Anthraycline-related cardiotoxicity in long-term survivors of lymphoma

描述（由申请方提供）：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]）治疗的主要药物。然而，蒽环类药物的使用受到蒽环类药物与心脏毒性风险（可导致充血性心力衰竭（CHF））之间剂量依赖性相关性的限制。与一般人群相比，淋巴瘤幸存者发生CHF的风险增加2至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-CHF诊断后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，伴有一段时间的无症状左心室（LV）功能障碍，其特征为LV腔扩张、心肌壁变薄和LV收缩末期壁应力（ESWS）增加，ESWS是一种先于其他收缩功能指标（LV射血分数[EF]和缩短分数[SF]）的公认前兆。传统上，检测蒽环类药物相关的LV功能障碍依赖于使用静息EF和SF的超声心动图筛查。然而，这些参数代表心肌功能的迟发性变化。当检测到EF和SF下降时，功能恶化基本上是不可逆的，强调需要有助于在早期阶段识别心脏损伤的生物标志物，以便有效的干预可以停止或逆转该过程并防止明显的CHF的发展。我们最近完成了一项研究，描述了敏感的超声心动图指标和血液生物标志物的儿童癌症幸存者，现在正在进行药物干预，以扭转心肌重塑的儿童癌症幸存者在高风险的CHF。在拟议的研究中，我们的目标是解决蒽环类药物暴露的淋巴瘤成人的这些差距。采用横断面研究设计，本提案将检查新型超声心动图（组织多普勒成像、心肌变形[斑点追踪超声心动图]、2D-M模式衍生的舒张期和收缩期指数）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）指数在检测接受蒽环类药物治疗的成人淋巴瘤存活者的LV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的淋巴瘤幸存者的异常程度。目前这项研究的创新在于它能够利用儿童癌症幸存者的现有信息， 非肿瘤学人群，以制定一个全面的评估心脏功能的成人淋巴瘤。从本研究中获得的信息可用于在风险人群中制定更全面的筛查策略，并使用这些中间终点进行药物干预，旨在预防早期LV功能障碍幸存者的CHF。

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.