Anthraycline-related cardiotoxicity in long-term survivors of lymphoma

描述(申请人提供)：蒽环类药物是淋巴瘤(霍奇金淋巴瘤和非霍奇金淋巴瘤[NHL])治疗的支柱。然而，蒽环类药物的使用受到剂量依赖关系的限制，这种关联与可能导致充血性心力衰竭(CHF)的心脏毒性风险之间存在相关性。与普通人群相比，淋巴瘤幸存者发生CHF的风险增加2-5倍；自体造血细胞移植(HCT)幸存者的风险尤其高。总体预后很差--诊断出心力衰竭后，5年存活率不到50%。蒽环类药物所致的CHF是一种进行性疾病，其特征是左室腔扩张、心肌壁变薄和左心室收缩末期壁应力(ESWS)增加，这是一种公认的先于其他收缩功能指标(左心室射血分数[EF]和短轴缩短率[SF])的先兆指标，表现为无症状左心室(LV)功能障碍。传统上，检测与蒽环类药物相关的左心功能障碍依赖于超声心动图对静息EF和SF的筛查。然而，这些参数代表了心肌功能的晚期变化。当检测到EF和SF下降时，功能恶化基本上是不可逆转的，强调需要有助于在早期阶段识别心脏损害的生物标记物，以便有效的干预可以停止或逆转这一过程，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数和血液生物标志物，目前正在进行一项药物干预，以逆转CHF高危儿童癌症幸存者的心肌重构。在这项拟议的研究中，我们的目标是解决暴露于蒽环类药物的患有淋巴瘤的成年人的这些差距。采用横断面研究设计，这项建议将检验新的超声心动图(组织多普勒成像、心肌变形[斑点跟踪超声心动图]、2D-M模式衍生的舒张期和收缩指数)和血液(心肌肌钙蛋白、利钠肽、Galectin-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心功能障碍(异常ESWS)中的作用。我们还将在年龄和性别匹配的健康对照组中测量这些指数，以确定非暴露于蒽环类药物的个体的范围，并使用这些值来描述暴露于蒽环类药物的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儿童癌症幸存者和 非肿瘤学人群对成人淋巴瘤患者的心功能进行全面评估。从这项研究中获得的信息可能被用于在高危人群中开发更全面的筛查策略，并将这些中间终点用于药物干预，旨在预防早期左心功能不全幸存者的心力衰竭。

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.