Document Detail

Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: relationship to structural, functional myocardial changes and to light chain amyloid deposition.
MedLine Citation:
PMID:  19808299     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition has an accelerated clinical course and a worse prognosis compared with non-light chain cardiac amyloidoses (ie, forms associated with wild-type or mutated transthyretin [TTR]). We therefore tested the hypothesis that determinants of proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) would have distinct patterns and contribute to the pathogenesis of AL-CMP versus TTR-related amyloidosis.
METHODS AND RESULTS: We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, ie, senile systemic amyloidosis (involving wild-type TTR) or mutant TTR, and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and -9, TIMP-1, -2, and -4, brain natriuretic peptide values, and echocardiography were determined. AL-CMP and TTR-related amyloidosis groups had similar degrees of increased left ventricular wall thickness. However, brain natriuretic peptide, MMP-9, and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group versus no or minimal increases in the TTR-related amyloidosis group. Brain natriuretic peptide, MMPs, and TIMPs were not correlated with the degree of left ventricular wall thickness but were correlated to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in TTR-related amyloidosis hearts.
CONCLUSIONS: Despite comparable left ventricular wall thickness with TTR-related cardiac amyloidosis, AL-CMP patients have higher brain natriuretic peptide, MMPs, and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and extracellular matrix proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP, distinct from the other non-light chain cardiac amyloidoses.
Andreia Biolo; Sujata Ramamurthy; Lawreen H Connors; Carl J O'Hara; Hans K Meier-Ewert; Pamela T Soo Hoo; Douglas B Sawyer; David C Seldin; David S Seldin; Flora Sam
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-10-14
Journal Detail:
Title:  Circulation. Heart failure     Volume:  1     ISSN:  1941-3297     ISO Abbreviation:  Circ Heart Fail     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2009-10-07     Completed Date:  2009-11-10     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  101479941     Medline TA:  Circ Heart Fail     Country:  United States    
Other Details:
Languages:  eng     Pagination:  249-57     Citation Subset:  IM    
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MeSH Terms
Amyloid / chemistry,  metabolism*
Amyloidosis / blood*,  classification*,  complications,  diagnosis,  physiopathology
Biological Markers / blood
Cardiomyopathies / blood*,  complications,  diagnosis,  physiopathology
Extracellular Matrix
Heart Ventricles / ultrasonography
Immunoglobulin Light Chains / metabolism*
Kidney Diseases / etiology
Matrix Metalloproteinase 9 / blood
Matrix Metalloproteinases / blood*
Myocardium / metabolism,  pathology
Natriuretic Peptide, Brain / blood
Peptide Hydrolases / blood
Prealbumin / genetics,  metabolism*
Tissue Inhibitor of Metalloproteinase-1 / blood
Tissue Inhibitor of Metalloproteinases / blood*
Ventricular Function, Left
Ventricular Remodeling
Grant Support
Reg. No./Substance:
0/Amyloid; 0/Biological Markers; 0/Immunoglobulin Light Chains; 0/Prealbumin; 0/Tissue Inhibitor of Metalloproteinase-1; 0/Tissue Inhibitor of Metalloproteinases; 114471-18-0/Natriuretic Peptide, Brain; EC 3.4.-/Peptide Hydrolases; EC 3.4.24.-/Matrix Metalloproteinases; EC Metalloproteinase 9
Erratum In:
Circ Heart Fail. 2009 May;2(3):e3
Note: Seldin, David S [corrected to Seldin, David C]

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