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Biomedical subjects

S E Epstein

Publications and source records attributed to S E Epstein.

At least 73 records · Page 4Linked to original sources
PubMed1994

Basic fibroblast growth factor enhances myocardial collateral flow in a canine model.

Basic fibroblast growth factor (FGF) is a multifunctional peptide that may play an integral role in angiogenesis associated with coronary collateral formation and myocardial infarct healing. We sought to determine the effects of exogenously administered basic FGF on collateral blood flow to ischemic myocardium. Ameroid constrictors were used to cause gradual occlusion of the left circumflex coronary artery in dogs. Basic FGF (110 micrograms, n = 9) or saline (n = 12) was given as a daily bolus injection directly into the collateral-dependent zone, beginning 10 days after placement of the Ameroid and continuing for 28 days. Collateral flow was assessed weekly as the ratio of collateral to normal zone (CZ/NZ) blood flow during maximal pharmacologically induced coronary vasodilation. The CZ/NZ increased in both treated and control dogs as a function of time; however, transmural collateral flow in basic FGF-treated dogs significantly exceeded that of control dogs by the second week of treatment. Final CZ/NZ blood flow ratios were 0.49 +/- 0.05 and 0.35 +/- 0.02 in the treated and control groups, respectively (means +/- SE, P = 0.0002). Treatment with basic FGF was also associated with significant increases in the numerical density of distribution vessels and endothelial cell DNA synthesis within the CZ. We also found that basic FGF had acute effects as a coronary vasodilator. Thus exogenous administration of basic FGF enhances maximal collateral blood flow in dogs with myocardial ischemia secondary to single-vessel coronary occlusion, an effect that is likely mediated through the direct angiogenic effects of the peptide, although its acute vasodilatory effects may also play a role.

Animals↗
PubMed1994

Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs.

BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is angiogenic in vitro and in vivo. It has been hypothesized that VEGF plays a role in myocardial collateral formation; however, the effects of VEGF on collateral flow to ischemic myocardium are unknown. METHODS AND RESULTS: We studied the effect of VEGF on collateral blood flow in dogs subjected to gradual occlusion of the left circumflex coronary artery (LCx). Beginning 10 days after placement of an LCx-constricting device, VEGF 45 micrograms (n = 9) or saline (n = 12) was administered daily via an indwelling catheter in the distal LCx, at a point just beyond the occlusion. Treatment was maintained for 28 days. Collateral blood flow was determined with microspheres 7 days before treatment, immediately before treatment (day 0), and 7, 14, 21, and 28 days into the treatment period. Collateral blood flow was quantified during chromonar-induced maximal vasodilation and expressed as a collateral zone/normal zone (CZ/NZ) ratio. Treatment with VEGF was associated with a 40% increase in collateral blood flow (final CZ/NZ blood flow ratios of 0.49 +/- 0.06 and 0.35 +/- 0.02 in the VEGF-treated and control groups, respectively, P = .0037) as well as an 89% increase in the numerical density of intramyocardial distribution vessels (> 20 microns diameter) in the CZ (6.6 +/- 1.4 versus 3.5 +/- 0.7 vessels/mm2 in VEGF-treated and control dogs, respectively, P < .05). CONCLUSIONS: We conclude that intracoronary VEGF enhances the development of small coronary arteries supplying ischemic myocardium, resulting in marked augmentation of maximal collateral blood flow delivery. These results demonstrate the feasibility of pharmacological enhancement of collateral growth and suggest a new therapeutic approach for the treatment of myocardial ischemia.

Animals↗
PubMed1993

Heparin-binding transforming growth factor alpha-Pseudomonas exotoxin A. A heparan sulfate-modulated recombinant toxin cytotoxic to cancer cells and proliferating smooth muscle cells.

TGF alpha-PE40, a recombinant toxin in which transforming growth factor alpha (TGF alpha) is fused to a mutant form of Pseudomonas exotoxin, is selectively cytotoxic to cells bearing epidermal growth factor (EGF) receptors. Heparin binding EGF-like growth factor is a potent mitogen for smooth muscle cells capable of binding to both the EGF receptor and to immobilized heparin (Higashiyama, S., Abraham, J., Miller, J., Fiddes, J., and Klagsbrun, M. (1991) Science 251, 936-938). To study the effect of the heparin-binding domain in a chimeric toxin targeted to the EGF receptor, we fused the DNA sequence corresponding to the putative NH2-terminal heparin-binding (HB) domain of HB-EGF to chimeric toxins composed of TGF alpha and two different recombinant forms of Pseudomonas exotoxin (PE). One of these is a truncated form of PE devoid of the binding domain (TGF alpha-PE38); another is a mutant form of full-length toxin containing inactivating mutations in the binding domain and an altered carboxyl terminus (TGF alpha-PE4EKDEL). The resulting chimeric toxins HB-TGF alpha-PE38 and HB-TGF alpha-PE4EKDEL were expressed in Escherichia coli as inclusion bodies, refolded, and purified by heparin affinity chromatography. Both of the toxins were eluted from heparin at 0.8 M NaCl, in contrast to their respective TGF alpha toxins which were eluted at 0.15 M. Binding studies on A431 cells showed that the HB-TGF alpha toxins bound to the EGF receptor with an affinity similar to that of the TGF alpha toxins. However, cell killing studies on a panel of malignant cell lines showed that cytotoxicity was strongly affected by the presence of the HB domain. Cell lines expressing high numbers of EGF receptors such as A431 and KB were less sensitive to toxins containing the HB domain. Cells with low number of EGF receptors had similar responses to both types of toxins (MCF-7 and LNCaP) or were more sensitive to the toxin with the added HB domain (HEP-G2). HB-TGF alpha-PE4EKDEL was over 10-fold more cytotoxic against proliferating vascular smooth muscle cells (VSMC) than to quiescent VSMC. Moreover, HB-TGF alpha-PE4EKDEL was 6-fold more potent than TGF alpha-PE4EKDEL to proliferating VSMC. Competition studies with EGF and/or heparin showed that heparin blocks the cytotoxicity of HB-TGF toxins and the inhibitory action of heparin is stronger in cells expressing lower number of EGF receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1993

Prognostic implications of myocardial ischemia during daily life in low risk patients with coronary artery disease.

OBJECTIVES: The purpose of this study was to determine the incidence and prognostic importance of myocardial ischemia detected by ambulatory monitoring in low risk, medically managed patients with coronary artery disease. BACKGROUND: Previous studies have demonstrated that certain high risk subsets of patients with coronary artery disease have improved survival with revascularization. The remaining low risk medically managed patients may still have episodes of silent ischemia during daily living, but the frequency and prognostic implications of such episodes in this group are unknown. METHODS: We prospectively studied the incidence and prognostic significance of ST segment changes recorded during daily activities in 116 asymptomatic or mildly symptomatic low risk patients with native coronary artery disease who were followed up for 29 +/- 13 months. Low risk patients were selected after excluding patients with 1) left main disease; 2) three-vessel coronary artery disease and left ventricular dysfunction at rest; 3) three-vessel disease and inducible ischemia during exercise; and 4) two-vessel disease, left ventricular dysfunction and inducible ischemia. RESULTS: Forty-five patients (39%) had transient episodes of ST segment depression during 48-h electrocardiographic (ECG) monitoring (total 217 episodes, lasting 7,223 min, 82% of episodes silent). There were eight acute cardiac events (seven myocardial infarctions, one episode of unstable angina) and nine patients underwent elective revascularization. Seven of the eight acute events occurred in patients without silent ischemia during monitoring. Kaplan-Meier survival analysis revealed no significant differences in event-free survival from either acute or total events in subgroups with or without silent ischemia during ambulatory ECG monitoring. None of the clinical, treadmill exercise, radionuclide ventriculographic or cardiac catheterization variables were predictive of outcome by Cox multivariate proportional hazard function analysis. Analysis of coronary arteriograms before and after acute cardiac events revealed that in five of the six patients studied, acute occlusion occurred in a coronary artery different from the artery with the severest stenosis on initial angiography. CONCLUSIONS: In patients categorized as at low risk on the basis of the results of cardiac catheterization and stress testing, silent myocardial ischemia during daily life was not uncommon, and its presence failed to predict future coronary events.

Activities of Daily Living↗
PubMed1993

Inhibitory effects of antisense oligodeoxynucleotides targeting c-myc mRNA on smooth muscle cell proliferation and migration.

Smooth muscle cell (SMC) proliferation and migration play pivotal roles in restenosis following angioplasty. c-myc is an immediate early response gene induced by various mitogens, and several lines of evidence derived from experiments using transformed or hematopoietic cell lines, or transgenic mice, suggest its protein product plays a role in numerous signaling transduction pathways, including those modulating cell division. We therefore reasoned that a strategy employing oligodeoxynucleotides (ODNs) complementary to c-myc mRNA (antisense ODNs) might be potent inhibitors of SMC proliferation and, perhaps, of SMC migration. To evaluate this concept, we tested several antisense ODNs targeted to c-myc mRNA (15- or 18-mer ODNs complementary to different c-myc mRNA sequences) by introducing them individually into the medium of cultured rat aortic SMCs. Phosphoroamidate-modified ODNs were employed to retard degradation. Antisense ODNs inhibited, in a concentration-dependent manner, SMC proliferation and SMC migration. Maximal inhibitory effect was 50% for proliferation and > 90% for migration. These effects were associated with decreased SMC expression of c-myc-encoded protein by Western immunoblotting and immunocytochemical staining. ODNs with the same nucleotides but a scrambled sequence caused no effect. These results indicate that the c-myc gene product is involved in the signal transduction pathways mediating SMC proliferation and migration in the in vitro model we employed. The results also suggest a potential role of antisense strategies designed to inhibit c-myc expression for the prevention of coronary restenosis.

Animals↗
PubMed1993

Angiogenic effects of low molecular weight heparin in patients with stable coronary artery disease: a pilot study.

OBJECTIVES: The study was designed to assess the feasibility of conducting a trial to investigate whether exercise and low molecular weight heparin therapy with dalteparin sodium (Fragmin) would improve collateral function to the ischemic myocardium in patients with coronary artery disease. BACKGROUND: The severity of myocardial ischemia in patients with coronary artery disease is at least partly dependent on the status of the collateral circulation. Therefore, improvement in collateral function would potentially provide a unique way of alleviating myocardial ischemia. Because the combination of ischemia and heparin has previously been demonstrated to enhance collateral growth, we studied the anti-ischemic effects of combined treatment with dalteparin sodium and exercise-induced ischemia in patients with coronary artery disease. METHODS: Twenty-three patients with stable coronary artery disease were randomized to receive either subcutaneous dalteparin sodium or placebo for a 4-week period. Patients received either placebo or 10,000 IU of dalteparin sodium by subcutaneous injection once daily for weeks 1 and 2 and 5,000 IU daily for weeks 3 and 4. During the 1st 2 weeks, patients were exercised to ischemia three times a day. At baseline and 4 weeks after treatment, treadmill exercise testing, exercise radionuclide ventriculography and 48-h ambulatory ST segment monitoring were performed. RESULTS: Eight (80%) of the 10 dalteparin sodium-treated patients compared with 4 (31%) of 13 placebo-treated patients (p < 0.02) had an increased rate-pressure product at the onset of 1 mm of ST segment depression. The duration of exercise to ischemia increased in all patients treated with low molecular weight heparin and in 62% of placebo-treated patients (p < 0.03). The number and duration of episodes of ST segment depression during ambulatory monitoring decreased by 30% and 35%, respectively (p < 0.05), in the dalteparin sodium group but were unchanged in the placebo group. The decrease in left ventricular ejection fraction with exercise was lower in 80% of dalteparin sodium-treated patients compared with 54% of placebo-treated patients (p = 0.06). When all five factors reflecting collateral function were considered together in a multivariate analysis of variance, there was a significant improvement in low molecular weight heparin-treated patients compared with placebo-treated patients (p = 0.014). CONCLUSIONS: This study provides preliminary evidence suggesting that exercise and low molecular weight heparin therapy with dalteparin sodium lessen myocardial ischemia and that the improvement is likely to be mediated by enhanced collateral function.

Aged↗
PubMed1993

Myocardial ischemia detected by thallium scintigraphy is frequently related to cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy.

OBJECTIVES: The purpose of this study was to determine the frequency of myocardial ischemia as a potential mechanism for cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy who experienced such complications. BACKGROUND: Sudden cardiac death and syncope occur frequently in patients with hypertrophic cardiomyopathy. Although ventricular arrhythmias account for most of these events in adult patients, the mechanism responsible for cardiac arrest and syncope in young patients has not been established. METHODS: Twenty-three patients with hypertrophic cardiomyopathy, aged 6 to 23 years, with previous cardiac arrest (n = 8), syncope (n = 7) or a family history of sudden cardiac death (n = 8) were evaluated to determine the prevalence of spontaneous ambulatory ventricular tachycardia (24- to 72-h electrocardiographic [ECG] monitoring), exercise-induced myocardial ischemia (thallium scintigraphy) and inducibility of ventricular tachycardia (electrophysiologic studies). RESULTS: Three of 15 patients with a history of cardiac arrest or syncope had ventricular tachycardia on ambulatory ECG monitoring. However, all 15 patients, had inducible ischemia by thallium scintigraphy compared with only 3 (37%) of 8 patients with no such history (p < 0.01). In contrast, ventricular tachycardia induction was uncommon in all of the young patients (27% in those with cardiac arrest or syncope; 0% in the others). During therapy for ischemia with verapamil alone or in combination with beta-adrenergic blocking agents, only 4 of the 15 patients with cardiac arrest or syncope had further episodes. In three of the four patients, these events were temporally related to discontinuation of verapamil. Among eight patients who had a repeat exercise thallium study while receiving anti-ischemic therapy, seven (88%) had improved regional thallium uptake, of whom three had normal thallium studies. CONCLUSIONS: These data suggest that in young patients with hypertrophic cardiomyopathy, sudden cardiac arrest or syncope is frequently related to ischemia rather than to a primary arrhythmogenic ventricular substrate.

Adolescent↗
PubMed1993

Effect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension.

OBJECTIVES: This study was designed to determine whether antihypertensive treatment can restore the impaired endothelium-dependent vasodilation of patients with essential hypertension. BACKGROUND: The endothelium regulates vascular tone through the release of vasoactive agents that act on the underlying vascular smooth muscle. This endothelial function is impaired in certain cardiovascular conditions, including essential hypertension. METHODS: The vascular responses to acetylcholine (endothelium-dependent vasodilator, 7.5, 15 and 30 micrograms/min) and sodium nitroprusside (direct dilator of smooth muscle, 0.8, 1.6, 3.2 micrograms/min) were studied in 15 patients (11 men and 4 women with a mean age of 54.1 +/- 12 years) on two occasions: after withdrawal of medications, when the patients were hypertensive, and during the medical treatment that reduced blood pressure to within normal limits in each patient. The results were compared with those obtained in 15 normal control subjects (10 men and 5 women with a mean age of 52.3 +/- 7 years). Drugs were infused into the brachial artery, and forearm blood flow response was measured by strain gauge plethysmography. RESULTS: The blood flow and vascular resistance responses to acetylcholine were significantly reduced in the hypertensive patients (p < 0.0001); maximal forearm flow (ml/min per 100 ml) was 7.0 +/- 4 ml in the patients and 16.7 +/- 5 in the control subjects (p < 0.005). However, no significant differences between groups were observed in the responses to sodium nitroprusside. In patients with essential hypertension, the vascular responses to acetylcholine and sodium nitroprusside were not modified by medical therapy. Maximal forearm flow with acetylcholine (ml/min per 100 ml) was 7.2 +/- 2 during antihypertensive therapy and 7.0 +/- 4 after medication withdrawal. CONCLUSIONS: Clinically effective antihypertensive therapy does not restore the impaired endothelium-dependent vascular relaxation of patients with essential hypertension. This indicates that such endothelial dysfunction is either primary or becomes irreversible once the hypertensive process has become established.

Acetylcholine↗
PubMed1993

A model to assess interventions to improve collateral blood flow: continuous administration of agents into the left coronary artery in dogs.

OBJECTIVE: The aim was to develop an experimental model in which angiogenic growth factor(s) could be targeted locally to enhance myocardial collateral formation. A preparation was developed in which agents could be infused selectively into the left main coronary artery on a chronic basis to assess the potential of acidic fibroblast growth factor (FGF) to improve collateral blood flow. METHODS: Ameroid constrictors were placed on the left circumflex coronary artery of mixed hounds. Five weeks after ameroid placement, the artery was ligated and transected at the point of ameroid occlusion; a catheter was inserted and passed retrogradely into the left main coronary artery. The catheter was connected to an implantable infusion pump that provided continuous intracoronary drug infusion for 4 weeks. Dogs were randomised to receive acidic FGF with heparin (30 micrograms.h-1 and 30 IU.h-1, respectively, n = 16) or heparin alone (30 IU.h-1, n = 14). Regional myocardial blood flow was determined in the conscious state at the beginning and end of treatment. RESULTS: There were no deaths or important surgical complications related to the establishment of the coronary artery infusions. During the treatment interval (5-9 weeks after ameroid placement) the ratio of maximum ischaemic zone/normal zone blood flow increased from 0.39(SD 0.10) to 0.50(0.11) (p < 0.01) in dogs treated with acidic FGF plus heparin; however, similar improvement was noted in dogs treated with heparin alone. Ischaemic zone and normal zone vascular density was also equivalent in the two groups. CONCLUSIONS: This preparation makes possible the chronic intracoronary administration of agents which may promote myocardial angiogenesis, and allows assessment of collateral blood flow before and after treatment. As given in this investigation, acidic FGF had no demonstrable effect on collateral blood flow; however, this model may facilitate the identification of agents that do enhance myocardial collateral formation.

Animals↗
PubMed1993

Cytotoxic effects of vascular smooth muscle cells of the chimeric toxin, heparin binding TGF alpha-Pseudomonas exotoxin.

OBJECTIVE: Smooth muscle cell proliferation appears to be very important in restenosis after angioplasty. A chimeric toxin created by genetically fusing the gene encoding TGF alpha (targets the EGF receptor) to the gene encoding Pseudomonas exotoxin (PE) preferentially kills rapidly proliferating smooth muscle cells. Recently, a heparin binding EGF-like growth factor (HB-EGF) has been identified. The HB domain enhances the mitogenic activity for smooth muscle cells. The purpose of this study was to design a new chimeric toxin, having both heparin binding and EGF receptor binding function, and to determine whether it is more cytotoxic to smooth muscle cells. METHODS: By recombinant DNA techniques, a new chimeric toxin, HB-TGF alpha-PE4EKDEL, was synthesised. Cytotoxic assays were performed by assessing the capacity to inhibit protein synthesis of rat vascular smooth muscle cells. RESULTS: The toxin preferentially killed rapidly proliferating smooth muscle cells (p < 0.025). The HB domain increased the cytotoxicity of the molecule when compared to the other chimeric toxins tested against smooth muscle cells. The cytotoxic effect of the new molecule was significantly decreased by exogenously added heparin (p < 0.05). CONCLUSIONS: The presence of a heparin binding domain increases the smooth muscle cell cytotoxicity of the TGF alpha fusion toxin, perhaps because HB-TGF alpha-PE4EKDEL functions as a molecule with two ligands. It will be important to determine whether the greater smooth muscle cell cytotoxicity that exists in vitro will facilitate the specific targeting and killing of rapidly proliferating cells in vivo.

Animals↗
PubMed1993

Extracardiac to coronary anastomoses support regional left ventricular function in dogs.

Intramyocardial implantation of a systemic artery [the internal mammary artery (IMA)] causes angiogenesis, with formation of systemic to coronary anastomoses. In dogs, we assessed the magnitude of IMA-derived nutritive flow and determined its influence on regional contraction. We also sought to determine whether acidic fibroblast growth factor (FGF), an angiogenic peptide, could enhance myocardial neovascularization. Ameroid constrictors and hydraulic balloon occluders were placed on the left anterior descending coronary artery (LAD) of 23 dogs, and the left IMA was implanted in the LAD territory. Dogs were randomized to receive continuous infusions of acidic FGF with heparin, heparin alone, or placebo directly into the IMA for 8 wk. Regional myocardial blood flow was assessed in the conscious state 3 days and 8 wk after operation. Left ventricular function was determined in the anesthetized state at the 8-wk conclusion of treatment. In all dogs, IMA occlusion reduced mean maximal LAD zone perfusion by 28% (P < 0.001), without influencing regional contraction. When IMA occlusion was superimposed on left circumflex coronary artery (LCX) occlusion, LAD zone perfusion declined by 34% (relative to LCX occlusion alone), significantly impairing regional contraction. Treatment with either acidic FGF plus heparin or heparin alone improved IMA-derived collateral flow; however, addition of acidic FGF to heparin afforded no additional advantage over heparin by itself. We conclude that acidic FGF did not enhance myocardial angiogenesis in this model. IMA-derived collateral flow has significant functional importance; however, it is evident in the dog only when other sources of collateral flow are compromised.

Anastomosis, Surgical↗
PubMed1993

Smooth muscle cell abundance and fibroblast growth factors in coronary lesions of patients with nonfatal unstable angina. A clue to the mechanism of transformation from the stable to the unstable clinical state.

BACKGROUND: The mechanisms responsible for the transformation of stable angina to unstable angina, a major cause of morbidity and mortality, are commonly believed to be plaque rupture and thrombosis. We determined whether additional mechanisms are operative by analyzing the histopathology and immuno-histopathology of coronary plaques retrieved by directional atherectomy of patients with unstable angina in whom no intraluminal thrombus was demonstrated by angiography. METHODS AND RESULTS: The histological findings of atherectomy specimens from 34 patients with unstable angina were compared with those of 24 patients with postangioplasty restenosis, whose lesions are known to be composed of smooth muscle cells (SMCs), and 10 patients with stable angina, whose lesions contain relatively few SMCs. We also studied the expression of acidic and basic fibroblast growth factors (aFGF and bFGF), whose role in the vascular response to injury has been established. Specimens from unstable angina resembled those from postangioplasty restenosis in regard to SMC abundance (scale, 0 to 3; 1.4 +/- 0.9 versus 1.7 +/- 0.9; P = NS), and both differed from those of stable angina. Thrombus and/or hemorrhage occurred in only 34% of patients with unstable angina (compared with 8% of restenosis patients and in none of stable angina patients). Active lesions (defined as lesions (defined as lesions containing one or more of the following: thrombus, hemorrhage, abundant and disorganized SMCs in the presence of loose connective tissue, or inflammatory infiltrate) were observed in 56% of the unstable angina patients and in 50% of the restenosis patients but in none of the stable angina patients. The expression of aFGF and bFGF was detected in 80% to 100% of unstable angina (n = 11) and restenosis (n = 10) specimens but in only 1 of 5 stable angina specimens. CONCLUSIONS: Microscopic evidence of thrombosis and plaque rupture occurred in only one third of unstable angina patients, selected because they had no angiographic evidence of intracoronary thrombus. Moreover, their lesions resembled those of restenosis patients in regard to SMC abundance, lesion activity, and the expression of aFGF and bFGF. Our findings therefore suggest that an alternative mechanism to plaque rupture and thrombus formation may be operative in the precipitation of unstable angina; namely, in a subset of patients, SMC proliferation may lead to gradual plaque expansion and thereby to lumenal narrowing and unstable angina. Our data also suggest a role for aFGF and bFGF in this process.

Adult↗
PubMed1993

Efficient and selective adenovirus-mediated gene transfer into vascular neointima.

BACKGROUND: Previous attempts to target arterial smooth muscle cells (SMCs) for gene delivery using liposomal or retroviral methods were limited by low transfection efficiency. We therefore evaluated the efficiency of adenovirus-mediated gene delivery in cultured vascular SMCs and in an in vivo model of balloon injury-induced SMC cell proliferation. METHODS AND RESULTS: We used a recombinant adenovirus, Ad.RSV beta gal, which contained the beta-galactosidase (beta-gal) histochemical marker gene. For in vitro studies, rat aortic SMCs were incubated in media containing Ad.RSV beta gal for 5 to 120 minutes. The proportion of SMCs expressing the beta-gal gene product increased from 25% (5-minute exposure) to 80% (120-minute exposure). For in vivo studies, uninjured and injured rat carotid segments were incubated with 0.5 to 1.0 x 10(9) pfu Ad.RSV beta gal for 45 minutes. Uninjured arteries showed adenovirus-mediated gene transfer limited to the endothelium. Injured arteries were exposed to adenovirus 0, 3, 7, or 12 days after injury. In these segments, beta-gal expression was minimal with infection at 0 or 3 days after injury but marked when infection was delayed until 7 or 12 days after injury. Neointimal cells constituted the dominant target of adenovirus gene transfer, with efficiency of gene transfer ranging from 10% to > 75%. Medial SMCs, whether covered or uncovered by neointimal cells, were minimally infected. Infection with a control adenovirus vector showed no beta-gal staining. CONCLUSIONS: Recombinant adenovirus selectively targets neointimal cells with high-efficiency gene transfer. This suggests that adenovirus vectors should be useful in targeting cells for the delivery of genes whose products may be relevant to the treatment of restenosis.

Adenoviridae↗
PubMed1993

Efficient gene transfer into myocardium by direct injection of adenovirus vectors.

Previous studies have established that gene transfer into myocardial cells in vivo is detectable after direct injection of plasmid DNA. Recently, adenovirus vectors have been shown to provide an efficient method for gene transfer into a wide range of tissues. Therefore, this study sought to assess the efficiency and stability of adenovirus-mediated gene transfer into myocardium and to compare this method with that using plasmid-based gene transfer techniques. Adult rats underwent myocardial injection via a subdiaphragmatic approach. Gene transfer efficiency was compared using direct injection of an adenovirus vector encoding for the marker gene beta-galactosidase (beta-gal), a control adenovirus vector encoding for the cystic fibrosis transmembrane conductance regulator gene, a plasmid encoding for beta-gal, or a control plasmid. Hearts infected with an adenovirus vector containing the beta-gal gene showed significantly increased beta-gal enzymatic activity compared with hearts injected with beta-gal plasmid. Histological examination revealed that cardiac myocytes were the target of adenovirus-mediated gene transfer. A time course of gene expression showed that beta-gal enzymatic activity peaked during the first week following injection. Adenovirus vectors provide an efficient but transient method for in vivo gene expression in myocardium.

Adenoviridae↗
PubMed1992

Role of increases in heart rate in determining the occurrence and frequency of myocardial ischemia during daily life in patients with stable coronary artery disease.

OBJECTIVES: The goal of this study was to investigate the role of increases in heart rate in the development of ischemic episodes recorded during ambulatory electrocardiographic (ECG) monitoring in patients with stable coronary artery disease and to establish the importance of such increases in determining the frequency of ambulatory myocardial ischemia. BACKGROUND: The factors that determine the occurrence and frequency of episodes of myocardial ischemia that patients with stable coronary artery disease experience during daily life have not been clearly defined. In particular, the role of increases in heart rate in the development of myocardial ischemia is controversial. METHODS: To address these issues, 54 patients (42 men and 12 women, mean age 60.5 +/- 8 years) with proved coronary artery disease who had > or = 1 mm ST segment depression during exercise testing underwent an exercise treadmill test with use of the National Institutes of Health combined protocol and a 48-h period of ambulatory ECG monitoring. The exercise ischemic threshold was determined as the heart rate at the onset of ST segment depression during exercise testing. RESULTS: During monitoring, 48 (89%) of the 54 patients had at least one episode of ST segment depression (mean +/- SD 6.6 +/- 5 episodes, range 0 to 22). The majority (320 of 359 or 89%) of ischemic episodes were preceded by an increase in heart rate > or = 10 beats/min; the most significant increase (22.3 +/- 10 beats/min) occurred during the 5-min period before the onset of the episode. An ischemic episode occurred 80% of the times the heart rate reached the exercise ischemic threshold. A strong correlation was observed between the number of times the exercise ischemic threshold was reached during monitoring and both the number and the duration of ischemic episodes (r = 0.90 and 0.71, respectively, p < 0.0001). CONCLUSIONS: Increases in heart rate that exceed the exercise ischemic threshold are commonly observed before the onset of episodes of ambulatory myocardial ischemia in patients with stable coronary artery disease. Moreover, such increases constitute an important determinant of the frequency of myocardial ischemia during daily life. These findings may explain the variability observed in the number of ischemic episodes and may have important implications for the mechanisms that contribute to myocardial ischemia in daily life and for the clinical evaluation of patients with coronary artery disease.

Activities of Daily Living↗
PubMed1992

Long-term variation in myocardial ischemia during daily life in patients with stable coronary artery disease: its relation to changes in the ischemic threshold.

Long-term variation in the frequency of myocardial ischemia during daily activity in patients with coronary artery disease who do not experience symptomatic changes has not been documented. Because at one point in time, the magnitude of such ischemia is strongly related to the ischemic threshold measured during exercise testing, this study was undertaken to determine whether patients with stable coronary artery disease show long-term variations in the frequency and duration of myocardial ischemia and to establish whether such variability is related to parallel changes in the ischemic threshold during exercise testing. Forty consecutive patients (mean age 61 +/- 8 years) who showed a stable clinical course over greater than or equal to 12 months were studied with a repeat exercise treadmill test and ambulatory electrocardiographic (ECG) monitoring after withdrawal of antianginal medications. The ischemic threshold was determined as the exercise time at 1 mm of ST segment depression. The mean interval to both follow-up evaluations was 15 +/- 3 months. Among the 23 patients with myocardial ischemia on ambulatory ECG monitoring at initial evaluation, the number and duration of ischemic episodes at follow-up were increased in 5 patients (mean increase 3.6 +/- 2 episodes and 123 +/- 98 min), unchanged in 1 patient and decreased in 17 patients (mean decrease 2.6 +/- 2 episodes and 98 +/- 72 min). Of the 17 patients without ischemic episodes at initial evaluation, 3 had evidence of ischemia on follow-up ambulatory ECG monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗