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 (lowdose 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.

Cardiac Effects of Echinocandins in Endotoxemic Rats

“…Regarding the LDH serum levels of our in vivo rat studies, we only found a trend toward elevated LDH values in anidulafungin-treated animals compared to that in control group animals. These results are in line with data form previous studies that did not observe micafungin-induced cardiac impairment (10)(11)(12)(13). This fact may be explained by the hypothesis that micafungin, which is water-soluble compared with the other two lipophilic agents, would be unable to penetrate the tissue and cause serious cell damage.…”

“…Hemodynamic measurements after central venous administration of high doses of anidulafungin or caspofungin in adult rats provided evidence of significantly reduced cardiac output, which was associated with a significantly reduced survival rate compared to that in control animals (12). These results, which suggest a dose-depending mechanism of echinocandin-induced cardiac depression, were also confirmed by a study of rats treated with different doses of echinocandins (13).…”

“…Performing spectrophotometric measurements of rat left ventricular cardiac tissue after echinocandin treatment, we were not able to detect any altered mitochondrial enzyme activity (12). Previous studies on septic cardiomyopathy demonstrated the importance of mitochondrial dysfunction and reduced ATP generation (22,23).…”

“…Previous investigations claimed mitochondrial toxicity to represent the underlying mechanism behind echinocandin-induced cardiac failure (10,13,14,28). However, spectrophotometric measurements in echinocandin-treated rats did not reveal any altered mitochondrial enzyme activity (12).…”

“…Animals were handled and hemodynamic data were obtained as described previously (12,27). Briefly, after endotracheal intubation with a 16G catheter, animals were ventilated with a rodent respirator (Inspira; Harvard Apparatus, MA, USA) using volume-controlled ventilation in a weight-adjusted manner.…”