Dual antiplatelet therapy reduces stroke but increases bleeding at the time of carotid endarterectomy.

OBJECTIVE: Controversy persists regarding the perioperative management of clopidogrel among patients undergoing carotid endarterectomy (CEA). This study examined the effect of preoperative dual antiplatelet therapy (aspirin and clopidogrel) on in-hospital CEA outcomes. METHODS: Patients undergoing CEA in the Vascular Quality Initiative were analyzed (2003-2014). Patients on clopidogrel and aspirin (dual therapy) were compared with patients taking aspirin alone preoperatively. Study outcomes included reoperation for bleeding and thrombotic complications defined as transient ischemic attack (TIA), stroke, or myocardial infarction. Secondary outcomes were in-hospital death and composite stroke/death. Univariate and multivariable analyses assessed differences in demographics and operative factors. Propensity score-matched cohorts were derived to control for subgroup heterogeneity. RESULTS: Of 28,683 CEAs, 21,624 patients (75%) were on aspirin and 7059 (25%) were on dual therapy. Patients on dual therapy were more likely to have multiple comorbidities, including coronary artery disease (P < .001), congestive heart failure (P < .001), and diabetes (P < .001). Patients on dual therapy were also more likely to have a drain placed (P < .001) and receive protamine during CEA (P < .001). Multivariable analysis showed that dual therapy was independently associated with increased reoperation for bleeding (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.20-2.42; P = .003) but was protective against TIA or stroke (OR, 0.61; 95% CI, 0.43-0.87; P = .007), stroke (OR, 0.63; 95% CI, 0.41-0.97; P = .03), and stroke/death (OR, 0.66; 95% CI, 0.44-0.98; P = .04). Propensity score matching yielded two groups of 4548 patients and showed that patients on dual therapy were more likely to require reoperation for bleeding (1.3% vs 0.7%; P = .004) but less likely to suffer TIA or stroke (0.9% vs 1.6%; P = .002), stroke (0.6% vs 1.0%; P = .04), or stroke/death (0.7% vs 1.2%; P = .03). Within the propensity score-matched groups, patients on dual therapy had increased rates of reoperation for bleeding regardless of carotid symptom status. However, asymptomatic patients on dual therapy demonstrated reduced rates of TIA or stroke (0.6% vs 1.5%; P < .001), stroke (0.4% vs 0.9%; P = .01), and composite stroke/death (0.5% vs 1.0%; P = .02). Among propensity score-matched patients with symptomatic carotid disease, these differences were not statistically significant. CONCLUSIONS: Preoperative dual antiplatelet therapy was associated with a 40% risk reduction for neurologic events but also incurred a significant increased risk of reoperation for bleeding after CEA. Given its observed overall neurologic protective effect, continued dual antiplatelet therapy throughout the perioperative period is justified. Initiating dual therapy in all patients undergoing CEA may lead to decreased neurologic complication rates.

Bone marrow aspirate injection for treatment of critical limb ischemia with comparison to patients undergoing high-risk bypass grafts.

OBJECTIVE: Bone marrow cell therapy (BMCT) for patients with critical limb ischemia (CLI) is a potential treatment in candidates with poor options for standard revascularization procedures. Whereas clinical trials are ongoing, there are few comparative data to assess its efficacy compared with bypass. METHODS: Patients with poor revascularization options underwent BMCT between 2011 and 2013. Outcomes were compared with those of a cohort of CLI patients undergoing infrainguinal bypass thought to be at high risk for graft failure (tissue loss, a tibial target, and a previous endovascular treatment or bypass). BMCT patients underwent harvest of bone marrow that was then concentrated and injected intramuscularly into the ischemic limb. RESULTS: There were 20 BMCT patients and 35 high-risk bypass patients. All BMCT patients had either rest pain (80%) or tissue loss (80%). The majority (65%) had a prior intervention (bypass, 30%; endovascular, 58%) compared with high-risk bypass patients, all of whom had previous revascularization attempts (bypass, 43% [P = .35]; endovascular, 77% [P = .14]). Mean follow-up was 773 days after BMCT and 972 days after high-risk bypass. All patients tolerated BMCT without issues or complications. A second BMCT treatment was performed in 21% because of clinical deterioration. Wound healing occurred in 75% at 1.5 years, including patients receiving second injections, all of which resolved. Rest pain improved in 87.5% of patients. Pain completely resolved in 58% at 1.5 years. Ankle-brachial index improvement was 0.23 (±0.25). Three BMCT patients went on to amputation. One-year freedom from major amputation or death was 78% for BMCT vs 69% for high-risk bypass (P = .60). CONCLUSIONS: BMCT is a potential option in CLI patients who are not candidates for bypass or endovascular intervention. Limb salvage is unexpectedly high in this population with few other options.

Lesion complexity drives the cost of superficial femoral artery endovascular interventions.

OBJECTIVE: Patients who undergo endovascular treatment of superficial femoral artery (SFA) disease vary greatly in lesion complexity and treatment options. This study examined the association of lesion severity and cost of SFA stenting and to determine if procedure cost affects primary patency at 1 year. METHODS: A retrospective record review identified patients undergoing initial SFA stenting between January 1, 2010, and February 1, 2012. Medical records were reviewed to collect data on demographics, comorbidities, indication for the procedure, TransAtlantic Inter-Society Consensus (TASC) II severity, and primary patency. The interventional radiology database and hospital accounting database were queried to determine cost drivers of SFA stenting. Procedure supply cost included any item with a bar code used for the procedure. Associations between cost drivers and lesion characteristics were explored. Primary patency was determined using Kaplan-Meier survival curves and a log-rank test. RESULTS: During the study period, 95 patients underwent stenting in 98 extremities; of these, 61% of SFA stents were performed for claudication, with 80% of lesions classified as TASC II A or B. Primary patency at 1 year was 79% for the entire cohort. The mean total cost per case was $10,333. Increased procedure supply cost was associated with adjunct device use, the number of stents, and TASC II severity. Despite higher costs of treating more complex lesions, primary patency at 1 year was similar at 80% for high-cost (supply cost >$4000) vs 78% for low-cost (supply cost <$4000) interventions. CONCLUSIONS: SFA lesion complexity, as defined by TASC II severity, drives the cost of endovascular interventions but does not appear to disadvantage patency at 1 year. Reimbursement agencies should consider incorporating disease severity into reimbursement algorithms for lower extremity endovascular interventions.

Age-related loss of SirT1 expression results in dysregulated human vascular smooth muscle cell function.

Loss of vascular smooth muscle cell (VSMC) function is a hallmark of vascular disease. VSMCs become increasingly dysregulated, apoptotic, and senescent as we age. Sirtuin 1 (SirT1) is a deactylase that regulates substrates associated with stress mitigation, metabolism, and aging. Our aim was to examine the role of SirT1 in vascular aging and the function this protein plays in the context of cellular response to stress and senescence. We compared endogenous SirT1 expression in young and old human donors. Human VSMC (HuVSMC) from donors ranging in age from 12 to 88 (n = 14) were isolated and cultured. In cultured HuVSMC the levels of endogenous SirT1 were examined by Western blot analysis. We found that endogenous SirT1 protein expression inversely correlated with donor age. Additionally, we demonstrated that age-related loss of SirT1 correlated in functional deficits, diminished stress response, reduced capacity for migration, and proliferation and increased senescence. Manipulation of SirT1 levels in young cells confirmed the role of SirT1 in cellular migration and proliferation capability. Furthermore, we demonstrated that age-related loss of SirT1 was associated with the induction of VSMC senescence. With correlation to symptomatic disease, we demonstrated a significant difference in SirT1 levels from HuVSMC isolated from aged arteries that were occluded with atherosclerotic lesions (n = 7), compared with patent sections of the same artery. Having demonstrated that endogenous SirT1 is lost with age, which correlates with a loss of capacity for vascular repair, our data explain one of the molecular changes that occurs in the aged vasculature.

The financial implications of endovascular aneurysm repair in the cost containment era.

OBJECTIVE: Endovascular aneurysm repair (EVAR) is associated with significant direct device costs. Such costs place EVAR at odds with efforts to constrain healthcare expenditures. This study examines the procedure-associated costs and operating margins associated with EVAR at a tertiary care academic medical center. METHODS: All infrarenal EVARs performed from April 2011 to March 2012 were identified (n = 127). Among this cohort, 49 patients met standard commercial instruction for use guidelines, were treated using a single manufacturer device, and billed to Medicare diagnosis-related group (DRG) 238. Of these 49 patients, net technical operating margins (technical revenue minus technical cost) were calculated in conjunction with the hospital finance department. EVAR implant costs were determined for each procedure. DRG 238-associated costs and length of stay were benchmarked against other academic medical centers using University Health System Consortium 2012 data. RESULTS: Among the studied EVAR cohort (age 75, 82% male, mean length of stay, 1.7 days), mean technical costs totaled $31,672. Graft implants accounted for 52% of the allocated technical costs. Institutional overhead was 17% ($5495) of total technical costs. Net mean total technical EVAR-associated operating margins were -$4015 per procedure. Our institutional costs and length of stay, when benchmarked against comparable centers, remained in the lowest quartile nationally using University Health System Consortium costs for DRG 238. Stent graft price did not correlate with total EVAR market share. CONCLUSIONS: EVAR is currently associated with significant negative operating margins among Medicare beneficiaries. Currently, device costs account for over 50% of EVAR-associated technical costs and did not impact EVAR market share, reflecting an unawareness of cost differential among surgeons. These data indicate that EVAR must undergo dramatic care delivery redesign for this practice to remain sustainable.

Retrospective review of superficial femoral artery stenting in diabetic patients: thiazolidinedione use may decrease reinterventions.

BACKGROUND: Diabetics are known to have inferior outcomes following peripheral vascular interventions. Thiazolidinediones are oral diabetic agents which improve outcomes following coronary bare metal stenting. No studies have been performed evaluating thiazolidinedione use and outcomes following lower extremity endovascular interventions. We hypothesize that diabetic patients taking thiazolidinediones at the time of primary superficial femoral artery (SFA) stenting have fewer reinterventions. METHODS: A retrospective review was performed to identify diabetic patients undergoing primary SFA stenting. The unit of analysis was the extremity. The primary outcome was freedom from target lesion revascularization stratified by thiazolidinedione use, evaluated by Kaplan Meier curves and a log rank test. A Cox proportional hazards model was constructed to determine variables associated with freedom from target lesion revascularization. RESULTS: SFA stents were placed in 138 extremities in 128 diabetic patients between August 1, 2001 and July 15, 2012. Twenty-four patients were taking thiazolidinediones at the time of SFA stenting. All patients taking thiazolidinediones had TASC A or B lesions. Twenty-seven extremities in the non-thiazolidinedione group had TASC C or D lesions and were excluded to control for disease severity. Freedom from target lesion revascularization was significantly higher in diabetics taking thiazolidinediones at 2 years, 88.5% vs. 59.4%, P = 0.02, SE < 10%. Cox modeling identified a protective trend for thiazolidinedione use (thiazolidinedione use HR 0.33, 95% CI 0.09-1.13), whereas critical limb ischemia and insulin use were associated with trends for worse freedom from target lesion revascularization. CONCLUSIONS: This pilot, translation study demonstrates that diabetic patients taking thiazolidinediones at the time of primary SFA stenting have decreased reintervention rates at 2 years. These results may be explained by higher adiponectin levels or other anti-inflammatory effects in patients taking thiazolidinedione. National and regional quality improvement registries should consider collecting information regarding specific diabetic regimens and use of PPAR agonists such as cilostazol and fibrates.

Vascular smooth muscle cell-derived adiponectin: a paracrine regulator of contractile phenotype.

Adiponectin is a cardioprotective adipokine derived predominantly from visceral fat. We recently demonstrated that exogenous adiponectin induces vascular smooth muscle cell (VSMC) differentiation via repression of mTORC1 and FoxO4. Here we report for the first time that VSMC express and secrete adiponectin, which acts in an autocrine and paracrine manner to regulate VSMC contractile phenotype. Adiponectin was found to be expressed in human coronary artery and mouse aortic VSMC. Importantly, siRNA knock-down of endogenous adiponectin in VSMC significantly reduced the expression of VSMC contractile proteins. Contractile protein deficiency was also observed in primary VSMC isolated from Adiponectin(-/-) mice. This deficiency could be rescued by culturing Adiponectin(-/-) VSMC in conditioned media from wild type (WT) VSMC. Moreover, the paracrine effect of VSMC-derived adiponectin was confirmed as adiponectin neutralizing antibody blocked the rescue. Overexpressed adiponectin also exerted paracrine effects on neighboring untransfected VSMC, which was also blocked by adiponectin neutralizing antibody. Interestingly, adiponectin expression was inducible by the PPARγ agonist rosiglitazone. Our data support an important role for VSMC-derived adiponectin in maintaining VSMC contractile phenotype, contributing to critical cardioprotective functions in the vascular wall. This article is part of a Special Issue entitled "Local Signaling in Myocytes".

The impact of adjunctive iliac stenting on femoral-femoral bypass in contemporary practice.

OBJECTIVES: Most reports of femoral-femoral bypass (FFB) were published before the era of endovascular intervention. This study examines the utilization and impact of adjunctive endovascular intervention on FFB in contemporary practice. METHODS: We reviewed 253 FFB performed in 247 patients between 1984 and 2010. Primary endpoints, including graft patency, primary-assisted patency, limb salvage, and survival, were assessed using Kaplan-Meier life-table analysis. Univariate and multivariate analyses were performed to determine predictors of primary endpoints. RESULTS: The indication for FFB included claudication (27%; n = 69) and critical limb ischemia (72%; n = 184). Forty-eight patients (19%) were treated urgently for acute ischemia. Mean follow-up was 5.6 ± 5.5 years. Over the study interval, adjunctive iliac percutaneous transluminal angioplasty (PTA)/stent placement increased significantly from 0% to 54% (P trend < .001), while the rate of axillofemoral bypass or no inflow procedure decreased from 100% to 46% (P trend < .001). Despite increased utilization, iliac PTA/stenting was associated with decreased 5-year primary graft patency of 44% compared with 74% for axillofemoral bypass patients and 71% in patients with no adjunctive inflow procedure (P = .004). Patients with inflow iliac PTA/stents also had diminished 5-year assisted primary patency of 61% compared with 85% for axillofemoral bypass patients and 87% in patients without inflow revascularization (P = .002). Adjunctive iliac PTA/stenting did not impact limb salvage or overall survival. Five-year primary patency among claudicants and critical leg ischemia patients was 65% and 68%, respectively. CONCLUSIONS: The incidence of iliac PTA/stent placement in conjunction with FFB has increased significantly over time in contemporary practice. Reliance on iliac stent placement for FFB inflow is paradoxically associated with both diminished primary and assisted primary graft patency when compared with historical controls. These findings highlight the importance of patient selection and inflow consideration when performing FFB.

Variation in thromboembolic complications among patients undergoing commonly performed cancer operations.

OBJECTIVE: There is widespread evidence that cancer confers an increased risk of deep venous thrombosis (DVT). This risk is thought to vary among different cancer types. The purpose of this study is to better define the incidence of thrombotic complications among patients undergoing surgical treatment for a spectrum of prevalent cancer diagnoses in contemporary practice. METHODS: All patients undergoing one of 11 cancer surgical operations (breast resection, hysterectomy, prostatectomy, colectomy, gastrectomy, lung resection, hepatectomy, pancreatectomy, cystectomy, esophagectomy, and nephrectomy) were identified by Current Procedural Terminology and International Classification of Diseases, Ninth Revision codes using the American College of Surgeons National Surgical Quality Improvement Program database (2007-2009). The study endpoints were DVT, pulmonary embolism (PE), and overall postoperative venous thromboembolic events (VTE) within 1 month of the index procedure. Multivariate logistic regression was utilized to calculate adjusted odds ratios for each endpoint. RESULTS: Over the study interval, 43,808 of the selected cancer operations were performed. The incidence of DVT, PE, and total VTE within 1 month following surgery varied widely across a spectrum of cancer diagnoses, ranging from 0.19%, 0.12%, and 0.28% for breast resection to 6.1%, 2.4%, and 7.3%, respectively, for esophagectomy. Compared with breast cancer, the incidence of VTE ranged from a 1.31-fold increase in VTE associated with gastrectomy (95% confidence interval, 0.73-2.37; P = .4) to a 2.68-fold increase associated with hysterectomy (95% confidence interval, 1.43-5.01; P = .002). Multivariate logistic regression revealed that inpatient status, steroid use, advanced age (≥60 years), morbid obesity (body mass index ≥35), blood transfusion, reintubation, cardiac arrest, postoperative infectious complications, and prolonged hospitalization were independently associated with increased risk of VTE. CONCLUSIONS: The incidence of VTE and thromboembolic complications associated with cancer surgery varies substantially. These findings suggest that both tumor type and resection magnitude may impact VTE risk. Accordingly, such data support diagnosis and procedural-specific guidelines for perioperative VTE prophylaxis and can be used to anticipate the risk of potentially preventable morbidity.

Adiponectin induces vascular smooth muscle cell differentiation via repression of mammalian target of rapamycin complex 1 and FoxO4.

OBJECTIVE: The adipocyte-secreted hormone adiponectin exerts important cardioprotective and antidiabetic effects. Little is known about its effect on vascular smooth muscle cells (VSMC), key cells in restenosis, hypertension, and atherosclerosis. METHODS AND RESULTS: Using human coronary artery VSMC, we found that recombinant adiponectin in the high-molecular-weight or trimeric forms but not the globular form induced VSMC differentiation through a mechanism similar to the classic feedback signaling used by rapamycin, a drug known to effectively inhibit restenosis on drug-eluting stents. Using a combination of pharmacological agents, small interfering RNA, and overexpression approaches, we demonstrated that adiponectin activated 5'-AMP-activated protein kinase α2 isoform, leading to inhibition of mammalian target of rapamycin complex 1 and S6K1. This in turn stabilized insulin receptor substrate-1, driving Akt2-mediated inhibition of FoxO4 and subsequent contractile protein induction. Although adiponectin and rapamycin have similarly beneficial effects on VSMC phenotype in both cell and organ culture, a direct comparison of the effects of rapamycin versus adiponectin on endothelial cells revealed distinct differences: rapamycin inhibited Akt phosphorylation, whereas adiponectin maintained it. Importantly, Akt activity preserves endothelial function. CONCLUSION: Adiponectin promotes VSMC differentiation and preserves endothelial cell Akt signaling, suggesting that targeting the adiponectin pathway may have advantages over rapamycin in developing new drug-eluting stent therapeutics.

Long-term results of open and endovascular revascularization of superficial femoral artery occlusive disease.

BACKGROUND: First-line treatment for patients with superficial femoral arterial (SFA) occlusive disease has yet to be determined. This study compared long-term outcomes between primary SFA stent placement and primary femoral-popliteal bypass. Periprocedural patient factors were examined to determine their effect on these results. METHODS: All femoral-popliteal bypasses and SFA interventions performed in consecutive patients with symptoms Rutherford 3 to 6 between 2001 and 2008 were reviewed. Time-dependent outcomes were analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards were performed to determine predictors of graft patency. Multivariate analysis was completed to identify patient covariates most often associated with the primary therapy. RESULTS: A total of 152 limbs in 141 patients (66% male; mean age, 66 ± 22 years) underwent femoral-popliteal bypass, and 233 limbs in 204 patients (49% male; mean age, 70 ± 11 years) underwent SFA interventions. Four-year primary, primary-assisted, and secondary patency rates were 69%, 78%, and 83%, respectively, for bypass patients and 66%, 91%, and 95%, respectively, for SFA interventions. Six-year limb salvage was 80% for bypass vs 92% for stenting (P = .04). Critical limb ischemia (CLI) and renal insufficiency were predictors of bypass failure. Claudication was a predictor of success for SFA stenting. Three-year limb salvage rates for CLI patients undergoing surgery and SFA stenting were 83%. Amputation-free survival at 3 years for CLI patients was 55% for bypass and 59% for SFA interventions. Multivariate predictors (odds ratios and 95% confidence intervals) of covariates most frequently associated with first-line SFA stenting were TransAtlantic Inter-Society Consensus II A and B lesions (5.9 [3.4-9.1], P < .001), age >70 years (2.1 [1.4-3.1], P < .001), and claudication (1.7 [1.1-2.7], P = .01). Regarding bypass as first-line therapy, claudicant patients were more likely to have nondiabetic status (5.6 [3.3-9.4], P < .001), creatinine <1.8 mg/dL (4.6 [1.5-14.9], P = .01), age <70 years (2.7 [CI, 1.6-8.3], P < .001), and presence of an above-knee popliteal artery target vessel (1.9 [CI, 1.1-3.4] P = .02). CONCLUSION: Indication, patient-specific covariates, and anatomic lesion classification have significant association when determining surgeon selection of SFA stenting or femoral-popliteal bypass as first-line therapy. Patients with SFA disease can have comparable long-term results when treatment options are well matched to patient-specific and anatomic characteristics.

Completion duplex ultrasound predicts early graft thrombosis after crural bypass in patients with critical limb ischemia.

OBJECTIVE: To determine if intraoperative distal graft end-diastolic velocity (EDV) using completion duplex ultrasound (CDU) predicts patency of crural bypass in patients with critical limb ischemia (CLI). METHODS: Records of 116 non-consecutive patients who underwent crural revascularization with vein conduit and CDU between 1998 and 2008 were reviewed. Bypass grafts were performed for rest pain (34%) or tissue loss (66%), while 56% of the reported cases were categorized as "disadvantaged" because of compromised vein quality or diseased arterial outflow. A 10-MHz low-profile transducer was used to image the entire bypass at case completion. Technical adequacy of the grafts was verified by absence of retained valves, arteriovenous fistulas, or localized velocity increases and presence of bypass-dependent distal pulses. Modified Rutherford scores were calculated as surrogate markers of runoff resistance and compared to distal graft EDV. The primary study end point was graft patency during a 1-year posttreatment period. Patency rates were determined using Kaplan-Meier life table methodology and compared using the log-rank test. Predictors of graft patency were determined by Cox proportional hazards. RESULTS: Primary, primary-assisted, and secondary patency for all crural bypasses were 62%, 66%, and 70% at 1 year, respectively. When stratified by tertiles of distal graft EDV (0 - <5 cm/s, 5-15 cm/s, >15 cm/s), 1-year primary patency rates were 32%, 64%, and 84% (P = .001). Low (0 - < 5 cm/s) distal graft EDV (hazard ratio [HR], 3.3 confidence interval [CI], 1.74-6.41; P < .001), poor-quality conduit (HR, 2.5; CI, 1.19-5.21; P = .016), age <70 (HR, 2.08; CI, 1.06-4.00; P = .031), and lack of statin use (HR, 2.04; CI, 1.04-4.00; P = .038) were independent predictors of graft failure. While the modified Rutherford score correlated with distal graft EDV (P = .05), it was not an independent predictor of patency (P = .58). Predictors of low EDV (<5 cm/s) included single-vessel runoff (odds ratio [OR], 3.33; CI, 1.14-9.71; P = .027), poor conduit (OR, 2.94; CI, 1.16-7.41; P = 0.024), and diabetes (OR, 2.86; CI, 1.14-7.21; P = .025). CONCLUSIONS: Distal graft EDV predicts crural vein graft patency in patients with CLI. Grafts with EDV <5 cm/s remain at high risk for early failure. The impacts on patency of statins, age, and poor-quality conduit are, again, confirmed. These results highlight the value of EDV using intraoperative CDU for anticipating and, possibly, improving results of open crural revascularization.

Targeting smooth muscle cell phenotypic switching in vascular disease.

OBJECTIVE: The phenotypic plasticity of vascular smooth muscle cells (VSMCs) is central to vessel growth and remodeling, but also contributes to cardiovascular pathologies. New technologies including fate mapping, single cell transcriptomics, and genetic and pharmacologic inhibitors have provided fundamental new insights into the biology of VSMC. The goal of this review is to summarize the mechanisms underlying VSMC phenotypic modulation and how these might be targeted for therapeutic benefit. METHODS: We summarize findings from extensive literature searches to highlight recent discoveries in the mechanisms underlying VSMC phenotypic switching with particular relevance to intimal hyperplasia. PubMed was searched for publications between January 2001 and December 2020. Search terms included VSMCs, restenosis, intimal hyperplasia, phenotypic switching or modulation, and drug-eluting stents. We sought to highlight druggable pathways as well as recent landmark studies in phenotypic modulation. RESULTS: Lineage tracing methods have determined that a small number of mature VSMCs dedifferentiate to give rise to oligoclonal lesions in intimal hyperplasia and atherosclerosis. In atherosclerosis and aneurysm, single cell transcriptomics reveal a striking diversity of phenotypes that can arise from these VSMCs. Mechanistic studies continue to identify new pathways that influence VSMC phenotypic plasticity. We review the mechanisms by which the current drug-eluting stent agents prevent restenosis and note remaining challenges in peripheral and diabetic revascularization for which new approaches would be beneficial. We summarize findings on new epigenetic (DNA methylation/TET methylcytosine dioxygenase 2, histone deacetylation, bromodomain proteins), transcriptional (Hippo/Yes-associated protein, peroxisome proliferator-activity receptor-gamma, Notch), and ß3-integrin-mediated mechanisms that influence VSMC phenotypic modulation. Pharmacologic and genetic targeting of these pathways with agents including ascorbic acid, histone deacetylase or bromodomain inhibitors, thiazolidinediones, and integrin inhibitors suggests potential therapeutic value in the setting of intimal hyperplasia. CONCLUSIONS: Understanding the molecular mechanisms that underlie the remarkable plasticity of VSMCs may lead to novel approaches to treat and prevent cardiovascular disease and restenosis.

Lovastatin induces VSMC differentiation through inhibition of Rheb and mTOR.

It is becoming increasingly clear that cholesterol-independent effects of statins also contribute to the cardioprotective effects, but these mechanisms remain poorly understood. We investigated the effects of lovastatin on vascular smooth muscle phenotype. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin induces vascular smooth muscle cell (VSMC) differentiation. We found that lovastatin also inhibits mTORC1 signaling and that this inhibition is required for VSMC differentiation. Lovastatin inhibition of mTORC1 was farnesylation dependent, suggesting the farnesylated G protein Rheb (Ras homologue enriched in brain), a known upstream activator of mTORC1. Rheb overexpression induced mTORC1 activity and repressed contractile protein expression, but a farnesylation-deficient mutant (C18S) elicited the opposite effect. Rheb knockdown with small interfering RNA was also sufficient to inhibit mTORC1 and induce contractile protein expression, and it prevented statin-induced VSMC differentiation. Notably, mTORC1 activity was elevated in VSMC isolated from an intimal hyperplastic patient lesion compared with normal media, and lovastatin treatment inhibited mTORC1 activity in these cultures. Furthermore, lovastatin inhibited mTORC1 activity and prevented the downregulation of contractile protein expression in an ex vivo angioplasty model. In conclusion, these findings illustrate a mechanism for the cardioprotective effects of lovastatin through inhibition of Rheb and mTORC1 and promotion of a differentiated VSMC phenotype.

Long-term results of combined common femoral endarterectomy and iliac stenting/stent grafting for occlusive disease.

BACKGROUND: Common femoral artery (CFA) endarterectomy with iliac stenting or stent grafting can be an alternative to traditional open surgery in patients with aortoiliac occlusive disease. We report the long-term outcomes of this approach. METHODS: Patients undergoing CFA endarterectomy with simultaneous iliac stenting/stent grafting between 1997 and 2006 were retrospectively reviewed. Technical success, clinical and hemodynamic outcomes, and 5-year patency using life-table methodology were determined. Factors associated with reintervention and mortality were determined by logistic regression analysis. RESULTS: A total of 171 patients (mean age, 67 +/- 10 years; 38% female; 35% diabetic) underwent 193 CFA endarterectomies and iliac stent/stent grafting. Indications were rest pain (32%), tissue loss (22%), and claudication (46%). External iliac artery (EIA) lesions were present in 39%, and combined common iliac artery (CIA) and EIA lesions were seen in 61% of patients. Complete CIA/EIA occlusions were present in 41% of patients. Stent grafts were used in 41% of patients. Technical success occurred in 98% of patients. Clinical improvement was seen in 92% of patients. Mean ankle-brachial index increased from 0.38 +/- 0.32 to 0.72 +/- 0.24. Median length of stay was 2 days (range, 1-51 days). Thirty-day mortality was 2.3% and 5-year survival was 60%. Five-year primary, primary-assisted, and secondary patencies were 60%, 97%, and 98% respectively. Endovascular reintervention was required in 14% of patients; inflow surgical procedures were required in 10%. By logistic regression analysis, use of stent grafts compared with bare stents was associated with significantly higher primary patency (87% +/- 5% vs 53% +/- 7%; P < .01). CONCLUSION: Combined CFA endarterectomy with iliac intervention yield acceptable long-term results. The use of stent grafts compared with bare stents is associated with improved primary patency.

Below-Knee Amputation Failure and Poor Functional Outcomes Are Higher Than Predicted in Contemporary Practice.

OBJECTIVE: The perceived functional benefit of below-knee amputation (BKA) must be carefully weighed against the need for potential reinterventions. This study sought to examine the contemporary clinical and functional outcomes of patients undergoing BKA in the endovascular era. METHODS: All patients who underwent BKA from January 2008 to December 2014 at a single tertiary medical center were retrospectively reviewed. Demographics, comorbidities, ambulation status, and transcutaneous oximetry (TcPO2) values were recorded. Study end points included freedom from conversion to above-knee amputation (AKA), freedom from conversion to AKA or death, BKA healing, and ambulation. Statistical modeling was performed to determine associations with BKA failure. RESULTS: Over the study interval, 130 limbs underwent BKA in 120 patients. Transcutaneous oximetry studies were obtained in 65% (n = 85). Thirty-eight percent (n = 46) of all BKA patients went on to heal and ambulate. Twenty-five percent (n = 33) required reintervention, 24 with conversion to AKA, and 9 with BKA revision. One-year freedom from conversion to AKA was 76% and was decreased among those with lower TcPO2 levels (60% TcPO2 <40 vs 81% TcPO2 ≥40; P = .04). One-year composite freedom from conversion to AKA/death was 60% and was decreased among those with lower TcPO2 readings (39% TcPO2 <40 vs 69% TcPO2 ≥40; P = .01). CONCLUSION: Despite a perceived functional bias toward knee salvage at the time of major amputation, most patients failed to postoperatively ambulate. Those with decreased TcPO2 levels (<40 mm Hg) have a 2-fold higher risk of AKA conversion or death, while nearly one-fourth of all BKA patients will succumb to the same fate irrespective of TcPO2. This suggests that many BKA patients in the endovascular era fail to derive the perceived benefit of knee salvage at the time of their index amputation. These findings highlight the need for careful patient selection and for a shared decision-making model in this frail population.