title: T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy.
abstract: BACKGROUND
  Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations seem to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV).
  
  
  RESULTS
  Sarcomere mutation carriers with LVH (G+/LVH+, n=37) and without LVH (G+/LVH-, n=29), patients with HCM without mutations (sarcomere-negative HCM, n=11), and healthy controls (n=11) underwent contrast cardiac magnetic resonance, measuring T1 times pre- and postgadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared with controls, ECV was increased in patients with overt HCM, as well as G+/LVH- mutation carriers (ECV=0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH-, controls, respectively; P≤0.001 for all comparisons). ECV correlated with N-terminal probrain natriuretic peptide levels (r=0.58; P<0.001) and global E' velocity (r=-0.48; P<0.001). Late gadolinium enhancement was present in >60% of overt patients with HCM but absent from G+/LVH- subjects. Both ECV and late gadolinium enhancement were more extensive in sarcomeric HCM than sarcomere-negative HCM.
  
  
  CONCLUSIONS
  Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development of myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. cho@partners.org
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Ho
authors.forename: Siddique A
authors.initials: SA
authors.lastname: Abbasi
authors.forename: Tomas G
authors.initials: TG
authors.lastname: Neilan
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Shah
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Chen
authors.forename: Bobak
authors.initials: B
authors.lastname: Heydari
authors.forename: Allison L
authors.initials: AL
authors.lastname: Cirino
authors.forename: Neal K
authors.initials: NK
authors.lastname: Lakdawala
authors.forename: E John
authors.initials: EJ
authors.lastname: Orav
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.forename: Michael
authors.initials: M
authors.lastname: Jerosch-Herold
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Kwong
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D002312:Cardiomyopathy, Hypertrophic / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D003094:Collagen / Q000097:blood; D003287:Contrast Media; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D019786:Gadolinium DTPA; D020022:Genetic Predisposition to Disease; D006439:Hemodynamics; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016015:Logistic Models; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology*; D020257:Ventricular Remodeling / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003287:Contrast Media; D003094:Collagen; D019786:Gadolinium DTPA
keywords: MRI; fibrosis; gadolinium; genetics; hypertrophic cardiomyopathy
references.citation: Heart. 2000 Nov;84(5):476-82
references.pmid: 11040002
references.citation: Radiology. 2001 Mar;218(3):703-10
references.pmid: 11230643
references.citation: J Am Coll Cardiol. 2008 Nov 4;52(19):1574-80
references.pmid: 19007595
references.citation: Circ Cardiovasc Imaging. 2012 Nov;5(6):726-33
references.pmid: 23071146
references.citation: J Am Coll Cardiol. 2010 Sep 7;56(11):875-87
references.pmid: 20667520
references.citation: Cell. 2001 Feb 23;104(4):557-67
references.pmid: 11239412
references.citation: J Cardiovasc Magn Reson. 2012 Oct 29;14:76
references.pmid: 23107451
references.citation: Circulation. 2010 Jul 13;122(2):138-44
references.pmid: 20585010
references.citation: Circ Heart Fail. 2010 Jan;3(1):51-8
references.pmid: 19850699
references.citation: Circ Heart Fail. 2008 Sep;1(3):184-91
references.pmid: 19808288
references.citation: Circulation. 2002 Jun 25;105(25):2992-7
references.pmid: 12081993
references.citation: J Am Coll Cardiol. 2010 Sep 7;56(11):867-74
references.pmid: 20688032
references.citation: J Am Coll Cardiol. 2009 Jan 20;53(3):284-91
references.pmid: 19147047
references.citation: Heart. 2005 Aug;91(8):1036-40
references.pmid: 16020591
references.citation: BMC Med Imaging. 2010 Jul 30;10:16
references.pmid: 20673350
references.citation: Mayo Clin Proc. 2008 Jun;83(6):630-8
references.pmid: 18533079
references.citation: Circulation. 1999 Nov 9;100(19):1992-2002
references.pmid: 10556226
references.citation: J Am Coll Cardiol. 2000 Jan;35(1):36-44
references.pmid: 10636256
references.citation: JACC Cardiovasc Imaging. 2011 Feb;4(2):150-6
references.pmid: 21329899
references.citation: Circ Cardiovasc Genet. 2009 Aug;2(4):314-21
references.pmid: 20031602
references.citation: Circ Cardiovasc Imaging. 2010 Nov;3(6):727-34
references.pmid: 20855860
references.citation: Circulation. 2009 Oct 6;120(14):1390-400
references.pmid: 19770399
references.citation: J Magn Reson Imaging. 2009 Oct;30(4):778-84
references.pmid: 19787718
references.citation: Circulation. 2002 May 28;105(21):2512-7
references.pmid: 12034658
references.citation: J Am Soc Echocardiogr. 2005 Dec;18(12):1440-63
references.pmid: 16376782
references.citation: Heart. 1997 Feb;77(2):130-2
references.pmid: 9068395
references.citation: J Am Coll Cardiol. 2003 May 7;41(9):1561-7
references.pmid: 12742298
references.citation: J Am Coll Cardiol. 2003 May 21;41(10):1776-82
references.pmid: 12767664
references.citation: J Am Coll Cardiol. 2008 Apr 8;51(14):1369-74
references.pmid: 18387438
references.citation: Magn Reson Med. 1999 Jul;42(1):206-9
references.pmid: 10398969
references.citation: Circulation. 1996 Dec 15;94(12):3318-26
references.pmid: 8989146
references.citation: Circ Cardiovasc Imaging. 2012 Jan;5(1):51-9
references.pmid: 22135399
references.citation: J Am Coll Cardiol. 2002 Dec 18;40(12):2156-64
references.pmid: 12505229
references.citation: Circulation. 2000 Nov 28;102(22):2700-6
references.pmid: 11094035
references.citation: J Am Coll Cardiol. 2004 Jun 2;43(11):2028-35
references.pmid: 15172408
references.citation: J Cardiovasc Magn Reson. 2012 Sep 11;14:64
references.pmid: 22967246
references.citation: Science. 2007 Jun 8;316(5830):1481-4
references.pmid: 17556586
references.citation: Hum Pathol. 2000 Aug;31(8):988-98
references.pmid: 10987261
references.citation: Eur Heart J. 2012 May;33(10):1268-78
references.pmid: 22279111
references.citation: Am J Physiol Heart Circ Physiol. 2008 Sep;295(3):H1234-H1242
references.pmid: 18660445
references.citation: Am J Cardiol. 2001 Aug 1;88(3):275-9
references.pmid: 11472707
references.citation: N Engl J Med. 2010 Aug 5;363(6):552-63
references.pmid: 20818890
references.citation: Am J Cardiol. 2002 Jul 1;90(1):29-34
references.pmid: 12088775