Peripheral Blood Levels of Matrix Metalloproteinases in Patients Referred for Percutaneous Balloon Mitral Valve Commissurotomy Robert J. Garr 1 , Richard A. Krasuski 1 , Robert E. Eckart 2 , Andrew Wang 3 , Cynthia Pierce 3 , Katherine B. Kisslo 3 , J. Kevin Harrison 3 , Thomas M. Bashore 3 1 Wilford Hall Medical Center, Lackland Air Force Base, Texas, 2 Brooke Army Medical Center, Fort Sam, Houston, Texas, 3 Duke University Medical Center, Raleigh, North Carolina, USA For decades, the course of stenotic, valvular heart disease has been described as a slow, progressive, degeneration resulting from hemodynamic stresses. The results of recent studies have suggested that inflammation might play a central role in the patho- physiology of heart disease, particularly in non-rheu- matic aortic stenosis (1-3). Histologic examinations have demonstrated the presence of inflammatory cells, including macrophages and lymphocytes, in the con- nective tissue of stenotic aortic valves. Extracellular bone matrix proteins such as osteopontin and tenascin- C (TN-C) have been identified on diseased aortic valves in association with macrophage accumulation (4,5). Additionally, hydroxymethylglutaryl coenzyme- A (HMG-CoA) reductase inhibitors - drugs that reduce systemic inflammation - may slow the progression of aortic stenosis (6,7). Today, the most common cause of mitral stenosis in the developed world is believed to be rheumatic fever (8). The acute illness resolves over the course of days to weeks, but the time that elapses from the actual infec- tion to the onset of significant mitral stenosis is usual- ly on the order of decades (9). Whether there is ongoing inflammation during this apparently ‘quies- cent’ period was previously unknown. A recent study in patients with rheumatic mitral stenosis revealed activity resembling active bone formation within valvular tissue (10). A similar process has been described in patients with non-rheumatic aortic steno- sis. In addition, elevated levels of plasma inflammato- ry markers have been demonstrated in patients with both aortic and mitral stenosis (3,11-13). These findings suggest that, in spite of different risk factors for the development of these two stenotic lesions, a similar pathogenesis may exist. The matrix metalloproteinases (MMPs) are zinc- and calcium-based proteolytic endopeptidases, which are produced by inflammatory cells (14). They play a cen- tral role in remodeling of the extracellular matrix (ECM) in both physiological and pathological states (15). The MMP family can be divided into four sub- classes: (i) collagenases (MMP-1, MMP-8, and MMP- 13), which degrade type 1 and type 4 collagen; (ii) gelatinases (MMP-2 and MMP-9), which degrade Address for correspondence: Richard A. Krasuski MD, Desk F15, Cardiovascular Division, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA e-mail: krasusr@ccf.org © Copyright by ICR Publishers 2006 Background and aim of the study: Inflammation may play a central role in the progression of stenotic valvular heart disease. Serum levels of matrix metal- loproteinases (MMPs), markers of extracellular matrix (ECM) turnover and potential markers of active inflammation, have been recently demonstrat- ed in several inflammatory processes. The present study was designed to examine whether systemic evidence of ECM turnover was present in advanced stenotic mitral valve disease. Methods: Serum levels of MMP-1, -3 and -9 were measured in 114 patients with mitral stenosis referred for percutaneous balloon mitral valve com- missurotomy, and compared to those in 48 healthy, age- and gender-matched controls. Results: Serum levels of MMP-1, -3 and -9 did not vary according to hemodynamic profile or heart fail- ure class at the time of blood sampling. Levels of MMP-1 and -3 were not significantly different between those patients with mitral stenosis and con- trols. The level of MMP-9 was significantly higher in patients with mitral stenosis than in controls, and did not appear to be altered by commissurotomy. Conclusion: Serum levels of MMP-9 were elevated in patients with mitral stenosis, providing further evi- dence that inflammation and ECM remodeling plays an important role in the pathophysiology of valvular heart disease. The Journal of Heart Valve Disease 2006;15:369-374