Published online before print October 14, 2008, doi: 10.1161/CIRCHEARTFAILURE.108.788687
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Original Articles |
Matrix Metalloproteinases and Their Tissue Inhibitors in Cardiac Amyloidosis
Relationship to Structural, Functional Myocardial Changes and to Light Chain Amyloid Deposition
From the Whitaker Cardiovascular Institute (F.S.); Cardiovascular Section (A.B., H.K.M.-E., F.S.) and Evans Department of Medicine (A.B., S.R., H.K.M.-E., D.S.S., F.S.); Alan and Sandra Gerry Amyloid Research Laboratory in the Amyloid Treatment and Research Program (L.H.C., C.J.O., P.T.S.H., D.S.S.); Department of Biochemistry, Boston University School of Medicine (L.H.C.), Boston, Mass; and Vanderbilt University Medical Center (D.B.S.), Nashville, Tenn.
Correspondence to Flora Sam, MD, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, Room W601, Boston, MA 02118. E-mail flora.sam{at}bmc.org
Received April 25, 2008; accepted September 23, 2008.
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 amyloidois (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.
Key Words: amyloid • cardiomyopathy • metalloproteinases • remodeling • immunoglobulin light chains