Abstract 18574: Functional Impairment of Human Resident Cardiac Stem Cells Contributes to Trastuzumab (Herceptin®) Cardiotoxicity
Background: Trastuzumab (TZM), a monoclonal antibody against the ERBB2 protein, increases survival in ERBB2-positive breast cancer patients. Its clinical use, however, is limited by cardiotoxicity. We sought to evaluate whether TZM cardiotoxicity involves inhibition of human adult cardiac-derived stem cells (hCDCs), in addition to previously-reported direct adverse effects on cardiomyocytes.
Methods and Results: We found that ERBB2 mRNA and protein (measured by real time PCR and flow cytometry, respectively) were expressed in hCDCs (n=8 patients) at levels comparable to human myocardium. While clinically-relevant concentrations of TZM had no effect on proliferation (by colorimetric quantitative assay), apoptosis, or size of the c-kit positive hCDC subpopulation (both by flow cytometry), in vitro assays demonstrated diminished potential for cardiogenic differentiation (p<0.01; assay: cardiogenic sulfonyl hydrazone compounds induced expression of the firefly luciferase reporter driven by a cardiac-specific promoter) and impaired ability to form microvascular networks (angiogenesis assay, p<0.01) in TZM-treated cells. The functional benefit of hCDCs injected into the border zone of acutely infarcted mouse hearts was abrogated by TZM: infarcted animals treated with TZM+hCDCs had a lower ejection fraction (28.4±3.2% vs. 36.7±1.2%, p=0.02); thinner infarct scar (0.11±0.01 vs. 0.21±0.04mm, p=0.01); and reduced capillary density (0.009±0.001 vs. 0.013±0.001; isolectin B4-fluorescein signal divided by the total number of nuclei, p=0.02) in the remote, non-infarcted myocardium compared to animals that received hCDCs alone (n=12 per group).
Conclusion: Collectively, these results indicate that TZM inhibits the cardiomyogenic and angiogenic capacities of hCDCs in vitro, and abrogates the morphological and functional benefits of hCDC transplantation in vivo. Thus, functional impairment of human resident cardiac stem cells may represent a novel mechanism of TZM cardiotoxicity.
- © 2010 by American Heart Association, Inc.