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M Y Flugelman

Publications and source records attributed to M Y Flugelman.

At least 19 recordsLinked to original sources
PubMed2006

Effects of fibulin-5 on attachment, adhesion, and proliferation of primary human endothelial cells.

BACKGROUND: Fibulin-5 is a novel extracellular protein that is thought to act as a bridging peptide between elastin fibers and cell surface integrins in blood vessel wall. Fibulin-5 binding to endothelial cell (EC) surface integrins may effect cell proliferation and cell attachment to extracellular matrix (ECM) or to artificial surfaces. In this paper, we describe the effects of fibulin-5 on attachment, adhesion, and proliferation of primary human EC. After demonstrating that fibulin-5 over-expression inhibited EC proliferation, we tested the hypothesis that co-expression of fibulin-5 and VEGF165 will lead to unique EC phenotype that will exhibit increased adherence properties and retain its proliferation capacity. METHODS AND RESULTS: Fibulin-5 and VEGF165 gene transfer to primary human saphenous vein endothelial cells was accomplished using retroviral vectors encoding the two genes. Transgene expression was verified using immunohistochemistry, Western blotting, and ELISA. Fibulin 5 over-expression tended to improve immediate EC attachment (30 min after seeding) and improved significantly adhesion (>40%) under shear stress tested 24h after EC seeding. The effects of fibulin-5 and VEGF165 on EC proliferation in the presence or absence of basic FGF were also tested. EC expressing fibulin-5 had reduced proliferation while VEGF165 co-expression ameliorated this effect. CONCLUSION: Fibulin-5 improved EC attachment to artificial surfaces. Dual transfer of fibulin-5 and VEGF165 resulted in EC phenotype with increased adhesion and improved proliferation. This unique EC phenotype can be useful for tissue engineering on endovascular prostheses.

Cell Adhesion↗
PubMed2001

Increased vascular endothelial growth factor 165 binding to kinase insert domain-containing receptor after infection of human endothelial cells by recombinant adenovirus encoding the Vegf(165) gene.

BACKGROUND: The angiogenic effect of vascular endothelial growth factor (VEGF(165)) is mediated mainly through the high-affinity tyrosine kinase receptor VEGF-R2 (KDR/flk-1). This study examined the effects of VEGF overexpression by primary human endothelial cells (ECs), which do not express VEGF under physiological conditions, on cell proliferation, VEGF binding to the kinase insert domain-containing receptor (KDR), and KDR expression. METHODS AND RESULTS: Human primary ECs and SMCs were infected by recombinant adenoviral vector encoding VEGF(165) (rAdVEGF). Proliferation rate, bromodeoxyuridine incorporation, (125)I-labeled VEGF(165) binding to the KDR receptor, and KDR expression were tested in the infected cells and in cells supplemented with VEGF protein. Enhanced proliferation and a significant increase in (125)I-VEGF(165) binding to the KDR receptor were induced by rAdVEGF infection of ECs (autocrine effect) as well as by addition of recombinant VEGF(165) to noninfected cells. Infection of ECs by rAdVEGF led to posttranscriptional upregulation of the KDR receptor, whereas KDR mRNA expression levels remained unchanged. Similar effects were observed with supplemented recombinant VEGF(165) to noninfected ECs; nevertheless, this phenomenon occurred only with high VEGF(165) concentrations (10 ng/mL). CONCLUSIONS: The effect of VEGF(165) on proliferation and upregulation of KDR receptor expression demonstrated an autocrine phenomenon of EC sensitization. The fact that high concentrations of VEGF may be achieved in vivo by local continuous overexpression of VEGF(165) by gene transfer emphasizes the potential advantage of gene transfer over protein supplementation for therapeutic angiogenesis.

Adenoviridae↗
PubMed2001

Perceived benefit after participating in positive or negative/neutral heart failure trials: the patients' perspective.

BACKGROUND: Clinical trials, the gold standard for the evaluation of new therapeutic strategies, may prove a drug to be beneficial, harmful or neutral according to its effect on the end-point(s) under study. AIMS: To study the reaction and perspective of the patients participating in a clinical heart failure trial, particularly in relation to whether the trial subsequently proved to be positive, negative or neutral. METHODS: Anonymous self-completed questionnaire was sent to 78 and returned by 70 consecutive patients 1--6 months after participating in six clinical heart failure trials. The trial was neutral or negative regarding the primary end-point in four (47 patients) of the six studies (MACH-1 trial of mibefradil, REACH trial of bosentan, CASCO trial of calcium sensitizer, ecadotril trial of neutral endopeptidase inhibitor) and positive in two (23 patients) (ICARUS Israel carvedilol study, exercise study of candesartan cilexetil). RESULTS: Most patients reported subjective global clinical benefit (78% for positive, 74% for negative or neutral trial, NS) after participating in a clinical trial. After adjustment for age, sex, level of education, previous research, perceived comprehension, and treatment allocation (active drug/placebo) in a stepwise regression model, perceived global improvement was greater in older patients (P=0.02), after participation in a positive trial (P=0.05) and in females (P=0.07). The major reason given by the patient for perceived clinical improvement was better follow-up, some believed it was due to change in medication, particularly those who had participated in a positive trial. CONCLUSIONS: More than 70% of patients participating in clinical trials of new drugs for heart failure reported perceived global improvement. Clinical improvement was greater in, but not limited to, patients who participated in positive trials. These salutary findings support the continued recruitment of patients to clinical heart failure trials.

Aged↗
PubMed2000

Similar late revascularization rates 10 to 12 years after angioplasty or bypass surgery for multivessel coronary artery disease: a report from the Lady Davis Carmel Medical Center (LDCMC) Registry.

We compared completed long-term outcome and late repeat revascularization rates in 272 consecutive patients with multivessel coronary disease who underwent revascularization (95 angioplasty cohort, 177 surgical cohort) between 1984 and 1986. Long-term survival was similar at 12 years in the angioplasty (70%) and surgical (74%) cohorts (p = NS), and repeat revascularization, although more frequent in the angioplasty patients during the first 5 years of follow-up, was performed equally in the 2 patient cohorts after 10 to 12 years of follow-up.

Aged↗
PubMed2000

Late-onset heart failure as a mechanism for adverse long-term outcome in diabetic patients undergoing revascularization (a 13-year report from the Lady Davis Carmel Medical Center registry).

The adverse long-term prognosis following myocardial revascularization in diabetic patients has been ascribed to accelerated coronary disease, a higher incidence of late coronary restenosis after revascularization, and myocardial dysfunction. To examine the development of heart failure and its prognostic implications in diabetic patients, we analyzed the long-term (13-year) follow-up data of 363 patients-193 percutaneous transluminal coronary angioplasties and 170 coronary artery bypass operations-revascularized in a single cardiovascular center from 1984 to 1986. Baseline characteristics (age, previous infarction, baseline ventricular function) were similar in the 80 diabetic and 283 nondiabetic patients; multivessel disease and hypertension were marginally more common in diabetics (p = NS). Cumulative incidence of hospitalization for heart failure was high in the diabetic cohort (25% vs 11%, p = 0.001), with a rapidly increasing incidence after 5 years. Survival after first hospitalization for heart failure was markedly reduced in diabetics (11 of 20 [55%] vs 25 of 31 [81%] at 3 years; p = 0.04), as was survival free of further hospitalization for heart failure (5 of 20 [25%] vs 20 of 30 [63%]; p <0.005). Long-term 13-year survival (43% vs 78%, p <0.0001) and survival free of heart failure (33% vs 71%, p <0.0001) were decreased in diabetics, especially those with reduced ventricular function at baseline (17% vs 42%, p = 0.07). Multivariate analysis showed diabetes to be the strongest independent predictor of decreased survival (odds ratio 3. 6, 95% confidence interval 2.0 to 6.2; p <0.0001) and survival free of heart failure (odds ratio 4.0, 95% confidence interval 2.2 to 7. 1; p <0.0001) in patients undergoing revascularization. In summary, late-onset heart failure was frequent in diabetic patients after percutaneous transluminal coronary angioplasty or coronary artery bypass grafting, and once present heralded an unrelenting progressive downhill clinical course.

Angioplasty, Balloon, Coronary↗
PubMed2000

Therapeutic angiogenesis for ischemic syndromes.

Disease caused by atherosclerosis are the most common causes of morbidity and mortality in western societies. The inadequacy of current therapeutic modalities is most pronounced in the significant proportion of patients with arterial obstructive disease, in whom anatomical and technical limitations rule out the possibility of angioplasty or surgery. Therefore, less invasive approaches are necessary to treat these patients. The development of collateral circulation improves blood flow to ischemic tissues and to alleviate ischemia-related symptoms. Our project concentrates on enhancement of the natural mechanism of angiogenesis by adenoviral based vector encoding vascular endothelial growth factor as an angiogenic factor. The aim of our study was to determine the efficacy of human vascular cell infection by adenoviral based vectors in vitro and in vivo. Human saphenous vein endothelial cells and smooth muscle cells were infected by adenoviral vectors encoding the lacZ and VEGF genes (rAdlacZ, rAdVEGF). VEGF expression by adenoviral vector-infected cells was detected by western analysis and its biological activity was examined by proliferation assay. The feasibility of adenoviral based gene transfer in vivo was evaluated after direct femoral artery injection of rAdlacZ in the rat. Vascular endothelial and smooth muscle cells expressed high levels of VEGF following rAdVEGF infection. The mitogenic effect of VEGF was validated by threefold increase in EC proliferation rate in comparison to the control groups. In vivo gene transfer was demonstrated using lacZ gene transfer to arterial wall cells in the superficial femoral artery. Efficient adenoviral based gene delivery was demonstrated both in vitro and in vivo. VEGF over-expression enhanced endothelial cell proliferation, which is the key step for induction of angiogenesis.

Adenoviridae↗
PubMed1999

Same-day combined coronary angioplasty and minimally invasive coronary surgery.

Integrated myocardial revascularization combines the advantages of angioplasty, stenting, and minimally invasive surgery to revascularize patients with multivessel coronary artery disease without cardiopulmonary bypass. This pilot study showed that a new same-day management strategy, consisting of percutaneous coronary intervention followed immediately by minimally invasive surgery, was feasible and provided complete all-arterial revascularization with minimal surgical trauma, short hospital stay, and excellent early therapeutic result in 14 patients with multivessel coronary disease.

Aged↗
PubMed1998

Long-term (10-year) outcome in patients with unstable angina pectoris treated by coronary balloon angioplasty.

OBJECTIVES: We sought to examine completed 10-year survival and event-free survival in patients with stable and unstable angina pectoris treated by coronary balloon angioplasty. BACKGROUND: Patients with unstable angina are at increased risk for recurrent acute coronary events. METHODS: The study included 208 consecutive patients (133 with stable and 75 with unstable angina pectoris) undergoing angioplasty from 1984 to 1986. The balloon crossed the lesion in 185 patients (121 with stable and 64 with unstable angina pectoris). Angioplasty was performed in patients with unstable angina pectoris 12+/-15 days (median 8) after symptom onset. Patients with unstable angina pectoris were classified retrospectively into Braunwald class I (n=3), class II (n=20), class III (n=28), class B (n=52) and class C (n=12). Follow-up data were obtained from hospital charts, telephone interview and official death certificates where applicable. The study had >80% power to detect a clinically significant 20% difference in survival and a 20% difference in event-free survival between the stable and unstable patient groups. RESULTS: Despite similar baseline characteristics, early (40-day) mortality was slightly higher in patients with unstable angina (4.7% [3 of 64 patients] vs. 0.8% [1 of 121 patients], p=NS). Long-term outcome was not different, because survival curves were parallel thereafter (10-year survival was 83% for those with stable and 77% for those with unstable angina, p=NS). Survival free of myocardial infarction or coronary artery bypass graft surgery at 10 years was 53% in patients with stable and 47% in patients with unstable angina (p=NS), and survival free of infarction, bypass surgery or repeat angioplasty was 32% for both groups at 10 years. In patients with Braunwald class III unstable angina, 10-year survival was 80%, as compared with 85% in other patients with unstable angina, due to the early hazard (p=NS). Survival and event-free survival were similar in patients who had had a recent myocardial infarction (Braunwald class C) and in patients with acute electrocardiographic changes. Repeat hospital admissions were not more frequent in patients with unstable angina (3.1+/-3.5 vs. 3.0+/-2.6, p=NS). CONCLUSIONS: Ten-year survival and event-free survival were similar in patients with stable and unstable angina pectoris treated by coronary balloon angioplasty, with no evidence of an increased rate of recurrent cardiovascular events in the unstable group.

Aged↗
PubMed1998

Importance of diabetes mellitus and systemic hypertension rather than completeness of revascularization in determining long-term outcome after coronary balloon angioplasty (the LDCMC registry). Lady Davis Carmel Medical Center.

The study examined the 10-year outcome in a cohort of 227 unselected, consecutive patients (age 58+/-10 years) undergoing coronary balloon angioplasty between 1984 and 1986 and followed in a single cardiac center (Lady Davis Carmel Medical Center registry). In particular, we sought to identify the relative importance of the systemic risk factors diabetes and hypertension and the extent of coronary disease as opposed to procedure-related technical variables, the immediate success of the procedure, or completeness of revascularization. By life-table analysis (99% follow-up), 94% of the patients were alive at 5 years, and 77% at 10 years after angioplasty. Ten-year survival was reduced in patients with diabetes mellitus (59% vs 83%, p = 0.0008), in patients with previous myocardial infarction (68% vs 85%, p = 0.01), in patients with ejection fraction <50% (55% vs 82%, p = 0.005), and in patients with 3-vessel disease (58% vs 84% and 86% for 1- and 2-vessel disease, respectively, p = 0.04). Diabetes mellitus was the major independent predictor of poor survival (adjusted odds ratio 3.1, 95% confidence interval 1.55 to 6.19, p = 0.001). Survival at 10 years was identical in 199 patients in whom angioplasty was complete and in 25 in whom the balloon catheter did not cross the lesion, although bypass surgery was more frequent in the latter group (45% vs 21%, p = 0.001). Incomplete revascularization did not predict poor survival (72% vs 79% with complete angioplasty, p = NS). Event-free survival at 10 years for the whole group was 29%, and 49% of patients survived with no event other than a single repeat angioplasty procedure. Multivessel disease, hypertension, and diabetes mellitus were independent predictors of decreased event-free survival, but incomplete revascularization was not. Thus, long-term outcome after coronary balloon angioplasty was related to diabetes mellitus, systemic hypertension, and extent of coronary disease, but not to the immediate success of the procedure or completeness of revascularization.

Adult↗
PubMed1997

Ventricular remodeling: from bedside to molecule.

The multiple mechanisms that bring about the decompensation of the hypertrophic remodeled myocardium are synergistic and not fully understood. Our current hypothesis is that the increased stress on the ventricle is initially offset by compensatory myocardial hypertrophy. In many instances, however, progressive ventricular dilatation and heart failure occur as a result of maladaptive hypertrophy (abnormal myosin-actin production), programmed cell death (apoptosis) and/or changes in the interstitial vasculature and collagen composition. The molecular and genetic background to these processes includes changes in myocardial gene expression, activation of the local tissue renin-angiotensin and other neurohormonal systems, increased matrix metalloproteinase activity (including collagenase), and expression of certain components of the immune system, such as TNF-alpha. Future research will hopefully provide better methods for limiting the remodeling-ventricular dilatation process by novel pharmacotherapies, gene therapy and, possibly, surgical therapy, and determine the impact of such interventions on survival.

Animals↗
PubMed1997

Angiogenesis by gene therapy: a new horizon for myocardial revascularization?

The concept of therapeutic angiogenesis is based on the premise that the potential for vascular growth inherent in vascular tissue can be utilized to promote the development of new blood vessels under the influence of the appropriate growth factors. Direct application of growth factors of the fibroblast (acidic, basic fibroblast growth factor, FGF-5), endothelial (vascular endothelial growth factor) and other series has been effective in preliminary studies. Angiogenesis by gene transfer provides an attractive alternative, with the advantage that the protein may continue to be secreted for a longer period of time and that the gene may be targeted to specific tissues to enhance efficacy and reduce systemic side effects. Angiogenesis by gene transfer is currently under investigation using a variety of growth factors and a wide array of potential delivery systems. These include application of the gene as naked DNA or by viral vector in the proximal vessel by direct intravascular injection, interventional cardiologic techniques (hydrogel coating on balloon, double balloon system, stent implantation) or by direct application to adventitia, pericardium or ischemic tissue distal to the site of arterial obstruction. As our understanding of the molecular and genetic processes underlying angiogenesis increases, and as we examine the results of preliminary animal and human protocols, we hope to develop the potential of angiogenesis by gene transfer for therapeutic use.

Animals↗
PubMed1995

Vascular gene therapy.

Gene therapy is emerging as a new and exciting therapeutic modality for cardiovascular pathology. The work reported here was carried out in the National Heart, Lung and Blood Institute (NHLBI) in Bethesda, MD, USA, where genetically engineered endothelial cells were used to seed endovascular prostheses and cell adhesion to the prostheses was tested both in vitro and in vivo. Two catheter based systems were used to deliver genes to the arterial wall cells in vivo, employing retroviral and adenoviral vectors. Efficient gene transfer to vascular cells in vivo was achieved with adenoviral vectors.

Animals↗
PubMed1995

Importance of immediate and very early postprocedural angiographic and thallium-201 single photon emission computed tomographic perfusion measurements in predicting late results after coronary intervention.

We examined prospectively the hypothesis that the adequacy of initial dilatation may be a major determinant of the late result of coronary angioplasty and that a better assessment of initial dilatation can be made from a combined angiographic and perfusion study than from angiography alone. Angiographic and perfusion (thallium-201 single-photon-emission computed tomography) measurements were made very early (18 to 24 hours) after coronary angioplasty in 59 patients (67 lesions) and also immediately (37 +/- 16 minutes) after the procedures in 19 of them (23 lesions). The early measurements, singly, in combination, and as a restenosis index (restenosis index = thallium-201 ischemic score (units) - minimal luminal area (squared millimeters) were examined as predictors of the late angiographic result. At late angiography (5.5 +/- 2.2 months after angioplasty), residual stenosis was related to the immediate and very early postangioplasty minimal luminal dimension, thallium-201 ischemic score, and restenosis index, and also to day-1 loss and lesion length. The combination of a normal result in the immediate or early thallium-201 perfusion study with a large ( > or = 2 mm) angiographic luminal dimension stratified a group of patients with better long-term results after angioplasty and a lower incidence of late restenosis (p = 0.03). The findings emphasize the importance of the initial procedure as a determinant of the late result of angioplasty.

Aged↗
PubMed1995

Inhibition of intravascular thrombosis and vascular smooth muscle cell proliferation by gene therapy.

Intravascular thrombosis, smooth muscle cell proliferation and matrix production lead to arterial luminal narrowing and reduction of blood flow to various organs. Alteration of gene expression of the arterial wall cells to inhibit thrombosis and smooth muscle activation is emerging as a new and exciting therapeutic modality for cardiovascular pathology. We have used genetically modified endothelial cells to seed endovascular prostheses and tested cell adhesion to the prostheses both in vitro and in vivo. We also used two catheter-based systems to deliver genes directly to the arterial wall cells in vivo employing retroviral and adenoviral vectors. With efficient vectors for gene transfer and high level expression of proteins by the transduced cells, gene therapy will serve as a major therapy for post-angioplasty restenosis, unstable angina pectoris and vascular grafts stenosis.

Adenoviridae↗
PubMed1994

Usefulness of late potentials on the immediate postoperative signal-averaged electrocardiogram in predicting ventricular tachyarrhythmias early after isolated coronary artery bypass grafting.

The present study was undertaken to determine the value of abnormal late ventricular potentials on signal-averaged electrocardiograms (ECG) in identifying patients at risk of developing ventricular tachycardia or ventricular fibrillation in the early postoperative period after coronary artery bypass grafting. Signal-averaged ECGs were recorded immediately after operation in 72 patients. Abnormal late potentials were defined as the presence of 2 or 3 of the following: (1) root-mean-square amplitude of the last 40 ms of the QRS < 20 microV; (2) duration of the terminal QRS potentials (after 40 microV) > or = 39 ms; and (3) high-frequency QRS duration > 120 ms (in patients with conduction defects, only the first 2 criteria were used). Abnormal late ventricular potentials were present on the immediate postoperative signal-averaged ECG in 26 of the 72 patients (36%). Life-threatening ventricular tachyarrhythmias occurred in 6 patients. Late potentials were present in all 6 patients, but only in 20 of 66 (30%) who did not develop ventricular tachyarrhythmias (p < 0.005) (sensitivity 100%, specificity 70%, predictive accuracy 72%). Of 12 pre- and perioperative variables examined by univariate and multivariate regression analysis, the presence of late potentials on the signal-averaged ECG and low cardiac output postoperatively were found to be independent predictors of life-threatening tachyarrhythmias.

Action Potentials↗
PubMed1994

Anatomic barriers influence the distribution of in vivo gene transfer into the arterial wall. Modeling with microscopic tracer particles and verification with a recombinant adenoviral vector.

We evaluated the extent to which anatomic barriers to vector penetration might influence the distribution of successful in vivo gene transfer into the normal arterial wall. A double-balloon catheter technique with infusion pressures of 100 to 400 mm Hg was used to infuse microscopic tracer particles of the size range of liposomes and viral vectors into normal elastic arteries of sheep. Localization of the tracer particles in tissue sections by light, fluorescence, and electron microscopy suggested that vector-sized particles were delivered to the intima by direct infusion and to the adventitia via the arterial vasa vasorum. Particles were virtually absent from the arterial media. To test the predictions made from the particle studies, we repeated the infusion protocol with high-titer adenoviral vectors. Gene transfer occurred at high levels in the intima and along the adventitial vasa vasorum but again was virtually absent within the media. The ability of medial smooth muscle cells to be transduced was established in separate experiments with a high-pressure (5 atm) porous balloon infusion catheter. We conclude that (1) the anatomy of the normal elastic arterial wall imposes significant limitations on the penetration of particles in the size range of most gene-transfer vectors and (2) the distribution of in vivo gene transfer with adenoviral vectors is correctly predicted by the distribution of inert tracer particles. These findings have important implications for the design of arterial gene-transfer and gene-therapy protocols.

Adenoviridae↗