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Rainer Wessely

Publications and source records attributed to Rainer Wessely.

At least 19 recordsLinked to original sources
PubMed2006

Inducible cardiac-restricted expression of enteroviral protease 2A is sufficient to induce dilated cardiomyopathy.

BACKGROUND: Enterovirus infection is a cause of cardiomyopathy. We previously demonstrated that enteroviral protease 2A directly cleaves the cytoskeletal protein dystrophin. However, the direct effect of protease 2A in enteroviral cardiomyopathy is less clear because other viral proteins are also expressed with viral infection. METHODS AND RESULTS: A transgenic mouse with inducible cardiac-restricted expression of enteroviral protease 2A was generated. In the transgenic mouse, a tamoxifen-regulated Cre-loxP system, MerCreMer (MCM), was used to induce genetic recombination in cardiac myocytes, which led to protease 2A expression. Protease 2A and MCM double transgenic (2AxMCM) mice were treated with tamoxifen; the controls included 2AxMCM mice treated with diluents for tamoxifen and tamoxifen-treated MCM littermates. Protease 2A activity was significantly induced after tamoxifen in the 2AxMCM mice compared with controls. Echocardiographic analysis demonstrated an increase in left ventricular end-diastolic and end-systolic chamber size, with decreased fractional shortening in tamoxifen-treated 2AxMCM mice. There was an increase in heart weight-to-body weight ratio in 2AxMCM mice treated with tamoxifen. Only a small increase in interstitial fibrosis and inflammation was found in tamoxifen-treated 2AxMCM mice; however, ultrastructural analysis demonstrated myofibrillar collapse with abnormalities of intercalated discs and sarcolemmal membranes. Evans blue dye-positive myocytes with disruption of dystrophin were present in 2AxMCM mice treated with tamoxifen. Disruption of dystrophin was also found in cultured myocytes isolated from 2AxMCM mice with Cre in the nucleus. CONCLUSIONS: Protease 2A has a significant role in enteroviral cardiomyopathy and alone is sufficient to induce dilated cardiomyopathy, which is associated with disruption of the sarcolemmal membrane and cleavage of dystrophin with protease 2A expression.

Animals↗
PubMed2006

Vessel size and outcome after coronary drug-eluting stent placement: results from a large cohort of patients treated with sirolimus- or paclitaxel-eluting stents.

OBJECTIVES: This study sought to investigate the influence of vessel size on the outcomes of patients after drug-eluting stent (DES) implantation. BACKGROUND: There are no dedicated studies on the influence of vessel size on the outcomes of patients treated with different DES. METHODS: The study population was composed of 2,058 consecutive patients who received sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES). Patients were grouped into tertiles according to vessel size (<2.41 mm in the lower tertile, 2.41 to 2.84 mm in the middle tertile, and >2.84 mm in the upper tertile). The primary end point was target lesion revascularization (TLR). Secondary end points were binary angiographic restenosis and the composite of death or myocardial infarction. RESULTS: Vessel size did not influence the composite end point of death and myocardial infarction. The TLR rates were higher among patients in the lower tertile (12.1%) as compared with the middle (8.4%) and upper (8.0%) tertiles (p = 0.02). In a multivariate analysis, vessel size emerged an independent predictor of TLR (p = 0.009). The model showed also a significant interaction between DES type and vessel size regarding TLR (p = 0.008). There was a significant difference in TLR rates among patients treated with SESs (8.6%) and PESs (16.4%) in the lower tertile (p = 0.002), but not in the middle and upper tertiles. CONCLUSIONS: The influence of vessel size on restenosis is related to the specific DES used, with SESs providing better outcomes than PESs in small but not in large coronary vessels.

Aged↗
PubMed2006

Sirolimus and Paclitaxel on polymer-based drug-eluting stents: similar but different.

Recent clinical studies that investigated the efficacy of the two U.S. Food and Drug Administration-approved drug-eluting stent (DES) platforms Cypher (Cordis, Johnson and Johnson, Miami Lakes, Florida) and Taxus (Boston Scientific, Boston, Massachusetts) suggest that there are differences between both DES concerning neointimal growth. Both DES elute compounds that inhibit the cell cycle, but at different stages: Cypher stents elute sirolimus, which induces G1 cell cycle inhibition, and Taxus stents release paclitaxel, which predominantly leads to M-phase arrest. In an attempt to explain the differences observed in human studies, the properties of these stent-based compounds on critical molecular and cellular events associated with the pathophysiology of in-stent restenosis are discussed in detail with the conclusion that both sirolimus and paclitaxel are different in their pleiotropic anti-restenotic effects. This may be in part responsible for the differences observed in recent clinical studies.

Apoptosis↗
PubMed2006

Randomized trial of a nonpolymer-based rapamycin-eluting stent versus a polymer-based paclitaxel-eluting stent for the reduction of late lumen loss.

BACKGROUND: Although drug-eluting stents (DESs) constitute a major achievement in preventing restenosis, concerns remain regarding the increased inflammatory and thrombogenic responses associated with the polymers used. Recently, we showed that a nonpolymer on-site coating with rapamycin not only is feasible and safe but also leads to a dose-dependent reduction in restenosis. METHODS AND RESULTS: To assess whether polymer-free stents coated on-site with 2% rapamycin solution are inferior to polymer-based paclitaxel-eluting stents for the prevention of restenosis, we randomly assigned a total of 450 patients with de novo lesions in native coronary vessels, excluding the left main trunk, to either the polymer-free, rapamycin-coated Yukon DES (rapamycin stent) or the polymer-based, paclitaxel-eluting Taxus stent (paclitaxel stent). The primary end point was in-stent late lumen loss. Secondary end points were angiographic restenosis and target lesion revascularization. The study was designed to test the noninferiority of the rapamycin stent compared with the paclitaxel stent with respect to late lumen loss according to a noninferiority margin of 0.13 mm. Follow-up angiography was completed in 81% of the patients. The mean difference in in-stent late lumen loss between the rapamycin-stent group and the paclitaxel-stent group was 0.002 mm, and the upper limit of the 1-sided 95% confidence interval was 0.10 mm (P=0.02 from test for noninferiority). No significant differences were observed regarding angiographic restenosis rates (14.2% with the rapamycin stent and 15.5% with the paclitaxel stent) and target lesion revascularization rates due to restenosis (9.3% in both groups). CONCLUSIONS: The polymer-free, rapamycin-coated stent has an antirestenotic effect that is not inferior to that observed with the polymer-based paclitaxel-eluting stent.

Aged↗
PubMed2005

Local statin therapy differentially interferes with smooth muscle and endothelial cell proliferation and reduces neointima on a drug-eluting stent platform.

OBJECTIVE: Therapeutic strategies to provide local inhibition of mitogen mediated proliferation and migration of human coronary artery smooth muscle cells (CASMC) by means of drug-eluting stents have been shown to enable effective limitation of neointimal hyperplasia. However, currently available drug-eluting stents utilize compounds that may also adversely affect endothelial regrowth, thus possibly precipitating subsequent cardiac events. Accordingly, identification of compounds that differentially inhibit smooth muscle and endothelial cell migration and proliferation could be of substantial clinical usefulness. METHODS AND RESULTS: In addition to lipid lowering, statins are known to display auxiliary pleiotropic activities. The purpose of this study was to evaluate the effect of local administration of cerivastatin on proliferation, migration and cytotoxicity of CASMC as well as coronary artery endothelial cells (CAEC) and to evaluate the effect of cerivastatin-coated stents on the inhibition of neointima formation as well as endothelial regrowth within the stented vessel. Cerivastatin displayed a differential effect on CASMC as compared to CAEC with regard to proliferation and migration; both were more profoundly inhibited in CASMC. Appreciable cytotoxicity and pro-apoptotic effects were low in both cell lines at therapeutic concentrations. Cerivastatin-elution led to significant inhibition of neointima formation in the rat carotid stent model, endothelial coverage of in-stent vascular tissue was similar with control and cerivastatin-eluting stents. CONCLUSIONS: As proof of principle, our study provides evidence that local application of a HMG-CoA reductase inhibitor on a drug-eluting stent platform can efficiently limit neointima formation. Consequently, these compounds warrant further clinical evaluation to confirm this finding. Our data further suggest that the anti-restenotic effect of local statin administration might be associated with a more protective interaction with the endothelium than that observed with compounds currently employed on drug-eluting stents.

Animals↗
PubMed2005

Paclitaxel-eluting or sirolimus-eluting stents to prevent restenosis in diabetic patients.

BACKGROUND: Drug-eluting stents are highly effective in reducing the rate of in-stent restenosis. It is not known whether there are differences in the effectiveness of currently approved drug-eluting stents in the high-risk subgroup of patients with diabetes mellitus. METHODS: We enrolled 250 patients with diabetes and coronary artery disease: 125 were randomly assigned to receive paclitaxel-eluting stents, and 125 to receive sirolimus-eluting stents. The primary end point was in-segment late luminal loss. Secondary end points were angiographic restenosis (defined as in-segment stenosis of at least 50 percent at follow-up angiography) and the need for revascularization of the target lesion during a nine-month follow-up period. The study was designed to show noninferiority of the paclitaxel stent as compared with the sirolimus stent, defined as a difference in the extent of in-segment late luminal loss of no more than 0.16 mm. RESULTS: The extent of in-segment late luminal loss was 0.24 mm (95 percent confidence interval, 0.09 to 0.39) greater in the paclitaxel-stent group than in the sirolimus-stent group (P=0.002). In-segment restenosis was identified on follow-up angiography in 16.5 percent of the patients in the paclitaxel-stent group and 6.9 percent of the patients in the sirolimus-stent group (P=0.03). Target-lesion revascularization was performed in 12.0 percent of the patients in the paclitaxel-stent group and 6.4 percent of the patients in the sirolimus-stent group (P=0.13). CONCLUSIONS: In patients with diabetes mellitus and coronary artery disease, use of the sirolimus-eluting stent is associated with a decrease in the extent of late luminal loss, as compared with use of the paclitaxel-eluting stent, suggesting a reduced risk of restenosis.

Aged↗
PubMed2005

Vascular remodeling in mice lacking the cytoplasmic domain of tissue factor.

Tissue factor (TF), the cell surface receptor for the serine protease FVIIa supports cell migration by interaction with the cytoskeleton. Intracellular signaling pathways dependent on the cytoplasmic domain of TF modify cell migration and may alter vascular remodeling. Vascular remodeling was analyzed in a femoral artery injury and a blood flow cessation model in mice with a targeted deletion of the 18 carboxy-terminal intracellular amino acids of TF (TF(Deltact/Deltact)) and compared with TF wild-type mice (TF(wt/wt)). Morphometric analysis revealed a decrease in the intima/media ratio after vascular injury in arteries from TF(Deltact/Deltact) compared with TF(wt/wt) mice (femoral artery injury: 2.4+/-0.3 TF(wt/wt) versus 0.6+/-0.3 TF(Deltact/Deltact), n=9 to 10, P=0.002; carotis ligation: 0.45+0.11 TF(wt/wt) versus 0.22+0.03 TF(Deltact/Deltact), n=12 to 14, P=0.09). This was caused by an increase in the media by 54% (P=0.04) in the femoral artery model and by 32% (P=0.03) after carotis ligation and was associated with an increased number of proliferating cells. Isolated aortic smooth muscle cells (SMCs) of TF(wt/wt) mice showed an increased migratory response toward the TF ligand active site-inhibited FVIIa that was abolished in TF(Deltact/Deltact) SMC. In contrast, the unstimulated proliferation rate was increased in TF(Deltact/Deltact) SMC compared with TF(wt/wt) SMCs. Thus, retention of SMCs attributable to a migratory defect and increased proliferation results in thickening of the media and in decrease in neointima formation after arterial injury. TF cytoplasmic domain signaling alters vascular remodeling and, thereby, may play a role in the development of restenosis, atherosclerotic disease, and neovascularization.

Animals↗
PubMed2005

Prevention of restenosis by a novel drug-eluting stent system with a dose-adjustable, polymer-free, on-site stent coating.

AIMS: Drug-eluting stents (DES) represent a major advance in interventional cardiology. Along with the success shown, current DES also present limitations related to the presence of polymer-coating, fixed drug, and dose used. With the ISAR (Individualized Drug-Eluting Stent System to Abrogate Restenosis) project, a DES system has been developed that permits individualized choice of the drug and dose to use for the given patient. The objective of this prospective dose finding study was to assess the feasibility, safety, and efficacy of a polymer-free on-site stent coating with increasing rapamycin doses. METHODS AND RESULTS: In this dose finding study, 602 patients were sequentially enrolled in four groups: microporous bare metal stent (BMS), DES stents coated with a 0.5, 1.0, and 2.0% rapamycin solution. The angiographic in-segment restenosis rate at follow-up angiography was the primary study endpoint. In-segment restenosis was significantly reduced from 25.9% with BMS to 18.9, 17.2, and 14.7% with 0.5, 1.0, and 2.0% rapamycin-eluting stents, respectively (P=0.024). Similarly, the need for target lesion revascularization at 1 year follow-up was reduced from 21.5% with BMS to 16.4, 12.6, and 8.8% with 0.5, 1.0, and 2.0% rapamycin-eluting stents, respectively (P=0.006). CONCLUSION: The placement of polymer-free stents coated on-site with rapamycin is feasible and safe. Furthermore, a dose-dependent efficacy in restenosis prevention is achievable with this new DES concept.

Aged↗
PubMed2005

Interference by interferons: Janus faces in vascular proliferative diseases.

Interferons (IFNs) display pleiotropic properties; not only do they protect cells from viral infections but they may also modulate cell growth and differentiation as well as innate and adaptive immune responses. Therapeutic applications of IFNs have proven efficacy in a variety of illnesses, including hepatitis, multiple sclerosis, and some forms of cancer. Emerging evidence has been obtained during recent years that interferons impact on molecular and cellular mechanisms implicated in the development of vascular proliferative diseases such as atherosclerosis, restenosis, and cardiac allograft vasculopathy. Further appreciation and delineation of the precise mechanisms on how interferons influence vascular proliferative disease processes could potentially facilitate the development of novel treatment options attenuating these common causes of cardiovascular morbidity and mortality.

Animals↗
PubMed2005

Targeting 2A protease by RNA interference attenuates coxsackieviral cytopathogenicity and promotes survival in highly susceptible mice.

BACKGROUND: Enteroviridae such as coxsackievirus B3 (CVB3) are important infectious agents involved in viral heart disease, hepatitis, and pancreatitis, but no specific antiviral therapy is available. METHODS AND RESULTS: The aim of the present study was to evaluate the impact of RNA interference on viral replication, cytopathogenicity, and survival. Small interfering RNA (siRNA) molecules were designed against the viral 2A region (siRNA-2A), which is considered to be highly conserved and essential for both virus maturation and host cytopathogenicity. siRNA-2A exhibited a significant protective effect on cell viability mediated by marked inhibition of CVB3 gene expression and viral replication. In highly susceptible type I interferon receptor-knockout mice, siRNA-2A led to significant reduction of viral tissue titers, attenuated tissue damage, and prolonged survival. Repeated siRNA-2A transfection was associated with a further improvement of survival. Various control siRNA molecules had no protective effect in vitro or in vivo. CONCLUSIONS: RNA interference directed against the 2A protease encoding genomic region effectively confers intracellular immunity toward CVB3-mediated cell injury and improves survival, suggesting a potential role for RNA interference for future treatment options targeting enteroviral diseases.

Animals↗
PubMed2005

Inhibition of neointima formation by a novel drug-eluting stent system that allows for dose-adjustable, multiple, and on-site stent coating.

OBJECTIVE: The risk of in-stent restenosis can be considerably reduced by stents eluting cytostatic compounds. We created a novel drug-eluting stent system that includes several new features in the rapidly evolving field of stent-based drug delivery. METHODS AND RESULTS: The aim of the present study was the preclinical evaluation of a stent-coating system permitting individual, on-site coating of stents with a unique microporous surface allowing for individualizable, dose-adjustable, and multiple coatings with identical or various compounds, designated ISAR (individualizable drug-eluting stent system to abrogate restenosis). Stents were coated with 0.75% rapamycin solution, and high-performance liquid chromatography (HPLC)-based determination of drug release profile indicated drug release for >21 days. Rapamycin-eluting microporous (REMP) stents implanted in porcine coronary arteries were safe. To determine the efficacy of REMP stents, this novel drug-eluting stent platform was compared with the standard sirolimus-eluting stent. At 30 days, in-stent neointima formation in porcine coronary arteries was similar in both groups, yielding a significant decrease of neointimal area and injury-dependent neointimal thickness compared with bare-metal stents. CONCLUSIONS: The ISAR drug-eluting stent platform as a novel concept for stent coating allows for a safe, effective, on-site stent coating process, thus justifying further clinical evaluation to decrease in-stent restenosis in humans.

Animals↗
PubMed2005

Recurrence of in-stent restenosis in cardiac allograft vasculopathy following implantation of a sirolimus-eluting stent.

Coronary lesions in patients with advanced cardiac allograft vasculopathy (CAV) are frequently treated with percutaneous coronary intervention. Despite high primary success rates, long-term outcome is significantly impaired by a high incidence of restenosis. In nontransplanted patients, the use of drug-eluting stents (DES) significantly decreases the rate of coronary in-stent restenosis. We report a case treated for cardiac allograft coronary in-stent restenosis with a sirolimus-eluting stent presenting with recurrent in-stent restenosis at follow up. However, the pattern of in-stent restenosis changed from diffuse proliferative disease in the bare-metal stent to a focal pattern in the sirolimus-eluting stent concordant with observations in nontransplanted patients. This case highlights the need for further studies addressing the effect of DES for the prevention of restenosis both in de novo as well as in-stent restenotic lesions in patients with CAV.

Angioplasty, Balloon, Coronary↗