Biomedical subjects

K Craig Kent

Publications and source records attributed to K Craig Kent.

At least 19 recordsLinked to original sources

PubMed2007

Protein kinase C-delta regulates migration and proliferation of vascular smooth muscle cells through the extracellular signal-regulated kinase 1/2.

BACKGROUND: Smooth muscle cell (SMC) migration and proliferation are early and crucial events in the pathogenesis of intimal hyperplasia, the primary cause of restenosis after vascular intervention. We tested the hypothesis that protein kinase C-delta (PKCdelta), a ubiquitously expressed intracellular protein kinase, regulates vascular SMC proliferation and migration. METHODS: Exogenous PKCdelta was expressed in cultured SMCs via stable transfection or adenovirus-mediated gene transfer. Conversely, endogenous PKCdelta was inhibited by means of targeted gene deletion (gene knock-out). Cell proliferation and migration were determined by (3)H-thymidine incorporation and 24-well transwell assay, respectively. RESULTS: We isolated and examined three A10 SMC lines in which PKCdelta was stably transfected. Compared with cells that were transfected with an empty vector, cells transfected with PKCdelta exhibited reduced ability to proliferate. Moreover, PKCdelta transfection inhibited SMC migration toward platelet-derived growth factor-BB. Similar inhibitory effects on proliferation and migration were also observed when PKCdelta was introduced into primary aortic SMCs via an adenoviral vector. Interestingly, SMCs isolated from PKCdelta knockout mice also displayed decreased chemotaxis and proliferation compared with PKCdelta(+/+) littermates, suggesting a complex yet critical role for PKCdelta. We studied the mitogen-activated protein kinase extracellular signal-regulated kinases (ERK) 1/2 as a possible signaling pathway for PKCdelta's inhibitory effect. PKCdelta overexpression diminished ERK1/2 activity. Molecular restoration of ERK activation reversed the inhibitory effect of PKCdelta on SMC proliferation and migration. CONCLUSIONS: We demonstrate that although normal migration and proliferation is lessened in SMCs deficient in PKCdelta, its prolonged activation also diminishes those behaviors. This suggests a dual, critical role for PKCdelta in SMC proliferation and migration, and thus intimal hyperplasia and restenosis.

Animals↗

PubMed2006

Analysis of outcomes following failed endovascular treatment of chronic limb ischemia.

Despite recent studies highlighting the advantages of endoluminal intervention in the management of chronic limb ischemia (CLI), outcomes following failed peripheral angioplasty remain less well described. We present a retrospective analysis of failed transluminal infrainguinal percutaneous arterial angioplasty with or without stenting (PTA/S) in patients with CLI. A database of patients undergoing infrainguinal PTA/S between 2002 and 2005 was maintained. Patients underwent duplex scanning follow-up at 2 weeks, 3 months, and every 6 months after the intervention. Angiograms were reviewed in all cases to assess lesion characteristics. Results were standardized to current Transatlantic Inter-Society Consensus (TASC) criteria. Kaplan-Meier survival analyses were performed to assess time-dependent outcomes. In total, our analysis involved 246 patients who underwent treatment for CLI using PTA/S. Eighteen percent of procedures (n = 46) were considered an intervention failure secondary to restenosis by duplex ultrasound, returning clinical symptoms, a nonhealing foot lesion, or the absence of a prior palpable pulse. Indications for the original procedure in patients whose PTA/S failed were tissue loss in 44%, claudication in 44%, and rest pain in 12%, while TASC lesion grades were A (0%), B (18%), C (18%), and D (64%). Of patients failing PTA/S, 4% failed in the first 30 days, 78% failed between 1 and 18 months, while 18% failed following 18 months, with a mean time to failure of 8.7 months. Also, 82% of PTA/S failures were candidates for a second endovascular procedure, 11% were suitable for only traditional open bypass, and 4% demonstrated progression of disease necessitating amputation. Of patients undergoing a second endovascular procedure, limb salvage rates were 86% at 12-month follow-up and there was a single periprocedural mortality and complication rate of 6.6%. Of patients requiring open surgical bypass after failed PTA/S, 20% (n = 1) required a major amputation and there were no mortalities. Failure of endoluminal therapy for treatment of lower extremity arterial occlusive disease is amenable to subsequent endovascular intervention for limb salvage with limited morbidity and mortality.

Adult↗

PubMed2006

Cerebral ischemia associated with PercuSurge balloon occlusion balloon during carotid stenting: Incidence and possible mechanisms.

BACKGROUND: Interruption of antegrade cerebral perfusion results in transient neurologic intolerance in some patients undergoing carotid angioplasty and stenting (CAS). This study sought to evaluate factors that contributed to the development of cerebral ischemia during PercuSurge balloon occlusion and techniques used to allow successful completion of the CAS procedure. METHODS: The PercuSurge occlusion balloon was used in 43 of 165 patients treated with CAS for high-grade stenosis (mean stenosis, 90%). All 43 patients were at increased risk for endarterectomy (7 restenosis, 3 irradiation, 3 contralateral occlusion, and 30 Goldman class II-III); 20% were symptomatic. Symptoms of cerebral hypoperfusion during temporary occlusion of the internal carotid artery occurred in 10 of 43 and included dysarthria (7/10), agitation (6/10), decreased level of consciousness (5/10), and focal hemispheric deficit (3/10). An incomplete circle of Willis or contralateral carotid artery occlusion, or both, was present in 8 of 10 patients. Symptoms resulting from PercuSurge balloon occlusion were managed by balloon deflation with or without evacuation of blood from the internal carotid artery using the Export catheter. All symptoms resolved completely without deficit after deflation of the occlusion balloon. RESULTS: The development of neurologic symptoms after initial PercuSurge balloon inflation and occluded internal carotid artery flow was associated with a decrease in the mean Glasgow Coma Scale (GCS) from 15 to 10 (range, 9 to 14); the GCS returned to normal after occlusion balloon deflation and remained normal during subsequent reinflation. The mean time to spontaneous recovery of full neurologic function was 8 minutes (range, 4 to 15 minutes). No thrombotic or embolic events were present on cerebral angiography or computed tomography scan. Balloon reinflation was performed after a mean reperfusion interval of 10 minutes after full neurologic recovery (range, 4 to 20 minutes). The mean subsequent procedure duration was 11.9 minutes (range, 6 to 21 minutes). No recurrence of neurologic symptoms occurred when the occlusion balloon was reinflated. All 10 patients underwent successful CAS without occlusion, dissection, cerebrovascular accident, or death. CONCLUSION: Several factors may contribute to the development of neurologic intolerance during CAS with balloon occlusion. Elucidation of the protective cellular mechanisms that invoke ischemic tolerance after the initial transient ischemic event may enable CAS with embolic protection in patients who cannot tolerate initial interruption of antegrade cerebral perfusion.

Aged↗

PubMed2006

PKCdelta is necessary for Smad3 expression and transforming growth factor beta-induced fibronectin synthesis in vascular smooth muscle cells.

OBJECTIVE: The purpose of these studies is to investigate the mechanism by which transforming growth factor (TGF)beta1 regulates the synthesis of the extracellular matrix protein fibronectin (FN). METHODS AND RESULTS: TGFbeta1 elicited a time-dependent induction of FN protein and mRNA in A10 rat aortic smooth muscle cells (SMCs). Ectopic expression of Smad3 in A10 cells stimulated both basal and TGFbeta1-induced FN expression, whereas expression of Smad7 eliminated the TGFbeta response. Because TGFbeta activated PKCdelta in SMCs, we tested the role of PKCdelta in regulation of FN expression. Inhibition of PKCdelta activity by rottlerin or dominant-negative adenovirus (AdPKCdelta DN) blocked TGFbeta1's induction of FN, whereas overexpression of PKCdelta enhanced TGFbeta's effect. Moreover, aortic SMCs isolated from PKCdelta(-/-) mice exhibited diminished FN induction in response to TGFbeta. Furthermore, we found that Smad3 protein and mRNA were markedly reduced in AdPKCdelta DN-treated A10 cells and in PKCdelta null cells. Finally, restoring Smad3 in rottlerin-treated A10 and PKCdelta null cells rescues the ability of TGFbeta to upregulate FN protein and mRNA expression. CONCLUSIONS: Our data suggest that TGFbeta-activated PKCdelta is critical to maintain normal expression of Smad3, which in turn is required for the induction of fibronectin. PKCdelta represents a promising target for treating the fibroproliferative response after arterial injury.

Adenoviridae↗

PubMed2006

Superficial femoral artery occlusive disease severity correlates with MR cine phase-contrast flow measurements.

PURPOSE: To evaluate how cine phase-contrast (PC) flow data correlate with the severity of peripheral vascular disease (PVD). MATERIALS AND METHODS: Flow waveforms were obtained in 48 patients proximal and distal to superficial femoral artery (SFA) disease using the 2D cine PC technique with velocity encoding (venc) = 100 cm/second. Flow data were correlated with SFA disease severity and compared with data from nine healthy volunteers. RESULTS: Of 96 arterial segments in 48 patients, 26 were patent or only mildly stenotic, 35 had moderate-to-severe stenosis, and 35 were occluded. The flow patterns tended to become low-resistant below severe stenoses or occlusion. The mean peak flow velocity above/below SFA lesions was significantly higher in patients with severe disease (1.9 +/- 1.0, P = 0.01) or occlusion (2.0 +/- 1.0, P = 0.003) compared to normal volunteers (1.4 +/- 0.6). The delay in peak velocity below the lesions showed a significant positive correlation with lesion severity (r = 0.65, P < 0.001). The mean flow volume ratio above/below SFA lesions was greater in patients with occluded vessels compared to normal volunteers (3.9 and 2.3 respectively; P = 0.04). CONCLUSION: Cine PC flow waveform changes across atherosclerotic lesions correlate with disease severity. This may help determine which lesions are hemodynamically significant.

Aged↗

PubMed2006

The development of endotension is associated with increased transmission of pressure and serous components in porous expanded polytetrafluoroethylene stent-grafts: characterization using a canine model.

OBJECTIVE: This study used a canine model of abdominal aortic aneurysms (AAAs) to compare intra-aneurysmal pressure and thrombus formation after exclusion with Dacron and expanded polytetrafluoroethylene (ePTFE) stent-grafts. METHODS: Prosthetic AAAs with implanted strain-gauge pressure transducers were treated by stent-graft exclusion using Food and Drug Administration-approved devices in 10 mongrel dogs: five Dacron (AneuRx) and five ePTFE (original Excluder). Intra-aneurysmal pressure was measured over 4 weeks after AAA exclusion and indexed to the systemic pressure, represented as a percentage of a simultaneously obtained systemic pressure (value = 1.0). Magnetic resonance imaging (MRI) of the intra-aneurysmal thrombus was performed at 1, 2, and 4 weeks after exclusion and expressed as a signal-to-noise ratio (S:N) to control for background signal intensity. Comparisons of pressures and S:N between the two stent-grafts was analyzed with the Student's t test. Intra-aneurysmal thrombus was characterized histologically. RESULTS: In animals excluded with both Dacron and ePTFE stent-grafts, the intra-aneurysmal pressure was nonpulsatile and reduced to <30% of systemic pressure. Significantly greater pressure transmission was observed after AAA exclusion using ePTFE compared with Dacron stent grafts (systolic pressure: ePTFE, 0.28 +/- 0.12 vs Dacron, 0.11 +/- 0.02, P < .001; mean pressure: ePTFE, 0.16 +/- 0.08 vs Dacron, 0.06 +/- 0.02, P < .001). MRI confirmed the absence of perfusion in all aneurysms. The T1-weighted signal intensity remained persistently elevated (S:N at 1 week, 2.7 +/- 0.4 vs 2 weeks, 4.0 +/- 0.2 vs 4 weeks, 5.4 +/- 1.3) in ePTFE-treated intra-aneurysmal thrombus, suggesting an absence of thrombus organization. In contrast, progressive evolution of T1 signal intensity in aneurysms excluded by Dacron stent-grafts was consistent with maturation from intact red blood cells (S:N at 1 week, 3.3 +/- 0.4) to methemoglobin (S:N at 2 weeks, 6.1 +/- 0.8), and then hemosiderin and ferritin (S:N at 4 weeks, 2.4 +/- 0.5). Histologically, ePTFE-excluded aneurysms contained poorly organized thrombus with red blood cell fragments and haphazardly arranged fibrin deposition indicative of active remodeling and continued influx of transudated serum. In aneurysms excluded by Dacron stent-grafts, dense, mature collagenous connective tissue and organized fibrin were present, indicative of greater thrombus organization. CONCLUSIONS: Stent-graft treatment reduces intra-aneurysmal pressure to <30% of systemic pressure when no endoleak is present; however, significantly greater pressure is present in aneurysms treated with porous ePTFE stent-grafts than Dacron grafts. Histologic and MRI imaging analysis suggest that active transudation of serous blood components may be contributing to this increased intra-aneurysmal pressure.

Animals↗

PubMed2006

Successful percutaneous treatment of gluteal claudication secondary to isolated bilateral hypogastric stenoses.

We report an unusual case of bilateral buttock claudication at ambulation of less than two blocks in a 57-year-old man with normal lower-extremity segmental pressure on noninvasive exercise testing. He was found to have bilateral high-grade internal iliac artery stenoses on arteriography. Both sides were successfully treated in a staged fashion via a contralateral approach with percutaneous transluminal angioplasty and a balloon-expandable stent, with complete symptom resolution. A clinical vascular examination with normal findings of the common iliac, external iliac, and common and superficial femoral arteries eliminates significant vascular obstruction as a cause of claudication. However, internal iliac occlusive disease may be suspected when symptoms are limited to the gluteal musculature and other causes are eliminated. Percutaneous interventions can be of diagnostic and therapeutic value.

Angioplasty, Balloon↗

PubMed2006

Percutaneous endovascular treatment of acute sequential systemic emboli.

A 65-year-old woman was evaluated for acute right lower-extremity ischemia secondary to embolization from atrial fibrillation and subtherapeutic anticoagulation. Her symptoms quickly evolved in a dynamic fashion to involve multiple vascular beds, including a transient ischemic attack, abdominal pain secondary to mesenteric ischemia, and contralateral lower-extremity ischemia. Synchronous emboli were treated by using mechanical and pharmacologic thrombolysis via an endovascular approach under local anesthesia. This intervention allows prompt evaluation of multiple vascular beds with good short-term outcomes and minimal morbidity.

Abdominal Pain↗

PubMed2006

Trends, complications, and mortality in peripheral vascular surgery.

BACKGROUND: The recent evolution in treatments for peripheral vascular disease has dated available mortality statistics for vascular intervention. Moreover, many of our current mortality statistics are derived from single-institution studies that are often not reflective of outcomes in general practice. To provide current and generalizable data regarding mortality and trends for peripheral vascular interventions, we examined two national data sets (Nationwide Inpatient Sample, 1998-2003, and National Hospital Discharge Survey, 1979-2003) and four states (New York, California, Florida, and New Jersey, 1998-2003). METHODS: Four procedures--abdominal aortic aneurysm repair (nonruptured), lower extremity revascularization, amputation, and carotid revascularization--were selected by cross-referencing International Classification of Diseases, 9th Revision, diagnostic and procedural codes. For significance, the t test was used for continuous variables, the chi2 test was used for dichotomous variables, and the chi2 test was used for mortality trends. RESULTS: From 1998 to 2003, there was a progressive decrease in the national per capita rate of amputations: 13.2% overall and 21.2% for major amputations (P < .0001). Nationally and regionally, mortality has only slightly declined. For lower extremity revascularization, after a sharp increase during the 1980s to 100,000 open procedures, the volume remained constant for 10 years and began to decline in 1998, reaching 70,000 cases in 2003. In contrast, since 1996, endovascular interventions have increased 40%. Mortality during the 1998 to 2003 period remained virtually stable at 1.5% to 2% for endovascular procedures and 3% to 4% for open procedures. The overall volume of abdominal aortic aneurysm repair has not changed substantially for the past 6 years; however, endovascular repair is now used for nearly half the cases (46.5% regional and 43.0% national). Mortality for open repair has not changed, remaining at approximately 5%, whereas for endovascular repair, mortality has declined from 2.6% in 2000 to less than 1.5% in 2003. After the rapid increase in open carotid revascularization in the early 1990s, the total volume has declined 5% nationally from 1998 to 2003. Regional data demonstrated an overall 12% reduction in carotid revascularization volume since 1998; this reduction was due to a 16% decline in open carotid revascularization. During this same period, the use of angioplasty-stent carotid revascularization doubled. Mortality for the open procedures is 0.5% and is significantly higher (2%-3%) for endovascular carotid revascularization. Stroke rates for endovascular carotid revascularization are also higher: 2.13% vs 1.28% for open procedures (P < .0001). CONCLUSIONS: Dramatic shifts in the management of peripheral vascular disease have occurred together with an overall decline in mortality. There seems to be a significant mortality advantage for endovascular as compared with traditional surgery except for carotid endarterectomy. The increasing safety of vascular interventions should be considered when deciding which patients to treat but with the caveat that endovascular interventions are not always safer than open repair.

Amputation, Surgical↗

PubMed2006

Outcomes of endovascular treatment of ruptured abdominal aortic aneurysms.

INTRODUCTION: The successful application of endovascular techniques for the elective repair of abdominal aortic aneurysms (AAAs) has stimulated a strong interest in their possible use in dealing with a long-standing surgical challenge: the ruptured abdominal aortic aneurysm (RAAA). The use of a conventional open procedure to repair ruptured aneurysms is associated with a high operative mortality of 45% to 50%. In this study, we evaluated the current frequency of endovascular repair of RAAAs in four large states and the impact of this technique on patient outcome. METHODS: We examined discharge data sets from 2000 through 2003 from the four states of California, Florida, New Jersey, and New York, whose combined population represents almost a third of the United States population. Proportions and trends were analyzed by chi2 analysis and continuous variables by the Student's t test. RESULTS: We found that since the year 2000, endovascular repair has begun to emerge as a viable treatment option for RAAAs, accounting for the repair of 6.2% of cases in 2003. During the same period, the use of open procedures for RAAAs declined. The overall mortality rate for the 4-year period was significantly lower for endovascular vs open repair (39.3% vs. 47.7%, P = .005). Moreover, compared with open repair, endovascular repair resulted in a significantly lower rate of pulmonary, renal, and bleeding complications. Survival after endovascular repair correlated with hospital experience, as assessed by the overall volume of elective and nonelective endovascular procedures. For endovascular repairs, mortality ranged from 45.9% for small volume hospitals to 26% for large volume hospitals (P = .0011). Volume was also a determinant of mortality for open repairs, albeit to a much lesser extent (51.5% for small volume hospitals, 44.3% for large volume hospitals; P < .0001). CONCLUSION: We observed a benefit to using endovascular procedures for RAAAs in institutions with significant endovascular experience; however, the analysis of administrative data cannot rule out selection bias as an explanation of better outcomes. These data strongly endorse the need for prospective studies to clarify to what extent the improved survival in RAAA patients is to be attributed to the endovascular approach rather than the selection of low-risk patients.

Aortic Aneurysm, Abdominal↗

PubMed2006

Analysis of parameters associated with hypotension requiring vasopressor support after carotid angioplasty and stenting.

INTRODUCTION: Systemic hypotension has been observed for up to 36 hours in response to stimulation of the carotid baroreceptor by carotid angioplasty and stenting (CAS). The aim of this study was to identify risk factors and cardiac outcomes for postprocedural hypotension requiring vasopressor support after CAS. METHODS: Between 2003 and 2005, 143 patients (87 men; mean age, 75 years) with high-grade carotid artery stenosis (mean, 87.3%) were treated with CAS and prospectively entered into a vascular registry. Data were retrospectively analyzed to determine factors predictive of hypotension requiring vasopressor support after CAS. Atropine and appropriate intravenous crystalloid solution were administered during CAS. For the first 30 patients, atropine was only used for symptomatic patients but then became routine and was used for all patients with primary carotid stenosis. Hypotension (systolic blood pressure <90 mm Hg or a mean arterial blood pressure <50 mm Hg) unresponsive to conservative measures was treated with vasopressors (phenylephrine or norepinephrine). Patients were stratified into three groups based on hypotension requiring vasopressors: (1) no vasopressors, (2) vasopressors for < or = 24 hours (short duration), and (3) vasopressors for >24 hours (prolonged duration). Risk factors for hypotension requiring vasopressors were analyzed by univariate and multivariate logistic regression analysis. RESULTS: Postprocedural hypotension requiring vasopressor treatment was seen in 16 (11%) of 143 of patients, with 6 (4%) requiring vasopressor support for >24 hours. Mean duration of vasopressor administration for all patients was 17 +/- 10 hours (range, 6 to 36 hours). By univariate analysis, a history of a previous myocardial infarction (P = .02) or use of the PercuSurge occlusion balloon (P = .05) were both associated with increased incidence of short duration (</=24 hours) use of vasopressors, and female sex (P = .03) and age >80 years old (P = .02) were associated with prolonged (>24 hours) vasopressor requirement. On multivariate analysis adjusted for age and sex, a history of myocardial infarction (odds ratio [OR], 4.1; 95% confidence interval [CI], 1.0 to 16.4; P = .05) remained an independent predictor of short-duration vasopressors. On multivariate analysis, female sex (OR, 10.9; 95% CI, 1.2 to 100.4; P = .04) and age >80 years old (OR, 13.8, 95% CI, 1.5 to 127.2; P = .02) remained independent predictors of prolonged vasopressor use. The incidence of periprocedural myocardial infarctions, arrhythmias, or congestive heart failure did not differ between those patients who did not receive vasopressors (5/127) and those who received vasopressors for a short (< or = 24 hours) duration (1/10, P = NS) or prolonged (>24 hours) duration (0/6, P = NS). CONCLUSION: Prolonged hypotension requiring vasopressor support occurs in a minority of patients after CAS, with higher incidences in older women. In contrast, hypotension requiring a more limited duration of vasopressor use occurs more commonly in patients who had a prior myocardial infarction, independent of age or sex. In this cohort of patients, vasopressors required for hypotension were not associated with an increased incidence of periprocedural cardiac complications. Despite the increased incidence of prolonged hypotension in older women, this study demonstrates that CAS can be performed without an increase in cardiac morbidity in older women.

Aged↗

PubMed2006

Evaluation of the accuracy of a wireless pressure sensor in a canine model of retrograde-collateral (type II) endoleak and correlation with histologic analysis.

BACKGROUND: The utility of intra-aneurysmal pressure determination is dependent on the ability to measure pressure in the presence of endoleak and thrombosis. In this study, the accuracy of a CardioMEMS wireless pressure sensor (CardioMEMS, Atlanta, Ga) transducer in the presence of thrombus associated with type II endoleak was measured. METHODS: Type II endoleaks were created in four mongrel dogs by implanting four collateral arterial side branches (lumbar and caudal mesenteric arteries) as a Carrel patch onto a 3-cm prosthetic polytetrafluoroethylene abdominal aortic aneurysm (AAA). The aneurysm was excluded 2 weeks later from antegrade perfusion by a stent graft. The wireless pressure sensor was positioned in the AAA external to the stent graft. A Konigsberg intraluminal solid-state strain-gauge pressure transducer (Konigsberg Instruments, Pasadena, Calif) that is accurate in the presence of thrombus served as the control to determine AAA pressure. Both of the transducers were implanted on the luminal surface of the aneurysm, 180 degrees opposite from the Carrel patch and endoleak channel. Intra-aneurysmal pressure resulting from the type II endoleak was measured twice daily for 4 weeks using both transducers. A total of 56 pre-exclusion and 224 post-exclusion distinct pressure determinations were made. Intra-aneurysmal pressure was indexed to the systemic pressure that was simultaneously measured by a strain-gauge pressure transducer implanted in the native aorta. Histologic analysis of the aneurysm contents was performed with hematoxylin and eosin. RESULTS: The intra-aneurysmal systolic, mean, and pulse pressures produced by the type II endoleak were significantly lower than systemic pressure in all animals and were < 60% of systemic pressure (P < .001). Close correlation between the wireless transducer and the control strain-gauge transducer was observed (R = 0.83, P < .001). Arteriography and Doppler ultrasound documented retrograde flow through the aneurysm side branches and persistent endoleak patency up to the time of euthanasia. Pathologic analysis demonstrated the endoleak channel to be patent and separated from the transducers by thrombus, which surrounded both transducers. CONCLUSIONS: Intra-aneurysmal pressure generated by type II endoleaks may be accurately measured through thrombus using a wireless pressure sensor in the canine model. The wireless sensor has the potential for clinical applicability in diagnosing and characterizing type II endoleaks.

Angioplasty↗

PubMed2006

Simulation improves resident performance in catheter-based intervention: results of a randomized, controlled study.

OBJECTIVES: Surgical simulation has been shown to enhance the training of general surgery residents. Since catheter-based techniques have become an important part of the vascular surgeon's armamentarium, we explored whether simulation might impact the acquisition of catheter skills by surgical residents. METHODS: Twenty general surgery residents received didactic training in the techniques of catheter intervention. Residents were then randomized with 10 receiving additional training with the Procedicus, computer-based, haptic simulator. All 20 residents then participated in 2 consecutive mentored catheter-based interventions for lower extremity occlusive disease in an OR/angiography suite. Resident performance was graded by attending surgeons blinded to the resident's training status, using 18 procedural steps as well as a global rating scale. RESULTS: There were no differences between the 2 resident groups with regard to demographics or scores on a visuospatial test administered at study outset. Overall, residents exposed to simulation scored higher than controls during the first angio/OR intervention: procedural steps (simulation/control) (50 +/- 6 vs. 33 +/- 9, P = 0.0015); global rating scale (30 +/- 7 vs. 19 +/- 5, P = 0.0052). The advantage provided by simulator training persisted with the second intervention (53 +/- 6 vs. 36 +/- 7, P = 0.0006); global rating scale (33 +/- 6 vs. 21 +/- 6, P = 0.0015). Moreover, simulation training, particularly for the second intervention, led to enhancement in almost all of the individual measures of performance. CONCLUSION: Simulation is a valid tool for instructing surgical residents and fellows in basic endovascular techniques and should be incorporated into surgical training programs. Moreover, simulators may also benefit the large number of vascular surgeons who seek retraining in catheter-based intervention.

Angiography↗

PubMed2006

Evolution of the treatment of carotid occlusive disease: indications for carotid angioplasty and stenting versus carotid endarterectomy.

Carotid endarterectomy (CEA) was established as the gold standard for treatment of carotid occlusive disease by several landmark papers published in the 1990's. Several decades of experience with CEA, however, has revealed high-risk subsets of patients in whom CEA carries increased risk of adverse events. These patients have subsequently been the focus of several randomized trials and registry databases which evaluated and proved non-inferiority of carotid angioplasty and stenting (CAS) in recent years. CAS is now considered an appropriate and equivalent alternative to CEA in these high-risk patients, defined by the presence of severe cardiac, pulmonary, or renal disease or by the presence of local factors such as prior neck radiation, prior neck operations, contralateral carotid occlusion, or surgically inaccessible lesions. Although ongoing trials in normal-risk patients may ultimately expand the indications for CAS, there is currently insufficient evidence to recommend CAS in these patients over CEA. In addition, specific subsets of patients, such as octogenarians or those with anatomic complexity, may have increased incidence of adverse events with CAS and are best served by CEA.

Angioplasty↗

PubMed2006

Safety and efficacy of carotid angioplasty and stenting in high-risk patients.

Performance of carotid endarterectomy (CEA) may be associated with an increased risk in patients with significant comorbid medical conditions, neck irradiation, or previous CEA. This study compared the results of CEA with carotid angioplasty and stenting (CAS) in high-risk patients treated for carotid stenosis. Five hundred forty-five patients who underwent CEA and 148 patients who underwent CAS were evaluated. For patients undergoing CEA, general anesthesia was used in 91 per cent, electroencephalographic monitoring was used in 63 per cent, and shunting was performed in 19.8 per cent. Cerebral protection devices were used in 145/148 of CAS cases, and self-expanding stents were used in all cases. Evaluated end points included major cardiovascular events, and a composite of death, stroke, or myocardial infarction for the duration of the follow-up. Mean follow-up was 18 months for CAS and 23 months for CEA. Significant differences were present in patient age (CAS, 75 +/- 11.0 years vs CEA, 71 +/- 9 years, P = 0.012), however, there were no significant differences (P = NS) in gender or smoking history. The mean modified Goldman Score was significantly higher for CAS (21.1 +/- 14.8 [95% confidence interval = 18, 24]) than for CEA (6.3 +/- 6.8 [95% confidence interval = 5.7, 6.9]; P = 0.0001) patients. The incidence of periprocedural complications did not vary significantly between patients treated with CAS (CVA, 1.4%; myocardial infarction [MI], 1.4%; death, 0.7%; CVA/MI/death, 3.4%) compared with CEA (CVA, 1.8%; MI, 1.1%; death, 0.4%; CVA/MI/death, 4.0%). CAS is equivalent to CEA in safety and efficacy, even when performed in patients who may be at increased surgical risk.

Age Factors↗

PubMed2005

Decreased neurotrophin TrkB receptor expression reduces lesion size in the apolipoprotein E-null mutant mouse.

BACKGROUND: Accumulation of macrophages and smooth muscle cells in the vascular wall is critical for the development of atherosclerotic lesions. Although much is known about the factors that regulate macrophage recruitment to the vascular wall, the ability of growth factors to regulate smooth muscle cell recruitment in lesion development in vivo is unclear. Our previous studies demonstrated that neurotrophins and their receptors, the Trk receptor tyrosine kinases, are potent chemotactic factors for smooth muscle cells, and the expression of brain-derived neurotrophic factor (BDNF) and its cognate receptor, TrkB, is upregulated in human atherosclerotic lesions. METHODS AND RESULTS: TrkB(+/-) mice on a 129/B6 background were backcrossed to apolipoprotein E (ApoE)-null (ApoE(-/-)) mice on the C57Bl/6 background for 6 to 8 generations. Immunohistochemical analysis demonstrated BDNF immunoreactivity in areas of macrophage and smooth muscle cell infiltration, whereas TrkB immunoreactivity was predominant in areas of neointimal smooth muscle cells. Moreover, haplodeficient expression of TrkB in ApoE(-/-) mice was associated with a 30% to 40% reduction in lesion size compared with ApoE(-/-) mice with normal expression of TrkB and a 45% decrease in smooth muscle cell accumulation in the lesions. Finally, reconstitution with bone marrow from ApoE(-/-) mice with normal TrkB expression did not restore lesion development in TrKB(+/-)/ApoE(-/-) mice. CONCLUSIONS: These results suggest that TrkB expression on smooth muscle cells contributes to lesion development in the cholesterol-fed ApoE-null mutant mouse. These data demonstrate, for the first time, a role for the neurotrophin TrkB receptor in atherosclerotic lesion development.

Animals↗

PubMed2005

Protein kinase C delta induces apoptosis of vascular smooth muscle cells through induction of the tumor suppressor p53 by both p38-dependent and p38-independent mechanisms.

Apoptotic death of vascular smooth muscle cells (SMCs) is a prominent feature of blood vessel remodeling. In the present study, we examined the novel PKC isoform protein kinase C delta (PKCdelta) and its role in vascular SMC apoptosis. In A10 SMCs, overexpression of PKCdelta was sufficient to induce apoptosis, whereas inhibition of PKCdelta diminished H2O2-induced apoptosis. Moreover, evidence is provided that the tumor suppressor p53 is an essential mediator of PKCdelta-induced apoptosis in SMCs. Activation of PKCdelta led to accumulation as well as phosphorylation of p53 in SMCs; this induction correlated with apoptosis. Furthermore, blocking p53 induction with small interference RNA or targeted gene deletion prevented PKCdelta-induced apoptosis, whereas restoring p53 expression rescued the ability of PKCdelta to induce apoptosis in p53 null SMCs. We also establish that PKCdelta regulates p53 at both transcriptional and post-translational levels. Specifically, the transcriptional regulation required p38 MAPK, whereas the post-translational modification, at least for serine 46, did not involve MAPK. Additionally, PKCdelta, p38 MAPK, and p53 co-associate in cells under conditions favoring apoptosis. Together, our data suggest that SMC apoptosis proceeds through a pathway that involves PKCdelta, the intermediary p38 MAPK, and the downstream target tumor suppressor p53.

Adenoviridae↗

PubMed2005

PDGF-BB regulates p27 expression through ERK-dependent RNA turn-over in vascular smooth muscle cells.

Cyclin-dependent kinase inhibitor p27, a critical determinant for cell cycle progression, is an important regulation target of mitogenic signals during arterial injury. In this study, we show in rat aortic smooth muscle cells that PDGF-BB down-regulated p27 protein and mRNA in an ERK-dependent mechanism. Inhibition of ERK, but not other subtypes of the mitogen-activated protein kinase family, prevented the reduction of p27 protein and mRNA. Conversely, direct activation of ERK via adenovirus-mediated expression of a constitutively active form of MEK led to a reduction of p27 protein and mRNA, further supporting the central role of ERK in regulation of p27 expression. Rapamycin, which potently inhibited PDGF-induced activation of p70 S6 kinase as well as proliferation of smooth muscle cells, did not alter the expression of p27. To delineate the molecular mechanism underlying the p27 down-regulation, we examined the effect of PDGF-BB on p27 promoter activity as well as mRNA stability. Stimulation with PDGF-BB significantly shortened the half-life of p27 mRNA without affecting its promoter activity. To further understand the PDGF-stimulated p27 mRNA turnover, we inserted the 5'- and/or 3'-untranslated regions of p27 cDNA into a non-PDGF-responsive luciferase gene. Only those chimeric genes that contained the 3'-untranslated region responded to PDGF-BB with reduced expression. Moreover, inhibition of ERK completely prevented the effect of PDGF on the chimera expression. In summary, our data suggest that p27 is down-regulated by PDGF-BB in vascular smooth muscle cells through an ERK-dependent posttranscriptional mechanism.

3' Untranslated Regions↗