Silencing suppressor of cytokine signaling 3 induces apoptosis and activates the p-STAT3/NF-κ B pathway in hypoxic cultivated H9c2 cells

Suppressor of cytokine signaling 3 (SOCS3) plays a significant role in the process of myocardial adaptation to chronic hypoxia. SOCS3 finely regulates cell signaling cross-talk that occurs between NF-κB and STAT3 during the compensatory protective response. However, the role and mechanism of SOCS3 in hypoxic cardiomyocytes are not fully understood. In the study, we investigated the effect of SOCS3 on the p65 and STAT3 signaling pathways and further examined the potential molecular mechanism involved in regulating apoptosis. Our data showed that SOCS3 silencing could upregulate Ac-p65, p-p65, and p-STAT3 expression in nuclear extracts of H9c2 cells that received hypoxic treatment for 24, 48, and 72 h. SOCS3 silencing also remarkably increased the DNA-binding activity of the p65 motif in hypoxic cultivated H9c2 cells. We also found that SOCS3 knockdown increased cleaved-caspase-3, Bax, and PUMA expression and decreased cleaved PARP and Bcl-2 in expression in hypoxic H9c2 cells. Silencing of SOCS3 caused an increase in LDH leakage from injured cardiomyocytes and reduced cell viability under conditions of hypoxic stress. Furthermore, SOCS3 silencing enhanced the apoptosis of H9c2 cells at 72 h of hypoxia. These findings suggest that knockdown of SOCS3 leads to excessive activation of the NF-κB pathway, which, in turn, might promote apoptosis under conditions of chronic hypoxia. (AU)

Silencing suppressor of cytokine signaling 3 induces apoptosis and activates the p-STAT3/NF-κ B pathway in hypoxic cultivated H9c2 cells

Suppressor of cytokine signaling 3 (SOCS3) plays a significant role in the process of myocardial adaptation to chronic hypoxia. SOCS3 finely regulates cell signaling cross-talk that occurs between NF-κB and STAT3 during the compensatory protective response. However, the role and mechanism of SOCS3 in hypoxic cardiomyocytes are not fully understood. In the study, we investigated the effect of SOCS3 on the p65 and STAT3 signaling pathways and further examined the potential molecular mechanism involved in regulating apoptosis. Our data showed that SOCS3 silencing could upregulate Ac-p65, p-p65, and p-STAT3 expression in nuclear extracts of H9c2 cells that received hypoxic treatment for 24, 48, and 72 h. SOCS3 silencing also remarkably increased the DNA-binding activity of the p65 motif in hypoxic cultivated H9c2 cells. We also found that SOCS3 knockdown increased cleaved-caspase-3, Bax, and PUMA expression and decreased cleaved PARP and Bcl-2 in expression in hypoxic H9c2 cells. Silencing of SOCS3 caused an increase in LDH leakage from injured cardiomyocytes and reduced cell viability under conditions of hypoxic stress. Furthermore, SOCS3 silencing enhanced the apoptosis of H9c2 cells at 72 h of hypoxia. These findings suggest that knockdown of SOCS3 leads to excessive activation of the NF-κB pathway, which, in turn, might promote apoptosis under conditions of chronic hypoxia. (AU)

Papel actual de las técnicas de imagen en la amiloidosis cardíaca / Current role of imaging techniques in cardiac amyloidosis

La amiloidosis cardíaca (AC) es una enfermedad infradiagnosticada, y si no se trata es rápidamente fatal. Los nuevos tratamientos disponibles aumentan la necesidad de desarrollar métodos diagnósticos no invasivos para su detección precoz y para la monitorización de la respuesta terapéutica. Los hallazgos típicos de la AC en ecocardiografía y resonancia magnética, no son suficientemente específicos para distinguir la AC de cadenas ligeras (AL) de la amiloidosis por transtiretina (ATTR). La captación de un radiofármaco óseo por el miocardio es altamente específica para la AC-ATTR cuando se ha excluido la discrasia de células plasmáticas. Ahora, este método diagnóstico está reemplazando la necesidad de biopsia en muchos pacientes. La detección precoz de la AC, la cuantificación de su carga y la evaluación de la respuesta al tratamiento son los siguientes pasos importantes para que las imágenes avancen en la evaluación y el tratamiento de la AC. (AU)

Cardiac amyloidosis (CA) is an underdiagnosed disease and, if left untreated, rapidly fatal. Emerging therapies for CA increase the urgency of developing non-invasive diagnostic methods for its early detection and for monitoring therapeutic response. Classic imaging features on echocardiography and cardiac magnetic resonance, although typical for cardiac amyloidosis, are not specific enough to distinguish light chain amyloidosis from transthyretin. Myocardial bone-avid radiotracer uptake is highly specific for transthyretin cardiac amyloidosis when plasma cell dyscrasia has been excluded; it is now replacing the need for biopsy in many patients. Detection of early cardiac amyloidosis, quantitation of its burden, and assessment of response to therapy are important next steps for imaging to advance the evaluation and management of cardiac amyloidosis. (AU)

A chronic low-dose magnesium L-lactate administration has a beneficial effect on the myocardium and the skeletal muscles

The purpose of this study was to determine whether magnesium L-lactate is responsible for having a beneficial effect on the myocardium and the skeletal muscles and how this substrate acts at the molecular level. Twenty seven young male Wistar rats were supplied with a magnesium L-lactate (L) solution, a magnesium chloride (M) solution and/or water (W) as a vehicle for 10 weeks. The treated animals absorbed the L and M solutions as they wished since they also had free access to water. After 9 weeks of treatment, in vivo cardiac function was determined ultrasonically. The animals were sacrificed at the end of the tenth week of treatment and the heart was perfused according to the Langendorff method by using a technique allowing the determination of cardiomyocyte activity (same coronary flow in the two groups). Blood was collected and skeletal muscles of the hind legs were weighed. The myocardial expressions of the sodium/proton exchange 1 (NHE1) and sodium/calcium exchange 1 (NCX1), intracellular calcium accumulation, myocardial magnesium content, as well as systemic and tissue oxidative stress, were determined. Animals of the L group absorbed systematically a low dose of L-lactate (31.5 ± 4.3 µg/100 g of body weight/day) which was approximately four times higher than that ingested in the W group through the diet supplied. Ex vivo cardiomyocyte contractility and the mass of some skeletal muscles (tibialis anterior) were increased by the L treatment. Myocardial calcium was decreased, as was evidenced by an increase in total CaMKII expression, without any change in the ratio between phosphorylated CaMKII and total CaMKII. Cardiac magnesium tended to be elevated. Our results suggest that the increased intracellular magnesium concentration was related to L-lactate-induced cytosolic acidosis and to the activation of the NHE1/NCX1 axis. Interestingly, systemic oxidative stress was reduced by the L treatment whereas the lipid profile of the animals was unaltered. (AU)

MicroRNA-451a attenuates angiotensin II–induced cardiac fibrosis and inflammation by directly targeting T-box1

Hypertension or angiotensin II (Ang II) induces cardiac inflammation and fibrosis, thus contributing to cardiac remodeling. MicroRNAs (miRNAs) are considered crucial regulators of cardiac homeostasis and remodeling in response to various types of stress. It has been reported that miR-451a is involved in regulating ischemic heart injury. However, its role in Ang II-induced cardiac fibrosis remains unknown. Cardiac remodeling was induced in mice by infusion of low-dose Ang II (490 ng/kg/min) with a minipump for 2 weeks. Echocardiography and histological examinations were performed to evaluate cardiac function and pathological changes. We observed that miR-451a expression was the most significantly downregulated in the hearts of Ang II-infused mice and in both primary cardiac myocytes and fibroblasts. Overexpression of miR-451a in mice significantly attenuated Ang II–induced cardiac fibrosis and inflammation. Conversely, knockdown of miR-451a in mice aggravated this effect. Bioinformatics analysis and a luciferase reporter assay revealed that TBX1 was a direct target of miR-451a. Mechanistically, miR-451a directly targeted TBX1 expression, which inhibited TGF-β1 production in both cardiac myocytes and fibroblasts, inactivating of TGF-β1/SMAD2/3 signaling, inhibiting myofibroblast differentiation and proinflammatory cytokine expression, and leading to attenuation of cardiac fibrosis and inflammation. In conclusion, these results indicate that miR-451a acts as a novel regulator of Ang II–induced cardiac fibrosis and inflammation by directly targeting TBX1, and may be a promising therapeutic target for treating hypertensive cardiac diseases. (AU)

Manifestaciones cardíacas de las enfermedades reumáticas / Cardiac manifestations of rheumatic diseases

Las enfermedades reumáticas autoinmunes son trastornos inflamatorios que pueden afectar a múltiples órganos, entre los que se incluye el corazón. El elevado riesgo de aparición de patología cardiovascular en estos pacientes no solo se debe a la presencia de factores de riesgo cardiovascular tradicionales, sino también a la inflamación crónica y la autoinmunidad. Todas las estructuras cardíacas pueden verse afectadas durante el curso de la enfermedad (válvulas, sistema de conducción, miocardio, endocardio, pericardio y arterias coronarias), por lo que las complicaciones cardíacas incluyen una amplia variedad de manifestaciones clínicas. La afectación cardíaca se asocia con un pronóstico desfavorable, por lo que es esencial detectar la lesión cardíaca subclínica en pacientes asintomáticos e instaurar el tratamiento de forma precoz. Este documento ofrece una revisión actualizada de las principales manifestaciones cardíacas de las enfermedades reumáticas, así como su manejo terapéutico. (AU)

Autoimmune rheumatic diseases are inflammatory disorders that can involve multiple organs, including the heart. The high risk of cardiovascular pathology in these patients is not only due to traditional cardiovascular risk factors, but also to chronic inflammation and autoimmunity. All cardiac structures may be affected during the course of systemic autoimmune diseases (valves, the conduction system, the myocardium, endocardium and pericardium, and coronary arteries), and the cardiac complications have a variety of clinical manifestations. As these are all associated with an unfavourable prognosis, it is essential to detect subclinical cardiac involvement in asymptomatic systemic autoimmune disease patients and begin adequate management and treatment early. In this review, we examine the multiple cardiovascular manifestations in patients with rheumatological disorders and available management strategies. (AU)

Perfil clínico y evolución de la amiloidosis cardiaca en un centro español de referencia / Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center

Introducción y objetivos La amiloidosis cardiaca (AC) se produce por depósito de fibras de amiloide en el miocardio. Las formas más frecuentes son la amiloidosis por cadenas ligeras (AL) y por transtiretina (ATTR). Nuestro objetivo es describir la experiencia en el diagnóstico, el tratamiento y el pronóstico en un centro especializado español. Métodos Se incluyó a todos los pacientes diagnosticados de AC en el Hospital Puerta de Hierro Majadahonda desde mayo de 2008 a septiembre de 2018 y se analizaron sus características clínicas, su evolución y su supervivencia. Resultados Se incluyó a 180 pacientes con AC, de los que 64 (36%) tenían AL (el 50% varones; edad, 65±11 años) y 116, ATTR (el 72% varones; edad, 79±11 años; 18 con ATTR hereditaria). La forma de presentación más frecuente fue la insuficiencia cardiaca en ambos grupos (el 81% con AL y el 45% con ATTR; p <0,01). Otras formas de presentación en pacientes con ATTR fueron arritmias auriculares (16%), trastornos de conducción (6%) e incidental (6%). Ya tenían otro diagnóstico establecido 70 pacientes (40%). Se pudo diagnosticar de manera no invasiva al 75% de los pacientes con ATTR. A pesar de que el retraso diagnóstico fue superior en la ATTR (2,8±4,3 frente a 0,6±0,7 años; p <0,001), la mortalidad fue mayor en los pacientes con AL (el 48 frente al 32%; p=0,028). El tipo de AL (HR=6,16; IC95%, 1,56-24,30; p=0,01), el sexo femenino (HR=2,35; IC95%, 1,24-4,46; p=0,01) y la clase funcional de la NYHA III-IV (HR=2,07; IC95%, 1,11-3,89; p=0,02) fueron predictores independientes de la mortalidad. Conclusiones La AC constituye un reto en la práctica clínica, con gran variabilidad en su presentación en función del subtipo y con un retraso diagnóstico y una mortalidad elevados. Son necesarias mejoras en el diagnóstico temprano y el tratamiento de estos pacientes. (AU)

Introduction and objectives Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center. Methods We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival. Results We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI,1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02). Conclusions CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients. (AU)

Miocarditis aguda: fenocopia de miocardiopatía hipertrófica apical / Acute myocarditis: phenocopy of apical hypertrophic cardiomyopathy

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La fibrosis intersticial miocárdica en la era de la medicina de precisión. El fenotipado basado en biomarcadores para un tratamiento personalizado / Myocardial interstitial fibrosis in the era of precision medicine. Biomarker-based phenotyping for a personalized treatment

La fibrosis intersticial miocárdica es un hallazgo constante en las cardiopatías estructurales que desarrollan insuficiencia cardiaca. Aunque la fibrosis facilita la progresión de la insuficiencia cardiaca, aún no se dispone de una estrategia terapéutica que la revierta. Probablemente, ello se deba al error de considerar la fibrosis intersticial miocárdica como una lesión homogénea y no como una lesión heterogénea en la que coexisten diferentes fenotipos. Hay que tener presente también que la heterogeneidad de la fibrosis intersticial miocárdica puede variar entre distintas cardiopatías. Por ello, el diagnóstico y el tratamiento de la fibrosis intersticial miocárdica suponen un verdadero desafío para la transición de un manejo convencional de la insuficiencia cardiaca a un manejo basado en los principios de la medicina de precisión. Como prueba de concepto, en este artículo revisamos cómo el fenotipado de pacientes con insuficiencia cardiaca atribuible a cardiopatía hipertensiva basado en las alteraciones histomoleculares principales de la fibrosis intersticial miocárdica permite identificar subgrupos de pacientes con características fisiopatológicas, clínicas y pronósticas diferentes. Además, discutimos la información disponible sobre el empleo de determinados biomarcadores circulantes y ciertos fármacos útiles para el diagnóstico no invasivo y el tratamiento personalizado, respectivamente, de dichos subgrupos de pacientes

Myocardial interstitial fibrosis is a constant pathological finding in structural heart diseases of various etiologies that evolve with heart failure. Although fibrosis facilitates heart failure progression, until now no therapeutic strategy has been developed that ensures its reversal. A possible explanation for this may lie in the vision of myocardial interstitial fibrosis as a homogeneous lesion instead of a heterogeneous lesion in which different phenotypes can be distinguished using appropriate criteria. In addition, the notion that the heterogeneity of myocardial interstitial fibrosis may be cardiac disease-specific must be also considered when approaching this entity. Therefore, we propose that myocardial interstitial fibrosis represents a true challenge for transitioning from usual care to biomarker-based personalized treatment and precision medicine in heart failure. As a proof-of-concept, in this review we discuss the phenotyping of myocardial interstitial fibrosis in patients with heart failure attributable to hypertensive heart disease based on its histomolecular alterations and provide evidence of the prognostic relevance of the resulting stratification. Furthermore, we discuss the available information on some circulating biomarkers and certain pharmacological agents useful for noninvasive identification and personalized treatment, respectively, of those phenotypes

Niveles plasmáticos de glucosa, triglicéridos, VLDL, leptina y resistina como potenciales biomarcadores de la grasa miocárdica en ratones / Plasma glucose, triglycerides, VLDL, leptin and resistin levels as potential biomarkers for myocardial fat in mice

Introducción: El incremento de grasa miocárdica ha sido propuesto como uno de los principales precursores de la disfunción miocárdica de etiología diabética independiente de la enfermedad arterial coronaria. Sin embargo, actualmente se carece de biomarcadores que reflejen el contenido de grasa miocárdica para la detección clínica de esta patología. Métodos: Las correlaciones entre el contenido de triglicéridos cardíacos y los niveles plasmáticos de las principales moléculas alteradas durante la diabetes y los niveles cardíacos de ARNm de genes implicados en el metabolismo cardíaco (Cd36 y Pdk4) han sido exploradas en un modelo murino de resistencia a la insulina inducida por una dieta con alto contenido en grasas. Resultados: En ratones resistentes a la insulina, la dieta grasa aumentó los niveles de triglicéridos del miocardio, en comparación con animales controles alimentados con una dieta estándar. El contenido de triglicéridos cardíacos se encontró directamente asociado con los niveles plasmáticos de glucosa, triglicéridos, VLDL, resistina y leptina. Además, se observó una correlación inversa entre el contenido de triglicéridos y los niveles cardíacos de ARNm de Cd36 y Pdk4. Conclusiones: Nuestros datos revelan que el contenido cardíaco de triglicéridos se encuentra asociado con un perfil bioquímico plasmático alterado y con una reprogramación de la expresión de genes dirigida a atenuar el impacto de la acumulación ectópica de lípidos en miocardio

Introduction: The increase in myocardial fat has been proposed as one of the main precursors of myocardial dysfunction due to diabetic aetiology, independently of coronary artery disease. However, biomarkers reflecting the myocardial fat content for the clinical detection of this pathology are currently lacking. Methods: Correlations between 4cardiac triglyceride content and plasma levels of major altered molecules during diabetes and cardiac mRNA levels of genes involved in cardiac metabolism (Cd36 and Pdk4) have been explored in a murine model of insulin resistance induced by a high-fat diet. Results: In insulin-resistant mice, the fatty diet increased myocardial triglyceride levels, compared to control animals fed with a standard diet. The content of cardiac triglycerides was directly associated with plasma levels of glucose, triglycerides, VLDL, resistin and leptin. In addition, an inverse correlation was observed between the content of cardiac triglycerides and the cardiac mRNA levels of Cd36 and Pdk4. Conclusions: Our data reveal that the cardiac triglyceride content is associated with altered plasma biochemical profile and reprogramming of gene expression aimed to mitigate the impact of ectopic lipid accumulation in the myocardium

The radioprotective effect of a wheat germ diet on rat myocardial tissue exposed to X-rays / Efecto radioprotector de una dieta de germen de trigo en tejido miocárdico de ratas expuestas a rayos X

Introduction: To determine whether a diet of wheat (Triticum aestivum) germ has a radioprotective effect on albino rat (Rattus rattus var. Albinus) myocardial tissue. Method: Rats between 200 and 250 g were divided into 4 groups of 6 each: Two groups were fed either a wheat diet or regular diet 16 days before and after a single exposure to 18 mSv of X-rays. The other two groups were fed the same diets but not exposed to X-rays. The animals were sacrificed, and heart tissue was submitted to histopathological study. Results: Rats fed a standard diet and exposed to X-rays presented marked hyperemia of blood vessels, necrosis, presence of connective tissue fibrocytes, loss of muscle architecture and radial arrangement. Exposed rats fed a wheat diet presented with only light necrosis and the presence of fibrocytes. Rats not exposed to X-rays had healthy myocardia. Conclusions: Wheat germ diet may have a radioprotective effect on rat myocardium

Introducción: Determinar si una dieta con germen de trigo (Triticum aestivum) tiene un efecto radio protector sobre el tejido miocárdico de ratas albinas (Rattus rattus var. Albinus) Método: Ratas con un peso entre 200 - 250 g fueron divididas en 4 grupos de 6 cada uno: Dos grupos fueron alimentadas con una dieta regular de germen de trigo durante 16 días antes y después de una única exposición a un grupo con 18 mSv de rayos X. Los otros dos grupos fueron alimentados con una dieta estándar, uno de ellos, fue expuesto a los rayos X. Los animales fueron sacrificados y se realizó un estudio histopatológico del tejido cardiaco. Resultados: Las ratas alimentadas con una dieta estándar y expuesta a los rayos X, presentaron marcada hiperemia de vasos sanguíneos, necrosis, presencia de fibrocitos en el tejido conectivo, pérdida de la arquitectura y disposición radial muscular. Las ratas expuestas y alimentadas con dieta de trigo presentaron solo una ligera necrosis y presencia de fibrocitos. Las ratas no expuestas a rayos X presentaron un miocardio saludable. Conclusiones: La dieta del germen de trigo puede tener un efecto radioprotector sobre el miocardio de rata

Chronic inhalation of 2, 2-dichlorovinyl dimethyl phosphate (DDVP) induces organ pathology in the adult albino rats

The acute toxic effects of the acetyl cholinesterase-inhibiting pesticide, DDVP, following oral and dermal exposure are well recorded in literature. The ability of DDVP to easily vaporize makes the aero-nasal route a possible means of exposure, albeit chronically. This study aimed to describe the pathology, if any, of the heart, kidney and liver following chronic exposure to various concentrations of DDVP via inhalation.Sixty male Wistar rats were divided into 6 groups (A-F) of 10 rats each. Rats in Group A were exposed to distilled water only, while rats in groups B, C, D, E and F were exposed to 20, 40, 60, 80 and 100% v/v concentrated fumes of DDVP respectively. Duration of inhalational exposure was for 90 days. The heart, liver and kidney of the rats in the groups were extracted for routine histopathology. Organ pathologies were semi-quantitatively scored and analyzed across and between the 6 groups.Generally, lesions were of progressive severity with increasing concentrations of DDVP. Across the organs, pathology was related to altered vascular and degenerative changes. Specifically, the heart, kidney and liver showed shredding of cardiomyocytes, sloughing of renal tubular epithelial cells with dilated tubular lumina, and hepatocellular degeneration and necrosis respectively. Inflammatory changes were limited to the livers of rats exposed to 80 and 100% v/v DDVP.It was concluded that DDVP induced altered vascular and degenerative changes following chronic exposure via inhalation. Safer alternatives to aerosolized DDVP-containing insecticides are recommended for the control of arthropod vectors in enclosures

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Estrés oxidativo mitocondrial y envejecimiento cardíaco / Mitochondrial oxidative stress and cardiac ageing

De acuerdo con diferentes organizaciones como la Asociación Americana del Corazón o la Organización Mundial de la Salud, las enfermedades cardiovasculares se han convertido en la primera causa de muerte en países occidentales. Aunque la exposición a diferentes factores de riesgo, en particular los relacionados con el estilo de vida, contribuyen de manera significativa a la etiopatogénesis de enfermedades cardíacas, el incremento en la esperanza de vida y el envejecimiento de la población asociado a él se consideran los determinantes principales del inicio y desarrollo de las mismas. Las mitocondrias y el estrés oxidativo se han señalado como factores relevantes tanto en el envejecimiento del corazón como en el desarrollo de enfermedades cardíacas como la insuficiencia cardíaca, la hipertrofia cardíaca y la miocardiopatía diabética. Durante el envejecimiento, diferentes procesos celulares relacionados con la función mitocondrial, como la bioenergética, procesos de apoptosis o de inflamación, se ven alterados, lo que conlleva una reducción en la supervivencia celular, y como consecuencia, disfunción cardíaca. Aumentar nuestro conocimiento sobre los mecanismos mitocondriales relacionados con el proceso de envejecimiento proporcionará nuevas estrategias para mejorar de forma más eficiente este proceso y las diferentes enfermedades relacionadas con él, en particular las cardiovasculares (AU)

According with different international organizations, cardiovascular diseases are becoming the first cause of death in western countries. Although exposure to different risk factors, particularly those related to lifestyle, contribute to the etiopathogenesis of cardiac disorders, the increase in average lifespan and aging are considered major determinants of cardiac diseases events. Mitochondria and oxidative stress have been pointed out as relevant factors both in heart aging and in the development of cardiac diseases such as heart failure, cardiac hypertrophy and diabetic cardiomyopathy. During aging, cellular processes related with mitochondrial function, such as bioenergetics, apoptosis and inflammation are altered leading to cardiac dysfunction. Increasing our knowledge about the mitochondrial mechanisms related with the aging process, will provide new strategies in order to improve this process, particularly the cardiovascular ones (AU)

A la búsqueda de la «huella metabólica» en la enfermedad cardiovascular / In search of the "metabolic footprint" in cardiovascular disease

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Papel del colágeno miocárdico en la estenosis aórtica grave con fracción de eyección conservada y síntomas de insuficiencia cardiaca / Role of myocardial collagen in severe aortic stenosis with preserved ejection fraction and symptoms of heart failure

Introducción y objetivos: Se ha estudiado la localización anatómica, las propiedades biomecánicas y el fenotipo molecular del colágeno miocárdico tisular en 40 pacientes con estenosis aórtica grave, fracción de eyección conservada y síntomas de insuficiencia cardiaca. Métodos: Se obtuvieron 2 biopsias transmurales de la pared libre del ventrículo izquierdo. La fracción del volumen de colágeno (FVC) se cuantificó mediante rojo picrosirio y la rigidez, mediante el módulo elástico de Young (YEM) evaluado con microscopia de fuerza atómica en regiones misiales y no misiales. Las FVC de tipos I y III se cuantificaron mediante microscopia confocal en áreas con determinación del YEM. Resultados: Comparados con sujetos de control, la FVC misial y no misial y el cociente FVC no misial:misial (p < 0,05) estaban incrementados en los pacientes. El cociente entre la velocidad pico de la onda E mitral y la velocidad E del anillo lateral mitral de los pacientes se correlacionaba con la FVC no misial (r = 0,330; p = 0,046) y con el cociente FVC no misial:misial (r = 0,419; p = 0,012). El cociente FVCI:FVCIII y el YEM aumentaban (p ≤ 0,001) en regiones no misiales respecto de las misiales, con correlación entre ellos (r = 0,895; p < 0,001). Conclusiones: En la estenosis aórtica grave con fracción de eyección conservada y síntomas de insuficiencia cardiaca, la disfunción diastólica se asocia con un depósito no misial de colágeno aumentado, predominantemente de tipo I y con mayor rigidez. Las características del colágeno tisular pueden contribuir a la disfunción diastólica en estos pacientes (AU)

Introduction and objectives: We investigated the anatomical localization, biomechanical properties, and molecular phenotype of myocardial collagen tissue in 40 patients with severe aortic stenosis with preserved ejection fraction and symptoms of heart failure. Methods: Two transmural biopsies were taken from the left ventricular free wall. Mysial and nonmysial regions of the collagen network were analyzed. Myocardial collagen volume fraction (CVF) was measured by picrosirius red staining. Young's elastic modulus (YEM) was measured by atomic force microscopy in decellularized slices to assess stiffness. Collagen types I and III were measured as CIVF and CIIIVF, respectively, by confocal microscopy in areas with YEM evaluation. Results: Compared with controls, patients exhibited increased mysial and nonmysial CVF and nonmysial:mysial CVF ratio (P < .05). In patients, nonmysial CVF (r = 0.330; P = .046) and the nonmysial:mysial CVF ratio (r = 0.419; P = .012) were directly correlated with the ratio of maximal early transmitral flow velocity in diastole to early mitral annulus velocity in diastole. Both the CIVF:CIIIVF ratio and YEM were increased (P ≤ .001) in nonmysial regions compared with mysial regions in patients, with a direct correlation (r = 0.895; P < .001) between them. Conclusions: These findings suggest that, in patients with severe aortic stenosis with preserved ejection fraction and symptoms of heart failure, diastolic dysfunction is associated with increased nonmysial deposition of collagen, predominantly type I, resulting in increased extracellular matrix stiffness. Therefore, the characteristics of collagen tissue may contribute to diastolic dysfunction in these patients (AU)

Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia/reperfusion of the intact heart

Ischemia/reperfusion (I/R) of the heart becomes injurious when duration of the ischemic insult exceeds a certain threshold (approximately ≥20 min). Mitochondrial bound hexokinase II (mtHKII) protects against I/R injury, with the amount ofmtHKII correlating with injury. Here, we examine whether mtHKII can induce the transition from non-injurious to injurious I/R, by detaching HKII from mitochondria during a non-injurious I/R interva l . Additionally, we examine possible underlying mechanisms (increased reactive oxygen species (ROS), increased oxygen consumption (MVO2) and decreased cardiac energetics) associated with this transition. Langendorff perfused rat hearts were treated for 20 min with saline, TAT-only or 200 nM TAT-HKII, a peptide that translocates HKII from mitochondria. Then, hearts were exposed to non-injurious 15-min ischemia, followed by 30-min reperfusion. I/R injury was determined by necrosis (LDH release) and cardiac mechanical recovery. ROS were measured by DHE fluorescence. Changes in cardiac respiratory activity (cardiac MVO2 and efficiency and mitochondrial oxygen tension (mitoPO2) using protoporphyrin IX) and cardiac energetics (ATP, PCr, ΔGATP) were determined following peptide treatment.When exposed to 15-min ischemia, control hearts had no necrosis and 85% recovery of function. Conversely, TAT-HKII treatment resulted in significant LDH release and reduced cardiac recovery (25%), indicating injurious I/R. This was associated with increased ROS during ischemia and reperfusion. TAT-HKII treatment reducedMVO2 and improved energetics (increased PCr) before ischemia, without affecting MVO2/RPP ratio or mitoPO2. In conclusion, a reduction in mtHKII turns non-injurious I/R into injurious I/R. Loss of mtHKII was associated with increased ROS during ischemia and reperfusion, but not with increased MVO2 or decreased cardiac energetics before damage occurs

Effect of fatty acid interaction on myoglobin oxygen affinity and triglyceride metabolism

Recent studies have suggested myoglobin (Mb) may have other cellular functions in addition to storing and transporting O2. Indeed, NMR experiments have shown that the saturated fatty acid (FA) palmitate (PA) can interact with myoglobin (Mb) in its ligated state (MbCO and MbCN) but does not interact with Mb in its deoxygenated state. The observation has led to the hypothesis that Mb can also serve as a fatty acid transporter. The present study further investigates fatty acid interaction with the physiological states of Mb using the more soluble but unsaturated fatty acid, oleic acid (OA). OA binds to MbCO but does not bind to deoxy Mb. OA binding to Mb, however, does not alter its O2 affinity. Without any Mb, muscle has a significantly lower level of triglyceride (TG). In Mb knock-out (MbKO) mice, both heart and skeletal muscles have lower level of TG relative to the control mice. Training further decreases the relative TG in the MbKO skeletal muscle. Nevertheless, the absence of Mb and lower TG level in muscle does not impair the MbKO mouse performance as evidenced by voluntary wheel running measurements. The results support the hypothesis of a complex physiological role for Mb, especially with respect to fatty acid metabolism