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1.
Internist (Berl) ; 61(11): 1114-1119, 2020 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-33025124

RESUMO

In recent decades, major advances in the treatment of malignant diseases have significantly improved long-term survival. However, this has increased the spectrum of side effects of these treatment methods, particularly for the cardiovascular system. Cardiotoxicity can be acute and chronic, including hypertension, heart failure, arrhythmias, acute myocardial infarction, venous thromboembolism, stroke, and valvular heart disease. While the occurrence of cardiotoxicity is known for many older cancer therapies, it needs to be largely evaluated for newer forms of therapy. Diagnosing possible cardiotoxic side effects is essential for optimal treatment, but remains a challenge. Troponin and the natriuretic peptides play an essential role as cardiac biomarkers in the diagnosis of conventional heart diseases. However, they also appear to play an important role in the detection of cardiotoxicity, as well as in the treatment of cardio-oncology patients. Elevated troponin or B-type natriuretic peptide (BNP)/N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels are associated with increased overall mortality and were associated with the development of heart failure in selected cohorts. Troponin can also be used to identify myocarditis associated with immune checkpoint inhibitor therapy. This overview summarizes the current knowledge about biomarkers for the detection of cardiotoxicity due to tumor therapy. Possible clinical recommendations for the detection of cardiotoxic effects using biomarkers are also outlined.


Assuntos
Antineoplásicos/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Peptídeos Natriuréticos/análise , Neoplasias/patologia , Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Cardiopatias , Insuficiência Cardíaca/diagnóstico , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico
2.
PLoS One ; 15(7): e0236923, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730329

RESUMO

Heart failure (HF) impairs diaphragm function. Animal models realistically mimicking HF should feature both the cardiac alterations and the diaphragmatic dysfunction characterizing this disease. The isoproterenol-induced HF model is widely used, but whether it presents diaphragmatic dysfunction is unknown. However, indirect data from research in other fields suggest that isoproterenol could increase diaphragm function. The aim of this study was to test the hypothesis that the widespread rodent model of isoproterenol-induced HF results in increased diaphragmatic contractility. Forty C57BL/6J male mice were randomized into 2 groups: HF and healthy controls. After 30 days of isoproterenol infusion to establish HF, in vivo diaphragmatic excursion and ex vivo isolated diaphragm contractibility were measured. As compared with healthy controls, mice with isoproterenol-induced HF showed the expected changes in structural and functional echocardiographic parameters and lung edema. isoproterenol-induced HF increased in vivo diaphragm excursion (by ≈30%, p<0.01) and increased by ≈50% both ex vivo peak specific force (p<0.05) and tetanic force (p<0.05) at almost all 10-100 Hz frequencies (p<0.05), with reduced fatigue resistance (p<0.01) when compared with healthy controls. Expression of myosin genes encoding the main muscle fiber types revealed that Myh4 was higher in isoproterenol-induced HF than in healthy controls (p<0.05), suggesting greater distribution of type IIb fibers. These results show that the conventional isoproterenol-induced HF model increases diaphragm contraction, a finding contrary to what is observed in patients with HF. Therefore, this specific model seems limited for translational an integrative HF research, especially when cardio-respiratory interactions are investigated.


Assuntos
Agonistas Adrenérgicos beta/toxicidade , Diafragma/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Isoproterenol/toxicidade , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/metabolismo , Edema Pulmonar/patologia , Animais , Diafragma/efeitos dos fármacos , Modelos Animais de Doenças , Insuficiência Cardíaca/induzido quimicamente , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Edema Pulmonar/induzido quimicamente
3.
Internist (Berl) ; 61(8): 854-859, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32504300

RESUMO

A case report is presented of fulminant hydroxychloroquine-induced cardiomyopathy in a 57 year-old female patient with a long history of systemic lupus erythematosus. Diagnosis was established based on clinical findings, imaging (echocardiography and cardiac magnetic resonance imaging) as well as endomyocardial biopsy. Despite immediate discontinuation of the medication, the patient died from heart failure within a few days. Since the rare adverse effect described here might be reversible, early diagnosis and discontinuation of hydroxychloroquine are crucial for the prognosis of these patients.


Assuntos
Cardiomiopatias/induzido quimicamente , Insuficiência Cardíaca/mortalidade , Hidroxicloroquina/efeitos adversos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Biópsia , Cardiomiopatias/mortalidade , Ecocardiografia , Evolução Fatal , Feminino , Coração/efeitos dos fármacos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Hidroxicloroquina/uso terapêutico , Imagem por Ressonância Magnética , Pessoa de Meia-Idade
4.
Orv Hetil ; 161(26): 1094-1102, 2020 06.
Artigo em Húngaro | MEDLINE | ID: mdl-32541088

RESUMO

INTRODUCTION: The incidence of dilated cardiomyopathy after anthracycline chemotherapy is mainly influenced by anthracycline cumulative dose. Previous researches showed doxorubicin treatment under cumulative dose of 450 mg/m2 associated with a low incidence of heart failure. Nowadays, doxorubicin is administered with a lower dose, the development of heart failure is largely determined by other factors. AIM: Our purpose was to identify the risk factors for heart failure due to doxorubicin therapy. METHOD: With the use of the Hungarian financial healthcare databases merged with the National Cancer Registry, we performed a retrospective study. All the patients having confirmation for breast carcinoma between 2004 and 2015 were enrolled. The subjects with a preceding period characterized by any chemotherapy or diagnoses suggesting heart failure were excluded. Heart failure outcome event was defined by the assignment of I50 diagnosis code at hospital discharge or in autopsy reports. STATISTICAL ANALYSIS: We used multivariate binary logistic regression to calculate odds ratios for heart failure. Besides the baseline characteristics, oncological state and cumulative doses of the chemotherapies were also taken into account. RESULTS: Among the analysed 3288, doxorubicin-treated patients, heart failure cumulative incidence was 6.2%. Doxorubicin cumulative dose over 400 mg/m2 increased the risk. The heart failure incidence was essentially influenced by age, even over 50 years the risk rose. Diabetes mellitus and the treatments with pyrimidine-analogues, carboplatin or bevacizumab were also associated with higher risk. CONCLUSION: By the integration of national financial and clinical databases, we could identify the risk factors for doxorubicin-associated heart failure. Orv Hetil. 2020; 161(26): 1094-1102.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Hungria , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
5.
Gan To Kagaku Ryoho ; 47(4): 609-613, 2020 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-32389962

RESUMO

BACKGROUND: In recent years, osimertinib has been increasingly used as a therapeutic drug for epidermal growth factor receptor(EGFR)mutation-positive lung cancer, with heart failure rarely reported as an adverse event. We report here a case of a significantly decreased ejection fraction and heart failure that were induced by osimertinib. We consider the case important and include a discussion of relevant previous reports. CASE: The patient was a 73-year-old woman who had been on oral gefitinib as first-line treatment for EGFR mutation-positive(exon19 deletion)non-small cell lung cancer for approximately 1 year and 2 months. Thereafter, she tested positive for an EGFR resistance mutation(T790M); and accordingly, oral osimerti- nib was started at 80mg/day as second-line treatment. After continuing this treatment for 6 months with no particular adverse events, she visited our hospital and was found to have dyspnea on exertion and increased pleural effusion. Based on these findings, cancer relapse was suspected, and the patient was hospitalized for detailed examinations. She was diagnosed with heart failure based on the elevated BNP level that was found in a blood test and CT and echocardiography findings, and her ejection fraction deteriorated to 19% from a pretreatment level of 59%. The conditions improved after diuretic and b- blocker treatment. Given the absence of any possible cause of heart failure or reduced ejection fraction in her past history of illness and medication, we concluded that these conditions were induced by osimertinib. CONCLUSION: While heart failure induced by EGFR-TKIs has been rarely reported, osimertinib may cause cardiomyopathy due to human epidermal growth factor receptor type 2(HER2)inhibitory activity.


Assuntos
Acrilamidas/efeitos adversos , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas , Insuficiência Cardíaca , Neoplasias Pulmonares , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cardiotoxicidade , Receptores ErbB , Feminino , Insuficiência Cardíaca/induzido quimicamente , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases , Volume Sistólico
6.
Am J Cardiol ; 125(10): 1577-1581, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32245636

RESUMO

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are one of the most widely used antihyperglycemic therapeutic classes in type 2 diabetes mellitus management. In April 2016 and August 2017, the US Food and Drug Administration (FDA) introduced sequential labelling requirements regarding heart failure risk related to DPP-4i. We explored longitudinal trends in prescription of DPP-4i before and after these FDA warnings in a multicenter health system. We identified all first-time prescriptions of DPP4i or their combinations across the Partners HealthCare system (Boston, MA) from October 2006 (FDA approval of first DPP-4i) to December 2018. Overall, 11,830 patients were newly prescribed DPP-4i during the study period. Primary care physicians (31.5%) were the most common prescribing specialty. Overall, 8.4%, 20.4%, and 11.6% had heart failure, atherosclerotic cardiovascular disease, and chronic kidney disease, respectively. Median number of background antihyperglycemic therapies was 2 [25th to 75th percentiles 1 to 2], commonly metformin (65.4%) and/or insulin (36.4%). The vast majority of prescriptions were sitagliptin (85.7%), followed by linagliptin (9.5%), saxagliptin (4.7%), and alogliptin (0.2%). Quarterly prescriptions rose gradually from 2006 to mid-2016, and have decreased consistently since then for each of the 4 DPP-4i. Declines in DPP-4i among high-risk groups and those initiated by endocrinologists were most pronounced. In conclusion, although DPP-4i remain a dominant oral antihyperglycemic therapy in clinical practice, new prescriptions have declined recently. These data may reflect relatively swift health system response to broad FDA safety communications regarding heart failure risk, which appeared to impact the entire DPP-4i class, including specific drugs that have not demonstrated any increased risk of heart failure.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Insuficiência Cardíaca/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Idoso , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Rotulagem de Produtos , Estados Unidos , United States Food and Drug Administration
7.
Arterioscler Thromb Vasc Biol ; 40(6): 1454-1463, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32295420

RESUMO

Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal physiology and disease. NSAIDs (non-steroidal anti-inflammatory drugs), which are among the most commonly used medications, ameliorate pain, fever, and inflammation by inhibiting COX (cyclooxygenase), which is the rate-limiting enzyme in the biosynthetic cascade of prostanoids. The use of NSAIDs selective for COX-2 inhibition increases the risk of a thrombotic event (eg, myocardial infarction and stroke). All NSAIDs are associated with an increased risk of heart failure. Substantial variation in clinical responses to aspirin exists and is associated with cardiovascular risk. Limited clinical studies suggest the involvement of prostanoids in vascular restenosis in patients who received angioplasty intervention. mPGES (microsomal PG [prostaglandin] E synthase)-1, an alternative target downstream of COX, has the potential to be therapeutically targeted for inflammatory disease, with diminished thrombotic risk relative to selective COX-2 inhibitors. mPGES-1-derived PGE2 critically regulates microcirculation via its receptor EP (receptor for prostanoid E) 4. This review summarizes the actions and associated mechanisms for modulating the biosynthesis of prostanoids in thrombosis, vascular remodeling, and ischemic heart disease as well as their therapeutic relevance.


Assuntos
Anti-Inflamatórios , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Descoberta de Drogas , Prostaglandinas/fisiologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Infarto do Miocárdio/induzido quimicamente , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Prostaglandina-E Sintases/efeitos dos fármacos , Prostaglandinas/biossíntese , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , Remodelação Vascular
8.
Int J Hematol ; 112(1): 115-117, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32152879

RESUMO

Until now, no studies have addressed the use of dasatinib in hemodialysis patients. Herein, we report the case of a 73-year-old hemodialysis patient with chronic myeloid leukemia (CML) who was treated with dasatinib. For 5 years prior, the patient had received nilotinib for the treatment of CML. Regular hemodialysis was initiated due to progression of hypertensive nephrosclerosis, whereupon nilotinib was discontinued and the patient began receiving 100 mg dose of dasatinib once daily. On dialysis days, dasatinib was administered immediately after completion of dialysis. Four months after starting dasatinib, we performed a pharmacokinetic study. The plasma concentrations of dasatinib before, immediately, and 2 h after the completion of hemodialysis were 7.4, 6.1, and 59.5 ng/mL, respectively. Ultrasound cardiography revealed a gradual decline in ejection fraction during dasatinib therapy. Because the patient's dasatinib trough concentration was higher (6.1 ng/mL) than the target level (1.5 ng/mL), we suspected the development of dasatinib-related heart dysfunction; thus, dasatinib was discontinued 6 months after its initiation. We concluded that hemodialysis patients are potentially vulnerable to the cardiotoxic effects of dasatinib; monitoring of cardiac function and plasma drug concentration may thus be useful in assessing their condition.


Assuntos
Cardiotoxinas , Dasatinibe/efeitos adversos , Dasatinibe/farmacocinética , Insuficiência Cardíaca/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Diálise Renal , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia , Idoso , Biomarcadores Farmacológicos/sangue , Dasatinibe/administração & dosagem , Dasatinibe/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/complicações , Masculino , Insuficiência Renal Crônica/etiologia , Volume Sistólico , Fatores de Tempo , Suspensão de Tratamento
9.
Heart Fail Clin ; 16(2): 231-241, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32143767

RESUMO

Several cancer treatments cause cardiotoxicity that can lead to heart failure, coronary artery disease, arrhythmia, and pericardial disease. In this review, representative cases of heart failure following cardiotoxicity caused by trastuzumab, anthracycline, and hematopoietic stem cell transplantation are described with case notes. Additionally, other important points regarding cardiotoxicity related to heart failure are reported. During and after potentially cardiotoxic therapy, periodic cardiac examinations are recommended to detect any cardiovascular disorders; these are ameliorated if appropriately diagnosed at an earlier stage. It is important for cardiologists and oncologists to understand the pathophysiology of representative cardiovascular disease cases following cancer treatment.


Assuntos
Antraciclinas/farmacologia , Insuficiência Cardíaca , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Neoplasias/tratamento farmacológico , Trastuzumab/farmacologia , Antineoplásicos/farmacologia , Cardiotoxicidade , Monitoramento de Medicamentos/métodos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos
10.
Ann Afr Med ; 19(1): 1-7, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32174608

RESUMO

We report three cases of heart failure (HF) associated with the use of cytotoxic drugs such as anthracycline, cyclophosphamide, and 5-fluorouracil in the treatment of breast cancer in Nigerians. The patients had systolic and diastolic HF: HF with reduced ejection fraction and preserved ejection fraction. The prevalence of breast cancer is increasing across Africa, and cytotoxics are some of the most common and best drugs used during management. The cardiotoxicity caused by these drugs limits their use as chemotherapeutic agents. Cytotoxic-induced HF is a preventable and manageable cause of cardiovascular disease (CVD) in Nigeria and Africa. This article discusses the pathophysiology of cytotoxic-induced HF and presents the risk factors that impair cardiovascular function. The importance of proper assessment and the prophylactic and therapeutic measures in the management of cytotoxic-induced HF are emphasized. The peculiar challenges in the management of cytotoxic-induced HF in Nigeria were also discussed. The need for early involvement of cardiologists by oncologists to improve on the chemotherapeutic and cardiovascular outcome in the management of patients with breast cancer was stressed. Perhaps, it is time to birth a new discipline of cardiooncology in Nigeria.


Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Fluoruracila/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Idoso , Antraciclinas/uso terapêutico , Cardiotoxicidade , Ciclofosfamida/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Pessoa de Meia-Idade
11.
Life Sci ; 249: 117476, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32119962

RESUMO

Mangiferin is a well-known xanthone extracted from mango leaves (Mangifera indica Linn). Mangiferin is widely distributed in the bark, peel, leaf, seed, stalk, and kernel of mango and higher plants. The pharmacological properties of mangiferin, including its antioxidant, anticancer, antiaging, antiviral, hepatoprotective, analgesic, and immunomodulatory activities, have been described in several studies. We investigated the effect of mangiferin on isoproterenol-induced apoptosis. Experimental heart failure was induced in rats by intraperitoneal administration of isoproterenol (5 mg/kg) for 7 consecutive days. Rats were divided into five groups: group I (sham rats), group II (isoproterenol alone control), group III (isoproterenol + 25 mg/kg mangiferin), group IV (isoproterenol + 50 mg/kg mangiferin), and group V (isoproterenol + 0.0225 mg/kg digitalis as a positive control). Hemodynamic parameters and body weight, heart weight and liver weight, apoptosis induction, and caspase-3, Bax, and Bcl-2 protein levels were measured, and a histopathological analysis of cardiomyocytes was performed. In addition, apoptosis and protein expression of caspase-3, cleaved caspase-3, Bax, and Bcl-2 were measured in cardiac H9c2 cells. Mangiferin supplementation significantly increased heart rate and improved the maximum rate of decrease in left ventricular (LV) pressure, the maximum rate of increase in LV pressure, and LV systolic pressure. Mangiferin reduced inflammatory cell infiltration and the number of broken myocardial fibers, and decreased apoptosis in cardiomyocytes by reducing proteins levels of caspase-3 and Bax and increasing those of Bcl-2. Our findings suggest that mangiferin has a cardioprotective effect against isoproterenol-induced apoptosis in cardiomyocytes.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Insuficiência Cardíaca/induzido quimicamente , Coração/efeitos dos fármacos , Xantonas/farmacologia , Animais , Cardiotônicos/administração & dosagem , Injeções Intraperitoneais , Isoproterenol/administração & dosagem , Isoproterenol/farmacologia , Ratos
12.
J Ethnopharmacol ; 252: 112618, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32006632

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sini decoction (SND) is a famous Traditional Chinese Medicine (TCM) formula composed of Acontium carmichaeli, Zingiber officinale and Glycyrrhiza uralensis, which is considered as an efficient formula against doxorubicin (DOX)-induced heart failure. But the compatibility mechanism of SND remains unclear. AIM OF THE STUDY: The present study aimed to investigate the compatibility mechanism of SND against DOX-induced heart failure in rats. MATERIALS AND METHODS: Mass spectrometry-based serum metabolomics were performed. The relative distance values (RDVs) of SND, A. carmichaeli-free decoction (ACFD), Z. officinale-free decoction (ZOFD) and G. uralensis-free decoction (GUFD) treated groups from the control/DOX groups in multidimensional space were calculated to provide a measure of compatibility effect of SND. SND, ACFD, ZOFD, GUFD-targeted metabolic pathways were identified and compared to investigate the synergistic mechanism of SND by computational systems analysis. Real-time quantitative PCR was further employed to validate the key metabolic pathways at the level of the gene. RESULTS: The RDVs combined with the hemodynamic and biochemical analysis showed that the protection effects were sorted as SND > GUFD > ZOFD > ACFD. It revealed that DOX-induced heart failure perturbed 16 metabolic pathways, and SND, GUFD, ZOFD and ACFD-treated groups could significantly reversed 12, 10, 7 and 6 metabolic pathways of these 16 metabolic pathways, respectively. Metabolic pathway and RT-PCR analysis indicated that both SND and GUFD could protect DOX-induced heart failure mainly by regulating PLA2-COX pathway and PLA2-CYP pathway. CONCLUSION: It can be concluded that A. carmichaeli played an essential role in attenuation of DOX-induced heart failure among the three herb constituents of SND and the constituent herbs mutually reinforced each other. This work demonstrated that metabolomics combined with computational systems analysis was a promising tool for uncovering the compatibility effects of TCM.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Insuficiência Cardíaca/sangue , Redes e Vias Metabólicas/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos , Biomarcadores/sangue , Doxorrubicina , Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Masculino , Espectrometria de Massas , Metabolômica , Ratos Sprague-Dawley
13.
Lab Invest ; 100(7): 974-985, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32051532

RESUMO

Novel molecular mechanisms of the pathophysiology of heart failure (HF) are continuously being discovered, including epigenetic regulation. Among epigenetic marks, the role of DNA hypomethylation in shaping heart morphology and function in vivo and the pathogenesis of cardiomyopathy and/or HF, especially in adults, has not been clearly established. Here we show that the strong expression of DNA methyltransferase 1 (Dnmt1) is obviously downregulated in the WT adult rat heart with age. By contrast, the expression of Dnmt1 is upregulated suddenly in heart tissues from pressure overload-induced HF mice and adriamycin-induced cardiac injury and HF mice, consistent with the increased expression of Dnmt1 observed in familial hypertrophic cardiomyopathy (FHCM) patients. To further assess the role of Dnmt1, we generated myocardium-specific Dnmt1 knockout (Dnmt1 KO) rats using CRISPR-Cas9 technology. Echocardiographic and histopathological examinations demonstrated that Dnmt1 deficiency is associated with resistance to cardiac pathological changes and protection at the global and organization levels in response to pathological stress. Furthermore, Dnmt1 deficiency in the myocardium restricts the expressional reprogramming of genes and activates pathways involved in myocardial protection and anti-apoptosis in response to pathological stress. Transcriptome and genome-wide DNA methylation analyses revealed that these changes in regulation are linked to alterations in the methylation status of genes due to Dnmt1 knockout. The present study is the first to investigate in vivo the impact of genome-wide cardiac DNA methyltransferase deficiency on physiological development and the pathological processes of heart tissues in response to stress. The exploration of the role of epigenetics in the development, modification, and prevention of cardiomyopathy and HF is in a very preliminary stage but has an infinite future.


Assuntos
Cardiomiopatia Dilatada , DNA (Citosina-5-)-Metiltransferase 1 , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca , Miocárdio/metabolismo , Animais , Cardiomiopatia Dilatada/induzido quimicamente , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Camundongos , Especificidade de Órgãos , Ratos , Ratos Transgênicos
14.
Circulation ; 141(7): 549-559, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32065766

RESUMO

BACKGROUND: The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern. METHODS: We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). RESULTS: The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14-3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11-2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88-2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82-1.72]). CONCLUSIONS: In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.


Assuntos
Inibidores da Aromatase , Isquemia Encefálica , Neoplasias da Mama , Bases de Dados Factuais , Insuficiência Cardíaca , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/mortalidade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Feminino , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/mortalidade , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/mortalidade , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Reino Unido/epidemiologia
16.
Eur J Cancer ; 126: 65-73, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31923729

RESUMO

INTRODUCTION: T-DM1 has been approved for the treatment of HER2+ breast cancer. Cardiac dysfunction is a side effect of trastuzumab, a component of T-DM1. However, little is known about T-DM1-associated cardiotoxicity. METHODS: We have conducted a pooled analysis of T-DM1 trials in advanced HER2+ breast cancer cases to understand the incidence, clinical presentation as well as to establish possible risk factors for T-DM1-associated cardiotoxicity. The primary endpoint was the incidence of cardiac events (CEs). CEs were categorized as follows: (1) congestive heart failure (CHF) or grade 3/4 LVEF drop; (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Secondary endpoints included CE recovery rate and impact of CEs on treatment discontinuation. Logistic regression was used to assess possible risk factors for CEs. RESULTS: Individual patient-level data from 1961 patients exposed to T-DM1 in seven trials were pooled. Of these, 1544 received T-DM1 and 417 T-DM1 + pertuzumab. CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%. The total CE rate was 3.37% (95% confidence interval (CI), 2.6%-4.3%). Multivariate analysis showed patient's age ≥65 (OR 3.0; 95% CI, 1.77-5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29-5.32; P-value 0.008) as risk factors. CEs resolved in most (79%) patients after treatment discontinuation. CONCLUSION: The incidence of CEs in patients receiving T-DM1 was low. Older patients receiving T-DM1 should be carefully followed for cardiac safety during treatment.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Arritmias Cardíacas/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Insuficiência Cardíaca/diagnóstico , Isquemia Miocárdica/diagnóstico , Ado-Trastuzumab Emtansina/uso terapêutico , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Neoplasias da Mama/metabolismo , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Feminino , Insuficiência Cardíaca/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/métodos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Isquemia Miocárdica/induzido quimicamente , Receptor ErbB-2/metabolismo
17.
Am J Physiol Heart Circ Physiol ; 318(2): H283-H294, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31834837

RESUMO

The ß3-adrenergic receptor (ß3AR) is related to myocardial fatty acid metabolism and its expression has been implicated in heart failure. In this study, we investigated the role of ß3AR in sepsis-related myocardial dysfunction using lipopolysaccharide (LPS)-induced endotoxemia as a model of cardiac dysfunction. We placed mice into three treatment groups and treated each with intraperitoneal injections of the ß3AR agonist CL316243 (CL group), the ß3AR antagonist SR59230A (SR group), or normal saline (NS group). Survival rates were significantly improved in the SR group compared with the other treatment groups. Echocardiography analyses revealed cardiac dysfunction within 6-12 h of LPS injections, but the outcome was significantly better for the SR group. Myocardial ATP was preserved in the SR group but was decreased in the CL-treated mice. Additionally, quantitative PCR analysis revealed that expression levels of genes associated with fatty acid oxidation and glucose metabolism were significantly higher in the SR group. Furthermore, the expression levels of mitochondrial membrane protein complexes were preserved in the SR group. Electron microscope studies showed significant accumulation of lipid droplets in the CL group. Moreover, inducible nitric oxide synthase (iNOS) protein expression and nitric oxide were significantly reduced in the SR group. The in vitro study demonstrated that ß3AR has an independent iNOS pathway that does not go through the nuclear factor-κB pathway. These results suggest that blockading ß3AR improves impaired energy metabolism in myocardial tissues by suppressing iNOS expression and recovers cardiac function in animals with endotoxin-induced heart failure.NEW & NOTEWORTHY Nitric oxide production through stimulation of ß3-adrenergic receptor (ß3AR) may improve cardiac function in cases of chronic heart failure. We demonstrated that the blockade of ß3AR improved mortality and cardiac function in endotoxin-induced heart failure. We also determined that LPS-induced inducible nitric oxide synthase has a pathway that is independent of nuclear factor-κB, which worsened cardiac metabolism and mortality in the acute phase of sepsis. Treatment with the ß3AR antagonist had a favorable effect. Thus, the blockade of ß3AR could offer a novel treatment for sepsis-related heart failure.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Propanolaminas/uso terapêutico , Trifosfato de Adenosina/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Ácidos Graxos/metabolismo , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/mortalidade , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/genética
18.
Biomed Pharmacother ; 123: 109803, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31877550

RESUMO

Heart failure is a major cause of morbidity and mortality worldwide. LongShengZhi capsule (LSZ), a traditional Chinese medicine, is used for treatment of patients with vascular diseases. Herein we investigated the effect of LSZ treatment on doxorubicin (DOX)-induced heart failure in mice. C57BL/6 mice randomly in 3 groups received following treatment: Control group, mice were fed normal chow; DOX group, mice were intraperitoneally injected DOX to induce heart failure and fed normal chow; and LSZ group, mice were injected DOX and fed normal chow containing LSZ. DOX induced heart failure as evidenced by increased serum creatine kinase, lactic dehydrogenase and α-hydroxybutyrate dehydrogenase, and cardiac fibrosis. However, LSZ treatment substantially inhibited DOX-induced heart failure parameters. Mechanistically, LSZ reduced collagen content and fibrosis by inhibiting expression of collagen type I α1 (COL1α1), COL1α2, α-smooth muscle actin and transforming growth factor ß1. In addition, DOX-induced cell apoptosis was inhibited by LSZ, coupled with reduced caspase 3 activity and mRNA expression. LSZ decreased inflammatory cytokine levels. More importantly, LSZ decreased oxidative stress by inducing expression of anti-oxidative stress enzymes including superoxide dismutase 1 (SOD1), SOD2, catalase and glutathione peroxidase 1 through activation of forkhead box O3A and sirtuin 3. In conclusion, our study demonstrates that LSZ reduces heart failure by reducing production of reactive oxygen species and inhibiting inflammation/apoptosis. Our study also suggests the potential application of LSZ for heart failure treatment.


Assuntos
Antioxidantes/uso terapêutico , Doxorrubicina/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Estresse Oxidativo , Animais , Apoptose/efeitos dos fármacos , Cápsulas , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Linhagem Celular , Colágeno/metabolismo , Citocinas/metabolismo , Fibrose , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
19.
O.F.I.L ; 30(4): 337-337, 2020.
Artigo em Espanhol | IBECS | ID: ibc-194515

RESUMO

Presentamos el caso clínico de una profesional sanitaria que ha sufrido una probable reacción adversa por hidroxicloroquina en el tratamiento dirigido para el SARS-Cov2. La paciente estuvo en tratamiento con hidroxicloroquina, azitromicina y cefditoreno y tras finalizar el tratamiento presentó alteraciones cardiovasculares tales como insuficiencia cardíaca y taquicardias. En el momento actual parece que el balance beneficio-riesgo es desfavorable al uso de la hidroxicloroquina en el tratamiento de la enfermedad por SARS-Cov2


We present the clinical case of a healthcare professional who has suffered a probable adverse reaction by hydroxychloroquine in the targeted treatment for SARS-Cov2. The patient was treated with hydroxychloroquine, azithromycin, and cefditoren, and after completing the treatment, she had cardiovascular disorders such as heart failure and tachycardia. At present, the benefit-risk balance appears to be unfavorable to the use of hydroxychloroquine in the treatment of SARS-Cov2 disease


Assuntos
Humanos , Feminino , Adulto , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pandemias , Hidroxicloroquina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Taquicardia/induzido quimicamente , Hidroxicloroquina/uso terapêutico
20.
J Ethnopharmacol ; 248: 112050, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31265887

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Miao-Yong-An decoction (SMYAD) is a traditional Chinese herbal formulation. SMYAD first appeared in the Eastern Han Dynasty according to the "Shen Yi Mi Zhuan". Then the formula was recorded in the "Yan Fang Xin Bian" edited by medical scientist Bao Xiangao in the Qing Dynasty. This well-known prescription has been traditionally used for gangrene and vascular vasculitis. It is mainly used for cardiovascular and endocrine diseases in current clinical applications and research. AIM OF STUDY: In this study, the potential mechanisms of SMYAD against cardiac fibrosis and hypertrophy in the ß-adrenoceptor agonist isoprenaline induced heart failure model were investigated. MATERIALS AND METHODS: The heart failure animal model was established via injected isoprenaline in rats. Echocardiography was used to detect the structure and function of the heart. HE staining and Masson's trichrome staining was performed to assess myocardial tissue morphology. The serum biochemical indexes were detected by dedicated biochemical kit. BNP was tested by ELISA kit. The levels of mRNA were detected by RT-qPCR. Cardiomyocyte morphology was assessed by immunofluorescence. Phosphorylated and total p38, Akt were analyzed by Western blot. The production of reactive oxygen species (ROS) was tested by CM-H2DCFDA probe. Formula identification of chemical constituents of SMYAD in plasma was disclosed through ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS). RESULTS: SMYAD was able to improve the heart function in ISO induced heart failure rat model via protecting rat from developing cardiac hypertrophy and fibrosis. SMYAD also decreased plasma expression of these biochemical indexes. It was found that SMYAD could regulate cardiac hypertrophy and fibrosis makers' mRNA levels in vitro and vivo. In addition, SMYAD inhibited the phosphorylation of p38 and Akt, which are key mediators in the pathological process of ISO-induced cardiac hypertrophy and myocardial fibrosis. It also showed that the components of SMYAD in rat plasma exerted myocardial cell protective activity. CONCLUSION: In summary, SMYAD may comprise more than one active ingredient to the pursuit of combination therapies instead of specifically target a single disease-causing molecule. These experimental results suggest that SMYAD may be a potential drug candidate in diseases of cardiac hypertrophy and myocardial fibrosis caused by ß-adrenoceptor abnormalities.


Assuntos
Cardiomegalia/prevenção & controle , Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Animais , Cardiomegalia/etiologia , Linhagem Celular , Doxorrubicina , Medicamentos de Ervas Chinesas/farmacologia , Fibrose , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Isoproterenol , Masculino , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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