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S E Epstein

Publications and source records attributed to S E Epstein.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris.

We sought to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of basic fibroblast growth factor (bFGF), administered as a single intracoronary injection, to subjects with stable angina pectoris secondary to coronary artery disease. bFGF, an angiogenic growth factor, has been shown to enhance collateral development in animal models of progressive coronary occlusion. To our knowledge, this study represents the initial introduction of parenteral bFGF into humans. This was a phase 1, randomized, dose-escalation trial of bFGF in 25 subjects with coronary artery disease and stable angina. Subjects were randomized 2:1 to a single dose of bFGF or placebo, injected into the left main coronary artery. bFGF doses ranged from 3 to 100 microg/kg, increasing in half-log increments. bFGF was generally well tolerated at doses of 3 to 30 microg/kg. Plasma clearance was 20 +/- 2 ml/kg/min, with an elimination half-life of 85 +/- 11 minutes. bFGF caused acute hypotension ( approximately 10%) that did not appear to be dose-related through the dose range studied. Of the 9 subjects who received 30 to 100 microg/kg bFGF, 2 had sustained hypotension, mild to moderate in severity, lasting 1 to 3 days, and 3 subjects developed bradycardia hours to days after bFGF administration. bFGF dilated epicardial coronary arteries (7.4 +/- 2.5% mean diameter increase, p <0.02). Transient mild thrombocytopenia and proteinuria were observed in some subjects in the 30-microg/kg cohort. No subject had signs suggesting systemic angiogenesis. Thus, intracoronary bFGF, at doses of 3 to 30 microg/kg, was generally well tolerated in subjects with stable angina.

Angina Pectoris↗
PubMed2000

Electromagnetic guidance for catheter-based transendocardial injection: a platform for intramyocardial angiogenesis therapy. Results in normal and ischemic porcine models.

OBJECTIVES: To test the feasibility of myocardial angiogenic gene expression using a novel catheter-based transendocardial injection system. BACKGROUND: Angiogenesis has been induced by direct injection of growth factors into ischemic myocardium during open-heart surgery. Catheter-based transendocardial injection of angiogenic factors may provide equivalent benefit without need of surgery. METHODS: A new guidance system for intramyocardial therapy utilizes magnetic fields and catheter-tip sensors to locate a position in space and reconstruct three-dimensional left ventricular (LV) electromechanical maps without using fluoroscopy. A retractable 27G needle was coupled with the guidance system for LV transendocardial injection. In 12 pigs, the catheter was used to inject 0.1 ml of methylene-blue (MB) dye and 8 pigs had myocardial injections of adenoviral vector (1 x 10(10) particles per site) containing the LacZ transgene. Ten pigs underwent catheter-based transendocardial injection and six pigs were injected using transepicardial approach with the gene encoding adenovirus vascular endothelial growth factor-121 (Ad.VEGF121; 1 x 10(10) viral particles x 6 sites) and sacrificed at 24 h. Injection sites were identified with ultraviolet light by coinjection of fluorescent beads. RESULTS: Overall, 138 of 152 attempted injection MB tracks (91%) were found after sacrifice. Tissue staining was 7.1+/-2.1 mm in depth and 2.3+/-1.8 mm in width. No animal had pericardial effusion or tamponade. In Ad.LacZ injected animals, gross pathology showed positive staining in injected zones, and histology confirmed positive myocyte staining. Adenovirus vascular endothelial growth factor-121 injected sites showed high levels of VEGF121 production that was of similar magnitude whether injected using the transendocardial (880.4+/-412.2 pg VEGF121/mg protein) or transepicardial (838.3+/-270 pg VEGF121/mg protein) delivery approach (p = 0.62). CONCLUSIONS: Using this magnetic guidance catheter-based navigational system, transgenes can effectively be transfected into designated myocardial sites. Thus, if it is determined that direct intramyocardial injection of angiogenic factors enhances collateral function in patients, this less invasive catheter-based system offers a similar gene delivery efficiency and, thus, may have clear advantages compared with the surgically-based transepicardial injection approach.

Animals↗
PubMed2000

Delivery strategies to achieve therapeutic myocardial angiogenesis.

The use of recombinant genes or growth factors to enhance myocardial collateral blood vessel function may represent a new approach to the treatment of cardiovascular disease. Proof of concept has been demonstrated in animal models of myocardial ischemia, and clinical trials are underway. Currently, it is unknown which is the safest and most effective delivery strategy to induce clinically important therapeutic angiogenic responses in ischemic myocardium. Most strategies for transcatheter delivery of angiogenic factors have used an intracoronary route, which may have limitations because of imprecise localization of genes or proteins and systemic delivery to noncardiac tissue. The effect of direct intraoperative intramyocardial injection of angiogenic factors on collateral function has been reported in experimental models, and angiogenesis is being studied after direct intramyocardial injection of angiogenic peptides or plasmid vectors during open heart surgery in patients. Catheter-based transendocardial injection of angiogenic factors may provide equivalent benefit without the need for surgery. Intrapericardial delivery of angiogenic factors may offer a theoretical advantage of prolonged exposure of either coronary or myocardial tissue to the administered drug as result of a reservoir function of the pericardium. In this article, we review the different modes of administration for therapeutic myocardial angiogenesis therapy.

Animals↗
PubMed2000

Effects of total pathogen burden on coronary artery disease risk and C-reactive protein levels.

Infection and inflammation have been suggested to play roles in coronary artery disease (CAD). We hypothesized that: (1) CAD risk is associated with the aggregate number of pathogens (pathogen burden), and (2) increased pathogen burden is associated with elevated levels of C-reactive protein (CRP), a marker of inflammation. We evaluated 233 patients for CAD. Blood samples from each patient were tested for immunoglobulin-G (IgG) antibodies to cytomegalovirus (CMV), Chlamydia pneumoniae, hepatitis A virus (HAV), herpes simplex virus type 1 (HSV-1) and HSV type 2 (HSV-2), and for the CRP levels. Of the 233 study subjects, 68% had evidence of CAD by coronary angiography. Although the prevalence of seropositivity for each pathogen tended to be higher in the patients with CAD than those without, only the association between CAD and seropositivity to HAV was significant in multivariate analysis. Over 75% of study subjects had been exposed to > or =3 of the 5 pathogens tested, and analysis determined that increasing pathogen burden was significantly associated with increasing CAD risk, even after adjustment for traditional CAD risk factors. The prevalence of CAD was 48%, 69%, and 85% in individuals with antibodies to < or =2 pathogens, to 3 or 4 pathogens, and to 5 pathogens, respectively. A similar association between increasing pathogen burden and CRP levels was also found. The pathogen burden remained a significant predictor of CRP levels after multivariate analysis. Our data suggest that infection does play a role in the genesis of atherosclerosis. However, the risk posed by infection is related to the pathogen burden that may contribute to CAD through inflammatory responses.

Adult↗
PubMed2000

Chronic non-vascular cytomegalovirus infection: effects on the neointimal response to experimental vascular injury.

OBJECTIVE: Epidemiologic and mechanistic evidence implicates a role for cytomegalovirus (CMV) in atherogenesis. Recently, we demonstrated that CMV has the capacity to causally contribute to atherogenesis; acute infection of rats with rat CMV (RCMV) 1 day after carotid artery injury increased neointimal accumulation. Importantly, in the injured vessel infectious virus could not be detected and viral genome was present only transiently, suggesting that additional mechanisms play a role in the virus-induced exacerbation of the vascular injury response other than the changes caused by direct infection of vessel wall cells. The present investigation was designed to determine whether chronic persistent RCMV infection, more relevant to the clinical situation, also exacerbates the response to injury and, if so, whether similar mechanisms are operative. METHODS: Sixty 3-week-old male Spraque-Dawley rats received an i.p. injection of either 10(6) TCID50 RCMV (Priscott strain) or normal saline. The left carotid artery was balloon-injured 3 months after infection. Rats were killed 6 weeks later. This model produces persistent infection, as demonstrated by presence of infectious virus in the salivary glands at time of sacrifice. RESULTS: The neointima to media (N/M) ratio of the injured vessel was 41% greater in the RCMV-infected than in control rats (1.40 +/- 0.48 vs. 0.99 +/- 0.45; P = 0.003). The aorta never contained infectious RCMV, and exhibited RCMV DNA, detected by PCR, only transiently. The persistent infection of non-vascular tissues was associated with increased serum levels of IL-2, IL-4 and IFN-gamma. CONCLUSIONS: CMV infection of young rats causes persistent infection of non-vascular tissues and increased cytokine levels. The neointimal response to subsequent vascular injury is increased, despite absence of virus from the vessel wall. These findings, as in acute infection following vascular injury, suggest that inflammatory and immune responses to chronic persistent CMV infection contribute to an exaggerated response to vascular injury.

Animals↗
PubMed2000

Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial.

OBJECTIVES: This phase I study was designed to evaluate the safety, tolerability and pharmacokinetics of intra-arterial basic fibroblast growth factor (bFGF) in patients with atherosclerotic peripheral arterial disease (PVD) and intermittent claudication. We also assessed the effects of basic fibroblast growth factor (bFGF) on calf blood flow as a measure of biologic activity. BACKGROUND: Preclinical studies have shown that bFGF, an angiogenic peptide, promotes collateral development in animal models of myocardial and hind limb ischemia. The safety and efficacy of bFGF in patients is unknown, and early clinical trials are underway in coronary and peripheral arterial disease. METHODS: A double-blind, placebo-controlled, dose-escalation trial was conducted in patients with claudication demonstrating ankle/brachial index <0.8. Patients were randomly assigned to placebo (n = 6), 10 microg/kg of bFGF (n = 4), 30 microg/kg of bFGF once (n = 5) and 30 microg/kg of bFGF on two consecutive days (n = 4). Study drug was infused into the femoral artery of the ischemic leg. Detailed safety information including retinal photography for neovascularization were obtained through one year. Calf blood flow was measured with strain gauge plethysmography in the two higher dose treatment groups and in four placebo patients at baseline, one month and three to seven months after treatment. RESULTS: Intra-arterial bFGF was safe and well-tolerated. The half-life was 46 +/- 21 min. Calf blood flow increased at one month by 66 +/- 26% (mean +/- SEM) and at six months by 153 +/- 51% in bFGF-treated patients (n = 9, p = 0.002). Flow did not change significantly in the placebo group. CONCLUSIONS: In this initial randomized, double-blind, placebo-controlled trial in patients with atherosclerotic PVD and claudication, bFGF was well-tolerated. The data suggest a salutary biologic effect, and initiation of phase 2 trials is warranted.

Aged↗
PubMed2000

Intracoronary basic fibroblast growth factor enhances myocardial collateral perfusion in dogs.

OBJECTIVE: In preparation for clinical trials of basic fibroblast growth factor (bFGF) to treat ischemic heart disease, we sought to identify a clinically feasible method of bFGF administration. BACKGROUND: Basic FGF has been shown to promote collateral development after experimentally induced coronary occlusion; however, methods of bFGF delivery that have been shown to be effective in previous investigations would not be practical for clinical use. METHODS: Four randomized, blinded, controlled investigations were conducted independently and sequentially in an established canine model. For all studies, dogs underwent operative placement of proximal left circumflex coronary artery ameroid constrictors. The four investigational regimens included: 1) bFGF by central venous bolus injection, 1,740 microg/day for one, two or seven days; 2) bFGF by intravenous infusion, 100 microg/kg body weight per day for seven days; 3) bFGF by pericardial instillation, 2,000 microg/day for 7 days; and 4) bFGF by intracoronary injection (Judkin's technique), 100 microg/kg per day for one or two days. Each substudy included a contemporaneous vehicle control group. Collateral perfusion (microspheres) was assessed during maximal coronary vasodilation during the first month after ameroid placement. RESULTS: Maximal collateral perfusion in dogs that received intracoronary bFGF for two days exceeded that of concurrent control dogs by 31% (p < 0.01). Perfusion was not increased in dogs that received single-dose intracoronary bFGF. Basic FGF administration by central venous bolus injection, intravenous infusion and pericardial injection failed to enhance collateral perfusion. CONCLUSIONS: Administration of bFGF by the intracoronary route, an intervention that is feasible in patients, augments collateral development in dogs. These data provide a rationale for clinical testing of intracoronary bFGF in ischemic heart disease.

Animals↗
PubMed2000

Chlamydia pneumoniae-induced transactivation of the major immediate early promoter of cytomegalovirus: potential synergy of infectious agents in the pathogenesis of atherosclerosis.

Both cytomegalovirus (CMV) and Chlamydia pneumoniae have been associated with atherosclerosis. CMV is believed to exist in host tissues in a latent state with periodic reactivation. This study was designed to determine whether C. pneumoniae infection stimulates the expression of CMV genes. Transactivation of the CMV major immediate early promoter (MIEP) is essential for viral gene expression and viral replication. HeLa cells were transfected with a construct containing a reporter gene (chloramphenicol acetyl transferase) controlled by the MIEP. The cells were then infected with Chlamydia at 102-106 infection-forming units (IFU) per well at various times before assay of MIEP activity (72 h after transfection). Peak transactivation occurred 6 h after infection at 104 IFU. C. pneumoniae increased MIEP activity in a dose-response manner; maximal increase was >2-fold. These results suggest that if CMV and C. pneumoniae do indeed contribute to atherosclerosis, their copresence may synergistically contribute to it.

Antigens, Viral↗
PubMed2000

Catheter-based plasmid-mediated transfer of genes into ischemic myocardium using the pCOR plasmid.

BACKGROUND: Direct transfer of genes holds promise for the sustained delivery of therapeutic proteins to treat cardiovascular diseases. This can be accomplished by several approaches, including use of adenoviral vectors and naked plasmid DNA vectors. We previously demonstrated achieval of effective delivery of genes into the myocardium with a left ventricular-guided catheter-based approach using an adenoviral vector. OBJECTIVE: To evaluate the levels and duration of expression of genes induced after injection of a specific plasmid vector, using the same delivery platform as that in our previous work. METHODS: The pCOR plasmids are narrow-host-range plasmid vectors designed for nonviral gene therapy. We tested the ability of the pCOR plasmid vector to express its transgene after injection into the myocardium of pigs with chronic experimental ischemia using a catheter-based transendocardial delivery system. Four animals were subjected to transendocardial injections of the luciferase reporter pCOR gene into ischemic and nonischemic zones using the Biosense intramyocardial injection catheter. Injections (1 mg per animal, 50 micrograms per injection site) were performed at 20 sites in ischemic and nonischemic zones. Measurements of luciferase activity were performed 3 and 7 days thereafter. RESULTS: We observed high levels of expression of luciferase gene in ischemic and nonischemic regions (on days 3 and 7, respectively, in ischemic zone 58,237 and 33,709 pg; in nonischemic zone 39,928 and 46,036 pg). Control noninjected samples from the left and right ventricles contained no detectable luciferase activity. CONCLUSIONS: With a catheter-based approach, the pCOR plasmid was successfully used to deliver genes into designated myocardial regions, and provides sustained expression of protein for at least 7 days, of roughly similar magnitudes in ischemic and nonischemic myocardium.

Animals↗
PubMed2000

Infection and atherosclerosis: potential roles of pathogen burden and molecular mimicry.

Infection has been implicated as a cause of atherosclerosis since the first half of the 19th century. Over the years, sporadic publications have appeared in the literature reflecting a persistent but relatively low level of research activity in this area. In the last decade, however, publications relating to this topic have increased markedly. And very recently, new epidemiological and mechanistic data relating infection to several different diseases, including atherosclerosis, have appeared, stimulating the emergence of important paradigm shifts in how we think about the causes of chronic disease. The following article reviews some of these newer concepts as they relate to a possible role of infection in atherosclerosis.

Arteriosclerosis↗
PubMed1999

Cytomegalovirus in the pathogenesis of atherosclerosis: the role of inflammation as reflected by elevated C-reactive protein levels.

OBJECTIVES: We hypothesized that cytomegalovirus (CMV) infection: 1) stimulates an inflammatory response, reflected by elevated C-reactive protein (CRP) levels, and 2) predisposes to coronary artery disease (CAD), in part, through CMV-induced inflammation. BACKGROUND: Although some studies show an association between CMV and atherosclerosis, others do not. We believed that CMV exerted an atherogenic effect by inducing inflammation, and the disparate results may derive partly from individual variability in the capacity to control CMV inflammatory activity. METHODS: Blood samples were tested for CMV seropositivity and CRP levels from 238 individuals being evaluated for CAD by coronary angiography. RESULTS: An elevated CRP level (>0.5 mg/dl) was a significant CAD determinant even after adjustment for traditional CAD risk factors (odds ratio [OR] = 2.4; p = 0.02). Moreover, CMV seropositivity was significantly associated with increased CRP levels (p = 0.04 after adjustment for CAD risk factors), suggesting that CMV could evoke a subclinical inflammatory response. However, considerable host variation existed in this response to CMV. When adjusted for CAD risk factors, the OR for CAD were 1.3 in the subgroup with CMV seropositivity alone (p = 0.7), 2.3 in the subgroup with elevated CRP levels alone (p = 0.2), and 4.3 in the subgroup with combined CMV seropositivity and elevated CRP levels (p = 0.01). CONCLUSIONS: Our results suggest that 1) CMV elicits a subclinical inflammatory response, but only in certain individuals, and 2) individuals with an inflammatory response appear susceptible to the atherogenic effects of CMV, whereas those without appear resistant. These results may partly explain the disparate results of studies attempting to relate CMV to atherogenesis.

Adult↗
PubMed1999

Cytomegalovirus infection of rats increases the neointimal response to vascular injury without consistent evidence of direct infection of the vascular wall.

BACKGROUND: Previous studies suggest that infection may play a role in restenosis and atherogenesis; cytomegalovirus (CMV) is one of the implicated pathogens. To determine a potential causal role of CMV in these disease processes, we assessed whether CMV infection increases the neointimal response to injury of the rat carotid artery. METHODS AND RESULTS: Carotid injury was performed on 60 rats; immediately thereafter, 30 rats were infected with rat CMV, and the other 30 were mock-infected. Six weeks later, rats were euthanized, and the salivary glands, spleen, and carotid arteries were harvested. CMV infection was associated with significant exacerbation of the neointimal response to injury (neointimal to medial ratio 0.81+/-0. 59 versus 0.31+/-0.38 in CMV-infected versus control rats; P<0.0001). This occurred despite absence of infectious virus from vascular tissues and detection of CMV DNA by polymerase chain reaction in the injured artery only at day 3 after infection. Persistent distant infection, associated with systemic cytokine response, was evidenced by isolation of infectious virus from homogenates of both salivary glands and spleen and by higher serum levels of interleukin (IL)-2 and IL-4 (but not interferon-gamma and tumor necrosis factor-alpha) in infected versus noninfected rats. CONCLUSIONS: CMV infection of immunocompetent adult rats increases the neointimal response to vascular injury, suggesting that CMV may play a causal role in atherosclerosis/restenosis. Importantly, this CMV-induced response occurs even without the presence of virus in the vascular wall, suggesting that inflammatory and immune responses to infection of nonvascular tissues may contribute to the vascular response to injury.

Animals↗
PubMed1999

Lack of association of restenosis following coronary angioplasty with elevated C-reactive protein levels or seropositivity to Chlamydia pneumoniae.

Seventy-five consecutive patients undergoing directional coronary atherectomy were evaluated by measuring anti-Chlamydia immunoglobulin G and anticytomegalovirus immunoglobulin G antibodies, and serum levels of C-reactive proteins (before atherectomy). The results showed that although both Chlamydia infection and elevated C-reactive protein levels are associated with coronary artery disease and coronary artery disease events, neither of these appears to play a role in the development of restenosis.

Adult↗
PubMed1999

Infection and atherosclerosis: emerging mechanistic paradigms.

Although definitive proof of a causal role of infection contributing to atherogenesis is lacking, multiple investigations have demonstrated that infectious agents evoke cellular and molecular changes supportive of such a role. Moreover, both Chlamydia pneumoniae and cytomegalovirus exacerbate lesion development in animal models of atherosclerosis and restenosis. The fact that multiple pathogens have been associated with atherosclerosis implies that many "atherogenic" pathogens exist, and recent data suggest that the risk of atherosclerosis conveyed by infection relates to the number of atherogenic pathogens with which an individual is infected. It also is evident that variability in host susceptibility to the atherogenic effects of pathogens exists; this variability appears to be related at least in part to whether the host can generate an immune response that successfully controls pathogen inflammatory activity and in part to the specific pattern of immune response--humoral or cellular. The latter may relate to host capacity to control pathogen activity and to a pathogen-induced autoimmune component of the atherogenic process. Additional animal and human studies are necessary to further test the validity of the infection/atherosclerosis link and to provide more insight into the mechanisms by which infection may contribute to atherosclerosis, information critical for devising strategies to reduce or eliminate any contribution to atherosclerosis caused by infection.

Arteriosclerosis↗
PubMed1999

Effects of human cytomegalovirus immediate-early proteins on p53-mediated apoptosis in coronary artery smooth muscle cells.

BACKGROUND: Restenotic and atherosclerotic lesions often contain smooth muscle cells (SMCs), which display high rates of proliferation and apoptosis. Human cytomegalovirus (HCMV) may increase the incidence of restenosis and predispose to atherosclerosis. Although the mechanisms contributing to these processes are unclear, studies demonstrate that one of the immediate-early (IE) gene products of HCMV, IE2-84, binds to and inhibits p53 transcriptional activity. Given the role of p53 in mediating apoptosis, we studied the ability of IE2-84 to inhibit p53-dependent apoptosis in human coronary artery SMCs. METHODS AND RESULTS: Apoptosis of SMCs was induced either by use of an adenovirus vector encoding human wild-type p53 protein or by treatment with doxorubicin. HCMV IE1-72 and IE2-84, the major IE proteins of HCMV, were overexpressed separately with adenovirus vectors encoding each protein, and the effects on p53-induced apoptosis were examined by both nick end-labeling (TUNEL) assay and flow cytometry. Expression of IE2-84, but not IE1-72, protected SMCs from p53-mediated apoptosis. CONCLUSIONS: These data indicate that an HCMV IE protein antagonizes p53-mediated apoptosis, suggesting a pathway by which HCMV infection predisposes to SMC accumulation and thereby contributes to restenosis and atherosclerosis.

Apoptosis↗
PubMed1999

The immediate early gene products of human cytomegalovirus increase vascular smooth muscle cell migration, proliferation, and expression of PDGF beta-receptor.

Evidence suggests that human cytomegalovirus (HCMV) infection contributes to the development of atherosclerosis and restenosis. Because smooth muscle cell (SMC) proliferation and migration are crucial events of both processes, and because PDGF beta-receptor modulates SMC migration, we determined whether HCMV infection affects SMC proliferation, migration, and PDGF beta-receptor expression. We employed a SMC model in which HCMV infection leads to expression of only the immediate early (IE) HCMV gene products-HCMV infection of rat SMCs. We found that HCMV infection significantly (i) increased SMC proliferation (from 0.9 x 10(6) +/- 0.024 x 10(6) to 1.4 x 10(6) +/- 0.051 x 10(6) cells/well, p < 0.001); (ii) augmented SMC migration toward PDGF (from 64 +/- 37 to 116 +/- 51 cells/high power field; p < 0.01); and (iii) enhanced PDGF beta-receptor expression in a time-dependent fashion. We conclude that HCMV infection of rat SMCs increases SMC proliferation, migration, and PDGF beta-receptor expression. These findings identify further mechanisms by which CMV may contribute to the development of atherosclerosis and restenosis.

Animals↗