Publications by authors named "Frank M Davis"

39 Publications

Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms.

J Exp Med 2021 Jun;218(6)

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

Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB-mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II-induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20201839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008365PMC
June 2021

Epigenetic regulation of the PGE2 pathway modulates macrophage phenotype in normal and pathologic wound repair.

JCI Insight 2020 09 3;5(17). Epub 2020 Sep 3.

Section of Vascular Surgery, Department of Surgery.

Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB-mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-β-induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b-mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.138443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526451PMC
September 2020

Recognizing the evolving and beneficial role of regulatory T cells in aneurysm growth.

J Vasc Surg 2020 09;72(3):1097

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvs.2019.09.045DOI Listing
September 2020

Palmitate-TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing.

Eur J Immunol 2020 12 20;50(12):1929-1940. Epub 2020 Jul 20.

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

Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4 ) or MyD88 (MyD88 ) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.202048651DOI Listing
December 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvs.2020.05.039DOI Listing
February 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1901263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443363PMC
May 2020

TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Department of Surgery.

A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines, such as TNF-α. Previous studies have shown that an altered epigenetic program directs diabetic macrophages toward a proinflammatory phenotype, contributing to a sustained inflammatory phase. Males absent on the first (MOF) is a histone acetyltransferase (HAT) that has been shown be a coactivator of TNF-α signaling and promote NF-κB-mediated gene transcription in prostate cancer cell lines. Based on MOF's role in TNF-α/NF-κB-mediated gene expression, we hypothesized that MOF influences macrophage-mediated inflammation during wound repair. We used myeloid-specific Mof-knockout (Lyz2Cre Moffl/fl) and diet-induced obese (DIO) mice to determine the function of MOF in diabetic wound healing. MOF-deficient mice exhibited reduced inflammatory cytokine gene expression. Furthermore, we found that wound macrophages from DIO mice had elevated MOF levels and higher levels of acetylated histone H4K16, MOF's primary substrate of HAT activity, on the promoters of inflammatory genes. We further identified that MOF expression could be stimulated by TNF-α and that treatment with etanercept, an FDA-approved TNF-α inhibitor, reduced MOF levels and improved wound healing in DIO mice. This report is the first to our knowledge to define an important role for MOF in regulating macrophage-mediated inflammation in wound repair and identifies TNF-α inhibition as a potential therapy for the treatment of chronic inflammation in diabetic wounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.132306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141388PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvs.2019.09.036DOI Listing
May 2020

Sepsis Induces Prolonged Epigenetic Modifications in Bone Marrow and Peripheral Macrophages Impairing Inflammation and Wound Healing.

Arterioscler Thromb Vasc Biol 2019 11 5;39(11):2353-2366. Epub 2019 Sep 5.

From the Section of Vascular Surgery, Department of Surgery (F.M.D., A.D., A.D.J., A.S.K., A.T.O., W.J.M., K.A.G.), University of Michigan, Ann Arbor.

Objective: Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined. Approach and Results: Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3-, CD19-, Ly6G-) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow-derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL [interleukin]-1β, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow-derived macrophages and wound macrophages. This demonstrated decreased expression of , an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow-derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in compared with nonseptic controls.

Conclusions: These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1-mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.119.312754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818743PMC
November 2019

A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis.

J Vasc Surg 2020 01 26;71(1):149-157. Epub 2019 Jul 26.

Division of Vascular Surgery, University of California Los Angeles, Los Angeles, Calif.

Objective: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015.

Methods: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation.

Results: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts.

Conclusions: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvs.2019.04.487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245161PMC
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2019.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703945PMC
August 2019

Invited commentary.

J Vasc Surg 2019 08;70(2):598-599

Ann Arbor, Mich.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvs.2018.10.010DOI Listing
August 2019

Volume Standards for Open Abdominal Aortic Aneurysm Repair Are Not Associated With Improved Clinical Outcomes.

Ann Vasc Surg 2020 Jan 14;62:1-7. Epub 2019 Jun 14.

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

Background: Volume-outcome relationships exist for many complex surgical procedures, prompting institutions to adopt surgical volume standards for credentialing. The current Leapfrog Group Hospital volume standard for open abdominal aortic aneurysm repair (OAR) is 15 per year. However, this is primarily based on data from the 1990s and may not be appropriate given the dramatic decline in OAR. We sought to quantify the proportion of hospitals meeting volume standards, the difference in perioperative outcomes between low-volume and high-volume hospitals, and the potential travel burden of volume credentialing on patients.

Methods: We identified Medicare beneficiaries for individuals aged ≥65 years undergoing OAR in 2013-2014. Hospital "all-payer" annual volume was estimated based on the national proportion of patients undergoing OAR covered by Medicare in the Vascular Quality Initiative. Hospital annual OAR volume was characterized as <5/year, 5-9/year, 10-14/year, and ≥15/year (high volume). Adjusted rates of postoperative morbidity, reoperation, failure to rescue, and mortality in 2014 were compared across volume cohorts. Distance between patients' home zip code and high-volume hospitals was calculated.

Results: A total of 21,191 OARs were performed at 1,445 hospitals between 2013 and 2014. The average hospital OAR annual volume was 7.8 (standard deviation [SD] ± 9.3) with a median of 4.5. Among the 1,445 hospitals, only 190 (13.1%) performed ≥15 OARs per year whereas 756 hospitals (53.3%) performed <5 per year. Among patients who underwent OAR in 2014, 5,395 (53.3%) received care at a hospital that performed <15 per year. There was no difference in complication, reoperation, or failure to rescue rates between high-volume and low-volume hospitals. Mortality did not significantly differ among OAR volume cohorts. Hospitals performing <5 OARs per year had a mortality rate of 5.7% compared with 5.6% at high-volume hospitals (P = 0.817). One-quarter of patients who received care at a low-volume hospital would have had to travel more than 60 miles to reach a high-volume hospital.

Conclusions: By conservative estimates, only 13% of hospitals performing OAR meet current volume standards. Triaging all patients to high-volume hospitals would require shifting over 5,000 patients annually with no associated improvement in perioperative outcomes. Implementation of the current OAR hospital volume standard may significantly burden patients and hospitals without improving surgical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.avsg.2019.05.012DOI Listing
January 2020

SIRT3 Regulates Macrophage-Mediated Inflammation in Diabetic Wound Repair.

J Invest Dermatol 2019 12 15;139(12):2528-2537.e2. Epub 2019 Jun 15.

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

Control of inflammation is critical for the treatment of nonhealing wounds, but a delicate balance exists between early inflammation that is essential for normal tissue repair and the pathologic inflammation that can occur later in the repair process. This necessitates the development of novel therapies that can target inflammation at the appropriate time during repair. Here, we found that SIRT3 is essential for normal healing and regulates inflammation in wound macrophages after injury. Under prediabetic conditions, SIRT3 was decreased in wound macrophages and resulted in dysregulated inflammation. In addition, we found that FABP4 regulates SIRT3 in human blood monocytes, and inhibition of FABP4 in wound macrophages decreases inflammatory cytokine expression, making FABP4 a viable target for the regulation of excess inflammation and wound repair in diabetes. Using a series of ex vivo and in vivo studies with genetically engineered mouse models and diabetic human monocytes, we showed that FABP4 expression is epigenetically upregulated in diabetic wound macrophages and, in turn, diminishes SIRT3 expression, thereby promoting inflammation. These findings have significant implications for controlling inflammation and promoting tissue repair in diabetic wounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2019.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185380PMC
December 2019

Variation in Hospital Door-to-Intervention Time for Ruptured AAAs and Its Association with Outcomes.

Ann Vasc Surg 2020 Jan 13;62:83-91. Epub 2019 Jun 13.

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

Background: A ruptured abdominal aortic aneurysm (rAAA) is a life-threatening condition that carries a high mortality rate. Recent guidelines have recommended a goal "door-to-intervention" time of ≤90 minutes despite a paucity of evidence to support this goal. The aim of this study was to analyze recent trends in door-to-intervention time for rAAAs and determine the effect of the 90-minute door-to-intervention benchmark on postoperative complications.

Methods: A retrospective analysis of all patients who underwent open aortic repair (OAR) or endovascular aneurysm repair (EVAR) of a rAAA in the Vascular Quality Initiative database (2003-2018) was performed. Variation in door-to-intervention time was analyzed at the patient and hospital level. Patients were dichotomized into ≤90 or >90 minute door-to-intervention time cohorts. Hierarchical modeling controlling for the hospital random effect and multivariate logistic models was used to analyze the association on 30-day mortality and major in-hospital complications.

Results: A total of 3,630 operative cases for rAAA were identified (1696 OAR and 1934 EVAR). For the OAR cohort, 1035 patients (61%) had a door-to-intervention time of ≤90 minutes. However, at the hospital level, a minority of hospitals (49%) reliably achieved the OAR goal door-to-intervention time. For OARs, there was no difference in 30-day risk-adjusted major complications or mortality between the ≤90- and > 90-minute cohorts. For EVAR, 1014 patients (53.8%) had a door-to-intervention time of ≤90 minutes and a minority of hospitals (40%) upheld the recommended ≤90 minute door-to-intervention threshold. In the EVAR group, patients with a ≤90 minute door-to-intervention time had higher rates of postoperative myocardial infarction (12.0% vs. 8.5%; P < 0.05) but no difference in 30-day risk-adjusted mortality.

Conclusions: A low percentage of rAAAs are being treated within the recommended door-to-intervention time. Despite this deficiency, the ≤90-minute benchmark has minimal impact on postoperative morbidity and mortality. Based on these findings, alternative quality metrics should be identified to improve the clinical care of patients with rAAA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.avsg.2019.05.009DOI Listing
January 2020

A multi-institutional experience in the aortic and arterial pathology in individuals with genetically confirmed vascular Ehlers-Danlos syndrome.

J Vasc Surg 2019 11 21;70(5):1543-1554. Epub 2019 May 21.

Division of Vascular Surgery, University of California Los Angeles, Los Angeles, Calif.

Objective: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder owing to pathogenic variants in COL3A1 that lead to impaired type III collagen production. We aim to describe the contemporary multi-institutional experience of aortic and arterial pathology in individuals with vEDS, to evaluate disease patterns and refine management recommendations.

Methods: This cross-sectional, retrospective study of individuals with genetically confirmed vEDS was conducted between 2000 and 2015 at multiple institutions participating in the Vascular Low Frequency Disease Consortium. Aortic and arterial events including aneurysms, pseudoaneurysms, dissections, fistulae, or ruptures were studied. Demographics, COL3A1 variants, management, and outcomes data were collected and analyzed. Individuals with and without arterial events were compared.

Results: Eleven institutions identified 86 individuals with pathogenic variants in COL3A1 (47.7% male, 86% Caucasian; median age, 41 years; interquartile range [IQR], 31.0-49.5 years; 65.1% missense COL3A1 variants). The median follow-up from the time of vEDS diagnosis was 7.5 years (IQR, 3.5-12.0 years). A total of 139 aortic/arterial pathologies were diagnosed in 53 individuals (61.6%; 50.9% male; 88.5% Caucasian; median age, 33 years; IQR, 25.0-42.3 years). The aortic/arterial events presented as an emergency in 52 cases (37.4%). The most commonly affected arteries were the mesenteric arteries (31.7%), followed by cerebrovascular (16.5%), iliac (16.5%), and renal arteries (12.2%). The most common management was medical management. When undertaken, the predominant endovascular interventions were arterial embolization of medium sized arteries (13.4%), followed by stenting (2.5%). Aortic pathology was noted in 17 individuals (32%; 58.8% male; 94.1% Caucasian; median age, 38.5 years; IQR, 30.8-44.7 years). Most notably, four individuals underwent successful abdominal aortic aneurysm repair with excellent results on follow-up. Individuals with missense mutations, in which glycine was substituted with a large amino acid, had an earlier onset of aortic/arterial pathology (median age, 30 years; IQR, 23.5-37 years) compared with the other pathogenic COL3A1 variants (median age, 36 years; IQR, 29.5-44.8 years; P = .065). There were 12 deaths (22.6%) at a median age of 36 years (IQR, 28-51 years).

Conclusions: Most of the vEDS arterial manifestations were managed medically in this cohort. When intervention is required for an enlarging aneurysm or rupture, embolization, and less frequently stenting, seem to be well-tolerated. Open repair of abdominal aortic aneurysm seems to be as well-tolerated as in those without vEDS; vEDS should not be a deterrent to offering an operation. Future work to elucidate the role of surgical interventions and refine management recommendations in the context of patient centered outcomes is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvs.2019.01.069DOI Listing
November 2019

Variation in the elective management of small abdominal aortic aneurysms and physician practice patterns.

J Vasc Surg 2019 10 2;70(4):1089-1098. Epub 2019 Mar 2.

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

Objective: Recent vascular societal guidelines have recommended an abdominal aortic aneurysm (AAA) size threshold for elective intervention; however, limited data have documented how well these AAA diameter benchmarks are being met. The objective of this study was to analyze variation in management of AAAs based on diameter and to determine the physician's rationale for intervention on small AAAs in relation to recommended treatment guidelines.

Methods: A retrospective review of a statewide vascular surgery registry of all elective endovascular or open surgical AAA repairs from January 2012 to January 2016 was performed. Patients were dichotomized on the basis of aortic diameter at time of intervention into either guideline size AAAs or small AAAs, which were defined as <5.5 cm in men, <5.0 cm in women, or with growth <1.0 cm/y. An internal review was conducted of all small AAAs to determine the physician's rationale for intervention. The primary outcomes were variation in adherence to recommended treatment guidelines and the physician's rationale for treatment of small AAAs. Risk-adjusted major complication and mortality rates were calculated at 30 days and 1 year using a propensity score matching analysis.

Results: Among the 3932 patients who underwent an elective AAA repair, 485 (12.3%) were repaired at diameters smaller than recommended by guidelines. The median AAA size in the small AAA cohort was 5.1 cm (interquartile range, 4.7-5.3 cm) vs 5.6 cm (interquartile range, 5.2-6.1 cm) in the guideline-based group. Percentage of small AAA repairs varied widely between hospitals from 1.4% to 44.4%. The physician's rationale for the majority of early interventions included the patient's anxiety (12.0%), combined aortoiliac occlusive disease (14.8%), aneurysm anatomy (28.2%), and does not adhere to guidelines (30%). The small AAA cohort had no significant difference in the 30-day or 1-year risk-adjusted mortality in comparison to guideline size AAAs.

Conclusions: Despite well-established aortic diameter threshold guidelines, marked variation exists both at the hospital level and in terms of the physician's rationale for the management of elective AAA repairs. These findings demonstrate the challenge of providing uniform care for patients with AAAs despite established guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvs.2018.12.024DOI Listing
October 2019

Updates of Recent Aortic Aneurysm Research.

Arterioscler Thromb Vasc Biol 2019 03;39(3):e83-e90

Saha Cardiovascular Research Center (A.D., H.S.L.), University of Kentucky, Lexington.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.119.312000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394847PMC
March 2019

Epigenetic Mechanisms in Monocytes/Macrophages Regulate Inflammation in Cardiometabolic and Vascular Disease.

Arterioscler Thromb Vasc Biol 2019 04;39(4):623-634

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

Cardiometabolic and vascular disease, with their associated secondary complications, are the leading cause of morbidity and mortality in Western society. Chronic inflammation is a common theme that underlies initiation and progression of cardiovascular disease. In this regard, monocytes/macrophages are key players in the development of a chronic inflammatory state. Over the past decade, epigenetic modifications, such as DNA methylation and posttranslational histone processing, have emerged as important regulators of immune cell phenotypes. Accumulating studies reveal the importance of epigenetic enzymes in the dynamic regulation of key signaling pathways that alter monocyte/macrophage phenotypes in response to environmental stimuli. In this review, we highlight the current paradigms of monocyte/macrophage polarization and the emerging role of epigenetic modification in the regulation of monocyte/macrophage phenotype in obesity, diabetes mellitus, atherosclerosis, and abdominal aortic aneurysms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.118.312135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438376PMC
April 2019

Histone Methylation Directs Myeloid TLR4 Expression and Regulates Wound Healing following Cutaneous Tissue Injury.

J Immunol 2019 03 1;202(6):1777-1785. Epub 2019 Feb 1.

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

Myeloid cells are critical for orchestrating regulated inflammation during wound healing. TLRs, particularly TLR4, and its downstream-signaling MyD88 pathway play an important role in regulating myeloid-mediated inflammation. Because an initial inflammatory phase is vital for tissue repair, we investigated the role of TLR4-regulated, myeloid-mediated inflammation in wound healing. In a cutaneous tissue injury murine model, we found that TLR4 expression is dynamic in wound myeloid cells during the course of normal wound healing. We identified that changes in myeloid TLR4 during tissue repair correlated with increased expression of the histone methyltransferase, mixed-lineage leukemia 1 (MLL1), which specifically trimethylates the histone 3 lysine 4 (H3K4me3) position of the TLR4 promoter. Furthermore, we used a myeloid-specific Mll1 knockout ( ) to determine MLL1 drives expression during wound healing. To understand the critical role of myeloid-specific TLR4 signaling, we used mice deficient in ( ), (), and myeloid-specific to demonstrate delayed wound healing at early time points postinjury. Furthermore, in vivo wound myeloid cells isolated from and wounds demonstrated decreased inflammatory cytokine production. Importantly, adoptive transfer of monocyte/macrophages from wild-type mice trafficked to wounds with restoration of normal healing and myeloid cell function in -deficient mice. These results define a role for myeloid-specific, MyD88-dependent TLR4 signaling in the inflammatory response following cutaneous tissue injury and suggest that MLL1 regulates TLR4 expression in wound myeloid cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1801258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401313PMC
March 2019

Targeting epigenetic mechanisms in diabetic wound healing.

Transl Res 2019 02 10;204:39-50. Epub 2018 Oct 10.

Department of Surgery, University of Michigan, Ann Arbor, Michgan. Electronic address:

Impaired wound healing is a major secondary complication of type 2 diabetes that often results in limb loss and disability. Normal tissue repair progresses through discrete phases including hemostasis, inflammation, proliferation, and remodeling. In diabetes, normal progression through these phases is impaired resulting in a sustained inflammatory state and dysfunctional epithelialization in the wound. Due to their plasticity, macrophages play a critical role in the transition from the inflammation phase to the proliferation phase. Diabetes disrupts macrophage function by impairing monocyte recruitment to the wound, reducing phagocytosis, and prohibiting the transition of inflammatory macrophages to an anti-inflammatory state. Diabetes also impedes keratinocyte and fibroblast function during the later phases resulting in impaired epithelialization of the wound. Several recent studies suggest that altered epigenetic regulation of both immune and structural cells in wounds may influence cell phenotypes and healing, particularly in pathologic states, such as diabetes. Specifically, it has been shown that macrophage plasticity during wound repair is partly regulated epigenetically and that diabetes alters this epigenetic regulation and contributes to a sustained inflammatory state. Epigenetic regulation is also known to regulate keratinocyte and fibroblast function during wound repair. In this review, we provide an introduction to the epigenetic mechanisms that regulate tissue repair and highlight recent findings that demonstrate, how epigenetic events are altered during the course of diabetic wound healing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trsl.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331222PMC
February 2019

Murine macrophage chemokine receptor CCR2 plays a crucial role in macrophage recruitment and regulated inflammation in wound healing.

Eur J Immunol 2018 09 26;48(9):1445-1455. Epub 2018 Jun 26.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA.

Macrophages play a critical role in the establishment of a regulated inflammatory response following tissue injury. Following injury, CCR2 monocytes are recruited from peripheral blood to wound tissue, and direct the initiation and resolution of inflammation that is essential for tissue repair. In pathologic states where chronic inflammation prevents healing, macrophages fail to transition to a reparative phenotype. Using a murine model of cutaneous wound healing, we found that CCR2-deficient mice (CCR2 ) demonstrate significantly impaired wound healing at all time points postinjury. Flow cytometry analysis of wounds from CCR2 and WT mice revealed a significant decrease in inflammatory, Ly6C recruited monocyte/macrophages in CCR2 wounds. We further show that wound macrophage inflammatory cytokine production is decreased in CCR2 wounds. Adoptive transfer of mT/mG monocyte/macrophages into CCR2 and CCR2 mice demonstrated that labeled cells on days 2 and 4 traveled to wounds in both CCR2 and CCR2 mice. Further, adoptive transfer of monocyte/macrophages from WT mice restored normal healing, likely through a restored inflammatory response in the CCR2-deficient mice. Taken together, these data suggest that CCR2 plays a critical role in the recruitment and inflammatory response following injury, and that wound repair may be therapeutically manipulated through modulation of CCR2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201747400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371802PMC
September 2018

Time Heals All Wounds … But Wounds Heal Faster with Lactobacillus.

Cell Host Microbe 2018 04;23(4):432-434

Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Chronic nonhealing wounds represent a significant clinical problem and cost the healthcare system $19 billion annually. Recently, Vågesjö et al. (2018) demonstrated a promising therapeutic approach for nonhealing wounds with topical application of CXCL12-producing Lactobacilli that enhanced healing through alterations in the wound microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2018.03.018DOI Listing
April 2018

Early Outcomes following Endovascular, Open Surgical, and Hybrid Revascularization for Lower Extremity Acute Limb Ischemia.

Ann Vasc Surg 2018 Aug 5;51:106-112. Epub 2018 Mar 5.

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

Background: Acute limb ischemia (ALI) of the lower extremity is a potentially devastating condition that requires urgent and definitive management. This challenging scenario is often treated with endovascular, open surgical, or hybrid revascularization (HyR) in an urgent basis, but the comparative effects of such therapies remain poorly defined. The purpose of this study was to compare the outcomes of endovascular, open surgical, and HyR for ALI in the contemporary era.

Methods: A large statewide cardiovascular consortium of 45 hospitals was queried for patients between January 2012 and June 2015 who underwent an endovascular, open surgical, or HyR for ALI deemed at high risk of limb loss if not treated within 24 hr (Rutherford class IIA or IIB). A propensity score weighted analysis was performed controlling for demographics, medical history, and procedure type for patients. The primary outcomes were 30-day morbidity and mortality.

Results: A total of 1,480 patients underwent endovascular revascularization (ER; n = 818), open surgical revascularization (OSR; n = 195), or hybrid revascularization (HyR; n = 467) for ALI. The mean age was similar across revascularization technique with an increased predominance of male gender in open surgery cohort. Comorbidities for all groups were consistent with peripheral arterial disease. The most common endovascular procedures were angioplasty (93%) and thrombolysis (49.8%), whereas the most common surgical revascularization was femoral to popliteal bypass (32.8%), femoral to tibial bypass (28.2%), and thrombectomy (19.0%); ER as compared with OSR and HyR procedures was associated with less transfusion (OSR versus ER, odds ratio [OR] 2.7; HyR versus ER, OR 2.8; P < 0.001) and major amputation (OSR versus ER, OR 3.4; HyR versus ER, OR 4.0; P < 0.001) within 30 days of intervention. There was no difference in 30-day freedom from reintervention, myocardial infarction (MI), or mortality.

Conclusions: Among patients requiring urgent revascularization for Rutherford grade IIA and IIB ischemia, ER has lower 30-day morbidity but similar mortality and rates of reintervention. Although long-term patency rates were not compared, ER may offer superior short-term outcomes compared with open surgery and hybrid revascularization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.avsg.2017.12.025DOI Listing
August 2018

Ly6C Blood Monocyte/Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus.

Arterioscler Thromb Vasc Biol 2018 05 1;38(5):1102-1114. Epub 2018 Mar 1.

From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., K.A.G.)

Objective: Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that is critical for proper healing, however, in diabetes mellitus, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown.

Approach And Results: Here, we characterized the kinetics and function of Ly6C [Lin (CD3CD19NK1.1Ter-119) Ly6GCD11b] and Ly6C [Lin (CD3CD19NK1.1Ter-119) Ly6GCD11b] monocyte/macrophage subsets in normal and diabetic wounds. Using flow-sorted -labeled Ly6C monocyte/macrophages, we show Ly6C cells transition to a Ly6C phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6C cells that fail transition to Ly6C. The second wave of Ly6C cells in diabetic wounds corresponded to a spike in MCP-1 (monocyte chemoattractant protein-1) and selective administration of anti-MCP-1 reversed the second Ly6C influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq-based transcriptome profiling was performed on flow-sorted Ly6C [LinLy6GCD11b] and Ly6C [LinLy6GCD11b] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6C cells demonstrated differences in proinflammatory and profibrotic genes compared with controls.

Conclusions: Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11bLy6C monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.118.310703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920725PMC
May 2018

Dysfunctional Wound Healing in Diabetic Foot Ulcers: New Crossroads.

Curr Diab Rep 2018 01 23;18(1). Epub 2018 Jan 23.

Department of Surgery, Section of Vascular Surgery, University of Michigan, 5364 Cardiovascular Center, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5867, USA.

Purpose Of Review: Diabetic foot ulcerations (DFU) affect 25% of patients with diabetes mellitus during their lifetime and constitute a major health problem as they are often recalcitrant to healing due to a constellation of both intrinsic and extrinsic factors. The purpose of this review is to (1) detail the current mechanistic understanding of DFU formation and (2) highlight future therapeutic targets.

Recent Findings: From a molecular perspective, DFUs exhibit a chronic inflammatory predisposition. In addition, increased local hypoxic conditions and impaired cellular responses to hypoxia are pathogenic factors that contribute to delayed wound healing. Finally, recent evidence suggests a role for epigenetic alterations, including microRNAs, in delayed DFU healing due to the complex interplay between genes and the environment. In this regard, notable progress has been made in the molecular and genetic understanding of DFU formation. However, further studies are needed to translate preclinical investigations into clinical therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11892-018-0970-zDOI Listing
January 2018

The Clinical Impact of Cardiology Consultation Prior to Major Vascular Surgery.

Ann Surg 2018 Jan;267(1):189-195

*Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI†Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor, MI‡Section of Vascular Surgery, Department Surgery, Spectrum Health Center, Grand Rapids, MI§Section of Vascular Surgery, Department Surgery, Bronson Healthcare System, Kalamazoo, MI¶Section of Vascular Surgery, Department Surgery, Henry Ford Health System, Detroit, MI.

Objective: To understand statewide variation in preoperative cardiology consultation prior to major vascular surgery and to determine whether consultation was associated with differences in perioperative myocardial infarction (poMI).

Summary Background Data: Medical consultation prior to major vascular surgery is obtained to reduce perioperative risk. Despite perceived benefit of preoperative consultation, evidence is lacking specifically for major vascular surgery on the effect of preoperative cardiac consultation.

Methods: Patient and clinical data were obtained from a statewide vascular surgery registry between January 2012 and December 2014. Patients were risk stratified by revised cardiac risk index category and compared poMI between patients who did or did not receive a preoperative cardiology consultation. We then used logistic regression analysis to compare the rate of poMI across hospitals grouped into quartiles by rate of preoperative cardiology consultation.

Results: Our study population comprised 5191 patients undergoing open peripheral arterial bypass (n = 3037), open abdominal aortic aneurysm repair (n = 332), or endovascular aneurysm repair (n = 1822) at 29 hospitals. At the patient level, after risk-stratification by revised cardiac risk index category, there was no association between cardiac consultation and poMI. At the hospital level, preoperative cardiac consultation varied substantially between hospitals (6.9%-87.5%, P <0.001). High preoperative consulting hospitals (rate >66%) had a reduction in poMI (OR, 0.52; confidence interval: 0.28-0.98; P <0.05) compared with all other hospitals. These hospitals also had a statistically greater consultation rate with a variety of medical specialties.

Conclusions: Preoperative cardiology consultation for vascular surgery varies greatly between institutions, and does not appear to impact poMI at the patient level. However, reduction of poMI was noted at the hospitals with the highest rate of preoperative cardiology consultation as well as a variety of medical services, suggesting that other hospital culture effects play a role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SLA.0000000000002014DOI Listing
January 2018

The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes.

Diabetes 2017 09 29;66(9):2459-2471. Epub 2017 Jun 29.

Department of Surgery, University of Michigan, Ann Arbor, MI

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-κB (NF-κB)-mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific knockout ( ) to determine the function of MLL1 in wound healing. mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-κB binding sites on inflammatory gene promoters. Of note, early wound macrophages from prediabetic mice displayed similarly decreased MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines compared with controls. Late wound macrophages from prediabetic mice demonstrated an increase in MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines. Prediabetic macrophages treated with an MLL1 inhibitor demonstrated reduced inflammation. Finally, monocytes from patients with type 2 diabetes had increased compared with control subjects without diabetes. These results define an important role for MLL1 in regulating macrophage-mediated inflammation in wound repair and identify a potential target for the treatment of chronic inflammation in diabetic wounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db17-0194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566299PMC
September 2017

Predictors of surgical site infection after open lower extremity revascularization.

J Vasc Surg 2017 06;65(6):1769-1778.e3

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

Objective: Surgical site infection (SSI) after open lower extremity bypass (LEB) is a serious complication leading to an increased rate of graft failure, hospital readmission, and health care costs. This study sought to identify predictors of SSI after LEB for arterial occlusive disease and also potential modifiable factors to improve outcomes.

Methods: Data from a statewide cardiovascular consortium of 35 hospitals were used to obtain demographic, procedural, and hospital risk factors for patients undergoing elective or urgent open LEB between January 2012 and June 2015. Bivariate comparisons and targeted maximum likelihood estimation were used to identify independent risk factors of SSI. Adjusted odds ratios (ORs) were calculated for patient demographics, comorbidities, operative details, and hospital-level factors.

Results: Our study population included 3033 patients who underwent 703 femoral-femoral bypasses, 1431 femoral-popliteal bypasses, and 899 femoral-distal vessel bypasses. An SSI was diagnosed in 320 patients (10.6%) ≤30 days after the index operation. Adjusted patient and procedural predictors of SSI included renal failure currently requiring dialysis (OR, 4.35; 95% confidence interval [CI], 3.45-5.47; P < .001), hypertension (OR, 4.29; 95% CI, 2.74-6.72; P < .001), body mass index ≥25 kg/m (OR, 1.78; 95% CI, 1.23-2.57; P = .002), procedural time >240 minutes (OR, 2.95; 95% CI, 1.89-4.62; P < .001), and iodine-only skin preparation (OR, 1.73; 95% CI, 1.02-2.91; P = .04). Hospital factors associated with increased SSI included hospital size <500 beds (OR, 2.22; 95% CI, 1.09-4.55; P = .028) and major teaching hospital (OR, 1.66; 95% CI, 1.07-2.58; P = .024). SSI resulted in increased risk of major amputation and surgical reoperation (P < .01), but did not affect 30-day mortality.

Conclusions: SSI after LEB is associated with an increase in rate of amputation and reoperation. Several patient, operative, and hospital-related risk factors that predict postoperative SSI were identified, suggesting that targeted improvements in perioperative care may decrease complications and improve vascular patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvs.2016.11.053DOI Listing
June 2017

The effects of preoperative cardiology consultation prior to elective abdominal aortic aneurysm repair on patient morbidity.

Vascular 2017 Aug 6;25(4):390-395. Epub 2017 Jan 6.

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

Objectives The relationship between preoperative medical consultations and postoperative complications has not been extensively studied. Thus, we investigated the impact of preoperative consultation on postoperative morbidity following elective abdominal aortic aneurysm repair. Methods A retrospective review was conducted on 469 patients (mean age 72 years, 20% female) who underwent elective abdominal aortic aneurysm repair from June 2007 to July 2014. Data elements included detailed medical history, preoperative cardiology consultation, and postoperative complications. Primary outcomes included 30-day morbidity, consult-specific morbidity, and mortality. A bivariate probit regression model accounting for the endogeneity of binary preoperative medical consult and patient variability was estimated with a maximum likelihood function. Results Eighty patients had preoperative medical consults (85% cardiology); thus, our analysis focuses on the effect of cardiac-related preoperative consults. Hyperlipidemia, increased aneurysm size, and increased revised cardiac risk index increased likelihood of referral to cardiology preoperatively. Surgery type (endovascular versus open repair) was not significant in development of postoperative complications when controlling for revised cardiac risk index ( p = 0.295). After controlling for patient comorbidities, there was no difference in postoperative cardiac-related complications between patients who did and did not undergo cardiology consultation preoperatively ( p = 0.386). Conclusions When controlling for patient disease severity using revised cardiac risk index risk stratification, preoperative cardiology consultation is not associated with postoperative cardiac morbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1708538116685946DOI Listing
August 2017