Carnitine and cardiac dysfunction in childhood cancer survivors treated with anthracyclines.
Childhood cancer survivors are at high risk of developing congestive heart failure (CHF) compared with the general population, and there is a dose-dependent increase in CHF risk by anthracycline dose. The mechanism by which this occurs has not been fully elucidated. Metabolomics, the comprehensive profile of small-molecule metabolites, has the potential to provide insight into the pathogenesis of disease states and discover diagnostic markers for therapeutic targets. We performed echocardiographic testing and blood plasma metabolomic analyses (8 pathways; 354 metabolites) in 150 asymptomatic childhood cancer survivors previously treated with anthracyclines. Median time from cancer diagnosis to study participation was 12.4 years (2.6-37.9 years); 64% were treated for a hematologic malignancy; median anthracycline dose was 350 mg/m(2) (25-642 mg/m(2)). Thirty-five (23%) participants had cardiac dysfunction-defined as left ventricular end-systolic wall stress >2SD by echocardiogram. Plasma levels of 15 compounds in three metabolic pathways (carbohydrate, amino acid, and lipid metabolism) were significantly different between individuals with cardiac dysfunction and those with normal systolic function. After adjusting for multiple comparisons, individuals with cardiac dysfunction had significantly lower plasma carnitine levels [relative ratio (RR), 0.89; P < 0.01] in relation to those with normal systolic function. These findings may facilitate the development of primary prevention (treatment of carnitine deficiency before/during anthracycline administration) and secondary prevention strategies (screening and treatment in long-term survivors) in patients at highest risk for CHF. Cancer Epidemiol Biomarkers Prev; 23(6); 1109-14. ©2014 AACR.
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan sarmenian@coh.org.
Saro H
SH
Armenian
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Sarah K
SK
Gelehrter
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Tabitha
T
Vase
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MichiganAuthors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Rajkumar
R
Venkatramani
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Wendy
W
Landier
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Karla D
KD
Wilson
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Claudia
C
Herrera
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Leah
L
Reichman
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MichiganAuthors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
John-David
JD
Menteer
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MichiganAuthors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Leo
L
Mascarenhas
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MichiganAuthors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
David R
DR
Freyer
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Kalyanasundaram
K
Venkataraman
Authors' Affiliations: Division of Outcomes Research, Department of Population Sciences, Department of Cardiology, City of Hope, Duarte; Divisions of Hematology, Oncology, and Blood & Marrow Transplantation and Cardiology, Children's Hospital Los Angeles; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
Smita
S
Bhatia
D000293:Adolescent; D000328:Adult; D018943:Anthracyclines / Q000009:adverse effects*; D009202:Cardiomyopathies; D002318:Cardiovascular Diseases / Q000209:etiology*; D002331:Carnitine / Q000009:adverse effects / Q000172:deficiency*; D002648:Child; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases; D009369:Neoplasms / Q000097:blood; D017741:Survivors; D055815:Young Adult
D018943:Anthracyclines; D002331:Carnitine