Cardiac effects of echinocandins after central venous administration in adult rats

Abstract

Echinocandins have become the agents of choice for early and specific antifungal treatment in critically ill patients. In vitro studies and clinical case reports revealed a possible impact of echinocandin treatment on cardiac function. The aim of our study was to evaluate echinocandin-induced cardiac failure. Using an in vivo rat model, we assessed hemodynamic parameters and time to hemodynamic failure after central venous application (vena jugularis interna) of anidulafungin (low-dose group, 2.5 mg/kg body weight [BW]; high-dose group, 25 mg/kg BW), caspofungin (low-dose group, 0.875 mg/kg BW; high-dose group, 8.75 mg/kg BW), micafungin (low-dose group, 3 mg/kg BW; high-dose group, 30 mg/kg BW), and placebo (0.9% sodium chloride). Left ventricular heart tissue was collected to determine mitochondrial enzyme activity via spectrophotometric measurements. mRNA expression of transcriptional regulators and primary mitochondrial transcripts, mitochondrial DNA (mtDNA) content, and citrate synthase activity were also explored. Animals receiving high-dose anidulafungin or caspofungin showed an immediate decrease in hemodynamic function. All of the subjects in these groups died during the observation period. Every animal in the untreated control group survived (P < 0.001). Hemodynamic failure was not noticed in the anidulafungin and caspofungin low-dose groups. Micafungin had no impact on cardiac function. In analyzing mitochondrial enzyme activity and mitochondrial transcripts, we found no association between echinocandin administration and the risk for hemodynamic failure. Further experimental studies are needed to elucidate the underlying mechanisms involved in cardiotoxic echinocandin effects. In addition, randomized controlled clinical trials are needed to explore the clinical impact of echinocandin treatment in critically ill patients.

FIG 1

Hemodynamic measurements in control and anidulafungin (ANID) high- and low-dose-treated rats. Animals treated with high-dose anidulafungin showed a large decrease in arterial blood pressure (A), cardiac output (B), and left ventricular ejection fraction (C). (D) Left ventricular end-diastolic volume decreased during the observation. Open squares, sham group; filled circles, low-dose (2.5 mg/kg BW) anidulafungin group; filled squares, high-dose (25 mg/kg BW) anidulafungin group. Data are mean percentages of baseline levels ± SEM; n = 6/group.

FIG 2

Survival analysis (Kaplan-Meier curves) of controls and rats treated with micafungin, caspofungin, and anidulafungin. (Top) Control and micafungin-treated animals. No animal died in the control group or the group treated with low-dose micafungin. In the high-dose micafungin group, 5 out of 6 animals survived. (Middle) Control and caspofungin-treated animals. Rats treated with high-dose caspofungin died within 150 min after drug administration. Five out of 6 rats in the low-dose group survived during the observation period. (Bottom) Control and anidulafungin-treated animals. Animals treated with low-dose anidulafungin survived during the observation period. Those treated with high-dose anidulafungin showed significantly increased mortality. Data are mean percentages of baseline levels ± SEM. ***, P < 0.001.

FIG 3

Hemodynamic measurements in controls and rats treated with high- and low-dose micafungin. Low-dose and high-dose groups did not show significant changes compared to controls in arterial blood pressure (A), cardiac output (B), left ventricular ejection fraction (C), or left ventricular end-diastolic volume (D). Open squares, sham group; filled circles, low-dose (3 mg/kg BW) micafungin group; filled squares, high-dose (30 mg/kg BW) micafungin group. Data are mean percentages of baseline levels ± SEM; n = 6/group.

FIG 4

Hemodynamic measurements in controls and rats treated with high- and low-dose caspofungin. Animals treated with high-dose caspofungin showed a strong decrease in arterial blood pressure (A) and cardiac output (B). Left ventricular end-diastolic volume decreased during the observation (D). Rats treated with low-dose caspofungin showed no difference in left ventricular ejection fraction (C) or EDV. Open squares, sham group; filled circles, low-dose (0.875 mg/kg BW) caspofungin group; filled squares, high-dose (8.75 mg/kg BW) caspofungin group. Data are mean percentages of baseline levels ± SEM; n = 6/group.

FIG 5

Spectrophotometric measurement of LV mitochondrial enzyme activity (complexes I to III, cytochrome c oxidase, succinate dehydrogenase) in left ventricular tissue samples of echinocandin-treated rats. Ctrl, sham animals; L, low dose; H, high dose. Data are means ± SEM; n = 6/group. *, P < 0.05 compared to control.