Magnetic resonance imaging contrast-enhancement with superparamagnetic iron oxide nanoparticles amplifies macrophage foam cell apoptosis in human and murine atherosclerosis.

AIMS: (Ultra) Small superparamagnetic iron oxide nanoparticles, (U)SPIO, are widely used as magnetic resonance imaging contrast media and assumed to be safe for clinical applications in cardiovascular disease. As safety tests largely relied on normolipidaemic models, not fully representative of the clinical setting, we investigated the impact of (U)SPIOs on disease-relevant endpoints in hyperlipidaemic models of atherosclerosis. METHODS AND RESULTS: RAW264.7 foam cells, exposed in vitro to ferumoxide (dextran-coated SPIO), ferumoxtran (dextran-coated USPIO), or ferumoxytol [carboxymethyl (CM) dextran-coated USPIO] (all 1 mg Fe/mL) showed increased apoptosis and reactive oxygen species accumulation for ferumoxide and ferumoxtran, whereas ferumoxytol was tolerated well. Pro-apoptotic (TUNEL+) and pro-oxidant activity of ferumoxide (0.3 mg Fe/kg) and ferumoxtran (1 mg Fe/kg) were confirmed in plaque, spleen, and liver of hyperlipidaemic ApoE-/- (n = 9/group) and LDLR-/- (n = 9-16/group) mice that had received single IV injections compared with saline-treated controls. Again, ferumoxytol treatment (1 mg Fe/kg) failed to induce apoptosis or oxidative stress in these tissues. Concomitant antioxidant treatment (EUK-8/EUK-134) largely prevented these effects in vitro (-68%, P < 0.05) and in plaques from LDLR-/- mice (-60%, P < 0.001, n = 8/group). Repeated ferumoxtran injections of LDLR-/- mice with pre-existing atherosclerosis enhanced plaque inflammation and apoptosis but did not alter plaque size. Strikingly, carotid artery plaques of endarterectomy patients who received ferumoxtran (2.6 mg Fe/kg) before surgery (n = 9) also showed five-fold increased apoptosis (18.2 vs. 3.7%, respectively; P = 0.004) compared with controls who did not receive ferumoxtran. Mechanistically, neither coating nor particle size seemed accountable for the observed cytotoxicity of ferumoxide and ferumoxtran. CONCLUSIONS: Ferumoxide and ferumoxtran, but not ferumoxytol, induced apoptosis of lipid-laden macrophages in human and murine atherosclerosis, potentially impacting disease progression in patients with advanced atherosclerosis.

Multicenter experience of upper extremity access in complex endovascular aortic aneurysm repair.

PURPOSE: Upper extremity access (UEA) for antegrade cannulation of aortic side branches is a relevant part of endovascular treatment of complex aortic aneurysms and can be achieved using several techniques, sites, and sides. The purpose of this study was to evaluate different UEA strategies in a multicenter registry of complex endovascular aortic aneurysm repair (EVAR). METHODS: In six aortic centers in the Netherlands, all endovascular aortic procedures from 2006 to 2019 were retrospectively reviewed. Patients who received UEA during complex EVAR were included. The primary outcome was a composite end point of any access complication, excluding minor hematomas. Secondary outcomes were access characteristics, access complications considered individually, access reinterventions, and incidence of ischemic cerebrovascular events. RESULTS: A total of 417 patients underwent 437 UEA for 303 fenestrated/branched EVARs and 114 chimney EVARs. Twenty patients had bilateral, 295 left-sided, and 102 right-sided UEA. A total of 413 approaches were performed surgically and 24 percutaneously. Distal brachial access (DBA) was used in 89 cases, medial brachial access (MBA) in 149, proximal brachial access (PBA) in 140, and axillary access (AA) in 59 cases. No significant differences regarding the composite end point of access complications were seen (DBA: 11.3% vs MBA: 6.7% vs PBA: 13.6% vs AA: 10.2%; P = .29). Postoperative neuropathy occurred most after PBA (DBA: 1.1% vs MBA: 1.3% vs PBA: 9.3% vs AA: 5.1%; P = .003). There were no differences in cerebrovascular complications between access sides (right: 5.9% vs left: 4.1% vs bilateral: 5%; P = .75). Significantly more overall access complications were seen after a percutaneous approach (29.2% vs 6.8%; P = .002). In multivariate analysis, the risk for access complications after an open approach was decreased by male sex (odds ratio [OR]: 0.27; 95% confidence interval [CI]: 0.10-0.72; P = .009), whereas an increase in age per year (OR: 1.08; 95% CI: 1.004-1.179; P = .039) and diabetes mellitus type 2 (OR: 3.70; 95% CI: 1.20-11.41; P = .023) increased the risk. CONCLUSIONS: Between the four access localizations, there were no differences in overall access complications. Female sex, diabetes mellitus type 2, and aging increased the risk for access complications after a surgical approach. Furthermore, a percutaneous UEA resulted in higher complication rates than a surgical approach.

Nationwide Experience with EVAS Relining of Previous Open or Endovascular AAA Treatment in The Netherlands.

OBJECTIVE: Relining of a previously placed surgical graft or endograft for an abdominal aortic aneurysm (AAA) is a reintervention to treat progression of disease or failure of the primary (endo)graft. Endovascular Aneurysm Sealing (EVAS) relining is a technique with potential advantages due to the absence of a bifurcation, the possibility for a unilateral approach, and sealing concept of the endobags. The purpose of this study was to describe the nationwide experience with EVAS relining of previous AAA repair in the Netherlands. METHODS: A retrospective analysis of all patients who underwent EVAS relining in 7 high volume vascular centres in the Netherlands between 2014 and 2019 was performed. Primary outcomes were technical and clinical success. Secondary outcomes were perioperative outcomes, complications and survival. RESULTS: Thirty-three patients underwent EVAS relining of open (n = 10) or endovascular (n = 23) repair. 26 were elective cases, 5 were urgent and 2 were acute (ruptured). Mean time between primary treatment and EVAS relining was 99 ± 74 months. Indications after open repair were proximal progression of disease (n = 7) and graft defect (n = 3). Indications after EVAR were type IA (n = 10), type IB (n = 3), type IIIA (n = 4), type IIIB (n = 3) endoleak, and endotension (n = 3). 18 patients underwent regular EVAS, 4 unilateral EVAS and 11 chimney-EVAS. In-hospital mortality was 6% (both patients with rAAA). Technical success was achieved in 97%. Median follow-up after EVAS relining was 20 months (range 0-43). Freedom from reintervention at 1-year and 2-year were 83% and 61% and the estimated survival 79% and 71%, respectively. EVAS relining after open repair had a clinical success of 90% at 1-year and of 70% at latest follow-up, while after EVAR clinical success rates were 70% and 52%, respectively. CONCLUSION: EVAS relining of previous AAA repair is associated with high technical success, however with limited clinical success at median follow-up of 20 months. Clinical success was higher in patients with EVAS relining after open repair than after EVAR. In patients with failed AAA repair, EVAS relining should only be considered, when established techniques such as fenestrated repair or open conversion are not available or indicated.

Association of Hospital Volume with Perioperative Mortality of Endovascular Repair of Complex Aortic Aneurysms: A Nationwide Cohort Study.

OBJECTIVE: We evaluate nationwide perioperative outcomes of complex EVAR and assess the volume-outcome association of complex EVAR. SUMMARY OF BACKGROUND DATA: Endovascular treatment with fenestrated (FEVAR) or branched (BEVAR) endografts is progressively used for excluding complex aortic aneurysms (complex AAs). It is unclear if a volume-outcome association exists in endovascular treatment of complex AAs (complex EVAR). METHODS: All patients prospectively registered in the Dutch Surgical Aneurysm Audit who underwent complex EVAR (FEVAR or BEVAR) between January 2016 and January 2020 were included. The effect of annual hospital volume on perioperative mortality was examined using multivariable logistic regression analyses. Patients were stratified into quartiles based on annual hospital volume to determine hospital volume categories. RESULTS: We included 694 patients (539 FEVAR patients, 155 BEVAR patients). Perioperative mortality following FEVAR was 4.5% and 5.2% following BEVAR. Postoperative complication rates were 30.1% and 48.7%, respectively. The first quartile hospitals performed <9 procedures/yr; second, third, and fourth quartile hospitals performed 9-12, 13-22, and ≥23 procedures/yr. The highest volume hospitals treated the significantly more complex patients. Perioperative mortality of complex EVAR was 9.1% in hospitals with a volume of < 9, and 2.5% in hospitals with a volume of ≥13 (P = 0.008). After adjustment for confounders, an annual volume of ≥13 was associated with less perioperative mortality compared to hospitals with a volume of < 9. CONCLUSIONS: Data from this nationwide mandatory quality registry shows a significant effect of hospital volume on perioperative mortality following complex EVAR, with high volume complex EVAR centers demonstrating lower mortality rates.

Use of thoracic stent grafts to control major iliac vein bleeding.

Major venous bleeding is a feared complication during abdominal surgery. Management usually consists of open repair or ligation, despite technically demanding surgical exposure. We present two cases of major iliac vein hemorrhage during abdominal surgery that were controlled by using thoracic stent grafts.

Outcome of Fenestrated Endovascular Aneurysm Repair in Octogenarians: A Retrospective Multicentre Analysis.

OBJECTIVE: An ageing population leads to more age related diseases, such as complex abdominal aortic aneurysms (AAA). Patients with complex AAAs and multiple comorbidities benefit from fenestrated endovascular aneurysm repair (FEVAR), but for the elderly this benefit is not completely clear. METHODS: Between 2001 and 2016 all patients treated for complex AAA by FEVAR at two tertiary referral centres were screened for inclusion. Group 1 consisted of patients aged 80 years and older and group 2 of patients younger than 80 years of age. The groups were compared for peri-operative outcome, as well as patient and re-intervention free survival, and target vessel patency during follow up. RESULTS: Group 1 consisted of 42 patients (median age 82 years; interquartile range [IQR] 81-83 years) and group 2 of 230 patients (median age 72 years; IQR 67-77 years). No differences were seen in pre-operative comorbidities, except for age and renal function. Renal function was 61.4 mL/min/1.73 m2vs.74.5 mL/min/1.73 m2 (p < .01). No differences were seen between procedures, except for a slightly longer operation time in group two. Median follow up was 26 and 32 months, respectively. No difference was seen between the groups for estimated cumulative overall survival (p = .08) at one, three, and five years, being 95%, 58%, and 42% for group 1, and 88%, 75%, and 61% for group 2, respectively. There was no difference seen between groups for the estimated cumulative re-intervention free survival (p = .95) at one, three, and five years, being 84%, 84%, and 84% in group 1, respectively, and 88%, 84%, and 82% in group 2, respectively. Ultimately, no difference was seen between groups for the estimated cumulative target vessel patency (p = .56) at one, three, and five years, being 100%, 100%, and 90% for group 1, and 96%, 93% and 92% for group 2, respectively. CONCLUSION: Age itself is not a reason to withhold FEVAR in the elderly, and choice of treatment should be based on the patient's comorbidities and preferences.

Diagnostic algorithms and treatment strategies in primary aortic and aortic graft infections.

Aortic infections and aortic graft infections are one of the most dreadful clinical entities that a vascular surgeon can face. Clinical presentation of the patient can vary greatly and diagnosis can be difficult to make. In this manuscript, diagnostic modalities are reviewed and a diagnostic algorithm suggested. Further, results of present treatment options are evaluated and treatment strategies for different clinical scenarios suggested.

Coagulation on endothelial cells: the underexposed part of Virchow's Triad.

The process of thrombin generation involves numerous plasma proteases and cofactors. Interaction with the vessel wall, in particular endothelial cells (ECs), influences this process but data on this interaction is limited. We evaluated thrombin generation on EA.hy926, human coronary arterial ECs (HCAECs) and patient-derived human venous ECs (HVECs) by means of a modified calibrated automated thrombogram (CAT) method and especially looked into contribution of the intrinsic and extrinsic pathways. Thrombin generation was measured in presence of confluent ECs with normal pooled and factor XII-deficient (FXII-deficient) platelet-poor plasma, with/without active site inhibited factor VIIa (ASIS) to block the extrinsic pathway and corn trypsin inhibitor for blocking contact activation (intrinsic pathway). Fetal bovine serum (FBS) was removed from culture conditions as FXIIa from the serum retained on ECs apparently, thereby inducing strong contact activation. In serum-free conditions, EA.hy926 and patient-derived HVECs induced thrombin generation mainly via the contact activation pathway with minor influence of ASIS on peak height and very low thrombin generation curves in FXII-deficient plasma. HVECs derived from coronary arterial bypass graft (CABG) patients showed increased thrombin generation compared to control patients, which could be ascribed to increased contact activation. Contribution of the extrinsic pathway on patient-derived ECs was limited. We conclude that the CAT method in combination with serum-free cultured ECs offers a valuable high-throughput method to evaluate endothelial influences on thrombin generation, which appears to involve predominantly contact activation on ECs. Contact activation-mediated thrombin generation was increased on ECs from CABG patients compared to controls.

Use of the reversed Zenith iliac limb extension in the treatment of iliac artery aneurysms and various aortoiliac pathologies: outcome in midterm follow-up.

PURPOSE: To report the midterm follow-up after treatment of various aortoiliac pathologies in an acute setting using reversed Zenith iliac limb extensions when appropriately sized stent-grafts were not available. METHODS: From 2005 to 2007, 12 patients (10 men; mean age 71.5 ± 7.3 years) were treated with reversed Zenith iliac limb extensions for solitary iliac artery aneurysms (n = 8), an abdominal aortic aneurysm (AAA) in a small caliber aorta (n = 1), an anastomotic pseudoaneurysm in an aortobi-iliac graft (n = 1), a hypogastric artery aneurysm (n = 1), and a ruptured AAA secondary to a late type Ib endoleak after Talent stent-graft implantation (n = 1). The Zenith iliac limb extensions were deployed on the back table and reloaded in a reversed manner to treat aneurysms and other lesions with a broad range of different diameter necks and landing zones. RESULTS: The technical success rate was 100%, and no endoleaks were present at the end of the procedures. The endoleak patient with the ruptured AAA died owing to respiratory insufficiency. The other 11 patients have a mean follow-up of 29±9 months. In this period, 2 patients received a femorofemoral crossover bypass because of an occluded iliac limb extension. One patient had a type II endoleak without growth of the iliac aneurysm. Two patients died of a ruptured 4.4-cm AAA at 16 months and of respiratory insufficiency due to metastases at 47 months, respectively. CONCLUSION: When necessary, it is feasible to use a revered Zenith limb extension to treat solitary iliac aneurysms and other aortoiliac pathologies, achieving satisfactory midterm outcomes.

Collective experience with hybrid procedures for suprarenal and thoracoabdominal aneurysms.

Not every patient is fit for open thoracoabdominal aortic aneurysm (TAAA) repair, nor is every TAAA or juxtarenal abdominal aortic aneurysm suitable for branched or fenestrated endovascular exclusion. The hybrid procedure consists of debranching of the renal and visceral arteries followed by endovascular exclusion of the aneurysm and might be an alternative in these patients. Between May 2004 and March 2006, 16 patients were treated with a hybrid procedure. The indications were recurrent suprarenal or thoracoabdominal aneurysms after previous abdominal and/or thoracic aortic surgery (n = 8), type I to III TAAAs (n = 3), proximal type I endoleak after endovascular repair (n = 2), penetrating ulcer of the juxtarenal aorta (n = 1), visceral patch aneurysm after type IV open repair (n = 1), and primary suprarenal aneurysm (n = 1). Eight (50%) of 16 patients were judged to be unfit for open TAAA repair. The hospital mortality rate was 31% (5 of 16). Four of five deceased patients were unfit for thoracophrenic laparotomy. Two patients died from cardiac complications and three from visceral ischemia. No spinal cord ischemia was detected, and temporary renal failure occurred in four patients (25%). The mean follow-up was 13 months (range 6-28 months). During follow-up, no additional grafts occluded and no patients died. Hybrid procedures are technically feasible but have substantial mortality (31%), especially in patients unfit for open repair (80%). They might be indicated when urgent TAAA surgery is required or when vascular anatomy is unfavorable for fenestrated endografts in patients with extensive previous open aortic surgery.

Surgical correction of failed thoracic endovascular aortic repair.

OBJECTIVE: The number of thoracic aortic endovascular procedures is increasing rapidly, and the clinical outcome largely depends on the underlying aortic pathology. When primary stent grafting is unsuccessful, secondary endovascular solutions are most often feasible. However, in recurrent endovascular failure without further minimally invasive options, conservative treatments or conversion to open surgery are the only remaining therapeutic strategies. METHODS: In our experience, 106 patients received thoracic aortic endovascular treatment. Five of these patients and three from other centers underwent conversion to open repair because of 4 type Ia endoleaks (3 thoracic aortic aneurysms, 1 traumatic rupture), 2 retrograde type A dissections, 1 type Ib endoleak with contained rupture, and 1 secondary false aneurysm rupture due to stent graft migration. The latter four were surgical emergencies; the other four were urgent or elective procedures. Three patients underwent supracoronary arch replacement through sternotomy. One patient had arch and proximal descending aortic replacement, three had hemiarch and descending aortic replacement, and one had descending aortic replacement through left thoracotomy. Five stent grafts were totally removed, and three endografts were left in situ. All conversions were performed according to a protocol including total extracorporeal circulation (n = 7) or left heart bypass (n = 1), cerebrospinal fluid drainage and monitoring motor-evoked potentials, transcranial Doppler, and electroencephalography. RESULTS: All patients survived the surgical procedure. Six patients had an uneventful postoperative course, whereas necrotic cholecystitis developed in one patient who required cholecystectomy and prolonged intensive care stay. One polytrauma patient died from secondary rupture due to prosthesis infection 24 days after stent graft explantation. No stroke, paraplegia, renal failure, or other major complication occurred. With a mean follow-up of 14 months (range, 4-71 months), seven patients are alive without any sign of recurrent aortic problems. CONCLUSION: Failure of thoracic endovascular aortic repair comprises a new aortic pathology. Secondary endovascular treatment is feasible in most patients; however, some patients will require open surgery to repair failures of thoracic endovascular aortic treatment. These procedures constitute a large surgical trauma and require an extensive protocol, including extracorporeal circulation, neuromonitoring, and adjunctive modalities to provide organ protection. We recommend that these procedures be performed in centers with experience and the infrastructure to offer these protective measures.

Assessment of spinal cord integrity during thoracoabdominal aortic aneurysm repair.

BACKGROUND: Monitoring motor-evoked potentials (MEPs) is an accurate technique to assess spinal cord integrity during thoracoabdominal aortic aneurysm (TAAA) repair, guiding surgical strategies to prevent paraplegia. METHODS: In 210 consecutive patients with type I (n = 75), type II (n = 103), and type III (n = 32) TAAA surgical repair was performed using left heart bypass, cerebrospinal fluid drainage, and MEPs monitoring. RESULTS: Reliable MEPs were registered in all patients. The median total number of patent intercostal and lumbar arteries was five. After proximal aortic crossclamping, MEP decreased below 25% of base line in 72 patients (34%) indicating critical spinal cord ischemia, which could be corrected by increasing distal aortic pressure. By using sequential clamping it appeared that in 43% of type I and II cases spinal cord circulation was supplied between T5 and L1, and 57% between L1 and L5. In type II and III cases cord perfusion was dependent upon lower lumbar arteries in 16% and pelvic circulation in 8%, necessitating reattachment of these segmental arteries. In 9% of patients critical ischemic MEP changes occurred without visible arteries, requiring aortic endarterectomy and selective grafting. One patient suffered early paraplegia and 2 delayed, and 2 patients had temporary neurologic deficit (5 of 210; 2.4%). CONCLUSIONS: In patients with TAAA, blood supply to the spinal cord depends upon a highly variable collateral system. Monitoring MEPs is an accurate technique for detecting cord ischemia, guiding surgical tactics to reduce neurologic deficit (2.4%).