Mesenchymal stem cells reduce left ventricular mass in rats with doxorubicin-induced cardiomyopathy / Las células madre mesenquimales reducen la masa ventricular izquierda en ratas con miocardiopatía inducida por doxorrubicina

SUMMARY: Doxorubicin is a drug that used by a majority in the treatment of carcinomas. The most obvious known side effect is cardiomyopathy. Many studies have been carried out to eliminate side effects of the doxorubicin, and stem cell studies have been added in recent years. In this study, it was aimed to investigate fetal-derived mesenchymal stem cells (F-MSCs) treatment of doxorubicininduced cardiomyopathy by morphological methods. A total of 24 rats which were divided into three separate groups (Control, sham, treatment), each consisting of 8 male rats were used. In sham and treatment group, Adriamycin was administered in a single dose by tail injection to perform cardiotoxicity. In the treatment group, F-MSCs were intra-peritoneally administrated. Then, rats were euthanized and their hearts were photographed at the level of papillary muscle. and thickness, diameters and surface area levels were measured. Left ventricular mass (LVM) and left ventricular mass index (LVMI) were calculated after measurement. The sham group, LVM and LVMI levels were found to significantly lower (p<0.05) than control and treatment group. In the one hand, LVMI levels of rats in treatment group was statistically similar (p>0.05) to control group. Similarly, LVM levels of control and treatment groups were close to each other while this level of sham group was lower. It has been shown that F-MSC administrations in rats with doxorubicin-induced cardiomyopathy have adverse effect on LVM and LVMI values. In addition, the intra-peritoneal MSC administrations may be an alternative to other injection routes such as intra-venous and intra-cardiac administrations.

RESUMEN: La doxorrubicina es un medicamento usado ampliamente en el tratamiento de carcinomas. El efecto secundario más conocido es la miocardiopatía. Se han llevado a cabo muchos estudios para eliminar los efectos secundarios de la doxorrubicina, y en los últimos años se han agregado estudios con células madre. mediante métodos morfológicos, se intentó investigar el tratamiento de las células madre mesenquimales (F-MSCs) derivadas del feto, de la miocardiopatía inducida por doxorrubicina. Se utilizó un total de 24 ratas que se dividieron en tres grupos (control, simulación, tratamiento), cada uno de las cuales consistía en 8 ratas macho. En el tratamiento simulado y en el grupo tratamiento, se administró doxorrubicina en una dosis única mediante inyección en la cola de la rata para realizar cardiotoxicidad. En el grupo tratamiento, las FMSC se administraron intraperitonealmente. Luego, las ratas fueron sacrificadas y sus corazones fueron fotografiados a nivel de los músculos papilares, y se midieron los espesores, los diámetros y los niveles de área superficial. Después de las mediciones se calcularon la masa ventricular izquierda (MVI) y el índice de masa ventricular izquierda (IMVI). En el grupo simulado, los niveles de MVI y IMVI se encontraron significativamente inferiores (p <0.05) que en los grupos control y tratamiento. Por un lado, los niveles de IMVI de las ratas en el grupo de tratamiento fueron estadísticamente similares (p> 0,05) al grupo de control. De forma similar, los niveles de MVI de los grupos control y tratamiento se aproximaban uno al otro, mientras que este nivel era más bajo en el grupo simulado. Se ha demostrado que la administracion de F-MSC en ratas con miocardiopatía inducida por doxorrubicina tiene un efecto adverso sobre los valores de MVI y IMVI. Además, la administracion de MSC intraperitoneal puede ser una alternativa a otras rutas de inyección tal como las administración intravenosa e intracardíaca.

Effects of thymoquinone against cisplatin-induced cardiac injury in rats

PURPOSE: T o investigate the possible protective effect of thymoquinone (TQ) in cisplatin (CP) induced myocardial injury. METHODS: A total of 28 adult male Wistar-Albino rats were randomly and equally divided into four groups as follows: Group 1 (control), Group 2 (CP at 15 mg/kg dose), Group 3 (TQ 40 mg/kg/day for two days prior to CP injection and on third day, CP at 15 mg/kg dose was intraperitoneally administered and TQ treatment continued until fifth day) and Group 4 (TQ at 40mg/kg/day dose for five days). RESULTS: There was a significant increment in CP group in terms of congestion, edema and pycnotic nuclei in myocardial fibers, comparing with other groups. TQ group exhibited significant increase in expression of antiapoptotic protein Bcl-2, comparing with CP group (p<0.05). In only CP administered group, expression of antiapoptotic protein Bcl-2 was lowest comparing with other groups. CONCLUSION: Established data indicate that cisplatin is cardiotoxic and thymoquinone may be useful in treating CP-induced cardiac injury.

A Novel Angiotensin Type I Receptor Antagonist, Fimasartan, Prevents Doxorubicin-induced Cardiotoxicity in Rats

Angiotensin receptor blockers (ARBs) have organ-protective effects in heart failure and may be also effective in doxorubicin-induced cardiomyopathy (DOX-CMP); however, the efficacy of ARBs on the prevention of DOX-CMP have not been investigated. We performed a preclinical experiment to evaluate the preventive effect of a novel ARB, fimasartan, in DOX-CMP. All animals underwent echocardiography and were randomly assigned into three groups: treated daily with vehicle (DOX-only group, n=22), 5 mg/kg of fimasartan (Low-fima group, n=22), and 10 mg/kg of fimasartan (High-fima group, n=19). DOX was injected once a week for six weeks. Echocardiography and hemodynamic assessment was performed at the 8th week using a miniaturized conductance catheter. Survival rate of the High-fima group was greater (100%) than that of the Low-fima (75%) and DOX-only groups (50%). Echocardiography showed preserved left ventricular (LV) ejection fraction in the High-fima group, but not in the DOX-only group (P=0.002). LV dimensions increased in the DOX-only group; however, remodeling was attenuated in the Low-fima and High-fima groups. Hemodynamic assessment showed higher dP/dt in the High-fima group compared with the DOX-only group. A novel ARB, fimasartan, may prevent DOX-CMP and improve survival rate in a dose-dependent manner in a rat model of DOX-CMP and could be a treatment option for the prevention of DOX-CMP.

Anthracycline-mediated cardiomyopathy: Basic molecular knowledge for the cardiologist / Miocardiopatía inducida por antraciclinas: conocimientos moleculares básicos para el cardiólogo

Anthracyclines are cytostatic antibiotics discovered almost half a century ago exerting their action through inhibition of topoisomerase II. The two most representative drugs are doxorubicin and daunorubicin and they have been proven as useful antineoplastics and are widely prescribed in daily oncology practice; unfortunately, cardiotoxicity has been a limiting factor when it comes to their use. Diverse mechanisms have been involved in anthracycline cardiotoxicity, none of which are capable of causing the whole clinical picture by itself. Traditionally, reactive oxygen species (ROS) have received more attention, although recently basic research has proven other factors to be as important as ROS. These factors mainly involve sarcomeric structure disruption, toxic accumulation of metabolites, iron metabolism, energetic alterations and inflammation. The role of genetics has been studied by some groups, although a clear genotype-response relationship is yet to be elucidated. With the improved survival from different oncologic diseases we are witnessing more cases of chemotherapy-induced cardiotoxicity and the advent of new anticancer drugs poses several challenges for the cardiologist, highlighting the importance of a deep knowledge of the main mechanisms inducing this toxicity.

Hace casi medio siglo se descubrieron las antraciclinas; estas son antibióticos citostáticos inhibidores de la topoisomerasa II. Los 2 fármacos más representativos de este grupo son la doxorrubicina y la daunorrubicina. Estos fármacos han demostrado ser eficaces antineoplásicos y han sido ampliamente utilizados en la práctica oncológica. Desafortunadamente, la cardiotoxicidad sigue siendo un elemento limitante para su uso. Los mecanismos mediante los cuales estos fármacos ocasionan cardiotoxicidad son múltiples pero ninguno de ellos de forma individual es capaz de explicar el cuadro clínico por completo. Casi siempre se ha considerado que la formación de especies reactivas de oxígeno era responsable de gran parte de la toxicidad, sin embargo la experimentación básica reciente ha demostrado que hay otros factores, entre los que destacan las alteraciones en la estructura sarcomérica, la acumulación de metabolitos tóxicos, las alteraciones del metabolismo del hierro o de los mecanismos energéticos, y la liberación de mediadores de inflamación. Por otra parte, diversos grupos han investigado la intervención que la genética podría tener en el desarrollo de esta enfermedad, si bien no se puede definir aún una clara correlación genotipo-respuesta. Con el aumento de la supervivencia por el tratamiento de diversas enfermedades oncológicas, se están detectando más casos de cardiotoxicidad mediada por quimioterapia; y con la aparición de nuevos fármacos quimioterápicos se añaden nuevos retos, con lo que se demuestra la importancia del estudio profundo de los mecanismos causales.

Simultaneous interstitial pneumonitis and cardiomyopathy induced by venlafaxine / Pneumonite intersticial e miocardiopatia simultâneas induzidas por venlafaxina

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor used as an antidepressant. Interindividual variability and herb-drug interactions can lead to drug-induced toxicity. We report the case of a 35-year-old female patient diagnosed with synchronous pneumonitis and acute cardiomyopathy attributed to venlafaxine. The patient sought medical attention due to dyspnea and dry cough that started three months after initiating treatment with venlafaxine for depression. The patient was concomitantly taking Centella asiatica and Fucus vesiculosus as phytotherapeutic agents. Chest CT angiography and chest X-ray revealed parenchymal lung disease (diffuse micronodules and focal ground-glass opacities) and simultaneous dilated cardiomyopathy. Ecocardiography revealed a left ventricular ejection fraction (LVEF) of 21%. A thorough investigation was carried out, including BAL, imaging studies, autoimmune testing, right heart catheterization, and myocardial biopsy. After excluding other etiologies and applying the Naranjo Adverse Drug Reaction Probability Scale, a diagnosis of synchronous pneumonitis/cardiomyopathy associated with venlafaxine was assumed. The herbal supplements taken by the patient have a known potential to inhibit cytochrome P450 enzyme complex, which is responsible for the metabolization of venlafaxine. After venlafaxine discontinuation, there was rapid improvement, with regression of the radiological abnormalities and normalization of the LVEF. This was an important case of drug-induced cardiopulmonary toxicity. The circumstantial intake of inhibitors of the CYP2D6 isoenzyme and the presence of a CYP2D6 slow metabolism phenotype might have resulted in the toxic accumulation of venlafaxine and the subsequent clinical manifestations. Here, we also discuss why macrophage-dominant phospholipidosis was the most likely mechanism of toxicity in this case.

A venlafaxina é um inibidor de recaptação de serotonina e noradrenalina utilizado como antidepressivo. A variabilidade individual ou interações entre fitoterápicos e fármacos podem causar toxicidade induzida por drogas. Relatamos o caso de uma paciente de 35 anos diagnosticada com pneumonite intersticial e miocardiopatia dilatada atribuídas à venlafaxina. A paciente procurou atendimento médico devido a dispneia e tosse seca, que começaram três meses após iniciar tratamento com venlafaxina para depressão. Concomitantemente tomava suplementos fitoterápicos contendo Centella asiatica e Fucus vesiculosus. A radiografia e a CT de tórax revelaram doença pulmonar parenquimatosa (micronódulos difusos e opacidades em vidro fosco) e, simultaneamente, foi diagnosticada uma miocardiopatia por ecocardiograma, que revelou uma fração de ejeção ventricular esquerda (FEVE) de 21%. Uma investigação ampla foi realizada, incluindo LBA, estudos de imagem, detecção de doenças autoimunes, cateterismo cardíaco direito e biópsia miocárdica. Após a exclusão de outras etiologias e a aplicação da Escala de Probabilidade de Reações Adversas a Medicamentos de Naranjo, foi assumido o diagnóstico de pneumonite/miocardiopatia síncronas associadas à venlafaxina. Já foi demonstrado que os suplementos fitoterápicos utilizados pela paciente podem inibir a isoenzima do complexo enzimático citocromo P450, responsável pelo metabolismo da venlafaxina. Após a descontinuação da venlafaxina, verificou-se uma rápida melhora clínica com regressão das alterações radiológicas e normalização da FEVE. Este é um importante caso de toxicidade cardiopulmonar induzida por droga. A administração circunstancial de inibidores da isoenzima CYP2D6 e a presença de um fenótipo de metabolização lenta de CYP2D6 podem ter resultado na acumulação tóxica da venlafaxina e na manifestação clínica subsequente. Aqui, é discutida a hipótese de a fosfolipidose macrofágica ser o mecanismo de toxicidade.

Anatomopathological study of cardiomyopathy induced by doxorubicin in rats / Estudo anatomopatológico da miocardiopatia induzida pela doxorrubicina em ratos

Purpose: The development of an experimental model of myocardiopathy induced by Doxorubicin in rats. Methods: 16 wistar male rats were randomized in two groups: Group I (placebo) and Group II (Doxorubicin - 5mg/kg). After six months, the animals were subjected to cardiotomy and their hearts were weighted and submitted to transversal cuts, from which fragments for a macro and micro study were obtained. These fragments were studied considering their external and internal diameters and the thickness of the left ventricle (LV). The histological pieces were analyzed for the presence of fibrosis, cytoplasmic vacuolization, necrosis and size of nucleus variation. Data obtained was submitted to statistical analysis with Student's t test. Results: The hearts of the animals in Group II increased 41 percent in relation to their weight; 33 percent in the internal diameter and 14 percent in the external diameter of the LV cavity; and 24 percent in the thickness of the wall. Fibrosis of the myocardial tissue was observed in 75 percent of the animals of Group II; all the animals presented miocyte cytoplasmatic vacuolization; myocardial necrosis was present in 75 percent of the animals; and 87/ percent presented variation in the size of myocite nuclei. The presence of polymorphonuclear cells was also observed. Conclusion: Doxorubicin was effective in the promotion of macro and microscopic alterations in the cardiac tissue of rats, possibly constituting a model for the experimental study of myocardiopathy.

Objetivo: Desenvolver um modelo experimental de miocardiopatia induzida por doxorrubicina em ratos. Métodos: 16 ratos Wistar machos foram randomizados em 2 grupos: Grupo I (placebo) e Grupo II (doxorrubicina 5mg/kg). Após 6 meses, os animais foram submetidos a cardiotomia e seus corações foram pesados e submetidos a cortes transversais. Estes fragmentos foram estudados considerando seus diâmetros externos e internos e a espessura do ventrículo esquerdo. As peças histológicas foram analisadas quanto à presença de fibrose, vacuolização citoplasmática, necrose e variação do tamanho do núcleo. Os resultados foram submetidos a análise estatística pelo teste t de Student. Resultados: Os corações dos animais do grupo II aumentaram 41 por cento em relação ao peso; 33 por cento no diâmetro interno e 14 por cento no diâmetro externo; e 24 por cento na espessura da parede do VE. Fibrose do tecido miocárdico foi observada em 75 por cento dos animais do grupo II; todos os animais apresentaram vacuolização citoplasmática dos miócitos; Houve necrose miocárdica em 75 por cento dos animais e 87 por cento apresentaram variação no tamanho do núcleo. A presença de células polimorfonucleares também foi observada. Conclusão: A doxorrubicina foi efetiva na promoção de alterações macro e microscópicas no tecido cardíaco de ratos, possivelmente constituindo-se num modelo experimental para estudo da miocardiopatia.

Lesões perinatais em cordeiros induzidas pela administração de Tetrapterys multiglandulosa (Malpighiaceae) a ovelhas em diferentes estágios de gestação / Perinatal lesions caused in lambs by feedingTetrapterys multiglandulosa (Malpighiaceae) to sheep at different stages of their pregnancy

Foi realizada a intoxicação experimental em ovelhas em diferentes dias de gestação, 12 ovelhas foram dividas em quatro grupos. As ovelhas do Grupo 1 consumiram quatro doses de 5g/kg de folhas verdes durante quatro dias; ovinos do Grupo 2 consumiram duas doses de 10g/kg durante dois dias, o Grupo 3 consumiu uma dose de 20g/kg em um único dia e os ovinos do Grupo 4 não consumiram a planta (controle-negativo). Para testar a toxicidade da planta um ovino macho consumiu 5g/kg até manifestação dos sintomas. Não foram observados sinais clínicos da intoxicação nas ovelhas, mas três cordeiros tiveram morte perinatal, e um cordeiro morreu com três meses de idade; o ovino controle-positivo morreu após 38 dias de consumo diário da planta e os sinais clínicos foram taquipnéia, taquicardia, sonolência, incoordenação e fraqueza. Todos os quatro cordeiros e o ovino controle-positivo foram necropsiados e os achados de necropsia foram áreas esbranquiçadas no miocárdio, evidenciação do padrão lobular do fígado, pulmão vermelho enegrecido e rúmen acentuadamente distendido com presença de gases livres. Os achados histopatológicos foram fibrose cardíaca, necrose dos cardiomiócitos, congestão e edema pulmonar, congestão hepática centrolobular e degeneração esponjosa na região subcortical do encéfalo. Tetrapterys multiglandulosa demonstrou ser tóxica para os fetos ovinos em dosagens que não foram suficientes para induzir sinais clínicos nas ovelhas prenhes, e que a intoxicação pode ocorrer com morte de cordeiros logo após o parto, mesmo após meses de ter cessada a ingestão da planta.

In order to verify the effects of non-lethal doses of Tetrapterys multiglandulosa on ovine fetuses, experimental poisoning in sheep at different days of pregnancy was performed. Green leaves of shooting plants were administered to 9 pregnant ewes divided into three experimental groups. Sheep from Group 1 received four doses of 5g/kg of fresh leaves for 4 days; those from Group 2 received 10g/kg for 2 days; Group 3 sheep received a dose of 20g/kg for one day, and sheep from Group 4 did not receive the plant and served as negative controls. To check the plant toxicity, a male sheep (positive control) received 5g/ kg until the onset of clinical signs. No signs of poisoning were observed in pregnant ewes; three lambs died 1-5 days after birth, and a fourth lamb died within 3 months after have been born. The positive control died after 38 days of daily consumption of the plant, presenting tachypnea, tachycardia, drowsiness, incoordination, weakness and sudden death. All four dead lambs and the positive control sheep were necropsied. The gross lesions were whitish areas in the myocardium, increased lobular pattern of the liver, dark red lungs, metabolization of pericardial fat, and ruminal distention with free gas. Histological findings were cardiac fibrosis, cardiomyocyte necrosis, pulmonary congestion and edema, and spongy degeneration in subcortical cerebral white matter. Tetrapterys multiglandulosa resulted toxic for ovine fetuses at doses that were not suffient to induce clinical signs in the pregnant ewes, demonstrating that the poisoning may be a cause of death of lambs soon after birth, even several months after the ingestion of the plant has been discontinued.

Dexrazoxane for Preventing Anthracycline Cardiotoxicity in Children with Solid Tumors

This study attempted to assess the incidence and outcome of anthracycline cardiotoxicity and the role of dexrazoxane as a cardioprotectant in childhood solid tumors. The dexrazoxane group included 47 patients and the control group of historical cohort included 42. Dexrazoxane was given in the 10:1 ratio to doxorubicin. Fractional shortening and systolic and diastolic left ventricular diameters were used to assess the cardiac function. The median follow-ups were 54 months in the dexrazoxane group and 86 months in the control group. The mean cumulative doses of doxorubicin were 280.8+/-83.4 mg/m2 in the dexrazoxane group and 266.1+/-75.0 mg/m2 in the control group. The dexrazoxane group experienced significantly fewer cardiac events (27.7% vs. 52.4%) and less severe congestive heart failure (6.4% vs. 14.3%) than the control group. Thirteen cardiotoxicities including one cardiac death and 2 congestive heart failures occurred in the dexrazoxane group, and 22 cardiotoxicities including 2 cardiac deaths and 4 congestive heart failures, in the control group. Five year cardiac event free survival rates were 69.2% in the dexrazoxane group and 45.8% in the control group (P=0.04). Dexrazoxane reduces the incidence and severity of early and late anthracycline cardiotoxicity in childhood solid tumors.

Resposta taquicárdica e controle autonômico no exercício físico em modelo genético de insuficiência cardíaca / Tachycardic response and autonomic control in physical exercise in genetic model of cardiac insufficiency

O aumento da atividade nervosa simpática e a taquicardia em repouso ou durante esforços físicos estão associados ao aumento da morbimortalidade, mesmo na ausência de sinais clínicos de doença cardíaca. Sabendo-se da importância dos receptores α2A/α2C-adrenérgicos na modulação da atividade nervosa e frequência cardíaca (FC), o presente trabalho utiliza um modelo genético de cardiomiopatia induzida por excesso de catecolaminas circulantes baseado na inativação gênica dos receptores α2A/α2C-adrenérgicos em camundongos (α2A/α2CKO) para verificar a resposta da FC ao exercício físico (EF), assim como o controle simpatovagal da FC ao EF. Testou-se a hipótese de que haveria resposta taquicárdica exacerbada durante o EF nos camundongos α2A/α2CKO mesmo quando a função cardíaca ainda estivesse preservada em repouso, sendo o receptor α2A-adrenérgico o principal responsável por essa resposta. Camundongos machos da linhagem C57Bl6J, controle (CO) e com inativação gênica para os receptores α2A (α2AKO), α2C α2CKO) e α2A/α2CKO foram submetidos a um teste de tolerância ao esforço físico. Outros dois grupos de camundongos, CO e α2A/α2CKO, foram submetidos ao bloqueio farmacológico dos receptores muscarínicos e β-adrenérgicos e ao EF progressivo para se avaliar a contribuição simpatovagal para a taquicardia de EF. Observou-se intolerância ao esforço físico (1.220 ± 18 e 1.460 ± 34 vs. 2.630 ± 42m, respectivamente) e maior taquicardia ao EF (765 ± 16 e 792 ± 13 vs. 603 ± 18bpm, respectivamente) nos camundongos α2AKO e α2A/α2CKO vs. CO. Além disso, o balanço autonômico estava alterado nos camundongos α2A/α2CKO pela hiperatividade simpática e menor efeito vagal cardíaco. Esses resultados demonstram a importância dos receptores α2A/α2C-adrenérgicos no controle autonômico não só no repouso, mas também durante o EF, sendo o receptor ...

Increase of sympathetic nervous activity and tachycardia at rest or during physical exertions are associated with increase of morbimortality, even in the absence of clinical signs of cardiac disease. Considering the importance of the α2A/α2C-adrenergic receptors in the modulation of the nervous activity and heart rate (HR), the present study uses a genetic model of cardiomyopathy induced by excess of circulating catecholamine in the gene inactivation of the α2A/α2 -adrenergic receptors in mice (α2A/α2CKO) to verify the HR response to physical exercise (PE), as well as the sympathetic-vagal control of the HR to PE. The hypothesis is that there would be exacerbated tachycardic response during PE in α2A/α2CKO mice even when the cardiac function was still preserved at rest, being the α2A-adrenergic receptor the main reason for this response. Male mice of the C57Bl6J lineage, control (CO) and with gene inactivation for the a2A (α2AKO), α2C α2CKO) and α2A/α2CKO receptors were submitted to tolerance to a physical exercise test. Two other groups of mice, CO and α2A/α2CKO, were submitted to pharmacological blocking of the muscarinic and β-adrenergic receptors as well as to progressive PE to assess the sympathetic-vagal contribution to PE tachycardia. Intolerance to physical exercise (1.220 ± 18 and 1.460 ± 34 vs. 2.630 ± 42m, respectively) and higher tachycardia to PE (765 ± 16 e 792 ± 13 vs. 603 ± 18 bpm, respectively) in the α2AKO and α2A/α2CKO vs. CO mice was observed. Moreover, the autonomic balance was altered in the α2A/α2CKO mice by the sympathetic hyperactivity and lower cardiac vagal effect. These outcomes demonstrated the importance of the α2A/α2C-adrenergic receptors in autonomic control not only at rest, but also during PE, being theα2A-adrenergic receptor responsible for the sympathetic hyperactivity and lower ...

La vía de señalización Rho a/ Rho kinasa se encuentra activada en el miocardio en ratas con fibrosis cardíaca inducida por isoprotenerol / Rho A/ Rho kinase pathway is activated in the myocardium of rats with isoprotenerol - induced fibrosis

Antecedentes: En pacientes con insuficiencia cardíaca la actividad adrenérgica está aumentada, lo que induce en el largo plazo, a cardiotoxicidad y mayor deterioro de la función ventricular. La administración experimental de Isoprotenerol, un agonista beta-adrenérgico, produce hipertrofia ventricular, daño y fibrosis miocárdica. La vía de señalización intracelular RhoA/Rho-Kinasa (ROCK) participa en el remodelamiento cardiovascular, no estando clara la relación entre la activación de esta vía y el desarrollo de fibrosis miocárdica. Objetivo: Determinar si existe activación de la vía ROCK en ratas con fibrosis miocárdica inducida experimentalmente por Isoprotenerol, mediante cuantificación de la fosforilación de la proteína blanco 1 de la fosfatasa de la miosina (MYPT1). Métodos: Se utilizaron ratas Sprague-Dawley machos (100 +/- 10 gr.); 10 como grupo control con administración de suero fisiológico y 10 en el grupo experimental con inyección subcutánea de Isoprotenerol Hemisulfato, 5 mg/kilo de peso por día, por un período de 10 días. Se determinó la presión arterial sistólica (PAS), la masa relativa ventricular izquierda (MRVI), la activación de ROCK a través de niveles de MYPT1 por Western Blot y se cuantificó la fibrosis en Ventrículo Izquierdo por análisis morfométrico del colágeno (en tinciones con Rojo de Picrosirio). Resultados (promedio +/- ES, =p<0,05): Los resultados en Presión Arterial Sistólica fueron 119,6 +/- 8,1 mmHg en el grupo control y 113,8 +/- 5,2 mmHg en el grupo tratado con Isoprotenerol, la MRVI fue de 358,3 +/- 10,9 mg/g en las controles y 495,3 +/- 42,02 mg/g en ratas Iso. La fracción volumétrica de colágeno (FVC) en miocardio y subendocardio fueron 3 +/- 0,3 y 3,3 +/- 0,4 en ratas control; en ratas Iso fueron 5,2 +/- 0,7 y 7,4 +/- 1,3 respectivamente.

Background: Patients with heart failure have increased adrenergic activity, which in turn induces cardiotoxicity, and further damage to the myocardium. lsoprotenerol induces ventricular hypertrophy with myocardial fibrosis. RHO A/ RHO Kinase pathway (ROCK) participates in myocardial remodeling, but it is not known whether ROCK is involved in the fibrotic process.Aim: To ascertain whether ROCK is activated in rats with Isoprotenerol -induced myocardial fibrosis, measuring ROCK by phosphon/ation of the myosin phosphatase (MYPTI). Methods: We used male Sprague-Dawley rats (100 +/- 10 g); 10 rats were used as controls and received sq saline,- 10 rats in the experimental group received sq Isoprotenerol (ISO rats) 5 mg/k body weight/day, during 10 days. We measured systolic blood pressure (SBP), left ventricular mass (LVM) and ROCK, which was measured by phophorylation of the MYPTI protein using Western Blot. Myocardial fibrosis was measured by morphometry of collagen in Picrosirius red stained samples, and was expressed as collagen volume fraction (CVF). Results were expressed as average +/- SEM; =p<005Results: SBP was 119,6 +/- 8,1 mmHg in controls and 113,8 +/- 5,2 mmHg in ISO rats; LVM was 358,3 +/- 10,9 mg/g in controls and 495,3 +/- 42,02 mg/g in ISO rats. CVF in the myocardium and subendocardium were 3 +/- 0,3 and 3,3 +/- 0,4 in control rats; values in ISO rats were 2 +/- 0,7 y 7,4 +/- 1,3 respectively. Total CVF were 3,2 +/- 0,4 in controls and 6,3 +/- 1,6 in ISO rats. ROCK, expressed as phosphorylated MYPTI /total MYPTI in control rats was 2,5 +/- 0,8 and 4,7 +/- 2,2 in ISO rats. Conclusion: ROCK pathway is significantly activated in the myocardium of ISO rats. ROCK antagonists for preventing myocardial fibrosis should be evaluated in this experimental model.

Myocardial Protective Effect of Tezosentan, an Endothelin Receptor Antagonist, for Ischemia-Reperfusion Injury in Experimental Heart Failure Models

The myocardial protective effects of endothelin antagonist in ischemic cardiomyopathy (ICMP), doxorubicin-induced cardiomyopathy (DOX) and pressure-overload hypertrophy by transverse aortic constriction (TAC) models have been predicted to be different. The objective of this experiment, therefore, is to evaluate the myocardial protective effect of tezosentan, an endothelin receptor antagonist, in various experimental heart failure models. Sprague-Dawley rats (6-8 weeks old, 200-300 g) were randomized to three experimental groups (n=30 each): ICMP; DOX; and TAC group. Each of these groups was randomly assigned further to the following subgroups (n=10 each): sham-operated ischemia-reperfusion subgroup (SHAM); tezosentan treated ischemia-reperfusion subgroup (Tezo); and tezosentan non-treated ischemia-reperfusion subgroup (N-Tezo). Total circulatory arrest was induced for 1 hr, followed by 2 hr of reperfusion. The left ventricular developed pressure, peak positive and negative first derivatives, and coronary blood flow were significantly different (P<0.05) among the SHAM, Tezo, and N-Tezo subgroups of the ICMP group at 30 min of reperfusion, but there were no statistically significant differences among the subgroups of the DOX and TAC groups. In conclusion, tezosentan, an endothelin receptor antagonist, showed myocardial protection effects only on the ischemic cardiomyopathy rat model, but not in the non-ischemic heart failure rat models.

High-resolution electrocardiography in dogs under doxorubicin-induced cardiomyopathy / Eletrocardiografia de alta resolução em cães com cardiomiopatia induzida pela doxorrubicina

The occurrence of late potentials in dogs under doxorubicin-induced cardiomyopathy and their relationship with the development of ventricular arrhythmias or sudden death were studied. Seven adult mongrel dogs of both sexes were used. Cardiomyopathy was induced by slow intravenous infusion of doxorubicin (30mg/m²) at 21-day intervals, until a total cumulative dose of 240mg/m² was reached. Animals were monitored by echocardiography. After the induction of cardiomyopathy, high-resolution electrocardiography was recorded. Late potentials were observed in two animals that suddenly died a few days later.

Determinaram-se a ocorrência de potencial tardio em cães com cardiomiopatia induzida pela doxorrubicina e sua relação com o desenvolvimento de arritmias ventriculares ou morte súbita. Sete cães adultos, sem raça definida, de ambos os sexos foram utilizados. A cardiomiopatia foi induzida por infusão venosa lenta de doxorrubicina (30mg/m²) em intervalos de 21 dias, até uma dose total cumulativa de 240mg/m². Os animais foram monitorados ecocardiograficamente. Após a confirmação da cardiomiopatia, foi feito o registro da eletrocardiografia de alta resolução. Potenciais tardios foram observados em dois animais que morreram subitamente poucos dias após.

Myocardial damage in hair dye poisoning--an uncommon presentation.

A 22-year-old female presented to us after consuming hair dye with features of angio-neurotic edema, asphyxia and irregular pulse. Serial ECGs revealed presence of ST segment elevation and T wave inversion in anterior chest leads. Strongly positive c-troponin-T test further confirmed the myocardial damage. This is a rare manifestation of para-phenylene diamine poisoning mentioned in literature. Patient also had elevated liver enzymes and oliguria.

effect of different levels of sodium chloride on round heart disease in the Turkey

Round heart disease is a disease of unknown etiology in turkey. The objective of this study was to examine the effect of different amounts of sodium chloride in inducing cardiomyopathy in turkey poults. There are some reports that hypoxia and furazolidone can induce cardiomyopathy in turkey. Two hundred 2- day-old turkey poults were wing-banded and placed randomly into 6 groups and 24 replicates [4 replicates for each group]. The 6 groups received commercial turkey starter diet contain 0.12, 0.17, 0.22. 0.27. 0.32 and 0.3 7% of sodium, respectively. They had access to food and water ad libitum. Suffering and dead birds were weighed and examined for post-mortem study. Live body weight of turkey poults measured individually on days 1, 2, 5 and 19. To study the hearts for presence of cardiomyopathy, on the day 19, all the poults were weighed and killed by cervical dislocation. The pieces of the hearts were placed into numbered tubes, flash frozen by liquid nitrogen and stored at -70°C for myoglobin and hemoglobin microassay. The assay was based on spectrophotometry and separated myoglobin and hemoglobin by ammonium sulphate extraction. For determination of cardiomyopathy the ratio of the inner cavity of left ventricle to the total diameter of the left ventricle [IC [IV]/TD [IV]] was calculated. Myopathic ratio for groups 1, 2, 3, 4, 5 and 6 were 0.1, 0.29, 0.3, 0.34, 0.35 and 0.36, respectively. Turkey poults which received excessive salts drank more water which produced volume overload, more cardial muscle activity, needed more oxygen and were more likely to develop myopathy. Cardiac muscle myoglobin and hemoglobin microassay showed that there was no significant relationship between the amount of myoglobin and hemoglobin with the amount of diet sodium

Cardiomiopatia induzida pela adriamicina: uma revisão / Adriamycin induced cardiomyopathy: a review

A adriamicina (ADR) encontra-se entre os mais importantes agentes antitumorais utilizados na prática oncológica, desempenhando importante papel no tratamento de diversas neoplasias humanas e animais. Seu valor clínico, porém, torna-se limitado diante de seu potencial cardiotóxico dose-dependente capaz de levar à insuficiência cardíaca congestiva irreversível. Por este motivo, estudos experimentais têm sido desenvolvidos em animais com o objetivo de minimizar tais efeitos por meio do melhor entendimento de seus mecanismos de ação, os quais constituem a chave para o estabelecimento de terapias coadjuvantes preventivas da doença cardíaca. Além disso, a adriamicina também tem sido utilizada em animais experimentais na obtenção de modelos de insuficiência cardíaca e cardiomiopatia dilatada, constituindo meio importante de indução e permitindo estudos fisiopatológicos detalhados de tais alterações. Métodos de monitoração de pacientes são fundamentais para a atenuação das graves complicações inerentes ao tratamento com adriamicina, por meio da associação de drogas cardioprotetoras e da adequação do tratamento de acordo com o risco do paciente em desenvolver sintomas de cardiotoxicidade, durante o tratamento. Nesta revisão, são mencionados conceitos básicos sobre a utilização da adriamicina bem como recentes estudos a respeito de seu mecanismo de ação e modulação, em modelos experimentais.

Serial Assessment of Myocardial Properties Using Cyclic Variation of Integrated Backscatter in an Adriamycin- Induced Cardiomyopathy Rat Model

Although adriamycin (Doxorubicin) is one of the most effective and useful antineoplastic agents for the treatment of a variety of malignancies, its repeated administration can induce irreversible myocardial damage and resultant heart failure. Currently, no marker to detect early cardiac damage is available. The purpose of this study was to investigate whether an assessment of the acoustic properties of the myocardium could enable the earlier detection of myocardial damage after adriamycin chemotherapy. Forty Wistar rats were treated with adriamycin (2 mg/kg, i.v.) once a week for 2, 4, 6 or 8 weeks consecutively. Left ventricular ejection fraction (LVEF) was calculated using M-mode echocardiography data. The magnitude of cardiac cycle dependent variation of integrated backscatter (CVIB) of the myocardium was measured in the mid segment of the septum and in the posterior wall of the left ventricle, using a real time two dimensional integrated backscatter imaging system. LVEF was significantly lower in the adriamycin-treated 8-week group than in the controls (75 +/- 9 vs 57 +/- 8%, p < 0.05). Myocyte damage was only seen in the 8-week adriamycin-treated group. However, no significant changes of CVIB were observed between baseline or during follow-up in the ADR or control group. In conclusion, serial assessment of the acoustic properties of the myocardium may not be an optimal tool for the early detection of myocardial damage after doxorubicin chemotherapy in a rat model.

Protective effect of Gingko biloba extract against doxorubicin-induced cardiotoxicity in mice.

Doxorubicin (DXR) causes dose dependent cardiotoxicity in experimental animals and in humans. In chronic doxorubicin cardiotoxicity model mice, the role of G. biloba extract (Gbe) which has an antioxidant property, was investigated. Doxorubicin treated animals showed higher mortality (68%), increased ascites, marked bradycardia, prolongation of ST and QT intervals and widening of QRS complex. Myocardial SOD and glutathione peroxidase activity were decreased and lipid peroxidation was increased. Ultrastructure of heart of DXR treated animals showed loss of myofibrils, swelling of mitochondria, vacuolization of mitochondria. G. biloba extract significantly protected the mice from cardiotoxic effects of doxorubicin as evidenced by lowered mortality, ascites, myocardial lipid peroxidation, normalization of antioxidant enzymes, reversal of ECG changes and minimal ultrastructural damage of the heart. The results indicate that administration of G. biloba extract protected mice from doxorubicin-induced cardiotoxicity.

Reversal of catecholamine induced cardiomyopathy in a patient with bilateral malignant pheochromocytoma.

A patient of catecholamine induced cardiomyopathy (CMP) due to bilateral malignant adrenal pheochromocytoma (PCC), successfully reversed on treatment is described here. To the best of our knowledge, this is first report of catecholamine induced CMP due to bilateral malignant adrenal PCC, which could be reversed after surgery.