Browsing by Author "Fajardo, Andres"
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Item Aggressive Surveillance Is Needed to Detect Endoleaks and Junctional Separation between Device Components after Zenith Fenestrated Aortic Reconstruction(Elsevier, 2019) Wang, S. Keisin; Lemmon, Gary W.; Gupta, Alok K.; Dalsing, Michael C.; Sawchuk, Alan P.; Motaganahalli, Raghu L.; Murphy, Michael P.; Fajardo, Andres; Surgery, School of MedicineBackground Junctional separation and resulting type IIIa endoleak is a well-known problem after EVAR (endovascular aneurysm repair). This complication results in sac pressurization, enlargement, and eventual rupture. In this manuscript, we review the incidence of this late finding in our experience with the Cook Zenith fenestrated endoprosthesis (ZFEN, Bloomington, IN). Methods A retrospective review was performed of a prospectively maintained institutional ZFEN fenestrated EVAR database capturing all ZFENs implanted at a large-volume, academic hospital system. Patients who experienced junctional separation between the fenestrated main body and distal bifurcated graft (with or without type IIIa endoleak) at any time after initial endoprosthesis implantation were subject to further evaluation of imaging and medical records to abstract clinical courses. Results In 110 ZFENs implanted from October 2012 to December 2017 followed for a mean of 1.5 years, we observed a 4.5% and 2.7% incidence of clinically significant junctional separation and type IIIa endoleak, respectively. Junctional separation was directly related to concurrent type Ib endoleak in all 5 patients. Three patients presented with sac enlargement. One patient did not demonstrate any evidence of clinically significant endoleak and had a decreasing sac size during follow-up imaging. The mean time to diagnosis of modular separation in these patients was 40 months. Junctional separation was captured in surveillance in 2 patients and reintervened upon before manifestation of endoleak. However, the remaining 3 patients completed modular separation resulting in rupture and emergent intervention in 2 and an aortic-related mortality in the other. Conclusions Junctional separation between the fenestrated main and distal bifurcated body with the potential for type IIIa endoleak is an established complication associated with the ZFEN platform. Therefore, we advocate for maximizing aortic overlap during the index procedure followed by aggressive surveillance and treatment of stent overlap loss captured on imaging.Item Cryopreserved Homografts in Infected Infrainguinal Fields Are Associated with Frequent Reinterventions and Poor Amputation-Free Survival(Elsevier, 2018) Wang, S. Keisin; Gutwein, Ashley R.; Drucker, Natalie A.; Murphy, Michael P.; Fajardo, Andres; Dalsing, Michael C.; Motaganahalli, Raghu L.; Lemmon, Gary W.; Surgery, School of MedicineBackground Single-length saphenous vein continues to be the conduit of choice in infected-field critical limb ischemia. However, half of these individuals have inadequate vein secondary to previous use or chronic venous disease. We reviewed our outcomes of infected-field infrainguinal bypasses performed with cryopreserved homografts (CHs), a widely accepted alternative to autogenous vein in this setting. Methods This is a retrospective, institutional descriptive analysis of infected-field infrainguinal revascularizations between 2012 and 2015. Results Twenty-four operations were performed in the same number of patients for limb ischemia with signs of active infection. The mean age of the cohort examined was 62.5 ± 14.4 (standard deviation) years. Mean Society of Vascular Surgery risk score was 3.9 with a baseline Rutherford's chronic ischemia score of 4.3 at presentation. Emergent procedures constituted 29% of cases, and the remainder cases were urgent procedures. The CH bypass captured was a reoperative procedure in all but one of the patients. Culture positivity was present in 75% of cases with Staphylococcus aureus (29%), the most commonly isolated organism. Thirty-day mortality and major adverse cardiovascular events were both 4%. Amputation-free survival (AFS) was 75% at 30 days. Similarly, 30-day reintervention was 38% with debridement (43%) and bleeding (29%), the most common indications. Average duration of follow-up was 27.9 ± 20.4 months (range: 0.5–60.4). Mean length of stay was 14.8 days. Reinfection requiring an additional procedure or antibiotic regimen separate from the index antibiotic course was 13%. Primary patency and AFS at 1 year was 50% and 58%, respectively. Primary patency and AFS at 2 years was 38% and 52%, respectively. Limb salvage at 1 and 2 years was 70% and 65%, respectively. Fifteen patients (63%) required reintervention during the follow-up period with 40% of those subjects undergoing multiple procedures. Conclusions CHs remain a marginal salvage conduit in the setting of infection and no autogenous choices. Therefore, clinicians should individualize usage of this high-cost product in highly selected patients only.Item Description of human AAA by cytokine and immune cell aberrations compared to risk-factor matched controls(Elsevier, 2018-08) Wang, S. Keisin; Green, Linden A.; Gutwein, Ashley R.; Drucker, Natalie A.; Motaganahalli, Raghu L.; Gupta, Alok K.; Fajardo, Andres; Murphy, Michael P.; Surgery, School of MedicineBACKGROUND: The pathogenesis driving the formation of abdominal aortic aneurysms continues to be poorly understood. Therefore, we systemically define the cytokine and circulating immune cell environment observed in human abdominal aortic aneurysm compared with risk-factor matched controls. METHODS: From 2015 to 2017, a total of 274 patients donated blood to the Indiana University Center for Aortic Disease. Absolute concentrations of circulating cytokines were determined, using enzyme-linked immunosorbent assays while the expression of circulating immune cell phenotypes were assayed via flow cytometric analysis. RESULTS: Human abdominal aortic aneurysm is characterized by a significant depletion of the antigen-specific, CD4+ Tr1 regulatory lymphocyte that corresponds to an upregulation of the antigen-specific, inflammatory Th17 cell. We found no differences in the incidence of Treg, B10, and myeloid-derived suppressor regulatory cells. Similarly, no disparities were noted in the following inflammatory cytokines: IL-1β, C-reactive protein, tumor necrosis factor α, interferon γ, and IL-23. However, significant upregulation of the inflammatory cytokines osteopontin, IL-6, and IL-17 were noted. Additionally, no changes were observed in the regulatory cytokines IL-2, IL-4, IL-13, TNF-stimulated gene 6 protein, and prostaglandin E2, but we did observe a significant decrease in the essential regulatory cytokine IL-10. CONCLUSION: In this investigation, we systematically characterize the abdominal aortic aneurysm-immune environment and present preliminary evidence that faulty immune regulation may also contribute to aneurysm formation and growth.Item Metformin does not reduce inflammation in diabetics with abdominal aortic aneurysm or at high risk of abdominal aortic aneurysm formation(Sage, 2018-12) Wang, S. Keisin; Green, Linden A.; Gutwein, Ashley R.; Kenyon, Bianca; Motaganahalli, Raghu L.; Fajardo, Andres; Gupta, Alok K.; Murphy, Michael P.; Surgery, School of MedicineIntroduction The protective effect of diabetes mellitus on abdominal aortic aneurysm formation and growth has been repeatedly observed in population studies but continues to be poorly understood. However, recent investigations have suggested that metformin, a staple antihyperglycemic medication, may be independently protective against abdominal aortic aneurysm formation and growth. Therefore, we describe the effect of metformin in abdominal aortic aneurysm and at-risk patients on markers of inflammation, the driver of early abdominal aortic aneurysm formation and growth. Methods Peripheral blood was collected from patients previously diagnosed with abdominal aortic aneurysm or presenting for their U.S. Preventive Task Force-recommended abdominal aortic aneurysm screening. Plasma and circulating peripheral blood mononuclear cells were isolated using Ficoll density centrifugation. Circulating plasma inflammatory and regulatory cytokines were assessed with enzyme-linked immunosorbent assays. CD4+ cell phenotyping was performed using flow cytometric analysis and expressed as a proportion of total CD4+ cells. To determine the circulating antibody to self-antigen response, a modified enzyme-linked immunosorbent assay was performed against antibodies to collagen type V and elastin fragments. Results Peripheral blood was isolated from 266 patients without diabetes mellitus (n=182), with diabetes mellitus not treated with metformin (n=34), and with diabetes mellitus actively taking metformin (n=50) from 2015 to 2017. We found no differences in the expression of Tr1, Th17, and Treg CD4+ fractions within diabetics ± metformin. When comparing inflammatory cytokines, we detected no differences in IL-1β, IL-6, IL-17, IL-23, IFN-γ, and TNF-α. Conversely, no differences were observed pertaining to the expression to regulatory cytokines IL-4, IL-10, IL-13, TSG-6, or TGF-β. Lastly, no differences in expression of collagen type V and elastin fragment antigen and/or antibodies were detected with metformin use in diabetics. Conclusion Metformin in diabetics at-risk for abdominal aortic aneurysm or diagnosed with abdominal aortic aneurysm does not seem to alter the peripheral inflammatory environment.Item Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small Abdominal Aortic Aneurysm(Elsevier, 2017) Wang, S. Keisin; Green, Linden A.; Gutwein, Ashley R.; Drucker, Natalie A.; Motaganahalli, Raghu L.; Fajardo, Andres; Babbey, Clifford C.; Murphy, Michael P.; Surgery, School of MedicineBackground Abdominal aortic aneurysms (AAAs) are a major source of morbidity and mortality despite continuing advances in surgical technique and care. Although the inciting factors for AAA development continue to be elusive, accumulating evidence suggests a significant periaortic inflammatory response leading to degradation and dilation of the aortic wall. Previous human trials have demonstrated safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of inflammation-related pathologies such as rheumatoid arthritis, graft versus host disease, and transplant rejection. Therefore, herein, we describe the Aortic Aneurysm Repression with Mesenchymal Stem Cells (ARREST) trial, a phase I investigation into the safety of MSC infusion for patients with small AAA and the cells' effects on modulation of AAA-related inflammation. Methods ARREST is a phase I, single-center, double-blind, randomized controlled trial (RCT) investigating infusion both dilute and concentrated MSCs compared to placebo in 36 small AAA (35–45 mm) patients. Subjects will be followed by study personnel for 12 months to ascertain incidence of adverse events, immune cell phenotype expression, peripheral cytokine profile, and periaortic inflammation. Maximum transverse aortic diameter will be assessed regularly for 5 years by a combination of computed tomography and duplex sonography. Results Four patients have thus far been enrolled, randomized, and treated per protocol. We anticipate the conclusion of the treatment phase within the next 24 months with ongoing long-term follow-up. Conclusions ARREST will be pivotal in assessing the safety of MSC infusion and provide preliminary data on the ability of MSCs to favorably modulate the pathogenic AAA host immune response. The data gleaned from this phase I trial will provide the groundwork for a larger, phase III RCT which may provide the first pharmaceutical intervention for AAA.Item Rationale and design of the Clinical and Histologic Analysis of Mesenchymal Stromal Cells in AmPutations (CHAMP) trial investigating the therapeutic mechanism of mesenchymal stromal cells in the treatment of critical limb ischemia(Elsevier, 2018-07) Wang, S. Keisin; Green, Linden A.; Drucker, Natalie A.; Motaganahalli, Raghu L.; Fajardo, Andres; Murphy, Michael P.; Surgery, School of MedicineOBJECTIVE: Currently, there are no accepted nonsurgical therapies that improve the delivery of blood-derived nutrients to patients with critical limb ischemia. Here, we describe the ongoing phase 1/2 Clinical and Histologic Analysis of Mesenchymal Stromal Cells in AmPutations (CHAMP) trial, which will provide crucial evidence of the safety profile of mesenchymal stromal cells (MSCs) and explore their therapeutic mechanisms in the setting of critical limb ischemia requiring below-knee amputation (BKA). METHODS: In the CHAMP and the parallel marrowCHAMP trials (hereafter grouped together as CHAMP), a total of 32 extremities with rest pain or tissue loss requiring BKA will be enrolled to receive intramuscular injections of allogeneic MSCs (CHAMP; n = 16) or autogenous concentrated bone marrow aspirate (marrowCHAMP; n = 16) along the distribution of the BKA myocutaneous flap and proximal tibialis anterior. After treatment, subjects are randomized to BKA at four time points after injection (days 3, 7, 14, and 21). At the time of amputation, skeletal muscle is collected at 2-cm increments from the tibialis injection site and used to determine proangiogenic cytokine description, MSC retention, quantification of proangiogenic hematopoietic progenitor cells, and histologic description. Clinical limb perfusion before and after treatment will be quantified using transcutaneous oximetry, toe-brachial index, ankle-brachial index, and indocyanine angiography. Additional clinical end points include all-cause mortality, need for amputation revision, and gangrene incidence during the 6-month post-treatment follow-up. RESULTS: Enrollment is under way, with 10 patients treated per protocol thus far. We anticipate full conclusion of follow-up within the next 24 months. CONCLUSIONS: CHAMP will be pivotal in characterizing the safety, efficacy, and, most important, therapeutic mechanism of allogeneic MSCs and autogenous concentrated bone marrow aspirate in ischemic skeletal muscle.Item Renal Autotransplant and Celiac Artery Bypass for Aneurysmal Degeneration Related to Neurofibromatosis Type 1(Sage, 2019-08) Drucker, Natalie A.; Blaibel, Maher F.; Nagaraju, Santosh; Wang, S. Keisin; Goggins, William; Fajardo, Andres; Surgery, School of MedicineWe present a case of an 18-year-old female with neurofibromatosis type 1 who presented with abdominal pain and weight loss secondary to chronic mesenteric ischemia due to celiac axis occlusion and was subsequently found to have multiple visceral artery aneurysms. Of clinical significance, 2 aneurysms of the right renal artery were noted at the hilum, with the larger one having a diameter of 2.4 cm. After initial endovascular treatment with stenting of a concurrent pancreaticoduodenal artery pseudoaneurysm, staged aorto-hepatic bypass and right nephrectomy with renal autotransplantation after back table resection of the aneurysmal segments were successfully completed.Item Sarcopenia is a Significant Predictor of Mortality After Abdominal Aortic Aneurysm Repair(JCSM, 2018) Kays, Joshua K.; Liang, Tiffany W.; Zimmers, Teresa A.; Milgrom, Daniel P.; Abduljabar, Hamzah; Young, Andrew; Kim, Bradford J.; Bell, Teresa M.; Fajardo, Andres; Murphy, Michael P.; Koniaris, Leonidas G.; Surgery, School of MedicineAims Repair of abdominal aortic aneurysms (AAA) decreases the incidence of rupture and death. In cancer patients, sarcopenia has been associated with increased surgical complications and mortality. The impact of sarcopenia on survival after AAA repair has yet to be described. Methods and Results Patient demographic, laboratory, body composition measurements and survival data were obtained from patients undergoing AAA repair at the Indiana University medical campus over a 5-year period. Univariate and multivariate analyses were performed to identify factors associated with overall survival. Overall, 58.2% presented with sarcopenia. Sarcopenic patients were older (71.8±8.3 versus 66.8±8.1 years; p<0.001), had lower body mass index (BMI) (26.3±5.2 versus 31.5±5.9 kg/m2; p<0.001), higher rates of myosteatosis (84.4% versus 52.%; p<0.001), greater AAA diameter (60.6±14.0 versus 57.8±11.7 mm; p=0.016), higher Charlson Comorbidity Index (CCI) (32.3% versus 25.1% ≥6; p=0.034), and increased rates of rupture (8.2% versus 3.8%; p=0.047). Sarcopenic and nonsarcopenic patients had no difference in 30-day morbidity (8.5% versus 8.5%; p=0.991) or mortality (3.7% versus 0.9%; p=0.07). Univariate analysis demonstrated age, sarcopenia, myosteatosis, CCI, and BMI to be associated with long-term survival. There was no correlation between BMI and sarcopenia. Both sarcopenia and myosteatosis resulted in decreased one-, three-, and five-year survivals compared to their counterparts. On multivariate analysis sarcopenia is independently associated with survival, conferring a 1.6-fold increase in death (p=0.04). The combination of sarcopenia plus myosteatosis doubled the risk of death compared to sarcopenia alone. Conclusions This is the first study to demonstrate that over half of all patients undergoing AAA repair are sarcopenic, a condition associated with increased mortality. Sarcopenia with myosteatosis is associated with double the mortality of sarcopenia alone. CT scan, but not BMI, accurately identifies sarcopenia and myosteatosis. Defining the mechanisms through which sarcopenia contributes to late death after AAA repair is critical to developing novel interventions that may improve survival in this high risk population.Item Spontaneous Iliac Vein Rupture Due to May-Thurner Syndrome and Its Staged Management(Sage, 2019) Ingram, Michael; Miladore, Julia; Gupta, Alok; Maijub, John; Wang, Keisin; Fajardo, Andres; Motaganahalli, Raghu; Surgery, School of MedicineWe present a case of a 58-year-old otherwise healthy women who presented with left lower extremity deep venous thrombosis and was found to have pulmonary embolism along with a ruptured left internal iliac vein. Our patient was hemodynamically stable upon presentation; therefore, a staged approach was undertaken. Initially, an inferior vena cava filter was placed and the patient was slowly advanced to therapeutic anticoagulation and subsequently discharged. She then returned 2 weeks after discharge for venogram, mechanical thrombectomy, and stenting. At 1-year follow-up in clinic, she was found to have patent stents and resolution of symptoms.Item TSG-6 is highly expressed in human abdominal aortic aneurysms(Elsevier, 2017-12) Wang, S. Keisin; Xie, Jie; Green, Linden A.; McCready, Robert A.; Motaganahalli, Raghu L.; Fajardo, Andres; Babbey, Clifford C.; Murphy, Michael P.; Surgery, School of MedicineBACKGROUND: The formation of abdominal aortic aneurysms (AAA) is characterized by a dominance of proinflammatory forces that result in smooth muscle cell apoptosis, extracellular matrix degradation, and progressive diameter expansion. Additional defects in the antiinflammatory response may also play a role but have yet to be fully characterized. TSG-6 (TNF-stimulated gene-6) is a potent antiinflammatory protein involved in extracellular matrix stabilization and cell migration active in many pathological conditions. Here, we describe its role in AAA formation. METHODS: Blood and/or aortic tissue samples were collected from organ donors, subjects undergoing elective AAA screening, and open surgical AAA repair. Aortic specimens collected were preserved for IHC or immediately assayed after tissue homogenization. Protein concentrations in tissue and plasma were assayed by ELISA. All immune cell populations were assayed using FACS. In vitro, macrophage polarization from monocytes was performed with young, healthy donor PBMCs. RESULTS: TSG-6 was found to be abnormally elevated in both the plasma and aortic wall of patients with AAA compared with healthy and risk-factor matched non-AAA donors. We observed the highest tissue concentration of TSG-6 in the less-diseased proximal and distal shoulders compared with the central aspect of the aneurysm. IHC localized most TSG-6 to the tunica media with minor expression in the tunica adventitia of the aortic wall. Higher concentrations of both M1 and M2 macrophages where also observed, however M1/M2 ratios were unchanged from healthy controls. We observed no difference in M1/M2 ratios in the peripheral blood of risk-factor matched non-AAA and AAA patients. Interesting, TSG-6 inhibited the polarization of the antiinflammatory M2 phenotype in vitro. CONCLUSIONS: AAA formation results from an imbalance of inflammatory forces causing aortic wall infiltration of mononuclear cells leading to the vessel breakdown. In the AAA condition, we report an elevation of TSG-6 expression in both the aortic wall and the peripheral circulation.