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1.
J Mol Cell Cardiol ; 195: 73-82, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39142438

RESUMEN

Sepsis-induced myocardial dysfunction (SIMD), also known as sepsis-induced cardiomyopathy (SICM), is linked to significantly increased mortality. Despite its clinical importance, effective therapies for SIMD remain elusive, largely due to an incomplete understanding of its pathogenesis. Over the past five decades, research involving both animal models and human studies has highlighted several pathogenic mechanisms of SICM, yet many aspects remain unexplored. Initially thought to be primarily driven by inflammatory cytokines, current research indicates that these alone are insufficient for the development of cardiac dysfunction. Recent studies have brought attention to additional mechanisms, including excessive nitric oxide production, mitochondrial dysfunction, and disturbances in calcium homeostasis, as contributing factors in SICM. Emerging clinical evidence has highlighted the significant role of myocardial edema in the pathogenesis of SICM, particularly its association with cardiac remodeling in septic shock patients. This review synthesizes our current understanding of SIMD/SICM, focusing on myocardial edema's contribution to cardiac dysfunction and the critical role of the bradykinin receptor B1 (B1R) in altering myocardial microvascular permeability, a potential key player in myocardial edema development during sepsis. Additionally, this review briefly summarizes existing therapeutic strategies and their challenges and explores future research directions. It emphasizes the need for a deeper understanding of SICM to develop more effective treatments.


Asunto(s)
Cardiomiopatías , Inflamación , Miocardio , Sepsis , Humanos , Sepsis/complicaciones , Sepsis/metabolismo , Animales , Miocardio/metabolismo , Miocardio/patología , Inflamación/metabolismo , Inflamación/patología , Cardiomiopatías/metabolismo , Cardiomiopatías/etiología , Edema/metabolismo , Edema/patología , Edema Cardíaco/metabolismo , Edema Cardíaco/etiología
2.
Oxid Med Cell Longev ; 2022: 5044046, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35222798

RESUMEN

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.


Asunto(s)
Angiotensina II/metabolismo , Cardiomegalia/metabolismo , Edema Cardíaco/metabolismo , Vasos Linfáticos/metabolismo , Angiotensina II/administración & dosificación , Animales , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Edema Cardíaco/tratamiento farmacológico , Edema Cardíaco/patología , Edema Cardíaco/fisiopatología , Células Endoteliales/metabolismo , Linfangiogénesis/efectos de los fármacos , Ratones , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Permeabilidad/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Receptor 3 de Factores de Crecimiento Endotelial Vascular/deficiencia , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo
3.
Am J Physiol Heart Circ Physiol ; 321(6): H1042-H1055, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34623182

RESUMEN

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.


Asunto(s)
Potenciales de Acción , Edema Cardíaco/complicaciones , Edema Cardíaco/metabolismo , Frecuencia Cardíaca , Hipernatremia/sangre , Hipernatremia/complicaciones , Síndrome de QT Prolongado/metabolismo , Miocitos Cardíacos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Sodio/sangre , Animales , Venenos de Cnidarios , Simulación por Computador , Modelos Animales de Enfermedad , Edema Cardíaco/patología , Edema Cardíaco/fisiopatología , Cobayas , Hipernatremia/fisiopatología , Preparación de Corazón Aislado , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Masculino , Modelos Cardiovasculares , Miocitos Cardíacos/patología
4.
Biomed Pharmacother ; 144: 112261, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34628163

RESUMEN

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.


Asunto(s)
Acuaporinas/antagonistas & inhibidores , Medicamentos Herbarios Chinos/farmacología , Edema Cardíaco/prevención & control , Insuficiencia Cardíaca/prevención & control , Miocardio/metabolismo , Administración Oral , Animales , Acuaporina 1/antagonistas & inhibidores , Acuaporina 1/genética , Acuaporina 1/metabolismo , Acuaporina 4/antagonistas & inhibidores , Acuaporina 4/genética , Acuaporina 4/metabolismo , Acuaporinas/genética , Acuaporinas/metabolismo , Agua Corporal/metabolismo , Cápsulas , Cardiotoxicidad , Enfermedad Crónica , Modelos Animales de Enfermedad , Doxorrubicina , Medicamentos Herbarios Chinos/administración & dosificación , Edema Cardíaco/inducido químicamente , Edema Cardíaco/metabolismo , Edema Cardíaco/patología , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Masculino , Miocardio/patología , Ratas Sprague-Dawley , Transducción de Señal , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos
5.
J Vet Med Sci ; 83(7): 1050-1058, 2021 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-34024870

RESUMEN

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.


Asunto(s)
Dibenzodioxinas Policloradas , Pez Cebra , Animales , Edema Cardíaco/metabolismo , Edema Cardíaco/veterinaria , Embrión no Mamífero/metabolismo , Peróxido de Hidrógeno/metabolismo , Larva/metabolismo , Estrés Oxidativo , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/metabolismo , Proteínas de Pez Cebra/metabolismo
6.
Trends Cardiovasc Med ; 31(4): 225-230, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-32276825

RESUMEN

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.


Asunto(s)
Edema Cardíaco , Miocarditis , Cardiomiopatía de Takotsubo , Animales , Biopsia , Edema Cardíaco/diagnóstico por imagen , Edema Cardíaco/metabolismo , Edema Cardíaco/patología , Edema Cardíaco/fisiopatología , Humanos , Mediadores de Inflamación/metabolismo , Imagen por Resonancia Magnética , Miocarditis/diagnóstico por imagen , Miocarditis/metabolismo , Miocarditis/patología , Miocarditis/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Transducción de Señal , Cardiomiopatía de Takotsubo/diagnóstico por imagen , Cardiomiopatía de Takotsubo/metabolismo , Cardiomiopatía de Takotsubo/patología , Cardiomiopatía de Takotsubo/fisiopatología
7.
Am J Physiol Heart Circ Physiol ; 318(4): H895-H907, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32142379

RESUMEN

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.


Asunto(s)
Seno Coronario/cirugía , Modelos Animales de Enfermedad , Edema Cardíaco/patología , Animales , Presión Sanguínea , Cauterización/efectos adversos , Seno Coronario/patología , Edema Cardíaco/etiología , Edema Cardíaco/metabolismo , Femenino , Fibrosis , Vasos Linfáticos/patología , Vasos Linfáticos/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Pericardio/patología
8.
Eur J Heart Fail ; 21(9): 1079-1087, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31127666

RESUMEN

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.


Asunto(s)
Diuréticos/uso terapéutico , Edema Cardíaco/terapia , Fluidoterapia/instrumentación , Furosemida/uso terapéutico , Insuficiencia Cardíaca/terapia , Equilibrio Hidroelectrolítico , Enfermedad Aguda , Anciano , Presión Venosa Central , Creatinina/metabolismo , Edema Cardíaco/metabolismo , Equipos y Suministros , Femenino , Fluidoterapia/métodos , Insuficiencia Cardíaca/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/metabolismo , Fragmentos de Péptidos/metabolismo , Solución Salina/uso terapéutico , Orina
9.
JACC Heart Fail ; 7(1): 47-55, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30409707

RESUMEN

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.


Asunto(s)
Fibrilación Atrial/epidemiología , Aleteo Atrial/epidemiología , Diuréticos/uso terapéutico , Edema Cardíaco/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Cardiotónicos/uso terapéutico , Comorbilidad , Dopamina/uso terapéutico , Disnea/fisiopatología , Edema Cardíaco/epidemiología , Edema Cardíaco/metabolismo , Femenino , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Humanos , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Natriuréticos/uso terapéutico , Péptido Natriurético Encefálico/metabolismo , Péptido Natriurético Encefálico/uso terapéutico , Fragmentos de Péptidos/metabolismo , Pronóstico , Modelos de Riesgos Proporcionales , Volumen Sistólico , Resultado del Tratamiento
10.
Circ Res ; 124(1): 101-113, 2019 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-30582443

RESUMEN

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.


Asunto(s)
Adrenomedulina/metabolismo , Conexina 43/metabolismo , Edema Cardíaco/metabolismo , Linfangiogénesis , Vasos Linfáticos/metabolismo , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Pericardio/metabolismo , Adrenomedulina/genética , Animales , Células Cultivadas , Conexina 43/genética , Modelos Animales de Enfermedad , Edema Cardíaco/genética , Edema Cardíaco/fisiopatología , Edema Cardíaco/prevención & control , Femenino , Uniones Comunicantes/metabolismo , Humanos , Vasos Linfáticos/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Infarto del Miocardio/genética , Infarto del Miocardio/fisiopatología , Pericardio/fisiopatología , Transducción de Señal , Función Ventricular Izquierda
11.
JCI Insight ; 3(24)2018 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-30568043

RESUMEN

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.


Asunto(s)
Músculo Esquelético/metabolismo , Enfermedades Musculares/genética , Enfermedades Musculares/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Oxo-Ácido-Liasas/genética , Oxo-Ácido-Liasas/metabolismo , Adulto , Animales , Modelos Animales de Enfermedad , Edema Cardíaco/metabolismo , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Células HEK293 , Hexosaminas/metabolismo , Humanos , Masculino , Músculo Esquelético/crecimiento & desarrollo , Enfermedades Musculares/fisiopatología , Mutación , Oxo-Ácido-Liasas/uso terapéutico , Enfermedad por Almacenamiento de Ácido Siálico/metabolismo , Adulto Joven , Pez Cebra/embriología
12.
Cell Mol Biol (Noisy-le-grand) ; 63(10): 49-53, 2017 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-29096743

RESUMEN

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.


Asunto(s)
Cardiotónicos/farmacología , Flavonoides/farmacología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Biomarcadores Farmacológicos/análisis , Cardiotónicos/uso terapéutico , Edema Cardíaco/tratamiento farmacológico , Edema Cardíaco/metabolismo , Flavonoides/uso terapéutico , Preparación de Corazón Aislado , Masculino , Infiltración Neutrófila/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Ratas , Ratas Wistar
13.
J Am Heart Assoc ; 6(6)2017 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-28637776

RESUMEN

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.


Asunto(s)
Fármacos Cardiovasculares/farmacología , Infarto del Miocardio/tratamiento farmacológico , Miocardio/metabolismo , Estabilidad del ARN , ARN/metabolismo , Ribonucleasa Pancreática/farmacología , Animales , Apoptosis/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Modelos Animales de Enfermedad , Edema Cardíaco/genética , Edema Cardíaco/metabolismo , Edema Cardíaco/patología , Edema Cardíaco/fisiopatología , Masculino , Ratones Endogámicos C57BL , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/patología , ARN/genética , Factores de Tiempo , Supervivencia Tisular/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos
14.
J Cardiovasc Magn Reson ; 17: 92, 2015 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-26538198

RESUMEN

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.


Asunto(s)
Edema Cardíaco/patología , Imagen por Resonancia Cinemagnética/métodos , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Animales , Agua Corporal/metabolismo , Modelos Animales de Enfermedad , Edema Cardíaco/metabolismo , Interpretación de Imagen Asistida por Computador , Masculino , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Porcinos , Factores de Tiempo
15.
Circ Arrhythm Electrophysiol ; 7(4): 718-27, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24988893

RESUMEN

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.


Asunto(s)
Ablación por Catéter , Edema Cardíaco/patología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/cirugía , Imagen por Resonancia Magnética , Animales , Medios de Contraste , Edema Cardíaco/metabolismo , Gadolinio DTPA , Ventrículos Cardíacos/metabolismo , Hierro/metabolismo , Modelos Animales , Necrosis , Valor Predictivo de las Pruebas , Porcinos , Factores de Tiempo
16.
Cell Physiol Biochem ; 32(5): 1320-30, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24280641

RESUMEN

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.


Asunto(s)
Acuaporina 1/fisiología , Puente Cardiopulmonar/efectos adversos , GMP Cíclico/metabolismo , Edema Cardíaco/etiología , Animales , Acuaporina 1/genética , GMP Cíclico/antagonistas & inhibidores , Edema Cardíaco/metabolismo , Femenino , Miocitos Cardíacos/metabolismo , Oxadiazoles/farmacología , Quinoxalinas/farmacología , Oveja Doméstica
17.
Transplant Proc ; 45(2): 523-7, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23498788

RESUMEN

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.


Asunto(s)
Corazón/efectos de los fármacos , Preservación de Órganos/métodos , Perfusión , Función Ventricular Izquierda/efectos de los fármacos , Animales , Frío , Edema Cardíaco/etiología , Edema Cardíaco/metabolismo , Edema Cardíaco/prevención & control , Glucosa/farmacología , Corazón/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , L-Lactato Deshidrogenasa/metabolismo , Masculino , Manitol/farmacología , Contracción Miocárdica/efectos de los fármacos , Miocardio/enzimología , Preservación de Órganos/efectos adversos , Perfusión/efectos adversos , Cloruro de Potasio/farmacología , Procaína/farmacología , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Factores de Tiempo , Presión Ventricular/efectos de los fármacos
18.
Int J Mol Med ; 31(3): 637-43, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23292298

RESUMEN

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.


Asunto(s)
Acuaporina 1/metabolismo , Puente Cardiopulmonar/efectos adversos , Conexina 43/metabolismo , Edema Cardíaco/metabolismo , Animales , Acuaporina 1/antagonistas & inhibidores , Acuaporina 1/genética , Soluciones Cardiopléjicas , Edema Cardíaco/etiología , Cabras , Ventrículos Cardíacos/metabolismo , Mercurio/farmacología , Miocardio/metabolismo , Agua
19.
Int J Cardiovasc Imaging ; 29(2): 343-54, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22790331

RESUMEN

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',N″,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.


Asunto(s)
Medios de Contraste , Edema Cardíaco/diagnóstico , Imagen por Resonancia Magnética , Miocardio/patología , Compuestos Organometálicos , Compuestos Organofosforados , Isótopos de Sodio , Animales , Diagnóstico Diferencial , Edema Cardíaco/metabolismo , Edema Cardíaco/patología , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Infarto del Miocardio/patología , Miocardio/metabolismo , Perfusión , Valor Predictivo de las Pruebas , Ratas , Ratas Wistar , Factores de Tiempo
20.
Int J Clin Exp Pathol ; 5(7): 651-9, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22977661

RESUMEN

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/ (kg•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.


Asunto(s)
Quemaduras/tratamiento farmacológico , Glutamina/farmacología , Cardiopatías/tratamiento farmacológico , Corazón/efectos de los fármacos , Sustancias Protectoras/farmacología , Adenosina Trifosfato/biosíntesis , Administración Oral , Animales , Aspartato Aminotransferasas/sangre , Biomarcadores/metabolismo , Quemaduras/metabolismo , Quemaduras/patología , Forma MB de la Creatina-Quinasa/sangre , Modelos Animales de Enfermedad , Edema Cardíaco/tratamiento farmacológico , Edema Cardíaco/metabolismo , Edema Cardíaco/patología , Glutamina/administración & dosificación , Glutatión/biosíntesis , Corazón/fisiopatología , Cardiopatías/metabolismo , Cardiopatías/patología , Pruebas de Función Cardíaca , L-Lactato Deshidrogenasa/sangre , Ácido Láctico/sangre , Masculino , Contracción Miocárdica , Miocardio/química , Miocardio/enzimología , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Sustancias Protectoras/administración & dosificación , Ratas , Ratas Wistar , Agua/análisis , Agua/metabolismo
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