Abstract 10301: Disruption of Nitric Oxide Synthase 3 Potentiates Cardiac Dysfunction and Reduces Survival in Doxorubucin and Trastuzumab Mediated Cardiomyopathy
Background: Anthracyclines, in particular Doxorubicin (Dox), are effective chemotherapeutic agents in the breast cancer setting, limited by its cardiotoxic side effects. The introduction of Trastuzumab (Trz) in the breast cancer setting compounds the issue of Dox mediated cardiac dysfunction. Amongst the potential mechanisms for the deleterious effects of this drug induced cardiomyopathy, the interaction of nitric oxide synthase 3 (NOS3) and oxidative stress has gained recent attention.
Objective: To determine whether disruption of NOS3 potentiates cardiac dysfunction in an acute murine model of Dox+Trz induced cardiotoxicity.
Methods: A total of 90 C57Bl/6 female mice (45 wild type (WT) and 45 NOS3-/-) were treated with either Dox (20mg/kg), Trz (10mg/kg) or Dox+Trz. Serial echocardiography was performed for a total of 10 days, after which the mice were euthanized for histological analysis.
Results: As compared to WT, NOS3-/- mice demonstrated increased cardiotoxicity following treatment with Dox+Trz. In WT female mice receiving Dox+Trz, left ventricular ejection fraction (LVEF) decreased from 75±3% at baseline to 56±2% at day 10 (p<0.05) (Figure 1). In NOS3-/- mice receiving Dox+Trz, LVEF decreased from 74±2% at baseline to 45±3% at day 10 (p<0.05) (Figure 1). As compared to WT, NOS3-/- mice also demonstrated increased mortality after treatment with Dox+Trz, corroborating the echocardiographic findings. Histological analysis using electron microscopy demonstrated an increased loss of cell integrity and enlargement of the smooth endoplasmic reticulum in the NOS3-/- mice.
Conclusion: Congenital absence of NOS3 potentiates the cardiotoxic effects of Dox+Trz in an acute female murine model of chemotherapy-induced cardiomyopathy. Figure 1:
- © 2011 by American Heart Association, Inc.