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Articles in PresS, published online ahead of print October 10, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00684.2002
Submitted on August 2, 2002
Accepted on October 8, 2002
1 Division of Cardiac Surgery, University of Toronto, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario, Canada
2 Division of Cardiology, University of Toronto,St. Michael's Hospital, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: paul.fedak{at}utoronto.ca.
Introduction: In the failing heart, an imbalance in the matrix metalloproteinases (MMPs) and their biologic 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. Methods and Results: Cardiomyopathic hamsters at 15 wks (normal), 25 wks (compensated stage) and 35 wks of age (overt failure) were compared to 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 to normal controls (74±5% at 25 wks, 69±10% at 35 wks; 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) while 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 wks (P<0.05). Collagen cross-linking (insoluble:soluble collagen) was reduced (P=0.003) as the LV 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 to non-failing 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). Conclusions: 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.
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