Characterization of TRPC6 to Predict and Prevent Chemotherapy-Related Cardiomyopathy and Heart Failure in Women

Heart failure and other cardiovascular disorders such as reduced pumping ability of the heart (cardiomyopathy) and irregular or abnormal heart rhythm (arrhythmia) are major side effects of some types of chemotherapy, such that patients with breast cancer and lymphoma are three times more at risk of developing heart failure compared with patients who did not have cancer. Not all patients treated with chemotherapy will experience these side effects, but methods to predict which patients are most at risk are lacking. Even if we were able to predict which patients will develop chemotherapy-induced heart failure, the patient would still require chemotherapy for treatment of their cancer and cardioprotective treatments are limited. There are some clinical factors that influence a patients risk of chemotherapy-related heart failure. For example, in pediatric lymphoma patients treated with a type of chemotherapy known as doxorubicin, young girls are at higher risk of heart failure compared to young boys. For breast cancer patients treated with doxorubicin, women >55 years old are more susceptible to heart failure than younger women. For both men and women treated with doxorubicin, it has been known since the 1970s that the probability of developing heart failure is dependent on the cumulative lifetime dose of the treatment, and once a patient reaches a set cumulative dose, the chemotherapy treatment is stopped, even if it is holding the cancer at bay. Overall, ~5% of patients experience heart failure at the safe cumulative dose, but there are some patients who tolerate much larger doses without adverse cardiac symptoms, and this is observed within studies of breast cancer patients, even after accounting for patient age and within pediatric studies when accounting for gender. Evidence from our group and others suggest that genetic differences between patients can account for some of the differences in adverse cardiac events. Identifying the genes and variations that cause chemotherapy-related heart failure, cardiomyopathy, and arrhythmia will be useful to: (1) better predict which cancer patients are at risk of adverse cardiac events, and (2) develop novel cardioprotective therapies that will enable patients to complete chemotherapy without later developing heart failure. Our study will use three approaches. First, we will use DNA samples from patients with lymphoma and breast cancer to identify genetic variants that are significantly more frequent in the patients with heart failure compared to those without. Second, we will characterize how each genetic variant causes changes within heart cells. Third, we will use a mouse model of chemotherapy-induced heart failure to test new cardioprotective therapies. Because models of heart failure in women and female mice are under-represented and because women with breast cancer, particularly older women are at increased risk of therapy-related heart failure, we will focus on the development of cardioprotective therapies for women's heart failure and examine the relationship between estrogen, chemotherapy-induced cardiotoxicity and the prevention of chemotherapy-related heart failure. These experiments will impact care plans and treatment strategies for prevention of chemotherapy-related cardiomyopathy, arrhythmia and heart failure, particularly for women. Our proposed genetic studies will be centered on the gene, TRPC6. TRPC6 forms a channel on the surface of heart cells and the cells that form the lining of blood vessels, and acts as a channel for calcium to enter into the cell. Calcium is required for heart cells to contract. Maintaining the correct amount of calcium inside each cell is crucial. Too little calcium will affect contractility, but too much calcium may cause heart cells to die. Our early work has shown that genetic variants in the TRPC6 gene are more frequent in breast cancer patients with chemotherapy-induced heart failure, and our cell-based models suggest that ce