Faculty Bibliography

BACKGROUND. Angiogenesis requires degradation of the vessel's basal lamina and endothelial cell migration into the tissue stroma. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play important roles in this process. MMP activity is tightly regulated during vessel growth. This work was designed to characterize the effect of TIMP-1 upregulation on endothelial cell invasion of the extracellular matrix. METHODS. We constructed replication-deficient recombinant adenoviruses that encode either TIMP-1 (Ad.TIMP-1) or Escherichia coli lac Z (Ad.beta gal) cDNA. Bovine aortic endothelial (BAE) cells were infected with 100 infectious particles/cell. Gene expression was assessed by Northern and Western blotting. TIMP-1 activity in cell-conditioned media was measured by a resorufin-labeled casein protease assay. BAE cell migration was measured by Boyden chamber assays with 0.2% gelatin-coated, 8. 0-mcm polycarbonate membranes. RESULTS. TIMP-1 was overexpressed by Ad.TIMP-1-infected BAE cells relative to control, Ad. beta gal-infected or uninfected cells. TIMP-1 activity in Ad.TIMP-1 cell-conditioned medium was 2.8-fold higher than in control cells. By Boyden chamber assays with gelatin-coated membranes, Ad. TIMP-1-infected BAE cells showed 89.97 +/-1.64% (mean +/- SEM) reduction in migration relative to Ad.beta gal-infected cells (P < 0. 02) and 90.53 +/- 1.12% relative to uninfected cells (P < 0.02). Without gelatin coating, migration was equivalent in all groups. CONCLUSION. The replication-deficient recombinant adenovirus we constructed affords rapid and efficient upregulation of functional TIMP-1 in endothelial cells. Infection results in a dramatic decrease in cell migration and invasion of extracellular matrix. Thus, such a recombinant vector may provide a useful tool for the gene therapy of vascular remodeling and inhibition of angiogenesis.

BACKGROUND: Although minimally invasive techniques for valvular surgery have rapidly come into widespread use, whether such an approach can be safely applied to elderly patients remains an open question. To help resolve this issue, we reviewed our experience with minimally invasive port access (MIPA) valve surgery in elderly patients and compared it to the results obtained with the standard sternotomy (STD) approach in the same age group. METHODS: From January 1994 through December 1998, 370 consecutive patients at least 70 years of age underwent isolated aortic or mitral valve surgery at our institution. The standard sternotomy operative approach was used in 259 patients (mean age 77.5 years) and the minimally invasive port access approach was used in 111 patients (mean age 76.0; p=.006). A mitral valve procedure was performed more often in the MIPA patients than in the STD patients (49.5% vs. 35.9%; p < .001). RESULTS: Hospital mortality was comparable in the two groups, 9.7% (25/259) in the STD group and 7.2% (8/111) in the MIPA group (p = .50), as was the incidence of many perioperative complications. The MIPA group, however, had a significantly lower incidence of sepsis or wound complications (1.8% vs 7.7%; p = .027), required less fresh frozen plasma transfusion (median 1.0 unit vs 2.0 units; p =.04), and had a shorter length of hospital stay (11.6 days vs 17.6 days; p = .001). CONCLUSIONS: These results indicate that with appropriate surgical techniques the MIPA approach for isolated valve surgery can be safely applied to the elderly patient population with excellent results. In our initial experience the MIPA approach is associated with significantly less plasma transfusion, fewer postoperative complications, and shorter length of hospital stay

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