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Biomedical subjects

S Nikol

Publications and source records attributed to S Nikol.

At least 19 recordsLinked to original sources
PubMed2002

[Risk of thromboembolism and arteriosclerosis in women].

Young women are at a 3-fold higher risk of experiencing venous thromboembolism compared to young men. This risk is further increased by oral contraceptives, smoking, hereditary thrombophilia and/or low socioeconomic status. There are also hints for gender-specific differences in the arterial system. Coronary heart disease which is particularly important, develops in women 10-15 years later than in men. However, the clinical course in women is often more complicated. In women, thrombophilic predispositions play a more important role before menopause and metabolic risk factors after menopause compared to men. Thrombus formation needs to be initiated by disturbances of at least one element of the Virchow trias. There is principally no difference between men and women. However, all three elements are influenced by estrogen, resulting in gender-specific differences. There is a favorable influence on blood flow by the inhibition of atherogenesis and on the endothelial function by increased NO release, and the unfavorable influence on hemostasis resulting in hypercoagibility. Thus, particularly non-selective hormone replacement therapy for the inhibition of atherogenesis may be questionable due to increased thrombogenicity. The solution may be more selective estrogen receptor modulators. Clinical trials are still needed for both hormone replacement therapy and the therapy of venous and arterial thromboembolism, which have been studied in predominantly male patient cohorts so far.

Adult↗
PubMed2002

Local perivascular application of low amounts of a plasmid encoding for vascular endothelial growth factor (VEGF165) is efficient for therapeutic angiogenesis in pigs.

Clinical trials have demonstrated therapeutic benefit in inducing angiogenesis in chronic occlusive arterial disease. The route of application mostly used was the intramuscular injection of high dosages of plasmid. Therefore, a local perivascular application of low amounts of vascular endothelial growth factor (VEGF) plasmid was used in an interventional occlusion model, and the effect of VEGF on coronary and peripheral occlusions compared in the same animal model. Coronary and peripheral arteries were chronically occluded in Pietrain pigs using a non-surgical, interventional approach. Adventitial delivery of the DNA for VEGF was performed with a needle injection catheter. The DNA was applied as lipoplexes using the novel cationic liposomes DOCSPER. Optimized transfer conditions were used. Angiography, polymerase chain reaction (PCR), reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry were undertaken within a follow-up period of 6 months. Expression of the transfected VEGF gene was observed at 1 and 3 weeks following application. The DNA was detected up to 5 months following application. Around occluded coronary arteries, there was formation of new collaterals and arterial prolongation, whereas surrounding occluded peripheral arteries there was no collateralization but development of new arterial branches was seen. Results demonstrate that the response to VEGF is also sufficient, when minimal amounts of plasmid encoding for VEGF are applied locally into the perivasculature allowing for more safety of this therapy. Comparison of treatment of chronic coronary and peripheral arterial disease revealed differences in angiogenesis following VEGF application during a total follow-up period of almost 6 months which may be related to their different developmental origins. This may have important implications for developing future therapeutic strategies using VEGF in different vessels.

Animals↗
PubMed2001

Quiescence, cell viability, apoptosis and necrosis of smooth muscle cells using different growth inhibitors.

Smooth muscle cells and endothelial cells play an important role in cardiovascular diseases and may therefore be a potential target for gene therapy. Most in vitro experiments are performed using proliferating cell cultures. Nevertheless, non-dividing cells would represent more realistic in vivo conditions for gene therapy. Therefore, a simple method to achieve physiologically quiescence in cell cultures is needed for experiments. Growth to confluence is sufficient for endothelial cells to reach quiescence, in contrast to smooth muscle cells. Alternative techniques were investigated to achieve quiescence for smooth muscle cells. N-acetyl-cysteine, heparin, aphidicolin and serum-free medium are known inhibitors of smooth muscle cell proliferation and were tested for cell viability, necrosis and apoptosis. The inhibition status was evaluated counting cells in a cell counter. Toxicity, necrosis and apoptosis were determined using FACS analysis. Then, smooth muscle cells and endothelial cells were transfected with plasmid containing the beta-galactosidase gene using liposomes. Analysis of gene expression in transfected cells included a quantitative beta-galactosidase assay and X-gal staining. Growth inhibition was achieved with all agents tested. Using N-acetyl-cysteine, only slightly reduced growth rates were observed. Aphidicolin stopped cell growth almost immediately, but demonstrated enhanced toxicity. The amount of apoptotic and necrotic cells was lowest using heparin in the presence of foetal calf serum. Transfection experiments using stationary cultures of smooth muscle cells using heparin or aphidicolin demonstrated 5-10-fold lower transfection rates compared to transfected proliferating cell cultures serving as controls. Transfection experiments using stationary cultures of endothelial cells using growth inhibition through confluence demonstrated 40-fold lower transfection rates than transfected proliferating cell cultures. Transfer efficiency was much lower in endothelial cells compared to smooth muscle cells. In conclusion, quiescent cells simulate more realistically the in vivo situation and may therefore represent a better model for future in vivo experiments based on in vitro findings.

Animals↗
PubMed2001

Evaluation of endovascular techniques for creating a porcine femoral artery occlusion model.

PURPOSE: To determine the optimal endovascular approach to achieve long-term occlusion of large arteries, while preserving the integrity of periarterial tissue, in an animal model of ischemia. METHODS: Femoral artery occlusions were created in 16 pigs using detachable balloons, coils, or blinded stent-grafts. Feasibility, safety, primary and long-term success, and the degree of neovascularization were determined over a 6-month period by serial angiography and histological analyses. Four animals served as untreated controls. RESULTS: Overall primary success for all occlusion devices was 100%. The 6-month occlusion rate using detachable balloons or coils was 33% and 0%, respectively; however, all arteries occluded with blinded stent-grafts remained obstructed to the end of the study. There was no significant difference in capillary densities and collateralization of periarterial areas when occluded arteries were compared with nonoccluded controls in the same animal. No increase in collateralization was observed following endovascular arterial occlusion. CONCLUSIONS: Percutaneous insertion of blinded stent-grafts easily, safely, and reliably creates long-term arterial occlusion in pigs, which may make this a more appropriate model for studying the effects of angiogenic factors in vivo.

Anatomy, Cross-Sectional↗
PubMed2001

Preclinical and clinical experience in vascular gene therapy: advantages over conservative/standard therapy.

No systemic pharmacological treatment has been shown to convincingly reduce the incidence of restenosis after angioplasty or increase the formation of collaterals in ischemic tissue in patients. The lack of success of many pharmaceutical agents in reducing restenosis rates or in inducing angiogenesis post-angioplasty and following stent implantation has encouraged the development of new technological treatment approaches. Gene therapy is a novel strategy with the potential to prevent some of the sequelae after arterial injury, particularly cell proliferation, and to induce growth of new vessels or remodeling of pre-existing vessel branches, which may help patients with critical ischemia. Gene therapy strategies have the advantage of minimizing systemic side effects and may have a long-term effect as the encoded protein is released. Most clinical trials investigating gene therapy for vascular disease have been uncontrolled phase I and IIa trials. Gene therapy into vessels with the genes for growth factors has been demonstrated to be feasible and efficient. Local drug delivery devices have been used in combination with gene therapy in several trials to maximize safety and efficiency. Data from experimental animal work indicates that gene therapy may modify intimal hyperplasia after arterial injury, but there are few clinical trials on restenosis in patients. Preliminary clinical results show only limited success in altering restenosis rates. In vitro and experimental in vivo investigations into gene therapy for angiogenesis demonstrate increased formation of collaterals and functional improvement of limb ischemia. There is some evidence of increased collateral formation and clinical improvement in patients with critical limb ischemia. Results of placebo-controlled and double-blind trials of gene therapy for vascular disease are awaited.

Clinical Trials as Topic↗
PubMed2000

Optimization of nonviral gene transfer of vascular smooth muscle cells in vitro and in vivo.

Gene therapy strategies for the prevention of restenosis postangioplasty are promising. Nonviral gene transfer to the arterial wall in vivo has so far been limited by poor efficiency. This study aimed to optimize transfection of primary vascular smooth muscle cells using cationic nonviral formulations based on cholesterol derivates (DC-, DAC-, DCQ-, and Sp-Chol), double-chained amphiphils (LipofectAMINE, DOTMA, DOSGA, DOSPER, and DOCSPER), or heterogeneous reagents (Superfect, Effectene, and Tfx-50). Estimation of transfection efficiencies was performed using galactosidase assays at different ratios of transfection reagent to plasmid DNA with reporter gene. Toxicity was monitored by analyzing cell metabolism. Transfer efficiency and safety were determined in a porcine restenosis model for local gene therapy using morphometry, histology, galactosidase assays, and reverse-transcriptase polymerase chain reaction. The highest in vitro transfection efficiency was achieved using the recently developed DOCSPER liposomes, with transfer rates of at least 20% in vascular smooth muscle cells. Transfer efficiency was further enhanced up to 20% by complexing with poly-L-lysine. Transfection efficiency in vivo in a porcine restenosis model was up to 15% of adventitial cells using DOCSPER versus 0.1% using LipofectAMINE. Toxicity in vivo and in vitro was lowest using DOCSPER. Increased biological effects were demonstrated following optimization of transfer conditions.

Angioplasty↗
PubMed2000

Prevention of Restenosis Using the Gene for Cecropin Complexed with DOCSPER Liposomes under Optimized Conditions.

Up to 30% of patients undergoing coronary angioplasty develop a renarrowing of treated vessels following percutaneous transluminal coronary angioplasty with or without stent implantation, called restenosis. Smooth muscle cell proliferation, among other mechanisms, is an important factor in restenosis leading to neointima formation and consequent arterial lumen narrowing. Cecropins are antimicrobial peptides with antiproliferative properties in mammalian cells which have been shown to suppress neointimal formation. In this investigation, a plasmid carrying the gene for pre-pro-cecropin A, complexed with new generation liposomes optimized for transfer conditions for vascular cells was delivered to the adventitia of arteries in a porcine arterial injury model using a needle injection catheter. Retention of the plasmid in treated arteries was demonstrated for at least 21 days following delivery. Whereas previous experiments using first generation liposomes demonstrated significant but not complete neointima inhibition, the use of new liposomes under optimized conditions resulted in almost total suppression of neointimal proliferation. Thus, in vivo gene transfer of cecropins may be therapeutically applicable in restenosis prevention.

Journal Article↗
PubMed2000

[Therapeutic neoangiogenesis of peripheral arteries].

The identification of angiogenic growth factors was the basis for the development of novel strategies for the treatment of occlusive vascular diseases. Therapeutic angiogenesis resulting in capillary sprouting (angiogenesis) and collateral vessel development (arteriogenesis) may be a potential alternative for patients suffering from critical limb ischemia. Extensive investigations performed in vitro and in vivo demonstrated therapeutic efficacy through the enhancement of collateral growth resulting in augmented blood flow in ischemic tissues following administration of both, recombinant growth factors and genes encoding for such factors. Advantages of gene therapy strategies over the use of proteins include minimal systemic adverse effects and a slow and continuous release of the encoded angiogenic factor which may lead to a long-lasting therapeutic effect. Several uncontrolled phase-I and -IIa trials demonstrated the feasibility and safety of the use of angiogenic growth factors. However, the results of placebo-controlled and double-blind trials are needed to prove their therapeutic potential.

Angiogenesis Inducing Agents↗
PubMed1999

Neointimal growth can be influenced by local adventitial gene manipulation via a needle injection catheter.

Revascularization by percutaneous transluminal coronary angioplasty is limited in the long-term by restenosis, which is luminal renarrowing in the first 6 months after the procedure. Smooth muscle cell proliferation is thought to be an important factor in restenosis; this leads to neointima formation and arterial lumen narrowing. Local therapy delivered perivascularly may have an effect on events in the neointima and reduce restenosis. The effect of delivering expression vector plasmids for senescent cell-derived inhibitor SDI-1, which regulates cell proliferation, and its antisense, into the perivascular tissue of injured arteries was investigated in a porcine arterial injury model using a needle injection catheter. Transfection efficiency, biological effect and plasmid dissemination were evaluated in arterial and organ tissue sections between 2 days and 4 months. A limited number of adventitial, medial and neointimal cells were transfected up to 4 months. sdi gene transfer did not result in a change in neointima. Transfer of antisense sdi resulted in an increase in neointima after 3 weeks. No DNA plasmid was detected in control tissues. Liposomally-mediated adventitial local gene delivery is feasible and safe using the needle injection catheter in a porcine model. A limited number of cells was transfected, with expression of transfected genes up to 4 months after delivery. A transient biological effect with increased neointima was observed after delivery of the antisense sdi gene.

Analysis of Variance↗
PubMed1999

Needle injection catheter delivery of the gene for an antibacterial agent inhibits neointimal formation.

Percutaneous transluminal coronary angioplasty is a routinely used non-surgical revascularization technique for patients with coronary artery disease. Up to 30% of patients undergoing coronary angioplasty develop a renarrowing of treated vessels, called restenosis. Smooth muscle cell proliferation is thought to be an important factor in restenosis; this leads to neointima formation and arterial lumen narrowing. Neointima may be reduced by the transfer of genes encoding proteins with antiproliferative effects. Cecropins are antimicrobial peptides with antiproliferative properties in mammalian cells. Cecropin A is one member of this family of peptides. In this article, a plasmid carrying the gene for the immature form, pre-pro-cecropin A, complexed with liposomes was locally delivered to perivascular tissue in a porcine arterial injury model using a needle injection catheter. Retention of the plasmid in the treated arteries was demonstrated at both 8 and 21 days following application. Transferred plasmid DNA was not detected in any other tissues analyzed. Pre-pro-cecropin A-specific transcripts could also be found in treated arteries. Balloon-injured vessels demonstrated significantly reduced neointima at 21 days in vessels treated with the pre-pro-cecropin A gene compared with neointimal area in those given a control gene (P < 0.05). The needle injection catheter appears to be useful for local intravascular gene delivery. In vivo gene transfer of cecropins may be of therapeutic relevance in restenosis prevention by limiting cell proliferation.

Angioplasty, Balloon, Coronary↗
PubMed1998

Restenosis in human vein bypass grafts.

The restenosis rate in vein bypass grafts is higher than in native coronary arteries, and both the cascade of regulatory factors and the vessel reaction may be altered. In this study, vein bypass atherectomy specimens were classified as primary (n = 10) or restenotic (n = 12). Immunohistochemistry with 11 primary antibodies showed low levels of proliferation in both tissues and similar amounts of extracellular matrix components in both primary and restenotic specimens at the time points at which tissue was removed for clinical reasons. Inflammation appeared increased in restenotic specimens. Using in situ hybridization, transforming growth factor-beta1 messenger RNA was detected in both primary and restenotic tissue, with a trend to higher expression in restenosis (8.4 +/- 5.3 vs. 9.4 +/- 7.4 grains/nucleus) and further increased expression in multiple compared with single restenoses (15.1 +/- 6.1 vs. 5.6 +/- 5.1 grains/nucleus, P < 0.05). Hence, there were no great differences in cell proliferation or extracellular matrix formation between primary and restenosis vein graft tissue, in contrast to previously described findings in arterial tissue. This suggests that primary vein graft tissue is already in a chronic 'restenosis-like' state and subsequent injury creates minimal additional upregulation.

Antigens, CD↗
PubMed1998

Conservative treatment of a paracardial abscess following post-infarct patch grafting.

A patient with previous patch grafts at the site of a ventricular aneurysm and over an ischaemic septal defect presented with an oval hypodense mediastinal mass consistent with a mediastinal abscess with blood cultures positive for Staphylococcus aureus. Surgical re-operation in this region was considered to be too risky and conservative treatment was pursued. Antibiotics were continued for a total of nearly 5 months of treatment. A computed tomographic scan prior to discharge indicated that the abscess was completely resolved.

Abscess↗
PubMed1998

Use of nuclear magnetic resonance imaging angiography to follow-up arterial remodeling in an animal model.

Appropriately sized arteries in small animals may be possible models for studying the remodeling process as occurs after arterial balloon injury in humans. Magnetic resonance imaging (MRI) is able to noninvasively image tissue in vivo. To date, small animal angiography models have mostly used research-dedicated instruments and resolution, which are not universally available. Experiments were carried out on a rat aorta model of remodeling in vivo (n=40). Arteries were injured by oversized balloon dilation; control arteries were uninjured. Angiography imaging was performed immediately before sacrifice with an unmodified clinical MRI unit, a 1.5 Tesla MR tomograph with a 20-cm-diameter coil. Longitudinal MRI pictures of the aorta and morphometry of tissue sections to measure luminal and arterial wall areas were analyzed with use of computer-assisted techniques. Comparison of dimensions demonstrated correlation between MRI and histology measurements of the lumen. MRI and morphometry showed a gradual increase in mean luminal area over 6 weeks following injury. The lumen increase correlated with total arterial area and thickness. In this rat aorta model, remodeling documented at histology was followed-up in vivo. The use of such clinical MRI scanners has potential to reduce animal numbers needed to follow-up the remodeling process after therapeutic intervention.

Angioplasty, Balloon↗
PubMed1998

Gene Therapy for Restenosis: Progress or Frustration?

No systemic pharmacological treatment has been shown to convincingly reduce the incidence of restenosis after angioplasty in patients. The lack of success of many pharmaceutical agents in reducing restenosis rates post-angioplasty and following stent-implementation shown in dozens of clinical trials has encouraged the development of new technological approaches as treatment. Gene therapy has the potential to prevent some of the sequelae after arterial injury, particularly cell proliferation. Mechanical methods of preventing restenosis, such as sophisticated local drug delivery strategies and biodegradable stents using new materials in combination with gene therapy, may be of use to maximize safety and efficiency.

Journal Article↗
PubMed1997

Differential expression of nonmuscle myosin II isoforms in human atherosclerotic plaque.

Intimal proliferation and functional changes involving vascular smooth muscle cells are key events in the development of atherosclerosis, including restenosis after percutaneous transluminal angioplasty. Nonmuscle myosin (NMM) is required for cytokinesis and has been shown in cultures of vascular smooth muscle cells to undergo changes of isoform expression depending on the stage of proliferation and differentiation. The purpose of this study was to examine the differential expression of the two most recently identified nonmuscle myosin heavy chain isoform II (NMMHC-II) isoforms A and B in atherosclerotic plaque. Primary atherosclerotic and restenotic atherectomy specimens and non-atherosclerotic controls, were analyzed by Western Blot analysis, immunohistochemistry and in situ hybridization. Nonmuscle myosin heavy chain isoform IIA (NMMHC-IIA) was equally expressed in all types of tissue specimens both at the protein and mRNA levels. In contrast, NMMHC-IIB protein was found in restenotic specimens and normal artery but was at very low levels in primary atherosclerotic plaque. By in situ hybridization NMMHC-IIB mRNA levels were significantly greater in restenotic versus primary atherosclerotic lesions. NMMHC-IIB expression is associated with vascular restenosis but is downregulated in stable atherosclerotic lesions, whereas NMMHC-IIA is expressed in both. These results indicate that these new myosin isoforms have different functions and should be regarded separately with respect to smooth muscle proliferation and restenosis. They should prove to be useful molecular markers for the study of atherosclerosis and restenosis.

Aged↗
PubMed1997

Novel uses and potential for calcium antagonists in revascularization.

Calcium antagonists affect the arterial wall and blood components in many ways: these include their classical vasomotor functions, as well as newly-documented effects on platelet aggregation, rheology, the platelet membrane receptor glycoprotein IIb/IIIa complex and on tissue factor, a glycoprotein that initiates the clotting cascade. Calcium antagonists slow atherogenesis in animals, perhaps through inhibiting calcium incorporation, lowering heart rate or reducing thrombus formation, although no benefits were shown in prospective clinical studies of stenosis progression. However, it has been possible to attenuate proliferation in in vitro and in vivo experimental models. These discoveries are leading to novel calcium antagonist applications in revascularization. They have the potential to act synergistically in thrombolysis, but so far there has been very little evaluation of this. During coronary intervention, the myocardial protective action of calcium antagonists could be of benefit against stunning and in the no-reflow phenomenon. Their action on vasomotor tone and thrombus formation might affect acute closure or restenosis, although clinical studies have not yet shown this, perhaps because systemic administration of calcium antagonists does not achieve a high enough local concentration. Local drug delivery into the arterial wall may have potential. Calcium antagonists could be of use in cardiac surgery by preventing spasm or providing myocardial protection.

Animals↗