Document Detail


Reduced in vivo high-energy phosphates precede adriamycin-induced cardiac dysfunction.
MedLine Citation:
PMID:  20495142     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
M Y Maslov; V P Chacko; G A Hirsch; A Akki; M K Leppo; C Steenbergen; R G Weiss
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-05-21
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-30     Completed Date:  2010-08-30     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H332-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism*
Animals
Antibiotics, Antineoplastic*
Disease Models, Animal
Down-Regulation
Doxorubicin*
Energy Metabolism*
Magnetic Resonance Imaging, Cine
Magnetic Resonance Spectroscopy
Male
Mice
Mice, Inbred C57BL
Myocardial Contraction
Myocardium / metabolism*
Phosphocreatine / metabolism*
Stroke Volume
Time Factors
Ventricular Dysfunction, Left / chemically induced,  metabolism*,  physiopathology
Ventricular Function, Left*
Grant Support
ID/Acronym/Agency:
HL-63030/HL/NHLBI NIH HHS; R01 HL039752/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 020IUV4N33/Phosphocreatine; 80168379AG/Doxorubicin; 8L70Q75FXE/Adenosine Triphosphate
Comments/Corrections

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