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1.
Br J Radiol ; 93(1105): 20190289, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31617732

RESUMO

OBJECTIVE: This study investigated the occurrence of cardiotoxicity-related left-ventricular (LV) contractile dysfunction in breast cancer patients following treatment with antineoplastic chemotherapy agents. METHODS: A validated and automated MRI-based LV contractility analysis tool consisting of quantization-based boundary detection, unwrapping of image phases and the meshfree Radial Point Interpolation Method was used toward measuring LV chamber quantifications (LVCQ), three-dimensional strains and torsions in patients and healthy subjects. Data were acquired with the Displacement Encoding with Stimulated Echoes (DENSE) sequence on 21 female patients and 21 age-matched healthy females. Estimates of patient LVCQs from DENSE acquisitions were validated in comparison to similar steady-state free precession measurements and their strain results validated via Bland-Altman interobserver agreements. The occurrence of LV abnormalities was investigated via significant differences in contractility measurements (LVCQs, strains and torsions) between patients and healthy subjects. RESULTS: Repeated measures analysis showed similarities between LVCQ measurements from DENSE and steady-state free precession, including cardiac output (4.7 ± 0.4 L, 4.6 ± 0.4 L, p = 0.8), and LV ejection fractions (59±6%, 58±5%, p = 0.2). Differences found between patients and healthy subjects included enlarged basal diameter (5.0 ± 0.5 cm vs 4.4 ± 0.5 cm, p < 0.01), apical torsion (6.0 ± 1.1° vs 9.7 ± 1.4°, p < 0.001) and global longitudinal strain (-0.15 ± 0.02 vs. -0.21 ± 0.04, p < 0.001), but not LV ejection fraction (59±6% vs. 63±6%, p = 0.1). CONCLUSION: The results from the statistical analysis reveal the possibility of LV abnormalities in the post-chemotherapy patients via enlarged basal diameter and reduced longitudinal strain and torsion, in comparison to healthy subjects. ADVANCES IN KNOWLEDGE: This study shows that subclinical LV abnormalities in post-chemotherapy breast cancer patients can be detected with an automated technique for the comprehensive analysis of contractile parameters.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico por imagem , Algoritmos , Feminino , Humanos , Pessoa de Meia-Idade , Contração Miocárdica
2.
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
3.
Magn Reson Imaging ; 62: 94-103, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31254595

RESUMO

PURPOSE: This study applied a novel and automated contractility analysis tool to investigate possible cardiotoxicity-related left-ventricular (LV) dysfunction in breast cancer patients following treatment with anti-neoplastic chemotherapy agents (CTA). Subclinical dysfunction otherwise undetected via LV ejection fraction (LVEF) was determined. METHODS: Deformation data were acquired with the Displacement Encoding with Stimulated Echoes (DENSE) MRI sequence on 16 female patients who had CTA-based treatment. The contractility analysis tool consisting of image quantization-based boundary detection and the meshfree Radial Point Interpolation Method was used to compare chamber quantifications, 3D regional strains and torsion between patients and healthy subjects (N = 26 females with N = 14 age-matched). Quantifications of patient LVEFs from DENSE and Steady-State Free Precession (SSFP) acquisitions were compared, Bland-Altman interobserver agreements measured on their strain results and differences in contractile parameters with healthy subjects determined via Student's t-tests. RESULTS: A significant difference was not found between DENSE and SSFP-based patient LVEFs at 58 ±â€¯7% vs 57 ±â€¯9%, p = 0.6. Bland-Altman agreements were - 0.01 ±â€¯0.05 for longitudinal strain and 0.1 ±â€¯1.3° for torsion. Differences in basal diameter indicating enlargement, 5.2 ±â€¯0.5 cm vs 4.5 ±â€¯0.5 cm, p < 0.01, and torsion, 4.7 ±â€¯1.0° vs 8.1 ±â€¯1.1°, p < 0.001 in the mid-ventricle and 5.9 ±â€¯1.2° vs 10.2 ±â€¯0.9°, p < 0.001 apically, were seen between patients and age-matched healthy subjects and similarly in longitudinal strain, but not in LVEF. CONCLUSIONS: Results from the statistical analysis reveal the likelihood of LV remodeling in this patient subpopulation otherwise not indicated by LVEF measurements.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/complicações , Cardiotoxicidade/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Remodelação Ventricular , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Imagem Tridimensional , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Contração Muscular , Sobreviventes , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda
4.
PLoS One ; 14(5): e0215579, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120912

RESUMO

BACKGROUND: Cancer patients undergoing Doxorubicin (DOX) treatment are susceptible to acute and chronic cardiac anomalies, including aberrant arrhythmias, ventricular dysfunction, and heart failure. To stratify patients at high risk for DOX -related heart failure (CHF), diagnostic techniques have been sought. While echocardiography is used for monitoring LVEF and LV volumes due to its wide-availability and cost-efficiency, it may not identify early stages of the initiation of DOX-induced systolic heart failure. To address these limitations, PET tracers could also provide noninvasive assessment of early and reversible metabolic changes of the myocardium. OBJECTIVE: Herein, we report a preliminary investigation of 68Ga-Galmydar potential to monitor Dox-induced cardiomyopathy in vivo, ex vivo, and in cellulo employing both nuclear- and optical imaging. METHODS AND RESULTS: To assess 68Ga-Galmydar ability for monitoring DOX-induced cardiomyopathy, microPET imaging was performed 5 d post treatment of rats either with a single dose of DOX (15 mg/kg) or vehicle as a control (saline) and images were co-registered for anatomical reference using CT. Following tail-vein injection of the radiotracer in rats at 60 min, micro-PET/CT static scan (10 min acquisition), 68Ga-Galmydar demonstrated 1.91-fold lower uptake in hearts of DOX-treated (standard uptake value; SUV: 0.92, n = 3) rats compared with their vehicle treated (SUV: 1.76, n = 3) control counterparts. For correlation of PET imaging data, post-imaging quantitative biodistribution studies were also performed, wherein excised organs were counted for γ activity, and normalized to injected dose. The post imaging pharmacokinetic data also demonstrated heart uptake values of 2.0 fold lower for DOX treated rats(%ID/g; DOX: 0.44 ± 0.1, n = 3) compared to their vehicle-treated controls (%ID/g; Control: 0.89 ± 0.03, n = 3, p = 0.04). Employing the fluorescent traits of Galmydar, live cell fluorescence imaging indicated a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2 cells following DOX-treatment, while indicating dose-dependent and time-dependent uptake profiles. Following depolarization of electronegative transmembrane gradients at the mitochondrial membrane, the uptake of the probe was decreased in H9c2 cells, and the uptake profiles were found to be identical, using both fluorescence and radiotracer bioassays. Finally, the decreased uptake of the metalloprobe in H9c2 cells also correlated with caspase-3 expression resulting from DOX-induced cardiotoxicity and cell death. CONCLUSIONS: 68Ga-Galmydar could provide a noninvasive assessment of DOX-related and likely reversible metabolic changes at earliest stages. Further studies with other chemotherapeutics (potentially capable of inducing cardiomyopathy) are underway.


Assuntos
Cardiotoxicidade/diagnóstico por imagem , Complexos de Coordenação/administração & dosagem , Doxorrubicina/efeitos adversos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Animais , Cardiotoxicidade/metabolismo , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Modelos Animais de Doenças , Ratos , Sensibilidade e Especificidade , Distribuição Tecidual , Microtomografia por Raio-X
5.
Rev Med Suisse ; 15(652): 1074-1080, 2019 May 22.
Artigo em Francês | MEDLINE | ID: mdl-31116522

RESUMO

Cardiologists increasingly must face not only the cardiotoxicity of certain cancer therapies, but also the burden of morbidity related to previous chemotherapy in cancer survivors. Due to the formidable effectiveness of novel oncology treatments, cancer patients are treated with drugs with limited experience of their use and systemic toxicity profile, notably their cardiotoxic effects. Echocardiography is recognized as a must in the evaluation of patients before, during and after their potentially cardiotoxic treatment. We discuss how certain echocardiographic parameters, including the evaluation of left ventricular ejection fraction but also other factors that can help guide the management of cancer patients throughout their treatment and beyond.


Assuntos
Antineoplásicos , Cardiotoxicidade , Ecocardiografia , Neoplasias , Antineoplásicos/uso terapêutico , Cardiotoxicidade/diagnóstico por imagem , Humanos , Neoplasias/tratamento farmacológico , Função Ventricular Esquerda
6.
Oncol Res Treat ; 42(7-8): 375-381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31132772

RESUMO

BACKGROUND: It is known that chemotherapeutic agents cause myocardial cell damage leading to left ventricular dysfunction and heart failure. Fragmented QRS is an indication of fibrosis developing as a result of myocardial cell damage. The aim of this study is to assess whether there is a relationship between the chemotherapeutic treatment and the development of the fragmented QRS complex in electrocardiography (ECG). PATIENTS AND METHODS: Among 130 patients who were diagnosed with non-Hodgkin lymphoma and received an R-CHOP treatment regimen, the potential emergence of fragmented QRS on ECG as well as the changes in the left ventricular ejection fraction (LVEF) (on transthoracic echocardiography) in response to various chemotherapeutic regimens were sought. RESULTS: New development of a fragmented QRS pattern was observed in 53 of the 130 patients (40.8%). These patients were found to have lower LVEF values along with higher numbers of chemotherapy courses and cumulative doses. In the logistic regression analysis, age (OR = 1.042; 95% CI 1.009-1.076; p = 0.012) and number of courses (OR = 1.848; 95% CI 1.409-2.423; p < 0.001) were found to be the most important predictors of fragmented QRS development. In subjects with a fragmented QRS pattern, there was a significant difference between the initial and repeat LVEF values (p < 0.001). Importantly the emergence of a fragmentation pattern occurred much earlier compared to the drop in LVEF values (10.62 ± 4.04 vs. 15.24 ± 7.49 months). CONCLUSION: Development of a fragmented QRS pattern in response to cancer therapy emerges as a new parameter potentially predictive of chemotherapy-induced cardiotoxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cardiotoxicidade/diagnóstico por imagem , Linfoma não Hodgkin/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Eletrocardiografia , Feminino , Humanos , Modelos Logísticos , Linfoma não Hodgkin/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Estudos Retrospectivos , Rituximab/efeitos adversos , Função Ventricular Esquerda , Vincristina/efeitos adversos
7.
Chemosphere ; 227: 551-560, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004822

RESUMO

Precise in vivo toxicological assays to determine the cardiotoxicity of pharmaceuticals and their waste products are essential in order to evaluate their risks to humans and the environment following industrial release. In the present study, we aimed to develop the sensitive imaging-based cardiotoxicity assay and combined 3D light-sheet microscopy with a zebrafish model to identify hidden cardiovascular anomalies induced by valproic acid (VPA) exposure. The zebrafish model is advantageous for this assessment because its embryos remain transparent. The 3D spatial localization of fluorescence-labeled cardiac cells in and around the heart using light-sheet technology revealed dislocalization of the heart from the outflow tract in two-day-old zebrafish embryos treated with 50 µM and 100 µM VPA (P < 0.01) and those embryos exposed to 20 µM VPA presented hypoplastic distal ventricles (P < 0.01). These two observed phenotypes are second heart field-derived cardiac defects. Quantitative analysis of the light-sheet imaging demonstrated that folic acid (FA) supplementation significantly increased the numbers of endocardial and myocardial cells (P < 0.05) and the accretion of second heart field-derived cardiomyocytes to the arterial pole of the outflow tract. The heart rate increased in response to the cellular changes occurring in embryonic heart development (P < 0.05). The present study disclosed the cellular mechanism underlying the role of FA in spontaneous cellular changes in cardiogenesis and in VPA-associated cardiotoxicity. The 3D light-sheet assay may be the next-generation test to evaluate the risks of previously undetected pharmaceutical and environmental cardiotoxicities in both humans and animals.


Assuntos
Cardiotoxicidade/diagnóstico por imagem , Ácido Fólico/uso terapêutico , Cardiopatias Congênitas/induzido quimicamente , Ácido Valproico/toxicidade , Peixe-Zebra/embriologia , Animais , Bioensaio/métodos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Diagnóstico por Imagem/métodos , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Microscopia Intravital/métodos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia
8.
Breast Cancer Res Treat ; 176(2): 261-270, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31020471

RESUMO

BACKGROUND: There is a lack of consensus to guide which breast cancer patients require left ventricular function assessment (LVEF) prior to anthracycline therapy; the cost-effectiveness of screening this patient population has not been previously evaluated. METHODS: We performed a retrospective analysis of the Yale Nuclear Cardiology Database, including 702 patients with baseline equilibrium radionuclide angiography (ERNA) scan prior to anthracycline and/or trastuzumab therapy. We sought to examine associations between abnormal baseline LVEF and potential cardiac risk factors. Additionally, we designed a Markov model to determine the incremental cost-effectiveness ratio (ICER) of ERNA screening for women aged 55 with stage I-III breast cancer from a payer perspective over a lifetime horizon. RESULTS: An abnormal LVEF was observed in 2% (n = 14) of patients. There were no significant associations on multivariate analysis performed on self-reported risk factors. Our analysis showed LVEF screening is cost-effective with ICER of $45,473 per QALY gained. For a willingness-to-pay threshold of $100,000/ QALY, LVEF screening had an 81.9% probability of being cost-effective. Under the same threshold, screening was cost-effective for non-anthracycline cardiotoxicity risk of RR ≤ 0.58, as compared to anthracycline regimens. CONCLUSIONS: Age, preexisting cardiac risk factors and coronary artery disease did not predict a baseline abnormal LVEF. While the prevalence of an abnormal baseline LVEF is low in patients with breast cancer, our results suggest that cardiac screening prior to anthracycline is cost-effective.


Assuntos
Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/diagnóstico por imagem , Imagem do Acúmulo Cardíaco de Comporta/economia , Trastuzumab/uso terapêutico , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adulto , Idoso , Antraciclinas/efeitos adversos , Neoplasias da Mama/patologia , Cardiotoxicidade/economia , Análise Custo-Benefício , Feminino , Humanos , Cadeias de Markov , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Autorrelato , Trastuzumab/efeitos adversos , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/economia , Função Ventricular Esquerda
9.
Circ Heart Fail ; 12(3): e005234, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30871347

RESUMO

Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1-25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R2=0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 µm2; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R2=0.91; P=0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1-/-) and wild-type littermates. MuRF1-/- mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines.


Assuntos
Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Coração/efeitos dos fármacos , Proteínas Musculares/genética , Atrofia Muscular/induzido quimicamente , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Animais , Antineoplásicos/administração & dosagem , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Ecocardiografia , Expressão Gênica , Coração/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Injeções Intraperitoneais , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima
10.
J Am Coll Cardiol ; 73(7): 779-791, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30784671

RESUMO

BACKGROUND: Anthracycline-induced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed. OBJECTIVES: The purpose of this study was to identify early doxorubicin-induced cardiotoxicity by serial multiparametric cardiac magnetic resonance (CMR) and its pathological correlates in a large animal model. METHODS: Twenty pigs were included. Of these, 5 received 5 biweekly intracoronary doxorubicin doses (0.45 mg/kg/injection) and were followed until sacrifice at 16 weeks. Another 5 pigs received 3 biweekly doxorubicin doses and were followed to 16 weeks. A third group was sacrificed after the third dose. All groups underwent weekly CMR examinations including anatomical and T2 and T1 mapping (including extracellular volume [ECV] quantification). A control group was sacrificed after the initial CMR. RESULTS: The earliest doxorubicin-cardiotoxicity CMR parameter was T2 relaxation-time prolongation at week 6 (2 weeks after the third dose). T1 mapping, ECV, and left ventricular (LV) motion were unaffected. At this early time point, isolated T2 prolongation correlated with intracardiomyocyte edema secondary to vacuolization without extracellular space expansion. Subsequent development of T1 mapping and ECV abnormalities coincided with LV motion defects: LV ejection fraction declined from week 10 (2 weeks after the fifth and final doxorubicin dose). Stopping doxorubicin therapy upon detection of T2 prolongation halted progression to LV motion deterioration and resolved intracardiomyocyte vacuolization, demonstrating that early T2 prolongation occurs at a reversible disease stage. CONCLUSIONS: T2 mapping during treatment identifies intracardiomyocyte edema generation as the earliest marker of anthracycline-induced cardiotoxicity, in the absence of T1 mapping, ECV, or LV motion defects. The occurrence of these changes at a reversible disease stage shows the clinical potential of this CMR marker for tailored anthracycline therapy.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/diagnóstico por imagem , Doxorrubicina/efeitos adversos , Imagem por Ressonância Magnética , Animais , Antibióticos Antineoplásicos/administração & dosagem , Cardiotoxicidade/etiologia , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Esquema de Medicação , Masculino , Suínos , Fatores de Tempo
11.
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
12.
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
13.
J Nucl Cardiol ; 25(6): 2159-2167, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30443750

RESUMO

Current cancer therapy has led to tremendous improvements in outcomes. These therapies rely both on established therapies, such as anthracyclines and radiation, and molecularly-targeted therapies, such as tyrosine kinase inhibitors and immune modulators. Integrative care for patients with cancer must consider the potential effects of these therapies on a variety of organ systems, including the cardiovascular system. As a result, specialties such as cardio-oncology have developed to identify these effects, determine how to best monitor for these effects, and how to treat and ultimately prevent these effects while allowing the patient to receive the therapy they require for their cancer. This review provides a basis for understanding the cardiovascular effects of cancer therapies so that the most appropriate imaging modality may be selected to prevent and treat these effects.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/diagnóstico por imagem , Radioterapia/efeitos adversos , Antraciclinas/efeitos adversos , Cardiotoxicidade/prevenção & controle , Humanos , Proteínas Tirosina Quinases/antagonistas & inibidores , Trastuzumab/efeitos adversos
14.
PLoS One ; 13(10): e0203602, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30273351

RESUMO

In order to determine the role of the adrenergic system in bupivacaine-induced cardiotoxicity, a series of experiments were performed. In an animal experiment, male Sprague-Dawley (SD) rats under chloral hydrate anesthesia received intravenous bupivacaine, followed by an intravenous injection of adrenalin or isoprenalin, and the electrocardiogram (ECG), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), the maximum rate of rise of left ventricular pressure (+dP/dtmax) and the maximum rate of pressure decrease (-dP/dtmax) were continually monitored. In a cellular experiment, freshly isolated adult SD rat ventricular myocytes were perfused with bupivacaine at different concentrations in the presence or absence of isoprenalin, with or without esmolol. The percentage of the sarcomere shortening (bl% peak h), departure velocity (dep v) of sarcomere shortening and time to 50% of the peak speed of myocyte contraction (Tp50) was assessed by a video-based edge-detection system. In an additional experiment, Swiss mice pretreated with saline, isoprenalin, esmolol or dexmedetomidine received bupivacaine to determine the 50% lethal dose (LD50) of bupivacaine. Electron microscopy of myocardial mitochondria was performed to assess damage of these structures. To test mitochondrial reactive oxygen species (ROS) production, freshly isolated SD rat ventricular myocytes were incubated with bupivacaine in the presence of isoprenalin, with or without esmolol. First, our results showed that bupivacaine significantly reduced the LVSP and +dP/dtmax, as well as enhanced the LVEDP and -dP/dtmax (P < 0.05, vs. control, and vs. baseline). Adrenalin and isoprenalin induced a further reduction of LVSP and +dP/dtmax (P < 0.05, vs. before adrenalin or isoprenalin delivery, and vs. control). Second, bupivacaine induced a dose-dependent cardiomyocyte contractile depression. While 5.9 µmol/L or 8.9 µmol/L of bupivacaine resulted in no change, 30.0 µmol/L of bupivacaine prolonged the Tp50 and reduced the bl% peak h and dep v (P < 0.05, vs. control and vs. baseline). Isoprenalin aggravated the bupivacaine-induced cardiomyocyte contractile depression, significantly prolonging the Tp50 (P < 0.05, vs. bupivacaine alone) and reducing the dep v (P < 0.05, vs. bupivacaine alone). Third, esmolol and dexmedetomidine significantly enhanced, while isoprenalin significantly reduced, the LD50 of bupivacaine in mice. Fourth, bupivacaine led to significant mitochondrial swelling, and the extent of myocardial mitochondrial swelling in isoprenalin-pretreated mice was significantly higher than that compared with mice pretreated with saline, as reflected by the higher mitochondrial damage score (P < 0.01). Meanwhile, esmolol pretreatment significantly reduced the mitochondrial damage score (P < 0.01). Fifth, bupivacaine significantly increased the ROS in freshly isolated cardiomyocytes, and added isoprenalin induced a further enhancement of ROS production (P < 0.05, vs. bupivacaine alone). Added esmolol significantly decreased ROS production (P < 0.05, vs. bupivacaine + isoprenalin). Our results suggest that bupivacaine depressed cardiac automaticity, conductivity and contractility, but the predominant effect was contractile dysfunction which resulted from the disruption of mitochondrial energy metabolism. ß-adrenergic activation aggravated the cellular metabolism disorder and therefore contractile dysfunction.


Assuntos
Cardiotoxicidade/fisiopatologia , Epinefrina/administração & dosagem , Isoproterenol/administração & dosagem , Contração Miocárdica/efeitos dos fármacos , Anestesia/efeitos adversos , Animais , Pressão Sanguínea/efeitos dos fármacos , Bupivacaína/administração & dosagem , Bupivacaína/efeitos adversos , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Hidrato de Cloral/administração & dosagem , Modelos Animais de Doenças , Eletrocardiografia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Camundongos , Contração Miocárdica/fisiologia , Propanolaminas/administração & dosagem , Ratos , Espécies Reativas de Oxigênio/metabolismo
15.
Curr Cardiol Rep ; 20(12): 142, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367282

RESUMO

PURPOSE OF REVIEW: Advancements in cancer treatment have resulted in improved cancer-related survival and consequently an increase in the number of cancer survivors. Unfortunately, associated with this increase in cancer-related survivorship, cardiac events have occurred with increasing frequency in cancer survivors. Recognition that cancer survivors are at increased risk for cardiovascular (CV) morbidity has generated interest to develop cardiac imaging techniques that identify subclinical CV disease during receipt of potentially cardiotoxic cancer treatment. Since subclinical cardiovascular disease precedes future cardiac events, early recognition of subclinical CV disease during receipt of potentially cardiotoxic cancer treatment offers the opportunity to initiate strategies that prevent further evolution of subclinical CV disease as well as cardiac events. RECENT FINDINGS: Cardiovascular magnetic resonance imaging (CMR) is an advanced imaging technique that identifies imaging markers of subclinical cardiovascular disease in patients receiving potentially cardiotoxic cancer treatment regimens. In this article, we review the use of CMR for identifying subclinical cardiac disease in patients receiving potentially cardiotoxic cancer treatment regimens. The ability of contemporary CMR to accurately define cardiac anatomy, function, and tissue characteristics may represent a critical tool to assess patients with cancer.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/diagnóstico por imagem , Doenças Cardiovasculares/diagnóstico por imagem , Sistema Cardiovascular/diagnóstico por imagem , Imagem por Ressonância Magnética , Neoplasias/tratamento farmacológico , Cardiotoxicidade/patologia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/patologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/patologia , Humanos , Medição de Risco , Sobreviventes
16.
Curr Probl Cancer ; 42(4): 386-396, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30297038

RESUMO

Recent advances in cancer treatments have significantly improved survival rates, reemphasizing the focus on reducing the potential complications associated with some therapies. Cardiovascular disease associated with chemotherapies is a major cause of morbidity and mortality in cancer survivors. Early detection of cardiotoxicity improves cardiac outcomes among cancer patients. The review will focus on imaging modalities used to assess cardiotoxicity - the cardiovascular consequences of chemotherapies. The review will discuss the benefits and limitations associated with each technique, as well as the guidelines available to help identify at risk patients. We will discuss novel techniques that may help detect earlier signs of cardiotoxicity, directing management that may improve clinical outcomes.


Assuntos
Antineoplásicos/efeitos adversos , Técnicas de Imagem Cardíaca/métodos , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/diagnóstico , Neoplasias/tratamento farmacológico , Cardiotoxicidade/etiologia , Humanos , Prognóstico , Fatores de Risco
17.
Curr Opin Cardiol ; 33(5): 493-497, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30028729

RESUMO

PURPOSE OF REVIEW: We aim to summarize the utility of strain in monitoring the effects of cancer therapy-related cardiotoxicity (CTRC) on the development of left ventricular (LV) dysfunction. RECENT FINDINGS: Serial assessment of cardiac function at baseline and during treatment is recommended in patients undergoing cancer treatment. Historically, the use of left ventricular ejection fraction (LVEF) has been used to monitor for cardiac toxicity from cancer therapies but myocardial mechanic parameters, in particular global longitudinal strain (GLS), have emerged as powerful adjunctive tools. On the basis of longitudinal cohort studies in patients treated with anthracyclines and trastuzumab and retrospective studies of childhood survivors of cancers, strain has been used to detect subclinical LV dysfunction prior to changes in LVEF. Strain parameters decrease during both anthracycline and trastuzumab and these changes can persist after completion of therapy. Baseline GLS and changes in GLS during therapy can be independently prognostic for developing CTRC. Further, GLS has appeared to have an additive predictive value in addition to the traditional clinical parameters and baseline LVEF in the development of cardiotoxicity. The inclusion of strain parameters in clinical decision making and therapeutic planning is an area of intense research. SUMMARY: This review seeks to highlight the importance of echocardiographic strain measurements in early detection, treatment and prevention of LV dysfunction from CTRC.


Assuntos
Cardiotoxicidade/diagnóstico por imagem , Ecocardiografia/métodos , Função Ventricular Esquerda , Antineoplásicos/efeitos adversos , Sobreviventes de Câncer , Cardiotoxicidade/etiologia , Humanos , Disfunção Ventricular Esquerda
18.
Cell Death Dis ; 9(6): 692, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29880809

RESUMO

The lysosomal cysteine protease Cathepsin K is elevated in humans and animal models of heart failure. Our recent studies show that whole-body deletion of Cathepsin K protects mice against cardiac dysfunction. Whether this is attributable to a direct effect on cardiomyocytes or is a consequence of the global metabolic alterations associated with Cathepsin K deletion is unknown. To determine the role of Cathepsin K in cardiomyocytes, we developed a cardiomyocyte-specific Cathepsin K-deficient mouse model and tested the hypothesis that ablation of Cathepsin K in cardiomyocytes would ameliorate the cardiotoxic side-effects of the anticancer drug doxorubicin. We used an α-myosin heavy chain promoter to drive expression of Cre, which resulted in over 80% reduction in protein and mRNA levels of cardiac Cathepsin K at baseline. Four-month-old control (Myh-Cre-; Ctsk fl/fl) and Cathepsin K knockout (Myh-Cre+; Ctsk fl/fl) mice received intraperitoneal injections of doxorubicin or vehicle, 1 week following which, body and tissue weight, echocardiographic properties, cardiomyocyte contractile function and Ca2+-handling were evaluated. Control mice treated with doxorubicin exhibited a marked increase in cardiac Cathepsin K, which was associated with an impairment in cardiac structure and function, evidenced as an increase in end-systolic and end-diastolic diameters, decreased fractional shortening and wall thickness, disruption in cardiac sarcomere and microfilaments and impaired intracellular Ca2+ homeostasis. In contrast, the aforementioned cardiotoxic effects of doxorubicin were attenuated or reversed in mice lacking cardiac Cathepsin K. Mechanistically, Cathepsin K-deficiency reconciled the disturbance in cardiac energy homeostasis and attenuated NF-κB signaling and apoptosis to ameliorate doxorubicin-induced cardiotoxicity. Cathepsin K may represent a viable drug target to treat cardiac disease.


Assuntos
Cardiotônicos/metabolismo , Cardiotoxicidade/prevenção & controle , Catepsina K/metabolismo , Doxorrubicina/efeitos adversos , Miócitos Cardíacos/metabolismo , Animais , Apoptose , Cálcio/metabolismo , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/patologia , Sobrevivência Celular , Fibrose , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Especificidade de Órgãos , Transdução de Sinais
19.
J Nucl Cardiol ; 25(6): 2148-2158, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29736616

RESUMO

Cancer therapeutics-related cardiac dysfunction (CTRCD) is a well-established adverse effect resulting from a number of cancer therapeutics. Newer immunotherapy has been associated with cardiomyopathy and myocarditis making comprehensive imaging useful for early recognition. Cardiac MRI (CMR) offers a comprehensive evaluation to detect CTRCD. Established guidelines for monitoring left ventricular ejection fraction for potential cardiotoxicity have recently incorporated CMR. We will review the utility of CMR in contemporary evaluation for potential oncologic cardiotoxicity.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/diagnóstico por imagem , Coração/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Cicatriz/diagnóstico por imagem , Humanos , Radioterapia/efeitos adversos , Sístole/fisiologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda
20.
Mol Pharm ; 15(7): 2594-2605, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29763568

RESUMO

We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near-infrared (NIR) light absorptivity (λmax = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PG accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG (2 mg of Pc 1 equivalent/kg) induced a greater tumor volume reduction (-74 ± 5%) when compared to high dose ZnPc (8 mg/kg, -50 ± 12%). At higher treatment doses (8 mg of Pc 1 equivalent/kg), 1-PG reduced tumor volume maximally (-91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PG as a useful photosensitizer candidate for clinical PDT.


Assuntos
Indóis/administração & dosagem , Nanoconjugados/química , Neoplasias/tratamento farmacológico , Compostos Organometálicos/administração & dosagem , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Ecocardiografia , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/farmacocinética , Fotoquimioterapia/efeitos adversos , Fármacos Fotossensibilizantes/efeitos adversos , Fármacos Fotossensibilizantes/farmacocinética , Ácido Poliglutâmico/química , Ratos , Ratos Endogâmicos WKY , Distribuição Tecidual
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