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.

Public Health Relevance

Cardiovascular complications are a leading cause of morbidity and mortality in long-term survivors of lymphoma due, in large part, to cardiotoxic therapeutic exposures such as anthracyclines. This proposal aims to understand the role of novel imaging studies and blood biomarkers in early detection of cardiac dysfunction in cancer survivors at risk for congestive heart failure (CHF). At its completion, information obtained from this proposal may then be used to develop more comprehensive screening strategies in at risk cancer survivor populations, or for the development of intermediate endpoints for pharmacologic interventions aimed at preventing CHF.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA178344-01
Application #
8569676
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Program Officer
Shelburne, Nonniekaye F
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$189,963
Indirect Cost
$58,092
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Armenian, Saro H; Gelehrter, Sarah K; Vase, Tabitha et al. (2014) Carnitine and cardiac dysfunction in childhood cancer survivors treated with anthracyclines. Cancer Epidemiol Biomarkers Prev 23:1109-14