Effects of doxorubicin on diastolic function, contractile reserve, and ventricular-vascular coupling in piglets

The use of doxorubicin as an anticancer drug is limited by its cardiac toxicity. To examine the adverse effects of doxorubicin on cardiac function and ventricular-vascular coupling in piglets, eight piglets received five doses of intravenous doxorubicin, 1.5 mg/kg/dose, every 4-7 days starting at 3 weeks of age. A control group consisted of eight normal piglets. Using conductance and manometric catheters, indices of cardiac function, including end systolic elastance (E-es), preload-recruitable stroke work, dP/dt(max), tau, dP/dt(min), dV/dt(max), and end systolic stiffness, were calculated from volume and pressure measurements at rest and during infusion of isoproterenol. Ventricular-vascular coupling was examined by measuring arterial elastance (E-a) and E-a/E-es. Significant differences in relaxation were found between groups. Indices of diastolic stiffness and of contractile function were not different between groups. Baseline contractile efficiency was increased in the doxorubicin group. E-a and E-a/E-es were lower in the doxorubicin group. E-a/E-es was near 1 at baseline in the doxorubicin group, indicating that conditions were optimized for performance of external stroke work. Therefore, the reserve to increase external cardiac work was diminished. The finding of altered diastolic function suggests the importance of screening of diastolic indices to detect the earliest disturbances in cardiac function caused by doxorubicin.