Biomedical subjects

Michael S Conte

Publications and source records attributed to Michael S Conte.

32 records · Page 2Linked to original sources

PubMed2003

Preoperative risk factors for carotid endarterectomy: defining the patient at high risk.

PURPOSE: The efficacy of carotid endarterectomy (CEA) for prevention of stroke has been demonstrated in randomized trials; however, the optimal approach in patients excluded from these trials or who have other significant comorbid conditions remains controversial, particularly with the advent of percutaneous interventions. We examined the influence of putative risk factors on outcome of CEA in a single-center experience. METHODS: A retrospective analysis of 1370 consecutive CEA performed from 1990 to 1999 was undertaken. Preoperative risk factors examined included age older than 80 years, congestive heart failure, chronic obstructive pulmonary disease, renal failure (serum creatinine concentration > 2.0 mg/dL), contralateral carotid artery occlusion, recurrent ipsilateral carotid artery stenosis, ipsilateral hemispheric symptoms within 6 weeks, and recent coronary bypass grafting (CABG). The Fisher exact test was used to identify baseline variables associated with perioperative (30 days) risk for stroke or death. Multivariate analysis with Poisson regression was used to study the effect of all univariate criteria in combination. RESULTS: In the overall cohort, there were 32 adverse events (2.3%), including 11 deaths (0.8%), 6 disabling strokes (0.4%), and 10 nondisabling strokes (0.7%). There was no significant difference in incidence of perioperative stroke or death between patients with one or more risk factors (n = 689) and those with no risk factors (low risk, n = 681). Thirty-day mortality was significantly greater in patients with two or more risk factors compared with patients with no risk factors (2.8% vs 0.3%; P =.04), but no significant difference was noted in perioperative stroke rate (2.3% vs 1.0%). Univariate analysis demonstrated that contralateral carotid occlusion (n = 75) was the only significant predictor of adverse outcome (5 events, 6.7%) among the variables tested; this was confirmed with multivariate analysis (relative risk, 4.3; 95% confidence interval, 1.2-12.3; P =.01). Five-year survival for patients with two or more risk factors was notably diminished compared with that for patients with no risk factors (38.7% +/- 5.9% vs 75.0% +/- 2.6%; P <.001). Contralateral occlusion was also associated with reduced 5-year survival (38 +/- 11% vs 67 +/- 2%; P <.004). CONCLUSION: CEA can be safely performed in patients deemed at high risk, including those aged 80 years or older and others with significant comorbid conditions, with combined stroke and mortality rates comparable to those found in randomized trials, ie, the Asymptomatic Carotid Atherosclerosis Study and the North American Symptomatic Carotid Endarterectomy Trial. Contralateral occlusion may be a predictor for moderately increased perioperative risk and for reduced long-term survival. Caution may be warranted in asymptomatic patients with multiple risk factors, in whom presumed long-term benefit of CEA may be compromised by markedly reduced 5-year survival.

Aged↗

PubMed2003

Outcome in patients at high risk after open surgical repair of abdominal aortic aneurysm.

OBJECTIVE: Outcomes after surgical repair of abdominal aortic aneurysm (AAA) in patients at high risk remain poorly defined. We investigated the short-term and long-term results of open repair of infrarenal AAA in a high-risk and comparison low-risk patient population. METHODS: Conventional open surgical repair of nonruptured infrarenal AAA was performed in 572 consecutive patients from 1990 to 2000. Patients were considered at high risk if they had one or more of the following criteria: age 80 years or more, creatinine level 3.0 mg/dL or higher, severe pulmonary insufficiency, severe cardiac dysfunction, or hepatic failure. A retrospective review was carried out to determine relative risks, perioperative morbidity and mortality, and long-term survival. A P value of less than.05 was considered statistically significant. RESULTS: One hundred twenty-eight of the study patients (22%) were at high risk and 444 were at low risk. Patients at high risk were older (77 versus 69 years; P <.001), were more likely female (26% versus 16%; P <.009), and had larger (mean, 5.9 versus 5.6 cm; P <.024), more symptomatic (20% versus 13%; P <.001) aneurysms. The 30-day operative mortality rate for the high-risk group was 4.7%, compared with 0.0% (P <.001) in the low-risk group. Overall and major morbidity rates were 29% and 14% in the high-risk cohort versus 17% (P <.003) and 5% in the low-risk cohort, respectively. The 5-year survival rate was 46% (standard deviation, 5.2%) in the high-risk group versus 74% (standard deviation, 2.6%) in the low-risk group (P <.001). On multivariate analysis, age 80 years or more (P <.046), creatinine level 3.0 mg/dL or higher (P <.022), prior stroke (P <.012), and pulmonary dysfunction were significant predictors of poor operative outcome (30-day mortality and major morbidity), and female gender (P <.035), cardiac dysfunction (P <.004), creatinine level 3.0 mg/dL or higher (P <.0001), prior stroke (P <.005), and pulmonary dysfunction (P <.0001) negatively impacted long-term survival rates. CONCLUSION: This study shows that open repair of infrarenal AAA in patients at high risk can be performed with relative safety and with results that offer a benchmark with which endovascular repair can be compared. Poor long-term survival in this population, however, highlights the importance of patient selection and raises the question of whether repair of many patients at high risk is warranted.

Aged↗

PubMed2003

Transcription factor decoys for the prevention of vein bypass graft failure.

Failure of vein bypass grafts, performed for either coronary or lower extremity arterial occlusions, is a common clinical problem that incurs significant morbidity and mortality. Vein grafts provide a unique opportunity for genetic interventions, since the target tissue is available for manipulation ex vivo prior to implantation, and prior to the onset of the pathophysiologic events that lead to graft disease. Smooth muscle cell proliferation is a hallmark of neointimal hyperplasia in vein grafts and arteries, and is an attractive target for molecular therapy. Gene blockade strategies can be accomplished by delivery of small oligodeoxynucleotides (ODN) that target specific mRNAs ('antisense') or that competitively inhibit transcription factors ('decoys'). Transcription factors are attractive targets for molecular therapy since they influence the expression of a large number of genes involved in a coordinated cellular program. An ODN decoy approach has been developed targeting the transcription factor E2F, which is critically involved in cell cycle progression. Brief (10 minute) incubation of the ODN in solution, using non-distending pressure, results in efficient delivery of the ODN to >80% of cells in the vein wall. Preclinical studies in a rabbit model of vein grafting and hypercholesterolemia demonstrated a marked reduction in neointima formation, as well as prolonged resistance to graft atherosclerosis. Phase I/II studies conducted in lower extremity and coronary bypass patients have demonstrated safety and feasibility, and have also suggested possible efficacy. Large, randomized multicenter, phase III trials are currently under way to evaluate the efficacy of E2F decoy treatment on preventing vein bypass failure in both peripheral and coronary grafting procedures. These studies herald the arrival of a new class of molecular agents into the armamentarium of cardiovascular therapies.

Animals↗

PubMed2002

Inhibitor of apoptosis protein survivin regulates vascular injury.

Survivin (also termed Birc5) belongs to the family of genes known as inhibitors of apoptosis, and it has been implicated in both prevention of cell death and control of mitosis. The survivin pathway is exploited in cancer, but its potential role in vascular injury is unknown. Here, we show that balloon-mediated arterial injury in rabbits resulted in expression of survivin in vascular cells. Serum or PDGF-AB stimulated survivin expression in cultured smooth-muscle cells (SMCs), which suppressed apoptosis and prevented caspase activation. Adenoviral delivery of a phosphorylation-defective survivin mutant reversed the cytoprotective effect of PDGF in SMCs without affecting mitotic progression, suppressed neointimal formation in wire-injured mouse femoral arteries, and induced vascular cell apoptosis in vivo. These data identify survivin as a critical regulator of SMC apoptosis after acute vascular injury. Disrupting the survivin pathway may provide a novel therapy to limit pathological vessel-wall remodeling.

Adenoviridae↗

PubMed2002

Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids.

Vascular smooth muscle cell (SMC) migration and proliferation contribute to neointimal hyperplasia and restenosis after vascular injury. The epoxyeicosatrienoic acids (EETs), which are products of cytochrome P450 (CYP) epoxygenases, possess vasodilatory, antiinflammatory, and fibrinolytic properties. To determine whether these compounds also possess antimigratory and antiproliferative properties, we stimulated rat aortic SMCs with either 20% serum or platelet-derived growth factor (PDGF-BB, 20 ng/mL). In a concentration-dependent manner, treatment with EETs, particularly 11,12-EET, inhibited SMC migration through a modified transwell filter by 53% to 60%. EETs, however, have no inhibitory effects on PDGF-stimulated SMC proliferation. Adenoviral-mediated overexpression of the CYP isoform, CYP2J2, in SMCs also inhibited serum- and PDGF-induced SMC migration by 32% and 26%, respectively; both effects of which were reversed by the CYP inhibitors SKF525A or clotrimazole, but not by the K(Ca) channel blocker, charybdotoxin, or the cyclooxygenase inhibitor, diclofenac. The effect of EETs correlated with increases in intracellular cAMP levels. Indeed, forskolin and 8-bromo-cAMP exert similar inhibitory effects on SMC migration as 11,12-EET and the effects of 11,12-EET were blocked by cAMP and protein kinase A (PKA) inhibitors. These findings indicate that EETs possess antimigratory effects on SMCs through the cAMP-PKA pathway and suggest that CYP epoxygenase-derived eicosanoids may play important roles in vascular disease and remodeling.

8,11,14-Eicosatrienoic Acid↗

PubMed2002

Endothelial cell seeding influences lesion development following arterial injury in the cholesterol-fed rabbit.

OBJECTIVE: A functionally intact endothelial monolayer is thought to be critical for the adaptive process of vascular remodeling. This study was undertaken to examine the hypothesis that endothelial restoration is a critical determinant of remodeling after balloon angioplasty. METHODS: Rabbits (N=12) were fed a cholesterol-supplemented diet (0.5%) and were subjected to bilateral balloon catheter injury of the iliofemoral arteries. At the time of injury, autologous venous endothelial cells (ECs) were implanted on one artery; the contralateral vessel served as control. A mean of 42 days after injury, arteriography was performed, followed by vessel harvest and histologic analysis. RESULTS: High grade (> or =70%) stenoses or occlusion were present in 55% of control and none of the EC-seeded arteries. EC-seeding was associated with improved mean (1.0 +/- 0 vs. 0.7 +/- 0.1, P<0.001) and minimal (0.7 +/- 0.1 vs. 0.4 +/- 0.1, P<0.001) luminal diameters by angiography. Seeded arteries demonstrated decreased medial area (0.69 +/- 0.04 vs. 1.04 +/- 0.09 mm(2), P<0.001), a more uniform range of final lumen area (P<0.0001), and a positive remodeling index. Neointimal area was not significantly different. Stenoses were characterized primarily by larger neointimal area (2.02 +/- 0.18 vs. 1.38 +/- 0.09 mm(2), stenotic vs. non-stenotic, P<0.005). Final lumen area was strongly influenced by both neointimal growth and vessel remodeling. CONCLUSIONS: These data support the concept that endothelial restoration is a critical determinant of the outcome of vessel wall repair, particularly in the context of hypercholesterolemia.

Animals↗

PubMed2002

Usefulness of autogenous bypass grafts originating distal to the groin.

PURPOSE: Infrainguinal bypass grafting with a proximal anastomosis distal to the groin has been used increasingly to conserve available conduit and reduce wound morbidity and recovery time. The usefulness of the liberalized use of distal origin grafts (DOGs) is unknown. METHODS: Consecutive autogenous DOG procedures that were performed between 1978 and 2000 were reviewed retrospectively with a computerized registry. Procedures performed as revisions to earlier infrainguinal bypass grafting procedures and for popliteal aneurysm were excluded. RESULTS: In the 22-year study period, 249 autogenous DOG procedures were performed in 217 patients. Comparison of the 159 DOGs in patients with diabetes mellitus (+DM) with the 90 grafts in patients without diabetes mellitus (-DM) revealed more associated renal disease (33% vs 9%), preoperative foot necrosis (80% vs 52%), distal popliteal artery graft origins (49% vs 37%), and non-greater saphenous conduits used (30% vs 19%) among the +DM subgroup than the -DM subgroup (P <.05). The operative mortality rate was 2.0%, the major morbidity rate was 8.8%, the early graft failure rate was 6.4%, and the early amputation rate was 2.4%, with no differences related to diabetes mellitus. Follow-up was complete in 92% of patients in a mean interval of 27 months. At 5 years, cumulative primary graft patency rates were 62% overall, 73% for the +DM subgroup, and 45% for the -DM subgroup (P <.001). The overall limb salvage rate after DOG procedures for critical ischemia was 79%, and it was 84% for the +DM subgroup and 69% for the -DM subgroup (P <.04). The overall patient survival rate was 45%, with no difference related to diabetes mellitus. CONCLUSION: Outcome after autogenous DOG revascularization is satisfactory overall. Graft patency and limb salvage after DOG for critical ischemia are significantly better among patients with diabetes mellitus than patients without diabetes mellitus, despite significantly more bypass grafting procedures performed for foot necrosis. DOG revascularization appears to be an appropriate preference for patients with diabetes mellitus with good inflow below the groin; it should be used less liberally among patients without diabetes mellitus.

Adult↗

PubMed2002

Initial experience with minimally invasive in situ bypass procedure with blind valvulotomy.

OBJECTIVE: The in situ vein (ISV) bypass is uniquely suited to technical modifications designed to reduce the wound morbidity of infrainguinal revascularization. A technique of "blind" valvulotomy and selective vein branch ligation was used, and a preliminary study was performed to assess safety and efficacy. METHODS: From November 1998 to July 2001, all patients for infrainguinal bypass procedures underwent evaluation for inclusion in the study. Thirty-five patients underwent ISV bypass procedures with an expandable, self-centering valvulotome (ESV). Intraoperative selection of veins suitable for the study was assisted with venography and duplex scanning. The ISV bypass procedures were performed with initial groin and distal incisions, with smaller incisions to ligate significant arteriovenous fistulae (AVF). Duplex graft scanning was performed at routine intervals after surgery. RESULTS: Thirty-seven ISV grafts were performed from the common femoral artery to the popliteal (n = 14), tibial (n = 20), and dorsalis pedis (n = 3) arteries. In 35 cases (95%), a full-length incision was avoided. With ESV, all valves in 34 cases (92%) were effectively lysed. Proximal extension of the distal incision was performed in four cases (10.8%). The mean number of incisions per case was 3.1 +/- 1.7. One graft failed within 30 days (2.7%), with successful revision. During the early follow-up period (9.9 +/- 7.3 months; range, 1 to 33 months), 44% of residual AVF closed spontaneously (15 of 34 AVF; 16 patients) and two anastomotic stenoses and two symptomatic AVF were corrected surgically. Four late graft occlusions occurred, with a 1-year cumulative primary patency rate of 77% and a secondary patency rate of 92%. CONCLUSION: Blind valvulotomy with ESV facilitates safe and effective minimally invasive ISV bypass. Resultant graft patency rates appear comparable with results with open techniques. This preliminary experience warrants further study to refine patient selection criteria and operative technique and to better clarify the natural history of residual AVF.

Aged↗

PubMed2002

Bypass in the absence of ipsilateral greater saphenous vein: safety and superiority of the contralateral greater saphenous vein.

PURPOSE: The purposes of this study were to evaluate the long-term results of different autogenous conduits used for infrainguinal bypass when ipsilateral greater saphenous vein (IGSV) is absent or inadequate and to determine the impact on the contralateral lower extremity. METHODS: The study was performed as a retrospective evaluation of a prospective vascular registry together with review of patient records and telephone follow-up. RESULTS: From January 1990 to June 2000, 226 autogenous infrainguinal reconstructions were performed in 203 patients without adequate IGSV. The patients consisted of 128 men and 98 women, with a mean age of 69 years. Prevalent risk factors included diabetes (51%) and prior coronary bypass (46%). Limb salvage was the predominant indication (93%), and 59% of the procedures were secondary reconstructions. All bypasses were completed with autogenous vein, which included contralateral greater saphenous vein (CGSV; 31%), single-segment lesser saphenous vein (5%), single-segment arm vein (19%), and autogenous composite vein (45%). Bypasses were performed to the tibial and pedal arteries in 84% of the cases. The 30-day mortality and graft occlusion rates were 1% and 9%, respectively. The overall postoperative morbidity rate was 24%, with a 7% rate of major complications. Follow-up was complete in 95% of patients over a mean period of 24 months (range, 0.1 to 106 months). The 5-year primary patency rates were significantly better for CGSV compared with autogenous composite vein grafts (61% +/- 7% versus 39% +/- 6%; P <.009). The 5-year secondary patency (60% to 73%) and limb salvage (78% to 81%) rates did not differ significantly between the three groups. Follow-up of the contralateral lower limb revealed that nine of 226 limbs (4%) were amputated at a mean of 36 months after the ipsilateral bypass. The overall 5-year contralateral limb preservation rate was 90% +/- 3%. Contralateral vein harvest and the presence of diabetes did not affect the need for bypass or amputation of the contralateral limb. CONCLUSION: For most patients with inadequate IGSV, the CGSV is the alternative conduit of choice because of its length, superior performance, ease of harvest, and minimal risk to the donor limb.

Aged↗

PubMed2002

Genetic interventions for vein bypass graft disease: a review.

The failure of vein bypass grafting in the coronary or lower extremity circulation is a common clinical occurrence that incurs significant morbidity, mortality, and cost. Vein grafts are uniquely amenable to intraoperative genetic modification because of the ability to manipulate the tissue ex vivo with controlled conditions. Although the pathophysiology of vein graft failure is incompletely understood, numerous relevant molecular targets have been elucidated. Interventions designed to influence cell proliferation, thrombosis, inflammation, and matrix remodeling at the genetic level have been described, and many have been tested in animal models. Both gene delivery and gene blockade strategies have been investigated, with the latter now reaching the stage of advanced clinical trials. This review describes the basic and translational science of genetic interventions for vein graft disease and the current state of application in the clinic.

Animals↗

PubMedDate not supplied

Transaortic endarterectomy for primary mesenteric revascularization.

The optimal approach to revascularization for chronic mesenteric ischemia has not been firmly established during the past three decades. The present study was undertaken to evaluate the safety and results of primary mesenteric revascularization for chronic mesenteric ischemia by transaortic endarterectomy. A descriptive retrospective analysis of 14 patients who underwent trap-door transaortic endarterectomy for primary mesenteric revascularization was performed. Clinical presentations of the patients included abdominal pain (n=13) and weight loss (n=7). All patients underwent preoperative aortography and subsequent elective reconstruction. Demographic features, perioperative, and long-term outcomes were analyzed. The study population consisted of 12 females and two males with a mean age of 67 years. The mean operative duration was 3 hours with an ischemic time of 33 minutes. The initial success rate of mesenteric revascularization was 93%. One early graft failure was salvaged with urgent embolectomy without bowel resection. There was no hospital mortality, but the overall postoperative morbidity rate was 50% (n=7). Thirteen patients (93%) were discharged within 2 weeks. Late recurrent ischemia and intestinal infarction developed in one patient, requiring emergency bowel resection. Sustained relief of symptoms was achieved in 13 of 14 patients (93%). The overall survival rates were 85% +/-10.0% and 77% +/-11.7% at 1 and 3 years, respectively. Transaortic endarterectomy is a safe and effective technique for elective primary mesenteric revascularization for patients with chronic mesenteric ischemia. This approach allows simultaneous revascularization of multiple visceral arteries and achieves durable relief of symptoms.

Aged↗

PubMedDate not supplied

Gene therapy for the extension of vein graft patency: a review.

The mainstay of treatment for long-segment small-vessel chronic occlusive disease not amenable to endovascular intervention remains surgical bypass grafting using autologous vein. The procedure is largely successful and the immediate operative results almost always favorable. However, the lifespan of a given vein graft is highly variable, and less than 50% will remain primarily patent after 5 years. The slow process of graft malfunction is a result of the vein's chronic maladaptive response to the systemic arterial environment, its primary component being the uncontrolled proliferation of vascular smooth muscle cells (SMCs). It has recently been suggested that this response might be attenuated through pre-implantation genetic modification of the vein, so-called gene therapy for the extension of vein graft patency. Gene therapy seems particularly well suited for the prevention or postponement of vein graft failure since: (1) the stimulation of SMC proliferation appears to largely be an early and transient process, matching the kinetics of current gene transfer technology; (2) most veins are relatively normal and free of disease at the time of bypass allowing for effective gene transfer using a variety of systems; and (3) the target tissue is directly accessible during operation because manipulation and irrigation of the vein is part of the normal workflow of the surgical procedure. This review briefly summarizes the current knowledge of the incidence and basic mechanisms of vein graft failure, the vector systems and molecular targets that have been proposed as possible pre-treatments, the results of experimental genetic modification of vein grafts, and the few available clinical studies of gene therapy for vascular proliferative disorders.

Arterial Occlusive Diseases↗

PubMedDate not supplied

Design and rationale of the PREVENT III clinical trial: edifoligide for the prevention of infrainguinal vein graft failure.

Surgical bypass of peripheral arterial occlusive disease with autologous vein grafts provides an effective means of restoring blood flow to the lower extremity, and has been a standard therapy for patients with disabling claudication or critical limb ischemia (CLI). However, failure rates may run as high as 50% within 5 years. These graft failures occur as a result of neointimal hyperplasia, a ubiquitous biologic response of blood vessel walls to injury, which is characterized by the migration and proliferation of smooth muscle cells (SMC). The E2F family of transcription factors regulates the expression of genes controlling SMC proliferation. Edifoligide (E2F Decoy) is a novel therapy that inhibits E2F function, thus attenuating neointimal hyperplasia. Its use in conjunction with a patented drug delivery pressurization chamber is under investigation. Using this system, edifoligide is administered to vein grafts in a single, ex vivo treatment following vein harvest and before implantation, resulting in minimal systemic drug exposure and excellent patient compliance. This Phase 3, randomized, double-blind, multicenter clinical trial is designed to evaluate the safety and efficacy of edifoligide in a population of approximately 1400 patients with CLI undergoing infrainguinal bypass for peripheral arterial disease (PAD). The primary outcome measure will be the time to occurrence of non-technical graft failure resulting in either graft revision or major amputation at 12 months after enrollment. A governing Clinical Events Classification committee (CEC) will adjudicate each graft failure to determine its etiology. The PREVENT III trial is the largest multicenter trial ever performed in patients receiving autologous vein bypass grafts for CLI. This landmark study will determine if edifoligide is safe and effective at preventing vein graft failure in patients undergoing lower extremity bypass, but it also provides a unique opportunity to observe current treatment practices in vascular surgery.

Arterial Occlusive Diseases↗

PubMedDate not supplied

Genetic therapy for vein bypass graft disease: current perspectives.

Although continued progress in endovascular technology holds promise for less invasive approaches to arterial diseases, surgical bypass grafting remains the mainstay of therapy for patients with advanced coronary and peripheral ischemia. In the United States, nearly 400,000 coronary and 100,000 lower extremity bypass procedures are performed annually. The autogenous vein, particularly the greater saphenous vein, has proven to be a durable and versatile arterial substitute, with secondary patency rates at 5 years of 70 to 80% in the extremity. However, vein graft failure is a common occurrence that incurs significant morbidity and mortality, and, to date, pharmacologic approaches to prolong vein graft patency have produced limited results. Dramatic advances in genetics, coupled with a rapidly expanding knowledge of the molecular basis of vascular diseases, have set the stage for genetic interventions. The attraction of a genetic approach to vein graft failure is based on the notion that the tissue at risk is readily accessible to the clinician prior to the onset of the pathologic process and the premise that genetic reprogramming of cells in the wall of the vein can lead to an improved healing response. Although the pathophysiology of vein graft failure is incompletely understood, numerous relevant molecular targets have been elucidated. Interventions designed to influence cell proliferation, thrombosis, inflammation, and matrix remodeling at the genetic level have been described, and many have been tested in animal models. Both gene delivery and gene blockade strategies have been investigated, with the latter reaching the stage of advanced clinical trials.

Anastomosis, Surgical↗