on October 14, 2008
Published online before print October 14, 2008, doi: 10.1161/CIRCHEARTFAILURE.108.788687
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Original Article |
Matrix Metalloproteinases and their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural, Functional Myocardial Changes and to Light Chain Amyloid Deposition
1 Boston University School of Medicine and Boston Medical Center;
2 Boston University School of Medicine;
3 Vanderbilt University Medical Center
4 E-mail: flora.sam{at}bmc.org
Background—Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix (ECM) disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition, has an accelerated clinical course and a worse prognosis compared to non-light chain cardiac amyloidoses i.e., forms associated with wild-type or mutated transthyretin (TTR). We therefore tested the hypothesis that determinants of proteolytic activity of the ECM, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), would have distinct patterns and contribute to the pathogenesis of AL-CMP vs. TTR.
Methods and Results—We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, i.e., senile systemic amyloidois (SSA, involving wild-type TTR) or mutant TTR (ATTR), and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and -9, TIMP-1, -2 and -4, brain natriuretic peptide (BNP) values and echocardiography were determined. AL-CMP and SSA-ATTR groups had similar degrees of increased left ventricular wall thickness (LVWT). However, BNP, MMP-9 and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group vs. no or minimal increases in the SSA-ATTR group. BNP, MMPs and TIMPs were not correlated with the degree of LVWT 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 SSA or ATTR hearts.
Conclusions—Despite comparable LVWT with TTR-related cardiac amyloidosis, AL-CMP patients have higher BNP, MMPs and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and ECM 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.
Key Words: amyloid • cardiomyopathy • metalloproteinases • remodeling • immunoglobulin light chains