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Biomedical subjects

J M Isner

Publications and source records attributed to J M Isner.

At least 181 records · Page 10Linked to original sources
PubMed1994

Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.

Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiologic and pathologic angiogenesis. In this study we investigated the hypothesis that the angiogenic potential of VEGF is sufficient to constitute a therapeutic effect. The soluble 165-amino acid isoform of VEGF was administered as a single intra-arterial bolus to the internal iliac artery of rabbits in which the ipsilateral femoral artery was excised to induce severe, unilateral hind limb ischemia. Doses of 500-1,000 micrograms of VEGF produced statistically significant augmentation of collateral vessel development by angiography as well as the number of capillaries by histology; consequent amelioration of the hemodynamic deficit in the ischemic limb was significantly greater in animals receiving VEGF than in nontreated controls (calf blood pressure ratio, 0.75 +/- 0.14 vs. 0.48 +/- 0.19, P < 0.05). Serial angiograms disclosed progressive linear extension of the collateral artery of origin (stem artery) to the distal point of parent vessel (reentry artery) reconstitution in seven of nine VEGF-treated animals. These findings establish proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit. Such a strategy might ultimately be applicable to patients with severe limb ischemia secondary to arterial occlusive disease.

Angiography↗
PubMed1994

Time course of recombinant protein secretion after liposome-mediated gene transfer in a rabbit arterial organ culture model.

BACKGROUND: Little information exists regarding the time course of gene expression after arterial transfection. Accordingly, we sought to determine the time course of gene expression after liposome-mediated arterial gene transfer (lipofectin) using an arterial organ culture model. EXPERIMENTAL DESIGN: Explanted segments of rabbit descending thoracic aorta were maintained in organ culture. Arterial gene transfer, facilitated by cationic liposomes (Lipofectin), was performed with the plasmid pXGH5 encoding the human growth hormone (hGH) under the control of mouse metallothionein-1 promoter. RESULTS: The time course of hGH production after transfection with the plasmid pXGH5 was evaluated. Significant levels (181.0 +/- 33.9 ng/24 hours/gm) of hGH were detected within 24 hours post-transfection, reached a peak on day 7 (238.4 +/- 35.3 ng/24 hours/gm), and declined after day 10. At day 21, hGH could be observed in 50% of the arteries. Immunostaining with a monoclonal antibody for hGH revealed that only a small number of arterial cells (< 1%) were responsible for production of hGH. CONCLUSIONS: The organ culture model is a feasible and efficient means for investigating the kinetics of arterial gene transfer. Transfection of pXGH5 results in significant levels of hGH for up to 3 weeks, despite anatomic evidence of only limited gene expression. These data thus support the notion that the magnitude and/or duration of gene expression may be disproportionately high, relative to anatomic assessment of transfection efficiency in the case of a transgene encoding for a secreted protein.

Animals↗
PubMed1994

Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia.

BACKGROUND: Despite major advances in both surgical and percutaneous revascularization techniques, limb salvage and relief of ischemic pain cannot be achieved in many patients with diffuse peripheral vascular disease. Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiological and pathological angiogenesis. In this study, the therapeutic potential of intramuscularly administered VEGF was investigated in a rabbit model of chronic hindlimb ischemia. METHODS AND RESULTS: Ischemia was induced in the hindlimb of 24 New Zealand White rabbits by ligation of the distal external iliac artery and complete excision of the femoral artery. Ten days after the induction of limb ischemia (day 0), saline (group A, n = 7) or the 165-amino acid isoform of recombinant human VEGF (group B: 200 micrograms, n = 6; group C: 500 micrograms, n = 7; group D: 1000 micrograms, n = 4) was administered intramuscularly into the ischemic limb daily for 10 days. Angiography on day 30 after initiation of therapy revealed statistically significant dose-dependent augmentation of collateral vessels in the ischemic limb (angiographic score: group A, 13.0 +/- 1.1; group B, 21.2 +/- 1.8; group C, 27.3 +/- 1.4; group D, 31.5 +/- 2.5). Capillary density in the thigh muscles on day 30 was 1.6 times greater in VEGF groups versus controls (176 +/- 15.3 versus 113 +/- 27.3 per square millimeter, P < .05). Amelioration of the hemodynamic deficit in the ischemic limb was documented by calf systolic blood pressure ratio (group A, 0.52 +/- 0.02; group B, 0.67 +/- 0.02; group C, 0.73 +/- 0.01; group D, 0.82 +/- 0.03). "Clinical" improvement (incidence of calf muscle atrophy and distal limb necrosis: group A, 85.7%; group B, 33.3%; group C, 14.3%; group D, 0%) was greater in VEGF-treated than in control animals, again in a dose-dependent fashion. CONCLUSIONS: These findings demonstrate a significant dose-dependent augmentation in limb perfusion accompanied by evidence of increased collateral formation after intramuscular administration of VEGF in ischemic rabbit hindlimbs. This study thus supports the hypothesis that administration of VEGF to stimulate angiogenesis may represent a new therapeutic modality in the management of arterial insufficiency.

Animals↗
PubMed1994

Pathology of mitral commissurotomy performed with the Inoue catheter: implications for mechanisms and complications.

Pathologic findings were analyzed in 11 patients who had undergone percutaneous transvenous mitral commissurotomy (PTMC) from 1986 to 1992. Nine valves were obtained at mitral valve replacement and two were obtained at necropsy. These 11 specimens represented all cases studied pathologically among 96 patients undergoing PTMC at a single institution (St. Elizabeth's Medical Center) over this time period. Valvuloplasty was performed using a single balloon in three patients, double balloons in three patients, and the Inoue balloon in five patients. Regardless of the balloon used, fracture of commissural fusion was found to be the fundamental mechanism of success for PTMC. Conditions leading to failure of PTMC included inability to cross the valve, incomplete fracture of commissures, and severe subvalvular disease. Complications included hemodynamically significant atrial septal defect (ASD) and mitral regurgitation (MR). Etiology of MR included failure of leaflet coaptation, ruptured leaflet, and torn chordae, commissure, or papillary muscle. In this selected group of patients, no cases of left ventricular perforation were observed regardless of the technique employed. Hemodynamically significant ASD was observed only with standard single- and double-balloon techniques. MR, restenosis, and failed PTMC were observed with both standard and Inoue techniques.

Catheterization↗
PubMed1994

Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries.

Proteoglycans are important constituents of blood vessels and accumulate in various forms of vascular disease. Little is known concerning the proteoglycan composition of restenotic lesions formed after angioplasty and whether the proteoglycan composition of these lesions differs from that of primary atherosclerosis. Accordingly, we sought to characterize the distribution of two proteoglycans, biglycan and decorin, in primary atherosclerotic and restenotic lesions of human coronary arteries. Restenosis (n = 37) and primary (n = 11) lesions obtained from 48 patients by directional atherectomy of human coronary arteries were stained with antibodies against biglycan and decorin. To further characterize the extracellular matrix of restenotic tissues, we studied the co-distribution of these proteoglycans with collagen types I, III, and IV. The loose fibroproliferative tissue seen predominantly in restenosis lesions consistently stained positively for biglycan in patterns of deposition ranging from disseminated to homogeneous. The density and intensity of biglycan staining was correlated with the density of collagen type I and III fiber networks, both of which were observed to interweave among the loose fibroproliferative tissue. The compact connective tissue of primary atherosclerotic plaque was characterized by strong biglycan staining which co-localized with intense collagen type I and III staining. Only basement membrane-like structures rich in collagen type IV demonstrated negative biglycan staining. In contrast, loose fibroproliferative tissue exhibited no significant staining for decorin. Strong immunostaining for decorin, however, was found in primary atherosclerotic plaque. There are thus regional differences in the distribution of extracellular matrix proteoglycans of restenotic and primary human atherosclerotic lesions; these observations suggest that differences established for the biological roles of biglycan and decorin in other organ systems may extend as well to pathologically altered human coronary arteries.

Angioplasty, Balloon↗
PubMed1993

In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle.

5-Fluorouracil (5-FU) is a commonly employed chemotherapeutic agent. Among the various toxicities associated with 5-FU, cardiovascular toxicity, consisting principally of acute myocardial ischemia and/or myocardial infarction, has been reported in up to 8.5% of patients treated with this drug. While 5-FU-induced coronary vasospasm has been considered as a potential basis for such clinical toxicity, this hypothesis remains unsubstantiated by laboratory investigation. Accordingly, the present study was designed to investigate the hypothesis that 5-FU induces reversible vasoconstriction of vascular smooth muscle and to study the cellular mechanisms of such vasomotor alterations. To investigate the effects of 5-FU on the vasoreactivity of vascular smooth muscle, 479 exposures were performed in 105 rings of aorta freshly isolated from 23 New Zealand white rabbits. Vasoconstriction was documented in 20 of 86 (23%) rings exposed to 5-FU at 7 x 10(-5) M, 45 of 83 (54%) rings exposed to 5-FU at 7 x 10(-4) M, and 41 of 49 (84%) rings exposed to 5-FU at 7 x 10(-3) M. In each case, 5-FU-induced vasoconstriction was endothelium independent. Pretreatment of rings with 10(-9) M staurosporine, a protein kinase C (PK-C) inhibitor, reduced 5-FU-induced vasoconstriction from 25.0 +/- 6.5 to 2.5 +/- 1.7 mg; staurosporine at a concentration of 10(-8) M abolished 5-FU-induced vasoconstriction. Pretreatment of rings with 10(-7) M phorbol-12,13-dibutyrate, an activator of PK-C, increased the magnitude of 5-FU-induced vasoconstriction 23-fold, from 49.7 +/- 11.1 mg before to 1163.6 +/- 276.4 mg after phorbol-12,13-dibutyrate (P = 0.0002). Neomycin, an inhibitor of phosphoinositide turnover, did not alter the magnitude of 5-FU-induced vasoconstriction. Membrane receptor blockers, including the alpha-adrenergic receptor blocker phentolamine, the beta-adrenergic receptor blocker propranolol, the H1 receptor inhibitor diphenhydramine, the H2 receptor inhibitor cimetidine, the Ca2+ channel blockers verapamil and diltiazem, and the cyclooxygenase inhibitor indomethacin all failed to alter the magnitude of 5-FU-induced vasoconstriction. Furthermore, the 5-FU-related compounds uracil and floxuridine did not produce vasoconstriction. Finally, 5-FU-induced vasoconstriction was abolished by nitroglycerin. These results indicate that (a) 5-FU causes direct, endothelium-independent vasoconstriction of vascular smooth muscle in vitro, (b) this vasomotor response involves activation of PK-C, and (c) this response is independent of vasoactive cell membrane receptors, phosphoinositide turnover, or activation of the cyclooxygenase pathway.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Comparison of results of percutaneous balloon valvuloplasty in patients with mild and moderate mitral stenosis to those with severe mitral stenosis. The North American Inoue Balloon Investigators.

Most reported studies of percutaneous balloon valvuloplasty in adults with acquired mitral stenosis have used patients with severely stenosed valves. The risks and benefits of valvuloplasty were examined in a multicenter registry of patients to determine whether balloon valvuloplasty can effectively dilate less severely obstructed valves, and to clarify the role of this procedure in symptomatic patients with mild and moderate mitral stenosis. The study groups were derived from the North American Inoue Balloon Valvuloplasty Registry. Full hemodynamic data were available in 264 patients; 45 (17%) with mild or moderate mitral stenosis (mitral valve area > or = 1.3 cm2) were compared with the remaining 219 with severe mitral stenosis (valve area < 1.3 cm2). Percutaneous balloon valvuloplasty was performed using the anterograde transseptal technique with an Inoue balloon. The mean age of patients with mild and moderate mitral stenosis was 53 +/- 13 years, and all were symptomatic with a mean New York Heart Association functional class of 2.9 +/- 0.7. Balloon valvuloplasty resulted in an increase in calculated mitral valve area from 1.4 +/- 0.1 to 2.3 +/- 0.7 cm2 (p < 0.05), and a final valve area > or = 1.9 cm2 was achieved in 37 patients (82%). There were no procedural deaths, but complications included right atrial perforation, transient ischemic attack and emergency surgery for severe mitral regurgitation. One-year follow-up evaluation revealed symptomatic improvement in most patients (mean New York Heart Association class 1.4 +/- 0.6; p < 0.0001). However, 2 patients needed repeat valvuloplasty for restenosis, and 5 had mitral valve replacements.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Combined physiologic and anatomic assessment of percutaneous revascularization using a Doppler guidewire and ultrasound catheter.

Previous investigations have established the utility of intravascular ultrasound (IVUS) examination for the evaluation of arterial dimensions and qualitative changes following percutaneous revascularization. More recently, the feasibility of obtaining intravascular physiology findings before and/or after percutaneous revascularization by use of an intravascular Doppler Flowire (Cardiometrics) has been demonstrated. Accordingly, we investigated the feasibility of using this combined physiologic/anatomic approach to evaluate individuals undergoing percutaneous revascularization of stenotic or occluded coronary and peripheral arteries. A total of 76 patients were evaluated using the Flowire to guide an IVUS catheter. Revascularization of coronary and peripheral vascular stenoses and/or occlusions was achieved in these patients by balloon angioplasty, directional atherectomy, excimer laser angioplasty, and thrombolytic therapy, alone or in combination. Physiologic findings obtained with the Flowire reinforced conclusions regarding morphologic severity of candidate stenoses and anatomic adequacy of revascularization following IVUS examination. In certain ambiguous cases, information gained by one modality clarified information obtained with the other. Finally, one modality may also serve as an alternative when logistics preclude the serial use of both. The preliminary experience obtained in this feasibility trial confirmed that IVUS and the Flowire may be combined to assess both candidate lesions as well as postprocedural patency in patients undergoing percutaneous revascularization. The combination of anatomic and physiologic data available from IVUS and Flowire provides a far more sensitive and possibly more accurate analysis of the adequacy of revascularization than has been possible by angiography alone. The extent to which such a detailed investigation is required to optimize interventional therapy on a routine basis is the subject of subsequent investigations.

Angioplasty, Balloon↗
PubMed1993

Relation between activated smooth-muscle cells in coronary-artery lesions and restenosis after atherectomy.

BACKGROUND: Neointimal proliferation leading to restenosis frequently develops after coronary angioplasty. This process is associated with a change in vascular smooth-muscle cells from a contractile (quiescent) phenotype to a synthetic or proliferating (activated) one. We investigated whether the presence of activated smooth-muscle cells in coronary lesions at the time of coronary atherectomy predisposes patients to subsequent restenosis. METHODS: We used in situ hybridization to study the expression of messenger RNA in coronary-atherectomy specimens from 20 patients. Plaque material was hybridized with a probe for the B isoform of human nonmuscle myosin heavy chain, a major nonmuscle myosin isoform in activated, but not quiescent, smooth-muscle cells. Angiographic follow-up data were obtained a mean (+/- SD) of 174 +/- 54 days after atherectomy in 16 of the 20 patients, and the extent of recurrent luminal narrowing was analyzed quantitatively. The presence of restenosis was assessed by exercise thallium scintigraphy in the other four patients. RESULTS: Atherectomy specimens from 10 of the 20 patients showed hybridization with the probe, defined as the clustering of more than 20 silver grains per cell nucleus in more than 10 nuclei in five high-power fields (x250); specimens from the other 10 patients showed no such hybridization. At follow-up, restenosis had developed in 8 of the 10 patients with positive hybridization results, but was absent in 9 of the 10 patients with negative results (P = 0.007). The degree of late loss in luminal diameter was significantly higher in patients with positive hybridization results than in those with negative results (ratio of late loss to immediate gain after atherectomy, 0.76 +/- 0.3 vs. 0.36 +/- 0.3; P < 0.001). CONCLUSIONS: We conclude that the expression of the B isoform of nonmuscle myosin heavy chain is increased in some coronary atherosclerotic plaques and that this increase in expression identifies a group of lesions at high risk for restenosis after atherectomy.

Adult↗
PubMed1993

Effect of balloon size and stepwise inflation technique on the acute results of Inoue mitral commissurotomy. Inoue Balloon Catheter Investigators.

Currently percutaneous transvenous mitral commissurotomy (PTMC) is performed by most operators using stepwise inflation of the Inoue balloon beginning at a small diameter and increasing size by a sequence of inflations to nominal diameter. The effect of balloon size on procedure results using the Inoue balloon has not been evaluated. In 260 patients final balloon inflation was to nominal size in 42% of pts, larger than nominal size (overinflated) in 10%, and less than nominal size (underinflated) in 48% of pts. The average number of inflations was 3 (range 1-9). Pressure gradient and Doppler mitral regurgitation (MR) were assessed after each inflation. When MR increased, further inflations were not done. Patients in whom the balloon was overinflated underwent more balloon inflations than those in whom it was inflated to nominal size (5.0 +/- 2.1 vs. 2.9 +/- 1.4, p < 0.01). Those with balloon underinflation had fewer balloon inflations (2.4 +/- 1.2 vs. 2.9 +/- 1.4, p < 0.01). The post PTMC valve area in patients with overinflation was slightly less than those with nominal inflations (1.6 +/- 0.4 vs. 1.8 +/- 0.7), and with underinflation the valve area was no different compared to nominal inflation. Using a stepwise procedure, if mitral regurgitation was noted to increase after a balloon inflation, the procedure would be stopped even if less than an ideal result was achieved. Fewer inflations were done in patients in whom the balloon was inflated to less than nominal size because of the appearance of mitral regurgitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Calibration↗
PubMed1993

Inhibition of endothelium-dependent vasorelaxation by sickle erythrocytes.

Interactions between erythrocytes and vascular endothelium have been implicated in the pathogenesis of vaso-occlusion in sickle cell anemia. Sickle erythrocytes adhere to endothelial cells and facilitate trapping of rigid sickle cells in microvessels. Compensatory dilation of precapillary arterioles may mitigate the occlusion. The endothelium regulates vasoreactivity by elaborating endothelium-derived relaxing factor (EDRF), a small molecule that passes freely into vascular smooth muscle where it initiates vasorelaxation by activating soluble guanylate cyclase in the smooth muscle cell cytoplasm. Endothelial release of EDRF can be stimulated by agonists such as acetylcholine. It is highly sensitive to decomposition by superoxide anions and is rapidly bound and inactivated by oxyhemoglobin in solution. The purpose of this study was to determine whether sickle cell interaction with endothelium disrupts this mechanism of endothelial regulation of vasomotor tone. Transverse strips of rabbit aorta, mounted isometrically in organ baths, were contracted with norepinephrine, and relaxation responses to acetylcholine or other agonists were determined. Responses were measured under control conditions and again in the presence of oxyhemoglobin A or S, or erythrocytes or ghosts from normal control subjects or patients with homozygous sickle cell anemia. Sickle erythrocytes inhibited vasorelaxation to acetylcholine by 83%. Approximately half of the inhibition was attributable to a small amount of oxyhemoglobin S that was leaked into the buffer from the erythrocytes. Consistent with this, sickle erythrocyte ghosts inhibited vasorelaxation to acetylcholine by up to 45%. Ghosts from normal erythrocytes did not inhibit vasorelaxation to acetylcholine, and the inhibition seen with normal erythrocytes was entirely attributable to leakage of oxyhemoglobin A into the bath buffer.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Recommendations for training in vascular medicine. American College of Cardiology Peripheral Vascular Disease Committee.

Each trainee in vascular medicine must be eligible for the board certification examination of the American Board of Internal Medicine or its equivalent. Training faculty, preferably at least two members, should meet the qualifications and training requirements described in this report. They must be dedicated, effective teachers and should spend most of their time in research, education and patient care related to peripheral vascular diseases. A curriculum of training should be established. Faculty experts in related specialties and in the related basic sciences should be available for teaching. The institution should have a fully equipped noninvasive vascular laboratory and areas where catheter revascularization techniques and vascular surgery are performed. The period of training should not be less than 1 year, preferably continuous.

Cardiology↗
PubMed1993

Coronary artery perforation during excimer laser coronary angioplasty. The percutaneous Excimer Laser Coronary Angioplasty Registry.

OBJECTIVES: The aim of this study was to analyze the risk of vessel perforation during excimer laser angioplasty. BACKGROUND: Vessel perforation is a serious complication of angioplasty. METHODS: A total of 764 patients had 858 stenoses treated with excimer laser angioplasty. Laser catheters had a diameter of 1.4, 1.7 or 2 mm. Laser energy was delivered in pulses of 135 ns, at a frequency of 25 s-1 and at a fluence of 30 to 60 mJ/mm2. Follow-up angiography was requested for all patients who did not require emergency bypass surgery. RESULTS: In the 764 consecutive patients treated with excimer laser coronary angioplasty, vessel perforation occurred in 23 patients (3%). Nine patients had a major complication resulting directly from vessel perforation (cardiac tamponade, myocardial infarction or need for bypass surgery) and 14 had no clinical complications after successful sealing of the puncture site. No patient with a perforation died. Multivariate analysis showed that bifurcation lesions (odds ratio [OR] = 3.5; p = 0.049), diabetes mellitus (OR = 3.15; p = 0.029) and female gender (OR = 2.86; p = 0.013) were associated with an increased risk of vessel perforation. Lesions > 10 mm in length (OR = 0.45; p = 0.206), calcified stenoses (OR = 0.26; p = 0.088) and saphenous vein graft lesions (OR = 0.50; p = 0.295) were not at increased risk. Vessel perforation was seen in 10 (8.3%) of 120 lesions in which the laser catheter was equivalent in diameter to the target vessel (< or = 0.5 mm smaller in size) but in only 8 (1.5%) of 525 lesions in which the laser catheter was > 1 mm smaller than the target vessel (p = 0.001). CONCLUSIONS: Most lesions thought to be suitable for excimer laser treatment are not at increased risk of perforation. The complication may be avoided by improved patient and laser catheter size selection.

Adult↗