Biomedical subjects
Publications and source records attributed to Elliot L Chaikof.
Biotin chain-terminated glycopolymers were generated by cyanoxyl-mediated free-radical polymerization using a biotin-derivatized arylamine initiator with high conversion (75%) and low polydispersity (1.30). Streptavidin-biotinylated glycopolymer binding was verified by SDS-PAGE gel shift assay and patterned glycocalyx-mimetic surfaces successfully fabricated.
The ability of a soluble heparin-binding oligopeptide sequence derived from the von Willebrand factor (vWF) to modulate the adhesion and chemokinetic migration behavior of arterial smooth muscle cells was assessed using a novel glass microsphere centrifugation assay and automated time-lapse fluorescence videomicroscopy, respectively. Treatment of cells grown on fibronectin-coated substrates with the heparin-binding peptide resulted in the disassembly of focal adhesions, as assessed by immunohistochemical staining. These observations were consistent with six-fold decrease in cell--substrate adhesive strength (P<0.001), a biphasic effect on migration speed (P<0.05), as well as a dose-dependent reduction in the percentage of motile cells and the cell dispersion coefficient (mu=S(2)T/2). The specificity of this response to the vWF-derived heparin-binding peptide was supported by the absence of an observed effect in the presence of either a scrambled peptide or a consensus heparin-binding peptide sequence of similar heparin affinity. These data support the notion that competitive interactions between cell surface heparan sulfates with heparin-binding peptide domains located in soluble peptide fragments may modulate chemokinetic cell migration behavior and other adhesion-related processes.
Options for the treatment of abdominal and thoracic aortic aneurysms are in a state of evolutionary change. The development and continued refinement of the endoluminal approaches has decreased the need for open aortic aneurysm surgery. Endovascular stent graft technology is an area of active research in which both the delivery systems and the endografts are undergoing continued improvement so that patients with what was previously thought to be unfavorable anatomy may be treated by these means. The design and deployment techniques of the currently available endografts, as well as those in clinical trials, are presented.
BACKGROUND: Atheroembolization following aortoiliac stent placement is uncommon. The purpose of this study was to examine the management and risk factors of lower extremity atheroembolization following aortoiliac stent placement for occlusive disease. MATERIALS AND METHODS: From March 1993 to February 2001, the hospital records of all patients who developed thromboembolic events following aortoiliac stent placement were reviewed. Risk factor analysis was performed by comparing with the control group, which consisted of 493 patients treated with aortoiliac stents during the study period who did not develop atheroembolic complications. Patients with cardiac etiologies or aortic aneurysms as the source of embolization as well as those who developed acute embolization following stent deployment (<30 days) were excluded. RESULTS: Atheroembolization occurred in eight patients (12 iliac artery stents and 1 aortic stent) at intervals ranging from 9 to 43 months (mean 22 months) following aortoiliac stent placement. Arteriography in all patients implicated the stented artery as the source of atheroembolism. Five corrective operations (two aorto-bifemoral bypasses, one ileofemoral bypass, and two aortoiliac endarterectomies) along with two concomitant femoropopliteal thrombectomies were performed successfully in five patients. The remaining three patients were treated with either thrombolysis and/or additional stent placement, which resulted in either iliac occlusion or recurrent embolic symptoms (P < 0.05). All 3 patients subsequently underwent bypass procedures (one ileofemoral and two femorofemoral bypasses). There was no perioperative mortality. During a mean follow-up of 16 months (range 3 to 45 months), two patients required minor amputations, whereas one required major leg amputation. No further episodes of atheroembolism occurred in the involved limbs following surgical bypass procedures. Risk factor analysis failed to identify potential variables that correlated with atheroembolism following aortoiliac stent placement. CONCLUSION: Patients with atheromatous embolization following aortoiliac stent placement should be evaluated aggressively. The treatment of choice is surgical correction or bypass with exclusion of the offending embolic source. Although intra-arterial stent placement in the atheroembolic stented iliac artery is feasible, it may provide a less durable result.
BACKGROUND: The traditional repair of hemodialysis graft pseudoaneurysms has been to surgically replace that segment of involved PTFE graft material or autogenous vein. We report a novel approach to these lesions, employing a covered stent (Wallgraft) for exclusion of arteriovenous graft (AVG) and arteriovenous fistula (AVF) pseudoaneurysms. METHODS: Ten patients with AVG or AVF pseudoaneurysms were treated endoluminally by covered stent exclusion. Wallgraft implantations were performed in the operating room with interventional capabilities under local anesthesia through a percutaneous access. Follow-up included physical examination at 2 weeks and duplex ultrasound of AVG/ AVF at 6 months after surgery. RESULTS: Ten patients with pseudoaneurysmal degeneration of their AVG/AVF were identified. The mean diameter of the pseudoaneurysmal segment was 3 cm (range, 1.5-5 cm). Immediately following covered stent implantation all the patients had palpable pulses in the pseudoaneurysms despite adequate coverage by angiography. At the 2-week follow-up visit all had lost the palpable pseudoaneurysm pulsation while the AVGs remained functional in nine patients. One patient had early thrombosis of the AVG. The follow-up duplex scans at 6 months showed complete exclusion of the pseudoaneurysms in seven patients. Two patients had thrombosis of their dialysis access, at 3 weeks (n = 1) and 3 months (n = 1) post-implantation. CONCLUSION: Endovascular covered stent exclusion of AV dialysis access pseudoaneurysms is safe and technically feasible in eliminating flow through dialysis access pseudoaneurysms and represents a novel and simple approach to this common problem, prolonging the functional life of the access site.
Although vascular disease may present with symptoms that are representative of a focal exacerbation of atherosclerosis, it is inherently a systemic disease. Consequently, vascular surgeons must be capable of recommending to their patients pharmacologic approaches that will decrease future risk of cardiovascular-related morbidity and death. Antiplatelet treatments, in particular, have been shown to reduce future cerebrovascular and coronary events. Moreover, these medications have utility in maintaining peripheral vessel and graft patency after surgical bypass, endarterectomy, or percutaneous translumenal angioplasty. The future of optimal antiplatelet therapy will consist of strategies that block multiple platelet activation pathways simultaneously. Moreover, the use of directed antiplatelet medications promises more effective control of platelet physiology with a concomitant increase in safety. The authors review herein current recommendations for the use of aspirin, thienopyridines, and GP IIb/IIIa inhibitors in patients with peripheral vascular disease.
Acute limb ischemia is a common, recognized complication of intra-aortic balloon pump (IABP) placement in patients with failing myocardium, and an operative femorofemoral bypass graft is often necessary in IABP-dependent patients as a means of maintaining the lower-limb perfusion. In this report, we present a minimally invasive endovascular technique for creating a percutaneous temporary femorofemoral bypass graft at bedside in patients with IABP-induced limb ischemia. This temporary bypass grafting technique may obviate a potential graft infection or wound complications associated with a formal femorofemoral bypass graft.
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In this study, we postulated that acute mechanical strain of the arterial wall induces changes in syndecan-4 expression that in turn may modulate cellular events, which promote neointima formation. Correlative in vivo and in vitro studies were performed to determine whether: (1) balloon injury of the rat carotid artery induces spatially and temporally regulated changes in syndecan-4 messenger RNA (mRNA) and protein expression; (2) the application of biaxial mechanical strain to cultured vascular wall cells regulates the expression of syndecan-4 mRNA and protein and its cell surface distribution and surface shedding; and (3) shed syndecan-4 directly effects cell motility behavior. We observed that syndecan-4 mRNA and protein expression were regulated in a temporally and spatially specific manner, such that initial expression of syndecan-4 was localized to adventitial cells followed by later expression in the neointima. Notably, in vitro stimulation of isolated adventitial fibroblasts with a mechanical stretch protocol that was designed to mimic in vivo balloon injury produced a rapid increase in syndecan-4 (4.3-fold increase; P <.001) that was accompanied both by enhanced protein shedding and by the disassembly of focal adhesions. Also significant was that shed syndecan-4, induced with mechanically conditioned media, appeared to be responsible for a chemotactic response of adventitial fibroblasts (P =.005). These results indicate that mechanical strain tightly regulates syndecan-4 expression, which may, in part, provide a mechanism for the activation of myofibroblast migration from the tunica adventitia into the neointima.
BACKGROUND: The primary purpose of this study was to evaluate compliance, side effects, and safety associated with prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms (AAAs). A secondary goal was to determine how treatment with doxycycline influences circulating levels of matrix metalloproteinase-9 (MMP-9) in this patient population. METHODS: Thirty-six patients with AAAs (30 men and 6 women; mean age, 69 +/- 1 years) were enrolled into a 6-month phase II study to evaluate treatment with doxycycline (100 mg orally twice a day). Aneurysm size was measured before and after treatment, and compliance and side effects were monitored. Plasma levels of doxycycline were measured midway through the study, and plasma MMP-9 concentrations were measured at baseline, 3 months, and 6 months. RESULTS: Thirty-three of the 36 patients (92%) completed 6 months of doxycycline treatment. Significant treatment-related side effects occurred in five patients (13.9%), including three with cutaneous photosensitivity reactions (8.3%), one with tooth discoloration (2.8%), and one with yeast infection (2.8%). A high rate of compliance with treatment was seen, despite minor but frequent side effects, including nonspecific gastrointestinal symptoms (25%), easily managed episodes of photosensitivity (22.2%), and reversible tooth discoloration (5.5%). The mean plasma doxycycline level after 3 months was 4.62 +/- 0.68 ug/mL (median, 3.64 microg/mL; range, 1.31 to 14.39 microg/mL; n = 23 patients). No significant change was seen in AAA diameter (42.7 +/- 1.3 mm at 6 months versus 41.0 +/- 0.9 mm at baseline), and the overall rate of AAA expansion was 0.63% +/- 0.25% per month. The mean plasma MMP-9 level (n = 19 patients) was elevated at baseline (118.9 +/- 37.9 ng/mL; upper limit of normal, 85 ng/mL) but subsequently decreased to 83.8 +/- 32.9 ng/mL at 3 months (not significant versus baseline) and to 66.4 +/- 24.2 ng/mL at 6 months (P =.022 versus baseline). Only 21% of patients had an elevated level of plasma MMP-9 after 6 months of treatment compared with 47% at baseline (P <.05). CONCLUSION: Prolonged administration of doxycycline is safe and well tolerated by patients with small asymptomatic AAAs and is associated with a gradual reduction in plasma MMP-9 levels. Further studies are needed to evaluate the long-term effects of doxycycline on the rate and extent of aneurysm growth and the potential use of plasma MMP-9 levels as a biomarker of aneurysm disease progression.
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PURPOSE: Hypogastric artery embolization (HAE) is often performed in endovascular aortoiliac aneurysm repair to prevent potential endoleak, and this can be associated with pelvic ischemic sequelae. This prospective study was performed to evaluate the clinical outcome of HAE in patients who underwent endovascular aortoiliac aneurysm repair. METHODS: During a 15-month period, 12 patients who underwent either unilateral or bilateral HAE for endovascular aortoiliac aneurysm repair were prospectively evaluated. All patients underwent preoperative and postoperative penile pressure measurement and pulse-volume recording evaluation. Angiographic features relating to pelvic collaterals and clinical outcomes relating to pelvic ischemia were evaluated. RESULTS: Unilateral HAE was performed in eight patients (67%), and bilateral HAE was performed in four patients (33%). Mean reductions in penile brachial index (PBI) after unilateral and bilateral HAE were 13 +/- 6% (not significant) and 39 +/- 14% (P <.05), respectively. Erectile dysfunction occurred in three patients for unilateral HAE (38%) and in two patients for bilateral HAE (50%), with an overall PBI reduction of 36 +/- 12% (P <.01). No significant change in thigh brachial or ankle brachial index occurred after HAE. Hip and buttock claudication occurred in four patients for unilateral HAE (50%) and in two patients for bilateral HAE (50%), with an overall PBI reduction of 18 +/- 9% (P <.05). Other associated pelvic ischemic complications after bilateral HAE included one scrotal skin sloughing (25%) that occurred 3 days after aortic endografting and one sacral decubitus (25%) that occurred 4 months after aortic endografting. With analysis of angiographic collateral patterns, diseased profunda femoral artery (PFA; >50% stenosis) was noted in four patients, all in whom post-HAE pelvic ischemic symptoms developed (P <.05). In contrast, only four of the remaining eight patients with normal or mild PFA disease had pelvic ischemic sequelae after HAE. CONCLUSION: Erectile dysfunction after HAE correlates with significant reduction in PBI. Severe pelvic ischemic symptoms are more likely to occur after bilateral HAE, which should be avoided if possible. Moreover, patients with diseased PFA are at risk of development of pelvic ischemia after HAE. Our data suggest a potential role of concomitant profundapalsty at the time of aortic endografting to improve pelvic collateral flow and reduce pelvic ischemia in this subset of patients with HAE.
OBJECTIVE: The impact of co-morbid conditions on early and late clinical outcomes after endovascular treatment of abdominal aortic aneurysm (AAA) was assessed in concurrent cohorts of patients stratified with respect to risk for intervention. SUMMARY BACKGROUND DATA: As a minimally invasive strategy for the treatment of AAA, endovascular repair has been embraced with enthusiasm for all prospective patients who are suitable anatomical candidates because of the promise of achieving a durable result with a reduced risk of perioperative morbidity and mortality. METHODS: From April 1994 to March 2001, endovascular AAA repair was performed in 236 patients using commercially available systems. A subset of patients considered at increased risk for intervention (n = 123) were categorized, as such, based on a preexisting history of ischemic coronary artery disease, with documentation of myocardial infarction (60%) or congestive heart failure (35%), or due to the presence of chronic obstructive disease (21%), liver disease, or malignancy. RESULTS: Perioperative mortality (30-day) was 6.5% in the increased-risk patients as compared to 1.8% among those classified as low risk (P = NS). There was no difference between groups in age (74 +/- 9 years vs. 72 +/- 6 years; mean +/- SD), surgical time (235 +/- 95 minutes vs. 219 +/- 84 minutes), blood loss (457 +/- 432 mL vs. 351 +/- 273 mL), postoperative hospital stay (4.8 +/- 3.4 days vs. 4.0 +/- 3.9 days), or days in the ICU (1.3 +/- 1.8 days vs. 0.5 +/- 1.6 days). Patients at increased risk of intervention had larger aneurysms than low-risk patients (59 +/- 13 mm vs. 51 +/- 14 mm; P <.05). Stent grafts were successfully implanted in 116 (95%) increased-risk versus 107 (95%) low-risk patients (P = NS). Conversion rates to open operative repair were similar in increased-risk and low-risk groups at 3% and 5%, respectively. The initial endoleak rate was 22% versus 20%, based on the first CT performed (either at discharge or 1 month; P = NS). To date, increased-risk patients have been followed for 17.4 +/- 15 months and low-risk patients for 16.3 +/- 14 months. Kaplan-Meier analysis for cumulative patient survival demonstrated a reduced probability of survival among those patients initially classified as at increased risk for intervention (P <.05, Mantel-Cox test). Both cohorts had similar two-year primary and secondary clinical success rates of approximately 75% and 80%, respectively. CONCLUSIONS: Early and late clinical outcomes are comparable after endovascular repair of AAA, regardless of risk-stratification. Notably, 2 years after endovascular repair, at least one in five patients was classified as a clinical failure. Given the need for close life-long surveillance and the continued uncertainty associated with clinical outcome, caution is dictated in advocating endovascular treatment for the patient who is otherwise considered an ideal candidate for standard open surgical repair.
Most approaches currently pursued or contemplated within the framework of reparative medicine, including cell-based therapies, artificial organs, and engineered living tissues, are dependent on our ability to synthesize or otherwise generate novel materials, fabricate or assemble materials into appropriate 2-D and 3-D forms, and precisely tailor material-related physical and biological properties so as to achieve a desired clinical response. This paper summarizes the scientific and technological opportunities within the fields of biomaterials science and molecular engineering that will likely establish new enabling technologies for cellular and molecular therapies directed at the repair, replacement, or reconstruction of diseased or damaged organs and tissues.
Syndecan-4 is a unique membrane-associated heparan sulfate proteoglycan that colocalizes with integrin heterodimers in focal adhesion complexes. Because focal adhesions serve as a putative mechanotransduction system, we postulated that physical forces that are sensed by focal adhesions may regulate the expression and intracellular distribution of syndecan-4 and thereby modulate cell movement and orientation. In this report, syndecan-4 was identified as a transcriptionally regulated, immediate-early gene in response to the application of oscillatory stress. This fluctuation was associated with coordinate changes in the concentration and compartmentalization of syndecan-4 proteins. Specifically, syndecan-4 was lost from the dorsal aspect of the cell membrane and translocated from its intracellular pool to the ventral cell surface. Dissociation of syndecan-4 and vinculin from focal adhesions may contribute to promoting cell motility, because overexpression of syndecan-4, in part, blocked this dissociation and also retarded mechanical stretch-induced cell migration. These studies suggest that mechanical stress induces cell locomotion, in part, by the dynamic regulation of syndecan-4 expression and relocation.
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