title: Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases in cardiac amyloidosis.
abstract: BACKGROUND
  Cardiac amyloidosis due to amyloid fibril deposition in the heart results in cardiomyopathy (CMP) with heart failure (HF) and/or conduction disturbances. Immunoglobulin light chain-related CMP (AL-CMP) features rapidly progressive HF with an extremely poor prognosis compared with a CMP due to the deposition of mutant (ATTR) amyloidosis or wild-type (senile systemic amyloidosis, SSA) transthyretin (TTR) proteins. Amyloid fibril deposition disrupts the myocardial extracellular matrix (ECM) homeostasis, which is partly regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). We therefore tested the hypothesis that circulating levels of MMPs and TIMPs in patients with AL-CMP and TTR-related CMP (TTR-CMP) are dissimilar and indicative of cardiac amyloid disease type.
  
  
  RESULTS
  Fifty AL-CMP patients were compared with 50 TTR-CMP patients (composed of 38 SSA and 12 ATTR patients). Clinical and laboratory evaluations including echocardiography were performed at the initial visit to our center and analyzed. Serum MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were determined by ELISA. Compared with TTR-CMP patients, AL-CMP patients had higher levels of brain natriuretic peptide (BNP), troponin I (TnI), MMP-2, TIMP-1, and MMP-2/TIMP-2 ratio, despite less left ventricular (LV) hypertrophy and better preserved LV ejection fraction. Mortality was worse in AL-CMP patients than in TTR-CMP patients (log-rank P<0.01). MMP-2/TIMP-2 plus BNP and TnI showed the highest discriminative ability for distinguishing AL-CMP from TTR-CMP. Female sex (HR, 2.343; P=0.049) and BNP (HR, 1.041; P<0.01) were predictors for mortality for all patients with cardiac amyloidoses. Only BNP was a predictor of death in AL-CMP patients (HR, 1.090; P<0.01). There were no prognostic factors for all-cause death in TTR-CMP patients.
  
  
  CONCLUSIONS
  Circulating concentrations of MMPs and TIMPs may be useful in differentiating patients with AL-CMP from those with TTR-CMP, resulting in earlier diagnostic vigilance, and may add prognostic information. In addition to an elevated BNP level, female sex increased the risk of death in patients with cardiac amyloidoses.
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Komei
authors.initials: K
authors.lastname: Tanaka
authors.forename: Eric E
authors.initials: EE
authors.lastname: Essick
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Doros
authors.forename: Kahraman
authors.initials: K
authors.lastname: Tanriverdi
authors.forename: Lawreen H
authors.initials: LH
authors.lastname: Connors
authors.forename: David C
authors.initials: DC
authors.lastname: Seldin
authors.forename: Flora
authors.initials: F
authors.lastname: Sam
mesh_terms: D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000097:blood* / Q000150:complications / Q000000981:diagnostic imaging; D000686:Amyloidosis / Q000097:blood* / Q000150:complications / Q000000981:diagnostic imaging; D009202:Cardiomyopathies / Q000097:blood* / Q000000981:diagnostic imaging / Q000209:etiology; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020782:Matrix Metalloproteinases / Q000097:blood*; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000097:blood; D013318:Stroke Volume; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood*; D019210:Troponin I / Q000097:blood; D014463:Ultrasonography
chemical_list: C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019210:Troponin I; D020097:Natriuretic Peptide, Brain; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
references.citation: J Am Coll Cardiol. 2007 Nov 27;50(22):2101-10
references.pmid: 18036445
references.citation: Circulation. 2005 Sep 27;112(13):2047-60
references.pmid: 16186440
references.citation: Circ Heart Fail. 2011 Mar;4(2):121-8
references.pmid: 21191093
references.citation: Arch Intern Med. 2005 Jun 27;165(12):1425-9
references.pmid: 15983293
references.citation: Prog Cardiovasc Dis. 2011 Sep-Oct;54(2):86-96
references.pmid: 21875508
references.citation: Eur Heart J. 2004 Sep;25(17):1509-16
references.pmid: 15342170
references.citation: Am J Hematol. 2005 Aug;79(4):319-28
references.pmid: 16044444
references.citation: J Clin Oncol. 2011 May 10;29(14):1924-33
references.pmid: 21483018
references.citation: J Am Coll Cardiol. 2002 May 1;39(9):1414-21
references.pmid: 11985901
references.citation: Eur Heart J. 2008 Sep;29(17):2116-24
references.pmid: 18614523
references.citation: Circulation. 2003 May 20;107(19):2440-5
references.pmid: 12719281
references.citation: Blood. 2004 Sep 15;104(6):1881-7
references.pmid: 15044258
references.citation: Amyloid. 1999 Mar;6(1):54-8
references.pmid: 10211412
references.citation: N Engl J Med. 2002 Jun 6;346(23):1786-91
references.pmid: 12050338
references.citation: Blood. 2011 Oct 20;118(16):4346-52
references.pmid: 21828140
references.citation: Biochim Biophys Acta. 1998 Sep 30;1407(3):185-92
references.pmid: 9748569
references.citation: J Am Soc Echocardiogr. 1989 Sep-Oct;2(5):358-67
references.pmid: 2698218
references.citation: Circulation. 1981 Jun;63(6):1285-8
references.pmid: 7014028
references.citation: J Clin Oncol. 2004 Sep 15;22(18):3751-7
references.pmid: 15365071
references.citation: Circ Res. 2004 Apr 30;94(8):1008-10
references.pmid: 15044325
references.citation: N Engl J Med. 1999 Sep 2;341(10):709-17
references.pmid: 10471456
references.citation: JACC Cardiovasc Imaging. 2010 Feb;3(2):155-64
references.pmid: 20159642
references.citation: Blood. 2009 Dec 3;114(24):4957-9
references.pmid: 19797517
references.citation: Circulation. 2001 Oct 2;104(14):1594-7
references.pmid: 11581134
references.citation: Circulation. 2006 May 2;113(17):2089-96
references.pmid: 16636176
references.citation: Hypertension. 2005 Sep;46(3):555-61
references.pmid: 16043662
references.citation: Am J Cardiol. 2011 Aug 1;108(3):440-4
references.pmid: 21600538
references.citation: Front Biosci (Landmark Ed). 2009 Jan 01;14:699-716
references.pmid: 19273096
references.citation: Lancet. 2003 May 24;361(9371):1787-9
references.pmid: 12781539
references.citation: Am J Cardiol. 1985 Jun 1;55(13 Pt 1):1645
references.pmid: 4003314
references.citation: Circulation. 2000 Nov 28;102(22):2700-6
references.pmid: 11094035
references.citation: Circ Heart Fail. 2008 Nov;1(4):249-57
references.pmid: 19808299
references.citation: Physiol Rev. 2007 Oct;87(4):1285-342
references.pmid: 17928585
references.citation: Blood. 2012 Feb 23;119(8):1844-7
references.pmid: 21917755
references.citation: Circulation. 2009 Sep 29;120(13):1203-12
references.pmid: 19752327
references.citation: Kidney Int. 2005 Oct;68(4):1590-603
references.pmid: 16164636
references.citation: Am J Physiol Cell Physiol. 2001 Jan;280(1):C53-60
references.pmid: 11121376
references.citation: Am J Cardiol. 1986 Feb 15;57(6):450-8
references.pmid: 2936235
references.citation: Biometrics. 1988 Sep;44(3):837-45
references.pmid: 3203132
references.citation: Circulation. 1998 May 5;97(17):1708-15
references.pmid: 9591765
references.citation: J Am Coll Cardiol. 2005 Sep 20;46(6):1076-84
references.pmid: 16168294