RESUMO
BACKGROUND: Advances in Lymphoma management have resulted in significant improvements in patient outcomes over the last 50 years. Despite these developments, cardiotoxicity from lymphoma treatments remains an important cause of mortality and morbidity in this cohort of patients. We outlined the most common cardiotoxicities associated with lymphoma treatments and their respective investigation and management strategies, including the role of cardiac pre-assessment and late effects monitoring.
Assuntos
Antineoplásicos , Linfoma , Neoplasias , Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Coração , Humanos , Linfoma/complicações , Linfoma/terapia , Neoplasias/tratamento farmacológicoRESUMO
Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury.
Assuntos
Cardiologia , Oncologia , Infarto do Miocárdio , Acidente Vascular Cerebral , Animais , Antineoplásicos/efeitos adversos , Cardiologia/métodos , Cardiologia/tendências , Citoproteção , Humanos , Precondicionamento Isquêmico Miocárdico/métodos , Oncologia/métodos , Oncologia/tendências , Traumatismo por Reperfusão Miocárdica/prevenção & controleRESUMO
PURPOSE: Anthracyclines cause chronic irreversible cardiac failure, but the mechanism remains poorly understood. Emerging data indicate that cardiac damage begins early, suggesting protective modalities delivered in the acute stage may confer prolonged benefit. Ischaemic preconditioning (IPC) activates the pro-survival reperfusion injury salvage kinase (RISK) pathway which involves PI3-kinase and MAPK/ERK1/2. METHODS: We investigated whether simulated IPC (sIPC), in the form of a sublethal exposure to a hypoxic buffer simulating ischaemic conditions followed by reoxygenation, protects primary adult rat cardiomyocytes against anthracycline-induced injury. PI3-kinase and MAPK/ERK1/2 were inhibited using LY294002, and PD98059. The role of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm) and mitochondrial permeability transition pore (mPTP) were also investigated in doxorubicin-treated cells. We further examined whether sIPC protected HeLa cancer cells from doxorubicin-induced death. RESULTS: sIPC protected cardiomyocytes against doxorubicin-induced death (35.4 ± 1.7% doxorubicin vs 14.7 ± 1.5% doxorubicin + sIPC; p < 0.01). This protection was abrogated by the PI3-kinase inhibitor, LY294002, but not the MAPK/ERK1/2 inhibitor, PD98059. A ROS scavenger failed to rescue cardiomyocytes from doxorubicin toxicity, and no significant influence on Δψm or mPTP opening was identified after subjecting cells to a doxorubicin insult. Importantly, sIPC did not protect HeLa cancer cells from doxorubicin-induced death. CONCLUSION: sIPC is able to protect cardiomyocytes against anthracycline injury via a pathway involving PI3-kinase. This mechanism appears to be independent of ROS, changes to Δψm, and mPTP. Further investigation of the mechanism of sIPC-induced protection against anthracycline-injury is warranted.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Cardiopatias/prevenção & controle , Precondicionamento Isquêmico Miocárdico , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Animais , Cardiotoxicidade , Hipóxia Celular , Feminino , Células HeLa , Cardiopatias/induzido quimicamente , Cardiopatias/enzimologia , Cardiopatias/patologia , Humanos , Masculino , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/patologiaRESUMO
PURPOSE: To explore the use and reproducibility of magnetic resonance-derived myocardial T1 mapping in patients with iron overload. MATERIALS AND METHODS: The research received ethics committee approval and all patients provided written informed consent. This was a prospective study of 88 patients and 67 healthy volunteers. Thirty-five patients underwent repeat scanning for reproducibility. T1 mapping used the shortened modified Look-Locker inversion recovery sequence (ShMOLLI) with a second, confirmatory MOLLI sequence in the reproducibility group. T2 * was performed using a commercially available sequence. The analysis of the T2 * interstudy reproducibility data was performed by two different research groups using two different methods. RESULTS: Myocardial T1 was lower in patients than healthy volunteers (836 ± 138 msec vs. 968 ± 32 msec, P < 0.0001). Myocardial T1 correlated with T2 * (R = 0.79, P < 0.0001). No patient with low T2 * had normal T1 , but 32% (n = 28) of cases characterized by a normal T2 * had low myocardial T1 . Interstudy reproducibility of either T1 sequence was significantly better than T2 *, with the results suggesting that the use of T1 in clinical trials could decrease potential sample sizes by 7-fold. CONCLUSION: Myocardial T1 mapping is an alternative method for cardiac iron quantification. T1 mapping shows the potential for improved detection of mild iron loading. The superior reproducibility of T1 has potential implications for clinical trial design and therapeutic monitoring.
Assuntos
Sobrecarga de Ferro/diagnóstico , Imageamento por Ressonância Magnética/métodos , Miocárdio/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Sobrecarga de Ferro/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: The acute administration of high-dose erythropoietin (EPO) on reperfusing ischaemic myocardium has been reported to halve myocardial infarct (MI) size in preclinical studies, but its effect in ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention (PPCI) remains unknown. We investigated whether high-dose EPO administered as an adjunct to PPCI reduces MI size. DESIGN: Double-blinded, randomised, placebo-controlled. SETTING: Single tertiary cardiac centre. PATIENTS: Fifty-one ST elevation myocardial infarction patients undergoing PPCI. INTERVENTIONS: Patients were randomly assigned to receive either a single intravenous bolus of EPO (50,000 IU) prior to PPCI with a further bolus given 24 h later (n=26) or placebo (n=25). MAIN OUTCOME MEASURES: MI size measured by 24 h area under the curve troponin T and cardiac magnetic resonance imaging performed on day 2 and at 4 months. RESULTS: EPO treatment failed to reduce MI size (troponin T area under the curve: 114.6±78 µg/ml EPO vs 100.8±68 µg/ml placebo; infarct mass by cardiac magnetic resonance: 33±16 g EPO vs 25±16 g placebo; both p>0.05). Unexpectedly, EPO treatment doubled the incidence of microvascular obstruction (82% EPO vs 47% placebo; p=0.02) and significantly increased indexed left ventricular (LV) end-diastolic volumes (84±10 ml/m(2) EPO vs 73±13 ml/m(2) placebo; p=0.003), indexed LV end-systolic volumes (41±9 ml/m(2) EPO vs 35±11 ml/m(2) placebo; p=0.035) and indexed myocardial mass (89±16 g/m(2) EPO vs 79±11 g/m(2) placebo; p=0.03). At 4 months, there were no significant differences between groups. CONCLUSIONS: High-dose EPO administered as an adjunct to PPCI failed to reduce MI size. In fact, EPO treatment was associated with an increased incidence of microvascular obstruction, LV dilatation and increased LV mass. Clinical Trial Registration Information http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=4058 Unique Identifier=Study ID 4058.