronary sinus cauterization (CSC), with associated dilation of cardiac lymphatics. By 24 h, males displayed significant cardiovascular contractile dysfunction. In contrast, female mice exhibited a temporal delay in the formation of myocardial edema, with onset of cardiovascular dysfunction by 24 h. Furthermore, myocardial edema induced a ring of fibrosis around the epicardial surface of the left ventricle in both sexes that included fibroblasts, immune cells, and increased lymphatics. Interestingly, the pattern of fibrosis and the cells that make up the fibrotic epicardial ring differ between sexes. We conclude that a novel surgical model of myocardial edema without infarct was established in mice. Cardiac lymphatics compensated by exhibiting both an acute dilatory and chronic growth response. Transient myocardial edema was sufficient to induce a robust epicardial fibrotic and inflammatory response, with distinct sex differences, which underscores the sex-dependent differences that exist in cardiac vascular physiology.NEW & NOTEWORTHY Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and high blood pressure. Cardiac lymphatics regulate interstitial fluid balance and, in a myocardial infarction model, have been shown to be therapeutically targetable by increasing heart function. Cardiac lymphatics have only rarely been studied in a noninfarct setting in the heart, and so we characterized the first murine model of increased coronary sinus pressure to induce myocardial edema, demonstrating distinct sex differences in the response to myocardial edema. The temporal pattern of myocardial edema induction and resolution is different between males and females, underscoring sex-dependent differences in the response to myocardial edema. This model provides an important platform for future research in cardiovascular and lymphatic fields with the potential to develop therapeutic interventions for many common cardiovascular diseases.
Assuntos
Seio Coronário/cirurgia , Modelos Animais de Doenças , Edema Cardíaco/patologia , Animais , Pressão Sanguínea , Cauterização/efeitos adversos , Seio Coronário/patologia , Edema Cardíaco/etiologia , Edema Cardíaco/metabolismo , Feminino , Fibrose , Vasos Linfáticos/patologia , Vasos Linfáticos/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pericárdio/patologiaRESUMO
AIMS: Safe and effective decongestion is the main goal of therapy in acute heart failure (AHF). In the non-randomized, prospective TARGET-1 and TARGET-2 studies (NCT03897842), we investigated whether adding the Reprieve System® (which continuously monitors urine output and delivers a matched volume of hydration fluid sufficient to maintain the set fluid balance rate) to standard diuretic-based regimen improves decongestion in AHF. METHODS AND RESULTS: The population consisted of 19 patients hospitalized with AHF (mean age 67 ± 10 years, 18 male, ejection fraction 34 ± 15%, median N-terminal pro-B-type natriuretic peptide 4492 pg/mL). Patients served as their own controls: each patient underwent 24 h of standard diuretic therapy followed by 24 h of diuretics with Reprieve therapy (with normal saline used for matched volume replacement). The primary efficacy endpoint of actual fluid loss not exceeding the target fluid loss at the end of therapy was met in all 19 (100%) patients. The mean diuresis during Reprieve therapy was 6284 ± 2679 mL (vs. 1966 ± 1057 mL 24 h before therapy) and 2053 ± 888 mL (24 h after therapy) (both P < 0.0001). At the end of therapy, patient global assessment improved from 7.7 ± 1.1 to 3.0 ± 1.3 points (P < 0.001), central venous pressure decreased from 15.5 ± 5.3 mmHg to 12.8 ± 4.8 mmHg (P < 0.05) and the median urine sodium loss was 9.7 [3-13] mmol/h. The Reprieve therapy was safe, systolic blood pressure remained stable, mean creatinine dropped from 1.45 ± 0.4 mg/dL to 1.26 ± 0.4 mg/dL (P < 0.001) and biomarkers of renal injury did not change during treatment. CONCLUSIONS: The Reprieve System in conjunction with diuretic therapy supports safe and controlled decongestion in AHF.
Assuntos
Diuréticos/uso terapêutico , Edema Cardíaco/terapia , Hidratação/instrumentação , Furosemida/uso terapêutico , Insuficiência Cardíaca/terapia , Equilíbrio Hidroeletrolítico , Doença Aguda , Idoso , Pressão Venosa Central , Creatinina/metabolismo , Edema Cardíaco/metabolismo , Equipamentos e Provisões , Feminino , Hidratação/métodos , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Solução Salina/uso terapêutico , UrinaRESUMO
RATIONALE: Cardiac lymphangiogenesis contributes to the reparative process post-myocardial infarction, but the factors and mechanisms regulating it are not well understood. OBJECTIVE: To determine if epicardial-secreted factor AM (adrenomedullin; Adm=gene) improves cardiac lymphangiogenesis post-myocardial infarction via lateralization of Cx43 (connexin 43) in cardiac lymphatic vasculature. METHODS AND RESULTS: Firstly, we identified sex-dependent differences in cardiac lymphatic numbers in uninjured mice using light-sheet microscopy. Using a mouse model of Adm hi/hi ( Adm overexpression) and permanent left anterior descending ligation to induce myocardial infarction, we investigated cardiac lymphatic structure, growth, and function in injured murine hearts. Overexpression of Adm increased lymphangiogenesis and cardiac function post-myocardial infarction while suppressing cardiac edema and correlated with changes in Cx43 localization. Lymphatic function in response to AM treatment was attenuated in mice with a lymphatic-specific Cx43 deletion. In vitro experiments in cultured human lymphatic endothelial cells identified a novel mechanism to improve gap junction coupling by pharmaceutically targeting Cx43 with verapamil. Finally, we show that connexin protein expression in cardiac lymphatics is conserved between mouse and human. CONCLUSIONS: AM is an endogenous, epicardial-derived factor that drives reparative cardiac lymphangiogenesis and function via Cx43, and this represents a new therapeutic pathway for improving myocardial edema after injury.
Assuntos
Adrenomedulina/metabolismo , Conexina 43/metabolismo , Edema Cardíaco/metabolismo , Linfangiogênese , Vasos Linfáticos/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Pericárdio/metabolismo , Adrenomedulina/genética , Animais , Células Cultivadas , Conexina 43/genética , Modelos Animais de Doenças , Edema Cardíaco/genética , Edema Cardíaco/fisiopatologia , Edema Cardíaco/prevenção & controle , Feminino , Junções Comunicantes/metabolismo , Humanos , Vasos Linfáticos/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Pericárdio/fisiopatologia , Transdução de Sinais , Função Ventricular EsquerdaRESUMO
OBJECTIVES: This study sought to characterize the course of decongestion among patients hospitalized for acute heart failure (AHF) by history of atrial fibrillation (AF) and/or atrial flutter (AFL). BACKGROUND: AF/AFL and chronic heart failure (HF) commonly coexist. Little is known regarding the impact of AF/AFL on relief of congestion among patients who develop AHF. METHODS: We pooled patients from 3 randomized trials of AHF conducted within the Heart Failure Network, the DOSE (Diuretic Optimization Strategies) trial, the ROSE (Renal Optimization Strategies) trial, and the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial. The association between history of AF/AFL and in-hospital changes in various metrics of congestion was assessed using covariate-adjusted linear and ordinal logistic regression models. RESULTS: Of 750 unique patients, 418 (56%) had a history of AF/AFL. Left ventricular ejection fraction was higher (35% vs. 27%, respectively; p < 0.001), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were nonsignificantly lower at baseline (4,210 pg/ml vs. 5,037 pg/ml, respectively; p = 0.27) in patients with AF/AFL. After adjustment of covariates, history of AF/AFL was associated with less substantial loss of weight (-5.7% vs. -6.5%, respectively; p = 0.02) and decrease in NT-proBNP levels (-18.7% vs. -31.3%, respectively; p = 0.003) by 72 or 96 h. History of AF/AFL was also associated with a blunted increase in global sense of well being at 72 or 96 h (p = 0.04). There was no association between history of AF/AFL and change in orthodema congestion score (p = 0.67) or 60-day composite clinical endpoint (all-cause mortality or any rehospitalization; hazard ratio: 1.21; 95% confidence interval: 0.92 to 1.59; p = 0.17). CONCLUSIONS: More than half of the patients admitted with AHF had a history of AF/AFL. History of AF/AFL was independently associated with a blunted course of in-hospital decongestion. Further research is required to understand the utility of specific therapies targeting AF/AFL during hospitalization for AHF.
Assuntos
Fibrilação Atrial/epidemiologia , Flutter Atrial/epidemiologia , Diuréticos/uso terapêutico , Edema Cardíaco/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Cardiotônicos/uso terapêutico , Comorbidade , Dopamina/uso terapêutico , Dispneia/fisiopatologia , Edema Cardíaco/epidemiologia , Edema Cardíaco/metabolismo , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Natriuréticos/uso terapêutico , Peptídeo Natriurético Encefálico/metabolismo , Peptídeo Natriurético Encefálico/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Volume Sistólico , Resultado do TratamentoRESUMO
Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.
Assuntos
Músculo Esquelético/metabolismo , Doenças Musculares/genética , Doenças Musculares/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Oxo-Ácido-Liases/genética , Oxo-Ácido-Liases/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Edema Cardíaco/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Células HEK293 , Hexosaminas/metabolismo , Humanos , Masculino , Músculo Esquelético/crescimento & desenvolvimento , Doenças Musculares/fisiopatologia , Mutação , Oxo-Ácido-Liases/uso terapêutico , Doença do Armazenamento de Ácido Siálico/metabolismo , Adulto Jovem , Peixe-Zebra/embriologiaRESUMO
Oxidative stress plays a critical task in the biochemical and pathological alteration linked with myocardial ischemic-reperfusion injury (IRI). This warrants identifying agents with a potential for preventing such damage in an effective way. A novel plant based product, Pycnogenol, obtained from the French maritime pine (Pinus pinaster ssp. atlantica) bark extract was known for its tremendous antioxidant potential (both in vivo, in vitro). It was able to attenuate the symptoms of immune dysfunction through restoring a cellular antioxidant status in low micronutrient-induced immune deficient mice. Consequently, the present study was deals with the determination of protective effect of Pycnogenol in ischemic-reperfusion injury (IRI) in rats via Non-recirculating Langendorff's technique. The effect of Pycnogenol on the level of various key biomarkers in the rat heart homogenate was determined, such as, myocardial thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation), lactic dehydrogenase (LDH) (a marker of tissue injury) and effect on endogenous antioxidants, e.g., superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx). The activity of these biomarkers appreciably improved in Pycnogenol-treated group than IRI group (P < 0.05). The effect of Pycnogenol was further confirmed via histopathological examination of cardiac tissues, which suggests that, it considerably improved the injury related to tissue damage through suppression of edema and infiltration of neutrophil compared to IRI group. It also showed modulation of the expression of apoptotic factors, e.g. Bcl-2, bax and caspase-9 as confirmed by western blot analysis.
Assuntos
Cardiotônicos/farmacologia , Flavonoides/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Biomarcadores Farmacológicos/análise , Cardiotônicos/uso terapêutico , Edema Cardíaco/tratamento farmacológico , Edema Cardíaco/metabolismo , Flavonoides/uso terapêutico , Preparação de Coração Isolado , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Ratos , Ratos WistarRESUMO
BACKGROUND: Following myocardial infarction (MI), peri-infarct myocardial edema formation further impairs cardiac function. Extracellular RNA (eRNA) released from injured cells strongly increases vascular permeability. This study aimed to assess the role of eRNA in MI-induced cardiac edema formation, infarct size, cardiac function, and survival after acute MI and to evaluate the therapeutic potential of ribonuclease 1 (RNase-1) treatment as an eRNA-degrading intervention. METHODS AND RESULTS: C57BL/6J mice were subjected to MI by permanent ligation of the left anterior descending coronary artery. Plasma eRNA levels were significantly increased compared with those in controls starting from 30 minutes after ligation. Systemic application of RNase-1, but not DNase, significantly reduced myocardial edema formation 24 hours after ligation compared with controls. Consequently, eRNA degradation by RNase-1 significantly improved the perfusion of collateral arteries in the border zone of the infarcted myocardium 24 hours after ligation of the left anterior descending coronary artery, as detected by micro-computed tomography imaging. Although there was no significant difference in the area at risk, the area of vital myocardium was markedly larger in mice treated with RNase-1 compared with controls, as detected by Evans blue and 2,3,5-triphenyltetrazolium chloride staining. The increase in viable myocardium was associated with significantly preserved left ventricular function, as assessed by echocardiography. Moreover, RNase-1 significantly improved 8-week survival following MI. CONCLUSIONS: eRNA is an unrecognized permeability factor in vivo, associated with myocardial edema formation after acute MI. RNase-1 counteracts eRNA-induced edema formation and preserves perfusion of the infarction border zone, reducing infarct size and protecting cardiac function after MI.
Assuntos
Fármacos Cardiovasculares/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Estabilidade de RNA , RNA/metabolismo , Ribonuclease Pancreático/farmacologia , Animais , Apoptose/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Modelos Animais de Doenças , Edema Cardíaco/genética , Edema Cardíaco/metabolismo , Edema Cardíaco/patologia , Edema Cardíaco/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , RNA/genética , Fatores de Tempo , Sobrevivência de Tecidos/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
BACKGROUND: Several T2-mapping sequences have been recently proposed to quantify myocardial edema by providing T2 relaxation time values. However, no T2-mapping sequence has ever been validated against actual myocardial water content for edema detection. In addition, these T2-mapping sequences are either time-consuming or require specialized software for data acquisition and/or post-processing, factors impeding their routine clinical use. Our objective was to obtain in vivo validation of a sequence for fast and accurate myocardial T2-mapping (T2 gradient-spin-echo [GraSE]) that can be easily integrated in routine protocols. METHODS: The study population comprised 25 pigs. Closed-chest 40 min ischemia/reperfusion was performed in 20 pigs. Pigs were sacrificed at 120 min (n = 5), 24 h (n = 5), 4 days (n = 5) and 7 days (n = 5) after reperfusion, and heart tissue extracted for quantification of myocardial water content. For the evaluation of T2 relaxation time, cardiovascular magnetic resonance (CMR) scans, including T2 turbo-spin-echo (T2-TSE, reference standard) mapping and T2-GraSE mapping, were performed at baseline and at every follow-up until sacrifice. Five additional pigs were sacrificed after baseline CMR study and served as controls. RESULTS: Acquisition of T2-GraSE mapping was significantly (3-fold) faster than conventional T2-TSE mapping. Myocardial T2 relaxation measurements performed by T2-TSE and T2-GraSE mapping demonstrated an almost perfect correlation (R(2) = 0.99) and agreement with no systematic error between techniques. The two T2-mapping sequences showed similarly good correlations with myocardial water content: R(2) = 0.75 and R(2) = 0.73 for T2-TSE and T2-GraSE mapping, respectively. CONCLUSIONS: We present the first in vivo validation of T2-mapping to assess myocardial edema. Given its shorter acquisition time and no requirement for specific software for data acquisition or post-processing, fast T2-GraSE mapping of the myocardium offers an attractive alternative to current CMR sequences for T2 quantification.
Assuntos
Edema Cardíaco/patologia , Imagem Cinética por Ressonância Magnética/métodos , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Animais , Água Corporal/metabolismo , Modelos Animais de Doenças , Edema Cardíaco/metabolismo , Interpretação de Imagem Assistida por Computador , Masculino , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Suínos , Fatores de TempoRESUMO
BACKGROUND: Both intrinsic contrast (T1 and T2 relaxation and the equilibrium magnetization) and contrast agent (gadolinium)-enhanced MRI are used to visualize and evaluate acute radiofrequency ablation lesions. However, current methods are imprecise in delineating lesion extent shortly after the ablation. METHODS AND RESULTS: Fifteen lesions were created in the endocardium of 13 pigs. A multicontrast inversion recovery steady state free precession imaging method was used to delineate the acute ablation lesions, exploiting T1-weighted contrast. T2 and Mo(*) maps were also created from fast spin echo data in a subset of pigs (n=5) to help characterize the change in intrinsic contrast in the lesions. Gross pathology was used as reference for the lesion size comparison, and the lesion structures were confirmed with histological data. In addition, a colorimetric iron assay was used to measure ferric and ferrous iron content in the lesions and the healthy myocardium in a subset of pigs (n=2). The lesion sizes measured in inversion recovery steady state free precession images were highly correlated with the extent of lesion core identified in gross pathology. Magnetic resonance relaxometry showed that the radiofrequency ablation procedure changes the intrinsic T1 value in the lesion core and the intrinsic T2 in the edematous region. Furthermore, the T1 shortening appeared to be correlated with the presence of ferric iron, which may have been associated with metmyoglobin and methemoglobin in the lesions. CONCLUSIONS: The study suggests that T1 contrast may be able to separate necrotic cores from the surrounding edematous rims in acute radiofrequency ablation lesions.
Assuntos
Ablação por Cateter , Edema Cardíaco/patologia , Ventrículos do Coração/patologia , Ventrículos do Coração/cirurgia , Imageamento por Ressonância Magnética , Animais , Meios de Contraste , Edema Cardíaco/metabolismo , Gadolínio DTPA , Ventrículos do Coração/metabolismo , Ferro/metabolismo , Modelos Animais , Necrose , Valor Preditivo dos Testes , Suínos , Fatores de TempoRESUMO
BACKGROUND/AIMS: Most cardiac procedures involve the use of cardiopulmonary bypass (CPB), which pumps oxygenated blood to the body while the heart and lungs are isolated. CPB can cause profound alterations V in the homeostasis of physiological fluids, which often results in myocardial edema. In our study, we used sheep CPB model of in vivo and in vitro to assess the relationship between cGMP and AQP1 during CPB. METHODS: ODQ, a specific inhibitor of soluble guanylate cyclase (sGC), was used to treat the CPB animals or cardiomyocytes. Left ventricular function of each group was determined by pressure-volume system. Water content of myocardial tissue was assessed by dry-wet weight, and cardiomyocytes water permeability was also calculated. The concentration of cGMP was determined by Radioimmunoassay (RIA). mRNA and protein expression of AQP1 were detected by real-time PCR and western blot, respectively. RESULTS: The relative expression level of AQP1 mRNA and protein at each time point (0, 6, 12, 24 or 48 h) after CPB was significantly increased (1.18-fold at 12 h, 1.77-fold at 24 h and 2.18-fold at 48h) compared with each sham group, the protein expression of AQP1 also showed a rising trend after CPB. The degree of myocardial edema (75.1% at 12 h, 79.3% at 24 h and 81.0% at 48h) increased following the CPB surgery. The mRNA expression level of AQP1 was significantly decreased by 39.7% (p<0.01) upon treatment with ODQ compared with the CPB-only group, and inhibition of cGMP pathway also can significantly decrease the degree of myocardial edema (84.7% in control group, while 75.2% in ODQ group) and improve cardiac function in sheep after CPB. Results of in vitro experiments showed the same changing trends as in vivo. CONCLUSION: cGMP pathway controls water channels and then affects water intake during CPB through an AQP1-mediated pathway.
Assuntos
Aquaporina 1/fisiologia , Ponte Cardiopulmonar/efeitos adversos , GMP Cíclico/metabolismo , Edema Cardíaco/etiologia , Animais , Aquaporina 1/genética , GMP Cíclico/antagonistas & inibidores , Edema Cardíaco/metabolismo , Feminino , Miócitos Cardíacos/metabolismo , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Carneiro DomésticoRESUMO
BACKGROUND: Clinically, donor hearts cannot be preserved for >6 hours between explantation and recipient implantation. A better approach is needed to preserve donor hearts for a longer time. We tested whether low-flow perfusion (LFP) could satisfactorily preserve isolated rat hearts with histidine-tryptophan-ketoglutarate (HTK) solution or Fuwai modified (FWM) solution. METHODS: We divided 32 male Sprague-Dawley rats randomly into 4 groups (n = 8): H1, H2, F1, and F2. The Langendorff heart model immersed isolated hearts in the H1 and F1 groups in HTK or FWM solution for 8 hours at 4 °C. Isolated hearts in the H2 and F2 groups were low-flow perfused with HTK solution and FWM solution for 8 hours at a pressure of 10 cmH(2)O at 4 °C. After 60 minutes reperfusion, we measured recovery of cardiac function, myocardial water content, and leakage of myocardial enzymes. RESULTS: After reperfusion, no cardiac rebeating was observed among F1 group hearts; in addition, they showed significantly higher myocardial water content and lactate dehydrogenase leakage compared with the other 3 groups (P < .05). The recovery rates of cardiac function among H2 hearts were better than the other 3 groups (P < .05); their myocardial water content and enzyme leakage were less than the other 3 groups (P < .05). CONCLUSIONS: Hypothermic LFP was better than static storage to preserve isolated rat hearts. HTK solution afforded better myocardial protection than FWM.
Assuntos
Coração/efeitos dos fármacos , Preservação de Órgãos/métodos , Perfusão , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Temperatura Baixa , Edema Cardíaco/etiologia , Edema Cardíaco/metabolismo , Edema Cardíaco/prevenção & controle , Glucose/farmacologia , Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Masculino , Manitol/farmacologia , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Preservação de Órgãos/efeitos adversos , Perfusão/efeitos adversos , Cloreto de Potássio/farmacologia , Procaína/farmacologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Fatores de Tempo , Pressão Ventricular/efeitos dos fármacosRESUMO
Myocardial stunning, which is closely related to myocardial edema, is a severe complication that may occur following cardiac surgery. In this study, we examined the expression of aquaporin 1 (AQP1) and Connexin 43 (Cx43) following cardiopulmonary bypass (CPB) surgery in goats. We assessed myocardial muscle tissue water content according to changes in dry-wet weight. Our results showed that AQP1 expression and myocardial muscle tissue water content increased significantly 6 h after CPB surgery, reaching peak levels 48 h after surgery; additionally, the protein expression of Cx43 was inversely correlated with AQP1 expression. Overexpression of AQP1 during CPB surgery enhanced the degree of myocardial edema, whereas the addition of water channel protein inhibitor Hg2+ in cold crystalloid cardioplegia and knockdown of AQP1 during surgery weakened the degree of myocardial edema. These findings revealed that the severity of myocardial edema after CPB surgery is correlated with AQP1 protein expression levels, suggesting the important role played by AQP1 protein in the regulation of Cx43 in the pathological progression of myocardial edema.
Assuntos
Aquaporina 1/metabolismo , Ponte Cardiopulmonar/efeitos adversos , Conexina 43/metabolismo , Edema Cardíaco/metabolismo , Animais , Aquaporina 1/antagonistas & inibidores , Aquaporina 1/genética , Soluções Cardioplégicas , Edema Cardíaco/etiologia , Cabras , Ventrículos do Coração/metabolismo , Mercúrio/farmacologia , Miocárdio/metabolismo , ÁguaRESUMO
Myocardial edema can arise in several disease states. MRI contrast agent can accumulate in edematous tissue, which complicates differential diagnosis with contrast-enhanced (CE)-MRI and might lead to overestimation of infarct size. Sodium Chemical Shift Imaging ((23)Na-CSI) may provide an alternative for edema imaging. We have developed a non-infarct, isolated rat heart model with two levels of edema, which was studied with (23)Na-CSI and CE-MRI. In edematous, but viable tissue the extracellular sodium (Na (e) (+)) signal is hypothesized to increase, but not the intracellular sodium (Na (i) (+)) signal. Isolated hearts were perfused at 60 (n = 6) and 140 mmHg (n = 5). Dimethyl methylphosphonate (DMMP) and phenylphosphonate (PPA) were used to follow edema formation by (31)P-MR Spectroscopy. In separate groups, Thulium(III)1,4,7,10 tetraazacyclododecane-N,N',Nâ³,N'''-tetra(methylenephosphonate) (TmDOTP(5-)) and Gadovist were used for (23)Na-CSI (n = 8) and CE-MRI (n = 6), respectively. PPA normalized signal intensity (SI) was higher at 140 versus 60 mmHg, with a ratio of 1.27 ± 0.12 (p < 0.05). The (DMMP-PPA)/dry weight ratio, as a marker of intracellular volume, remained unchanged. The mid-heart cross sectional area (CSA) of the left ventricle (LV) was significantly increased at 140 mmHg. In addition, at 140 mmHg, the LV Na (e) (+) SI increased with a 140 mmHg/60 mmHg ratio of 1.24 ± 0.18 (p < 0.05). Na (i) (+) SI remained essentially unchanged. With CE-MRI, a subendocardially enhanced CSA was identified, increasing from 0.20 ± 0.02 cm(2) at 60 mmHg to 0.31 ± 0.02 cm(2) at 140 mmHg (p < 0.05). Edema shows up in both CE-MRI and Na (e) (+) . High perfusion pressure causes more edema subendocardially than subepicardially. (23)Na-CSI is an attractive alternative for imaging of edema and is a promising tool to discriminate between edema, acute and chronic MI.
Assuntos
Meios de Contraste , Edema Cardíaco/diagnóstico , Imageamento por Ressonância Magnética , Miocárdio/patologia , Compostos Organometálicos , Compostos Organofosforados , Isótopos de Sódio , Animais , Diagnóstico Diferencial , Edema Cardíaco/metabolismo , Edema Cardíaco/patologia , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Perfusão , Valor Preditivo dos Testes , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Treatment with glutamine has been shown to reduce myocardial damage associated with ischemia/reperfusion injury. However, the cardioprotective effect of glutamine specifically after burn injury remains unclear. The present study explores the ability of glutamine to protect against myocardial damage in rats that have been severely burned. Seventy-two Wistar rats were randomly divided into three groups: normal controls (C), burned controls (B) and a glutamine-treated group (G). Groups B and G were subjected to full thickness burns comprising 30% of total body surface area. Group G was administered 1.5 g/ (kgâ¢d) glutamine and group B was given the same dose of alanine via intragastric administration for 3 days. Levels of serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST) and blood lactic acid were measured, as well as myocardial ATP and glutathione (GSH) contents. Cardiac function indices and histopathological changes were analyzed at 12, 24, 48 and 72 post-burn hours. In both burned groups, levels of serum CK, LDH, AST and blood lactic acid increased significantly, while myocardial ATP and GSH contents decreased. Compared with group B, CK, LDH, and AST levels were lower and blood lactic acid, myocardial ATP and GSH levels were higher in group G. Moreover, cardiac contractile function inhibition and myocardial histopathological damage were significantly reduced in group G compared to B. Taken together, these results show that glutamine supplementation protects myocardial structure and function after burn injury by improving energy metabolism and by promoted the synthesis of ATP and GSH in cardiac myocytes.
Assuntos
Queimaduras/tratamento farmacológico , Glutamina/farmacologia , Cardiopatias/tratamento farmacológico , Coração/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Trifosfato de Adenosina/biossíntese , Administração Oral , Animais , Aspartato Aminotransferases/sangue , Biomarcadores/metabolismo , Queimaduras/metabolismo , Queimaduras/patologia , Creatina Quinase Forma MB/sangue , Modelos Animais de Doenças , Edema Cardíaco/tratamento farmacológico , Edema Cardíaco/metabolismo , Edema Cardíaco/patologia , Glutamina/administração & dosagem , Glutationa/biossíntese , Coração/fisiopatologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Testes de Função Cardíaca , L-Lactato Desidrogenase/sangue , Ácido Láctico/sangue , Masculino , Contração Miocárdica , Miocárdio/química , Miocárdio/enzimologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Wistar , Água/análise , Água/metabolismoRESUMO
Myocardial edema occurs in a large number of myocardial pathologies particularly during ischemia-reperfusion, and may contribute to cell dysfunction and death occurring in these conditions. Cardiomyocyte cell volume is tightly regulated by modifications in cytosolic osmolality. Changes in membrane water permeability through aquaporin and connexin hemichannels also contribute to cell volume changes while caveolae may be important in sensing cell volume changes sensing and associated signaling. Ischemia-reperfusion alters these mechanisms and increases microvascular permeability by endothelial hypercontracture-induced gap formation, endothelial cell death and basal membrane disruption. Detection of myocardial edema by MRI has many useful diagnostic applications in acute myocardial infarction and other conditions. However, discrimination between intra and extracellular myocardial edema is presently difficult at the bench and impossible at the bedside. Developing methods to differentiate intra from extracellular myocardial water should allow a better understanding of the mechanisms and consequences of myocardial edema and, as a consequence lead to new diagnostic and therapeutic applications.