title: Quantification of cardiomyocyte hypertrophy by cardiac magnetic resonance: implications for early cardiac remodeling.
abstract: BACKGROUND
  Cardiomyocyte hypertrophy is a critical precursor to the development of heart failure. Methods to phenotype cellular hypertrophy noninvasively are limited. The goal was to validate a cardiac magnetic resonance-based approach for the combined assessment of extracellular matrix expansion and cardiomyocyte hypertrophy.
  
  
  RESULTS
  Two murine models of hypertension (n=18, with n=15 controls) induced by l-N(G)-nitroarginine methyl ester (L-NAME) and pressure overload (n=11) from transaortic constriction (TAC) were imaged by cardiac magnetic resonance at baseline and 7 weeks after L-NAME treatment or up to 7 weeks after TAC. T1 relaxation times were measured before and after gadolinium contrast. The intracellular lifetime of water (τic), a cell size-dependent parameter, and extracellular volume fraction, a marker of interstitial fibrosis, were determined with a model for transcytolemmal water exchange. Cardiomyocyte diameter and length were measured on FITC-wheat germ agglutinin-stained sections. The τic correlated strongly with histological cardiomyocyte volume-to-surface ratio (r=0.78, P<0.001) and cell volume (r=0.75, P<0.001). Histological cardiomyocyte diameters and cell volumes were higher in mice treated with L-NAME compared with controls (P<0.001). In the TAC model, cardiac magnetic resonance and histology showed cell hypertrophy at 2 weeks after TAC without significant fibrosis at this early time point. Mice exposed to TAC demonstrated a significant, longitudinal, and parallel increase in histological cell volume, volume-to-surface ratio, and τic between 2 and 7 weeks after TAC.
  
  
  CONCLUSIONS
  The τic measured by contrast-enhanced cardiac magnetic resonance provides a noninvasive measure of cardiomyocyte hypertrophy. Extracellular volume fraction and τic can track myocardial tissue remodeling from pressure overload.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (O.R.C.-F., R.V., T.G.N., R.K.); Department of Internal Medicine, State University of Campinas (UNICAMP), São Paulo, Brazil (O.R.C.-F., H.M.); Departments of Pathology (R.M.) and Radiology (M.J.-H.), Brigham and Women's Hospital, Boston, MA; and Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (B.S., A.R., S.D.).
authors.forename: Otavio R
authors.initials: OR
authors.lastname: Coelho-Filho
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Shah
authors.forename: Richard
authors.initials: R
authors.lastname: Mitchell
authors.forename: Tomas G
authors.initials: TG
authors.lastname: Neilan
authors.forename: Heitor
authors.initials: H
authors.lastname: Moreno
authors.forename: Bridget
authors.initials: B
authors.lastname: Simonson
authors.forename: Raymond
authors.initials: R
authors.lastname: Kwong
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: Saumya
authors.initials: S
authors.lastname: Das
authors.forename: Michael
authors.initials: M
authors.lastname: Jerosch-Herold
mesh_terms: D000465:Algorithms; D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications; D015415:Biomarkers; D001834:Body Water / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D048429:Cell Size; D003287:Contrast Media; D019786:Gadolinium DTPA; D006973:Hypertension / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D010641:Phenotype; D011897:Random Allocation; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D015415:Biomarkers; D003287:Contrast Media; D019786:Gadolinium DTPA; D019331:NG-Nitroarginine Methyl Ester
keywords: hypertrophy; magnetic resonance imaging
references.citation: Eur Heart J Cardiovasc Imaging. 2012 Oct;13(10):819-26
references.pmid: 22634740
references.citation: J Cardiovasc Magn Reson. 2011 Mar 04;13:16
references.pmid: 21375743
references.citation: Radiology. 2011 Oct;261(1):258-65
references.pmid: 21788528
references.citation: Circ Res. 2003 Jun 13;92(11):1171-5
references.pmid: 12805233
references.citation: Adv Clin Path. 2002 Jan;6(1):3-10
references.pmid: 17582942
references.citation: Ann Intern Med. 1969 Jul;71(1):89-105
references.pmid: 4239887
references.citation: Hypertension. 1993 Sep;22(3):380-7
references.pmid: 8349331
references.citation: J Clin Invest. 2007 Mar;117(3):568-75
references.pmid: 17332884
references.citation: Circulation. 2010 Jul 27;122(4):370-8
references.pmid: 20625113
references.citation: Am J Cardiol. 1996 Jul 1;78(1):61-5
references.pmid: 8712120
references.citation: Circulation. 2003 Feb 25;107(7):984-91
references.pmid: 12600911
references.citation: Exp Physiol. 1991 Mar;76(2):259-70
references.pmid: 2059429
references.citation: Circ Cardiovasc Imaging. 2013 Jan 1;6(1):134-41
references.pmid: 23159497
references.citation: Eur J Heart Fail. 2009 Feb;11(2):191-7
references.pmid: 19168518
references.citation: J Cardiovasc Magn Reson. 2012 Jul 28;14:50
references.pmid: 22839417
references.citation: Circ Cardiovasc Imaging. 2011 Nov;4(6):636-40
references.pmid: 21917782
references.citation: Circ Res. 2006 Feb 17;98(3):342-50
references.pmid: 16397142
references.citation: Cardiovasc Res. 1994 Aug;28(8):1199-208
references.pmid: 7954623
references.citation: J Clin Invest. 2007 Jun;117(6):1538-49
references.pmid: 17492053
references.citation: Circulation. 1989 Apr;79(4):744-55
references.pmid: 2522356
references.citation: Circulation. 2006 May 2;113(17):2089-96
references.pmid: 16636176
references.citation: Heart Vessels. 1991;6(3):129-42
references.pmid: 1833369
references.citation: Basic Res Cardiol. 1996 May-Jun;91(3):248-55
references.pmid: 8831944
references.citation: Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2118-22
references.pmid: 15604125
references.citation: Hypertension. 2008 Feb;51(2):289-95
references.pmid: 18086943
references.citation: Magn Reson Med. 1999 Sep;42(3):467-78
references.pmid: 10467291
references.citation: Circ Res. 1994 Jul;75(1):23-32
references.pmid: 8013079
references.citation: Lancet. 2002 Mar 23;359(9311):1004-10
references.pmid: 11937179
references.citation: Hypertension. 1997 Nov;30(5):1025-8
references.pmid: 9369250
references.citation: J Pharmacol Exp Ther. 2005 Mar;312(3):891-8
references.pmid: 15523000
references.citation: J Am Coll Cardiol. 2002 Oct 16;40(8):1431-6
references.pmid: 12392833
references.citation: J Am Coll Cardiol. 2002 Apr 17;39(8):1384-91
references.pmid: 11955860
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10140-5
references.pmid: 9707614
references.citation: Am J Hypertens. 2012 Oct;25(10):1101-9
references.pmid: 22717544
references.citation: Circulation. 2000 Jul 25;102(4):470-9
references.pmid: 10908222
references.citation: Circulation. 2010 Jul 13;122(2):138-44
references.pmid: 20585010
references.citation: Circulation. 2011 Jan 25;123(3):327-34
references.pmid: 21263005
references.citation: Biophys J. 2011 Dec 7;101(11):2833-42
references.pmid: 22261073
references.citation: Eur Heart J. 2012 May;33(10):1268-78
references.pmid: 22279111
references.citation: Circulation. 2004 Sep 14;110(11):1456-62
references.pmid: 15326072
references.citation: Nature. 2012 Aug 16;488(7411):394-8
references.pmid: 22810587
references.citation: Magn Reson Med. 2000 Oct;44(4):563-74
references.pmid: 11025512
references.citation: Cardiovasc Res. 1985 Dec;19(12):793-9
references.pmid: 4084937
references.citation: Physiol Res. 1999;48(5):353-62
references.pmid: 10625224
references.citation: PLoS One. 2011;6(7):e21985
references.pmid: 21779362
references.citation: NMR Biomed. 2005 May;18(3):173-85
references.pmid: 15578708
references.citation: Circulation. 2010 Sep 7;122(10):993-1003
references.pmid: 20733099