Metabolomic analysis of pressure-overloaded and infarcted mouse hearts.
BACKGROUND
Cardiac hypertrophy and heart failure are associated with metabolic dysregulation and a state of chronic energy deficiency. Although several disparate changes in individual metabolic pathways have been described, there has been no global assessment of metabolomic changes in hypertrophic and failing hearts in vivo. Hence, we investigated the impact of pressure overload and infarction on myocardial metabolism.


RESULTS
Male C57BL/6J mice were subjected to transverse aortic constriction or permanent coronary occlusion (myocardial infarction [MI]). A combination of LC/MS/MS and GC/MS techniques was used to measure 288 metabolites in these hearts. Both transverse aortic constriction and MI were associated with profound changes in myocardial metabolism affecting up to 40% of all metabolites measured. Prominent changes in branched-chain amino acids were observed after 1 week of transverse aortic constriction and 5 days after MI. Changes in branched-chain amino acids after MI were associated with myocardial insulin resistance. Longer duration of transverse aortic constriction and MI led to a decrease in purines, acylcarnitines, fatty acids, and several lysolipid and sphingolipid species but a marked increase in pyrimidines as well as ascorbate, heme, and other indices of oxidative stress. Cardiac remodeling and contractile dysfunction in hypertrophied hearts were associated with large increases in myocardial, but not plasma, levels of the polyamines putrescine and spermidine as well as the collagen breakdown product prolylhydroxyproline.


CONCLUSIONS
These findings reveal extensive metabolic remodeling common to both hypertrophic and failing hearts that are indicative of extracellular matrix remodeling, insulin resistance and perturbations in amino acid, and lipid and nucleotide metabolism.
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Brian E
BE
Sansbury
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Angelica M
AM
DeMartino
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Zhengzhi
Z
Xie
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Alan C
AC
Brooks
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Robert E
RE
Brainard
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Lewis J
LJ
Watson
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Andrew P
AP
DeFilippis
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Timothy D
TD
Cummins
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Matthew A
MA
Harbeson
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Kenneth R
KR
Brittian
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Sumanth D
SD
Prabhu
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Aruni
A
Bhatnagar
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
Steven P
SP
Jones
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.). bradford.hill@louisville.edu.
Bradford G
BG
Hill
D000818:Animals; D006332:Cardiomegaly / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004452:Echocardiography; D004734:Energy Metabolism / Q000502:physiology*; D006333:Heart Failure / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D013318:Stroke Volume; D053719:Tandem Mass Spectrometry
amino acids; glycolysis; heart failure; hypertrophy; metabolomics; mitochondria; oxidative stress