The Clinical Relevance of Anthracycline-Related Cardiac Remodeling in Childhood Cancer Survivors

PROJECT SUMMARY/ABSTRACT Anthracycline antibiotics are essential, lifesaving chemotherapies used in ~60% of pediatric cancer patients, but they confer a substantial dose-dependent risk of cardiac dysfunction and heart failure in long-term survivors. The standard heart failure management approach -- waiting for left ventricular ejection fraction decline and then starting afterload reduction therapy -- has been used for decades despite its limited success. Alternatively, an early, targeted treatment strategy guided by specific disease manifestations could improve outcomes. Adverse left ventricular remodeling (i.e., change in size and shape) precedes and may precipitate heart failure and could be used to guide such a strategy. However, there is a critical need to define the specific adverse features of left ventricular shape and to determine the relationship between remodeling and both modifiable risk factors and long-term dysfunction in childhood cancer survivors treated with anthracyclines. The overall objectives of this proposal are to define the anthracycline-related adverse features of left ventricular shape in childhood cancer survivors and to determine the associations between remodeling and both modifiable risk factors, including reduced physical activity, and dysfunction over time. The central hypothesis of this project is that anthracyclines cause specific adverse changes in 3D left ventricular shape; moderate to vigorous physical activity mitigates this remodeling process; and adverse remodeling is prognostic of subsequent dysfunction. To achieve these objectives, we will comprehensively analyze cardiac magnetic resonance imaging in cross-sectional and longitudinal cohorts of adolescent and young adult childhood cancer survivors. The Specific Aims are to 1) define the adverse features of left ventricular shape associated with anthracycline dose exposure; 2) determine the associations between left ventricular remodeling and modifiable risk factors, and 3) determine the relationship between left ventricular remodeling and subsequent dysfunction. The expected contributions of this research will yield new imaging-based disease markers; improve early detection, risk assessment, and clinical prognostication; and inform a future targeted intervention. Dr. Hari K. Narayan seeks this career development award to achieve his long-term goal of becoming an independent physician scientist focused on preventing anthracycline-related heart failure in childhood cancer survivors. Through the proposed training, he seeks to expand beyond his cardiovascular imaging and epidemiology background by developing skills in computational modeling and machine learning analysis, patient- oriented and physical activity research, and academic leadership. The mentorship team, which includes expertise in pediatric clinical trials, computational cardiac image analysis, physical activity in survivorship, and pediatric survivorship oncology, is optimally suited to guide him through training completion and his transition to independence. Dr. Narayan’s goal is to build upon the proposed training and research through the development of an early, targeted intervention to prevent anthracycline-related heart failure in childhood cancer survivors.