Abstract Body (Do not enter title and authors here): Background: Cancer treatment is increasingly recognized as a contributor to elevated cardiovascular disease risk. Ceramides, small bioactive lipids, play a critical role in various cellular processes, including apoptosis, oxidative stress, and inflammatory signaling pathways. Elevated circulating levels of ceramides have been associated with heart failure, underscoring their potential relevance in cancer therapy-related cardiac complications.
Objective: We sought to assess whether circulating ceramides were associated with the risk of left ventricular dysfunction in women with breast cancer undergoing potentially cardiotoxic chemotherapy.
Methods: This study is a secondary analysis of the UPBEAT trial (WF97415), which enrolled adult women with stage I to III breast cancer undergoing cancer therapy. Plasma ceramide levels were measured at baseline and again three months after the initiation of chemotherapy. Ceramide abundance was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cardiovascular magnetic resonance imaging was used to evaluate left ventricular ejection fraction (LVEF), allowing for the stratification of participants into two groups: those who experienced an LVEF decline of ≥10%, and those who did not.
Results: We studied 170 women, 56±11 years old; patients with ≥10% decline in LVEF showed an increase in C18:1/C16:0 ceramide ratio over 3 months of therapy compared to patients without LVEF decline (OR, 1.736, 95% CI, 1.164 – 2.590). These changes were independently associated with an increased risk of LVEF decline even after adjustment for age, race, cancer stage (OR, 1.689, 95% CI, 1.125 – 2.537), total cholesterol and triglyceride level (OR, 1.799, 95% CI, 1.194 – 2.717, C-Reactive Protein (OR, 1.671, 95% CI, 1.133 – 2.465), underlying comorbidities, such as hypertension, hyperlipidemia, diabetes, stroke, coronary artery disease, and smoking (OR, 1.652, 95% CI, 1.122 – 2.432), or receipt of potentially cardioprotective drugs (OR, 1.664, 95% CI, 1.127 – 2.457).
Conclusions: This finding suggests that disruptions of the relative abundance of the different species of ceramides may play a significant role in the development of chemotherapy-induced cardiotoxicity. Ceramide profiling could offer a promising avenue for early identification of patients at higher risk for cardiac dysfunction, potentially guiding more personalized monitoring and cardioprotective strategies.