Biomedical subjects

Arnd B Buchwald

Publications and source records attributed to Arnd B Buchwald.

5 recordsLinked to original sources

PubMed2006

Transfection of the DNA for the receptor KDR/flk-1 attenuates neointimal proliferation and luminal narrowing in a coronary stent angioplasty model.

BACKGROUND: Neointimal proliferation resulting in luminal renarrowing is the major cause of restenosis limiting the long-term success of coronary angioplasty in 20 to 30% of patients. Local transfection of the DNA encoding for VEGF has been shown to enhance re-endothelialization and reduce neointimal proliferation in an experimental model. We tested the hypothesis that transfection of the DNA for the receptor of vascular endothelial growth factor VEGF, KDR-flk-1, reduces neointimal proliferation after angioplasty. METHODS: In a minipig model, we performed coronary stent implantation, followed by injection of either KDR/flk-1 DNA (200 microg of linearized DNA in a CMV-promotor) or LacZ control in two coronary artery segments per animal in a randomized, blinded protocol (n = 22 animals). Expression of KDR/flk-1 was analyzed using in situ hybridization after 4, 7, and 14 days. RESULTS: In KDR-transfected coronary segments, expression of KDR/flk-1 occurred earlier and to much stronger extent compared to LacZ-transfected segments. After 4 weeks (n = 10) neointimal proliferation and luminal narrowing was significantly reduced in KDR/flk-1 transfected animals. No expression of locally transfected DNA was detected in other organs. CONCLUSION: The hypothesis is supported, that expression of the VEGF-receptor KDR/flk-1 can be rate-limiting for endothelial regeneration and that its transient overexpression at the time angioplasty can prevent excessive neointimal proliferation resulting in restenosis.

Angioplasty, Balloon, Coronary↗

PubMed2004

Shear stress insensitivity of endothelial nitric oxide synthase expression as a genetic risk factor for coronary heart disease.

Coronary heart disease (CHD) is based on the development of atherosclerosis in coronary arteries. Shear stress-induced endothelial nitric oxide (NO) release not only contributes to local blood pressure control but also effectively helps to retard atherosclerosis. Therefore, functionally relevant polymorphisms in the endothelial NO synthase (NOS-3) gene may contribute to the development of CHD. NOS-3 expression was analyzed in endothelial cells isolated from umbilical cords genotyped for the -786C/T single nucleotide polymorphism (SNP) of the human nos-3 gene. Moreover, NO-dependent relaxation was examined in segments of saphenous vein isolated from genotyped patients undergoing aortocoronary bypass surgery, and patients subjected to quantitative coronary angiography were genotyped to verify an association between this SNP and CHD. Shear stress-induced NOS-3 mRNA and protein expression was present in TT and CT genotype cells but absent in cells with CC genotype. Pretreatment of these cells with a decoy oligonucleotide comprising position -800 to -779 of the C-type nos-3 promoter reconstituted shear stress-induced NOS-3 expression. These results were confirmed by reporter gene analysis with the corresponding nos-3 promoter luciferase constructs. In addition, the NO-mediated relaxant response of vein grafts from CC genotype patients was significantly attenuated as compared with the CT or TT genotype, and in CHD-positive patients, the CC genotype was significantly more frequent (19.0%) than in CHD-negative patients (4.4%). The -786C/T SNP of the nos-3 gene thus constitutes a genetic risk factor for CHD, presumably due to binding of an inhibitory transcription factor to the C-type promoter blocking shear stress-dependent maintenance of NOS-3 expression.

Adult↗

PubMed2002

Decoy oligodeoxynucleotide against activator protein-1 reduces neointimal proliferation after coronary angioplasty in hypercholesterolemic minipigs.

OBJECTIVES: We sought to demonstrate, in an appropriate animal model, that co-medication with a transcription factor-blocking agent limits restenosis after percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Enhanced synthesis in the vessel wall of endothelin-1 (ET-1), a powerful co-mitogen for vascular smooth muscle cells, appears to be one mechanism that promotes restenosis after PTCA. Deformation-induced expression of prepro-ET-1 is governed by the transcription factor, activator protein-1 (AP-1). METHODS: An anti-AP-1 decoy oligodeoxynucleotide (dODN) strategy was devised in which the dODN-containing solution (20 nmol) was administered locally through a Dispatch catheter into the coronary arteries of hypercholesterolemic minipigs at the time of PTCA (AVE-GFX stent). RESULTS: Treatment with an AP-1 dODN, mimicking the consensus binding site of the transcription factor, significantly reduced neointimal formation in the coronary arteries of hypercholesterolemic minipigs (n = 10 to 12), compared with vehicle-treated coronary arteries, after four weeks of follow-up (neointimal area 2.64 +/- 0.33 vs. 4.81 +/- 1.04 mm(2) [mean +/- SEM]; p < 0.05). This effect was maintained after eight weeks (neointimal area 2.04 +/- 0.22 mm(2); n = 3) and correlated with a reduction in both nuclear translocation of AP-1 and ET-1 synthesis in the vessel wall 48 h after PTCA (n = 4). In contrast, an AP-1 mutant dODN, to which the transcription factor does not bind, showed no effect on neointimal formation at either time point (n = 3 to 7). Moreover, a consensus dODN directed against CCAAT/enhancer binding protein (C/EBP), another deformation-sensitive transcription factor, did not significantly affect neointimal formation after four weeks (n = 3). CONCLUSIONS: These findings demonstrate the feasibility, efficacy and specificity of the anti-AP-1 dODN approach to the treatment of restenosis, which principally but not exclusively targets deformation-induced ET-1 synthesis in the vessel wall. Provided that these findings can be extrapolated to the situation of patients with coronary artery disease, the observed extent of the inhibitory effect of the AP-1 dODN treatment suggests that this co-medication may greatly reduce the incidence of in-stent restenosis.

Angioplasty, Balloon, Coronary↗

PubMed2002

Closure of an iatrogenic aortocoronary arteriovenous fistula: transcatheter balloon embolization following failed coil embolization and salvage of coils that migrated into the coronary venous system.

We report a 50-year-old patient with successful percutaneous closure of a large inadvertent surgical aortocoronary arteriovenous fistula (shunt flow: 1.8 L/min). With initial embolization of multiple coils, no lasting occlusion of the large fistula could be achieved. Above that, two coils migrated into the coronary venous system. Following rescue of the migrated coils through a retrograde coronary sinus approach, the fistula was occluded using a detachable balloon. Follow-up angiograms confirmed successful closure of the fistula. In contrast to coil embolization, use of a detachable balloon seems to be the appropriate technique for percutaneous closure of such fistulas.

Arteriovenous Fistula↗

PubMed2002

[Gene therapy in interventional coronary interventions].

BACKGROUND: 30-50% of patients develop restenosis after PTCA. While most pharmacologic strategies fail to reduce restenosis rate, only implantation of stents and brachytherapy have shown to improve long-term outcome of coronary angioplasty significantly. GENE THERAPY: With expanding knowledge of the process resulting in activation and inhibition of gene expression after angioplasty, a number of studies showed by inhibiting overexpression of some genes or overexpressing down-regulated other genes significant and extensive reduction of neointimal hyperplasia in different angioplasty models. Until now there have no results of clinical trials to reduce restenosis by gene therapy been published. COMPARISON WITH OTHER STRATEGIES TO REDUCE RESTENOSIS RATE: Gene therapy offer the opportunity to specifically inhibit activation of genes resulting in restenosis. However, until now no single gene responsible for the restenosis process could be identified. Several strategies interfering with gene expression at different levels, such as ligand-receptor binding, cell cycle regulation or induction of apoptosis have reduced restenosis in animal experimental models. This variety of successful interventions supports the concept of a redundancy in signaling pathways leading to vessel wall proliferatioin and restenosis. Restenosis rates have been reduced by stents and brachytherapy. The first results of trials with a coated stent eluting an immunosuppressant suggest a further reduction. These data raise the question whether a clinically successful and safe specific gene therapy can be developed before the problem of restenosis is largely solved by unspecific inhibition of proliferation.

Angioplasty, Balloon, Coronary↗