Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: relationship to structural, functional myocardial changes and to light chain amyloid deposition.
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.


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.
Biolo
Andreia
A
Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
Ramamurthy
Sujata
S
Connors
Lawreen H
LH
O'Hara
Carl J
CJ
Meier-Ewert
Hans K
HK
Soo Hoo
Pamela T
PT
Sawyer
Douglas B
DB
Seldin
David C
DC
Seldin
David S
DS
Sam
Flora
F
D000368:Aged; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D000686:Amyloidosis / Q000097:blood* / Q000145:classification* / Q000150:complications / Q000175:diagnosis / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D009202:Cardiomyopathies / Q000097:blood* / Q000150:complications / Q000175:diagnosis / Q000503:physiopathology; D004452:Echocardiography; D005109:Extracellular Matrix; D005260:Female; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism*; D007674:Kidney Diseases / Q000209:etiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020782:Matrix Metalloproteinases / Q000097:blood*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010447:Peptide Hydrolases / Q000097:blood; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D000682:Amyloid; D015415:Biomarkers; D007147:Immunoglobulin Light Chains; D011228:Prealbumin; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D020097:Natriuretic Peptide, Brain; D010447:Peptide Hydrolases; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9