Ann Thorac Surg 2003;76:688
© 2003 The Society of Thoracic Surgeons
Invited commentary
Ian M. C. Dixon, PhDa,
D. H. Freed, MD, PhDa
a Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, University of Manitoba, 351 Tache Avenue, Winnipeg MB R2H 2A6 Canada
e-mail: idixon{at}sbrc.ca
The emerging roles of MMPs in the pathogenesis of different forms of cardiovascular disease has garnered increased attention from researchers in both clinical and basic sciences during the past decade. Fibrillar collagen, ie types I and III, confer tensile strength to tissues, and these proteins are constitutively expressed by specific nonmyocyte cells in heart and valves. Healthy cardiac valves depend upon ongoing collagen turnover (mediated by cardiac myofibroblasts) for maintenance of normal tissue structure and function. This phenomenon represents a balance struck between fibrillar collagen deposition and its removal by specific MMPs synthesized by myofibroblasts in the valve. Furthermore, the significance of TIMPs in inhibiting endogenous MMP activity in healthy and diseased myocardium is now generally acknowledged. Nonrheumatic aortic stenosis (NAS) is attended by a host of alterations including the genesis of fibrocalcific masses and loss of normal valvular geometry, ie thickening. These alterations are associated with the loss of passive mechanical and elastic properties of these tissues which are associated with the development of stenosis. In the setting of NAS, inflammatory responses and inappropriate collagen remodeling in valves are akin to those observed in other cardiac fibrotic disorders, including wound healing observed after large myocardial infarction. Despite the current repertoire of surgical interventions available to correct aortic stenosis, the mechanisms underlying the pathogenesis of this disease are not well understood.
While many cardiac fibroproliferative disorders are marked by excessive collagen synthesis and deposition in response to abnormal cytokine, mechanical stretch, and neurohormonal inputs, the current paper by Satta and colleagues provides evidence to support the hypothesis that persistent MMP-9 activation in the calcified valve is implicated in stenosis. The most striking contribution of the current work is the suggestion that abnormal MMP activation may due to a lack of sufficient inhibition provided by endogenous tissue TIMPs in the diseased valves. These findings are of considerable clinical interest and provide the basis for a novel mechanism for the development of NAS. The strong positive correlation between MMP-9 activity and the downregulation of TIMP function in valvular tissues is an attractive hypothesis; the current results are exciting developments insofar as they may provide a target on which to focus eventual therapeutic intervention, and this confers considerable promise for further investigation. An improved understanding of endogenous maladaptive changes within the stenotic valves may provide the basis for genetic or pharmacologic manipulation of TIMP expression or activity, respectively, in delaying the onset of chronic aortic stenosis.
