Genome-wide analysis in PC6 electroacupuncture to ameliorate carfilzomib-induced cardiotoxicity in mice.

Carfilzomib (CFZ), a proteasome inhibitor commonly used in the treatment of multiple myeloma (MM), exhibits limited clinical application due to its cardiotoxicity. In our study, electroacupuncture (EA) at Neiguan acupoint (PC6) effectively reversed CFZ-induced reduction in ejection fraction (EF) and fractional shortening (FS), demonstrating great potential effect for heart protection. Through comparative analysis of the transcriptome profile from heart samples of mice treated with DMSO control, CFZ injection, and EA stimulation, we identified a total of 770 differentially expressed genes (DEGs) in CFZ (vs. Control) group and 329 DEGs in EA (vs. CFZ) group. Specifically, CFZ (vs. Control) group exhibited 65 up-regulated DEGs and 705 down-regulated DEGs, while EA (vs. CFZ) group displayed 251 up-regulated DEGs and 78 down-regulated DEGs. Metascape analysis revealed that among these treatment groups, there were 137 co-expressed DEGs remarkably enriched in skeletal system development, cellular response to growth factor stimulus, negative regulation of Wnt signaling pathway, and muscle contraction. The expression patterns of miR-8114, Myl4, Col1a1, Tmem163, Myl7, Sln, and Fxyd3, which belong to the top 30 DEGs, were verified by quantitative real-time PCR (RT-qPCR). In summary, this study firstly discloses novel insights into the regulatory mechanisms underlying PC6-based EA therapy against CFZ-induced cardiotoxicity, potentially serving as a theoretical foundation for further clinical applications.

Extract from Arrabidaea chica (Fridericia chica) leaves show preventive action for the mitigation of doxorubicin-induced cardiotoxicity / [Extrato das folhas de Arrabidaea chica (Fridericia chica) mostrou potencial ação no combate à cardiotoxicidade induzida pela doxorrubicina]

A doxorrubicina (dox) é um medicamento antineoplásico que induz cardiotoxicidade por estresse oxidativo. Os flavonoides são antioxidantes extraídos de plantas como Camellia sinensis e Arrabidaea chica (Fridericia chica). Esta pesquisa objetivou avaliar efeitos protetores do extrato de A. chica (AC), comparado ao de C. sinensis (CS), frente ao estresse oxidativo induzido pela dox, no coração. Cardiomiócitos e células neoplásicas MDA-MB 231 foram incubados com AC e CS. Depois, adicionou-se dox e avaliaram-se taxas de viabilidade e morte celular. A citometria de fluxo para o ensaio de iodeto de propídeo (IP) em cardiomiócitos mostrou as seguintes taxas de morte celular: controle 53%; dox 78% (maior que controle, P=0,015); AC_12,5µg/mL + dox 65% (menor que dox, P=0,031); AC_25µg/mL + dox 62% (menor que dox, P=0,028); AC_50µg/mL + dox 63% (menor que dox, P=0,030); CS_12,5µg/mL + dox 71% (menor que dox, P=0,040); CS_25µg/ml + dox 69% (menor que dox, P=0,037); CS_50µg/mL + dox 74% (menor que dox, P=0,044). Resultados das células MDA-MB 231 mostraram que nenhum extrato interferiu na atividade antitumoral da dox. Os dados de IP foram corroborados pelos de MTT. Este estudo reporta promissora utilização de A. chica na prevenção da cardiotoxicidade induzida pela dox.(AU)

Exercise as a diagnostic and therapeutic tool for preventing cardiovascular morbidity in breast cancer patients- the BReast cancer EXercise InTervention (BREXIT) trial protocol.

BACKGROUND: Anthracycline chemotherapy (AC) is an efficacious (neo) adjuvant treatment for early-stage breast cancer (BCa), but is associated with an increased risk of cardiac dysfunction and functional disability. Observations suggest that regular exercise may be a useful therapy for the prevention of cardiovascular morbidity but it is yet to be interrogated in a large randomised trial. The primary aims of this study are to: 1) determine if 12-months of ET commenced at the onset of AC can reduce the proportion of BCa patients with functional disability (peak VO2, < 18 ml/kg/min), and 2) compare current standard-of-care for detecting cardiac dysfunction (resting left-ventricular ejection fraction assessed from 3-dimensional echocardiography) to measures of cardiac reserve (peak exercise cardiac output assessed from exercise cardiac magnetic resonance imaging) for predicting the development of functional disability 12-months following AC. Secondary aims are to assess the effects of ET on VO2peak, left ventricular morphology, vascular stiffness, cardiac biomarkers, body composition, bone mineral density, muscle strength, physical function, habitual physical activity, cognitive function, and multidimensional quality of life. METHODS: One hundred women with early-stage BCa (40-75 years) scheduled for AC will be randomized to 12-months of structured exercise training (n = 50) or a usual care control group (n = 50). Participants will be assessed at baseline, 4-weeks following completion of AC (4-months) and at 12-months for all measures. DISCUSSION: Women diagnosed with early-stage BCa have increased cardiac mortality. More sensitive strategies for diagnosing and preventing AC-induced cardiovascular impairment are critical for reducing cardiovascular morbidity and improving long-term health outcomes in BCa survivors. TRIAL REGISTRATION: Australia & New Zealand Clinical Trials Registry (ANZCTR), ID: 12617001408370 . Registered on 5th of October 2017.

[Application of a shared interdisciplinary and multiprofessional cardio-oncology in-hospital pathway]. / Applicazione di un percorso diagnostico-terapeutico assistenziale di cardioncologia per la rilevazione e la gestione del danno cardiaco da trattamenti oncologici in ambito ospedaliero.

The burden of cardiac side effects in oncology patients will dramatically increase in the near future as a result of the widespread use of anticancer agents affecting the cardiovascular system, the general population aging, the heightened attention in the detection of cardiac toxicity and the absolute gain in terms of overall survival. The relationship between cardiologists and oncologists should therefore be closer leading to the definition of cardio-oncology. The increased number of such patients requires the creation of a dedicated patient assistance program in order to guarantee every patient the possibility of an interdisciplinary and multiprofessional approach. A dedicated care pathway needs a reorganization of internal resources to ensure high standards of care. The proposed pathway is actually active at our institution and has been implemented taking into account available facilities and planned work amount. Our patient cardio-oncology program could be adapted with minimal changes to different hospitals.

Ação do extrato etanólico da casca do pequi (Caryocar brasiliense) na cardiotoxicidade crônica induzida por doxorrubicina em ratos / Caryocar brasiliense shell ethanol extract in chronic cardiotoxicity induced by doxorubicin in rats

A doxorrubicina (DOX) é um quimioterápico utilizado no tratamento de neoplasias malignas, porém possui a cardiotoxicidade como efeito colateral. O objetivo deste trabalho foi verificar quanto à ação do extrato etanólico da casca do pequi (Caryocar brasiliense) (EECP) por meio de avaliação morfológica (macroscópica, microscópica e ultramicroscópica), bem como avaliar a expressão de metaloproteinases (MMP2 e MMP9) e seus inibidores teciduais (TIMP1 e TIMP2) no miocárdio de ratos submetidos à cardiotoxicidade crônica pela DOX, tratados ou não com o EECP. O experimento teve duração de três meses e foram utilizados 30 ratos da raça Wistar, distribuídos em seis grupos de cinco animais. G1 e G2 receberam como pré-tratamento 300mg/kg e 600mg/kg de EECP, respectivamente, por gavagem, durante sete dias e mantiveram o tratamento durante os 21 dias de aplicação da DOX. Em G1, G2, G3, G4 e GC, a cardiotoxicidade foi induzida com aplicações semanais de 2mg/kg de DOX, via intraperitoneal, totalizando quatro aplicações (8mg/kg) e, nos ratos do grupo Sham (GS), foi aplicado 1ml de solução fisiológica. Os animais do G3 receberam diariamente 300mg/kg e os do G4 600mg/kg de EECP, por gavagem, durante os 21 dias de aplicação da DOX. Os do GC e GS receberam 1 ml de água, diariamente, também por gavagem. Após o término das aplicações, os animais foram mantidos por dois meses, totalizando três meses de experimento. A avaliação macroscópica foi realizada após 90 dias, momento em que foram colhidas amostras para análise em microscopia eletrônica, histopatologia e imunoistoquímica. Ao exame necroscópico foi observada ascite nos animais que receberam DOX. Houve baixo índice de mortalidade (3,33%), representado pela morte de um rato que desenvolveu pneumonia por falsa via. Não foi observada alteração no peso e nas medidas do coração dos ratos. Nas doses de 300 e 600mg/kg, o EECP atenuou a degeneração vacuolar miocítica. Na dose de 600mg/kg, o EECP reduziu a quantidade de células de Anitschkow e a fragmentação das miofibrilas. Não houve resultado significativo quanto à imunomarcação das MMP e, quanto a seus inibidores (TIMP), houve maior imunomarcação de TIMP2 no GC, grupo que recebeu apenas DOX. Concluiu-se que o extrato etanólico da casca do pequi (EECP) é eficiente em minimizar os efeitos da cardiotoxicidade crônica induzida pela DOX no miocárdio de ratos, considerando que nas doses de 300 e 600mg/kg o EECP atenua a degeneração vacuolar miocítica e, na dose de 600mg/kg, o EECP reduz a quantidade de células de Anitschkow e a fragmentação das miofibrilas.(AU)

Doxorubicin (DOX) is a chemotherapic drug used in the treatment of malignancies, but has the cardiotoxicity as collateral effect. The objective of this study was to evaluate the action of pequi shell etanolic extract (Caryocar brasiliense) (PSEE) through morphological evaluation (macroscopic, microscopic and ultramicroscopic), and to evaluate the expression of metalloproteinases (MMP2 and MMP9) and its tissue inhibitors (TIMP1 and TIMP2) in the myocardium of rats with chronic cardiotoxicity by DOX and treated or not with PSEE. The experiment lasted three months and 30 Wistar rats were divided into six groups of five animals. G1 and G2 received 300mg/kg and 600mg/kg of PSEE, respectively, as pretreatment, by gavage for seven days and continued treatment for 21 days of application of DOX. In G1, G2, G3, G4 and GC, cardiotoxicity was induced with weekly applications of 2mg/kg DOX, intraperitoneally, totaling four applications (8 mg/kg), and in the Sham group (GS) 1ml of saline solution was applied. G3 animals received daily 300mg/kg of PSEE, and G4, 600mg/kg, by gavage, for 21 days of application of DOX. The GC and GS received 1ml of water daily by gavage also. After the completion of the application, the animals were kept for two months, with three months of experiment. Macroscopic evaluation was performed after 90 days, at which time samples were taken for analysis in electron microscopy, histopathology and immunohistochemistry. At necropsy, ascites was observed in animals that received DOX. There was a low mortality rate (3.33%), being one mouse that developed false road pneumonia. There was no change in weights and measures of the rat hearts. At doses of 300 and 600mg/kg, the PSEE attenuates myocyte vacuolar degeneration. At a dose of 600mg/kg, PSEE reduces amount Anitschkow cells. There was no significant result on the immunostaining of MMP, but considering their inhibitors (TIMP) there was a greater immunostaining of TIMP2 in GC, the group that received only DOX. It was concluded that PSEE is effective in minimizing effects of chronic cardiotoxicity induced by DOX in the myocardium of rats, whereas at doses of 300 and 600mg/kg, PSEE attenuates vacuolar degeneration in myocytes and at the dose of 600mg/kg the PSEE reduces the amount of Anitschkow cells and myofibrils fragmentation.(AU)