Doxorubicin is 1 of the most broadly active antitumor agents; it is an essential element in modern therapy of breast, soft tissue sarcomas and other solid tumors. It is thought to be an essential element of curative combination chemotherapy for acute leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, and many childhood cancers. Unfortunately, 2% to 20% of patients receiving Doxorubicin develop congestive heart failure (CHF), a life altering condition in which forward cardiac output is compromised leading to breathlessness, collection of fluid in the lungs, and in 20% of cases, death. To date, existing technologies, with the exception of a direct biopsy of the heart during a minor surgical procedure, are unable to identify many individuals at risk for developing CHF. Early results from our center indicate that a newly developed noninvasive cardiovascular magnetic resonance (CMR) test can detect abnormalities in the heart muscle before it sustains a catastrophic injury due to the chemotherapy treatment. If this is found to be true in more subjects, this new advancement in CMR technology could be used to monitor patients receiving Doxorubicin. Potentially, patients without evidence of CMR heart muscle injury could receive the full benefit of their chemotherapeutic regimen without the concern of developing CHF. Patients with early evidence of injury could undergo modification of their chemotherapy so as to avoid permanent cardiac injury. Before further testing in patients proceeds, heightened understanding of our early CMR study results is required. In this proposal, we will utilize an established rat model of Doxorubicin induced cardiotoxicity to gain understanding of the relationship between CMR measures, and assessments of left ventricular (LV) ejection fraction, and of measured cell injury observed pathologically. We hypothesize that heightened signal intensity observed on a contrast enhanced CMR examination of the heart will precede the onset of a decrement in LV ejection fraction, and will be indicative of myocellular injury. The results from this study will be used to provide the understanding necessary to design human studies utilizing cardiovascular magnetic resonance as a protective screening procedure for heart muscle injury in patients receiving chemotherapy. In addition, further animal studies will be designed to identify treatment strategies for Doxorubicin induced cardiotoxicity.

R21CA109224

2006-04-05

2009-01-31