K. Craig Kent

Unplanned readmissions after vascular surgery

OBJECTIVEnExisting literature on readmission after vascular surgery is limited. The upcoming reduction in Medicare reimbursement for institutions with high readmission rates mandates an accurate understanding of this issue. In this study, we characterize the frequency and causes of 30-day unplanned readmissions after elective vascular surgery.nnnMETHODSnPatients who underwent elective carotid endarterectomy (CEA), endovascular aortic repair (EVAR), open abdominal aortic aneurysm (oAAA) repair, or infrainguinal bypass grafting (BPG) were identified from the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) 2011 database (n = 11,246). Multivariable logistic regression was used to determine variables that contributed to 30-day unplanned readmissions for each surgery type.nnnRESULTSnThe unadjusted unplanned readmission rates after the four vascular procedures ranged from 6.5% for CEA to 15.7% for BPG. In multivariable analyses, patient comorbidities were associated with unplanned readmission after BPG and CEA (P < .05), whereas postoperative complications were more consistently associated with unplanned readmission after EVAR and oAAA repair (P < .05). For all procedures, complications leading to readmission developed more frequently after discharge. Thirty-day mortality was significantly higher in readmitted patients after BPG (1.9% vs 0.3%), EVAR (3.9% vs 0.1%), and CEA (2.2% vs 0.2%; P < .001 for each), but not after oAAA repair.nnnCONCLUSIONSnSelect comorbidities and postoperative complications contribute to unplanned readmissions after vascular surgery. The characteristics of readmitted patients vary with the type of procedure. Interventions designed to mitigate these factors have the potential to reduce unplanned readmissions but likely need to vary with the type of vascular treatment.

A comparison of open surgery versus endovascular repair of unstable ruptured abdominal aortic aneurysms.

OBJECTIVEnTwo randomized trials to date have compared open surgery (OS) and endovascular (EVAR) repair for ruptured abdominal aortic aneurysm (rAAA); however, neither addressed optimal management of unstable patients. Single-center reports have produced conflicting data regarding the superiority of one vs the other, with the lack of statistical power due to low patient numbers. Furthermore, previous studies have not delineated between the outcomes of stable patients with a contained rupture vs those patients with instability. Our objective was to compare 30-day outcomes in patients undergoing OS vs EVAR for all rAAAs, focusing specifically on patients with instability.nnnMETHODSnPatients who underwent repair of rAAA were identified from the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database (2005 to 2010). Unstable patients with rupture were identified as those who were American Society of Anesthesiologists Physical Status Classification 4 or 5 requiring emergency repair with at least one of the following: preoperative shock, preoperative transfusion of >4 units, preoperative intubation, or preoperative coma or impaired sensorium. Univariable and multivariable logistic regression analyses were performed.nnnRESULTSnOf the 1447 patients with rAAA, 65.5% underwent OS and 34.5% EVAR. Forty-five percent were unstable, and for these patients, OS was performed in 71.3% and EVAR in 28.7%. The 30-day mortality rate was 47.9% (OS, 52.8%; EVAR, 35.6%; P < .0001) for unstable rAAAs and was 22.4% for stable rAAAs (OS, 26.3%; EVAR, 16.4%; P = .001). Amongst patients with unstable rAAA, 26% had a myocardial infarction or cardiac arrest ≤ 30 days (OS, 29.0%; EVAR, 19.1%; P = .006), and 17% needed postoperative dialysis (OS, 18.7%; EVAR, 12.8%; P = .04). Amongst patients with stable rAAA, 13.6% had a myocardial infarction or cardiac arrest ≤ 30 days (OS, 14.9%; EVAR, 11.6%; P = .20), and 11.5% needed postoperative dialysis (OS, 13.3%; EVAR, 8.7%; P = .047). Multivariable analyses showed OS was a predictor of 30-day mortality for unstable rAAA (odds ratio, 1.74; 95% confidence interval, 1.16-2.62) and stable rAAA (odds ratio, 1.64; 95% confidence interval, 1.10-2.43).nnnCONCLUSIONSnApproximately one-third of patients treated for rAAA undergo EVAR in NSQIP participating hospitals. Not surprisingly, unstable patients have less favorable outcomes. In both stable and unstable rAAA patients, EVAR is associated with a diminished 30-day mortality and morbidity.

Periadventitial application of rapamycin-loaded nanoparticles produces sustained inhibition of vascular restenosis.

Open vascular reconstructions frequently fail due to the development of recurrent disease or intimal hyperplasia (IH). This paper reports a novel drug delivery method using a rapamycin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs)/pluronic gel system that can be applied periadventitially around the carotid artery immediately following the open surgery. In vitro studies revealed that rapamycin dispersed in pluronic gel was rapidly released over 3 days whereas release of rapamycin from rapamycin-loaded PLGA NPs embedded in pluronic gel was more gradual over 4 weeks. In cultured rat vascular smooth muscle cells (SMCs), rapamycin-loaded NPs produced durable (14 days versus 3 days for free rapamycin) inhibition of phosphorylation of S6 kinase (S6K1), a downstream target in the mTOR pathway. In a rat balloon injury model, periadventitial delivery of rapamycin-loaded NPs produced inhibition of phospho-S6K1 14 days after balloon injury. Immunostaining revealed that rapamycin-loaded NPs reduced SMC proliferation at both 14 and 28 days whereas rapamycin alone suppressed proliferation at day 14 only. Moreover, rapamycin-loaded NPs sustainably suppressed IH for at least 28 days following treatment, whereas rapamycin alone produced suppression on day 14 with rebound of IH by day 28. Since rapamycin, PLGA, and pluronic gel have all been approved by the FDA for other human therapies, this drug delivery method could potentially be translated into human use quickly to prevent failure of open vascular reconstructions.

TGF-β/Smad3 Stimulates Stem Cell/Developmental Gene Expression and Vascular Smooth Muscle Cell De-Differentiation

Atherosclerotic-associated diseases are the leading cause of death in the United States. Despite recent progress, interventional treatments for atherosclerosis can be complicated by restenosis resulting from neo-intimal hyperplasia. We have previously demonstrated that TGF-β and its downstream signaling protein Smad3∶1) are up-regulated following vascular injury, 2) together drive smooth muscle cell (SMC) proliferation and migration and 3) enhance the development of intimal hyperplasia. In order to determine a mechanism through which TGF-β/Smad3 promote these effects, Affymetrix gene expression arrays were performed on primary rat SMCs infected with Smad3 and stimulated with TGF-β or infected with GFP alone. More than 200 genes were differentially expressed (>2.0 fold change, p<0.05) in TGF-β/Smad3 stimulated SMCs. We then performed GO term enrichment analysis using the DAVID bioinformatics database and found that TGF-β/Smad3 activated the expression of multiple genes related to either development or cell differentiation, several of which have been shown to be associated with multipotent stem or progenitor cells. Quantitative real-time PCR confirmed up-regulation of several developmental genes including FGF1, NGF, and Wnt11 (by 2.5, 6 and 7 fold, respectively) as well as stem/progenitor cell associated genes CD34 and CXCR4 (by 10 and 45 fold, respectively). In addition, up-regulation of these factors at protein levels were also confirmed by Western blotting, or by immunocytochemistry (performed for CXCR4 and NGF). Finally, TGF-β/Smad3 down regulated transcription of SMC contractile genes as well as protein production of smooth muscle alpha actin, calponin, and smooth muscle myosin heavy chain. These combined results suggest that TGF-β/Smad3 stimulation drives SMCs to a phenotypically altered state of de-differentiation through the up-regulation of developmental related genes.

Periadventitial drug delivery for the prevention of intimal hyperplasia following open surgery

BACKGROUNDnIntimal hyperplasia (IH) remains a major cause of poor patient outcomes after surgical revascularization to treat atherosclerosis. A multitude of drugs have been shown to prevent the development of IH. Moreover, endovascular drug delivery following angioplasty and stenting has been achieved with a marked diminution in the incidence of restenosis. Despite advances in endovascular drug delivery, there is currently no clinically available method of periadventitial drug delivery suitable for open vascular reconstructions. Herein we provide an overview of the recent literature regarding innovative polymer platforms for periadventitial drug delivery in preclinical models of IH as well as insights about barriers to clinical translation.nnnMETHODSnA comprehensive PubMed search confined to the past 15years was performed for studies of periadventitial drug delivery. Additional searches were performed for relevant clinical trials, patents, meeting abstracts, and awards of NIH funding.nnnRESULTSnMost of the research involving direct periadventitial delivery without a drug carrier was published prior to 2000. Over the past 15years there have been a surge of reports utilizing periadventitial drug-releasing polymer platforms, most commonly bioresorbable hydrogels and wraps. These methods proved to be effective for the inhibition of IH in various animal models (e.g. balloon angioplasty, wire injury, and vein graft), but very few have advanced to clinical trials. There are a number of barriers that may account for this lack of translation. Promising new approaches including the use of nanoparticles will be described.nnnCONCLUSIONSnNo periadventitial drug delivery system has reached clinical application. For periadventitial delivery, polymer hydrogels, wraps, and nanoparticles exhibit overlapping and complementary properties. The ideal periadventitial delivery platform would allow for sustained drug release yet exert minimal mechanical and inflammatory stresses to the vessel wall. A clinically applicable strategy for periadventitial drug delivery would benefit thousands of patients undergoing open vascular reconstruction each year.

Morbidity and mortality after use of iliac conduits for endovascular aortic aneurysm repair

OBJECTIVEnAlthough placement of an open iliac conduit for endovascular aortic aneurysm repair (EVAR) is generally felt to result in higher morbidity and mortality, published literature is scarce. Our objective was to assess 30-day outcomes after elective EVAR with an open iliac conduit using a multi-institutional database.nnnMETHODSnPatients who underwent elective EVAR (n = 14,339) for abdominal aortic aneurysm were identified from the American College of Surgeons National Surgical Quality Improvement Program 2005 to 2011 database. Univariable and multivariable logistic regression analyses were performed.nnnRESULTSnAn open iliac conduit was used in 231 patients (1.6%), and the remainder had femoral exposure or percutaneous EVAR. Women comprised 32% of patients with iliac conduits in contrast to 17% of those without iliac conduits. Patients with iliac conduits were older and had a lower body mass index. Univariable analysis showed patients with open iliac conduits had a higher incidence of postoperative pneumonia (3.0% vs 1.1%), ventilator dependence (4.8% vs 1.0%), renal failure (3.0% vs 0.7%), cardiac arrest or myocardial infarction (5.2% vs 1.1%), return to the operating room (9.1% vs 3.7%), major morbidity (16.0 vs 6.6%), and death (3.0% vs 0.9%). On multivariable analysis, the use of open iliac conduits was associated with higher risk of 30-day mortality (odds ratio, 2.7; 95% confidence interval, 1.2-6.0) and 30-day major morbidity (odds ratio, 2.3; 95% confidence interval, 1.6-3.3).nnnCONCLUSIONSnPatients with open iliac conduits for EVAR are more likely to be female and have higher postoperative morbidity and mortality. For patients with complex iliac artery disease, conduits are a viable alternative after EVAR to be performed, albeit at an increased risk. These data do suggest the need for lower-profile grafts and other alternative strategies for navigating complex iliac artery disease.

Evaluation and Application of Dimethylated Amino Acids as Isobaric Tags for Quantitative Proteomics of the TGF-β/Smad3 Signaling Pathway

Isobaric labeling has become a widespread tool for quantitative proteomic studies. Here, we report the development and evaluation of several dimethylated amino acids as novel isobaric tags for quantitative proteomics. Four-plex dimethylated alanine (DiAla), valine (DiVal), and leucine (DiLeu) have been synthesized, sharing common features of peptide tagging and reporter ion production. DiAla and DiLeu are shown to achieve complete labeling. These two tags impacts on peptide fragmentation and quantitation are further evaluated using HEK293 cell lysate. DiAla labeling generates more abundant backbone fragmentation whereas DiLeu labeling produces more intense reporter ions. Nonetheless, both tags enable accurate quantitative analysis of HEK293 cell proteomes. DiAla and DiLeu tags are then applied to study the TGF-β/Smad3 pathway with four differentially treated mouse vascular smooth muscle (MOVAS) cells. Our MS data reveal proteome-wide changes of AdSmad3 as compared to the GFP control, consistent with previous findings of causing smooth muscle cell (SMC) dedifferentiation.1 Additionally, the other two novel mutations on the hub protein Smad3, Y226A, and D408H, show compromised TGF-β/Smad3-dependent gene transcription and reversed phenotypic switch. These results are further corroborated with Western blotting and demonstrate that the novel DiAla and DiLeu isobaric tagging reagents provide useful tools for multiplex quantitative proteomics.

Unimolecular Micelle-Based Hybrid System for Perivascular Drug Delivery Produces Long-Term Efficacy for Neointima Attenuation in Rats

At present, there are no clinical options for preventing neointima-caused (re)stenosis after open surgery such as bypass surgery for treating flow-limiting vascular disease. Perivascular drug delivery is a promising strategy, but in translational research, it remains a major challenge to achieve long-term (e.g., > 3 months) anti(re)stenotic efficacy. In this study, we engineered a unique drug delivery system consisting of durable unimolecular micelles, formed by single multiarm star amphiphilic block copolymers with only covalent bonds, and a thermosensitive hydrogel formed by a poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) triblock copolymer (abbreviated as triblock gel) that is stable for about 4 weeks in vitro. The drug-containing unimolecular micelles (UMs) suspended in Triblock gel were able to sustain rapamycin release for over 4 months. Remarkably, even 3 months after perivascular application of the rapamycin-loaded micelles in Triblock gel in the rat model, the intimal/medial area ratio (a restenosis measure) was still 80% inhibited compared to the control treated with empty micelle/gel (no drug). This could not be achieved by applying rapamycin in Triblock gel alone, which reduced the intimal/medial ratio only by 27%. In summary, we created a new UM/Triblock gel hybrid system for perivascular drug delivery, which produced a rare feat of 3-month restenosis inhibition in animal tests. This system exhibits a real potential for further translation into an anti(re)stenotic application with open surgery.

Improving data quality and preserving HCD-generated reporter ions with EThcD for isobaric tag-based quantitative proteomics and proteome-wide PTM studies

Mass spectrometry (MS)-based isobaric labeling has undergone rapid development in recent years due to its capability for high throughput quantitation. Apart from its originally designed use with collision-induced dissociation (CID) and higher-energy collisional dissociation (HCD), isobaric tagging technique could also work with electron-transfer dissociation (ETD), which provides complementarity to CID and is preferred in sequencing peptides with post-translational modifications (PTMs). However, ETD suffers from long reaction time, reduced duty cycle and bias against peptides with lower charge states. In addition, common fragmentation mechanism in ETD results in altered reporter ion production, decreased multiplexing capability, and even loss of quantitation capability for some of the isobaric tags, including custom-designed dimethyl leucine (DiLeu) tags. Here, we demonstrate a novel electron-transfer/higher-energy collision dissociation (EThcD) approach that preserves original reporter ion channels, mitigates bias against lower charge states, improves sensitivity, and significantly improves data quality for quantitative proteomics and proteome-wide PTM studies. Systematic optimization was performed to achieve a balance between data quality and sensitivity. We provide direct comparison of EThcD with ETD and HCD for DiLeu- and TMT-labeled HEK cell lysate and IMAC enriched phosphopeptides. Results demonstrate improved data quality and phosphorylation localization accuracy while preserving sufficient reporter ion production. Biological studies were performed to investigate phosphorylation changes in a mouse vascular smooth muscle cell line treated with four different conditions. Overall, EThcD exhibits superior performance compared to conventional ETD and offers distinct advantages compared to HCD in isobaric labeling based quantitative proteomics and quantitative PTM studies.

Thirty-day readmission and mortality among Medicare beneficiaries discharged to skilled nursing facilities after vascular surgery

BACKGROUNDnReadmission within 30xa0d of an acute hospital stay is frequent, costly, and increasingly subject to penalties. Early readmission is most common after vascular surgery; these patients are often discharged to skilled nursing facilities (SNFs), making postacute care an essential partner in reducing readmissions. We characterize 30-day readmissions among vascular surgery patients discharged to SNF to provide evidence for this understudied segment of readmission after specialty surgery.nnnMETHODSnWe utilize the Centers for Medicare & Medicaid Services Chronic Conditions Warehouse, a longitudinal 5% national random sample of Medicare beneficiaries to study 30-day readmission or death after discharge to SNF following abdominal aortic aneurysm repair or lower extremity revascularization from 2005-2009. Descriptive statistics and logistic regression with Least Adaptive Shrinkage and Selection Operator were used for analysis.nnnRESULTSnTwo thousand one hundred ninety-seven patients underwent an abdominal aortic aneurysm procedure or lower extremity revascularization at 686 hospitals and discharged to 1714 SNFs. Eight hundred (36%) were readmitted or had died at 30xa0d. In adjusted analysis, predictors of readmission or death at 30xa0d included SNF for-profit status (OR [odds ratio]xa0=xa01.2; Pxa0=xa00.032), number of hospitalizations in the previous year (ORxa0=xa01.06; Pxa0=xa00.011), number of comorbidities (ORxa0=xa01.06; Pxa0=xa00.004), emergent procedure (ORxa0=xa01.69; Pxa0<xa00.001), renal complication (ORxa0=xa01.38; Pxa0=xa00.003), respiratory complication (ORxa0=xa01.45; Pxa0<xa00.001), thromboembolic complication (ORxa0=xa01.57; Pxa0=xa00.019), and wound complication (ORxa0=xa00.70; Pxa0=xa00.017).nnnCONCLUSIONSnPatients discharged to SNF following vascular surgery have exceptionally high rates of readmission or death at 30xa0d. Many factors predicting readmission or death potentially modify decision-making around discharge, making early detection, discharge planning, and matching patient needs to SNF capabilities essential to improving outcomes.