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1.
Mayo Clin Proc ; 94(9): 1852-1864, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451292

RESUMO

Physical inactivity and psychosocial stress are prevalent in residents of the United States. The purpose of this article is to review the interaction between these 2 conditions and examine the effects of exercise on stress and cardiovascular (CV) health. A query of scientific references between 1974 to 2018 was performed using the PubMed search engine accessing the MEDLINE database using the search terms psychosocial stress, CV disease (CVD), physical activity, exercise, cardiac rehabilitation, and team sports. Psychosocial stress is a strong independent risk factor for adverse CV events. Conversely, people who experience CV events subsequently have drastically elevated rates of new-onset mental health disorders, including depression and anxiety. Psychosocial stress and CVD often trigger self-reinforcing feedback loops that can worsen mental health and cardiac prognosis. Exercise predictably improves CV health and prognosis and also is effective at lowering levels of psychosocial stress. Group exercise in particular seems to provide social support while at the same time boosting fitness levels and, thus, may be the single most important intervention for patients with concomitant CVD and emotional stress. Collaborative physical activity, such as group exercise, team sports, interactive physical play, and cardiac rehabilitation programs, have the potential to improve mental health and CV prognosis.


Assuntos
Cardiotoxicidade/etiologia , Transtorno Depressivo/prevenção & controle , Exercício/fisiologia , Aptidão Física/fisiologia , Comportamento Sedentário , Estresse Psicológico/complicações , Ansiedade/etiologia , Ansiedade/prevenção & controle , Cardiotoxicidade/fisiopatologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Transtorno Depressivo/etiologia , Feminino , Humanos , Estilo de Vida , Masculino
2.
Am J Chin Med ; 47(5): 1075-1097, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31311298

RESUMO

Pirarubicin (THP) is an anthracycline antibiotic, frequently used for the treatment of various human cancers. Unfortunately, the clinical effectiveness of THP is limited by its dose-related cardiotoxicity. Apocynum leaf extract is an extract of the dried leaves of Apocynum venetum L. (a member of the Apocynaceae family, AVLE) that has many positive effects on the cardiovascular system and is widely consumed as tea in China. In this study we established a cardiactoxicity rat model, which showed that pretreatment with AVLE attenuated THP-induced myocardial histopathological injury, electrocardiogram abnormalities, and cardiac dysfunction. AVLE also significantly reduced serum levels of malondialdehyde (MDA), brain natriuretic peptide (BNP), creatine kinase (CK-MB), cardiac troponin (CTnT), and lactate dehydrogenase (LDH); and increased serum superoxide dismutase (SOD) levels. Treatment with AVLE or dexrazoxane (DZR) resulted in an increase Cytochrome C (cytc) in the mitochondria and reduced Cytc and cleaved-caspase-3 levels (p<0.05) in cytoplasm. We also found that AVLE significantly reduced voltage-dependent anion channel 1 (VDAC1), adenosine nucleotide transporter 1 (ANT1), and cyclophilin D (CYPD) mRNA expression (p<0.05). Furthermore, AVLE appeared to exert therapeutic effects in a dose-dependent manner. Our study suggests the anti-oxidant and anti-apoptotic properties of AVLE may be responsible for the observed cardioprotective effects.


Assuntos
Antioxidantes/administração & dosagem , Apocynum/química , Cardiotoxicidade/prevenção & controle , Medicamentos de Ervas Chinesas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Creatina Quinase/genética , Creatina Quinase/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Humanos , Masculino , Malondialdeído/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Folhas de Planta/química , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Troponina/genética , Troponina/metabolismo
3.
Pediatr Blood Cancer ; 66(9): e27868, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31148382

RESUMO

BACKGROUND: Treatment-associated cardiomyopathy is a leading cause of morbidity and mortality for childhood cancer survivors (CCS). As evidence is not available to guide the management of CCS at risk for cardiomyopathy, we aim to describe the collective opinion of regional experts for the care of these patients using a consensus-based Delphi methodology. PROCEDURE: Nineteen physicians from the New England region who care for CCS treated with cardiotoxic therapy (anthracyclines, thoracic radiation) participated in a Delphi panel querying their management approach, using three rounds of anonymous questionnaires formatted as five clinical scenarios. Consensus ≥ 89% agreement. RESULTS: The response rate was 100% for the first round and 95% for subsequent rounds. Panelists reached consensus on screening asymptomatic CCS with serial echocardiograms (94%) and electrocardiograms (89%), with some disagreement on frequency during pregnancy (83%). All panelists agreed with exercise promotion, with no restrictions on weight training. Consensus was reached on indications for referrals; cardiology for asymptomatic left ventricular dysfunction (ALVD) (100%) and maternal-fetal medicine for pregnancy (94%). In the scenario of ALVD, there was disagreement on the benefit of additional cardiac testing (50% cardiologists recommended cardiac MRI), and although all panelists endorsed treating with angiotension-converting enzyme (ACE) inhibitors, most adult cardiologists (75%) also recommended therapy with beta blockers, compared with none of the pediatric cardiologists or primary-care physicians. CONCLUSIONS: Despite a lack of evidence to guide the management of CCS at risk for cardiomyopathy, a panel of regional physicians reached consensus on managing most clinical scenarios. A controversial area requiring further study is the medical management of ALVD.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Antraciclinas , Sobreviventes de Câncer , Cardiomiopatias , Cardiotoxicidade , Cuidadores , Ecocardiografia , Eletrocardiografia , Neoplasias/tratamento farmacológico , Inquéritos e Questionários , Adulto , Antraciclinas/administração & dosagem , Antraciclinas/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiomiopatias/prevenção & controle , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/fisiopatologia , Cardiotoxicidade/prevenção & controle , Criança , Técnica Delfos , Feminino , Humanos , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle
4.
Hum Exp Toxicol ; 38(9): 1111-1124, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31179749

RESUMO

Cardiotoxicity is one of the most significant reasons of attrition in drug development. The present study assessed the sensitivity of various endpoints for early monitoring of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiac cells, including precursors as well as mature cardiomyocytes, by correlating changes in cardiac biomarker expression. Directed differentiation was induced and cardiac progenitor cell (CPC) population were treated with cardiotoxic drugs, namely, doxorubicin (Dox) and paclitaxel (Pac), and with noncardiotoxic drug, namely penicillin G. To assess cardiac-specific toxicity, the changes in the expression of key markers of cardiac lineage, such as Nkx2.5, Tbx5, α-myosin heavy chain α-MHC, and cardiac troponin T, were studied using quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry (FC). The half-maximal inhibition in the expression of these cardiac markers was analyzed from the dose-response curves. We also assessed the half-maximal inhibition (IC50) in cardiac cells using propidium iodide dye (IC50 PI) and by measuring disruption in the mitochondrial membrane potential (IC50 MMP). We observed that the most sensitive marker was α-MHC in the case of both Dox and Pac, and the order of sensitivity of the various prediction assays was MMP > protein expression by FC > gene expression by qRT-PCR > cell viability by PI staining. The results could enrich the screening of drug-induced cardiotoxicity in vitro and propose disruption in MMP along with downregulation of α-MHC protein as a potential biomarker of predicting cardiotoxicity earlier during drug safety evaluation.


Assuntos
Cardiotoxicidade/fisiopatologia , Doxorrubicina/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Paclitaxel/toxicidade , Biomarcadores/metabolismo , Cardiotoxicidade/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína Homeobox Nkx-2.5/genética , Humanos , Miócitos Cardíacos/fisiologia , Cadeias Pesadas de Miosina/genética , Penicilina G/farmacologia , Proteínas com Domínio T/genética
5.
Integr Cancer Ther ; 18: 1534735419843999, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30999765

RESUMO

INTRODUCTION: Doxorubicin (DOX) is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction (CR) and exercise have well-documented cardioprotective effects. No studies have investigated the effects of CR alone or the combined effects of CR and exercise on DOX cardiotoxicity. METHODS: Rats were divided into 4 groups based on their food intake (ad libitum or CR) and activity (sedentary or voluntary wheel running [WR]). After completing a 16-week treatment, animals received either DOX (15 mg/kg) or saline (SAL) and cardiac function was measured 5 days after treatment. Chromatography was used to quantify left ventricular DOX accumulation. RESULTS: Left ventricular developed pressure (LVDP), end systolic pressure (ESP), and left ventricular maximal rate of pressure development (dP/dtmax) were significantly higher in the CR + DOX group when compared with DOX. Fractional shortening, LVDP, ESP, dP/dtmax, and dP/dtmin were significantly higher in the CR + WR + DOX group compared with the DOX group. In addition, the CR + WR + DOX group showed significantly higher LVDP and ESP compared with the WR + DOX group. DOX accumulation in the heart was 5-fold lower ( P < .05) in the CR + WR + DOX group compared with the DOX group. CONCLUSION: This is the first study to demonstrate that CR can reduce cardiac DOX accumulation, and confirms the protective role of CR against DOX-induced cardiac dysfunction. Our data also show that combining a known cardioprotective intervention, exercise training, with CR results in additive benefits in the protection against DOX cardiotoxicity.


Assuntos
Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Doxorrubicina/efeitos adversos , Condicionamento Físico Animal/fisiologia , Animais , Pressão Sanguínea/fisiologia , Restrição Calórica/métodos , Feminino , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Ratos , Ratos Sprague-Dawley , Corrida/fisiologia
6.
Food Funct ; 10(5): 2651-2657, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31025676

RESUMO

Recurrent cardiotoxicity limits the clinical application of doxorubicin (DOX); however the detailed molecular mechanism of DOX cardiotoxicity remains unclear. In the current study, we found that a natural product extracted from Illicium verum, isodunnianol (IDN), mitigates DOX-induced cardiotoxicity by regulating autophagy and apoptosis both in vitro and in vivo. DOX suppressed protective autophagy and induced apoptosis in H9C2 cardiac myoblasts. Additionally, IDN demonstrated up-regulated autophagy and reduced apoptosis through the activation of the AMPK-ULK1 pathway. In addition, the beneficial effects of IDN on DOX which induced myocardial injury were dependent on AMPK and ULK1 phosphorylation. Similar results were also observed in a DOX-induced cardiotoxicity rat model. The combination of IDN and DOX resulted in decreased apoptosis and inflammatory myocardial fibrosis compared to the DOX mono-treatment group. In summary, our findings provide novel insights into the prevention of DOX-related toxicity by isodunnianol, a food source natural product, warranting further investigation.


Assuntos
Antineoplásicos/efeitos adversos , Autofagia/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Illicium/química , Sesquiterpenos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Humanos , Masculino , Mioblastos Cardíacos/citologia , Mioblastos Cardíacos/efeitos dos fármacos , Mioblastos Cardíacos/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ratos , Ratos Sprague-Dawley
7.
PLoS One ; 14(4): e0215992, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31034488

RESUMO

The clinical use of the chemotherapeutic doxorubicin (Dox) is limited by cardiotoxic side-effects. One of the early Dox effects is induction of a sarcoplasmic reticulum (SR) Ca2+ leak. The chaperone Glucose regulated protein 78 (GRP78) is important for Ca2+ homeostasis in the endoplasmic reticulum (ER)-the organelle corresponding to the SR in non-cardiomyocytes-and has been shown to convey resistance to Dox in certain tumors. Our aim was to investigate the effect of cardiac GRP78 gene transfer on Ca2+ dependent signaling, cell death, cardiac function and survival in clinically relevant in vitro and in vivo models for Dox cardiotoxicity.By using neonatal cardiomyocytes we could demonstrate that Dox induced Ca2+ dependent Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activation is one of the factors involved in Dox cardiotoxicity by promoting apoptosis. Furthermore, we found that adeno-associated virus (AAV) mediated GRP78 overexpression partly protects neonatal cardiomyocytes from Dox induced cell death by modulating Ca2+ dependent pathways like the activation of CaMKII, phospholamban (PLN) and p53 accumulation. Most importantly, cardiac GRP78 gene therapy in mice treated with Dox revealed improved diastolic function (dP/dtmin) and survival after Dox treatment. In conclusion, our results demonstrate for the first time that Ca2+ dependent CaMKII activation fosters Dox cardiomyopathy and provide additional insight into possible mechanisms by which GRP78 overexpression protects cardiomyocytes from Doxorubicin toxicity.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotoxicidade/enzimologia , Cardiotoxicidade/patologia , Doxorrubicina/toxicidade , Proteínas de Choque Térmico/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Cardiotoxicidade/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Homeostase , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Fosforilação , Ratos , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo
8.
Indian J Tuberc ; 66(1): 184-188, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30878066

RESUMO

BACKGROUND: Drug-Resistant Tuberculosis (DR-TB) patients for whom a WHO recommended regimen along with Bedaquiline (BDQ) cannot be prescribed, Delamanid (DLM) was added along with other drugs to provide a "Salvage Regimen". The experience of the Institute in respect of early efficacy and safety of both drugs given together is presented. OBJECTIVE: To ascertain the early efficacy, safety and tolerability of Bedaquline and Delamanid given together as a part of salvage regimen. METHODS: BDQ and DLM were used together to make regimens along with other drugs where four effective anti TB drugs could not be prescribed as per WHO recommendations. Patients were followed up for sputum smear and culture conversion and adverse events during the treatment. RESULTS: In this cohort study, 53 DR-TB patients (Median age-24) were initiated on regimens containing both BDQ and DLM. Sputum smear conversion was seen in 35% and 94% patients at the end of 1st week and 3rd month respectively. 84% patients had culture conversion at the end of 4th month. 29 adverse events (AE) were reported among 17 patients and there were 11 deaths. QTc prolongation more than 500 MS was seen in only 1 patient. CONCLUSION: BDQ and DLM given together in a salvage regimen is efficacious with low rate of adverse events. The combination provides hope to DR-TB patients with limited treatment options and should be provided as a life saving option.


Assuntos
Diarilquinolinas/uso terapêutico , Nitroimidazóis/uso terapêutico , Oxazóis/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Clofazimina/uso terapêutico , Diarilquinolinas/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Eletrocardiografia , Feminino , Humanos , Imipenem/uso terapêutico , Masculino , Moxifloxacina/uso terapêutico , Nitroimidazóis/efeitos adversos , Oxazóis/efeitos adversos , Terapia de Salvação/métodos , Escarro/microbiologia , Taxa de Sobrevida , Adulto Jovem
9.
Indian J Tuberc ; 66(1): 209-213, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30878071

RESUMO

BACKGROUND: Bedaquiline (BDQ) was approved for treatment of drug resistant TB (DR-TB) under Conditional Access Programme (CAP) of Revised National Tuberculosis Control Programme (RNTCP) and was also implemented in the National Institute of TB and Respiratory Diseases (NITRD). We present early efficacy and safety of BDQ containing regimens for DR-TB. OBJECTIVE: To ascertain the early efficacy and safety of Bedaquline containing regimens in treatment of DR-TB. METHODS: BDQ containing regimens along with other drugs were designed as per WHO recommendations for DR-TB patients. They were followed up for sputum smear and culture conversion, adverse events during the treatment. RESULTS: A cohort of 290 DR-TB patients (Median age-29.77) were initiated on BDQ containing regimens. Of the available Sputum results, smear conversion was seen in 51% and 91% patients at the end of 1st week and 3rd month respectively. Similarly, 93% and 98% patients had culture conversion at the end of 3rd and 6th month respectively. 201 adverse events (AE) including 47 deaths were reported among 109 patients. QTc prolongation was seen in 29% patients but only 4 required discontinuation of BDQ. Lost to follow up of treatment was about 6%. CONCLUSION: Bedaquiline along with an optimized background regimen has shown early sputum conversion in larger number of difficult to treat patients having additional resistance of second line drugs along with INH and Rifampicin. The regimen is feasible in programmatic conditions and is relatively safe.


Assuntos
Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Antituberculosos/efeitos adversos , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Clofazimina/uso terapêutico , Ciclosserina/uso terapêutico , Diarilquinolinas/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Eletrocardiografia , Etionamida/uso terapêutico , Feminino , Humanos , Índia , Linezolida/uso terapêutico , Masculino , Moxifloxacina/uso terapêutico , Programas Nacionais de Saúde , Escarro/microbiologia , Fatores de Tempo
10.
Echocardiography ; 36(3): 495-502, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30636342

RESUMO

BACKGROUND: Anthracycline-related cardiotoxicity has a poor prognosis; therefore, early detection of any change in LV function is critical. OBJECTIVE: The aim of this study was to evaluate the two-dimensional speckle tracking technique for the early detection of cardiac toxicity after low-dose anthracycline chemotherapy in the Chinese population. METHODS: Forty breast cancer patients were treated by chemotherapy using anthracycline for 4-6 cycles. Patients were examined by echocardiography before chemotherapy (T0) and after the second (T2), fourth (T4), and sixth (T6) cycle. LV ejection fraction (LVEF), LV global longitudinal strain (GLS) and endocardium, mid-myocardium, and epicardium global longitudinal strain (GLS-Endo, GLS-Mid, and GLS-Epi). Additionally, global circumferential strain (GCS), RV global longitudinal strain (RVGLS), and LA global longitudinal strain (LAGLS) were evaluated. RESULTS: Left ventricular ejection fraction was significantly reduced at T4 (P < 0.05). Compared with T0, GLS, GLS-Endo, GLS-Mid, and GLS-Epi were significantly reduced at T2, T4, and T6 (P < 0.05 for all), the apical septum wall (AS) was also reduced significantly at T2 (P < 0.05), and the apical anterior wall (AA) and the basal anterior wall (BA) longitudinal strains were significantly reduced at T4 (P < 0.05). GCS, RVGLS, and LAGLS were not significantly changed after treatment (P > 0.05). CONCLUSIONS: LV stratified strains and strain of the segments supplied by the left anterior descending coronary artery are more sensitive to the cardiac toxicity of anthracycline.


Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Ecocardiografia , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adulto , Antraciclinas/uso terapêutico , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/fisiopatologia , China , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Disfunção Ventricular Esquerda/fisiopatologia
11.
Hum Exp Toxicol ; 38(1): 45-55, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29774748

RESUMO

Trazodone (TRZ) is an antidepressant drug commonly used in the treatment of depression, anxiety, and insomnia. Although some studies demonstrated the adverse effects of TRZ related to cardiovascular system, the conflicting results were observed in these studies. Therefore, we aimed to investigate the cardiac adverse effects of TRZ in rats at repeated doses in our study. In accordance with this purpose, TRZ was administered orally to rats at 5, 10, and 20 mg/kg doses for 28 days. Electrocardiogram records, serum aspartate aminotransferase (AST), lactate dehydrogenase, creatine kinase-myoglobin band, cardiac troponin-T (cTn-T) levels, DNA damage in cardiomyocytes, and histologic view of heart tissues were evaluated. In addition, glutathione (GSH) and malondialdehyde (MDA) levels were measured to determine the oxidative status of cardiac tissue after TRZ administration. Heart rate was decreased, PR interval was prolonged, and QRS and T amplitudes were decreased in 20 mg/kg TRZ-administered group compared to the control group. Serum AST and cTn-T levels were significantly increased in 10 and 20 mg/kg TRZ-administered rats with respect to control rats. DNA damage was significantly increased in these groups. Additionally, degenerative histopathologic findings were observed in TRZ-administered groups. Although there was no difference in MDA levels between groups, GSH levels were significantly decreased in 10 and 20 mg/kg TRZ-administered groups compared to the control group. Our results have shown that TRZ induced cardiotoxicity in rats dose-dependently. It is assumed that oxidative stress related to GSH depletion may be accompanied by these adverse effects.


Assuntos
Antidepressivos de Segunda Geração/toxicidade , Cardiotoxicidade , Trazodona/toxicidade , Administração Oral , Animais , Aspartato Aminotransferases/sangue , Cardiotoxicidade/sangue , Cardiotoxicidade/patologia , Cardiotoxicidade/fisiopatologia , Dano ao DNA , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Troponina T/sangue
12.
J Mol Cell Cardiol ; 126: 129-139, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30500377

RESUMO

Cardiac failure is a common complication in cancer survivors treated with anthracyclines. Here we followed up cardiac function and excitation-contraction (EC) coupling in an in vivo doxorubicin (Dox) treated mice model (iv, total dose of 10 mg/Kg divided once every three days). Cardiac function was evaluated by echocardiography at 2, 6 and 15 weeks after the last injection. While normal at 2 and 6 weeks, ejection fraction was significantly reduced at 15 weeks. In order to evaluate the underlying mechanisms, we measured [Ca2+]i transients by confocal microscopy and action potentials (AP) by patch-clamp technique in cardiomyocytes isolated at these times. Three phases were observed: 1/depression and slowing of the [Ca2+]i transients at 2 weeks after treatment, with occurrence of proarrhythmogenic Ca2+ waves, 2/compensatory state at 6 weeks, and 3/depression on [Ca2+]i transients and cell contraction at 15 weeks, concomitant with in-vivo defects. These [Ca2+]i transient alterations were observed without cellular hypertrophy or AP prolongation and mirrored the sarcoplasmic reticulum (SR) Ca2+ load variations. At the molecular level, this was associated with a decrease in the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) expression and enhanced RyR2 phosphorylation at the protein kinase A (PKA, pS2808) site (2 and 15 weeks). RyR2 phosphorylation at the Ca2+/calmodulin dependent protein kinase II (CaMKII, pS2814) site was enhanced only at 2 weeks, coinciding with the higher incidence of proarrhythmogenic Ca2+ waves. Our study highlighted, for the first time, the progression of Dox treatment-induced alterations in Ca2+ handling and identified key components of the underlying Dox cardiotoxicity. These findings should be helpful to understand the early-, intermediate-, and late- cardiotoxicity already recorded in clinic in order to prevent or treat at the subclinical level.


Assuntos
Cardiotoxicidade/fisiopatologia , Doxorrubicina/efeitos adversos , Acoplamento Excitação-Contração , Potenciais de Ação , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Testes de Função Cardíaca , Masculino , Camundongos Endogâmicos C57BL , Retículo Sarcoplasmático/metabolismo , Fatores de Tempo
13.
J Clin Oncol ; 37(1): 12-21, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30379624

RESUMO

PURPOSE: Late cardiotoxicity after pediatric acute myeloid leukemia therapy causes substantial morbidity and mortality. The impact of early-onset cardiotoxicity on treatment outcomes is less well understood. Thus, we evaluated the risk factors for incident early cardiotoxicity and the impacts of cardiotoxicity on event-free survival (EFS) and overall survival (OS). METHODS: Cardiotoxicity was ascertained through adverse event monitoring over the course of follow-up among 1,022 pediatric patients with acute myeloid leukemia treated in the Children's Oncology Group trial AAML0531. It was defined as grade 2 or higher left ventricular systolic dysfunction on the basis of Common Terminology Criteria for Adverse Events (version 3) definitions. RESULTS: Approximately 12% of patients experienced cardiotoxicity over a 5-year follow-up, with more than 70% of incident events occurring during on-protocol therapy. Documented cardiotoxicity during on-protocol therapy was significantly associated with subsequent off-protocol toxicity. Overall, the incidence was higher among noninfants and black patients, and in the setting of a bloodstream infection. Both EFS (hazard ratio [HR], 1.6; 95% CI, 1.2 to 2.1; P = .004) and OS (HR, 1.6; 95% CI, 1.2 to 2.2, P = .005) were significantly worse in patients with documented cardiotoxicity. Impacts on EFS were equivalent whether the incident cardiotoxicity event occurred in the absence (HR, 1.6; 95% CI, 1.1 to 2.2; P = .017) or presence of infection (HR, 1.6; 95% CI, 1.0 to 2.7; P = .069) compared with patients without documented cardiotoxicity. However, the reduction in OS was more pronounced for cardiotoxicity not associated with infection (HR, 1.7; 95% CI, 1.2 to 2.5; P = .004) than for infection-associated cardiotoxicity (HR, 1.3; 95% CI, 0.7 to 2.4; P = .387). CONCLUSION: Early treatment-related cardiotoxicity may be associated with decreased EFS and OS. Cardioprotective strategies are urgently needed to improve relapse risk and both short- and long-term mortality outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Leucemia Mieloide Aguda/tratamento farmacológico , Cardiotoxicidade/diagnóstico por imagem , Criança , Pré-Escolar , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Intervalo Livre de Doença , Ecocardiografia , Humanos , Incidência , Lactente , Recém-Nascido , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , Modelos de Riscos Proporcionais , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento
14.
Mol Biol Rep ; 46(1): 105-118, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30362071

RESUMO

Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague-Dawley rats were pre-treated with either fisetin (10, 20 and 40 mg/kg) or sitagliptin (10 mg/kg, p.o.) for 7 days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15 mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p < 0.05) inhibited by fisetin (20 and 40 mg/kg) treatment. Fisetin significantly decrease (p < 0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p < 0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-α, and IL-1ß mRNA, as well as protein expressions were significantly decreased (p < 0.05) by fisetin treatment. It also significantly (p < 0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-α, and IL-1ß), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Flavonoides/metabolismo , Flavonoides/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiotoxicidade/fisiopatologia , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Coração , Inflamação/patologia , Masculino , Miocárdio/metabolismo , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Troponina I/efeitos dos fármacos , Troponina I/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
15.
Yonsei Med J ; 60(1): 30-37, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30554488

RESUMO

PURPOSE: The present study aimed to investigate correlations between uridine glucuronosyltransferase 2B7 (UGT2B7) -161 single nucleotide polymorphism C to T (C>T) and the occurrence of cardiotoxicity in Chinese breast cancer (BC) patients undergoing epirubicin/cyclophosphamide-docetaxel (EC-D) adjuvant chemotherapy. MATERIALS AND METHODS: 427 BC patients who had underwent surgery were consecutively enrolled in this prospective cohort study. All patients were scheduled to receive EC-D adjuvant chemotherapy regimen, and they were divided into UGT2B7 -161 CC (n=141), UGT2B7 -161 CT (n=196), and UGT2B7 -161 TT (n=90) groups according to their genotypes. Polymerase chain reaction was performed for determination of UGT2B7 -161 genotypes. Cardiotoxicity was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10% points from baseline to a value less than 53%, heart failure, acute coronary artery syndrome, or fatal arrhythmia. RESULTS: LVEF values were lower at cycle (C) 4, C8, 3 months after chemotherapy (M3), M6, M9, and M12 compared to C0 (all p<0.001), in BC patients undergoing EC-D adjuvant chemotherapy. Cardiotoxicity was recorded for 4.2% of the overall population and was lowest in the UGT2B7 -161 TT group (1.1%), compared to UGT2B7 -161 CT (3.1%) and UGT2B7 -161 CC (7.8%) group (p=0.026). Multivariate logistic regression revealed that UGT2B7 -161 T allele could independently predict a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy (p=0.004). CONCLUSION: A UGT2B7 -161 T allele serves as a potential biomarker for predicting a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Cardiotoxicidade/genética , Ciclofosfamida/efeitos adversos , Docetaxel/efeitos adversos , Epirubicina/efeitos adversos , Glucuronosiltransferase/genética , Polimorfismo de Nucleotídeo Único/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotoxicidade/fisiopatologia , Quimioterapia Adjuvante , Ciclofosfamida/uso terapêutico , Docetaxel/uso terapêutico , Epirubicina/uso terapêutico , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Volume Sistólico
16.
Biosci Biotechnol Biochem ; 83(4): 653-658, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30558506

RESUMO

Doxorubicin (Dox) is an anthracycline antibiotic that has been used to treat different cancers. Dox-induced cardiotoxicity is common in clinical practice, while its mechanism is unknown. It has been proved that lncRNA FOXC2-AS1 may promote doxorubicin resistance and WNT1-inducible signaling pathway protein-1 (WISP1) blocks doxorubicin-induced cardiomyocyte death. Our study aimed to investigate the involvement of lncRNA FOXC2-AS1 and WISP1 in doxorubicin-induced cardiotoxicity and to explore their interactions. In our study we observed that FOXC2-AS1 and WISP1 mRNA were downregulated in heart tissues of mice with Dox-induced cardiotoxicity. FOXC2-AS1 and WISP1 mRNA expression were positively correlated in mice with Dox-induced cardiotoxicity but not in healthy mice. Overexpression of FOXC2-AS1 promoted to viability of mice cardiomyocytes under Dox treatment and also increased the expression level of WISP1. In contrast, WISP1 overexpression showed no significant effect on FOXC2-AS1. We therefore conclude that lncRNA FOXC2-AS1 may upregulate WISP1 to protect cardiomyocytes from doxorubicin-induced cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Proteínas de Sinalização Intercelular CCN/genética , Cardiotoxicidade/genética , Doxorrubicina/toxicidade , Fatores de Transcrição Forkhead/genética , Proteínas Proto-Oncogênicas/genética , RNA Longo não Codificante/genética , Animais , Pressão Sanguínea , Proteínas de Sinalização Intercelular CCN/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Coração/efeitos dos fármacos , Coração/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Plasmídeos/genética , Plasmídeos/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Transfecção
17.
J Oncol Pharm Pract ; 25(1): 229-233, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28914153

RESUMO

Carfilzomib is a second-generation proteasome inhibitor that irreversibly inhibits chymotrypsin-like (CT-L) activities of the proteasome, and is indicated for relapsed or refractory multiple myeloma. Cardiotoxicity is a well-established adverse effect of carfilzomib. The extent of cardiac toxicity in the literature spans anywhere from palpitations to cardiac arrest, with the most commonly reported manifestation being new-onset or worsening heart failure. A pre-clinical study of the pharmacokinetics and pharmacodynamics of carfilzomib given via intravenous bolus or 30-minute infusion in rats showed that carfilzomib can strongly induce apoptosis and potently damage cardiac myocytes at clinically relevant concentrations. Moreover, the mortality rate with the bolus administration was 44% whereas the same dose administered as a 30-minute infusion did not result in mortality. There remains limited clinical data regarding the safety of carfilzomib at doses of 27-56 mg/m2 based on infusion times as these doses have not been well studied. This retrospective review was conducted to evaluate the safety of carfilzomib at doses >27 mg/m2 at all infusion times.


Assuntos
Cardiotoxicidade/diagnóstico , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiotoxicidade/fisiopatologia , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/fisiopatologia , Estudos Retrospectivos
18.
Sci Total Environ ; 649: 1414-1421, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30308910

RESUMO

Macrolide antibiotics (MALs) are widely used for both human and animal health. Most MALs and their metabolites transfer into aquatic organisms and environment resulting in violent consequences. Previous studies show that MALs cause cardiotoxicity in humans and mammals. However, the potential risk of these chemicals in aquatic organisms remains unclear. Here, we used zebrafish embryos as a model to evaluate the toxicity of MALs. Zebrafish embryos were exposed to four typical MALs including azithromycin (AZM), clarithromycin (CLR), tilmicosin (TMS) and tylosin (TYL) to study their cardiotoxicity. The heart rate of zebrafish embryos showed similar biphasic distribution in the presence of four MALs at 2 days post-fertilization (dpf). The heart rate increased significantly at low levels of MALs while decreased obviously at high levels. Subsequently, TMS was chose to study its acute toxicity and developmental toxicity, which caused pericardial edema and spinal curvature in zebrafish embryos at 4 dpf. Furthermore, we found that TMS triggered oxidative stress, with decreased SOD activities and increased MDA contents. Lastly, apoptosis was observed in zebrafish embryos under TMS treatment, with up-regulation of apoptosis associated genes such as p53, bcl 2, bax, caspase 3 and caspase 9, confirmed by increased protein expression based on Western blot analysis. Taken together, these data indicate that MALs can cause serious toxicity in the development of zebrafish. Great caution should be taken due to the huge consumption of MALs for food animal production and treatments with TMS for infections in aquaculture.


Assuntos
Cardiotoxicidade/fisiopatologia , Embrião não Mamífero/efeitos dos fármacos , Macrolídeos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Antibacterianos/toxicidade , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Estresse Oxidativo/efeitos dos fármacos
19.
J Biochem Mol Toxicol ; 33(3): e22253, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30368987

RESUMO

Alcohol consumption is a major global risk factor for mortality and morbidity. We aimed to delineate the mechanisms underlying the potential ameliorative effects of hesperidin against chronically ethanol-induced cardiotoxicity. Sixty male albino rats were divided into normal control group, hesperidin-treated control group, untreated alcoholic group, and hesperidin-treated alcoholic group. Transcription factor-EB (TFEB) expression levels were estimated using real-time reverse transcription-polymerase chain reaction. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α), macrophage inflammatory protein-1 α, poly-(ADP-ribose)-polymerase-1 (PARP-1) activity, and tenascin C levels in cardiac tissues were estimated by enzyme-linked immunosorbent assay; while tissue malondialdehyde and total antioxidant capacity were evaluated spectrophotometrically. Our data portrayed promoting lysosomal biogenesis, as judged by upregulation of TFEB expression and its target PGC1-α, as well as decreased PARP-1 activity and offsetting inflammation, oxidative stress, and tissue injury as the principal culprits mediating the cardioprotective effect of hesperidin in alcohol-induced cardiotoxicity. In conclusion, hesperidin can be used as a cardioprotective agent in chronically ethanol-induced cardiotoxicity.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Cardiotoxicidade/tratamento farmacológico , Coração/efeitos dos fármacos , Hesperidina/farmacologia , Lisossomos/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/fisiologia , Cardiotônicos/farmacologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Quimiocina CCL3/genética , Etanol/toxicidade , Regulação da Expressão Gênica , Coração/fisiopatologia , Masculino , Miocárdio/metabolismo , Biogênese de Organelas , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Poli(ADP-Ribose) Polimerase-1/genética , Ratos , Tenascina/genética
20.
Breast J ; 25(1): 62-68, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30592128

RESUMO

Anthracycline-based chemotherapy is widely used in the management of breast cancer. Despite the lack of clinical evidence, obtaining prechemotherapy left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition scan is a widely adopted practice throughout the world. We present here the results of a retrospective analysis of breast cancer patients who had LVEF measurements in anticipation of an anthracycline chemotherapy to determine whether predefined cardiac risk factors predicted for poor cardiac function. Retrospective data were analyzed from 482 female breast cancer patients in whom LVEF was measured before starting anthracycline-based chemotherapy. Baseline demographics and multiple risk factors associated with congestive heart failure were collected. Twenty-six possible risk factors for CHF were defined, and the frequency of finding an abnormal LVEF as a function of total risk factors was assessed. Statistical tests include chi-squared and logistic regression analysis. The median age of the study population was 52 years. The original chemotherapy plan was changed in 7 patients (1.45%) based on LVEF findings, all of which had asymptomatic LV dysfunction (LVEF ranging 40%-50%). In 32 patients, despite normal LVEF results, anthracyclines were omitted secondary to prior cardiac issues. In 17 patients where LVEF was reported normal, anthracyclines were skipped based on patient's preference, tumor characteristics, or upstaging of the cancer based on imaging studies. No patient with ≤2 risk factors had an abnormal LVEF (N = 350). The probability of finding an abnormal LVEF in patients without any cardiac risk factors is extremely rare. Skipping baseline LVEF assessment may be an option in some patients with no cardiac risk factors undergoing anthracycline-based chemotherapy.


Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Função Ventricular Esquerda/fisiologia , Adulto , Idoso , Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Eletrocardiografia , Feminino , Humanos , Pessoa de Meia-Idade
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