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Biomedical subjects

A Farb

Publications and source records attributed to A Farb.

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

Estradiol attenuates directed migration of vascular smooth muscle cells in vitro.

Although the cardiovascular benefits of the hormone estrogen are at least, in part, mediated by its antiproliferative effect on vascular smooth muscle, its action on the migration of these cells is unknown. To explore this relationship, female rat aortic smooth muscle cells were grown in hormone-free medium, and the effect of various concentrations of beta-estradiol on directed cellular migration was measured in vitro using a microwell Boyden chamber apparatus. Migration of smooth muscle cells to the known chemoattractants platelet-derived growth factor, insulin-like growth factor-1, and fibronectin (all at peak doses for migratory activity) was attenuated by beta-estradiol (0.5 to 10 ng/ml) in a concentration-dependent manner relative to control cells treated with vehicle (0.01% ethanol). This response was insensitive to pretreatment with indomethacin and was stereospecific (17 alpha-estradiol lacked response). Like beta-estradiol, the synthetic estrogen diethylstilbestrol attenuated directed smooth muscle cell migration whereas the male hormone testosterone was ineffective. Additional studies showed that beta-estradiol-mediated suppression of migration was inhibited by the anti-estrogen ICI 164,384 and the gene transcription inhibitor actinomycin D. These are the first results demonstrating a reduction in directed smooth muscle cell migration by beta-estradiol. The mechanism of this estrogen-mediated response appears to involve conventional estrogen receptors.

Animals↗
PubMed1995

Sudden coronary death. Frequency of active coronary lesions, inactive coronary lesions, and myocardial infarction.

BACKGROUND: The reported frequency of active coronary lesions (plaque rupture and coronary thrombosis) in sudden death due to coronary artery atherosclerosis (sudden coronary death) has varied from < 20% to > 80% of cases in previous series. In hearts lacking an active coronary lesion, sudden death has usually been attributed to a healed myocardial infarction. The purpose of the present study was to determine the frequency of active and inactive coronary lesions and myocardial infarction in individuals with sudden coronary death. METHODS AND RESULTS: The hearts of persons who died as a result of sudden coronary death underwent perfusion-fixation and postmortem angiography. An active coronary lesion was defined as a disrupted plaque, luminal fibrin/platelet thrombus, or both. We defined an inactive lesion as having a cross-sectional luminal stenosis of > or = 75% with neither plaque disruption nor luminal thrombus. Ninety hearts were examined (from 72 men and 18 women; mean age at the time of death, 51 +/- 10 years). Acute myocardial infarction was present in 19 (21% [acute myocardial infarction only in 9, both acute and healed myocardial infarction in 10]), healed myocardial infarction only in 37 (41%), and no myocardial infarction in 34 (38%). Active coronary lesions were identified in 51 (57%): acute thrombi plus disrupted plaques in 27, acute thrombi only in 21, and disrupted plaques only in 3. In hearts with acute myocardial infarction, active coronary lesions were significantly more prevalent than in hearts with only healed myocardial infarction or hearts lacking an acute or a healed myocardial infarction (89%, 46%, and 50%, respectively; P < .005). Hearts without acute or healed myocardial infarction and without active lesions were similar to hearts with active lesions with respect to heart weight and severity of epicardial coronary disease. CONCLUSIONS: Acute changes in coronary plaque morphology (thrombus, plaque disruption, or both) were found in 57% of cases of sudden coronary death. In hearts with myocardial scars and no acute infarction, active coronary lesions were identified in 46% of cases. Neither myocardial infarction (acute or healed) nor an active coronary lesion was present in 19% of hearts.

Coronary Angiography↗
PubMed1995

Localized drug delivery in atherosclerotic arteries via a new balloon angioplasty catheter with intramural channels for simultaneous local drug delivery.

A dual-purpose angioplasty catheter with intramural channels and exterior pores for local drug delivery ("channeled balloon") was studied in eight atherosclerotic human necropsy arteries and in 22 rabbits with atherosclerotic peripheral arteries, in which markers (0.005 microns to 15 microns) were infused locally at 2 atmospheres during simultaneous angioplasty at 6 atmospheres. Thirteen of the rabbits were sacrificed at 4 or 24 h after procedure to determine the intramural retention over time. Histology confirmed effective angioplasty and revealed presence of markers in the arterial wall in 29 of 43 treated arteries (67%), whereas all control segments without local delivery had no marker staining. majority of the ineffective local delivery (12/14) occurred when 15 micron particles were infused (12/13 arteries without intramural markers), especially when examined 4 or 24 h later. Thus, in atherosclerotic arteries, the channeled balloon enabled simultaneous local drug delivery at low pressure during effective angioplasty, although particle size may play a role in successful intramural impregnation and retention.

Angioplasty, Balloon↗
PubMed1995

Coronary artery morphologic features after coronary rotational atherectomy: insights into mechanisms of lumen enlargement and embolization.

The coronary arteries and myocardium from two patients who died after coronary rotational atherectomy were analyzed to gain insights into the mechanisms of lumen enlargement and to document embolization of calcified plaque. Rotational atherectomy resulted in sharp cuts in plaque, producing a relatively smooth luminal surface. When extensive nodular calcific atherosclerosis was present, the luminal surface was focally uneven with exposure of jagged calcified plaque to blood flow. Deep plaque fissures and medial dissections were also seen. These fissures may have been created by the rotoblator or by adjunctive balloon angioplasty. Multiple calcific atheroemboli were present after rotoblator use in plaques containing extensive nodular calcification; in moderately calcified plaque only one small atheroembolus was found. Thus embolization of calcified plaque can occur after rotational atherectomy and may correlate with the severity of plaque calcification. Rotational atherectomy produces a focally smooth, sharp-edged, luminal surface, a lumen enlargement mechanism different from balloon angioplasty.

Aged↗
PubMed1995

Sudden death as a result of heart disease in morbid obesity.

Patients with morbid obesity have high rates of sudden, unexpected cardiac death. The mechanism of death in these patients is uncertain. Twenty-eight patients with morbid obesity (22 sudden cardiac deaths, 6 unnatural deaths) were compared to 11 age-matched nonobese patients with traumatic deaths. Heart weight, left ventricular cavity diameter, left and right ventricular wall thickness, ventricular septal thickness, epicardial fat thickness, and extent of coronary artery atherosclerosis were determined; myocyte size, nuclear size, and degree of interstitial fibrosis were calculated morphometrically. Mean heart weights in the patients with morbid obesity were increased but remained constant as a percentage of body weight. Of the gross parameters, only heart weight and left ventricular cavity size were independent predictors of obesity. Of microscopic parameters, only nuclear area was an independent predictor of obesity. Of 22 patients with morbid obesity, dilated cardiomyopathy was the most frequent cause of sudden cardiac death in (10 patients), followed by severe coronary atherosclerosis (6), concentric left ventricular hypertrophy without left ventricular dilatation (4), pulmonary embolism (1), and hypoplastic coronary arteries (1). The cardiomyopathy of morbid obesity is characterized by cardiomegaly, left ventricular dilatation, and myocyte hypertrophy in the absence of interstitial fibrosis. It is the most common cause of sudden cardiac death in these patients.

Adult↗
PubMed1995

A modified directional atherectomy catheter for resection of calcified atherosclerotic plaques.

BACKGROUND: The purpose of this study was to determine the feasibility of resecting calcified atherosclerotic plaques in human cadaveric vessels by using a modified directional coronary atherectomy catheter and to correlate these results with bench tests using an in-vitro sea coral model. METHODS: The conventional directional coronary atherectomy catheter was modified by changing the cutter blade to a tungsten carbide material and by increasing the torsional strength of the drive cable. The performance of the modified directional coronary atherectomy (DCA) catheter was compared with the conventional catheter using a sea coral model to simulate calcified material. Then, 10 human ex-vivo arteries (eight with calcification) were treated with both conventional and modified catheters, and the results studied with intravascular ultrasound and confirmed by histologic examination. RESULTS: Using the modified directional coronary atherectomy catheter it was possible to perform effective and consistent longitudinal cutting, and to resect a significantly larger amount of coral (1.0 +/- 0.1 mm2 versus 0.2 +/- 0.1 mm2 with conventional cutter, P < 0.0001). In heavily calcified ex-vivo arteries, the modified catheter was more effective in removing calcified plaques (13 +/- 11 mg versus 3.7 +/- 1.4 mg with conventional cutter, P = 0.07). Intravascular ultrasound confirmed the effective atherectomy (residual area stenosis 28 +/- 16% versus 47 +/- 10% with the conventional device, P < 0.05), and histologic examination showed calcified nodules in the atherectomy samples obtained with the modified cutter (area of calcium 1.43 +/- 0.89 mm2 versus 0.93 +/- 0.83 mm2 with the conventional cutter). CONCLUSIONS: The modified directional coronary atherectomy catheter effectively removed both non-calcified and calcified plaques in the ex-vivo human cadaveric arteries, thus demonstrating the feasibility of directional coronary atherectomy of calcified plaques. This modified device shows promise for treating calcified coronary lesions, especially in larger vessels.

Animals↗
PubMed1995

Problems in forensic cardiovascular pathology.

Do we have a magic yardstick that will establish whether SCD of the patient is definitely caused by the presence of an underlying abnormality? We are afraid that in most cases of cardiac disease the cause of death is at best probable, or even presumed. It has always been that circumstantial evidence has helped us establish that the cause of death is related to the anatomic abnormality. Even the presence of severe coronary artery disease in a patient who dies suddenly, especially in the absence of a thrombus, cannot be stated categorically to be the cause and effect. With the knowledge we have today, establishing cause and effect are difficult in most cases of SCD.

Adolescent↗
PubMed1995

Studies on the carcinogenic and myocardial effects of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) in nonhuman primates.

The heterocyclic aromatic amine 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) is one of three heterocyclic amine mutagens currently being evaluated for carcinogenic activity in nonhuman primates, primarily cynomolgus monkeys. IQ was administered by gavage five times a week at doses of 10 or 20 mg/kg. Thus far IQ induced tumors in 50 percent of the monkeys at the 10 mg/kg dose and in 85 percent of the monkeys at the 20 mg/kg dose. Because H and E sections of the myocardium from IQ-treated animals demonstrated inflammatory infiltrate and studies of IQ-DNA adducts in monkeys, by the 32P-postlabeling method, showed high levels of adducts in the heart a systematic study of cardiac pathologic changes associated with chronic administration of IQ was undertaken. Both light and electron microscopic abnormalities were seen. The possibility exists that heterocyclic aromatic amines may be etiologic factors for human cancer and myocardial disease.

Administration, Oral↗
PubMed1994

Long-term histologic patency after percutaneous transluminal coronary angioplasty is predicted by the creation of a greater lumen area.

OBJECTIVES: This study assessed the relation between histologic acute and long-term lumen size after coronary angioplasty. BACKGROUND: Angiographic studies suggest that the creation of a larger acute lumen is associated with a reduced incidence of restenosis. Histologic evaluation of the influence of the acute lumen on late outcome has not been previously reported. METHODS: Detailed histologic examination and planimetry were performed in 28 postmortem coronary arteries subjected to angioplasty at an average of 71 weeks antemortem. The lumen area on each histologic segment was defined as the final lumen area. The lumen area immediately after angioplasty, the acute lumen area, was defined by the sum of the neointimal area plus final lumen. A final lumen area > or = 25% of the arterial area was considered a long-term success; a final lumen area < 25% was considered a long-term failure. RESULTS: Arterial size and neointimal area were similar in long-term successes and failures. In successes, the mean (+/- SD) acute lumen area was greater than in failures (4.1 +/- 1.9 vs. 2.7 +/- 1.4 mm2, respectively, p < 0.001). The acute lumen area as a percent of arterial area was 46 +/- 10% in successes versus 27 +/- 11% in failures (p < 0.0001). The corresponding estimated mean acute lumen diameter stenosis was 24 +/- 8% in successes versus 42 +/- 12% in failures (p < 0.0001). Plaque area was greater in failures (7.1 +/- 3.2 mm2) than in successes (4.8 +/- 2.4 mm2, p < 0.002). CONCLUSIONS: Neointimal proliferation after angioplasty occurs in all dilated coronary arteries, and the amount of neointimal growth is independent of vessel size. The creation of a larger lumen and a larger lumen as a percent of vessel size were associated with an improved long-term histologic patency.

Angioplasty, Balloon, Coronary↗
PubMed1994

Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model.

OBJECTIVES: This study was performed to define the evolution of lesion morphology and its relation to thrombus formation and smooth muscle cell proliferation after experimental coronary stent placement. BACKGROUND: Restenosis after percutaneous revascularization may develop because of thrombus accumulation and smooth muscle cell proliferation. In animal models of restenosis, thrombus may assume a significant role in neointimal formation by providing an absorbable matrix into which smooth muscle cells proliferate. METHODS: Twenty-eight oversized stents were placed in the coronary arteries of 23 juvenile domestic pigs. The histologic degree of vessel injury, lesion morphometry and smooth muscle cell proliferation measured by immunolocalization with a monoclonal antibody to proliferating cell nuclear antigen (PCNA) were assessed at 24 h and 7, 14 and 28 days after stent placement. RESULTS: The area of thrombus was minimal at 24 h ([mean +/- SE] 0.44 +/- 0.12 mm2). Neointimal area at 7 days (0.72 +/- 0.20 mm2) was similar to the area of thrombus, followed by a significant increase at 14 days (3.15 +/- 0.39 mm2) and 28 days (3.30 +/- 0.28 mm2) (p < 0.0036, 24 h and 7 days vs. 14 and 28 days). At 14 and 28 days, neointimal thickness correlated with the histologic degree of vessel injury (p < 0.003). In arteries with severe injury, the increase in neointimal thickness is accounted for by replacement of the damaged media. The smooth muscle cell proliferation index was 18.6 +/- 3.5% at 7 days compared with 9.6 +/- 1.3% by 14 days (p = 0.0247) and declined to 1.1 +/- 0.97% by 28 days (p < 0.008, 7 and 14 days vs. 28 days). CONCLUSIONS: Early thrombus formation is minimal, and thrombus accounts for a small portion of subsequent neointimal formation. Smooth muscle cell proliferation and matrix formation are the major factors relating to neointimal formation in this proliferative model of restenosis. The evolution of neointimal formation after coronary stenting shows maximal smooth muscle cell proliferation at 7 days, with a decline to low levels by 28 days. Therefore, these data may be useful for developing effective therapies for restenosis.

Animals↗
PubMed1994

The contribution of tissue removal to lumen improvement after directional coronary atherectomy.

The contribution of tissue removal to lumen improvement after directional coronary atherectomy remains controversial. The purpose of this study was to validate the intravascular ultrasound measurement of plaque volume and use it to study the contribution of tissue removal to lumen improvement after directional coronary atherectomy. With use of intravascular ultrasound, 12 human coronary vessels were imaged in vitro. With use of computer-assisted planimetry, the external elastic membrane and lumen cross-sectional areas were manually traced and the plaque+media area was calculated at 1 mm axial intervals. Then, plaque+media volume was calculated by Simpson's rule. After imaging, ultrasound measurements of plaque+media volume were compared with histologic measurements. Similarly, volumetric intravascular ultrasound imaging was performed before and after directional atherectomy in 47 patients. In vitro, the mean plaque+media volume measured by intravascular ultrasound was 134.0 +/- 94.8 mm3 and compared well with that derived by histology (187.4 +/- 128.8 mm3, r = 0.96, p < 0.001). In vivo, the lumen volume increased from 27.2 +/- 12.3 to 58.7 +/- 30.3 mm3, and the mean plaque+media volume decreased from 122.0 +/- 74.0 to 97.5 +/- 63.5 mm3. The mean intravascular ultrasound atherectomy index was 76 +/- 23%. In 11 of the 47 patients (23.4%), tissue removal alone accounted for lumen improvement. Volumetric intravascular ultrasound image analysis indicates that the mechanism of directional coronary atherectomy primarily is tissue removal. As a result, the contribution of arterial remodeling (expansion and dissection) probably is less important.

Aged↗
PubMed1994

Placement and angiographic patency of the Strecker coronary stent.

The Strecker stent is a newer, balloon-expandable vascular prosthesis consisting of a single tantalum filament knitted into a flexible mesh tube. To test the placement characteristics and patency of this device, we implanted 29 stents in the coronary arteries of 24 juvenile Yorkshire swine. Seventeen stents were placed in the left anterior descending artery, and 12 were placed in the left circumflex system. All stents were deployed successfully. Four animals died within the first 24 hr of anesthesia-related complications. The remaining animals were sacrificed at 24 hr, 1 week, 2 weeks, or 4 weeks. Follow-up angiography demonstrated the patency of all stents. There were no episodes of stent migration or side branch occlusion. The Strecker stent has several favorable characteristics, including its unique delivery system, ease of deployment, flexibility, radiopacity, and radial strength. There was 100% patency at up to 4 weeks in this animal model. Further studies are required to define whether the knitted mesh design offers any advantage over previous models.

Angioplasty, Balloon, Coronary↗
PubMed1994

Coronary artery lumen volume measurement using three-dimensional intravascular ultrasound: validation of a new technique.

OBJECTIVE: To validate an automated algorithm for the measurement of lumen volumes of coronary arteries. BACKGROUND: Current intravascular ultrasound systems use absolute measurements of and changes in areas and diameters for the assessment of coronary artery disease. However, the coronary artery is a three-dimensional structure of complex geometry and volume. METHODS: We used a comprehensive imaging system designed to reconstruct planar intravascular ultrasound images in three dimensions. This system consisted of a 25 MHz transducer-tipped rigid probe (for in vitro studies) or a 25 MHz transducer-tipped catheter within a 3.9F monorail imaging sheath (for in vivo studies), a motorized catheter pullback device that withdrew the transducer at 0.5 mm/sec, and an image processing computer that stacked 15 image slices/mm of vessel axial length and then performed threshold-based three-dimensional image rendering and lumen volume measurement. We imaged 13 human coronary vessels (6 RCA, 6 LAD, 1 LCX) in vitro and 16 vessels (8 LAD, 6 RCA, 2 SVG) in vivo. RESULTS IN VITRO STUDIES: Lumen volumes derived by three-dimensional intravascular ultrasound were 171 +/- 121 mm3 and compared very well with those derived by histology (160 +/- 109 mm3, r = 0.97, SEE = 29 mm3, P < 0.001) and with those derived by manual planimetry of planar intravascular ultrasound images (150 +/- 106 mm3, r = 0.97, SEE = 30 mm3, P < 0.001). In vivo studies: Lumen volumes derived by three-dimensional intravascular ultrasound were 74 +/- 35 mm3 and compared well with those derived by quantitative angiography (52 +/- 20 mm3, r = 0.71, SEE = 25 mm3, P < 0.002). CONCLUSIONS: Three-dimensional intravascular ultrasound is a new technique that can accurately measure coronary artery lumen volumes. Further technical improvements may help to establish this technique as the new standard for lumen volume measurement.

Adult↗
PubMed1994

Cardiotoxicity of heterocyclic amine food mutagens in cultured myocytes and in rats.

Cooked meat contains a number of mutagenic/carcinogenic heterocyclic amines, including 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP). We recently observed that monkeys treated with IQ showed myocyte degeneration and mitochondrial changes. Thus, it was of interest to develop models to investigate heterocyclic amine cardiotoxicity. Primary cultures of fetal rat myocytes were exposed to the activated forms of the carcinogens (N-OH-IQ and N-OH-PhIP). LDH leakage increased in proportion to the carcinogen dose but was significantly greater in cells exposed to N-OH-IQ than that in cells exposed to N-OH-PhIP. Electron microscopy revealed that treated cells had swollen and irregular mitochondria and fewer organelles. However, DNA adducts, assessed using the 32P-postlabeling method, were significantly higher in myocytes exposed to N-OH-PhIP than in cells exposed to N-OH-IQ. The toxic effects of heterocyclic amines were also evaluated in rats given IQ or PhIP (100 mg/kg, po 10 doses over 2 weeks). Light microscopic and ultrastructural cardiac abnormalities were present in seven of eight rats exposed to IQ or PhIP. Whereas control animals had a normal cardiac morphology, carcinogen-treated animals had foci of chronic inflammation with myocyte necrosis, myofibrillar dissolution and disarray, and dilation of T-tubules. These results suggest that, in addition to being carcinogenic, food mutagens may play a role in cardiac degeneration.

Animals↗
PubMed1994

Coronary angioplasty from the perspective of atherosclerotic plaque: morphologic predictors of immediate success and restenosis.

High restenosis rates continue to plague the overall efficacy of percutaneous transluminal coronary balloon angioplasty (PTCA). It is not surprising that predictions of long-term success or failure of PTCA based on coronary angiography are of limited value because these images provide only a circumscribed view of the arterial lumen and offer little insight into underlying plaque morphologic characteristics. Coronary atherosclerotic lesions are quite diverse with respect to plaque characteristics (eccentricity, concentricity, and extent of fibrosis, necrosis, and calcification) and cardiac ischemic syndromes (stable angina, unstable angina, myocardial infarction, and sudden cardiac death). It could thus be expected that dissimilar plaques will respond differently to balloon dilatation, and that plaque morphologic features may play an important role in the immediate and long-term outcome after PTCA. Histologic evaluation of de novo atherosclerotic plaques underscores the heterogeneity of coronary atherosclerosis. From pathologic examination of human coronary arteries subjected to PTCA during life, expansion of the arterial circumference via medial damage is required for an effective increase in lumen size. Eccentric plaques and plaques with a large necrotic core are more likely to be successfully dilated compared to concentric, fibrotic lesions. Intravascular ultrasound studies of PTCA have supported histologic findings. Restenosis involves the complex interaction of growth factors and cytokines, cellular elements (endothelial cells, smooth muscle cells, platelets, and inflammatory cells), and the extent of arterial injury. The effects of underlying plaque morphologic features on the vascular biology of restenosis requires further clarification.

Angioplasty, Balloon, Coronary↗
PubMed1994

Hyperoxic reperfusion is required to reduce infarct size after intravenous therapy with perfluorochemical (Fluosol-DA 20%) or its detergent component (poloxamer 188) in a poorly collateralized animal model. Absence of a role of polymorphonuclear leukocytes.

OBJECTIVES: The aim of this study was to assess whether hyperoxic reperfusion contributes to the efficacy of Fluosol 20% or poloxamer 188 for infarct size reduction and whether suppression of polymorphonuclear leukocyte function is responsible for cardioprotection. BACKGROUND: The perfluorochemical Fluosol and its detergent component poloxamer 188 limit myocardial reperfusion-induced injury; however, the underlying mechanism(s) are uncertain. METHODS: A series of in vivo and ex vivo studies were performed in a 30-min temporary coronary occlusion rabbit model. Before reperfusion, rabbits received a 25-ml/kg infusion of 1) Fluosol; 2) poloxamer 188 (equivalent % w/v to Fluosol, 675 mg/kg body weight); or 3) 5% dextrose (control). In protocol A, animals were subjected to either normoxic or hyperoxic reperfusion; in protocols B and C, hyperoxic reperfusion was studied. In protocol B, myocardial blood flow was assessed. In protocol C, polymorphonuclear leukocyte function and myocardial myeloperoxidase were determined. RESULTS: In rabbits subjected to normoxic reperfusion, infarct size (normalized to risk region weight) was not significantly different among groups. In rabbits subjected to hyperoxic reperfusion, infarcts were significantly reduced with both poloxamer 188 and Fluosol treatment compared with control animals (p = 0.05 and p = 0.0004, respectively). Blood flow at 3 h of reperfusion within the ischemic endocardium was greater in the Fluosol and poloxamer 188 groups than in the control group (p = 0.001 and p = 0.08, respectively). Myeloperoxidase activity was not affected by treatment, nor was there suppression of polymorphonuclear leukocyte function. CONCLUSIONS: Fluosol and poloxamer 188 reduce infarct size in rabbits subjected to hyperoxic reperfusion. Suppression of polymorphonuclear leukocyte function was not demonstrated, suggesting a greater role for increased arterial oxygen delivery in salvaging ischemic myocardium.

Animals↗
PubMed1994

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

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

Adenoviridae↗