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Biomedical subjects

Christer Sylvén

Publications and source records attributed to Christer Sylvén.

At least 19 recordsLinked to original sources
PubMed2006

Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model.

OBJECTIVE: To compare gene transfer of plasmid (P) and adenovirus (Ad) encoding human vascular endothelial growth factor-A165 (hVEGF-A165) angiogenic efficacy and adverse effects as regards apoptosis and ectopic expression of the transgene in a rat myocardial infarction model. METHODS: Myocardial infarction was provoked in Fisher rats. One week later, PhVEGF-A165, PLacZ, AdhVEGF-A165, or AdLacZ was transferred intramyocardially along the border of the myocardial infarction. hVEGF-A expression was detected with ELISA. Myocardial vessel density was analyzed 1 and 4 weeks after gene transfer. Apoptosis was detected by TUNEL staining. Cardiac function was assessed with Tissue Doppler Velocity Imaging. RESULTS: Although AdhVEGF-A165 had substantially higher myocardial hVEGF-A expression than PhVEGF-A165, AdhVEGF-A165 and PhVEGF-A165 induced angiogenic effects to a similar extent with maintained increased arteriolar density after 4 weeks of gene transfer (p < 0.05). The two treatments also improved left ventricular function similarly. Adenoviral gene transfer induced a higher number of TUNEL positive cells than plasmid (p < 0.02). Ectopic expression of the transgene was present with both vectors but substantially higher after adenoviral gene transfer. CONCLUSIONS: AdhVEGF-A165 has no obvious angiogenic advantage over PhVEGF-A165 but more side effects at least in a rat myocardial infarction model. This indicates that PhVEGF-A165 might be more applicable for therapeutic angiogenesis than AdhVEGF-A165.

Adenoviridae↗
PubMed2006

Human mesenchymal stem cells do not differentiate into cardiomyocytes in a cardiac ischemic xenomodel.

AIM: As the capability of human mesenchymal stem cells (hMSC) to engraft, differentiate and improve myocardial function cannot be studied in humans, exploration was performed in a xenomodel. METHODS: The rats were divided into three groups depending on the type of rats used (Rowett nude (RNU) or Fischer rats +/- immunosuppression). Different groups were treated with intramyocardial injection of hMSC (1-2 million) either directly or three days after ligation of the left anterior descending artery (LAD). Myocardial function was investigated by echocardiography. The hMSC were identified with fluorescence in situ hybridization and myocardial differentiation was assessed by immunohistochemistry. RESULTS: When hMSC were injected directly after LAD ligation they could be identified in half (8/16) of the RNU rats (without immunosuppression) at 4 weeks. When injected 3 days after LAD ligation in immunosuppressed RNU rats they were identified in all (6/6) rats at 6 weeks. The surviving hMSC showed signs of differentiation into fibroblasts. No cardiomyocyte differentiation was observed. There was no difference in myocardial function in treated animals compared to controls. CONCLUSIONS: The hMSC survived in this xenomodel up to 6 weeks. However, hMSC required implantation into immunoincompetent animals as well as immunosuppression to survive, indicating that these cells are otherwise rejected. Furthermore, these cells did not differentiate into cardiomyocytes nor did they improve heart function in this xenomodel.

Animals↗
PubMed2006

Paradoxical effects of aurintricarboxylic acid and RG-13577: acute thrombosis and in-stent stenosis in a passive-coated stent.

PURPOSE: To investigate if a platelet inhibitor (aurintricarboxylic acid [ATA]) and a heparin-mimicking antagonist (RG-13577) of basic fibroblast growth factor 2 (bFGF2) could be combined as a stable compound and attached to conventional bare metal stents to hinder thrombus formation and inflammatory reactions of stenting. METHODS: Fifteen domestic pigs were stented with RG-13577/ATA-coated (n=6), ATA-coated (n=12), and bare metal stents (n=12) in the left anterior descending (LAD) and left circumflex (LCX) coronary arteries. All surviving pigs were evaluated with contrast angiography and intravascular ultrasonography (IVUS) after 4 weeks. Histological analysis of the stented arteries was performed after hematoxylin-eosin staining. Tissue factor (TF) staining and scanning electron microscopy (SEM) were performed in animals with acute stent thrombosis. RESULTS: Five of the 6 animals receiving an RG-13577/ATA-coated stent experienced acute stent thrombosis, while no adverse events occurred in the animals of the other 2 groups. Follow-up angiography did not show significant in-stent stenosis in either bare or ATA-coated stents. However, histomorphometry revealed larger neointimal area (3.54+/-0.69 mm2 versus 1.82+/-0.27 mm2, p<0.05) and outward plaque area (1.56+/-0.34 mm2 versus 0.61+/-0.12 mm2, p<0.05) in ATA-coated stents. Three-dimensional IVUS analysis showed analogous results, with significantly larger neointimal volume and outward plaque volume in ATA-coated stents. There was a slight increase in TF staining around the stent struts, while SEM showed increased platelet adhesion and activity in RG-13577/ATA-coated stents versus the ATA-coated and bare metal stents. CONCLUSION: RG-13577/ATA-coated stents lead to acute stent thrombosis. The ATA coating alone did not lead to acute events, but resulted in higher neointimal hyperplasia and expansive remodeling. These results underline the importance of preclinical studies before using new coated stents in human arteries.

Animals↗
PubMed2005

Risk stratification of chest pain patients by point-of-care cardiac troponin T and myoglobin measured in the emergency department.

A prospective multicenter study including 1410 chest pain patients with suspected acute coronary syndromes was carried out to examine the predictive value of biological cardiac markers for adverse events measured by a point-of-care system. Admission cardiac troponin T (cTnT) and myoglobin were measured in parallel on a point-of-care system in the emergency department and -- together with CK-MB mass -- on lab analyzers. In a one-year follow-up, cardiac and non-cardiac death, acute myocardial infarction, unstable angina pectoris and need for revascularization were registered. Median time between onset of symptoms and admission was 285 min; 172 patients (12.2%) had no event during follow-up. If the cTnT, measured either by the point-of-care system or a conventional lab analyzer, was >0.05 microg/L, then the chance of a cardiac event during the follow-up period was doubled (18% vs. 9%). Serial cTnT measurement did not add any further value to the predictive power of the admission cTnT. Myoglobin and CK-MB mass identified increasing risk with increasing concentration quartiles; cardiac event rates were 2.8- to 4.4-fold higher between the quartiles with the lowest and those with the highest analyte concentration, respectively. There was no difference in non-cardiac death rates between any concentration quartiles. In conclusion, the prediction of clinical events by cardiac troponin T and myoglobin measured with a point-of-care analyzer in the emergency department was as good as that of the same cardiac markers and CK-MB mass measured on lab analyzers.

Aged↗
PubMed2005

Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial.

OBJECTIVES: In the Euroinject One phase II randomized double-blind trial, therapeutic angiogenesis of percutaneous intramyocardial plasmid gene transfer of vascular endothelial growth factor (phVEGF-A(165)) on myocardial perfusion, left ventricular function, and clinical symptoms was assessed. BACKGROUND: Evidence for safety and treatment efficacy have been presented in phase I therapeutic angiogenesis trials. METHODS: Eighty "no-option" patients with severe stable ischemic heart disease, Canadian Cardiovascular Society functional class 3 to 4, were assigned randomly to receive, via the NOGA-MyoStar system (Cordis Corp., Miami Lakes, Florida), either 0.5 mg of phVEGF-A(165) (n = 40) or placebo plasmid (n = 40) in the myocardial region showing stress-induced myocardial perfusion defects on (99m)Tc sestamibi/tetrofosmin single-photon emission computed tomography. RESULTS: No differences among the groups were recorded at baseline with respect to clinical, perfusion, and wall motion characteristics. After three months, myocardial stress perfusion defects did not differ significantly between the VEGF gene transfer and placebo groups (38 +/- 3% and 44 +/- 2%, respectively). Similarly, semiquantitative analysis of the change in perfusion in the treated region of interest did not differ significantly between the two groups. Compared with placebo, VEGF gene transfer improved the local wall motion disturbances, assessed both by NOGA (p = 0.04) and contrast ventriculography (p = 0.03). Canadian Cardiovascular Society functional class classification of angina pectoris improved significantly in both groups but without difference between the groups. No phVEGF-A(165)-related adverse events were observed; however, NOGA procedure-related adverse events occurred in five patients. CONCLUSIONS: The VEGF gene transfer did not significantly improve stress-induced myocardial perfusion abnormalities compared with placebo; however, improved regional wall motion, as assessed both by NOGA and by ventriculography, may indicate a favorable anti-ischemic effect. This result should encourage more studies within the field. Transient VEGF overexpression seems to be safe.

Angina Pectoris↗
PubMed2004

Angiogenic and cardiac functional effects of dual gene transfer of VEGF-A165 and PDGF-BB after myocardial infarction.

Therapeutic angiogenesis is a potential treatment modality for myocardial ischemia. phVEGF-A(165), phPDGF-BB, or a combination of the two were injected into the myocardial infarct border zone in rats 7 days after ligation of the coronary left anterior descending artery. Cardiac function was measured by echocardiography. Hearts were harvested 1 and 4 weeks after plasmid injection. phVEGF-A(165) increased capillary density more than phPDGF-BB, and phPDGF-BB preferentially stimulated arteriolar growth. The combination increased both capillaries and arterioles but did not enhance angiogenesis any more than single plasmid treatments did. VEGF-A(165) and the combination of phVEGF-A(165) and phPDGF-BB counteracted left ventricular dilatation after 1 week but did not counteract further deterioration.

Animals↗
PubMed2004

ANP and BNP but not VEGF are regionally overexpressed in ischemic human myocardium.

Angiogenic gene therapy in angina pectoris has been disappointing so far. Reasons might be that the administered genes already are overexpressed in ischemic myocardium, or that atrial and brain natriuretic peptides (ANP and BNP) are overexpressed, as they have anti-angiogenic effects. Five stable angina pectoris patients without heart failure were studied. Left ventricular biopsies were taken during coronary by-pass surgery from a region with stress-inducible ischemia and from a normal region. Both ANP and BNP but not vascular endothelial growth factor (VEGF) and VEGF-receptor 1 and 2 were overexpressed in ischemic regions compared to non-ischemic regions as measured by real-time PCR. The expression of 15 other angiogenic genes measured by oligonucleotide arrays was not consistently increased in ischemic regions. The overexpression of ANP and BNP suggests an anti-angiogenic effect in ischemic heart disease. The lack of overexpression of angiogenic genes supports the concept of therapeutic overexpression of these genes.

Aged↗
PubMed2004

High-dose adenosine infusion provokes oscillations of chest pain without correlation to opioid modulation: a double-blind controlled study.

UNLABELLED: Adenosine is a neuromodulator with both excitatory and inhibitory effects in different organs. High-dose adenosine infusion provokes chest pain in patients and healthy volunteers. This study examines the nature of chest pain and whether it is modified by the mu opioid receptor agonist (beta-endorphin) or a nonselective opioid antagonist (naloxone). Ten healthy volunteers with a mean age of 26 +/- 3 years participated in the study. The study was performed during 3 sessions. During every session the subjects were given a high dose of adenosine infusion (140 microg/kg/min) for 22 minutes. After 5 minutes, the subjects were randomized in a double-blind order on 1 of the 3 categories: (1) as placebo, NaCl bolus for 2 minutes followed by NaCl infusion for 15 minutes; (2) beta-endorphin bolus followed by infusion; and (3) naloxone bolus followed by NaCl infusion. Hemodynamic and pain parameters were monitored. During adenosine infusion, all volunteers experienced chest pain with oscillations of pain intensity. The oscillations continued during beta-endorphin and naloxone. There were no significant differences between hemodynamic and pain parameters during beta-endorphin or naloxone compared to adenosine infusion. High-dose infusion of adenosine provokes chest pain with oscillations of algesia and pain-free intervals. Peripheral opioid administration did not influence the adenosine-provoked chest pain. PERSPECTIVE: Adenosine-induced oscillations of pain and pain-free intervals could theoretically be a sign of neuronal reflex activity dependent on spatiotemporal summation of adenosine excitatory and inhibitory properties. This could contribute to the complex nature of angina pectoris. Peripheral opioid receptors might not be involved in the oscillations.

Adenosine↗
PubMed2004

Factors controlling the efficiency of Tat-mediated plasmid DNA transfer.

BACKGROUND: The polycationic nanopeptide RKKRRQRRR is a fragment of HIV-Tat protein known to be a transfection enhancer. Such factors control the transfection efficiency of plasmid DNA complexed with tat peptide. However, their actions are poorly understood. METHODS AND RESULTS: Several cell lines and primary cells were used in transfection experiments. The optimal charge ratio of plasmid to the branched 8Tat peptide was 1:8 for all cell lines and primary cells tested except primary human skin fibroblasts where it was 1:4. The conditions of complex formation (volume, DNA-peptide-solution mixing order and the nature of solution (HEPES, 0.15 M NaCl or 5% dextrose)) influenced transfection efficiency. Chloroquine increased the transgene expression 50-fold in HeLa cells but had little impact on Cos7 cells or 3T3 fibroblasts. The integrity of plasmid DNA in the presence of DNase I was shown to be dependent on the DNA/Tat ratio and the nature of the complex solvent. Complexes with -/+ charge ratio of 1:8 formulated in NaCl and dextrose provided high degree of DNA resistance towards nuclease degradation. CONCLUSIONS: The conditions of DNA-peptide complex formation and DNA/Tat ratio have significant impact on the level of transgene expression and degree of DNA protection from nuclease attack. The level of elevation of gene delivery in the presence of chloroquine varied considerably between different cells, indicating possible different mechanisms of plasmid-peptide internalisation and intracellular trafficking. The efficiency of branched 8Tat peptide as a plasmid DNA carrier varied between different cell types and have to be optimised for each application.

Animals↗
PubMed2003

Role of adenosine and opioid-receptor mechanisms for pain in patients with silent myocardial ischemia or angina pectoris: a double-blind, placebo-controlled study.

UNLABELLED: Patients with silent myocardial ischemia have similar prognosis but fewer primary care and emergency care visits than patients with angina pectoris. Silent myocardial ischemia has been associated with an increased pain threshold because of an increased endogenous opioid receptor activity. In this double-blind, placebo-controlled study, we tested whether patients with silent myocardial ischemia would have less sensitivity to the ischemic pain messenger adenosine compared with angina pectoris patients and healthy controls. In addition, we tested whether this effect might be due to an increased opioid receptor activity. MATERIALS AND METHODS: Thirteen male patients with silent myocardial ischemia (mean age 58 +/- 10 years with BMI 25 +/- 3) were compared with 10 male patients with angina pectoris (mean age 57 +/- 9 years with BMI 29 +/- 5). Healthy volunteers (mean age 52 +/- 7 years with BMI 25 +/- 3, n = 10), acted as controls. Increasing doses of adenosine were injected rapidly into an antebrachial vein in a double-blind, randomized order. Central chest pain was provoked and quantified using psychophysical methods. The procedure was repeated after an injection of 0.4 mg of the non-selective opioid antagonist, naloxone. RESULTS: Patients with silent myocardial ischemia exhibited higher pain threshold than patients with angina pectoris and healthy volunteers. After naloxone, healthy volunteers and patients with angina pectoris tended to have more pain than patients with silent myocardial ischemia. CONCLUSION: In conclusion, patients with silent myocardial ischemia had a decreased sensitivity to adenosine-provoked chest pain compared with patients with angina pectoris. The decreased pain sensitivity was not related to opioid receptor activity.

Adenosine↗
PubMed2002

Electroporation in combination with a plasmid vector containing SV40 enhancer elements results in increased and persistent gene expression in mouse muscle.

Gene transfer into muscle upon injection of plasmid DNA is feasible but occurs with low frequency. However, by using electroporation after injection of plasmid DNA into mouse muscle it has been demonstrated that gene expression can be increased more than 150-fold. In this communication, we have used this technique in combination with plasmids containing a tandem repeat of three 72-bp DNA elements from the SV40 enhancer to study gene expression. Our results show that the combination of electroporation and a plasmid vector carrying these DNA elements results in increased and more persistent gene expression of the luciferase reporter gene in BALB/c mouse muscle. At 14 days after gene delivery, the gene expression was 16-fold higher in muscles injected and electroporated with the plasmid carrying the SV40 enhancers than with control plasmid. We have also studied the effects of the vehicle in which the plasmid was delivered, and the DNase inhibitor aurintricarboxylic acid (ATA), on gene expression. By combining ATA with 150 mM sodium phosphate buffer we were able to obtain a 2-fold increase in gene expression compared to delivery of the plasmid in physiological saline. These results are of importance for the development of efficient delivery techniques for naked DNA.

Animals↗
PubMed2002

Nonsurgical direct delivery of plasmid DNA into rat heart: time course, dose response, and the influence of different promoters on gene expression.

Transfer of genes encoding therapeutic proteins into the myocardium shows great potential for treatment of coronary artery disease. To quantitatively elucidate the behavior of plasmid DNA following cardiac gene transfer, time kinetics, dose-response relationship, systemic spread to the liver, and the influence of different promoters on plasmid DNA gene expression in rat hearts were examined using a novel nonsurgical direct delivery method that enables testing of large numbers of animals. Plasmids encoding either vascular endothelial growth factor A 165 or a fusion protein between enhanced green fluorescent protein (EGFP) luciferase were injected directly in rat hearts under echocardiographic guidance. The results show that gene expression is dose related and that the duration of gene expression is transient. These findings underscore the necessity to explore other efficient vectors or alternative methods of gene delivery to achieve increased and prolonged gene expression.

Animals↗
PubMed2002

Catheter-based transendocardial myocardial gene transfer.

BACKGROUND AND AIM: Local modulation of myocardial function by gene transfer or cell depositions constitutes a potential method of cardiac treatment. This study tested the morphology of myocardial plasmid gene transfer by catheter-based transendocardial injection (NOGA). METHODS: Left ventricular morphology and electrical and mechanical characteristics were mapped in three dimensions. In two pigs, 0.10 mL of toluidine blue was injected at ten sites. In seven pigs, seven to ten injections of 0.10 mL saline containing 0.10 mg pCMV-LacZ expressing the enzyme beta-galactosidase and 0.10 mg phVEGF-A165 were given. The pigs were sacrificed after 3 days and gene expression was determined. RESULTS: Macroscopically on the endocardial surface, all identified spots were located in the target area. However, along the transmyocardial axis, injections with color and plasmid were located randomly throughout the left ventricular wall from the endocardium to the epicardium. In each detected spot, gene expression of beta-galactosidase was observed in an approximate myocardial volume of 5 x 5 x 5 mm. Microscopically, the transfected cells were located typically at the tip of the injection scar. As a rule, 10 to 20 transfected cells were located at the end of the injection scar. In sections where expression of both transcripts was observed, 42% of the cells expressed both beta-galactosidase and vascular endothelial growth factors (VEGF), 32% only beta-galactosidase, and 26% only VEGF. CONCLUSIONS: Myocardial gene transfer following magnetic guidance can be located precisely on the left ventricular inner surface. Within the myocardium, gene expression is local around the distal tip of the injection scar and is located randomly at every level of depth of the left ventricular wall.

Animals↗
PubMed2002

Angiogenic gene therapy.

Angiogenesis, which is defined as the outgrowth of nutritive vessels from locally preexisting ones, is primarily based on the outgrowth of locally present endothelial cells and implies a delicate balance where both stimulating and inhibitory factors can influence the outcome. The primary players starting the process are the vascular endothelial growth factors (VEGFs), which stimulate endothelial cell growth, although some other key factors such as fibroblast growth factors (FGFs), placental growth factors (PIGFs), platelet-derived growth factors (PDGFs) and angiopoietins must come into play for vessels to mature and not deteriorate. Two possibilities exist in terms of local delivery of the angiogenic proteins. One is the delivery of the protein in a slow-release formulation. Fibrin or alginate formulations have been implanted, sub-epicardially releasing FGF. Another approach to get a local delivery over a period of time is gene therapy by local delivery of the vector carrying the therapeutic gene or with the development of vectors that are taken up and expressed only in the organ of interest. A transient overexpression, desirable for the treatment of ischemic heart disease, can be achieved with adenoviral vectors or naked plasmid. With VEGF gene transfection, angiogenesis and reendothelialization were demonstrated in animal cardiac ischemia models showing proof of principle for cardiac therapy and paving the way for clinical trials. Currently, about 200 patients have been treated with intramyocardial VEGF gene therapy for peripheral occlusive artery disease or for myocardial ischemia. Reported adverse events have been few and no worsening of atherosclerosis following treatment has been observed.

Angiogenesis Inducing Agents↗