TY - JOUR
T1 - Reduced in vivo high-energy phosphates precede adriamycin-induced cardiac dysfunction
AU - Maslov, M. Y.
AU - Chacko, Vadappuram P
AU - Hirsch, G. A.
AU - Akki, A.
AU - Leppo, M. K.
AU - Steenbergen, C.
AU - Weiss, R. G.
PY - 2010/8
Y1 - 2010/8
N2 - 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 31P magnetic resonance spectroscopy decreased at 6 wk after first ADR injection (1.79 ± 0.18 vs. 1.39 ± 0.30, means ± 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 ± 3.9 vs. 55.9 ± 4.2%, control vs. ADR, respectively, P < 0.002) and peak filling rate (0.56 ± 0.12 vs. 0.30 ± 0.13 μl/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.
AB - 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 31P magnetic resonance spectroscopy decreased at 6 wk after first ADR injection (1.79 ± 0.18 vs. 1.39 ± 0.30, means ± 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 ± 3.9 vs. 55.9 ± 4.2%, control vs. ADR, respectively, P < 0.002) and peak filling rate (0.56 ± 0.12 vs. 0.30 ± 0.13 μl/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.
KW - Magnetic resonance imaging
KW - P spectroscopy
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U2 - 10.1152/ajpheart.00727.2009
DO - 10.1152/ajpheart.00727.2009
M3 - Article
C2 - 20495142
AN - SCOPUS:77955442081
SN - 0363-6135
VL - 299
SP - H332-H337
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 2
ER -