Ashley R. Gutwein

Institutional experience with the Zenith Fenestrated aortic stent graft

Objective: The Zenith Fenestrated (ZFEN; Cook Medical, Bloomington, Ind) aortic stent graft system was approved for commercial use by the Food and Drug Administration in April 2012. We report our single‐center experience of 100 consecutive patients treated with the ZFEN platform from October 2012 to March 2017. Methods: A retrospective review of our prospectively maintained fenestrated endovascular aneurysm repair (FEVAR) database at a tertiary care academic institution located in the Midwest United States was performed for descriptive analysis. All continuous variables are reported as a mean ± standard deviation and compared using two‐sided Student t‐tests. Categorical variables were compared using two‐sided Fisher exact tests. Results: All but one of the procedures were elective in nature. Overall intraoperative characteristics included a mean blood loss (estimated blood loss) of 388 ± 385 mL, fluoroscopy time of 63 ± 30 minutes, radiation dose of 437 ± 272 rad, contrast material volume of 99 ± 36 mL, and operative time of 236 ± 87 minutes. Average number of visceral arteries stented was 2.1 ± 0.5. Technical success was achieved in 98% of the patients. Statistically significant (P < .05) improvement in estimated blood loss (2.1‐fold) was observed in the second half of our series. Interestingly, no improvements were made in terms of fluoroscopy time, radiation exposure, contrast material use, or operative time. However, procedural difficulty increased in the last half by number of visceral arteries stented as a surrogate (1.9 vs 2.2; P < .05). Mean length of stay was 3.6 ± 4.3 days. Perioperative mortality at 30 days was 2%. Perioperative morbidity included a 5% incidence of any bowel ischemia, 1% of spinal cord ischemia, 3% of renal failure requiring hemodialysis, 1% of stroke, and 4% of myocardial infarction. Average follow‐up was 1.7 ± 1.4 years. Reintervention during the follow‐up phase was 20%. Of the 209 visceral arteries stented, we noted 6 instances of stent thrombosis, 6 of kinking or stenosis, and 1 of stent fracture in follow‐up. Endoleak, most commonly type II, was present or could not be excluded in 15% of all FEVARs at last available computed tomography angiography. Conclusions: In our experience, FEVAR with the ZFEN system continues to be safe and effective. There is a significant rate of reintervention observed, and close monitoring is fundamental to maintaining good clinical results.

Osteopontin may be a driver of abdominal aortic aneurysm formation

Objective: Previous in vitro and animal studies have suggested that osteopontin (OPN), an inflammatory extracellular matrix protein, is involved in the formation and growth of abdominal aortic aneurysms (AAAs). However, the mechanism by which this occurs continues to be nebulous. The relationship between OPN and inflammation‐suppressing lymphocytes present in the human AAA condition was investigated and presented herein. Methods: Serum OPN concentrations were measured in healthy, risk factor‐matched non‐AAA and AAA patients by enzyme‐linked immunosorbent assay (ELISA). Immunohistochemistry was used to determine the source of OPN secretion using aortic tissue collected from multiorgan donors and AAA patients undergoing open surgical repair. Vascular smooth muscle cells (VSMCs) were exposed to various inflammatory mediators, and OPN expression was evaluated by quantitative reverse transcriptase‐polymerase chain reaction and ELISA. The inflammatory nature of OPN and the aortic wall was determined using a TR1 suppressor cell induction assay as a surrogate and characterized by ELISA and fluorescence‐activated cell sorting. Results: OPN was found to be elevated in both the plasma and aortic homogenate of AAA patients compared with controls. On immunohistochemistry, OPN localized to the tunica media of the diseased aorta but was minimally expressed in healthy aorta. In vitro, cigarette smoke extract was the most potent stimulator of OPN secretion by VSMCs and increased both messenger RNA and supernatant concentrations. OPN demonstrated an ability to inhibit the induction of interleukin 10‐secreting TR1 lymphocytes, a depleted population in the AAA patient, from naive precursors. Last, neutralizing receptor targets of OPN in the setting of AAA homogenate coincubation abrogated the inhibition of TR1 induction. Conclusions: OPN, secreted by the VSMCs of the tunica media, is elevated in the circulating plasma and aortic wall of patients with AAA. It can inhibit the induction of the TR1 suppressor cell, leading to an overall proinflammatory state contributing to progressive aortic wall breakdown and dilation. Clinical Relevance: Little is known about the initiating event of abdominal aortic aneurysm formation. However, the early histology of the ectatic aorta is characterized by massive infiltration of mononuclear cells and elaboration of matrix metalloproteinases, collagenases, and elastases. This runaway inflammatory response directly leads to extracellular matrix degradation and loss of aortic integrity. In this study, we report elevations of osteopontin (OPN), an extracellular matrix glycoprotein associated with inflammation in other pathologic processes. In addition, OPN demonstrated an ability to inhibit the expression of the TR1 lymphocyte, a potent suppressor of inflammation. Therefore, we argue that accumulation of OPN in the aortic wall may be a potent driver for abdominal aortic aneurysm propagation.

Temporizing amplatzer closure of an aorto-enteric fistula associated with a blind aortic stump via a translumbar approach

We present a case of an aorto-enteric fistula (AEF) with chronic, persistent bleeding from a blind aortic stump managed by endovascular means. This novel approach may have extended the life of a patient who would otherwise have been subject to a high perioperative morbidity or persistent bleeding and death. While our patient ultimately expired, we believe this technique can be considered for temporization in highly-selected patients.

Metformin does not reduce inflammation in diabetics with abdominal aortic aneurysm or at high risk of abdominal aortic aneurysm formation

Introduction 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 diabeticsu2009±u2009metformin. 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.

Description of human AAA by cytokine and immune cell aberrations compared to risk-factor matched controls

Background: 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‐1&bgr;, C‐reactive protein, tumor necrosis factor &agr;, interferon &ggr;, 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.

Ethnic minorities with critical limb ischemia derive equal amputation risk reduction from autologous cell therapy compared with whites

Objective: Ethnic minorities (nonwhites) with critical limb ischemia (CLI) have historically performed worse compared with whites with regard to major amputation risk reduction and amputation‐free survival (AFS) after peripheral vascular intervention. This post hoc analysis was completed to determine whether this precedent also extended to treatment of CLI without a suitable revascularization option with intramuscular injections of concentrated bone marrow aspirate (cBMA). Methods: The treatment arm of the randomized, double‐blind, multicenter MarrowStim PAD Kit for the Treatment of Critical Limb Ischemia in Subjects with Severe Peripheral Arterial Disease (MOBILE) trial was stratified by ethnicity and evaluated for demographics, comorbidities, and outcomes. The primary and therapeutic end point was 1‐year AFS and major amputation, respectively. Noninferiority analysis was performed with the margin set at historically reported hazard ratios. Results: Thirty‐seven minority (African American, Hispanic, other) CLI patients (9 placebo, 28 cBMA) with no suitable revascularization option were randomized to cBMA or placebo at a 3:1 ratio during the MOBILE trial. At 1‐year follow‐up for the treatment group, overall AFS was 80%. Of the 28 minority patients randomized to cBMA intervention, an 89% AFS rate was observed compared with 77% in whites. Specifically, 22 of 24 (92%) African Americans survived amputation free at 1‐year follow‐up. Noninferiority testing confirmed no difference between whites and the ethnic minority treated with cBMA with respect to major amputation reduction; however, noninferiority could not be confirmed with regard to AFS. No significant differences favoring whites treated with cBMA were noted in the secondary end points of vascular quality of life, limb pain, ankle‐brachial index, toe‐brachial index, transcutaneous oximetry, and 6‐minute walk testing. Conclusions: This post hoc analysis of the MOBILE trial demonstrates noninferiority of cBMA intervention in minorities with no‐option CLI for the therapeutic end point of major amputation prevention. cBMA represents a novel treatment paradigm and should be explored for minorities with poor revascularization options who face impending amputation secondary to progressive CLI.

Perioperative Outcomes are Adversely Affected by Poor Pretransfer Adherence to Acute Limb Ischemia Practice Guidelines

BACKGROUNDnThe accepted treatment for acute limb ischemia (ALI) is immediate systemic anticoagulation and timely reperfusion to restore blood flow. In this study, we describe the retrospective assessment of pretransfer management decisions by referring hospitals to an academic tertiary care facility and its impact on perioperative adverse events.nnnMETHODSnA retrospective analysis of ALI patients transferred to us via our Level I Vascular Emergency Program from 2010 to 2013 was performed. Patient demographics, comorbidities, Rutherford ischemia classification, time to anticoagulation, and time to reperfusion were tabulated and analyzed for correlation to incidence of major adverse limb events (MALEs), mortality, and bypass patency in the perioperative period (30-day postoperative). All intervals were calculated from the onset of symptoms and categorized into 3 subcohorts (<6xa0hr, 6-48xa0hr, and >48xa0hr).nnnRESULTSnEighty-seven patients with an average age of 64.0 (±16.2) years presented to outlying hospitals and were transferred to us with lower extremity ALI. The mean delay from symptom onset to initial referring physician evaluation was 18.3xa0hr. At that time of evaluation, 53.8% had Rutherford class IIA ischemia and 36.3% had class IIB ischemia. Seventy-six patients (87.4%) were started on heparin previous to transfer. However, only 44 patients (57.9%) reached therapeutic levels as measured by activated partial thromboplastin time before definitive revascularization. A delay of anticoagulation initiation >48xa0hr from symptom onset was associated with increased 30-day reintervention rates compared with the <6xa0hr group (66.7% vs. 23.5%; Pxa0<xa00.05). However, time to reperfusion had no statistically significant impact on MALE, 30-day mortality, or 30-day interventional patency in our small cohorts. Additionally, patients with a previous revascularization had a higher 30-day reintervention rate (46.5%; Pxa0<xa00.05).nnnCONCLUSIONSnThe practice of timely therapeutic anticoagulation of patients referred for ALI from community facilities occurs less frequently than expected and is associated with an increased perioperative reintervention rate.

Staged endovascular repair of an abdominal aortic aneurysm adjacent to a chronic high-flow iliocaval traumatic arteriovenous fistula

Large-vessel chronic traumatic arteriovenous fistulas are a rare complication after trauma. Delayed presentation can consist of one or more features of high-output cardiac failure, pulsatile abdominal mass, bruit, limb ischemia, and venous congestion. We describe a patient with a complex iliocaval fistula secondary to a remote gunshot wound associated with a large 8.5-cm aortic aneurysm. Informed consent of the patient was obtained for publication of the case.

Results of nonoperative management of acute limb ischemia in infants

Objective: Acute limb ischemia (ALI) in infants poses a challenge to the clinician secondary to poor operative outcomes, limb loss risk, and lifelong morbidity. This retrospective study reviewed a 10‐year institutional experience with the nonoperative management of ALI in infants. Methods: Infants (aged ≤12 months) diagnosed with ALI by duplex ultrasound and treated with initial nonoperative management at a tertiary care childrens hospital were identified through vascular laboratory arterial duplex ultrasound records and International Classification of Diseases and Current Procedural Terminology codes associated with ALI. Demographics of the patients, injury characteristics, treatment administered, and outcomes were abstracted by chart review and presented using descriptive statistics. Results: During the study period, a total of 25 (28% female) infant patients were diagnosed with ALI. The average age for this cohort was 3.5 ± 3.2 months (standard deviation). Most cases were secondary to iatrogenic injury (88%) from arterial cannulation. Injury sites were more concentrated to the lower extremities (84%) compared with the upper. Absence of Doppler signals was noted in 64% of infants, whereas limb cyanosis was observed in 60% at the time of presentation. Infants were initially treated with anticoagulation (80%) when possible. Two patients failed to respond to nonoperative management and required thrombolysis secondary to progression of thrombus burden while anticoagulated. There were no major (above‐ankle) amputations at 30 days. Three deaths occurred within 30 days; all were unrelated to limb ischemia. In the 30‐day survivors, overall duration of follow‐up was 53.5 ± 38.5 months. One infant required above‐knee amputation 6 weeks after diagnosis, resulting in an overall limb salvage rate of 96% on follow‐up. Long‐term morbidity included two patients with a chronic wound of the affected limb and one patient with limb length discrepancy. No subjects reported claudication at the latest follow‐up appointment. In addition, all patients were independently ambulatory except for one adolescent girl who was using a walker with leg braces. Conclusions: In contrast to the adult population, ALI in infants can be managed with anticoagulation alone with good results. Long‐term follow‐up continues to demonstrate excellent functional results and minimal disability.