Abstract 15834: Statins Mediate Recovery From Chemotheraphy-Induced Cardiotoxicity

IntroductionDoxorubicin (Dox) is a frequently used chemotherapeutic agent with heart failure as a major adverse event. Despite decades of study, no translatable therapies have emerged to reverse Dox-induced cardiotoxicity (Dox-CM). Statins, a widely-prescribed class of drugs with pleiotropic effects, have a small side-effect profile compared to current Dox-CM standard treatment.HypothesisStatin therapy can reverse Dox-induced cardiotoxicity.Methods/ResultsWild-type C57BL/6 mice administered Dox (10mg/kg bolus, IP) showed wide derangement of the cardiac transcriptome within 7 days and reduced fractional shortening after 14 days (figure, red squares) without evidence of cardiac hypertrophy or fibrosis. Dox induced significant activation of the DNA damage response in cardiomyocytes although apoptosis was limited to non-cardiomyocyte cells. Isolated neonatal rat cardiomyocytes have slower spontaneous contraction rates post-Dox, while electrical pacing thresholds to induce cardiac alternans was lower in whole heart preparations from Dox-CM mice. Accordingly, SERCA-2 protein expression was decreased while phospholamban and HAX-1 are upregulated in Dox-CM hearts vs control. Together, this data suggests that defective calcium handling underlies Dox-CM. Mice that received daily statin treatment post-Dox showed significant improvement in fractional shortening after 2 weeks (figure, green circles). Statin treatment significantly increased spontaneous cardiomyocyte contraction rate and increased pacing thresholds required to induce cardiac alternans. Analysis of whole heart lysates by western blotting revealed activation of HSP27-Akt signaling along with resolution of Dox-induced reduction in SERCA-2 protein expression.ConclusionsOur detailed analysis of Dox-CM suggests that contractile impairment is related to reversible changes in calcium handling, contrary to current theories of cardiomyocyte loss. Accordingly, the recovery of heart function through statin treatment represents a major step forward in the treatment of Dox-CM and is a readily translatable therapy for cancer survivors suffering from heart failure.