Faculty Bibliography

BACKGROUND: In younger patients requiring mitral valve replacement (MVR), mechanical prostheses (MPs) have been reported to give better freedom from all valve-related complications (VRCs) because of the high incidence of late valve degeneration (VD) associated with bioprostheses (BPs). In older patients, however, the risk of VD may be reduced because of the large competing risk of noncardiac death (NCD). Previous studies on VD in the elderly have used actuarial analysis, which overestimates the risk of VD in this population because it assumes that dead patients are still at risk. In contrast, cumulative incidence (actual) analysis acknowledges that patients who die have no risk of VD. This study compares the results of both 'actual' and 'actuarial' analyses of the freedom from VD in elderly patients undergoing MVR. METHODS AND RESULTS: From June 1976 through January 1996, 504 patients > or = 70 years of age underwent MVR at our institution. Isolated mitral operations were performed in 159 patients, and 169 had concomitant CABG. Hospital mortality was 59 of 374 (15.9%) for tissue prosthesis versus 24 of 130 (18.5%) for mechanical prosthesis (P = NS). For tissue versus mechanical prosthesis, 10-year freedom from noncardiac death was 75.0% versus 67.6% (P = NS); 10-year actuarial freedom from valve degeneration was 79.8% versus 93.4% (P = NS); 10-year actual freedom from valve degeneration was 92.6% versus 95.4% (P = NS); and 10-year actual freedom from all VRCs was 84.4% versus 92.3% (P = NS). CONCLUSIONS: In elderly patients undergoing MVR, actuarial analysis overestimates the 10-year risk of VD compared with actual analysis (20.2% versus 7.4% for BP, 6.6% versus 4.6% for MP). In these patients, the actual freedoms from VD and all VRCs do not differ significantly between BP and MP. Thus, in this age group, the necessity for anticoagulation or its avoidance may be the predominant factor in choosing a replacement mitral valve

BACKGROUND: Neointima formation after human saphenous vein grafting (hSVG) involves several matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). This study assessed the feasibility of modulating MMP activity in hSVGs by adenovirus-mediated gene transfer. METHODS: First, 1 x 10(9) plaque-forming units (pfu) of replication-deficient recombinant adenoviruses encoding either beta-galactosidase (ad beta gal), MMP-3 (AdMMP-3), or TIMP-1 (AdTIMP-1) were added into the lumen of hSVGs for 1 hour. After incubation at 37 degrees C for 24 hours, specimens were analyzed by immunohistochemistry, in situ zymography, and X-gal staining. RESULTS: By X-gal staining ad beta gal-infected hSVGs stained positively in the intima and occasionally in the media. Immunohistochemistry of AdMMP-3- and AdTIMP-1-infected hSVGs localized these proteins to the intima. In situ zymography showed increased MMP activity in the intima of AdMMP-3-infected hSVGs relative to AdTIMP-1- or Ad beta gal-infected vessels. CONCLUSIONS: MMP-3 and TIMP activity can be regulated in hSVGs by replication-deficient recombinant adenoviruses. We have previously demonstrated that MMP-3 or TIMP-1 transduction, or both, inhibit SMC migration in an in vitro reconstituted vessel wall. Modulation of MMP activity may thus afford high patency rates in genetically engineered hSVGs. However, adenovirus-mediated gene delivery is limited to the vessel's intima; strategies to infect medial smooth muscle cells need to be developed

BACKGROUND: Matrix metalloproteinase-2 (MMP-2), an enzyme involved in tumor invasion, is secreted as an inactive proenzyme and requires interaction with membrane-type 1 MMP (MT1-MMP) for activation. We have previously demonstrated that polymorphonuclear neutrophils (PMNs) release a soluble factor(s) that activates pro-MMP-2. Therefore, we tested the hypothesis that PMN-derived proteinases act in concert with MT1-MMP to activate pro-MMP-2. METHODS: Human HT-1080 cells transfected with MT1-MMP cDNA (HT-SE) or the corresponding antisense cDNA (HT-AS) or an empty vector (HT-V), which expressed differing levels of MT1-MMP, were incubated with serum-free, human PMN-conditioned medium with or without proteinase inhibitors. The culture supernatants were analyzed by gelatin zymography. RESULTS: Ht-1080 cells expressing basal (HT-V) or low levels (HT-AS) of MT1-MMP secreted MMP-2 in proenzyme from (72 kd). Ht-1080 cells with high levels of MT1-MMP (HT-SE) secreted pro MMP-2 and a 68 kd intermediate activation product. Addition of PMN-conditioned medium to either HT-SE or HT-V clones resulted in dose-dependent generation of active, 62 kd MMP-2. In contrast, when PMN-conditioned medium was added to HT-AS clones, no MMP-2 activation occurred. CONCLUSIONS: PMN-derived serine proteinases act in concert with MT1-MMP to activate proMMP-2. This finding indicates a potential role for inflammatory cells in promoting extracellular matrix breakdown during tumor invasion