Publications by authors named "Peter K Henke"

250 Publications

Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Imaging Predicts Vein Wall Scarring and Statin Benefit in Murine Venous Thrombosis.

Circ Cardiovasc Imaging 2021 Mar 16:CIRCIMAGING120011898. Epub 2021 Mar 16.

Cardiology Division, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA (C.W.K., G.Q., F.A.J.).

Background: The postthrombotic syndrome is a common, often morbid sequela of venous thrombosis (VT) that arises from thrombus persistence and inflammatory scarring of juxtaposed vein walls and valves. Noninvasive F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging can measure neutrophil inflammation in VT. Here, we hypothesized (1) early fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) VT inflammation can predict subsequent vein wall scarring (VWS) and (2) statin therapy can reduce FDG-PET VT inflammation and subsequent VWS.

Methods: C57BL/6J mice (n=75) underwent induction of stasis-induced VT of the inferior vena cava or jugular vein. Inferior vena cava VT mice (n=44) were randomized to daily oral rosuvastatin 5 mg/kg or saline starting at day -1. Subgroups of mice then underwent FDG-PET/CT 2 days after VT induction. On day 14, a subset of mice was euthanized, and VWS was assessed via histology. In vitro studies were further performed on bone marrow-derived neutrophils.

Results: Statin therapy reduced early day 2 FDG-PET VT inflammation, thrombus neutrophil influx, and plasma IL (interleukin)-6 levels. At day 14, statin therapy reduced VWS but did not affect day 2 thrombus mass, cholesterol, or white blood counts, nor reduce day 2 glucose transporter 1 or myeloperoxidase expression in thrombus or in isolated neutrophils. In survival studies, the day 2 FDG-PET VT inflammation signal as measured by mean and maximum standardized uptake values predicted the extent of day 14 VWS (area under the receiver operating characteristic curve =0.82) with a strong correlation coefficient () of =0.73 and =0.74, respectively. Mediation analyses revealed that 40% of the statin-induced VWS reduction was mediated by reductions in VT inflammation as quantified by FDG-PET.

Conclusions: Early noninvasive FDG-PET/CT imaging of VT inflammation predicts the magnitude of subsequent VWS and may provide a new translatable approach to identify individuals at risk for postthrombotic syndrome and to assess anti-inflammatory postthrombotic syndrome therapies, such as statins.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011898DOI Listing
March 2021

Exploring the rapid expansion of office-based laboratories and peripheral vascular interventions across the United States.

J Vasc Surg 2021 Feb 19. Epub 2021 Feb 19.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich.

Objective: To characterize the relationship between office-based laboratory (OBL) use and Medicare payments for peripheral vascular interventions (PVI).

Methods: Using the Centers for Medicare and Medicaid Services Provider Utilization and Payment Data Public Use Files from 2014 to 2017, we identified providers who performed percutaneous transluminal angioplasty, stent placement, and atherectomy. Procedures were aggregated at the provider and hospital referral region (HRR) level.

Results: Between 2014 and 2017, 2641 providers performed 308,247 procedures. The mean payment for OBL stent placement in 2017 was $4383.39, and mean payment for OBL atherectomy was $13,079.63. The change in the mean payment amount varied significantly, from a decrease of $16.97 in HRR 146 to an increase of $43.77 per beneficiary over the study period in HRR 11. The change in the rate of PVI also varied substantially, and moderately correlated with change in payment across HRRs (R = 0.40; P < .001). The majority of HRRs experienced an increase in rate of PVI within OBLs, which strongly correlated with changes in payments (R = 0.85; P < .001). Furthermore, 85% of the variance in change in payment was explained by increases in OBL atherectomy (P < .001).

Conclusions: A rapid shift into the office setting for PVIs occurred within some HRRs, which was highly geographically variable and was strongly correlated with payments. Policymakers should revisit the current payment structure for OBL use and, in particular atherectomy, to better align the policy with its intended goals.
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http://dx.doi.org/10.1016/j.jvs.2021.01.061DOI Listing
February 2021

Advances in understanding the interplay between adaptive and innate immunity in experimental venous thrombus resolution.

J Thromb Haemost 2021 Feb 17. Epub 2021 Feb 17.

University of Michigan Health System, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1111/jth.15249DOI Listing
February 2021

Using Payment Incentives to Decrease Atherectomy Overutilization.

Ann Vasc Surg 2021 Jan 21. Epub 2021 Jan 21.

Department of Surgery, University of Michigan, Ann Arbor, MI; Center for Healthcare Outcomes and Policy, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1016/j.avsg.2021.01.061DOI Listing
January 2021

Time-Restricted Salutary Effects of Blood Flow Restoration on Venous Thrombosis and Vein Wall Injury in Mouse and Human Subjects.

Circulation 2021 Mar 15;143(12):1224-1238. Epub 2021 Jan 15.

Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (W.L., C.W.K., M.O., L.W., A.T., F.A.J.).

Background: Up to 50% of patients with proximal deep vein thrombosis (DVT) will develop the postthrombotic syndrome characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. Although catheter-based interventions enabling the restoration of blood flow (RBF) have demonstrated little benefit on postthrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. In experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution.

Methods: First, experimental stasis DVT was generated in C57/BL6 mice (n=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical deligation with or without intravenous recombinant tissue plasminogen activator administered 2 days after deligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed inferior vena cava specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post hoc analysis of the ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores for specific symptom-onset-to-randomization timeframes.

Results: Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared with controls. In mice without RBF, recombinant tissue plasminogen activator administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. It is notable that, in mice already exhibiting RBF by day 4, recombinant tissue plasminogen activator administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate symptom-onset-to-randomization timeframe of 4 to 8 days demonstrated maximal benefits in Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores (between-group difference=8.41 and 1.68, respectively, <0.001 versus patients not receiving PCDT). PCDT did not improve postthrombotic syndrome scores for patients having a symptom-onset-to-randomization time of <4 days or >8 days.

Conclusions: Taken together, these data illustrate that, within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce postthrombotic syndrome in patients with DVT.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988304PMC
March 2021

Modeling the elective vascular surgery recovery after coronavirus disease 2019: Implications for moving forward.

J Vasc Surg 2020 Nov 25. Epub 2020 Nov 25.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich.

Objective: The delays in elective surgery caused by the coronavirus disease 2019 (COVID-19) pandemic have resulted in a substantial backlog of cases. In the present study, we sought to determine the estimated time to recovery for vascular surgery procedures delayed by the COVID-19 pandemic in a regional health system.

Methods: Using data from a 35-hospital regional vascular surgical collaborative consisting of all hospitals performing vascular surgery in the state of Michigan, we estimated the number of delayed surgical cases for adults undergoing carotid endarterectomy, carotid stenting, endovascular and open abdominal aortic aneurysm repair, and lower extremity bypass. We used seasonal autoregressive integrated moving average models to predict the surgical volume in the absence of the COVID-19 pandemic and historical data to predict the elective surgical recovery time.

Results: The median statewide monthly vascular surgical volume for the study period was 439 procedures, with a maximum statewide monthly case volume of 519 procedures. For the month of April 2020, the elective vascular surgery procedural volume decreased by ∼90%. Significant variability was seen in the estimated hospital capacity and estimated number of backlogged cases, with the recovery of elective cases estimated to require ∼8 months. If hospitals across the collaborative were to share the burden of backlogged cases, the recovery could be shortened to ∼3 months.

Conclusions: In the present study of vascular surgical volume in a regional health collaborative, elective surgical procedures decreased by 90%, resulting in a backlog of >700 cases. The recovery time if all hospitals in the collaborative were to share the burden of backlogged cases would be reduced from 8 months to 3 months, underscoring the necessity of regional and statewide policies to minimize patient harm by delays in recovery for elective surgery.
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http://dx.doi.org/10.1016/j.jvs.2020.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687586PMC
November 2020

Low to Moderate Risk Non-Orthopedic Surgical Patients do not Benefit from VTE Chemoprophylaxis.

Ann Surg 2020 Nov 18. Epub 2020 Nov 18.

Section of Vascular Surgery.

Objective: We hypothesized that a high rate of prescription of VTE chemoprophylaxis would be associated with decreased VTE incidence and mortality.

Summary Background Data: Recommendations for VTE prevention in surgical patients include chemoprophylaxis based upon preoperative risk stratification.

Methods: This retrospective cohort study analyzed VTE incidence, morbidity and mortality amongst post-surgical patients with and without VTE chemoprophylaxis between April 2013 - September 2017 from 63 hospitals within the Michigan Surgical Quality Collaborative. A VTE risk assessment survey was distributed to providers. Bivariate and multivariate comparisons were made, as well as using propensity score matched cohorts to determine if VTE chemoprophylaxis was associated with decreased VTE events. Hospitals were compared using risk-reliability adjusted VTE prophylaxis and postoperative VTE event rates.

Results: Within the registry, 80% of practitioners reported performing formal VTE risk assessment. Amongst 32,856 operations, there were 480 (1.46%) postoperative VTE, and an overall mortality of 609 (1.85%) patients. Using a propensity matched cohort, we found that rates of VTE were similar in those receiving UFH or LMWH compared to those not receiving chemoprophylaxis (1.22 vs. 1.13%, p = .57). When stratified further by VTE risk scoring, even the highest risk patients did not have an associated lower VTE rate (3.68 vs 4.22% p = .092). Postoperative transfusion (8.28 vs. 7.50%, p = .057) and mortality (2.00% vs. 1.62%, p = .064) rates were similar amongst those receiving and those not receiving chemoprophylaxis. No correlation was found between postoperative VTE chemoprophylaxis application and hospital specific risk adjusted postoperative VTE rates.

Conclusions: In modern day post-surgical care, VTE remains a significant occurrence, despite wide adoption of VTE risk assessment. While postoperative VTE chemoprophylaxis was broadly applied, after adjusting for confounders, no reduction in VTE was observed in at risk surgical patients.
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http://dx.doi.org/10.1097/SLA.0000000000004646DOI Listing
November 2020

Venous thrombosis epidemiology, pathophysiology, and anticoagulant therapies and trials in severe acute respiratory syndrome coronavirus 2 infection.

J Vasc Surg Venous Lymphat Disord 2021 01 8;9(1):23-35. Epub 2020 Sep 8.

Section of Vascular Surgery, Department of Surgery, Samuel and Jean Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Mich. Electronic address:

Objective: Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus confers a risk of significant coagulopathy, with the resulting development of venous thromboembolism (VTE), potentially contributing to the morbidity and mortality. The purpose of the present review was to evaluate the potential mechanisms that contribute to this increased risk of coagulopathy and the role of anticoagulants in treatment.

Methods: A literature review of coronavirus disease 2019 (COVID-19) and/or SARS-CoV-2 and cell-mediated inflammation, clinical coagulation abnormalities, hypercoagulability, pulmonary intravascular coagulopathy, and anticoagulation was performed. The National Clinical Trials database was queried for ongoing studies of anticoagulation and/or antithrombotic treatment or the incidence or prevalence of thrombotic events in patients with SARS-CoV-2 infection.

Results: The reported rate of VTE among critically ill patients infected with SARS-CoV-2 has been 21% to 69%. The phenomenon of breakthrough VTE, or the acute development of VTE despite adequate chemoprophylaxis or treatment dose anticoagulation, has been shown to occur with severe infection. The pathophysiology of overt hypercoagulability and the development of VTE is likely multifactorial, with evidence supporting the role of significant cell-mediated responses, including neutrophils and monocytes/macrophages, endothelialitis, cytokine release syndrome, and dysregulation of fibrinolysis. Collectively, this inflammatory process contributes to the severe pulmonary pathology experienced by patients with COVID-19. As the infection worsens, extreme D-dimer elevations, significant thrombocytopenia, decreasing fibrinogen, and prolongation of prothrombin time and partial thromboplastin time occur, often associated with deep vein thrombosis, in situ pulmonary thrombi, and/or pulmonary embolism. A new phenomenon, termed pulmonary intravascular coagulopathy, has been associated with morbidity in patients with severe infection. Heparin, both unfractionated heparin and low-molecular-weight heparin, have emerged as agents that can address the viral infection, inflammation, and thrombosis in this syndrome.

Conclusions: The overwhelming inflammatory response in patients with SARS-CoV-2 infection can lead to a hypercoagulable state, microthrombosis, large vessel thrombosis, and, ultimately, death. Early VTE prophylaxis should be provided to all admitted patients. Therapeutic anticoagulation therapy might be beneficial for critically ill patients and is the focus of 39 ongoing trials. Close monitoring for thrombotic complications is imperative, and, if confirmed, early transition from prophylactic to therapeutic anticoagulation should be instituted. The interplay between inflammation and thrombosis has been shown to be a hallmark of the SARS-CoV-2 viral infection.
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http://dx.doi.org/10.1016/j.jvsv.2020.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834652PMC
January 2021

Managing suspected venous thromboembolism when a pandemic limits diagnostic testing.

Thromb Res 2020 12 19;196:213-214. Epub 2020 Aug 19.

Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, United States of America; Department of Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, United States of America.

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http://dx.doi.org/10.1016/j.thromres.2020.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437535PMC
December 2020

Venous Thromboembolism Research Priorities: A Scientific Statement From the American Heart Association and the International Society on Thrombosis and Haemostasis.

Circulation 2020 Aug 8;142(6):e85-e94. Epub 2020 Jul 8.

Venous thromboembolism is a major cause of morbidity and mortality. The impact of the US Surgeon General's in 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in venous thromboembolism, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiological causative mechanisms for the 50% of patients with unprovoked venous thromboembolism and to better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing venous thromboembolism will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biological and environmental underpinnings of venous thromboembolism and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of venous thromboembolism.
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http://dx.doi.org/10.1161/CIR.0000000000000818DOI Listing
August 2020

Venous thromboembolism research priorities: A scientific statement from the American Heart Association and the International Society on Thrombosis and Haemostasis.

Res Pract Thromb Haemost 2020 Jul 8;4(5):714-721. Epub 2020 Jul 8.

Department of Pathology and Laboratory Medicine UNC Blood Research Center University of North Carolina at Chapel Hill Chapel Hill NC USA.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality. The impact of the Surgeon General's Call to Action in 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in VTE, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiologic causative mechanisms for the 50% of patients with unprovoked VTE and better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing VTE will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biologic and environmental underpinings of VTE and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of VTE.
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http://dx.doi.org/10.1002/rth2.12373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354403PMC
July 2020

Effect of concomitant deep venous reflux on truncal endovenous ablation outcomes in the Vascular Quality Initiative.

J Vasc Surg Venous Lymphat Disord 2021 03 24;9(2):361-368.e3. Epub 2020 Jun 24.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich.

Objective: Few studies have investigated outcomes after truncal endovenous ablation in patients with combined deep and superficial reflux and no studies have evaluated patient-reported outcomes.

Methods: We investigated the short- and long-term clinical and patient-reported outcomes among patients with and without deep venous reflux undergoing truncal endovenous ablation from 2015 to 2019 in the Vascular Quality Initiative. Preprocedural and postprocedural comparisons were performed using the t-test, χ, or their nonparametric counterpart when appropriate. Multivariable logistic regression models were used to assess for confounding.

Results: A total of 4881 patients were included, of which 2254 (46.2%) had combined deep and superficial reflux. The median follow-up was 336.5 days. Patients with deep reflux were less likely to be female (65.9% vs 69.9%; P = .003), more likely to be Caucasian (90.2% vs 86.5%; P = .003) and had no difference in BMI (30.6 ± 7.5 vs 30.6 ± 7.2; P = .904). Additionally, no difference was seen in rates of prior varicose vein treatments, number of pregnancies, or history of deep venous thrombosis; however, patients without deep reflux were more likely to be on anticoagulation at the time of the procedure (10.9% vs 8.1%; P < .001). Patients without deep reflux had slightly higher median preprocedural Venous Clinical Severity Score (VCSS) scores (8 [interquartile range (IQR), 6-10]) vs 7 [IQR, 6-10]; P = .005) as well as postprocedural VCSS scores (5 [IQR, 3-7] vs 4 [IQR, 2-6]; P < .001). The median change in VCSS from before to after the procedure was lower for patients without deep reflux (3 [IQR, 1.0-5.5] vs 3.5 [IQR, 1-6]; P = .006). Total symptom score was higher for patients without deep reflux both before (median, 14 [IQR, 10-19] vs median, 13.5 [IQR, 9.5-18]; P = .005) and postprocedurally (median, 4 [IQR, 1-9] vs median, 3.25 [IQR, 1-7]; P < .001), but no difference was seen in change in symptom score (median, 8 [IQR, 4-13] vs median, 9 [IQR, 4-13]; P = .172). Patients with deep reflux had substantially higher rates of complications (10.4% vs 3.0%; P < .001), with a particular increase in proximal thrombus extension (3.1% vs 1.1%; P < .001). After controlling for confounding, this estimate of effect size for any complication increased (odds ratio, 5.72; 95% confidence interval, 2.21-14.81; P < .001).

Conclusions: No significant difference is seen in total symptom improvement when patients undergo truncal endovenous ablation with concomitant deep venous reflux, although a greater improvement was seen in VCSS score in these patients. Patients with deep venous reflux had a significantly increased rate of complications, independent of confounding variables, and should be counseled appropriately before the decision for treatment.
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http://dx.doi.org/10.1016/j.jvsv.2020.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768610PMC
March 2021

Fenestrated repair improves perioperative outcomes but lacks a hospital volume association for complex abdominal aortic aneurysms.

J Vasc Surg 2021 Feb 27;73(2):417-425.e1. Epub 2020 May 27.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich. Electronic address:

Background: Complex abdominal aortic aneurysms (AAAs) have traditionally been treated with an open surgical repair (OSR). During the past decade, fenestrated endovascular aneurysm repair (FEVAR) has emerged as a viable option. Hospital procedural volume to outcome relationship for OSR of complex AAAs has been well established, but the impact of procedural volume on FEVAR outcomes remains undefined. This study investigated the outcomes of OSR and FEVAR for the treatment of complex AAAs and examined the hospital volume-outcome relationship for these procedures.

Methods: A retrospective review of a statewide vascular surgery registry was queried for all patients between 2012 and 2018 who underwent elective repair of a juxtarenal/pararenal AAA with FEVAR or OSR. The primary outcomes were 30-day mortality, myocardial infarction, and new dialysis. Secondary end points included postoperative pneumonia, renal dysfunction (creatine concentration increase of >2 mg/dL from preoperative baseline), major bleeding, early procedural complications, length of stay, and need for reintervention. To evaluate procedural volume-outcomes relationship, hospitals were stratified into low- and high-volume aortic centers based on a FEVAR annual procedural volume. To account for baseline differences, we calculated propensity scores and employed inverse probability of treatment weighting in comparing outcomes between treatment groups.

Results: A total of 589 patients underwent FEVAR (n = 186) or OSR (n = 403) for a complex AAA. After adjustment, OSR was associated with higher rates of 30-day mortality (10.7% vs 2.9%; P < .001) and need for dialysis (11.3% vs 1.8; P < .001). Postoperative pneumonia (6.8% vs 0.3%; P < .001) and need for transfusion (39.4% vs 10.4%; P < .001) were also significantly higher in the OSR cohort. The median length of stay for OSR and FEVAR was 9 days and 3 days, respectively. For those who underwent FEVAR, endoleaks were present in 12.1% of patients at 30 days and 6.1% of patients at 1 year, with the majority being type II. With a median follow-up period of 331 days (229-378 days), 1% of FEVAR patients required a secondary procedure, and there were no FEVAR conversions to an open aortic repair. Hospitals were divided into low- and high-volume aortic centers based on their annual FEVAR volume of complex AAAs. After adjustment, hospital FEVAR procedural volume was not associated with 30-day mortality or myocardial infarction.

Conclusions: FEVAR was associated with lower perioperative morbidity and mortality compared with OSR for the management of complex AAAs. Procedural FEVAR volume outcome analysis suggests limited differences in 30-day morbidity, although long-term durability warrants further research.
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http://dx.doi.org/10.1016/j.jvs.2020.05.039DOI Listing
February 2021

Call to Action to Prevent Venous Thromboembolism in Hospitalized Patients: A Policy Statement From the American Heart Association.

Circulation 2020 Jun 7;141(24):e914-e931. Epub 2020 May 7.

Venous thromboembolism (VTE) is a major preventable disease that affects hospitalized inpatients. Risk stratification and prophylactic measures have good evidence supporting their use, but multiple reasons exist that prevent full adoption, compliance, and efficacy that may underlie the persistence of VTE over the past several decades. This policy statement provides a focused review of VTE, risk scoring systems, prophylaxis, and tracking methods. From this summary, 5 major areas of policy guidance are presented that the American Heart Association believes will lead to better implementation, tracking, and prevention of VTE events. They include performing VTE risk assessment and reporting the level of VTE risk in all hospitalized patients, integrating preventable VTE as a benchmark for hospital comparison and pay-for-performance programs, supporting appropriations to improve public awareness of VTE, tracking VTE nationwide with the use of standardized definitions, and developing a centralized data steward for data tracking on VTE risk assessment, prophylaxis, and rates.
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http://dx.doi.org/10.1161/CIR.0000000000000769DOI Listing
June 2020

Practical diagnosis and treatment of suspected venous thromboembolism during COVID-19 pandemic.

J Vasc Surg Venous Lymphat Disord 2020 07 17;8(4):526-534. Epub 2020 Apr 17.

Department of Surgery, Section of Vascular Surgery, University of Michigan Health System, Ann Arbor, Mich. Electronic address:

A markedly increased demand for vascular ultrasound laboratory and other imaging studies in COVID-19-positive patients has occurred, due to most of these patients having a markedly elevated D-dimer and a presumed prothrombotic state in many of the very ill patients. In the present report, we have summarized a broad institutional consensus focusing on evaluation and recommended empirical therapy for COVID-19-positive patients. We recommend following the algorithms with the idea that as more data becomes available these algorithms may well change.
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http://dx.doi.org/10.1016/j.jvsv.2020.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162794PMC
July 2020

Bleeding and thrombotic outcomes associated with postoperative use of direct oral anticoagulants after open peripheral artery bypass procedures.

J Vasc Surg 2020 12 8;72(6):1996-2005.e4. Epub 2020 Apr 8.

Section of Vascular Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, Mich. Electronic address:

Objective: Widespread adoption of direct oral anticoagulants (DOACs) for atrial fibrillation and venous thromboembolism treatment has resulted in peripheral bypass patients receiving therapeutic anticoagulation with DOACs postoperatively. This study was undertaken to evaluate patient outcomes after open peripheral bypass based on anticoagulation treatment.

Methods: Postoperative treatment and outcomes of patients undergoing peripheral bypass operations between January 2012 and December 2017 from a statewide multicenter quality improvement registry were examined. Surgeons participating in the registry were surveyed on practice patterns regarding DOACs in bypass patients. Multivariate logistic regression was performed for 30-day transfusion outcomes, and multiple linear regression was performed for length of stay.

Results: Among 9682 patients, 7685 patients received no anticoagulation, whereas 1379 received a vitamin K antagonist (VKA) and 618 received a DOAC postoperatively. Patients receiving anticoagulation compared with no anticoagulation had a higher body mass index and were more likely to have preoperative anemia, congestive heart failure, and atrial fibrillation (all P < .001). Compared with patients receiving VKAs, patients receiving DOACs were less likely to have chronic kidney disease (P = .002) and more likely to have atrial fibrillation (P < .001). The shortest length of stay was among patients receiving no anticoagulation (median, 5 days; interquartile range, 3-9 days; P < .001), followed by DOACs (median, 6 days; interquartile range 3-11 days; P < .001) and VKAs (median, 8 days; interquartile range, 5-13 days; P < .001). Compared with patients receiving VKAs postoperatively, there was no difference in readmission for anticoagulation complications, bypass thrombectomy or thrombolysis, major amputation, or graft patency at 1 year among patients receiving DOACs. On multivariate logistic regression, patients receiving a DOAC (odds ratio, 0.743; confidence interval, 0.59-0.94; P = .011) or no anticoagulation (odds ratio, 0.792; confidence interval, 0.69-0.91; P = .001) were less likely to require transfusion within 30 days than patients taking VKAs. Approximately 70% of the surveyed surgeons reported that they "sometimes" or "always" use DOACs instead of VKAs for protection of a high-risk bypass.

Conclusions: Among patients undergoing lower extremity surgical bypass, those receiving a DOAC postoperatively had a shorter length of stay and were less likely to receive a transfusion in 30 days without compromising graft patency and readmission for anticoagulation complications, thrombectomy, or thrombolysis or affecting amputation rate compared with those receiving a VKA. A majority of surgeons within the quality collaborative have adopted the use of DOACs after peripheral bypass, suggesting the need for a prospective trial evaluating DOAC safety and efficacy in patients requiring anticoagulation for high-risk bypass grafts.
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http://dx.doi.org/10.1016/j.jvs.2020.02.021DOI Listing
December 2020

Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair.

J Immunol 2020 05 23;204(9):2503-2513. Epub 2020 Mar 23.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109;

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout ( ), we determined that MLL1 drives expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either ( ) or myeloid-specific resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation.
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http://dx.doi.org/10.4049/jimmunol.1901263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443363PMC
May 2020

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms.

Int J Mol Sci 2020 Mar 18;21(6). Epub 2020 Mar 18.

School of Medicine, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.

Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy.
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http://dx.doi.org/10.3390/ijms21062080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139924PMC
March 2020

Inflammatory biomarkers in deep venous thrombosis organization, resolution, and post-thrombotic syndrome.

J Vasc Surg Venous Lymphat Disord 2020 03;8(2):299-305

Section of Vascular Surgery, Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, Mich. Electronic address:

Objective: Venous thromboembolism (VTE) is a common disease with potentially devastating and long-term sequelae, such as pulmonary embolism and post-thrombotic syndrome (PTS). Given the mortality risk, prevalence of VTE, and limited access to diagnostic imaging, clinically relevant biomarkers for diagnosis and prognostication are needed. Therefore, this review aimed to summarize the data on clinically applicable biomarkers that best indicate acute VTE and chronic PTS.

Methods: We reviewed the medical and scientific literature from 2001 to 2019 for VTE biomarkers. Randomized controlled trials, meta-analyses, and review articles were included. Primary basic research papers with no clinical applicability, opinion papers, institutional guidelines, and case reports were excluded.

Results: We highlight the diagnostic value of D-dimer alongside other promising biomarkers, including cellular adhesion molecules, P-selectin, cytokines (interleukins 6 and 10), fibrin monomer complexes, and coagulation factors (factor VIII).

Conclusions: High-sensitivity D-dimer remains the most clinically established VTE biomarker. Current research endeavors are under way to identify more precise biomarkers of VTE and PTS.
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http://dx.doi.org/10.1016/j.jvsv.2019.09.008DOI Listing
March 2020

Ly6CLo Monocyte/Macrophages are Essential for Thrombus Resolution in a Murine Model of Venous Thrombosis.

Thromb Haemost 2020 Feb 30;120(2):289-299. Epub 2019 Dec 30.

Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States.

Venous thrombosis (VT) resolution is a complex process, resembling sterile wound healing. Infiltrating blood-derived monocyte/macrophages (Mo/MΦs) are essential for the regulation of inflammation in tissue repair. These cells differentiate into inflammatory (CD11bLy6C) or proreparative (CD11bLy6C) subtypes. Previous studies have shown that infiltrating Mo/MΦs are important for VT resolution, but the precise roles of different Mo/MΦs subsets are not well understood. Utilizing murine models of stasis and stenosis inferior vena cava thrombosis in concert with a Mo/MΦ depletion model (CD11b-diphtheria toxin receptor [DTR]-expressing mice), we examined the effect of Mo/MΦ depletion on thrombogenesis and VT resolution. In the setting of an 80 to 90% reduction in circulating CD11bMo/MΦs, we demonstrated that Mo/MΦs are not essential for thrombogenesis, with no difference in thrombus size, neutrophil recruitment, or neutrophil extracellular traps found. Conversely, CD11bMo/MΦ are essential for VT resolution. Diphtheria toxoid (DTx)-mediated depletion after thrombus creation depleted primarily CD11bLy6C Mo/MΦs and resulted in larger thrombi. DTx-mediated depletion did not alter CD11bLy6C Mo/MΦ recruitment, suggesting a protective effect of CD11bLy6C Mo/MΦs in VT resolution. Confirmatory Mo/MΦ depletion with clodronate lysosomes showed a similar phenotype, with failure to resolve VT. Adoptive transfer of CD11bLy6C Mo/MΦs into Mo/MΦ-depleted mice reversed the phenotype, restoring normal thrombus resolution. These findings suggest that CD11bLy6C Mo/MΦs are essential for normal VT resolution, consistent with the known proreparative function of this subset, and that further study of Mo/MΦ subsets may identify targets for immunomodulation to accelerate and improve thrombosis resolution.
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http://dx.doi.org/10.1055/s-0039-3400959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365023PMC
February 2020

Discussion: Prospective Study of Doppler Ultrasound Surveillance for Deep Venous Thromboses in 1000 Plastic Surgery Outpatients.

Authors:
Peter K Henke

Plast Reconstr Surg 2020 01;145(1):97-98

From the Section of Vascular Surgery, Department of Surgery, University of Michigan.

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http://dx.doi.org/10.1097/PRS.0000000000006407DOI Listing
January 2020

Adding thrombodynamic assessment to Caprini risk assessment to improve venous thromboembolism risk specificity.

Authors:
Peter K Henke

J Vasc Surg Venous Lymphat Disord 2020 01;8(1):42-43

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.jvsv.2019.08.013DOI Listing
January 2020

Accessing the academic influence of vascular surgeons within the National Institutes of Health iCite database.

J Vasc Surg 2020 05 9;71(5):1741-1748.e2. Epub 2019 Dec 9.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich. Electronic address:

Objective: A diverse array of measures are used to evaluate academic physicians. One critical factor is the scholarly influence an author has on the research discourse within a field. The National Institutes of Health recently developed the Relative Citation Ratio (RCR) as a method to quantify the influence of published research. The aim of this study was to examine the academic influence of vascular surgeons using RCR within common vascular disease research fields.

Methods: Using the PubMed and National Institutes of Health iCite databases, scientific fields of abdominal and thoracic aortic aneurysm, peripheral artery disease (PAD), cerebral vascular occlusive disease, deep venous thrombosis (DVT), and venous insufficiency were queried for the highest rated RCR articles in each category (2007-2012). To calculate the RCR, article citation rates are divided by an expected citation rate derived from performance of articles in the same field, with the resulting RCR being level and field independent. Article categories were divided into basic science, health services, and clinical research on the basis of two independent reviews. For articles, academic backgrounds of the first, second, and last authors ("influential authors") were collected analyzing procedural specialty: surgery, medicine subspecialty (cardiology, neurology, nephrology), radiology/engineering, and other (anesthesia and pediatrics). Statistical significance between scientific fields and academic background was determined using Student t-test or analysis of variance followed by Newman-Keuls post hoc test.

Results: The academic influence of vascular surgeons varied substantially by the scientific field. Vascular surgeons compared with medical specialists were found to have the highest academic influence in abdominal aortic aneurysm research, composing 51% of the influential authors on the highest rated RCR studies (5.9 ± 0.8 vs 5.6 ± 0.8; P = .6). In contrast, vascular surgeons composed only 13% of influential authors compared with medical specialists in DVT (RCR, 2.6 ± 0.3 vs 15.7 ± 1.7; P < .003) and 18% in PAD (RCR, 1.9 ± 0.5 vs 2.1 ± 0.2; P = .78) research fields. Grouping all vascular fields of study together, no difference in RCR was found between vascular surgery and radiology/engineering. However, the mean RCR was significantly lower for vascular surgeons compared with medical subspecialties (4.5 ± 0.4 vs 6.8 ± 0.5; P < .05).

Conclusions: Vascular surgeons exhibit a moderate academic influence in the field of aneurysmal disease but lag behind medical subspecialists in high-impact scientific contributions to the fields of PAD and DVT. Innovative strategies and collaborations are likely needed to increase the influence of vascular surgeons on the academic discourse of several vascular disease research fields.
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http://dx.doi.org/10.1016/j.jvs.2019.09.036DOI Listing
May 2020

Association of High Mortality With Postoperative Myocardial Infarction After Major Vascular Surgery Despite Use of Evidence-Based Therapies.

JAMA Surg 2020 02;155(2):131-137

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor.

Importance: Patients undergoing vascular surgery are at high risk of postoperative myocardial infarction (POMI). Postoperative myocardial infarction is independently associated with significant risk of in-hospital mortality.

Objective: To examine the association of patient and procedural characteristics with the risk of POMI after vascular surgery and determine the association of evidence-based therapies with longer-term outcomes.

Design, Setting, And Participants: A retrospective cohort study of prospectively collected data within a statewide quality improvement collaborative database between January 2012 and December 2017. Patient demographics, comorbid conditions, and perioperative medications were captured. Patients were grouped according to occurrence of POMI. Univariate analysis and logistic regression were used to identify factors associated with POMI. The collaborative collects data from private and academic hospitals in Michigan. Patients undergoing major vascular surgery, defined as endovascular aortic aneurysm repair, open abdominal aortic aneurysm, peripheral bypass, carotid endarterectomy, or carotid artery stenting were included. Analysis began December 2018.

Main Outcomes And Measures: The presence of a POMI and 1-year mortality.

Results: Of 26 231 patients identified, 16 989 (65.8%) were men and the overall mean (SD) age was 69.35 (9.89) years. A total of 410 individuals (1.6%) experienced a POMI. Factors associated with higher rates of POMI were age (odds ratio [OR], 1.032 [95% CI, 1.019-1.045]; P < .001), diabetes (OR, 1.514 [95% CI, 1.201-1.907]; P < .001), congestive heart failure (OR, 1.519 [95% CI, 1.163-1.983]; P = .002), valvular disease (OR, 1.447 [95% CI, 1.024-2.046]; P = .04), coronary artery disease (OR, 1.381 [95% CI, 1.058-1.803]; P = .02), and preoperative P2Y12 antagonist use (OR, 1.37 [95% CI, 1.08-1.725]; P = .009). Procedurally, open abdominal aortic aneurysm (OR, 4.53 [95% CI, 2.73-7.517]; P < .001) and peripheral bypass (OR, 2.375 [95% CI, 1.818-3.102]; P < .001) were associated with the highest risk of POMI. After POMI, patients were discharged and received evidence-based therapy with high fidelity, including β-blockade (296 [82.7%]) and antiplatelet therapy (336 [95.7%]). A high portion of patients with POMI were dead at 1 year compared with patients without POMI (113 [37.42%] vs 993 [5.05%]; χ2 = 589.3; P < .001).

Conclusions And Relevance: Despite high rates of discharge with evidence-based therapies, the long-term burden of POMI is substantial, with a high mortality rate in the following year. Patients with diabetes mellitus, coronary artery disease, congestive heart failure, and valvular disease warrant additional consideration in the preoperative period. Further, aggressive strategies to treat patients who experience a POMI are needed to reduce the risk of postoperative mortality.
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http://dx.doi.org/10.1001/jamasurg.2019.4908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902124PMC
February 2020

Outcomes and safety of electronic consult use in vascular surgery.

J Vasc Surg 2020 05 11;71(5):1726-1732. Epub 2019 Oct 11.

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich. Electronic address:

Objective: The objective of this study was to determine how electronic consults (eConsults) are used in vascular surgery in a veterans health care setting and whether their use is safe for patients.

Methods: A retrospective review was performed of all eConsults completed by the vascular surgery service at the Ann Arbor Veterans Affairs Healthcare System between October 10, 2012 and November 15, 2013. Patients' demographics and comorbidities were collected. eConsult recommendations and patient and provider compliance with recommendations were collected. Data on adverse outcomes up to 1 year after consultation and data on all-cause mortality at 1 year and 5 years were collected.

Results: Between October 10, 2012 and November 15, 2013, of 350 eConsults completed, 123 (35%) were for peripheral artery disease, 93 (27%) for carotid stenosis, and 57 (16%) for abdominal aortic aneurysm. Unique recommendations were made for 291 consults (83%). Medication recommendations were made in 140 consults (40%). The most commonly recommended medication was cilostazol. Compliance with medication recommendations ranged from 30% to 61%. Noninvasive imaging was recommended in 220 consults (60.3%). Procedures overall were recommended in only six consults (1.7%). Five-year all-cause mortality for categorized diagnoses ranged from 8.3% for nonabdominal aneurysm to 28.1% for abdominal aortic aneurysm.

Conclusions: Within the Veterans Affairs vascular surgery service, eConsults provide a safe and effective means of triaging and providing recommendations for patients with vascular disease. eConsults used to augment traditional consultations may provide an important means of reducing clinic congestion for providers and reducing time and cost for patients.
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http://dx.doi.org/10.1016/j.jvs.2019.08.231DOI Listing
May 2020

The Impact of Medicaid Expansion on Utilization of Vascular Procedures and Rates of Amputation.

J Surg Res 2019 11 1;243:531-538. Epub 2019 Aug 1.

Section of Vascular Surgery, Frankel Cardiovascular Center, Ann Arbor, Michigan.

Background: Although New York's Medicaid expansion increased coverage in 2001, little is known regarding changes in surgical care utilization among patients with vascular disease. We sought to measure the impact of expansion on the rates of both vascular procedures and amputations.

Materials And Methods: A retrospective analysis was performed using the State Inpatient Databases of New York and Arizona, 1998-2006. Patients aged 18-64 who underwent lower extremity vascular surgery procedures or amputations between 1998 and 2006 were included. Outcomes included rates of total vascular, open vascular, and endovascular procedures, in addition to rates of amputation. A difference-in-difference analysis measured changes in the rates of procedure types, while adjusting for temporal trends in both states.

Results: In this cohort (n = 112,624), Medicaid expansion was not associated with a change in mortality (odds ratio 0.92, P = 0.5). Expansion was associated with a lower incidence of total vascular procedures (incidence rate ratio [IRR] 0.65, P < 0.001) and open vascular procedures (IRR 0.92, P = 0.002), but a higher incidence of endovascular procedures (IRR 1.13, P < 0.001). There was no change in the rate of amputations (IRR 1.02, P = 0.58). In patients with chronic limb-threatening ischemia (n = 12,668), expansion was associated with a lower incidence of total procedures (IRR 0.59, P < 0.001) and endovascular procedures (IRR 0.59, P < 0.001) but a higher incidence of amputations (IRR 1.43, P = 0.001) and higher odds of mortality (odds ratio 2.21, P = 0.032).

Conclusions: After Medicaid expansion, the rates of total vascular procedures decreased, with no impact on amputations rates. Furthermore, the utilization of limb-saving procedures in patients with chronic limb-threatening ischemia did not increase.
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http://dx.doi.org/10.1016/j.jss.2019.07.010DOI Listing
November 2019

Patient information sources when facing repair of abdominal aortic aneurysm.

J Vasc Surg 2020 02 26;71(2):497-504. Epub 2019 Jul 26.

Department of Surgery and VA Outcomes Group, White River Junction VA Medical Center, White River Junction, Vt. Electronic address:

Objective: Shared medical decision making is most important when there are competing options for repair such as in treatment of abdominal aortic aneurysm (AAA). We sought to understand the sources of patients' pre-existing knowledge about AAA to better inform treating physicians about patients' needs for preoperative counseling.

Methods: We performed a multicenter survey of patients facing AAA repair at 20 Veterans Affairs hospitals across the United States as part of the Preferences for Open Versus Endovascular Repair of AAA study. A validated survey instrument was administered to examine the sources of information available and commonly used by patients to learn about their repair options. The survey was administered by study personnel before the patient had any interaction with the vascular surgeon because survey data were collected before the vascular clinic visit.

Results: Preliminary analysis of data from 99 patients showed that our cohort was primarily male (99%) and elderly (mean age 73 years). Patients commonly had a history of hypertension (86%), prior myocardial infarction (32%), diabetes (32%), and were overweight (58%). Patients arrived at their surgeon's office appointment with limited information. A majority of patients (52%) reported that they had not talked to their primary care physician at all about their options for AAA repair, and one-half (50%) reported that their view of the different surgical options had not been influenced by anyone. Slightly less than one-half of patients reported that they did not receive any information about open surgical aneurysm repair and endovascular aortic aneurysm repair (41% and 37%, respectively). Few patients indicated using the internet as their main source of information about open surgical aneurysm repair and endovascular aortic aneurysm repair (10% and 11%, respectively).

Conclusions: Patients are commonly referred for AAA repair having little to no information regarding AAA pathology or repair options. Fewer than one in five patients searched the internet or had accessed other sources of information on their own. Most vascular surgeons should assume that patients will present to their first vascular surgery appointment with minimal understanding of the treatment options available to them.
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http://dx.doi.org/10.1016/j.jvs.2019.04.460DOI Listing
February 2020

The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.

Immunity 2019 08 23;51(2):258-271.e5. Epub 2019 Jul 23.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) β, and under diabetic conditions, this IFNβ-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.
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http://dx.doi.org/10.1016/j.immuni.2019.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703945PMC
August 2019

Acute experimental venous thrombosis impairs venous relaxation but not contraction.

J Vasc Surg 2020 03 24;71(3):1006-1012.e1. Epub 2019 Jun 24.

Jobst Vascular Research Laboratory, Section of Vascular Surgery, University of Michigan, Ann Arbor, Mich. Electronic address:

Objective: Venous thrombosis (VT) damages the vein wall, both physically by prolonged distension and from inflammation. These factors contribute to post-thrombotic syndrome (PTS). Interleukin (IL)-6 might play a role in experimental PTS and vein wall responses. Previous assessments of post-thrombotic vein wall injury used static measures such as histologic examination and immunologic assays. The purpose of the present study was to use myography to quantify the changes in contraction and relaxation of murine vessels exposed to an acute VT.

Methods: Wild-type (WT) C57BL/6 mice were used to determine the baseline vein wall passive tension on a DMT 610m myograph (DMT-USA, Inc., Ann Arbor, Mich), including dosing concentrations of phenylephrine (Phe) and acetylcholine (Ach). WT and IL-6 mice underwent VT using inferior vena cava (IVC) ligation (complete stasis) and stenosis (partial stasis), with no-surgery mice used as controls. The mice were harvested at 2 days (2D) and analyzed using a myograph. The vessels were stimulated with Phe and Ach to stimulate a contraction and relaxation response. The endothelial responses to VT were quantified by CD31 immunohistochemistry, Greiss assay, polymerase chain reaction, and Evans blue assay.

Results: Optimal passive tension was determined to be 2 mN, with an optimal concentration of Phe and Ach of 7E-3M and 1E-5M, respectively. No significant differences were found in the contractions when exposed to Phe between the WT control, WT 2D ligation, and WT 2D stenosis IVC segments and the IL-6 mice with and without thrombus (P > .05 for all). When treated with Ach, significantly more relaxation was found in the nonthrombosed control IVC segments than in those IVC segments that had had a 2D thrombus from either ligation- or stenosis-derived thrombotic mechanisms in both WT and IL-6 mice. CD31 staining showed ∼20% less luminal endothelium after stasis thrombosis (P ≤ .01) but no loss in the controls (P > .05). Evans blue staining showed a trend toward increased leakiness in post-thrombotic vein walls. No significant difference in the endothelial gene markers or nitric oxide production was found.

Conclusions: Compared with the controls, acute thrombosis in the total or partial stasis models did not impair IVC contractile responses, suggesting no effect on the medial vascular smooth muscle response. The relaxation response was significantly reduced in the post-thrombotic groups, likely from direct endothelial injury. These findings suggest, at acute points, that VT impairs the endothelial function of a vein wall while retaining the vascular smooth muscle cell function and might be a mechanism that promotes PTS.
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http://dx.doi.org/10.1016/j.jvs.2019.03.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928442PMC
March 2020

Invited commentary.

Authors:
Peter K Henke

J Vasc Surg 2019 07;70(1):285

Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.jvs.2019.01.043DOI Listing
July 2019