Abstract 13856: Hydrogen Sulfide Donor, SG1002, Preserves Left Ventricular Global Function and Contractile Reserve in a Mouse Model of Doxorubicin Cardiotoxicity

Abstract

Background: Despite being one of the most widely used chemotherapeutic agents, Doxorubicin [DOX] is limited by its dose-dependent side effects, including cardiotoxicity and heart failure (HF). Reactive oxygen species, inflammation, mitochondrial dysfunction, and dysregulated autophagy have been proposed as potential mediators of cardiotoxicity. Hydrogen sulfide (H 2 S) has been shown to promote mitochondrial stability and reduce inflammation in the setting of myocardial infarction. Hypothesis: To determine if the orally active, slow-releasing H 2 S-compound SG1002 attenuates DOX-induced cardiotoxicity. Methods: Following baseline echocardiography, male C57BL mice (12 weeks old) were treated with DOX (5 doses of 5mg/kg, ip; once a week) over 5 weeks. One week before the first DOX treatment, mice were placed onSG1002-enriched chow to achieve a dosage of 40 mg/kg/day for the duration of the study. The control group received normal chow. Mice were followed up to 5 weeks after the last DOX treatment. Left ventricular (LV) function was assessed via echocardiography, including LV global longitudinal strain [GLS]. Contractile reserve was measured as a percent increase in LV ejection fraction (LVEF) following isoproterenol challenge (10ng/mouse). Results: The cumulative dose of 25mg/kg of DOX led to impaired cardiac contractile reserve in control mice, which was preserved in SG1002-fed mice (Fig.A). Despite no changes observed in LVEF throughout the study, LV GLS detected early signs of cardiac dyssynchrony following the DOX regimen (Fig.B). SG1002 treatment prevented the early decline in cardiac function following chemotherapy. Conclusion: Our results indicate that LV GLS and cardiac contractile reserve are able to detect early changes in LV contractility due to cardiotoxicity following DOX treatment, which can be prevented with SG1002. This further highlights the importance of early screening with advanced imaging to identify signs of cardiotoxicity.