Reduced in vivo high-energy phosphates precede adriamycin-induced cardiac dysfunction

Abstract

Adriamycin (ADR) is an established, life-saving antineoplastic agent, the use of which is often limited by cardiotoxicity. ADR-induced cardiomyopathy is often accompanied by depressed myocardial high-energy phosphate (HEP) metabolism. Impaired HEP metabolism has been suggested as a potential mechanism of ADR cardiomyopathy, in which case the bioenergetic decline should precede left ventricular (LV) dysfunction. We tested the hypothesis that murine cardiac energetics decrease before LV dysfunction following ADR (5 mg/kg ip, weekly, 5 injections) in the mouse. As a result, the mean myocardial phosphocreatine-to-ATP ratio (PCr/ATP) by spatially localized (31)P magnetic resonance spectroscopy decreased at 6 wk after first ADR injection (1.79 + or - 0.18 vs. 1.39 + or - 0.30, means + or - SD, control vs. ADR, respectively, P < 0.05) when indices of systolic and diastolic function by magnetic resonance imaging were unchanged from control values. At 8 wk, lower PCr/ATP was accompanied by a reduction in ejection fraction (67.3 + or - 3.9 vs. 55.9 + or - 4.2%, control vs. ADR, respectively, P < 0.002) and peak filling rate (0.56 + or - 0.12 vs. 0.30 + or - 0.13 microl/ms, control vs. ADR, respectively, P < 0.01). PCr/ATP correlated with peak filling rate and ejection fraction, suggesting a relationship between cardiac energetics and both LV systolic and diastolic dysfunction. In conclusion, myocardial in vivo HEP metabolism is impaired following ADR administration, occurring before systolic or diastolic abnormalities and in proportion to the extent of eventual contractile abnormalities. These observations are consistent with the hypothesis that impaired HEP metabolism contributes to ADR-induced myocardial dysfunction.

Fig. 1.

Survival curve for Adriamycin (ADR)-treated mice. MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy.

Fig. 2.

Typical transverse short-axis ¹H magnetic resonance images of a mouse thorax through the mid-left ventricle at end systole and end diastole.

Fig. 3.

³¹P spectra (top) from the anterior myocardium, as indicated by the region between the white lines on the images (bottom), are shown with the prominent peaks of phosphocreatine (PCr) and β-phosphate of ATP (β-ATP). ppm, Parts/million. The round object below the animal in each image is a fiducial ³¹P standard contained within the probe. The cardiac PCr-to-ATP ratio (PCr/ATP) declines at 6 wk of ADR administration.

Fig. 4.

Time course of in vivo cardiac energetic decline in ADR-treated mice. *P ≤ 0.05 compared with control.

Fig. 5.

A: relationship between in vivo cardiac PCr/ATP and peak filling rate (PFR) [maximal rate of volume change (−dV/dt_max)]: y = 0.27x + 0.05, R² = 0.35, R = 0.59, P < 0.001. B: relationship between in vivo cardiac PCr/ATP and cardiac output (CO): y = 5.5x + 7.7, R² = 0.38, R = 0.62, P < 0.001. C: relationship between in vivo cardiac PCr/ATP and ejection fraction (EF): y = 15.4x + 39.1, R² = 0.54, R = 0.73, P < 0.0001.