RESUMEN
Anthracyclines and HER2-targeted antibodies are very effective for the treatment of breast cancer, but their use is limited by cardiotoxicity. In this nested case-control study, we assessed the role of intermediary metabolism in 38 women with breast cancer treated with anthracyclines and trastuzumab. Using targeted mass spectrometry to measure 71 metabolites in the plasma, we identified changes in citric acid and aconitic acid that differentiated patients who developed cardiotoxicity from those who did not. In patients with cardiotoxicity, the magnitude of change in citric acid at three months correlated with the change in left ventricular ejection fraction (LVEF) and absolute LVEF at nine months. Patients with cardiotoxicity also demonstrated more pronounced changes in purine and pyrimidine metabolism. Early metabolic changes may therefore provide insight into the mechanisms associated with the development of chemotherapy-associated cardiotoxicity.
Asunto(s)
Antibióticos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Ciclo del Ácido Cítrico/efectos de los fármacos , Doxorrubicina/efectos adversos , Cardiopatías/inducido químicamente , Miocitos Cardíacos/efectos de los fármacos , Nucleósidos/sangre , Adulto , Biomarcadores/sangre , Cardiotoxicidad , Cromatografía Líquida de Alta Presión , Femenino , Cardiopatías/metabolismo , Cardiopatías/fisiopatología , Humanos , Metabolómica , Persona de Mediana Edad , Miocitos Cardíacos/metabolismo , Prueba de Estudio Conceptual , Estudios Prospectivos , Espectrometría de Masa por Ionización de Electrospray , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Trastuzumab/efectos adversos , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
BACKGROUND: During the development of heart failure (HF), the changes of contraction timing pattern and temporal heterogeneity of segmental contraction happen early and may precede both symptomatic HF and the decrease in left ventricular ejection fraction (LVEF). In patients treated with anthracyclines, both symptomatic HF and the decrease of LVEF are detected once significant myocardial injury has occurred. The aim of the current study was to investigate whether changes in the timing of contraction can be detected early after anthracyclines therapy. METHODS: Forty-one women (50 ± 11 years old) with newly diagnosed breast cancer were prospectively enrolled in two centers and underwent an echocardiogram before and after anthracyclines. Peak longitudinal myocardial systolic strain was measured on the apical four- and two-chamber views. The time to peak systolic longitudinal strain (TP), ejection time (ET), isovolumic contraction time (IVCT), systolic time, and diastolic time were measured using strain curves and Doppler tracings and compared before and after anthracyclines. The heterogeneity of contraction (dyssynchrony) was measured by the SD of the TP of all segments. RESULTS: Anthracyclines treatment was associated with an increase in heart rate (HR) and a decrease in TP. TP was correlated with HR. TP/ET was independent of HR and inversely correlated to peak strain both at baseline and after anthracyclines. TP/ET increased after anthracyclines (1.26 ± 0.19 to 1.31 ± 0.22; P < .001), and this increase was correlated with the decrease in strain. The increase in TP/ET was due to an increase in IVCT/ET. A similar degree of dyssynchrony was found at baseline and after anthracyclines. CONCLUSIONS: Anthracyclines treatment induces an increase in the duration of contraction, mainly by increasing the IVCT. This increase is correlated to the decrease in strain and may therefore have additional prognostic value.
Asunto(s)
Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Contracción Miocárdica/efectos de los fármacos , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/fisiopatología , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Boston , Neoplasias de la Mama/fisiopatología , Estudios Controlados Antes y Después , Acoplamiento Excitación-Contracción/efectos de los fármacos , Femenino , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Persona de Mediana Edad , Quebec , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Volumen Sistólico , Resultado del Tratamiento , Ultrasonografía/métodos , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients.
Asunto(s)
Antineoplásicos/efectos adversos , Cardiotoxicidad/diagnóstico , Cardiotoxicidad/prevención & control , Radioterapia/efectos adversos , Arritmias Cardíacas/etiología , Arritmias Cardíacas/terapia , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Cardiotónicos/uso terapéutico , Cardiotoxicidad/etiología , Cardiotoxinas/efectos adversos , Trombosis Coronaria/etiología , Trombosis Coronaria/terapia , Diagnóstico Precoz , Ecocardiografía Tridimensional , Humanos , Hipertensión/etiología , Hipertensión/terapia , Imagen por Resonancia Cinemagnética , Isquemia Miocárdica/etiología , Isquemia Miocárdica/terapia , Péptido Natriurético Encefálico/sangre , Neoplasias/terapia , Prevención Primaria , Factores de Riesgo , Troponina T/sangre , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/terapiaRESUMEN
BACKGROUND: Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS: In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS: Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10-1.71), P = 0.02; PlGF 3.78 (1.30-11.0), P = 0.047; GDF-15 1.71 (1.15-2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS: Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Cardiotoxicidad/diagnóstico , Cardiotoxinas/efectos adversos , Doxorrubicina/efectos adversos , Corazón/efectos de los fármacos , Trastuzumab/efectos adversos , Adulto , Biomarcadores/análisis , Mama/efectos de los fármacos , Proteína C-Reactiva/análisis , Cardiotoxicidad/etiología , Femenino , Galectina 3/análisis , Factor 15 de Diferenciación de Crecimiento/análisis , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Péptido Natriurético Encefálico/análisis , Fragmentos de Péptidos/análisis , Pronóstico , Troponina I/análisis , Receptor 1 de Factores de Crecimiento Endotelial Vascular/análisisRESUMEN
BACKGROUND: Trastuzumab, a HER2 monoclonal antibody, has transformed the prognosis of patients with the aggressive HER2-positive breast cancer type. Trastuzumab augments the cardiotoxic effects of anthracyclines, but its effect is thought to be at least partially reversible. The objective of this study was to examine the time trends of left ventricular (LV) size and function in a cohort of women treated with anthracyclines and trastuzumab. METHODS: Twenty-nine patients >18 years of age with first-time breast cancer treated with anthracyclines and trastuzumab were monitored using echocardiography before, at the completion of, and at a median follow-up of 24.7 months (interquartile range, 15.9-34 months) after the end of their cancer treatment. LV volume, LV ejection fraction, and global peak systolic longitudinal strain and strain rate were measured in the apical four- and two-chamber views. Left ventricular ejection fraction was measured using a modified Simpson's biplane method. RESULTS: LV end-diastolic and end-systolic volumes increased at the end of treatment compared with baseline and did not recover during follow-up. Left ventricular ejection fraction, strain, and strain rate decreased at the end of treatment compared with baseline (from 64 ± 6% to 59 ± 8%, from -20.0 ± 2.5% to -17.6 ± 2.6%, and from -1.26 ± 0.23 to -1.13 ± 0.16 sec(-1), respectively; P < .05 for all parameters) and remained decreased at follow-up. CONCLUSIONS: LV dilation and subclinical impairment in cardiac function persists >2 years after the end of anthracycline and trastuzumab treatment, without significant recovery after trastuzumab cessation, suggestive of long-term underlying cardiac damage and remodeling.
Asunto(s)
Antraciclinas/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Volumen Cardíaco/efectos de los fármacos , Volumen Sistólico/efectos de los fármacos , Taxoides/administración & dosificación , Trastuzumab/administración & dosificación , Función Ventricular Izquierda/efectos de los fármacos , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/fisiopatología , Relación Dosis-Respuesta a Droga , Ecocardiografía , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Factores de TiempoRESUMEN
The increased pericardial fat which often accompanies overall obesity is thought to alter cardiac structure/function and increase the risk for atrial fibrillation. We hypothesized that chronic exposure to bisphenol A (BPA) would induce pericardial fat, cardiac hypertrophy or arrhythmia. C57bl/6n dams were exposed to BPA (25 ng/ml drinking water) beginning on gestation day 11 and progeny continued on 2.5 ng BPA/ml drinking water. The progeny of control dams (VEH) and dams treated with diethylstilbestrol (DES, 1 µg/kg/day, gestation days 11â¿¿14) had tap water. After weaning progeny were fed either a control (CD) or high fat diet (HFD) for 3 months. Pericardial fat was present in CD-BPA and CD-DES and not CD-VEH mice, and was increased in all HFD mice. Catecholamine challenge revealed no differences in males, but BPA-exposed females had longer P-wave and QRS complex duration. Only CD-BPA and CD-DES females developed cardiac hypertrophy which was independent of increased blood pressure. Calcium homeostasis protein expression changes in HFD-BPA and HFD-DES mice predict reduced SERCA2 activity in males and increased SERCA2 activity in females. Thus, chronic BPA exposure induced pericardial fat in the absence of HFD, and female-specific changes in cardiac hypertrophy development and cardiac electrical conduction after a catecholamine challenge.
Asunto(s)
Antineoplásicos/efectos adversos , Cardiopatías/inducido químicamente , Cardiopatías/diagnóstico , Imagen Multimodal/normas , Neoplasias/tratamiento farmacológico , Adulto , Biomarcadores/análisis , Cardiología/normas , Consenso , Femenino , Humanos , Masculino , Oncología Médica/normas , Guías de Práctica Clínica como Asunto , Sociedades Médicas , Estados UnidosAsunto(s)
Quimioradioterapia/efectos adversos , Quimioradioterapia/normas , Imagen Multimodal/normas , Neoplasias/diagnóstico , Neoplasias/terapia , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etiología , Adulto , Cardiología/normas , Europa (Continente) , Femenino , Humanos , Masculino , Oncología Médica/normas , Guías de Práctica Clínica como Asunto , Radiología/normas , Estados Unidos , Disfunción Ventricular Izquierda/prevención & controlRESUMEN
OBJECTIVES: The aim of this study was to determine if individual or multiple biomarkers are associated with cardiotoxicity in patients with breast cancer undergoing cancer therapy. BACKGROUND: Current methods to identify patients at risk for cardiotoxicity from cancer therapy are inadequate. METHODS: We measured 8 biomarkers in a multicenter cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1, and galectin (gal)-3. Cardiotoxicity, defined by the Cardiac Review and Evaluation Committee criteria, was assessed every 3 months for up to 15 months. Hazard ratios (HRs) of cardiotoxicity risk were assessed for each biomarker at baseline, at visit 2 (3 months), and as a function of the difference between visit 2 and baseline. Joint models were assessed for the most promising biomarkers. RESULTS: TnI, CRP, GDF-15, MPO, PlGF, and sFlt-1 levels increased from baseline to visit 2 (p < 0.05). A greater risk of cardiotoxicity was associated with interval changes in TnI (HR: 1.38 per SD; 95% confidence interval: 1.05 to 1.81; p = 0.02) and MPO (HR: 1.34 per SD; 95% confidence interval: 1.00 to 1.80; p = 0.048) and in models combining both markers (p = 0.007 and p = 0.03, respectively). The risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (ΔTnI >121.8 µg/l; ΔMPO >422.6 pmol/l). CONCLUSIONS: Early increases in TnI and MPO levels offer additive information about the risk of cardiotoxicity in patients undergoing doxorubicin and trastuzumab therapy. Independent validation of these findings is necessary before application to clinical practice.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Enfermedades Cardiovasculares/sangre , Peroxidasa/sangre , Troponina I/sangre , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores/sangre , Neoplasias de la Mama/diagnóstico , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/diagnóstico , Estudios de Cohortes , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Taxoides/administración & dosificación , Taxoides/efectos adversos , Factores de Tiempo , Trastuzumab , Resultado del TratamientoRESUMEN
Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.
Asunto(s)
Ecocardiografía/normas , Corazón/efectos de la radiación , Imagen Multimodal/normas , Neoplasias/radioterapia , Traumatismos por Radiación/diagnóstico , Traumatismos por Radiación/terapia , Adulto , Relación Dosis-Respuesta en la Radiación , Ecocardiografía/métodos , Humanos , Persona de Mediana Edad , Imagen Multimodal/métodos , Radioterapia Adyuvante/efectos adversos , RiesgoRESUMEN
The detrimental effects of in utero exposure to the non-steroidal estrogen diethylstilbestrol (DES) are particularly marked in women. Fetal hearts express estrogen receptors, making them potentially responsive to DES. To examine whether gestational exposure to DES would impact the heart, we exposed pregnant C57bl/6n dams to DES (0.1, 1.0, and 10.0 µg·(kg body mass)(-1)·day(-1)) on gestation days 11.5-14.5, and examined the measured cardiac structure/function and calcium homeostasis protein expression in adult females. At baseline, echocardiography revealed eccentric hypertrophy in mice treated with 10.0 µg·(kg body mass)(-1)·day(-1) DES, and immunoblots showed increased SERCA2a in all DES-treated mice. Mice were swim-trained to assess cardiac remodeling. Swim-trained vehicle-treated mice developed eccentric hypertrophy without changing SERCA2 or calsequestrin 2 expression. In contrast, no DES-treated mice hypertrophied, and all increased in SERCA2a and calsequestrin 2 expression after training. To determine whether DES-induced changes in DNA methylation is part of the mechanism for its long-term effects, we measured DNA methyltransferase expression and DNA methylation. Global DNA methylation and DNA methyltransferase 3a expression were unchanged. However, DES-treated mice had increased DNA methylation in the calsequestrin 2 promoter. Thus, gestational exposure to DES altered female ventricular DNA, cardiac structure/function, and calcium homeostasis protein expression. We conclude that gestational exposure to estrogenizing compounds may impact cardiac structure/function in adult females.
Asunto(s)
Metilación de ADN/efectos de los fármacos , Dietilestilbestrol/toxicidad , Corazón Fetal/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Hipertrofia Ventricular Izquierda/inducido químicamente , Efectos Tardíos de la Exposición Prenatal , Función Ventricular Izquierda/efectos de los fármacos , Factores de Edad , Animales , Secuencia de Bases , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Calsecuestrina/genética , Calsecuestrina/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Femenino , Corazón Fetal/crecimiento & desarrollo , Corazón Fetal/metabolismo , Regulación de la Expresión Génica , Edad Gestacional , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Hemodinámica/efectos de los fármacos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Embarazo , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Conducta Sedentaria , Factores Sexuales , Intercambiador de Sodio-Calcio/genética , Intercambiador de Sodio-Calcio/metabolismo , Natación , Ultrasonografía , Remodelación Ventricular/efectos de los fármacosRESUMEN
Resistin is a circulating mediator of insulin resistance mainly expressed in human monocytes and responsive to inflammatory stimuli. Recent clinical studies have connected elevated resistin levels with the development and severity of heart failure. To further our understanding of the role of human resistin in heart failure, we studied a humanized mouse model lacking murine resistin but transgenic for the human Retn gene (Hum-Retn mice), which exhibits basal and inflammation-stimulated resistin levels similar to humans. Specifically, we explored whether resistin underlies acute anthracycline-induced cardiotoxicity. Remarkably, doxorubicin (25mg/kg ip) led to a 4-fold induction of serum resistin levels in Hum-Retn mice. Moreover, doxorubicin-induced cardiotoxicity was greater in the Hum-Retn mice than in littermate controls not expressing human resistin (Retn(-/-)). Hum-Retn mice showed increased cardiac mRNA levels of inflammatory and cell adhesion genes compared with Retn(-/-) mice. Macrophages, but not cardiomyocytes, from Hum-Retn mice treated with doxorubicin in vitro showed dramatic induction of hRetn (human resistin) mRNA and protein expression. We also examined resistin levels in anthracycline-treated breast cancer patients with and without cardiotoxicity. Intriguingly, serum resistin levels in women undergoing anthracycline-containing chemotherapy increased significantly at 3 months and remained elevated at 6 months in those with subsequent cardiotoxicity. Further, elevation in resistin correlated with decline in ejection fraction in these women. These results suggest that elevated resistin is a biomarker of anthracycline-induced cardiotoxicity and may contribute in the development of heart failure via its direct effects on macrophages. These results further implicate resistin as a link between inflammation, metabolism, and heart disease.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/efectos adversos , Insuficiencia Cardíaca/inducido químicamente , Resistina/metabolismo , Animales , Animales Recién Nacidos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Células Cultivadas , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Humanos , Macrófagos Peritoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Resistina/genética , TrastuzumabRESUMEN
Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.
Asunto(s)
Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología , Corazón/efectos de la radiación , Imagen Multimodal/normas , Neoplasias/radioterapia , Traumatismos por Radiación/diagnóstico , Traumatismos por Radiación/etiología , Radioterapia/efectos adversos , Adulto , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/terapia , Consenso , Relación Dosis-Respuesta en la Radiación , Europa (Continente) , Humanos , Traumatismos por Radiación/fisiopatología , Traumatismos por Radiación/terapia , Riesgo , Estados UnidosRESUMEN
In the context of modern cancer chemotherapeutics, cancer survivors are living longer and being exposed to potential comorbidities related to non-cancer side effects of such treatments. With close monitoring of cancer patients receiving potentially cardiotoxic medical therapies, oncologists, and cardiologists alike are identifying patients in both clinical and subclinical phases of cardiovascular disease related to such chemotherapies. Specifically, cardiotoxicity at the level of the myocardium and potential for the development of heart failure are becoming a growing concern with increasing survival of cancer patients. Traditional chemotherapeutic agents used commonly in the treatment of breast cancer and hematologic malignancies, such as anthracyclines and HER-2 antagonists, are well known to be associated with cardiovascular sequelae. Patients often present without symptoms and an abnormal cardiac imaging study performed as part of routine evaluation of patients receiving cardiotoxic therapies. Additionally, patients can present with signs and symptoms of cardiovascular disease months to years after receiving the chemotherapies. As the understanding of the physiology underlying the various cancers has grown, therapies have been developed that target specific molecules that represent key aspects of physiologic pathways responsible for cancer growth. Inhibition of these pathways, such as those involving tyrosine kinases, has lead to the potential for cardiotoxicity as well. In view of the potential cardiotoxicity of specific chemotherapies, there is a growing interest in identifying patients who are at risk of cardiotoxicity prior to becoming symptomatic or developing cardiotoxicity that may limit the use of potentially life-saving chemotherapy agents. Serological markers and novel cardiac imaging techniques have become the source of many investigations with the goal of screening patients for pre-clinical cardiotoxicity. Additionally, studies have been performed.
RESUMEN
Bisphenol A (BPA) is an estrogenizing endocrine disruptor compound of concern. Our objective was to test whether lifelong BPA would impact cardiac structure/function, calcium homeostasis protein expression, and the DNA methylation of cardiac genes. We delivered 0.5 and 5.0 µg/kg/day BPA lifelong from gestation day 11 or 200 µg/kg/day from gestation day 11 to postnatal day 21 via the drinking water to C57bl/6n mice. BPA 5.0 males and females had increased body weight, body mass index, body surface area, and adiposity. Echocardiography identified concentric remodeling in all BPA-treated males. Systolic and diastolic cardiac functions were essentially similar, but lifelong BPA enhanced male and reduced female sex-specific differences in velocity of circumferential shortening and ascending aorta velocity time integral. Diastolic blood pressure was increased in all BPA females. The calcium homeostasis proteins sarcoendoplasmic reticulum ATPase 2a (SERCA2a), sodium calcium exchanger-1, phospholamban (PLB), phospho-PLB, and calsequestrin 2 are important for contraction and relaxation. Changes in their expression suggest increased calcium mobility in males and reduced calcium mobility in females supporting the cardiac function changes. DNA methyltransferase 3a expression was increased in all BPA males and BPA 0.5 females and reduced in BPA 200 females. Global DNA methylation was increased in BPA 0.5 males and reduced in BPA 0.5 females. BPA induced sex-specific altered DNA methylation in specific CpG pairs in the calsequestrin 2 CpG island. These results suggest that continual exposure to BPA impacts cardiac structure/function, protein expression, and epigenetic DNA methylation marks in males and females.
Asunto(s)
Compuestos de Bencidrilo/toxicidad , Proteínas Portadoras/genética , Metilación de ADN/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Corazón/efectos de los fármacos , Fenoles/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Proteínas de Unión al Calcio/genética , ADN Metiltransferasa 3A , Relación Dosis-Respuesta a Droga , Ecocardiografía , Femenino , Edad Gestacional , Corazón/embriología , Corazón/crecimiento & desarrollo , Pruebas de Función Cardíaca , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Factores Sexuales , Intercambiador de Sodio-Calcio/genética , Factores de TiempoRESUMEN
BACKGROUND: Right ventricular (RV) diastolic dysfunction precedes RV systolic dysfunction. Improvement in noninvasive assessment of RV diastolic function may enable earlier detection of RV dysfunction, especially important in the assessment of patients with congenital heart disease. We investigated a new parameter we call RV end-diastolic wall stress (RVEDWS) in an effort to better characterize RV diastolic function. METHODS: We retrospectively studied consecutive adults with right-sided congenital heart disease between January 2005 and November 2006. RVEDWS was calculated with the Laplace law: r × p/λ, where r = basal RV dimension at end-diastole, p = RV end-diastolic pressure obtained from catheterization of the right side of the heart, and λ = thickness of RV free wall at end-diastole in the subcostal view. Calculated RVEDWS was correlated to echocardiographically derived right atrial (RA) measurements by means of the Pearson correlation. RESULTS: Twenty-four patients, aged 41 ± 15 years, were included in the study. Mean RVEDWS was 20 ± 11 g/cm(2) (range, 3-46 g/cm(2)). RVEDWS correlated significantly with RA area and volume (r = 0.71, P < 0.0001; r = 0.69, P < 0.001, respectively). An RVEDWS > 17 g/cm(2) had a sensitivity of 91% and specificity of 85% in predicting significant RA enlargement. RVEDWS was significantly higher in patients with RV volume overload compared with those with pressure or normal loading conditions (28 g/cm(2) vs 17 g/cm(2), P = 0.01). CONCLUSIONS: RVEDWS correlates significantly with RA size and differs considerably between RV volume and pressure overload states. Further work is needed to determine whether this RV diastolic parameter can be predictive of clinical outcomes in patients with RV loading lesions.
Asunto(s)
Diástole/fisiología , Atrios Cardíacos/patología , Cardiopatías Congénitas/fisiopatología , Función Ventricular Derecha/fisiología , Adulto , Estudios de Cohortes , Ecocardiografía Doppler , Femenino , Cardiopatías Congénitas/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Volumen Sistólico/fisiología , Presión Ventricular/fisiologíaRESUMEN
Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0µg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5-14.5. At 3months, male progeny were left sedentary or were swim trained for 4weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males.
Asunto(s)
Metilación de ADN/fisiología , Dietilestilbestrol/toxicidad , Estrógenos no Esteroides/toxicidad , Corazón/crecimiento & desarrollo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Biosíntesis de Proteínas/fisiología , Factores de Edad , Animales , Metilación de ADN/efectos de los fármacos , ADN Metiltransferasa 3A , Femenino , Corazón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Biosíntesis de Proteínas/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Childhood cancer survivors can develop significant cardiac dysfunction in adulthood as a consequence of their cancer treatment. Studies have linked heart failure during pregnancy to childhood doxorubicin (DOX) exposure. We hypothesized that DOX injection would reduce cardiac function peripartum and that DOX-treated dams would show greater cardiac remodeling postweaning. Weanling female Sprague-Dawley rats were injected with phospate-buffered saline, DOX (3 mg/kg), or DOX plus the cardioprotectant dexrazoxane (DEX; 60 mg/kg) and followed for 2 pregnancies. DOX and DOX:DEX dams were fertile, but had fewer pups and more pup losses. Echocardiography, 1-day postpartum after each pregnancy, revealed greater increases in cardiac mass and eccentric hypertrophy in DOX-treated dams and early dilation in DOX:DEX dams. The expression of calcium homeostasis proteins can change after DOX treatment and cardiac remodeling. SERCA2a expression did not change. Reductions in phospholamban and phospho-serine 16-specific phospholamban expression in DOX dams were not relieved by DEX coinjection. DOX binds and inactivates calsequestrin 2 expression so increased calsequestrin 2 expression in DOX:DEX-treated dams suggests some DEX compensation. The eccentric hypertrophy and dilation development, despite compensatory changes in proteins controlling calcium cycling, suggest DOX damage with repeat pregnancy that was not alleviated fully by DEX.