Oxysterols: a new tool to stratify toxicity in cardio-oncology

Abstract

A primary challenge in cardio-oncology is understanding the mechanisms underlying cardiotoxicities and developing better methods for their characterization, identification, and diagnosis. Current diagnostic tools include plasma biomarkers (troponin, NT-proBNP), cardiac imaging (TTE, CMR), and coronary angiography. However, these biomarkers are often non-specific and reflect cardiac damage that has already occurred, potentially arriving too late for optimal intervention. The main challenge is therefore to detect cardiotoxicity before clinical manifestation and assess individual patient vulnerability. By developing biomarkers for early diagnosis and treatment outcome prognosis, we aim to stratify individual risk and propose personalized monitoring protocols. Our project focuses on oxysterols as mechanistic biomarkers of chemotherapy-induced oxidative stress. Oxysterols are hydroxylated cholesterol derivatives produced endogenously through enzymatic pathways, with their formation also facilitated by reactive oxygen species. These molecules are known to be involved in inflammation, immunomodulation, cell death, and cholesterol metabolism. Moreover, several studies have demonstrated associations between oxysterol profiles and cardiovascular disease: doxorubicin-treated cardiomyocytes show modified oxysterol profiles with increased 7-ketocholesterol concentrations (1); pulmonary arterial hypertension patients exhibit plasmatic and lung tissue oxysterol accumulation (2); and heart failure patients display altered erythrocyte membrane oxysterol profiles (3). By reflecting early cardiac and systemic oxidative stress, mitochondrial metabolism, and cardiomyocyte responses to chemotherapy, these endogenous species could serve as valuable biomarkers for chemotherapy-induced cardiotoxicities. Our project establishes liquid chromatography-tandem mass spectrometry method to profile oxysterols in patients' plasma samples, as well as in cell culture supernatants. We focused on establishing oxysterol profiles in healthy patients with well-characterized cardiovascular and metabolic health before performing plasma oxysterol profiling in cardio-oncology patients. We successfully developed an analytical method enabling the precise quantification of 11 compounds in less than 10 minutes (figure 1). Once normal oxysterol profiles were computed, we compared them to those obtained in cardio-oncology patients in order to characterize cardiotoxicity-linked profil modification. In the near future, our method will allow us to explore chemotherapy-induced cardiotoxicity through patient-derived iPSC cardiomyocytes (with and w/o chemotherapy-induced cardiotoxicities). This integrative approach will support both mechanistic insights into cardiotoxicity pathways and clinical translation through personalized risk assessment, for a bench-to bedside cardio-oncology project.Chromatogram of 11 targeted oxysterols