Anthraycline-related cardiotoxicity in long-term survivors of lymphoma

淋巴瘤长期幸存者与蒽环类药物相关的心脏毒性

• 批准号: 8569676
• 负责人: Saro Armenian
• 金额: $ 19万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8569676
• 关键词: Address; Adult; Adult Lymphoma; Age; Anthracyclines; Autologous; Behavior; Biological Markers; Blood; Cancer Survivor; Cardiac; Cardiotoxicity; Cardiovascular system; Chest; Collagen; Congestive Heart Failure; Cross-Sectional Studies; Cyclophosphamide; Deceleration; Demographic Factors; Detection; Deterioration; Development; Diagnosis; Disease; Dose; EFRAC; Early Diagnosis; Early identification; Echocardiography; Functional disorder; Galectin 3; General Population; Health; High Dose Chemotherapy; High Prevalence; Hodgkin Disease; Image; Incidence; Individual; Injury; Intervention; Journals; Lead; Left; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Left Ventricular Function; Length; Life Style; Lipids; Long-Term Survivors; Lymphoma; Measurement; Measures; Morbidity - disease rate; Myocardial; Natriuretic Peptides; New England; Non-Hodgkin' s Lymphoma; Oncologist; Pathway interactions; Patients; Performance; Population; Populations at Risk; Prevalence; Process; Radiation; Recommendation; Relaxation; Renin-Angiotensin System; Research Design; Rest; Risk; Role; Shortening Fraction; Staging; Stress; Survivors; Therapeutic; Time; Tissues; Troponin; Two-Dimensional Echocardiography; Ventricular; Ventricular Remodeling; Vertebral column; Whole-Body Irradiation; cardiovascular risk factor; chemotherapy; childhood cancer survivor; cohort; conditioning; effective intervention; follow-up; functional disability; glucose metabolism; hematopoietic cell transplantation; high risk; indexing; innovation; metabolomics; mortality; novel; oncology; outcome forecast; oxidation; prevent; public health relevance; screening; sex

DESCRIPTION (provided by applicant): Anthracyclines form the backbone of therapy for lymphoma (Hodgkin [HL] and non-Hodgkin lymphoma [NHL]). However, the use of anthracyclines is limited by a dose-dependent association between anthracyclines and risk of cardiotoxicity that can lead to congestive heart failure (CHF). Lymphoma survivors are at a 2- to 5-fold increased risk of developing CHF when compared with the general population; autologous hematopoietic cell transplantation (HCT) survivors have an especially high risk. The overall prognosis is poor - five-year survival is less than 50% after CHF diagnosis. Anthracycline-induced CHF is a progressive disorder, with a period of asymptomatic left ventricular (LV) dysfunction characterized by dilation of the LV chamber, thinning of the myocardial wall, and increase in LV end-systolic wall stress (ESWS), a well-established precursor that precedes other indices of systolic function (LV ejection fraction [EF] and shortening fraction [SF]). Traditionally, detection of anthracycline-related LV dysfunction has relied upon echocardiographic screening using resting EF and SF. However, these parameters represent late-occurring changes in myocardial function. By the time decline in EF and SF are detected, functional deterioration is essentially irreversible, emphasizing the need for biomarkers that would facilitate identification of cardiac damage at an earlier stage, such that effective interventions can halt or reverse the process and prevent development of overt CHF. We have recently completed a study describing sensitive echocardiographic indices and blood biomarkers in childhood cancer survivors, and are now conducting a pharmacologic intervention to reverse myocardial remodeling in childhood cancer survivors at high risk for CHF. In the proposed study, we aim to address these gaps in anthracycline- exposed adults with lymphoma. Using a cross-sectional study design, this proposal will examine the role of novel echocardiographic (Tissue Doppler imaging, myocardial deformation [speckle tracking echocardiography], 2D- M-mode derived diastolic and systolic indices) and blood (cardiac troponins, natriuretic peptides, Galectin-3, ST-2, metabolomics) indices in detecting LV dysfunction (abnormal ESWS) in adult lymphoma survivors treated with anthracyclines. We will also measure these indices in age- and sex-matched healthy controls, in order to define the range for non-anthracycline-exposed individuals, and use these values to describe the magnitude of abnormality in the anthracycline-exposed lymphoma survivors. The current study's innovation lies in its ability to leverage existing information from childhood cancer survivors and non- oncology populations to develop a comprehensive assessment of cardiac function in adults with lymphoma. Information obtained from this study may be used to develop more comprehensive screening strategies in at risk populations, and to use these intermediate endpoints for pharmacologic interventions aimed at preventing CHF in survivors with early LV dysfunction.

描述（由申请人提供）：蒽环类药物是淋巴瘤（霍奇金淋巴瘤[HL]和非霍奇金淋巴瘤[NHL]）治疗的支柱。然而，蒽环类药物的使用受到限制，因为蒽环类药物与可导致充血性心力衰竭（CHF）的心脏毒性风险之间存在剂量依赖关系。与普通人群相比，淋巴瘤幸存者发生CHF的风险增加了2- 5倍；自体造血细胞移植（HCT）幸存者的风险尤其高。总体预后较差，诊断为CHF后5年生存率低于50%。蒽环类药物诱导的CHF是一种进行性疾病，伴有一段无症状的左室（LV）功能障碍，其特征为左室扩张、心肌壁变薄、左室收缩末期壁应力（ESWS）升高，这是其他收缩功能指标（左室射血分数[EF]和缩短分数[SF]）之前的一个明确的前兆。传统上，检测蒽环类药物相关的左室功能障碍依赖于静息EF和SF超声心动图筛查。然而，这些参数代表心肌功能的晚期变化。当检测到EF和SF的下降时，功能恶化基本上是不可逆的，这强调了对生物标志物的需求，这些生物标志物将有助于在早期阶段识别心脏损伤，这样有效的干预可以阻止或逆转这一过程，并防止显性CHF的发展。我们最近完成了一项研究，描述了儿童癌症幸存者的敏感超声心动图指标和血液生物标志物，目前正在进行药物干预，以逆转CHF高危儿童癌症幸存者的心肌重构。在拟议的研究中，我们的目标是在蒽环类药物暴露的成人淋巴瘤患者中解决这些差距。采用横断面研究设计，本研究将检验新型超声心动图（组织多普勒成像、心肌变形[斑点跟踪超声心动图]、2D- m模式衍生的舒张和收缩指标）和血液（心肌肌钙蛋白、利钠肽、半乳糖凝集素-3、ST-2、代谢组学）指标在检测接受蒽环类药物治疗的成年淋巴瘤幸存者左室功能障碍（异常ESWS）中的作用。我们还将在年龄和性别匹配的健康对照中测量这些指数，以确定非蒽环类药物暴露个体的范围，并使用这些值来描述蒽环类药物暴露淋巴瘤幸存者的异常程度。目前这项研究的创新之处在于它能够利用来自儿童癌症幸存者和癌症患者的现有信息