Safety of intracoronary administration of c-myc antisense oligomers after percutaneous transluminal coronary angioplasty (PTCA).

We wished to assess the clinical safety and pharmacokinetics of ascending doses of a synthetic oligodeoxynucleotide (LR-3280) administered after coronary angioplasty. Antisense oligodeoxynucleotides designed to hybridize with target messenger ribonucleic acid (mRNA) in a complementary fashion to inhibit the expression of corresponding protein also have the ability to bind to extracellular growth factors. LR-3280 has been shown to reduce c-myc expression, inhibit growth and collagen biosynthesis in human vascular cells, and reduce neointimal formation in animal models of vascular injury. After successful percutaneous transluminal coronary angioplasty (PTCA), 78 patients were randomized to receive either standard care (n = 26) or standard care and escalating doses of LR-3280 (n = 52) (doses from 1 to 24 mg), administered into target vessel through a guiding catheter. Overall safety was evaluated by clinical adverse events, laboratory tests, and electrocardiograms. Patency was evaluated by quantitative coronary angiography. There were no clinically significant differences between treated and control patients. No adverse effects of LR-3280 on the patency of dilated coronary arteries were observed. Pharmacokinetic data revealed that peak plasma concentrations of LR-3280 occurred at 1 minute over the studied dose range and rapidly decreased after approximately1 hour, with little LR-3280 detected in the urine between 0-6 hours and 12-24 hours. The intracoronary administration of LR-3280 is well tolerated at doses up to 24 mg and produces no adverse effects in dilated coronary arteries. These results provide the basis for the evaluation of local delivery of this phosphorothioate oligodeoxynucleotide for the prevention of human vasculoproliferative disease.

Oxidative stress and lipid retention in vascular grafts: comparison between venous and arterial conduits.

BACKGROUND: Because saphenous vein grafts (SVGs) exhibit greater cellular heterogeneity and worse clinical outcomes than arterial grafts (AGs), we examined oxidative stress and lipid retention in different vascular conduits. METHODS AND RESULTS: In a porcine model of graft interposition into carotid artery, superoxide anion (.O(2)(-)) was measured at 2 weeks after surgery. SVGs demonstrated increased.O(2)(-) production compared with AGs (SOD-inhibitable nitro blue tetrazolium reduction, P<0.01). The NAD(P)H oxidase inhibitor diphenyleneiodonium (P<0.01) abolished SVG-derived.O(2)(-), whereas the inhibitors of other pro-oxidant enzymes were ineffective. The change in oxidative stress was also reflected by lower activity of the endogenous antioxidant superoxide dismutase in SVGs than in AGs (P<0.001). SVG remodeling was associated with increased synthesis of sulfated glycosaminoglycans and augmented expression of a core protein, versican. These changes were accompanied by SVGs retaining significantly more (125)I-labeled LDL than AGs ex vivo (P<0.001). In hyperlipemic animals, lipid accumulation and oxidized epitopes were preferentially noted in the intima of SVGs at 1 month after surgery. CONCLUSIONS: This study demonstrated significant differences in the biology of SVGs and AGS: SVGs exhibited higher oxidative stress, LDL accumulation, and the presence of oxidized epitopes. These findings suggest that proatherogenic changes in SVGs may commence early after surgical revascularization.

The role of preoperative radial artery ultrasound and digital plethysmography prior to coronary artery bypass grafting.

OBJECTIVE: Doppler ultrasound and digital plethysmography are used at our institution to determine the suitability of the radial artery for harvest prior to coronary artery bypass grafting (CABG). The purpose of this study is to determine the value of this preoperative evaluation. METHODS: A retrospective analysis of non-invasive radial artery testing was performed on 187 CABG patients. Criteria used to exclude radial arteries from harvest were anatomic abnormalities (size<2 mm, diffuse calcifications), and perfusion deficits during radial artery occlusion (>40% reduction in digital pressure, non-reversal of radial artery flow, or minimal increase in ulnar velocity). A questionnaire was used to determine the incidence of postoperative hand ischemia or rehabilitation. RESULTS: In 187 patients, 346 arms were evaluated. Ninety-four arms (27.1%) were excluded for harvesting. Anatomical abnormalities included size<2 mm (1.5%), diffuse calcifications (8.7%), congenital anomalies (2.3%), and radial artery occlusion (0.3%). Circulatory abnormalities included non-reversal of flow (7.2%), abnormal digital pressures (5.5%), and inappropriate increase in ulnar velocity (1.7%). A total of 116 radial arteries were harvested. There were no episodes of hand ischemia. No patient required hand rehabilitation. CONCLUSIONS Doppler ultrasound and digital plethysmography identifies both perfusion (14.5%) and anatomical (12.7%) abnormalities that may make the radial artery less suitable as a bypass conduit.

Early injury to the media after saphenous vein grafting.

BACKGROUND: Injury to the smooth muscle cells of the media affects the remodeling process of vein grafts. The purpose of this study was to determine whether different techniques of surgical preparation influence the degree of medial smooth muscle injury. METHODS: Carotid-saphenous vein interposition grafting was performed in crossbred pigs (n = 32), using distended (n = 16) or nondistended (n = 16) conduits. After 3 to 90 days, the media was evaluated for the presence of smooth muscle cells (desmin stains), myofibroblast formation (transient alpha-SM actin expression), and apoptosis (TdT-mediated dUTP nick end-labeling [TUNEL]). RESULTS: Smooth muscle loss was uniformly severe; only 5% +/- 5% (p < 0.01) and 14% +/- 9% (p < 0.01) of the medial area of distended and nondistended veins were desmin positive in comparison with 80% +/- 9% of controls. Apoptosis appeared to contribute to medial smooth muscle loss (5.7% +/- 4.3% in vein grafts versus 0.0% +/- 0.0% of TUNEL-positive cells in controls; p = 0.05). There was a time dependent increase in medial myofibroblast formation (p < 0.05). CONCLUSIONS: Severe medial smooth muscle loss occurs in vein grafts, even when prepared without distension. Apoptosis contributes to the early disappearance of smooth muscle cells. Adjunctive measures, in addition to ideal surgical techniques, should be developed to prevent medial muscle loss.

Saphenous vein graft protection: effects of c-myc antisense.

OBJECTIVE: Saphenous vein grafting is associated with extensive medial remodeling, characterized by cellular proliferation, loss of smooth muscle cells, and an inflammatory response. In this study, we examined whether unfavorable responses to vein grafting could be modified by the intraoperative application of c-myc antisense oligomers. METHODS: The intragraft cell proliferation, macrophage infiltration, and medial preservation were examined in a porcine model in the control and antisense-treated groups (n = 36). RESULTS: Saphenous veins showed transmural distribution of oligomers within 30 minutes of the ex vivo incubation. A concentration-dependent inhibition of cell proliferation in the media of saphenous grafts was noted 3 days later (0 to 200 mumol/L, p = 0.005). The growth inhibition was sequence-specific, because control oligomers produced only insignificant effects (20 mumol/L). Vascular effects of c-myc antisense were associated with a significant attenuation of macrophage infiltration in saphenous grafts. A concentration-dependent decrease in tissue edema (p = 0.0005) and the attenuated loss of smooth muscle cells (p = 0.002) were noted in the media of the arterialized venous conduits after c-myc antisense. CONCLUSIONS: Direct application of synthetic DNA to harvested saphenous veins resulted in a rapid transmural distribution. The inhibition of the intragraft cell proliferation in vivo after c-myc antisense was sequence dependent. Decrease in vein graft injury resulted in an attenuated inflammatory response and better medial preservation. These findings provide a rationale for assessment of the long-term effects of vein graft protection with c-myc antisense.

Sustained reduction of neointima with c-myc antisense oligonucleotides in saphenous vein grafts.

BACKGROUND: Treatment of saphenous veins with c-myc antisense oligomers during preparation for grafting reduces medial cellular proliferation and macrophage infiltration, and preserves medial smooth muscle content at 3 days. Accordingly, the purpose of this study was to examine whether c-myc antisense oligomers have an impact on late vein graft remodeling. METHODS: Sixty-two pigs underwent unilateral saphenous vein-carotid artery interposition grafting. Harvested veins were incubated either in saline (control group) or 20-micromol/L or 200-micromol/L concentrations of c-myc antisense oligomers (treated groups) for 30 minutes intraoperatively. Three months after surgery, vein graft histology was assessed. RESULTS: Forty-five of 62 randomized animals survived the experiment; no differences in animal survival or graft patency among the groups were observed (p = NS, chi2). C-myc antisense oligomers significantly decreased neointimal and wall thickness, as well as increased lumenal index, in treated groups (p<0.04, p<0.03, and p<0.001, respectively, analysis of variance). In contrast, there was no difference in medial thickness or perivascular wound healing. CONCLUSION: Intraoperative treatment of saphenous veins with c-myc antisense oligomers decreased neointimal formation at 3 months after grafting. In conjunction with our previous reports, these findings suggest that early inhibition of cellular proliferation and inflammatory infiltration results in a sustained reduction in neointimal formation and favorable graft remodeling.