Cardiac toxicity of echinocandines

Objective: Unexplained circulatory decompensation and modulations of contractility have been observed during central venous administration of some echinocandins. While Amphotericin B, Anidulafungin and Caspofungin have been associated with reduced myocardial contractility in Langendorff experiments, the application of Micafungin led to an increased contractility. The aim of this study was to evaluate cardiotoxic effects in an in vitro model of cardiomyocyte apoptosis and necrosis to optimize treatment of patients with severe cardiac morbidities and after heart transplantation.

Methods: Primary cell cultures of cardiomyocytes were prepared from ventricles of neonatal Fischer 344 rats using a combined mechanical and enzymatic dissociation protocol. The purity of cardiomyocytes was increased through preplating. After cell culture in cardiomyocyte medium for 3 days, antifungal agents (Amphotericin B, Anidulafungin, Caspofungin, Micafungin) were added to the medium in physiologically relevant concentrations. After 3 days of incubation with antifungal agents, cells were detached by trypsinization and analyzed flow cytometrically for apoptotis (annexin V binding cells) and necrosis (propidium iodide positive cells).

Results: Primary cell cultures contained 42.5 ± 7.6% alpha-actinin positive cardiomyocytes 3 days after isolation. After 3 days of incubation with 8.6 µg/ml Anidulafungin cell cultures contained 21.90 ± 5.82% apoptotic cells, which was significantly higher than for untreated cells (16.68 ± 4.26%; p = 0.020). Cells treated with 2.0 µg/ml Amphotericin B also showed significantly increased apoptotis (21.95 ± 3.14%; p = 0.013). No significant difference in apoptosis rate was detected in cell cultures treated with 13.3 µg/ml Caspofungin (17.84 ± 5.37%; p = 0.452) and 10.1 µg/ml Micafungin (18.07 ± 6.85%; p = 0.261). The rate of necrotic cells was similar in all cell cultures (Anidulafungin: 15.39 ± 4.58%; p = 0.198; Amphotericin B: 17.35 ± 4.21%; p = 0.085; Caspofungin: 14.09 ± 3.86%; p = 0.361; Micafungin: 13.91 ± 4.03%; p = 0.411). No significant changes were observed in the rate of proliferation for all antifungal agents.

Conclusion: This study revealed no relevant cardiac toxicity of Caspofungin and Mycafungin unlike Anidulafungin and Amphotericin B and therefore suggests the use of these agents in patients with cardiac morbidities.