Calcium Handling in Experimental Models of Doxorubicin and Radiation-Induced Cardiotoxicity

As a result of more effective therapies, more patients recover from cancer. However, often they develop cardiotoxicity manifested, among others, as heart failure. Doxorubicin (Dox), a widely used and highly effective cancer chemotherapeutic agent, and radiation therapy (RT), when directed to the thorax, can affect cardiac function. Because intracellular Ca2+ fluxes underlie cardiac function, we investigated intracellular Ca2+ handling in mice treated with doxorubicin (Dox) or chest radiotherapy (RT). 12 weeks old, C57BL/6 male mice received 3 i.v. injections of 4 mg/Kg Dox each, reaching a cumulative dose of 12mg/kg of Dox. Data was obtained at 2, 6 and 15 weeks after last injection. RT-treated mice were locally irradiated with 2 and 16Gy localized to the heart, and experiments performed 20 and 50 weeks after irradiation. M-mode Echocardiography showed a significant reduction of the ejection fraction (EF) at 15w after last injection of Dox. Consistently, the amplitude of [Ca2+]i transients was decreased (F/F0: 4.10±0.25, n=11 control cells, vs 3.22±0.14, n=15 Dox, p<0.01) and slowed (Tau in ms: 138.98±6.17, n=11 control vs 169.63±11.91, n=15 Dox, p<0.05) at 15w with a significant increase in the frequency of Ca2+ sparks, but without changes on the SR Ca2+ content. RT induced a LV enlargement associated with a significant reduction of EF in low and high dose irradiated mice group at both time lapses. However, Ca2+ handling was minimally affected by RT. After 50w of 16Gy RT, we observed a faster decay of [Ca2+]i transients with unaltered amplitude and SR Ca2+ content. Our results indicate that the depressed cardiac function after Dox treatment involves [Ca2+]i transient reduction, while in RT-induced cardiotoxicity the Ca2+ alteration may not be involved likewise.