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1 Division of Cardiac Surgery, Toronto General Research Institute, University of Toronto, Toronto General Hospital, Toronto M5G 2C4; and 2 Roy and Ann Foss Interventional Cardiology Research Program, Division of Cardiology, Terrence Donnelly Heart Centre, University of Toronto, St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8
In the failing heart, an imbalance in
matrix metalloproteinases (MMPs) and their biological regulators, the
tissue inhibitors of MMPs (TIMPs), may result in cardiac dilatation
from matrix degradation. We hypothesized that a reduction of myocardial
TIMP-3 is associated with adverse matrix remodeling in both human and experimental heart failure. Cardiomyopathic hamsters at age 15 wk
(normal), 25 wk (compensated stage), and 35 wk (overt failure) were
compared with age-matched normal controls. MMP activity (gelatinase bioassay) was increased in cardiomyopathic hearts (P = 0.03) and peaked during the transition to overt heart failure. TIMP-3
content (immunoblot) was decreased compared with normal controls
(74 ± 5% at 25 wk, 69 ± 10% at 35 wk; P = 0.001) and its reduction was associated with increased MMP activity
(r = 
0.6; P = 0.004). TIMP-1
increased progressively (P = 0.001), whereas TIMP-2,
TIMP-4, and MMP protein levels were unchanged. Myocardial collagen
(hydroxyproline content) increased with time during the progression to
end-stage cardiac failure (P < 0.0001). Collagen
synthesis ([14C]proline uptake) was elevated in
cardiomyopathy at 15 and 25 wk (P < 0.05). The
collagen cross-linking ratio (insoluble:soluble collagen) was reduced
(P = 0.003) as the left ventricle dilated. By confocal
microscopy restricted to viable myocardium, collagen content was
reduced (P = 0.04) with fragmentation
(P < 0.0001) and thinning (P = 0.003)
of perimysial collagen fibers. Similarly, patients with end-stage
congestive heart failure (n = 7) compared with
nonfailing controls (n = 2) had elevated gelatinase MMP
activity (P = 0.02) associated with isolated reductions
in TIMP-3 (55 ± 5% of normal; P = 0.003).
Reductions of TIMP-3 parallel adverse matrix remodeling in the
cardiomyopathic hamster and the failing human heart. TIMP-3 may
contribute to the regulation of myocardial remodeling and its reduction
may promote a transition from compensated to end-stage congestive heart failure.
tissue inhibitor of matrix metalloproteinases
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