Circulating microRNA as biomarkers of clozapine-induced cardiotoxicity.

Purpose: This work investigated the utility of circulating microRNA (miRNA) as biomarkers of clozapine (CLZ)-induced cardiotoxicities: serious adverse events with an unusually high incidence in Australia and New Zealand.

Methods

Global plasma miRNA expression was analysed by microarray in patients taking CLZ, to investigate differential expression between CLZ-induced cardiotoxicity cases (n = 6) and matched control patients (n = 12). The results were validated by RT-qPCR using a panel of 17 miRNA, and their expression was examined in both CLZ-naïve healthy volunteers (n = 12) and an expanded cohort of CLZ-taking patients (n = 21). Temporal changes were also examined in two healthy volunteers and two CLZ-induced cardiotoxicity patients.

Results

No miRNA were differentially expressed between cases of CLZ-induced cardiotoxicity and control patients. Circulating levels of several miRNA were significantly altered in CLZ-taking patients compared to healthy volunteers, with miR-16-5p, miR-25-3p, miR-92a-3p, miR-320a-3p, and miR-486-3p upregulated and miR-22-3p, miR-126-3p, and miR-142-3p downregulated in the patients. Five of these (miR-16-5p, miR-22-3p, miR-92a-3p, miR-126-3p, miR-142-3p) were stably expressed over time in both CLZ-induced cardiotoxicity patients and CLZ-naïve healthy volunteers.

Conclusions

Plasma miRNA are not useful biomarkers of CLZ-induced cardiotoxicity, however patients taking CLZ have significantly altered circulating miRNA compared to healthy volunteers.