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K Craig Kent

Publications and source records attributed to K Craig Kent.

At least 37 records · Page 2Linked to original sources
PubMed2005

Rapamycin inhibits fibronectin-induced migration of the human arterial smooth muscle line (E47) through the mammalian target of rapamycin.

The matrix protein fibronectin (FN) is a potent agoinst of vascular smooth muscle cell (SMC) migration. The role of rapamycin and the mammalian target of rapamycin (mTOR) in matrix protein-induced migration has not yet been defined. In these studies, we found that rapamycin (10 nM) markedly diminished chemotaxis of E47 cells (a cell line derived from human atherosclerotic plaques) and rat aortic SMCs toward FN as well as type I collagen and laminin; however, a period of preincubation >20 h was required. Subsequently, we showed that treatment with FN induced a rapid activation of mTOR as well as its downstream effector, S6 kinase (S6K). Moreover, FN-induced activation of both proteins was inhibited by preincubation with rapamycin for only 30 min. We then explored the upstream signaling pathway through which FN might mediate mTOR activation. A blocking antibody to alpha(v)beta(3) inhibited FN-induced mTOR/S6K activation as well as E47 cell chemotaxis, implicating alpha(v)beta(3) as the integrin receptor responsible for initiating FN-induced migration. Moreover, preincubation of E47 cells with wortmannin or LY-294002 blocked FN-induced mTOR/S6K activation, demonstrating that phosphatidylinositol 3-kinase (PI3K) plays a critical role in this rapamycin-sensitive signaling pathway. It has been previously suggested that rapamycin's effect on migration maybe related to enhancement of p27(kip1). However, treatment of E47 cells with rapamycin did not alter the level of p27(kip1) in the presence or absence of FN. Taken together, our data demonstrate that rapamycin inhibits FN-induced SMC migration through a pathway that involves at least alpha(v)beta(3)-integrin, PI3K, mTOR, and S6K.

Androstadienes↗
PubMed2005

Tibial angioplasty as an alternative strategy in patients with limb-threatening ischemia.

The purpose of this study was to assess the technical feasibility and early outcome of tibial angioplasty for a subset of patients with limb-threatening ischemia who were not candidates for bypass grafting. A retrospective analysis was conducted of 19 patients (7 male, 12 female) who underwent crural angioplasty for limb-threatening ischemia using 0.018- or 0.014 inch-based systems. Contraindications to bypass were insufficient conduit in 7 patients and severe comorbid illness in 12. Concurrent treatment of inflow lesions was performed in 12 of 20 limbs via either angioplasty alone (5) or combined with stenting (12). Outcome measures were ankle-brachial indices (ABI), relief of rest pain, and healing or healed wounds. Twenty-three vessels were treated, including 14 tibial occlusions and 9 stenoses. The average length of diseased segment was 11 cm (range, 3-25 cm). Thirteen of 14 occlusions were treated with subintimal recanalization, the remainder with laser recanalization. Technical success was achieved in 22 of 23 treated vessels. Mean preoperative ABI was 0.53 and mean postoperative ABI was 0.85. Palpable pulses were present in 11 of 20 limbs (55%). There was one perioperative mortality (5.2%). Mean follow-up was 3 months. Three failures occurred requiring amputation (15.8%). The remaining 16 patients were improved with healing (8) or healed (4) wounds and relief of rest pain (4). These results indicate that technical success may be achieved with outflow lesion angioplasty in the majority of patients encountered. The durability of this method of therapy is unknown, and our length of follow-up is not sufficient to answer this question. However, an attempt at angioplasty appears justified before primary amputation and before surgical bypass in those patients at high risk for intervention.

Aged↗
PubMed2005

Percutaneous endovascular treatment for chronic limb ischemia.

Percutaneous transluminal methods of revascularization for chronic limb ischemia have traditionally been used as an adjunctive or secondary mode of treatment. This study examines the outcomes of patients treated via endovascular methods as the primary form of treatment. The records of 66 patients (average age, 71.3 years; range, 53 to 92) with chronic limb ischemia treated from November 2000 to January 2002 at a single institution with endovascular methods were retrospectively reviewed. Thirty-one patients had disabling claudication, 15 had rest pain, 17 had minor tissue loss, and 3 had major tissue loss. There were 94 lesions in the 66 limbs: 45 lesions in the superficial femoral artery, 28 lesions in the popliteal artery, and 21 lesions in tibial arteries. Occlusive lesions were treated by subintimal angioplasty. Stenoses were treated by percutaneous transluminal angioplasty (PTA). The median length of the lesions was 12 cm. Forty-six stents were placed in 32 patients; 34 patients did not receive stents. The approach was contralateral in 71% (47/66) and ipsilateral in 29% (19/66) of cases. Patients were followed up with physical exam, anklebrachial index (ABI), and duplex ultrasonography. Post-intervention medical treatment included aspirin and clopidogrel. Long-term patency was correlated with age, comorbidities, risk factors, and the use of stents in addition to angioplasty. Endovascular treatment was technically successful in 65 of 66 patients (98%). Residual stenosis (<30%) was found in three cases, two in patients with PTA alone and one patient with PTA and a stent. Mean length of follow-up was 6.3 months (range, 6 weeks to 15 months). Post-intervention ABI improved from a mean of 0.65 to a mean of 1.01 (p < 30.05). The perioperative complication rate was 9% and included three cases of hematoma and one case each of thrombosis, lymphocele, and rash reaction to medications. Outcome measures included primary patency (89%), assisted primary patency (96%), and limb salvage (97%) at 6 months. Restenosis of >50% occurred in four patients and occlusion occurred in two. At 6 months, patients with one or more stents had a patency rate of 84% (27/32), whereas those without a stent had a patency rate of 94% (32/34) (p = NS). Endovascular treatment is a safe, feasible, and effective method with a high short-term patency rate and may be used as an alternative to bypass for chronic limb ischemia.

Aged↗
PubMed2005

Multimodal percutaneous intervention for critical venous occlusive disease.

Critical deep venous thrombosis and occlusion constitutes a small percentage of patients with venous disease, who exhibit severe symptomatology. This study examined the results of multimodal percutaneous therapy for the treatment of complex critical venous thrombotic and occlusive disease. Twenty-five patients presented with critical venous thromboses or occlusions (11 with debilitating unilateral lower extremity edema causing ambulatory impairment, 2 with debilitating bilateral lower extremity edema, 3 with phlegmasia cerulea dolens, 2 with venous claudication, 2 with superior vena cava (SVS) syndrome with respiratory compromise, 4 with debilitating upper extremity edema, and 1 with renal insufficiency). Therapeutic modalities including thrombolysis, mechanical thrombectomy, percutaneous venoplasty and stent placement, temporary inferior vena cava filtration, and ultrasound guidance were used in all cases in conjunction with long-term systemic anticoagulation. The venous access site was determined by the anatomic location of the lesion and included popliteal, femoral, brachial, and lesser saphenous. Patients were followed with clinical exam and duplex surveillance. Resolution of symptoms was achieved in 18 of 25 patients (72%) and partial resolution occurred in 4 of 25 (16%). Failure of treatment identified as both lack of clinical response and evidence of continued venous thrombosis occurred 3 of 25 patients (12%). Restoration of arterial pulses and limb salvage was achieved in the three patients with phlegmasia cerulea dolens and acute limb-threatening ischemia. Both patients with SVC syndrome experienced resolution of respiratory compromise and facial edema. The mean length of follow-up was 11 +/- 2.7 months. Complications included transfusion requirement (2), hematuria (2), retroperitoneal hematoma (1), and cellulitis (1). Acute critical venous thrombotic and occlusive disease is responsive to multimodal percutaneous treatment. The relief of pain and resolution of acutely life and limb-threatening conditions in this most severely symptomatic subset of patients represents the immediate goal of treatment.

Algorithms↗
PubMed2005

Analysis of anatomic factors and age in patients undergoing carotid angioplasty and stenting.

Recent data suggest that patient age >80 years may be associated with increased risk of periprocedural complications from carotid angioplasty and stenting (CAS). In this study, we analyzed anatomic risk factors in patients undergoing CAS based on age >80 or <80 years. Our hypothesis was that patients >80 would have more challenging anatomy. Between February 2003 and August 2004, 82 patients underwent CAS. Images for 57 lesions were available for review. Eighteen patients were > or =80 years old and 39 were <80. Cerebral protection devices, including EPI Filterwire, Percusurge, Accunet, and Angioguard, were used in all but two cases; and self-expanding stents (Wallstent, NexStent, Acculink, Precise) were placed in all. Arterial anatomic characteristics were assigned a score based on complexity and associated procedural risk. Characteristics evaluated using angiographic images were aortic arch elongation classification, arch calcification, common carotid/innominate stenosis, common carotid tortuosity, internal carotid tortuosity, index lesion length, index lesion calcification, and index lesion stenosis. Statistical analysis was performed using Fisher's exact test. CAS was successfully completed in 98% of cases. The two patients in whom we could not perform CAS were 79 and 83 years old. The anatomic characteristics that were statistically significantly more complex/severe in patients > or =80 were arch calcification (p = 0.045), common carotid/innominate stenosis (p = 0.023), common carotid tortuosity (p = 0.049), and internal carotid tortuosity (p = 0.032). There was no statistically significant difference in arch elongation classification, lesion length, lesion calcification, or stenosis severity (p = nonsignificant). Overall, patients > or =80 years had an increased incidence of complex anatomic risk factors compared to younger patients (p < 0.001). Cerebrovascular accident without residual deficits occurred in two patients; both were >80 years old. Complex arterial anatomy is more often present in patients >80 years and may explain the increased complication rates associated with CAS. Pre- or intraoperative consideration of these characteristics may help provide better risk assessment in candidates for CAS.

Age Factors↗
PubMed2005

A canine model to study the significance and hemodynamics of type II endoleaks.

OBJECTIVE: The clinical significance of Type 2 endoleak after endovascular repair of abdominal aortic aneurysms (AAA) remains incompletely delineated. This study describes the development of a novel canine model that allows for continuous monitoring of intraaneurysmal pressure in the setting of Type 2 endoleak. METHODS: Infrarenal AAA were created in 10 mongrel dogs by implanting a prosthetic aneurysm containing an intraluminal, solid-state, strain gauge pressure transducer which is able to measure pressures in both solid and liquid media. A segment of native aorta with two or more patent side branch vessels was reimplanted into the prosthetic aneurysm using a Carrel patch. Four animals had two lumbar vessels implanted; two had two lumbar vessels and the caudal mesenteric artery implanted, and four control animals had no vessels reimplanted. Retrograde flow in the aneurysmal side branches caused a Type 2 endoleak after the aneurysm was excluded from antegrade flow by deploying a stent graft. Both systemic and intra-sac pressures were measured daily for up to 90 days after endovascular exclusion and indexed to systemic pressure. Endoleak patency and flow were assessed with digital subtraction angiography, duplex ultrasound, and cine-magnetic resonance angiography (MRA). Histological characterization of the intraaneurysmal contents was performed. RESULTS: Before endovascular exclusion, the systolic, mean arterial, and pulse pressure within the aneurysmal sac closely matched that of the systemic circulation (systolic, 0.96 +/- 0.22; mean, 0.94 +/- 0.21; pulse pressure, 0.97 +/- 0.22) (R value, 0.97). Endovascular exclusion in animals with no collateral side branch vessels resulted in no endoleak and significantly reduced intraaneurysmal pressure when compared to systemic pressure, with systolic, mean arterial, and pulse pressure 0.172 +/- 0.05, 0.137 +/- 0.05, and 0.098 +/- 0.02, respectively (P < 0.001). In animals with Type 2 endoleaks, the pressures were lower than systemic pressure, but statistically significant in their difference from the control group. The systolic pressure of those with Type 2 endoleaks was 0.702 +/- 0.048; mean arterial pressure was 0.784 +/- 0.028, and pulse pressure was 0.406 +/- 0.031 when indexed to systemic pressure (P < 0.001). Cine-MRA and Duplex ultrasound documented persistent patency of the Type 2 endoleaks throughout the study period in animals with multiple side branches. CONCLUSION: Intraaneurysmal pressure in the setting of Type 2 endoleaks may be accurately determined using this canine model. Intraaneurysmal pressure is maintained at a significant level in the context of this retrograde collateral perfusion, suggesting that persistent Type 2 endoleaks are of clinical significance. This model may serve to allow further evaluation and characterization of Type 2 endoleaks.

Angiography, Digital Subtraction↗
PubMed2005

Carotid angioplasty and stent-induced bradycardia and hypotension: Impact of prophylactic atropine administration and prior carotid endarterectomy.

OBJECTIVE: We compared the physiologic effect of selective atropine administration for bradycardia with routine prophylactic administration, before balloon inflation, during carotid angioplasty and stenting (CAS). We also compared the incidence of procedural bradycardia and hypotension for CAS in patients with primary stenosis vs those with prior ipsilateral carotid endarterectomy (CEA). METHODS: A total of 86 patients were treated with CAS at 3 institutions. Complete periprocedural information was available for 75 of these patients. The median degree of stenosis was 90% (range, 60%-99%). Indications for CAS were severe comorbidities (n = 49), prior CEA (n = 21), and prior neck radiation (n = 5). Twenty patients with primary lesions were treated selectively with atropine only if symptomatic bradycardia occurred (nonprophylactic group). Thirty-four patients with primary lesions received routine prophylactic atropine administration before balloon inflation or stent deployment (prophylactic group). The 21 patients with prior CEA received selective atropine treatment only if symptomatic bradycardia occurred (prior CEA group) and were analyzed separately. Mean age and cardiac comorbidities did not vary significantly either between the prophylactic and nonprophylactic atropine groups or between the primary and prior CEA patient groups. Outcome measures included bradycardia (decrease in heart rate >50% or absolute heart rate <40 bpm), hypotension (systolic blood pressure <90 mm Hg or mean blood pressure <50 mm Hg), requirement for vasopressors, and cardiac morbidity (myocardial infarction or congestive heart failure). RESULTS: The overall incidence of hypotension and bradycardia in patients treated with CAS was 25 (33%) of 75. A decreased incidence of intraoperative bradycardia (9% vs 50%; P < .001) and perioperative cardiac morbidity (0% vs 15%; P < .05) was observed in patients with primary stenosis who received prophylactic atropine as compared with patients who did not receive prophylactic atropine. CAS after prior CEA was associated with a significantly lower incidence of perioperative bradycardia (10% vs 33%; P < .05), hypotension (5% vs 32%; P < .05), and vasopressor requirement (5% vs 30%; P < .05), with a trend toward a lower incidence of cardiac morbidity (0% vs 6%; not significant) as compared with patients treated with CAS for primary carotid lesions. There were no significant predictive demographic factors for bradycardia and hypotension after CAS. CONCLUSIONS: The administration of prophylactic atropine before balloon inflation during CAS decreases the incidence of intraoperative bradycardia and cardiac morbidity in primary CAS patients. Periprocedural bradycardia, hypotension, and the need for vasopressors occur more frequently with primary CAS than with redo CAS procedures. On the basis of our data, we recommend that prophylactic atropine administration be considered in patients with primary carotid lesions undergoing CAS.

Aged↗
PubMed2005

Treatment of type II endoleaks with a novel polyurethane thrombogenic foam: induction of endoleak thrombosis and elimination of intra-aneurysmal pressure in the canine model.

OBJECTIVE: The clinical significance and treatment of retrograde collateral arterial perfusion of abdominal aortic aneurysms after endovascular repair (type II endoleak) have not been completely characterized. A canine abdominal aortic aneurysm model of type II endoleak with an implanted pressure transducer was used to evaluate the use of polyurethane foam to induce thrombosis of type II endoleaks. The effect on endoleak patency, intra-aneurysmal pressure, and thrombus histology was studied. METHODS: Prosthetic aneurysms with an intraluminal, solid-state, strain-gauge pressure transducer were created in the infrarenal aorta of 14 mongrel dogs. Aneurysm side-branch vessels were reimplanted into the prosthetic aneurysm of 10 animals by using a Carrel patch. Type II (retrograde) endoleaks were created by excluding the aneurysm from antegrade perfusion with an impermeable stent graft. Thrombosis of the type II endoleak was induced by implantation of polyurethane foam into the prosthetic aneurysm sac of four animals. Six animals with type II endoleaks were not treated. In four control animals, no collateral side branches were reimplanted, and therefore no endoleak was created. Intra-aneurysmal and systemic pressures were measured daily for 60 to 90 days after the implantation of the stent graft. Endoleak patency and flow were assessed during surgery and at the time of death by using angiographic imaging and duplex ultrasonography. Histologic analysis of the intra-aneurysmal thrombus was also performed. RESULTS: Intra-aneurysmal pressure values are indexed to systemic pressure and are represented as a percentage of the simultaneously obtained systemic pressure, which has a value of 1.0. All six animals with untreated type II endoleaks maintained patency of the endoleak and side-branch arteries throughout the study period. Compared with control aneurysms that had no endoleak, animals with patent type II endoleaks exhibited significantly higher intra-aneurysmal pressurization (systolic pressure: patent type II endoleak, 0.702 +/- 0.283; control, 0.172 +/- 0.091; P < .001; mean pressure: endoleak, 0.784 +/- 0.229; control, 0.137 +/- 0.102; P < .001; pulse pressure: endoleak, 0.406 +/- 0.248; control, 0.098 +/- 0.077; P < .001; P < .001 for comparison for all groups by analysis of variance). Treatment of the type II endoleak with polyurethane foam induced thrombosis of the endoleak and feeding side-branch arteries in all four animals with type II endoleaks. This resulted in intra-aneurysmal pressures statistically indistinguishable from the controls (systolic pressure, 0.183 +/- 0.08; mean pressure, 0.142 +/- 0.09; pulse pressure, 0.054 +/- 0.04; not significant). Angiography and histology documented persistent patency up to the time of death (mean, 64 days) for untreated type II endoleaks and confirmed thrombosis of polyurethane foam-treated endoleaks in all cases. CONCLUSIONS: Untreated type II endoleaks were associated with intra-aneurysmal pressures that were 70% to 80% of systemic pressure. Treatment with polyurethane foam resulted in a reduction of intra-aneurysmal pressure to a level that was indistinguishable from control aneurysms that had no endoleak. CLINICAL RELEVANCE: Endovascular repair of abdominal aortic aneurysms is dependent on the successful exclusion of the aneurysm from arterial circulation. Type II endoleaks originate from retrograde flow into the aneurysm sac. This study demonstrates the use of polyurethane foam to induce thrombosis in a canine model of a type II endoleak, thereby reducing intra-aneurysmal pressure to levels similar to levels in animals without endoleaks. This approach may be a strategy for future treatment of type II endoleaks.

Animals↗
PubMed2005

Aortoiliac occlusive disease in patients with known or suspected peripheral vascular disease: safety and efficacy of gadofosveset-enhanced MR angiography--multicenter comparative phase III study.

PURPOSE: To prospectively determine the safety and efficacy of the gadolinium-based blood pool magnetic resonance (MR) imaging contrast agent gadofosveset in patients known to have or suspected of having peripheral vascular disease. MATERIALS AND METHODS: Ethical committee approval and patient written informed consent were obtained. This study was compliant with the Health Insurance Portability and Accountability Act. Adults known or suspected to have peripheral vascular disease received gadofosveset (0.03 mmol per kilogram of body weight) for MR angiography of the aortoiliac region. Gadofosveset-enhanced MR angiography and unenhanced two-dimensional time-of-flight MR angiography were compared with the reference standard, conventional angiography, for the presence of vascular stenosis. All patients were monitored for adverse events with hematologic analysis, analysis of blood chemistry, urinalysis, and electrocardiographic parameters; these methods were analyzed to determine safety. RESULTS: A total of 274 patients were enrolled at 37 centers. Gadofosveset-enhanced MR angiography showed significant improvement (P < .001) compared with unenhanced MR angiography for each of the readers for diagnosis of clinically significant (> or = 50%) stenosis. Specificity and accuracy were significantly greater for three readers, and sensitivity increased significantly for two readers. For all readers, the area under the receiver operator characteristic curve for both quantitative and qualitative measures of significant disease increased (P < .001) for gadofosveset-enhanced MR angiography versus two-dimensional time-of-flight MR angiography. All readers also expressed more confidence in diagnosis (P < .001) and found fewer images to be uninterpretable (0.5% vs 11.0%). The most common adverse events were as follows: feeling hot, 12 (4.4%) patients; nausea, 10 (3.6%) patients; headache, nine (3.3%) patients; and burning sensation, eight (2.9%) patients. Only four serious adverse events were reported, in three patients, and all events were rated as unlikely related to the drug. No patients were excluded because of adverse events or laboratory abnormalities. There were no clinically important trends in the findings of hematologic analysis, blood chemistry, urinalysis, electrocardiography, or physical examination. CONCLUSION: On the basis of substantial improvements over non-contrast MR angiography in efficacy and a minimal and transient side-effect profile, gadofosveset was found to be safe and effective for MR angiography in patients known or suspected to have peripheral vascular disease.

Aged↗
PubMed2005

Comparison of results in endovascular interventions for infrainguinal lesions: claudication versus critical limb ischemia.

This study analyzed clinical success, patency, and limb salvage after endovascular repair in patients treated for chronic limb ischemia presenting with claudication versus critical limb ischemia. Between October 2001 and August 2004, 115 patients (mean age 71) underwent endovascular treatment for infrainguinal arterial disease. Techniques included subintimal angioplasty and transluminal angioplasty with or without stents. Lesions were classified according to Transatlantic InterSociety Consensus. Follow-up (mean 11 months) included physical exam, ankle-brachial index, and duplex ultrasound. Patency rates were determined using Kaplan-Meier and compared by log-rank analysis. One hundred ninety-nine lesions were treated in 121 limbs using percutaneous techniques. Comorbidities were similar except higher rates of diabetes mellitus (67% vs 41%, P < 0.001) and chronic renal insufficiency (22% vs 7%, P < 0.05) were found in critical limb ischemia patients. Primary patency for claudicants was 100 per cent, 98 per cent, and 85 per cent at 3, 6, and 12 months and 89 per cent, 80 per cent, and 72 per cent for critical limb ischemia, respectively (P = 0.06). Limb salvage was 91 per cent at 12 months for critical limb ischemia patients. Morbidity was similar between groups, and there was no perioperative mortality. Percutaneous intervention for both claudication and critical limb ischemia provides acceptable 12 month patency with limited morbidity.

Adult↗
PubMed2005

Endovascular stent graft selection for the treatment of abdominal aortic aneurysms.

Minimally invasive endovascular techniques for the treatment of abdominal aortic aneurysms (AAA) have significantly reduced the morbidity of these procedures as compared with standard surgical repair. In addition, patients with extensive comorbid medical illnesses in whom standard operative repair is contra-indicated, may be successfully treated using endovascular means. A variety of endovascular stent grafts are currently being used clinically for endovascular AAA repair. The characteristics of these stent grafts vary significantly. In selecting the specific stent graft to be used for endovascular AAA repair, these specific characteristics must be considered particularly with regard to the individual patient's anatomic and physiologic characteristics. The United States Food and Drug Administration (FDA) has approved 4 endovascular stent grafts for the treatment of AAA: the Medtronic AneuRx, the W. L. Gore Excluder, the Cook Zenith and the Guidant Ancure. The Zenith graft received approval for marketing in 2003 and has gained relatively wide usage, in part due to its ability to treat aneurysms with relatively large diameter implantations zones. Also in 2003 the Guidant Corporation withdrew the Ancure graft from marketing and distribution. Enrollment has also been recently completed for the phase II FDA trials of the Medtronic Talent graft and the Cordis Fortron graft. These devices have been approved for use in the European Union and are awaiting FDA panel meeting in the United States. Comparative analysis of several of the available stent grafts has been performed. Results have varied with regard to the need for secondary interventions, aneurysm sac size reduction and the occurrence of continued perfusion of the aneurysm sac. Several significant advances have also occurred recently in stent graft research and development. Of particular significance has been the initiation of the phase I trial of the Trivascular Enovus graft. Deployment of the Trivascular graft may be accomplished through a delivery system that is considerably reduced in profile. The potential for percutaneous application of the graft may be available in the future. The indications for use of endovascular grafts as compared to standard open surgery have not yet been fully defined. Endovascular stent grafts in current use have limitations and their use must be tempered accordingly, until their long-term effectiveness is more completely evaluated. This article describes the general principles of use for endovascular devices for the repair of AAAs. It details the features and results for the devices in current use and highlights the factors that influence the selection of specific stent graft types.

Aortic Aneurysm, Abdominal↗
PubMed2004

Type I collagen synergistically enhances PDGF-induced smooth muscle cell proliferation through pp60src-dependent crosstalk between the alpha2beta1 integrin and PDGFbeta receptor.

Smooth muscle cells (SMCs) are exposed to both platelet-derived growth factor (PDGF) and type I collagen (CNI) at the time of arterial injury. In these studies we explore the individual and combined effects of these agonists on human saphenous vein SMC proliferation. PDGF-BB produced a 5.5-fold increase in SMC DNA synthesis whereas CNI stimulated DNA synthesis to a much lesser extent (1.6-fold increase). Alternatively, we observed an 8.3-fold increase in DNA synthesis when SMCs were co-incubated with CNI and PDGF-BB. Furthermore, stimulation of SMCs with PDGF-BB produced a significant increase in ERK-2 activity whereas CNI alone had no effect. Co-incubation of SMCs with PDGF-BB and CNI resulted in ERK-2 activity that was markedly greater than that produced by PDGF-BB alone. In a similar fashion, PDGF-BB induced phosphorylation of the PDGF receptor beta (PDGFRbeta) and CNI did not, whereas concurrent agonist stimulation produced a synergistic increase in receptor activity. Blocking antibodies to the alpha2 and beta1 subunits eliminated this synergistic interaction, implicating the alpha2beta1 integrin as the mediator of this effect. Immunoprecipitation of the alpha2beta1 integrin in unstimulated SMCs followed by immunoblotting for the PDGFRbeta as well as Src family members, pp60(src), Fyn, Lyn, and Yes demonstrated coassociation of alpha2beta1 and the PDGFRbeta as well as pp60(src). Incubation of cells with CNI and/or PDGF-BB did not change the degree of association. Finally, inhibition of Src activity with SU6656 eliminated the synergistic effect of CNI on PDGF-induced PDGFRbeta phosphorylation suggesting an important role for pp60(src) in the observed receptor crosstalk. Together, these data demonstrate that CNI synergistically enhances PDGF-induced SMC proliferation through Src-dependent crosstalk between the alpha2beta1 integrin and the PDGFRbeta.

Animals↗
PubMed2004

Soft tissue enhancement on time-resolved peripheral magnetic resonance angiography.

PURPOSE: To evaluate the incidence and locations of soft tissue enhancement on time-resolved two-dimensional projection magnetic resonance angiography (MRA) of the calf and foot. MATERIALS AND METHODS: Time-resolved two-dimensional projection MRA of the knee, calf, and foot, performed at 1.5 Tesla using the head coil, was retrospectively reviewed in 326 patients. Soft tissue enhancement of the foot was identified and graded by blinded review. Subsequently, patient medical records were reviewed to determine the presence or absence of diabetes, cellulitis, gangrene, and ulceration of the foot and presence of neuropathic joints. RESULTS: Enhancing spots were identified in 228 patients. For those feet without clinical abnormalities, diabetic patients had an average of 1.2 enhancing spots per foot, while nondiabetics had only 0.6 (P < 0.001). Higher-grade lesions were more prevalent in diabetics and in heavier patients. Of 64 patients with follow-up, 8 (13%) developed cellulitis (N = 4) or ulceration (N = 4) at the location of an enhancing spot, including 5 diabetic and 3 nondiabetic patients. CONCLUSION: Pedal soft tissue enhancement frequently occurs on time-resolved gadolinium (Gd):MRA of the feet. The etiology is uncertain, but the high frequency in diabetic patients and observation of progression to cellulitis/ulceration suggest this soft tissue enhancement may identify sites of subclinical pedal soft tissue injury.

Adult↗
PubMed2004

Continuity in the treatment of carotid artery disease: results of a carotid stenting program initiated by vascular surgeons.

The treatment of carotid artery stenosis currently constitutes a major component of vascular surgical practice. Carotid angioplasty and stenting (CAS), however, is mainly performed by nonvascular surgeon interventionalists with cerebral protection devices available only through investigational protocols. This study reports the initial results of a CAS program initiated and performed by vascular surgeons using commercially available cerebral protection devices. Fifty-seven patients were enrolled in the study over a 14-month period. All patients were at high risk for conventional endarterectomy (7 resentosis, 4 irradiation, and 46 medically high-risk ASA III). Mean age was 75.7 years (range, 45-93 years). High-grade stenosis of the carotid artery was present in all cases (mean stenosis, 85%; range, 80-99%). Twenty-four percent of patients were symptomatic. Cerebral protection was performed with an occlusion balloon-wire in 32 cases and with a filter-wire device in 24; no cerebral protection was used in 1 patient with restenosis after endarterectomy. Initially in the study, atropine was administered selectively for the development of bradycardia. Currently atropine is administered routinely prior to the initial balloon angioplasty of the carotid bulb. Clopidogrel (75 mg/day) was administered for 5 days prior to CAS and for 30 days after CAS. All 57 patients underwent successful dilatation of their carotid stenoses without occlusion or dissection. Ten of 32 patients in whom balloon occlusion was used for cerebral protection exhibited transient evidence of cerebral ischemia during protection balloon occlusion. These symptoms resolved completely without permanent neurological deficit in all cases. Development of bradycardia with a heart rate <50 bpm was significantly reduced by routine administration of atropine prior to the initial dilatation within the carotid bulb (p = 0.01). Mean hospital length of stay was 1.33 days (range, 1-5 days). There were two periprocedure myocardial infarctions, two postprocedure transient ischemic attacks, and one reversible ischemic neurologic deficit. There was no 30-day mortality. There have been no instances of hemodynamically significant restenosis during a mean follow-up period of 5.4 months. From these results we have concluded that CAS can be performed effectively and safely using commercially available cerebral protection devices. A program initiated and performed exclusively by vascular surgeons is effective and should be the standard model used in the endovascular treatment of carotid artery stenosis.

Aged↗
PubMed2004

The role of phospholipase C and phosphatidylinositol 3-kinase in vascular smooth muscle cell migration and proliferation.

BACKGROUND: Vascular smooth muscle cell (SMC) proliferation and migration both contribute to the formation of intimal hyperplasia. Phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3-K) are ubiquitous signaling proteins that mediate multiple cellular events. In this study, we investigate the role of PLC and PI3-K in platelet-derived growth factor (PDGF) and extracellular matrix protein (ECM) induced SMC proliferation and migration. MATERIAL AND METHODS: Proliferation of human saphenous vein SMC was assessed by (3)H-thymidine incorporation. SMC migration was evaluated using a microchemotaxis chamber. U-73122 was used as a general inhibitor for PLC, and D609 and ET-18-OCH3, respectively, were used to block the isotypes of PLC, phosphatidylcholine- (PC-), and phosphatidylinositol- (PI-) specific PLC. PI3-K activity was inhibited using two selective inhibitors, LY-294002 and wortmannin. RESULTS: PDGF and Type 1 collagen (CN-I) stimulated SMC proliferation, whereas PDGF and four distinct extracellular matrix proteins CN-I, Type 4 collagen (CN-IV), fibronectin (FN), and laminin (LN) stimulated SMC migration. Both isotypes of PLC as well as PI3-K were necessary for PDGF- and CN-I-induced proliferation. Signaling for migration, however, was more specific. Of the various signaling proteins studied, only PI-PLC was necessary for PDGF-induced SMC migration. Conversely, PI3-K was the only signaling protein necessary for SMC migration in response to ECM proteins. CONCLUSION: The signaling pathways necessary for PDGF- and CN-I-induced SMC proliferation involve both isotypes of PLC as well as PI3-K. The signaling pathways used by growth factors and ECM to stimulate SMC migration are more selective. Understanding the intracellular signaling pathways required for SMC proliferation and migration may allow the development of tools to selectively block intimal hyperplasia.

Cell Division↗