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.

LUCY results show females have equivalent outcomes to males following endovascular abdominal aortic aneurysm repair despite more complex aortic morphology.

OBJECTIVE: Females remain underrepresented in studies of endovascular aneurysm repair (EVAR) owing to anatomic ineligibility for EVAR devices. The aim of the LUCY study is to explore the comparative safety and effectiveness of EVAR using a low-profile stent graft (Ovation; Endologix, Inc, Irvine, Calif) in females as well as males. METHODS: The LUCY registry was a prospective, nonrandomized, multicenter study where patient enrollment was stratified by sex in a two-to-one ratio (male-to-female). Main outcomes were procedural data, 30-day major adverse events, device-related adverse events confirmed with contrast-enhanced computed tomography scans, secondary interventions, and hospital readmissions. Adverse events were adjudicated by a clinical events committee. Patients were followed at their 1-month and 1-year follow-up visits. RESULTS: A total of 225 patients (76 females, 149 males) were enrolled at 39 U.S. centers. No statistically significant sex differences were observed in demographics or medical history. Females presented with smaller access vessels (6.2 vs 7.7 mm; P < .001), statistically smaller neck diameter (22 mm vs 23 mm; P = .001), similar neck angulation (11% vs 9% angulation >45°; P = .81), and smaller maximum abdominal aortic aneurysm (AAA) diameter (50 mm vs 53 mm; P = .01), however, these factors do not seem to be clinically significant. Technical success was 99%, and the median hospital stay was 1 day. The incidence of MAE through 30 days was 1.3% in females and 2.0% in males. There were no differences between sexes observed among the 30-day perioperative outcomes. The 30-day secondary intervention rate was 0.4%. The all-cause readmission rate through 30 days was 5.3% in females and 6.7% in males. There were no reports of limb occlusion or deaths within the first 30 days. At 1 year, there were no deaths in the female arm but nine deaths (6.0%) were observed in males, two of which were AAA related (1.3%). Through 1 year, there were eight type IA endoleaks (one female, seven males; P = .27) and three cases with limb occlusion (one female, two males). There were no reports of migration, AAA rupture, or surgical conversion through the end of follow-up. CONCLUSIONS: Despite more complex aortic morphology in females than males, EVAR with a low-profile stent graft was associated with comparable procedural and perioperative outcomes through 1 year between the sexes.

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.

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.

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.

Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition.

Vascular smooth muscle cells (VSMCs) undergo transcriptionally regulated reversible differentiation in growing and injured blood vessels. This dedifferentiation also contributes to VSMC hyperplasia after vascular injury, including that caused by angioplasty and stenting. Stents provide mechanical support and can contain and release rapamycin, an inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1). Rapamycin suppresses VSMC hyperplasia and promotes VSMC differentiation. We report that rapamycin-induced differentiation of VSMCs required the transcription factor GATA-6. Inhibition of mTORC1 stabilized GATA-6 and promoted the nuclear accumulation of GATA-6, its binding to DNA, its transactivation of promoters encoding contractile proteins, and its inhibition of proliferation. These effects were mediated by phosphorylation of GATA-6 at Ser(290), potentially by Akt2, a kinase that is activated in VSMCs when mTORC1 is inhibited. Rapamycin induced phosphorylation of GATA-6 in wild-type mice, but not in Akt2(-/-) mice. Intimal hyperplasia after arterial injury was greater in Akt2(-/-) mice than in wild-type mice, and the exacerbated response in Akt2(-/-) mice was rescued to a greater extent by local overexpression of the wild-type or phosphomimetic (S290D) mutant GATA-6 than by that of the phosphorylation-deficient (S290A) mutant. Our data indicated that GATA-6 and Akt2 are involved in the mTORC1-mediated regulation of VSMC proliferation and differentiation. Identifying the downstream transcriptional targets of mTORC1 may provide cell type-specific drug targets to combat cardiovascular diseases associated with excessive proliferation of VSMCs.

Contemporary management of median arcuate ligament syndrome provides early symptom improvement.

OBJECTIVE: Optimal diagnosis and management of median arcuate ligament (MAL) syndrome (MALS) remains unclear in contemporary practice. The advent and evolution of laparoscopic and endovascular techniques has redirected management toward a less invasive therapeutic algorithm. This study examined our contemporary outcomes of patients treated for MALS. METHODS: All patients treated for MALS at Dartmouth-Hitchcock Medical Center from 2000 to 2013 were retrospectively reviewed. Demographics and comorbidities were recorded. Freedom from symptoms and freedom from reintervention were the primary end points. Return to work or school was assessed. Follow-up by clinic visits and telephone allowed quantitative comparisons among the patients. RESULTS: During the study interval, 21 patients (24% male), with a median age of 42 years, were treated for MALS. All patients complained of abdominal pain in the presence of a celiac stenosis, 16 (76%) also reported weight loss at the time of presentation, and 57% had a concomitant psychiatric history. Diagnostic imaging most commonly used included duplex ultrasound (81%), computed tomography angiography (66%), angiography (57%), and magnetic resonance angiography (5%). Fourteen patients (67%) underwent multiple diagnostic studies. All patients underwent initial laparoscopic MAL release. Seven patients (33%) underwent subsequent celiac stent placement in the setting of recurrent or unresolved symptoms with persistent celiac stenosis at a mean interval of 49 days. Two patients required surgical bypass after an endovascular intervention failed. The 6-month freedom from symptoms was 75% and freedom from reintervention was 64%. Eighteen patients (81%) reported early symptom improvement and weight gain, and 66% were able to return to work. CONCLUSIONS: A multidisciplinary treatment approach using initial laparoscopic release and subsequent stent placement and bypass surgery provides symptom improvement in most patients treated for MALS. The potential placebo effect, however, remains uncertain. A significant minority of patients will require reintervention, justifying longitudinal surveillance and prudent patient selection. Patients can anticipate functional recovery, weight gain, and return to work with treatment.

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.

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.

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.

Resveratrol induces vascular smooth muscle cell differentiation through stimulation of SirT1 and AMPK.

Phenotypic plasticity in vascular smooth muscle cells (VSMC) is necessary for vessel maintenance, repair and adaptation to vascular changes associated with aging. De-differentiated VSMC contribute to pathologies including atherosclerosis and intimal hyperplasia. As resveratrol has been reported to have cardio- protective effects, we investigated its role in VSMC phenotypic modulation. We demonstrated the novel finding that resveratrol promoted VSMC differentiation as measured by contractile protein expression, contractile morphology and contraction in collagen gels. Resveratrol induced VSMC differentiation through stimulation of SirT1 and AMPK. We made the novel finding that low or high dose resveratrol had an initially different mechanism on induction of differentiation. We found that low dose resveratrol stimulated differentiation through SirT1-mediated activation of AKT, whereas high dose resveratrol stimulated differentiation through AMPK-mediated inhibition of the mTORC1 pathway, allowing activation of AKT. The health effects of resveratrol in cardiovascular diseases, cancer and longevity are an area of active research. We have demonstrated a supplemental avenue where-by resveratrol may promote health by maintaining and enhancing plasticity of the 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.

Functional outcomes following catheter-based iliac vein stent placement.

OBJECTIVES: Although previous reports have demonstrated the efficacy of catheter-directed thrombolytic therapy and iliac vein stent placement for the management of iliofemoral deep vein thrombosis (DVT), functional outcomes remain undefined. The purpose of this study was to determine midterm outcomes and functional quality of life among patients treated with iliac vein stenting. METHODS: Records of all the patients treated with iliac vein stent placement between March 2004 and March 2011 were examined for primary patency, assisted primary patency, and secondary patency. Midterm functional outcomes were measured quantitatively, including ongoing symptoms and return to work status. RESULTS: Over the study interval, 32 patients (33 limbs) underwent iliac vein stent placement. In all, 72% (n = 23) of these patients were female, with an average age of 43 years. In all, 78% (n = 25) of the patients were diagnosed with acute DVT, 89% of which occurred in the left leg. Catheter-directed thrombolysis was utilized in 92% (23 of 25) of the patients with acute DVT. All patients treated with thrombolysis and stent placement presented with pain and edema in the affected limb. One-year primary, assisted primary, and secondary patencies were 75%, 96%, and 96%, respectively. Freedom from reintervention at 1 year was 83%. Treatment was associated with a sustained significant reduction in pain (91% vs 6%, P < .001) and edema (97% vs 12%, P < .001) at a mean follow-up of 29 months (range 5-83 months), at which time 89% of the patients reported to be at their pre-DVT functional status. CONCLUSIONS: Aggressive therapy of symptomatic iliac vein stenosis or occlusion with venography, catheter-directed thrombolysis, and iliac vein stent placement provides durable patency and freedom from reintervention. Most patients can anticipate good functional recovery with decreased pain, decreased edema, and high likelihood of returning to work.

Outcomes of endovascular interventions for salvage of renal transplant allografts.

INTRODUCTION: Renal transplantation has been performed with increasing frequency, and interventions to preserve graft function and integrity have been steadily increasing. This study examines the outcomes of endovascular therapy based on indication for renal transplant allograft salvage. METHODS: A prospective transplant registry was queried for all patients undergoing endovascular interventions for transplant allograft salvage from 2002 to 2011. Demographics, perioperative data, and transplant function outcomes were extracted and analyzed. RESULTS: Among 34 renal transplant recipients (62% men) who underwent endovascular interventions for graft salvage, the mean age was 48.2 years (range, 18-74 years). The indications for intervention included worsening renal function in 15, renovascular hypertension in 11, and structural abnormalities identified on noninvasive imaging in eight. Transluminal angioplasty with and without stenting was done in 26 patients: 14 patients (41.2%) with significant transplant stenosis, 11 (32.4%) with peripheral arterial disease in proximal iliac vessels, and one patient with iliac dissection. Five arteriovenous fistulas and two pseudoaneurysms required embolization. One patient required lysis for deep venous thrombosis causing obstruction of allograft outflow. There were no periprocedural deaths, and 30-day morbidity was 17.6%. Renal function improved or stabilized in 67% of patients with worsening renal function. Better blood pressure control was achieved in patients with renovascular hypertension. Mean follow-up was 4.2 years. There were no significant differences in transplant allograft survival during the duration of follow-up based on primary indication for endovascular intervention, but transplant graft survival at follow-up was significantly better in patients with renovascular hypertension at the initial endovascular intervention. CONCLUSIONS: Endovascular salvage of renal allograft transplants can be safely done for various indications. The maximum benefit in renal function as assessed by serum creatinine and control of blood pressure is seen in patients with worsening renal function and in the presence of renovascular hypertension, respectively. Long-term transplant graft function was significantly better in patients with renovascular hypertension at the initial endovascular intervention.

Adiponectin in the heart and vascular system.

Adipose tissue is not only a storage depot for energy, but also an active endocrine tissue. Adipokines, hormones and cytokines secreted from adipocytes, relay information about energy stores to peripheral tissues throughout the body. Most adipokines are produced in direct proportion to fat mass, and many have proinflammatory or otherwise adverse effects on the cardiovascular system. The notable exception is the cardioprotective adipokine adiponectin, which is secreted in inverse proportion to fat mass. Circulating adiponectin levels are highest in lean individuals and inversely correlate with fat mass. Low levels of serum adiponectin are now appreciated as a risk factor in a variety of cardiovascular diseases including coronary artery disease and restenosis, type 2 diabetes mellitus, and hypertension. In this chapter, we provide an introduction to adiponectin and review the extensive evidence in humans and in mouse and in vitro models for adiponectin's cardioprotective effects.

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.