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Little data exist regarding the potential of external stents to mitigate long-term disease progression in saphenous vein grafts. We investigated the effect of external stents on the progression of saphenous vein graft disease. A total of 184 patients undergoing isolated coronary artery bypass grafting, using an internal thoracic artery graft and at least 2 additional saphenous vein grafts, were enrolled in 14 European centers. One saphenous vein graft was randomized to an external stent, and 1 nonstented saphenous vein graft served as the control. The primary end point was the saphenous vein graft Fitzgibbon patency scale assessed by angiography, and the secondary end point was saphenous vein graft intimal hyperplasia assessed by intravascular ultrasound in a prespecified subgroup at 2 years. Angiography was completed in 128 patients and intravascular ultrasound in the entire prespecified cohort (n = 51) at 2 years. Overall patency rates were similar between stented and nonstented saphenous vein grafts (78.3% vs 82.2%, P =.43). However, the Fitzgibbon patency scale was significantly improved in stented versus nonstented saphenous vein grafts, with Fitzgibbon patency scale I, II, and III rates of 66.7% versus 54.9%, 27.8% versus 34.3%, and 5.5% versus 10.8%, respectively (odds ratio, 2.02; P =.03). Fitzgibbon patency scale was inversely related to saphenous vein graft minimal lumen diameter, with Fitzgibbon patency scale I, II, and III saphenous vein grafts having an average minimal lumen diameter of 2.62 mm, 1.98 mm, and 1.32 mm, respectively (P <.05). Externally stented saphenous vein grafts also showed significant reductions in mean intimal hyperplasia area (22.5%; P <.001) and thickness (23.5%; P <.001). Two years after coronary artery bypass grafting, external stenting improves Fitzgibbon patency scales of saphenous vein grafts and significantly reduces intimal hyperplasia area and thickness. Whether this will eventually lead to improved long-term patency is still unknown. [Display omitted] Left: Basic design of the study. Center: Primary and secondary end points. Right: Main findings. [ABSTRACT FROM AUTHOR]

Objective: Approximately 50% of aortocoronary saphenous vein grafts are occluded 10 years after coronary revascularization surgery. Intimal hyperplasia, a critical component in saphenous vein graft failure, is defined by vascular smooth muscle cell proliferation, which is mediated in part by βγ subunits of heterotrimeric G proteins (Gβγ) and downstream effectors such as mitogen-activated protein kinases. A peptide consisting of the carboxyl-terminus of the β-adrenergic receptor kinase (βARKct) binds Gβγ, thereby inhibiting Gβγ signaling. Utilizing a recombinant adenovirus containing the coding sequence for the βARKct peptide (AdβARKct), this study investigates whether treatment of the vein graft with AdβARKct reduces intimal hyperplasia in a large animal model of aortocoronary saphenous vein graft intimal hyperplasia. Methods: Twenty-seven dogs (27-32 kg) underwent aortocoronary bypass grafting to the left anterior descending artery using autologous saphenous vein. Vein grafts were treated with saline (n = 8), an empty adenovirus (n = 8), or AdβARKct (n = 8). A subset of dogs (n = 3) were sacrificed on postoperative day 7 and βARKct expression confirmed by Northern blotting. Results: Arteriograms performed on postoperative day 90 confirmed that saphenous vein grafts were patent. At postoperative day 90, AdβARKct-treated grafts demonstrated reduced intimal area compared to empty virus and saline treated animals (P < .05). Additionally, AdβARKct treatment of isolated vascular smooth muscle cells in vitro inhibited mitogen-activated protein kinase activation and decreased overall vascular smooth muscle cell proliferation. Conclusion: This study demonstrates that βARKct expression in aortocoronary saphenous vein grafts reduces intimal hyperplasia and decreases vascular smooth muscle cell proliferation in vitro via inhibition of Gβγ-mediated mitogen-activated protein kinase activation. Modulation of Gβγ via βARKct may represent a novel therapy to reduce intimal hyperplasia and saphenous vein graft failure. [Copyright &y& Elsevier]

Objectives: Fifty percent of human aortocoronary saphenous vein grafts are occluded after 10 years. Intimal hyperplasia is an initial step in graft occlusion and consists of vascular smooth muscle cell proliferation. Phosphatidylinositol 3-kinase and its downstream regulator, the inositol 3-phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), are important regulators of vascular smooth muscle cell proliferation, migration, and cell death. This study tests whether overexpression of PTEN in aortocoronary saphenous vein grafts can reduce intimal hyperplasia. Methods: Adult dogs underwent aortocoronary bypass grafting to the left anterior descending artery by using the autologous saphenous vein. Saphenous vein grafts were treated with phosphate-buffered saline (n = 9), empty adenovirus (n = 8), or adenovirus encoding for PTEN (n = 8). Arteriography at 30 and 90 days assessed saphenous vein graft patency. A subset received saphenous vein grafts treated with a marker transgene (β-galactosidase, n = 3), empty adenovirus (n = 4), or adenovirus encoding for PTEN (n = 4) and were killed on postoperative day 3 to confirm expression. Vascular smooth muscle cells were isolated from canine saphenous vein infected with adenovirus encoding for PTEN, and immunoblotting and proliferation assays were performed. Results: Saphenous vein graft transgene expression was confirmed by means of immunohistochemistry, immunoblotting, and polymerase chain reaction. Arteriograms revealed all saphenous vein grafts to be patent. Saphenous vein grafts treated with adenovirus encoding for PTEN demonstrated reduced intimal area compared with those treated with empty adenovirus and phosphate-buffered saline (1.39 ± 0.11 vs 2.35 ± 0.3 and 2.57 ± 0.4 mm2, P < .05), and the intima/media ratio was lower in saphenous vein grafts treated with adenovirus encoding for PTEN (0.50 ± 0.05 vs 1.43 ± 0.18 and 1.11 ± 0.14, P < .005). PTEN overexpression in vascular smooth muscle cells inhibited platelet-derived growth factor-induced phosphorylation of Akt, a downstream effector of phosphatidylinositol 3-kinase. PTEN-treated vascular smooth muscle cells demonstrated decreased basal, platelet-derived growth factor-stimulated, and serum-stimulated proliferation. Conclusion: This study demonstrates that PTEN overexpression in aortocoronary saphenous vein grafts reduces intimal hyperplasia. The mechanism of this antiproliferative effect in vascular smooth muscle cells is likely due to inhibition of phosphatidylinositol 3-kinase signaling through Akt, with resultant decreases in vascular smooth muscle cell growth and survival. Therefore modulation of the phosphatidylinositol 3-kinase pathway through PTEN overexpression might represent a novel therapy to prevent saphenous vein graft intimal hyperplasia after coronary artery bypass grafting. [Copyright &y& Elsevier]