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Biomedical subjects

M Kearney

Publications and source records attributed to M Kearney.

At least 73 records · Page 4Linked to original sources
PubMed1996

Impact on ventricular function and quality of life of transcatheter ablation of the atrioventricular junction in chronic atrial fibrillation with a normal ventricular response.

We assessed left ventricular function and quality of life after atrioventricular junction ablation and pacemaker implant in 14 patients with chronic atrial fibrillation and normal ventricular response. A significant improvement in left ventricular ejection fraction, fractional shortening, and functional capacity were observed at follow-up, suggesting that in patients with chronic atrial fibrillation a regular heart beat may be preferable over rate control.

Aged↗
PubMed1996

Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion.

BACKGROUND: Striated muscle has been shown to be capable of taking up and expressing foreign genes transferred in the form of naked plasmid DNA, although typically with a low level of gene expression. In the case of genes that encode secreted proteins, however, low transfection efficiency may not preclude bio-activity of the secreted gene product. Accordingly, we investigated the hypothesis that intramuscular (IM) gene therapy with naked plasmid DNA encoding vascular endothelial growth factor (VEGF) could augment collateral development and tissue perfusion in an animal model of hindlimb ischemia. METHODS AND RESULTS: Ten days after ischemia was induced in one rabbit hindlimb, 500 micrograms of phVEGF165, or the reporter gene LacZ, was injected IM into the ischemic hindlimb muscles. Thirty days later, angiographically recognizable collateral vessels and histologically identifiable capillaries were increased in VEGF transfectants compared with controls. This augmented vascularity improved perfusion to the ischemic limb, documented by a superior calf blood pressure ratio for phVEGF165 (0.85 +/- 0.05) versus controls (0.64 +/- 0.05, P < .01), improved blood flow in the ischemic limb (measured with an intra-arterial Doppler wire) at rest (phVEGF165 = 21.3 +/- 3.9 mL/min, control = 14.6 +/- 1.6 mL/min, P < .01) and after a vasodilator (phVEGF165 = 54.2 +/- 12.0 mL/min, control = 37.3 +/- 8.9 mL/min, P < .01) and increased microspheres in the adductor (phVEGF165 = 4.3 +/- 1.6 mL.min-1.100 g of tissue-1, control = 2.9 +/- 1.2 mL.min-1.100 g of tissue-1, P < .05) and gastrocnemius (phVEGF165 = 3.9 +/- 1.0 mL.min-1.100 g of tissue-1, control = 2.8 +/- 1.4 mL.min-1.100 g of tissue-1, P < .05) muscles of the ischemic limb. CONCLUSIONS: Ischemic skeletal muscle represents a promising target for gene therapy with naked plasmid DNA. IM transfection of genes encoding angiogenic cytokines, particularly those that are naturally secreted by intact cells, may constitute an alternative treatment strategy for patients with extensive peripheral vascular disease in whom the use of intravascular catheter-based gene transfer is compromised and/or prohibited.

Animals↗
PubMed1996

Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer.

BACKGROUND: Delinquent reendothelialization (rET) has been shown to have a permissive, if not facilitatory, impact on smooth muscle cell proliferation. This inverse relation has been attributed to certain functions of the endothelium, including barrier regulation of permeability, thrombogenicity, and leukocyte adherence, as well as production of growth-inhibitory molecules. Accordingly, the present investigation was designed to test the hypothesis that an endothelial cell (EC) mitogen could serve as the basis for a novel gene therapy strategy designed to facilitate EC regeneration, reduce neointimal thickening, and promote recovery of EC dysfunction after balloon injury. METHODS AND RESULTS: New Zealand White rabbits underwent simultaneous balloon injury and gene transfer of one femoral artery with phVEGF165, encoding the 165-amino acid isoform of vascular endothelial growth factor (VEGF), or pGSVLacZ. In each animal transfected with phVEGF165 or pGSVLacZ, the contralateral femoral artery was also subjected to balloon injury but not to gene transfer. For pGSVLacZ, rET remained incomplete at 4 weeks after transfection; in contrast, phVEGF165 produced prompt rET, which was 95% complete by 1 week. Furthermore, rET in the contralateral, balloon-injured, nontransfected limb of the VEGF group was similarly accelerated. Consequently, intimal thickening was diminished, thrombotic occlusion was less frequent, and recovery of EC-dependent vasomotor reactivity was accelerated in VEGF transfectants compared with control animals. A similar benefit was observed for the contralateral, balloon-injured, nontransfected limb. CONCLUSIONS: Catheter-mediated, site-specific arterial gene transfer of phVEGF165 can accelerate rET at local and remote sites, leading to inhibition of neointimal thickening, reduction in thrombogenicity, and restoration of endothelium-dependent vasomotor reactivity. These findings support the notion that gene transfer encoding for an EC-specific mitogen may be useful for preventing the complications, including restenosis, of balloon angioplasty.

Angioplasty, Balloon↗
PubMed1996

Effect of subintimal resection on initial outcome and restenosis for native coronary lesions and saphenous vein graft disease treated by directional coronary atherectomy. A report from the CAVEAT I and II investigators. Coronary Angioplasty Versus Excisional Atherectomy Trial.

OBJECTIVES: This study was designed to determine whether the depth of tissue resection affected either immediate outcome or subsequent restenosis in patients treated by directional coronary atherectomy (DCA) in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT) I and II studies. BACKGROUND: The relation between the depth of tissue resection, immediate outcome and subsequent restenosis in lesions treated with DCA has been controversial. METHODS: In CAVEAT I, 412 patients undergoing DCA had tissue samples available for analysis by the core laboratory, whereas in CAVEAT II, 113 patients had vein graft tissue specimens available. RESULTS: Subintimal deep arterial wall resection was demonstrated in 169 patients (41%) in CAVEAT I and 40 (35%) in CAVEAT II. The depth of tissue resection did not affect initial procedural outcome in either CAVEAT I or CAVEAT II, nor did it affect subsequent restenosis rates at 6 months in native coronary lesions (CAVEAT I, 50.8% for intimal resection vs. 51.2% for subintimal resection). In patients treated with vein graft disease (CAVEAT II), restenosis rates varied; when resection was limited to the intima, a restenosis rate of 40.4% was documented, whereas in patients with subintimal resection, the restenosis rate was 57.1%. This difference was not statistically significant (p = 0.144). CONCLUSIONS: This combined randomized series of DCA for treatment of primary native coronary artery and vein graft stenoses with quantitative coronary angiography and core laboratory pathologic assessment resolves the controversy created by previous experimental and clinical data regarding deep vessel wall resection and immediate and longer outcome. Directional atherectomy with deep arterial wall resection as practiced in these studies is safe and does not jeopardize initial success rates. More important, deep wall resection is not associated with significantly increased restenosis rates.

Atherectomy, Coronary↗
PubMed1996

Elevated levels of basic fibroblast growth factor in patients with limb ischemia.

Basic fibroblast growth factor (bFGF), a prototypic member of a family of heparin-binding growth factors, is angiogenic both in vitro and in vivo. Increased levels and activity of bFGF have been documented in a variety of diseases, including tumors. We sought to determine whether bFGF might be similarly elevated in patients with clinical evidence of limb ischemia. Serum was obtained at the time of percutaneous revascularization from patients with symptomatic peripheral vascular disease (46 procedures were performed on 40 patients). An enzyme-linked immunoassay specific for bFGF was used (limit of detection, 1 pg/ml; range in normal subjects, 0 to 5 pg/ml). Among the 40 patients (28 men, 12 women, mean age 70 years) studied, elevated circulating bFGF (> or = 10 pg/ml) was detected in 36 samples (78%); levels ranged from 10 to 310 pg/ml (mean +/- SEM = 62 +/- 12). In 16 (89%) of 18 patients with both rest pain and nonhealing ischemic ulcers, serum bFGF levels were elevated up to 30 times normal values. In conclusion, circulating levels of bFGF are elevated in patients with vascular insufficiency and may reflect a physiologic response to limb ischemia.

Aged↗
PubMed1996

Radiofrequency ablation of atrial flutter and atrial tachycardias in patients with permanent indwelling catheters.

UNLABELLED: The presence of chronic indwelling leads in the area targeted for RF ablation may pose a technical challenge and reduce the chance of success of the ablation. In addition, application of lesions in close proximity to pacemaker leads or other permanent catheters could affect their function. Fourteen patients referred for RF ablation of atrial flutter/fibrillation and atrial tachycardia, who had a permanent dual chamber pacemaker (10 patients), ICD (1 patient), or both (3 patients) were studied to assess the safety, efficacy, and effects of the ablative procedure on device function. Lead impedance, R and P wave amplitude, and pacing threshold of the defibrillator and pacemaker were measured before and after ablation. The procedure was successful in all patients. In one patient who underwent both atrial flutter and atrial fibrillation ablation, the atrial pacing threshold increased from 1.0 preablation to 2.0 V postablation. No P wave was detectable after ablation. In another patient, the P wave amplitude went from 4.0 to 2.0 mV postablation. In both patients the device converted to the power reset mode. No changes were observed in the remaining patients. Postablation defibrillator testing showed no malfunction. Follow-up reinterrogation of the devices revealed no alterations. IN CONCLUSION: (1) RF ablation of atrial flutter and/or tachycardia is feasible even in patients with multiple chronic atrial and ventricular indwelling catheters; and (2) RF applications in close proximity of defibrillator and pacing catheters does not appear to alter their function unless lesions are produced in the area surrounding the distal pacing electrode.

Aged↗
PubMed1995

Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells.

Smooth muscle cells, macrophages, glial cells, keratinocytes, and transformed cells have been established as synthesis sites for vascular endothelial growth factor (VEGF). The modulating effects of VEGF are essentially limited to endothelial cells (ECs), the only cell type consistently shown to express VEGF receptors. VEGF has thus been considered to act exclusively via a paracrine pathway. We sought to determine whether the role of human ECs might, under selected conditions, extend beyond that of a target to involve contingency synthesis of VEGF. In both unstimulated human umbilical vein ECs (HUVECs) and human derma-derived microvascular ECs (HMECs), Northern analysis detected no VEGF transcripts. Phorbol-12-myristate 13-acetate (10(-7) M) treatment, however, induced VEGF mRNA expression in both HUVECs and HMECs, peaking at 3 and 6 h, respectively, and returning to undetectable levels by 12 h. In vitro exposure of HUVECs to a hypoxic environment (pO2 = 35 mm of mercury) for 12, 24, and 48 h and exposure of HMECs for 6, 12, 24, and 48 h induced VEGF mRNA in a time-dependent fashion. Re-exposure to normoxia (pO2 = 150 mm of mercury) for 24 h after 24 h of hypoxia returned VEGF mRNA transcripts to undetectable levels in HUVECs. Cobalt chloride and nickel chloride treatment each induced VEGF mRNA in ECs. Cycloheximide treatment further augmented expression of VEGF mRNA induced by cobalt chloride, nickel chloride, and hypoxia in HUVECs. VEGF protein production in hypoxia HUVECs was demonstrated immunohistochemically. Conditioned media from hypoxic HUVECs caused a 2-fold increase in the incorporation of tritiated thymidine. Finally, immune precipitates of anti-KDR probed with anti-Tyr(P) antibodies demonstrated evidence of receptor autophosphorylation in hypoxic but not normoxic HUVECs. These findings thus establish the potential for an autocrine pathway that may augment and/or amplify the paracrine effects of VEGF in stimulating angiogenesis.

Cell Hypoxia↗
PubMed1995

[An answer to an inquiry on diffuse panbronchiolitis. Now it has found its way here!].

Diffuse panbronchiolitis (DPB) is a disease characterised by chronic inflammation in the region of respiratory bronchioles. The condition has mainly been observed in Japanese patients, though isolated cases have been reported from other countries. In a review published in Läkartidningen (37/94), the question was raised of why this disease had not been seen in Scandinavia, and whether this might be the result of missed diagnosis. The diagnostic criteria were listed, and the question was posed of whether (Scandinavian) physicians existed who had encountered patients with chronic sinusitis, persistent cough and inexplicable nodular changes in lung x-rays. As a direct result of this enquiry, the present article reports what may well be the first Scandinavian patient to fulfil all the diagnostic criteria of DPB. The patient responded with improved lung function and normalised blood gases to a combined treatment regimen comprising immunosuppression (cyclophosphamide and prednisolone) and nebulised antibiotics (gentamicin).

Adult↗
PubMed1995

Apoptosis in human atherosclerosis and restenosis.

BACKGROUND: Apoptosis has been recognized in normal, including rapidly proliferating, cell populations and is inferred to be potentially responsible for the maintenance of stable cell numbers in tissues with various degrees of proliferative activity. Previous studies performed in rats indicated that despite the persistence of a relatively high level of injury-induced proliferative activity, total arterial smooth muscle content at 12 weeks remained unchanged from that measured at 2 weeks, suggesting that accrual of vascular smooth muscle cells is mitigated by cell death. The extent to which apoptosis may be observed in human atherosclerosis and/or restenosis, however, has not been previously established. METHODS AND RESULTS: We performed immunohistochemical studies on 56 specimens retrieved from patients undergoing directional atherectomy for primary atherosclerotic lesions or recurrent arterial narrowing after percutaneous revascularization (restenosis). Immunohistochemical staining disclosed evidence of apoptosis in 35 (63%) of the 56 specimens studied. When present, immunohistochemical evidence of apoptosis was typically limited to < 2% of cells in the specimen. The finding of apoptosis, however, was not distributed equally among four groups of specimens studied. Specimens retrieved from patients with restenosis were more frequently observed to contain foci of apoptosis than specimens retrieved from patients with primary atherosclerotic lesions. Among 14 peripheral arterial specimens from patients with restenosis, 13 (93%) contained foci of apoptosis; in contrast, apoptosis was observed in only 6 (43%) of 14 peripheral specimens from patients with primary lesions (P = .0046). Among coronary arterial specimens, apoptosis was observed in 12 (86%) of 14 specimens from patients with restenosis versus 6 (29%) of 14 specimens from patients with primary obstructions (P < .0075). CONCLUSIONS: Apoptosis is a feature of human vascular pathology, including restenotic lesions and, to a lesser extent, primary atherosclerotic lesions. The findings of the present study suggest that apoptosis may modulate the cellularity of lesions that produce human vascular obstruction, particularly those with evidence of more extensive proliferative activity.

Adult↗
PubMed1995

Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery.

BACKGROUND: Most strategies designed to reduce restenosis by the use of pharmacological or biological reagents involve direct inhibition of vascular smooth muscle cell (SMC) proliferation. Alternatively, SMC proliferation might be indirectly inhibited if reendothelialization could be specifically facilitated at sites of balloon-induced arterial injury. Accordingly, we investigated the hypothesis that application of an endothelial cell (EC)-specific mitogen to a freshly denuded intimal surface could accelerate reendothelialization and thereby attenuate intimal hyperplasia. METHODS AND RESULTS: The left carotid artery of 31 Sprague-Dawley rats was subjected to balloon injury, after which 16 rats were treated with a 30-minute incubation with 100 micrograms of vascular endothelial growth factor (VEGF), an EC-specific mitogen. Control animals (n = 15) received a 30-minute incubation with 0.9% saline. At 2 weeks after balloon injury, carotid artery reendothelialization was markedly superior in the VEGF-treated group compared with the control group (14.59 +/- 1.12 versus 7.96 +/- 0.51 mm2, P < 0.005). The extent of reendothelialization measured at 4 weeks after balloon injury remained superior for arteries treated with VEGF (18.04 +/- 0.90 mm2) versus saline (13.42 +/- 0.84 mm2, P < .005). Neointimal thickening was correspondingly attenuated to a statistically significant degree in arteries treated with VEGF versus the control group at both the 2-week and 4-week time points. Immunostaining for proliferating cell nuclear antigen (PCNA) disclosed a threefold increase in PCNA-positive cells in the neointima of control arteries versus VEGF-treated arteries at 2 weeks after injury. CONCLUSIONS: Application of VEGF, an EC-specific growth regulatory molecule, may be effectively used in vivo to promote reendothelialization and thereby indirectly attenuate neointimal thickening due to SMC proliferation.

Animals↗
PubMed1995

Identification of 92-kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina.

BACKGROUND: Acute coronary ischemia is usually initiated by rupture of atherosclerotic plaque, leading to intracoronary thrombosis and clinical sequelae. The proximate cause of plaque rupture is unknown. Accordingly, we investigated the potential role of the 92-kD gelatinase member of the matrix metalloproteinase family in acute coronary ischemia. METHODS AND RESULTS: Coronary atherectomy specimens from patients with atherosclerosis and an acute ischemic syndrome consistent with recent plaque rupture (unstable angina) (n = 12) were immunostained for the presence of 92-kD gelatinase; the results were compared with those obtained by identical study of atherectomy specimens from patients with atherosclerosis and angina but without acute ischemia (stable angina) (n = 12). Positive immunostaining for 92-kD gelatinase was present in 83% of specimens from both unstable and stable angina patients. However, intracellular localization of enzyme (indicating active synthesis) was documented in 10 of 10 positively stained specimens from patients with unstable angina compared with 3 of 10 positively stained specimens from patients with stable angina. Macrophages and smooth muscle cells were the major sources of 92-kD gelatinase in all specimens examined by immunostaining of adjacent sections. CONCLUSIONS: 92-kD gelatinase is commonly expressed in coronary arterial atherosclerotic lesions. Active synthesis of 92-kD gelatinase by macrophages and smooth muscle cells in atherosclerotic lesions may play a pathogenic role in the development of acute coronary ischemia.

Angina Pectoris↗
PubMed1995

One-year follow-up in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT I)

BACKGROUND: Directional atherectomy is a frequently used percutaneous revascularization strategy, but its long-term outcomes have not previously been compared with those of balloon angioplasty in a prospective trial. METHODS AND RESULTS: The 1012 patients enrolled in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT I) were followed for at least 1 year after randomization. Analyses of predetermined end points were performed, including a detailed analysis of the 14 patients who died. At 1 year, 11 patients had died in the atherectomy group compared with 3 in the angioplasty group (2.2% versus 0.6%, P = .035), with an excess of out-of-hospital deaths (2.2% versus 0.2%, P = .01) and late cardiac deaths (1.6% versus 0%, P = .01). Univariate predictors of death included age, abrupt closure, periprocedural enzyme elevation, and peripheral vascular complications. There was no evidence that the excess of deaths after atherectomy was linked to perforation, ectasia, or deep resection. Cumulative rates of myocardial infarction were higher in those who had been randomized to atherectomy than in those randomized to angioplasty (8.9% versus 4.4%, P = .005) with a trend toward excess Q-wave and non-Q-wave infarctions. By multivariate analysis, atherectomy was the only variable predictive of the combined end point of death or myocardial infarction. No clinical or angiographic characteristics added to this index. Rates of repeat percutaneous intervention at the target site (24.4% after atherectomy versus 25.9% after angioplasty), coronary artery bypass surgery (9.3% versus 9.1%), hospitalization (50% versus 47.1%), and stroke (1% in both groups) were not significantly different. CONCLUSIONS: Long-term follow-up of the 1012 patients randomized to atherectomy or angioplasty has revealed a statistically significant excess of deaths after directional atherectomy that was not evident at 6 months. This difference could be due to the chance occurrence of a low mortality rate in those randomized to angioplasty. The excess of myocardial infarctions after atherectomy remains statistically significant at 1 year. Further investigation is warranted to improve the safety of atherectomy.

Aged↗
PubMed1995

Epidermal growth factor receptor-targeted cytotoxin inhibits neointimal hyperplasia in vivo. Results of local versus systemic administration.

Smooth muscle cell accumulation is a key feature of restenosis that may be inhibited by the delivery of receptor-targeted cytotoxins. DAB389EGF is a recombinant fusion protein in which the receptor-binding domain of diphtheria toxin has been replaced by human epidermal growth factor (EGF). We investigated the effectiveness of DAB389EGF to inhibit neointimal hyperplasia in the balloon-injured rat carotid artery. Incubation of rat carotid arteries with 125I-labeled EGF revealed extensive EGF binding sites in the neointima of balloon-injured arteries. Sixty rats subsequently received either saline or DAB389EGF (total dose, 0.15 mg) delivered immediately following balloon injury either systemically, via 14-day continuous osmotic pump infusion, or locally, via 30-minute intraluminal incubation. The effect of both treatment strategies was measured 2 weeks after injury by cross-sectional morphometric analysis of intimal area, the ratio of intimal/medial area (I/M), and the percent luminal narrowing (%LN). In addition, proliferative activity was assessed by immunostaining for the presence of the proliferating cell nuclear antigen (PCNA). Compared with controls, systemic delivery of fusion toxin significantly reduced intimal area, I/M, and %LN by 40%, 40%, and 29%, respectively. However, these rats exhibited 2% weight loss, indicating mild systemic toxicity. Local, intraluminal administration of DAB389EGF yielded a more pronounced reduction in intimal area, I/M, and %LN by 74%, 79%, and 72%, respectively. This inhibitory effect was preserved at 3 weeks postinjury, and PCNA immunostaining of locally treated arteries revealed a virtual absence of proliferative activity in the neointima and media at this timepoint. In contrast to systemically treated rats, rats receiving fusion toxin locally gained weight at a rate similar to controls, indicating avoidance of systemic toxicity. We conclude that DAB389EGF is a potent inhibitor of neointimal hyperplasia in vivo and that whereas an inhibitory effect may be achieved by systemic delivery, local delivery appears to be more potent, avoids systemic toxicity, and thus represents a feasible strategy to preempt restenosis.

Animals↗
PubMed1995

Low-efficiency of percutaneous adenovirus-mediated arterial gene transfer in the atherosclerotic rabbit.

Recombinant adenoviruses are the most efficient vectors with which to perform arterial gene transfer. Previous in vivo studies of adenovirus-mediated arterial transfection, however, have been performed using normal or endothelium-denuded arteries. It is unclear whether these results can be extended to atherosclerotic arteries. Accordingly, this study was designed to (a) assess the feasibility of adenovirus-mediated gene transfer to atherosclerotic lesions, and (b) compare the transfection efficiency, anatomic distribution of transfected cells, and duration of transgene expression achieved in normal versus atherosclerotic arteries. A recombinant adenovirus including a nuclear-targeted beta-galactosidase gene was percutaneously delivered to the iliac artery of normal (n = 25) and atherosclerotic (n = 25) rabbits. Transgene expression, assessed by morphometric as well as chemiluminescent analyses, was documented in all normal and atherosclerotic arteries between 3 and 14 d after gene transfer, but was undetectable at later time points. Transfected cells were identified as smooth muscle cells located in the media of normal arteries, and in the neointima and the vasa-vasora of atherosclerotic arteries. Two percent of medial cells, but only 0.2% of medial and neointimal cells expressed the transgene in normal and atherosclerotic arteries, respectively (P = 0.0001). Similarly, nuclear beta-galactosidase activity was higher in normal than in atherosclerotic arteries (3.2 vs. 0.8 mU/mg protein, P = 0.02). These findings indicate that atherosclerosis reduces the transfection efficiency which can be achieved with adenoviral vectors, and thus constitutes a potential limitation to adenovirus-based, arterial gene therapy.

Adenoviruses, Human↗
PubMed1995

Time course of increased cellular proliferation in collateral arteries after administration of vascular endothelial growth factor in a rabbit model of lower limb vascular insufficiency.

Proliferation of vascular cells has been previously shown to contribute to spontaneous development of coronary collaterals. Recent studies from several laboratories have established that collateral artery growth in both the heart and limb can be enhanced by administration of angiogenic growth factors, or therapeutic angiogenesis. In this study, we sought (1) to define the extent and time course of endothelial cell (EC) and smooth muscle cell (SMC) proliferation accompanying spontaneous collateral development during limb ischemia and (2) to determine the extent to which proliferative activity of ECs and SMCs is augmented during therapeutic angiogenesis with vascular endothelial growth factor (VEGF), a heparin-binding EC-specific mitogen. Ten days after induction of limb ischemia by surgically excising the femoral artery of rabbits, either VEGF (500 to 1000 micrograms) or saline was administered as a bolus into the iliac artery of the ischemic limb. Cellular proliferation was evaluated by bromodeoxyuridine labeling for 24 hours at day 0 (immediately before VEGF administration) and at days 3, 5, and 7 after VEGF, EC proliferation in the midzone collaterals of VEGF-treated animals increased 2.8-fold at day 5 (P < 0.05 versus control), and returned to baseline levels by day 7. SMC proliferation in midzone collaterals also increased 2.7-fold in response to VEGF (P < 0.05). No significant increase in EC or SMC proliferation was observed in either the stem or re-entry collaterals of VEGF-treated animals compared with untreated ischemic control animals. Reduction of hemodynamic deficit in the ischemic limb measured by lower limb blood pressure was documented at day 7 after VEGF (P < 0.01 versus untreated, ischemic control). These data thus (1) establish the contribution of cellular proliferation to collateral vessel development in limb ischemia and (2) support the concept that augmented cellular proliferation contributes to the enhanced formation of collateral vessels after therapeutic angiogenesis with VEGF.

Animals↗
PubMed1994

Pathology of Unstable Angina: Analysis of Biopsies Obtained by Directional Coronary Atherectomy.

Background: The transient and generally nonfatal nature of unstable angina has impaired the accumulation of pathologic data and the definition of the pathoanatomy of this syndrome. Methods: Atherectomy specimens from patients enrolled in CAVEAT were examined for the presence of thrombus, foam cells, cholesterol clefts, media, and adventitia. Comparison of the pathologic findings was made according to clinical presentation in the following categories: stable angina, unstable angina, and recent myocardial infarction. Results: Patients with unstable angina had. a slightly higher incidence of thrombus when compared with patients presenting with stable angina (36% vs. 26%, p =.14). Within the unstable angina population some subgroups demonstrated a greater incidence of thrombus, including those whose pain was associated with ECG changes (43%, p =.07). The incidence of thrombus was highest among patients who had a myocardial infarction within 30 days (53%, p =.004) or within 14 days (58%, p =.003). No difference between the patient groups was detected with respect to the other histologic findings. Conclusions: Atherectomy specimens from patients with unstable angina demonstrated a trend toward increasing incidence of thrombus, but this trend did not achieve statistical significance. Specimens from patients with a recent myocardial infarction did not demonstrate a significant increase in the presence of thrombus. While thrombus is a component of the pathophysiology of unstable angina in a significant number of patients, continued study is required to determine the other factors that are responsible.

Journal Article↗
PubMed1994

Use of the rabbit ear artery to serially assess foreign protein secretion after site-specific arterial gene transfer in vivo. Evidence that anatomic identification of successful gene transfer may underestimate the potential magnitude of transgene expression.

BACKGROUND: The development of molecular strategies for the treatment of restenosis has been hindered by low efficiencies of in vivo arterial transfection. Expression of intracellular marker proteins is generally evident in < 1% of vascular smooth muscle cells after in vivo arterial transfection. Efforts to improve the efficiency of in vivo gene transfer have been further impeded by the use of transgenes encoding for intracellular marker proteins, necessitating tissue removal and limiting survey for expression to one point in time. METHODS AND RESULTS: To study gene expression on a serial basis in vivo and determine the relation between a secreted gene product and transfection efficiency after in vivo arterial gene transfer, a method for performing and serially monitoring gene expression in vivo was developed using the central artery of the rabbit ear. Liposome-mediated transfection of plasmid DNA containing the gene for human growth hormone (hGH) was successfully performed in 18 of 23 arteries. Serum hGH levels measured 5 days after transfection ranged from 0.1 to 3.8 ng/mL (mean, 0.97 ng/mL); in contrast, serum drawn from the control arteries demonstrated no evidence of hGH production. Serial measurement of hGH from transfected arteries demonstrated maximum hGH secretion 5 days after transfection and no detectable hormone after 20 days. Despite these levels of secreted gene product documented in vivo, immunohistochemical staining of sections taken from the rabbit ear artery at necropsy disclosed only rare cells in which there was evidence of successful transfection. CONCLUSIONS: These experiments demonstrate a useful method of performing serial in vivo analyses of gene expression after vascular transfection and that anatomic analyses of transfection efficiency may underestimate the potential magnitude of expression in the case of a secreted gene product. These findings have implications for the clinical application of somatic gene therapy because low-efficiency transfection with a gene encoding for a secreted protein may achieve therapeutic effects not realized by transfection with genes encoding for proteins that remain intracellular.

Animals↗