Prediman K. Shah

The VIVA Trial

Background—Recombinant human vascular endothelial growth factor protein (rhVEGF) stimulates angiogenesis in animal models and was well tolerated in Phase I clinical trials. VIVA (Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis) is a double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of intracoronary and intravenous infusions of rhVEGF. Methods and Results—A total of 178 patients with stable exertional angina, unsuitable for standard revascularization, were randomized to receive placebo, low-dose rhVEGF (17 ng · kg−1 · min−1), or high-dose rhVEGF (50 ng · kg−1 · min−1) by intracoronary infusion on day 0, followed by intravenous infusions on days 3, 6, and 9. Exercise treadmill tests, angina class, and quality of life assessments were performed at baseline, day 60, and day 120. Myocardial perfusion imaging was performed at baseline and day 60. At day 60, the change in exercise treadmill test (ETT) time from baseline was not different between groups (placebo, +48 seconds; low dose, +30 seconds; high dose, +30 seconds). Angina class and quality of life were significantly improved within each group, with no difference between groups. By day 120, placebo-treated patients demonstrated reduced benefit in all three measures, with no significant difference compared with low-dose rhVEGF. In contrast, high-dose rhVEGF resulted in significant improvement in angina class (P =0.05) and nonsignificant trends in ETT time (P =0.15) and angina frequency (P =0.09) as compared with placebo. Conclusions—rhVEGF seems to be safe and well tolerated. rhVEGF offered no improvement beyond placebo in all measurements by day 60. By day 120, high-dose rhVEGF resulted in significant improvement in angina and favorable trends in ETT time and angina frequency.

Inflammatory Cytokines and Oxidized Low Density Lipoproteins Increase Endothelial Cell Expression of Membrane Type 1-Matrix Metalloproteinase

We investigated whether inflammatory cytokines or oxidized low density lipoproteins (Ox-LDL) present in human atheroma modulate extracellular matrix degradation by inducing membrane type 1-matrix metalloproteinase (MT1-MMP) expression. Cultured human endothelial cells (EC) constitutively expressed MT1-MMP mRNA and protein with enzymatic activity. Tumor necrosis factor-α (TNF-α), interleukin-1α, or interleukin-1β caused a time-dependent increase in the steady-state MT1-MMP mRNA levels within 4 h of exposure, peaking about 4-fold by 6 h, and remaining elevated for 12 h. Increased MT1-MMP mRNA correlated with a 2.5-fold increase in MT1-MMP protein in EC membranes. Ox-LDL also increased MT1-MMP mRNA levels that varied with the duration of exposure and degree of LDL oxidation. The increase in MT1-MMP mRNA occurred within 6 h of exposure to Ox-LDL and peaked over 3-fold by 6 h. Ox-LDL, but not native LDL, increased MT1-MMP protein by 2-fold in EC membranes. A combination of TNF-α and Ox-LDL was additive in increasing MT1-MMP expression. Nuclear run-on assays showed that TNF-α or Ox-LDL augmented steady-state mRNA levels by increased transcription of the MT1-MMP gene. These findings indicate that activation of EC by inflammatory cytokines and/or Ox-LDL increase MT1-MMP expression. Since MT1-MMP promotes matrix degradation by activating pro-MMP-2, these results suggest a novel mechanism whereby cytokines or Ox-LDL may influence extracellular matrix remodeling.

755-2 Current Management of ST Elevation Myocardial Infarction and Outcome of Thrombolytic Ineligible Patients: Results of the Multicenter TIMI 9 Registry

Despite clear benefit of thrombolysis (Tlysis) and primary (1°) PTCA for acute MI, prior reports have indicated a low use of thrombolytic therapy in the U.S. Further, single center reports have suggested that mortality is up to 5 times higher when thrombolysis is not given. To evaluate the management and outcome of acute MI in 1994, we conducted a registry in 20 hospitals (16 with l° PTCA capability) and prospectively identified allconsecutive patients (ptsl presenting with acute MI and ST segment elevation or new LBBB. A total of 587 pts were identified, 200 were enrolled in the TIMI 9 thrombolytic trial of hirudin vs. heparin, and 387 in the TIMI 9 Registry. Tlysis was given to 356 of 587 (60.7%) pts (of whom 200/356 (56%) were enrolled in TIMI 9); l° PTCA was performed in 62/587 (10.5%) of the total population and medical therapy used in 169/587128.8%). Of the patients enrolled in the TIMI 9 Registry, those treated with l° PTCA were significantly younger, 60.7 years, vs. 64.9 for Tlysis and 66.1 for medical therapy(each pxa0lxa00.05) and were less oftenwomen, 20.0%, vs. 36.2% and 36.1%, respectively, (each pxa0lxa00.05). Time to presentation was significantly longer for medically treated pts: 13.8h vs. 4.4h for Tlysis and 3.3h for 1° PTCA (each pxa0lxa00.001). Delayg 12 hours was the reason cited most often for pts not treated with thrombolysis. Inhospital mortality is shown. Recurrent MI was similar in the 3 groups, 4.2%. Conclusions (1) In 1994 in the U.S., reperfusion therapy was used in 71% of pts with ST elevation MI at these hospitals. (2) The potential underutilization of l° PTCA in women deserves further study. (3) Early mortality was similar for Tlysis and l° PTCA, but highest for medically treated pts, which supports further expansion of reperfusion therapy in ST elevation MI (including use of strategies to shorten patient time to presentation) and the need for improved medical therapies for thrombolytic ineligible patients. Download : Download high-res image (51KB) Download : Download full-size image