Progressive cardiac dysfunction in adriamycin‐induced cardiomyopathy rats

Abstract

Cardiotoxicity is a limiting factor in the treatment of cancer with adriamycin. We administered adriamycin by a method which minimizes the risk of peritonitis in an adriamycin-induced cardiomyopathy rat model. Sixty male Wistar rats were given Ž . 1 mgrkg of adriamycin intraperitoneally 15 times over a 3-week period total dose, 15 mgrkg to induce the cardiomyopathy model. Fifteen control rats received 10 mlrkg body wt. saline 15 times over 3 weeks. The animals were observed for 12 weeks and assessed for mortality, and cardiac volume and function was analyzed by echocardiography at 4, 8, and 12 weeks. In rats treated with adriamycin, the cumulative mortality was 35.8% while in the controls, none of the rats died. Left ventricular Ž . Ž . diameter of the systole LVDs was significantly increased at 4 weeks 4.5 vs. 3.3 mm; P-0.001 . Left ventricular diameter of Ž . Ž . Ž . the diastole LVDd was significantly increased at 12 weeks 7.9 vs. 7.0 mm; P-0.01 and the % fractional shortening FS Ž . was significantly decreased at 8 weeks 33.4% vs. 50.0%; P-0.01 in the adriamycin-treated rats. This administration method appears to be useful for investigating the cardiac effect of adriamycin while avoiding the influence of peritonitis typically caused by an intraperitoneal injection of higher single doses of adriamycin. ᮊ

Fetal Rat Hearts Do Not Display Acute Cardiotoxicity in Response to Maternal Doxorubicin Treatment

“…During the acute phase of treatment, the adult rodent's left ventricular dysfunction is not consistent and in general is moderate (Luo et al, 1997;Teraoka et al, 2000). Our recent study on maternal and fetal cardiac function showed no acute dysfunction after anthracycline administration during pregnancy (Gziri et al, 2012b).…”

Protection from Doxorubicin-Induced Cardiomyopathy Using the Modified Anthracycline N-Benzyladriamycin-14-valerate (AD 198)

“…This is in contrast to data from human patients in which cumulative doses of Dox typically leads to an increase in end diastolic pressure. However, work by others suggests a Dox-induced increase in end diastolic pressure is a function of time such that at 4 weeks after Dox injection there is no change, whereas at 12 weeks after injection there is an increase in left ventricular diastole diameter (Teraoka et al, 2000). Thus, caution should be used comparing our results, using analysis at 3 days after injection from a single dose of Dox in rats, to humans.…”

A short-time model to study relevant indices of cardiotoxicity of doxorubicin in the rat

“…(2) Therefore, measurement of cardiospecific biomarkers can be a valid diagnostic tool for early identification, assessment, and monitoring of cardiotoxicity. Previous cardiotoxicity models include long term exposure to doxorubicin for [5][6][7][8][9][10][11][12] weeks. (5-7) LTMs are time consuming, and represent long-time stress for the animals, and high mortality rates have been reported.…”

“…(5-7) LTMs are time consuming, and represent long-time stress for the animals, and high mortality rates have been reported. (8,9) Therefore, it is of interest to develop and test short-time models (STM) when studying cardiotoxicity of anthracyclines. A combination of in vivo and ex vivo animal models has the advantage that it includes relevant pharmacokinetic phases after administration of drugs in vivo.…”