Dittmar Böckler

Inhibition of IL-17A Attenuates Atherosclerotic Lesion Development in ApoE-Deficient Mice

The importance of an (auto)immune response in atherogenesis is becoming increasingly well understood. IL-17A-expressing T cells modulate immune cell trafficking, initiating inflammation and cytokine production in (auto)immune diseases. In human carotid artery plaques, we previously showed the presence of IL-17A-producing T cells and IL-23; however, IL-17A effects on atherogenesis have not been studied. Aortic root sections from 8-wk-old apolipoprotein E-deficient mice fed a standard chow diet were examined after 12 wk for lesion area, plaque composition, cellular infiltration, cytokine expression, and apoptosis. The treatment group (n = 15) received anti-IL-17A Ab and the controls (n = 10) received irrelevant Abs. Inhibition of IL-17A markedly reduced atherosclerotic lesion area (p < 0.001), maximal stenosis (p < 0.001), and vulnerability of the lesion. IL-17A mAb-treated mice showed reduced cellular infiltration, down-regulation of activation markers on endothelium and immune cells (e.g., VCAM-1), and reduced cytokine/chemokine secretion (e.g., IL6, TNFα, CCL5). To investigate possible mechanisms, different atherogenic cell types (e.g., macrophages, dendritic cells, HUVECs, vascular smooth muscle cells) were stimulated with IL-17A in addition to TNF-α, IFN-γ, or LPS to induce cellular activation or apoptosis in vitro. Stimulation with IL-17A induced proinflammatory changes in several atherogenic cell types and apoptotic cell death in murine cells. Functional blockade of IL-17A reduces atherosclerotic lesion development and decreases plaque vulnerability, cellular infiltration, and tissue activation in apolipoprotein E-deficient mice. The present data support a pathogenic role of IL-17A in the development of atherosclerosis by way of its widespread proinflammatory and proapoptotic effects on atherogenic cells.

Hybrid procedures for thoracoabdominal aortic aneurysms and chronic aortic dissections – A single center experience in 28 patients

OBJECTIVE We report our 6-year experience with the visceral hybrid procedure for high-risk patients with thoracoabdominal aortic aneurysms (TAAA) and chronic expanding aortic dissections (CEAD). METHODS Hybrid procedure includes debranching of the visceral and renal arteries followed by endovascular exclusion of the aneurysm. A series of 28 patients (20 male, mean age 66 years) were treated between January 2001 and July 2007. Sixteen patients had TAAAs type I-III, one type IV, four thoracoabdominal placque ruptures, and seven patients CEAD. Patients were treated for asymptomatic, symptomatic, and ruptured aortic pathologies in 20, and 4 patients, respectively. Two patients had Marfans syndrome; 61% had previous infrarenal aortic surgery. The infrarenal aorta was the distal landing zone in 70%. In elective cases, simultaneous approach (n = 9, group I) and staged approach (n = 11, group II) were performed. Mean follow-up is 22 months (range 0.1-78). RESULTS Primary technical success was achieved in 89%. All stent grafts were implanted in the entire thoracoabdominal aorta. Additionally, three patients had previous complete arch vessel revascularization. Left subclavian artery was intentionally covered in three patients (11%). Thirty-day mortality rate was 14.3% (4/28). One patient had a rupture before the staged endovascular procedure and died. Overall survival rate at 3 years was 70%, in group I 80%, and in group II 60% (P = .234). Type I endoleak rate was 8%. Permanent paraplegia rate was 11%. Three patients required long-term dialysis (11%). Peripheral graft occlusion rate was 11% at 30 days. Gut infarction with consecutive bowel resection occurred in two patients. There was no significant difference between group I and II regarding paraplegia and complications. CONCLUSIONS Early results of visceral hybrid repair for high-risk patients with complex and extended TAAAs and CEADs are encouraging in a selected group of high risk patients in whom open repair is hazardous and branched endografts are not yet optional.

Short and midterm results after left subclavian artery coverage during endovascular repair of the thoracic aorta

BACKGROUND To analyze the sequelae of the intentional left subclavian artery (LSA) coverage during thoracic endovascular aortic repair (TEVAR). METHODS Retrospective analysis of prospectively collected data in a single center. Between March 1997 and October 2008, 88 of 220 patients (40%) had thoracic aortic lesions that required LSA coverage during TEVAR. Thirty-four of our patients (39%) were treated under urgent or emergent conditions for acute pathologies. The proximal landing zone was zone 0 in 10 patients (11%), zone 1 in 24 patients (27%), and zone 2 in 54 patients (61%). Debranching procedures of the supra-aortic vessels were performed in patients who were to undergo zone 0 or zone 1 deployment. Primary LSA revascularization was performed in 22 of the 88 patients (25%) at a median of 6 days before TEVAR. Median follow-up was 26.4 months (1-98 months). RESULTS Technical success was achieved in 97%. Five primary (9%) and two secondary (4%) type Ia endoleaks in patients who underwent zone 2 deployment were observed and required further interventions. Fourteen (16%) primary type II endoleaks were observed; 10 of them fed by the LSA. Paraplegia rate was lower in patients with LSA coverage without revascularization than in other patients (1.5% vs 1.9%; odds ratio [OR], 0.774; 95% confidence interval [CI], 0.038-6.173; P = 1.000). Prior or concomitant infrarenal aortic replacement (P = .0019), renal insufficiency (glomerular filtration rate < 90 mL/min/1.73 m(2)) (P = .0024) and long segment aortic coverage (>200 mm) (P = .0157) were associated with significant higher risk of postoperative paraplegia. Stroke rate was lower in patients with LSA coverage without revascularization than in other patients (3% vs 3.9%; OR, 0.570; 95% CI, 0.118-2.761; P = .7269). Two patients (3%) developed left upper extremity symptoms and another two patients (3%) subclavian steal syndrome and required secondary LSA revascularization. The technical success rate for LSA revascularization was 94%. CONCLUSION By using a selective approach to the LSA revascularization, coverage of the LSA can be used to extend the proximal seal zone for TEVAR without increasing the risk of spinal cord ischemia or stroke. Indications for revascularization include long segment aortic coverage, prior or concomitant infrarenal aortic replacement, and renal insufficiency. In addition, a hypoplastic right vertebral artery, a patent left internal mammary artery graft, and a functioning dialysis fistula in the left arm would also be indications to perform revascularization.

CXCL4 Downregulates the Atheroprotective Hemoglobin Receptor CD163 in Human Macrophages

Rationale: CXCL4 is a platelet-derived chemokine that promotes macrophage differentiation from monocytes. Deletion of the PF4 gene that encodes CXCL4 reduces atherosclerotic lesions in ApoE−/− mice. Objective: We sought to study effects of CXCL4 on macrophage differentiation with possible relevance for atherogenesis. Methods and Results: Flow cytometry for expression of surface markers in macrophage colony–stimulating factor (M-CSF)– and CXCL4-induced macrophages demonstrated virtually complete absence of the hemoglobin scavenger receptor CD163 in CXCL4-induced macrophages. mRNA for CD163 was downregulated as early as 2 hours after CXCL4. CD163 protein reached a minimum after 3 days, which was not reversed by treatment of cells with M-CSF. The CXCL4 effect was entirely neutralized by heparin, which bound CXCL4 and prevented CXCL4 surface binding to monocytes. Pretreatment of cells with chlorate, which inhibits glycosaminoglycan synthesis, strongly inhibited CXCL4-dependent downregulation of CD163. Similar to recombinant CXCL4, releasate from human platelets also reduced CD163 expression. CXCL4-differentiated macrophages were unable to upregulate the atheroprotective enzyme heme oxygenase-1 at the RNA and protein level in response to hemoglobin–haptoglobin complexes. Immunofluorescence of human atherosclerotic plaques demonstrated presence of both CD68+CD163+ and CD68+CD163− macrophages. PF4 and CD163 gene expression within human atherosclerotic lesions were inversely correlated, supporting the in vivo relevance of CXCL4-induced downregulation of CD163. Conclusions: CXCL4 may promote atherogenesis by suppressing CD163 in macrophages, which are then unable to upregulate the atheroprotective enzyme heme oxygenase-1 in response to hemoglobin.

Endovascular Repair of Acute Uncomplicated Aortic Type B Dissection Promotes Aortic Remodelling: 1 Year Results of the ADSORB Trial

OBJECTIVES Uncomplicated acute type B aortic dissection (AD) treated conservatively has a 10% 30-day mortality and up to 25% need intervention within 4 years. In complicated AD, stent grafts have been encouraging. The aim of the present prospective randomised trial was to compare best medical treatment (BMT) with BMT and Gore TAG stent graft in patients with uncomplicated AD. The primary endpoint was a combination of incomplete/no false lumen thrombosis, aortic dilatation, or aortic rupture at 1 year. METHODS The AD history had to be less than 14 days, and exclusion criteria were rupture, impending rupture, malperfusion. Of the 61 patients randomised, 80% were DeBakey type IIIB. RESULTS Thirty-one patients were randomised to the BMT group and 30 to the BMT+TAG group. Mean age was 63 years for both groups. The left subclavian artery was completely covered in 47% and in part in 17% of the cases. During the first 30 days, no deaths occurred in either group, but there were three crossovers from the BMT to the BMT+TAG group, all due to progression of disease within 1 week. There were two withdrawals from the BMT+TAG group. At the 1-year follow up there had been another two failures in the BMT group: one malperfusion and one aneurysm formation (p = .056 for all). One death occurred in the BMT+TAG group. For the overall endpoint BMT+TAG was significantly different from BMT only (p < .001). Incomplete false lumen thrombosis, was found in 13 (43%) of the TAG+BMT group and 30 (97%) of the BMT group (p < .001). The false lumen reduced in size in the BMT+TAG group (p < .001) whereas in the BMT group it increased. The true lumen increased in the BMT+TAG (p < .001) whereas in the BMT group it remained unchanged. The overall transverse diameter was the same at the beginning and after 1 year in the BMT group (42.1 mm), but in the BMT+TAG it decreased (38.8 mm; p = .062). CONCLUSIONS Uncomplicated AD can be safely treated with the Gore TAG device. Remodelling with thrombosis of the false lumen and reduction of its diameter is induced by the stent graft, but long term results are needed.

Multicenter Nellix EndoVascular Aneurysm Sealing system experience in aneurysm sac sealing

OBJECTIVE Despite improvements in endograft devices, operator technique, and patient selection, endovascular repair has not achieved the long-term durability of open surgical aneurysm repair. Persistent or recurrent aneurysm sac flow from failed proximal sealing, component failure, or branch vessel flow underpins a significant rate of reintervention after endovascular repair. The Nellix device (Endologix, Irvine, Calif) employs a unique design with deployment of polymer-filled EndoBags surrounding the endograft flow lumens, sealing the aneurysm sac space and potentially reducing complications from persistent sac flow. This retrospective analysis represents the initial experience in consecutive patients treated with the device in real-world practice. METHODS This study was performed at six clinical centers in Europe and one in New Zealand during the initial period after commercialization of the Nellix device. Patients underwent evaluation with computed tomography and other imaging modalities following local standards of care. Patients were selected for treatment with Nellix and treated by each institution according to its endovascular repair protocol. Clinical and imaging end points included technical success (successful device deployment and absence of any endoleak at completion angiography), freedom from all-cause and aneurysm-related mortality, endoleak by type, limb occlusion, aneurysm rupture, and reintervention. RESULTS During a 17-month period, 171 patients with abdominal aortic aneurysms were treated with the Nellix device and observed for a median of 5 months (range, 0-14 months). The 153 male and 18 female patients with mean age of 74 ± 7 years had aneurysms 61 ± 9 mm in diameter with an average infrarenal neck length of 28 ± 15 mm and infrarenal angulation of 37 ± 22 degrees. Technical success was achieved in all but two patients (99%); one patient had a type Ib endoleak and another had a type II endoleak. Through the last available follow-up, type Ia endoleak was observed in five patients (3%), type Ib endoleak in four patients (2%), and type II endoleak in four patients (2%). There were eight limb occlusions (5%), among which seven were evident at the 1-month follow-up visit. Aneurysm-related reinterventions were performed in 15 patients (9%). There were no aneurysm ruptures or open surgical conversions. CONCLUSIONS This first multicenter postmarket report of the Nellix device for infrarenal abdominal aortic aneurysm repair demonstrates satisfactory results during the initial learning phase of this new technology. The rate of aneurysm exclusion was high, and frequency of complications was low. More definitive conclusions on the value of this novel device await the results of the ongoing Nellix EVAS FORWARD Global Registry and the EVAS FORWARD investigational device exemption trial.

Complications after aortic arch hybrid repair

OBJECTIVES To analyze early and midterm complications after hybrid aortic arch repair (HAR). METHODS Between January 1997 and November 2009 among 259 patients receiving thoracic endovascular aortic repair, HAR has been performed in 47 patients (median age, 64.5 years; range, 41-84). A retrospective analysis was performed. Complete supra-aortic debranching was performed in 15 patients (32%) and partial debranching in 23 patients (49%). Isolated left subclavian artery revascularization prior to thoracic endovascular aortic repair has been used in nine patients (19%). Emergency procedures were performed in 34% of all patients. RESULTS The overall in-hospital mortality was 19% (9/47 patients), 27% after complete and 15.6% after partial debranching. Postoperative complications occurred in 32 patients (68%). Cardiocirculatory complications were observed in seven patients (15%). Pulmonary complications occurred in 12 patients (26%). A total of five patients (11%) experienced renal complications requiring hemodialysis. The stroke rate was 6.3%. Paraplegia was seen in three patients (6%). Proximal type I endoleaks were observed in seven patients. Retrograde aortic arch dissection was seen in three patients (6.3%). Cox proportional hazard regression showed the necessity for an emergency procedure as an independent predictor of death (hazard ratio, 2.9; 95% confidence interval, 1.1-7.5; P = .023). The reintervention rate was 27.6% with three patients requiring open conversion. CONCLUSIONS Hybrid aortic arch repair in high-risk patients is associated with a relevant morbidity, mortality, and reintervention rate. Patient selection is crucial and indication should be limited to patients not suitable for conventional aortic arch repair or emergency cases at present. Therefore, we recommend performing HAR only in high-volume centers with cardiovascular surgical cooperation.

Endovascular aortic arch reconstruction with supra-aortic transposition for symptomatic contained rupture and dissection: early experience in 8 high-risk patients.

Purpose: To report our initial experience with total and subtotal endovascular aortic arch reconstruction combined with supra-aortic vessel transposition in high-risk patients and to present a new morphological classification of thoracic aortic lesions for patient and procedure selection. Methods: Among 80 patients treated with thoracic stent-grafts at our department between 1997 and 2003, 8 patients (6 men; mean age 71 years, range 45–81) unfit for open repair were not candidates for standard endovascular repair due to inadequate proximal landing zones on the aortic arch. Commercially available endografts (Excluder, Zenith, Endofit, Talent) were used to repair the arch after supra-aortic vessel transposition was performed. The endograft was implanted transfemorally or via an iliac Dacron conduit graft with standardized endovascular techniques and deployed during intravenous adenosine-induced asystole. The imaging data from all thoracic endograft patients was analyzed to classify thoracic and thoracoabdominal lesions according to a 4-level anatomical system. Results: Deployment success was 100% after staged supra-aortic vessel transposition, but 1 patient died of endograft-related rupture of the proximal aortic arch. There was no neurological complication. Mean follow-up was 16 months (range 1–36). Patency of all endografts and conventional bypasses was 100%, and no migration was observed. One minor type II endoleak was demonstrated. Conclusions: Initial results are encouraging for endovascular aortic arch repair in combination with supra-aortic transposition in selected high-risk patients with complex aortic pathologies.

Early Results from the ENGAGE Registry: Real-world Performance of the Endurant Stent Graft for Endovascular AAA Repair in 1262 Patients

OBJECTIVE The ENGAGE registry was undertaken to examine the real-world outcome after endovascular abdominal aortic aneurysm (AAA) repair (EVAR) with the Endurant Stent Graft in a large, contemporary, global series of patients. METHODS From March 2009 to April 2011, 1262 AAA patients (89.6% men; mean age 73.1 years, range 43-93 years) were enrolled from 79 sites in 30 countries and treated with Endurant. Results are described following the reporting standards for EVAR. Follow-up data were tabulated for all 1262 patients at a 30-day follow-up and for the first 500 patients at a 1-year follow-up. RESULTS Intra-operative technical success was achieved in 99.0% of cases. Within 30 days, adverse events were reported in 3.9% of patients, including a 1.3% mortality rate. Type-I or -III endoleaks were identified in 1.5% of cases. Estimated overall survival, aneurysm-related survival and freedom from secondary interventions at 1 year were 91.6%, 98.6% and 95.1%, respectively. At 1 year, aneurysm size increased ≥ 5 mm in 2.8% and decreased ≥ 5 mm in 41.3% of cases. CONCLUSION Early results from this real world, global experience are promising and indicate that endovascular AAA repair with the Endurant Stent Graft is safe and effective across different geographies and standards of practice. Longer-term follow-up is necessary to assess durability of these results.

Surgical Therapy of Extracranial Carotid Artery Aneurysms: Long-Term Results over a 24-Year Period

BACKGROUND To evaluate long-term results of surgical therapy of extracranial carotid artery aneurysms (ECCA) and to provide a morphologic classification for individual surgical reconstruction techniques. PATIENT AND METHODS This retrospective analysis includes 57 patients (43 male, mean age 61.9 years.) with 64 carotid reconstructions for ECCA between 1980 and 2004. In 29 (50.9%) of the patients there was found a cerebral ischemic event as an initial symptom (18 transient ischemic attacks, 11 strokes). In patients without cerebral events, the presenting symptom was pulsatile cervical mass in 19 and cranial nerve dysfunction in 3 cases. ECCA was morphologically stratified in Type I=isolated aneurysms of the internal carotid artery (n=25), Type II=aneurysms of the complete internal carotid artery with involvement of the bifurcation (n=8), Type III=aneurysms of the carotid bifurcation (n=20), Type IV=combined aneurysm of the internal and common carotid artery (n=5) and Type V=isolated aneurysm of the common carotid artery (n=6). RESULTS Perioperative stroke rate was 1.6%. 4 patients suffered from transient ischemic attacks (6.3%). Permanent and transient cranial nerve injury rate was 6.3% and 20.3% respectively. After 5, 10, 15 and 20 years the actuarial survival was 90%, 77%, 65% and 57%. The ipsilateral stroke-free time was 96%, 96%, 93% and 87%, respectively. CONCLUSIONS Surgical reconstruction of extracranial carotid aneurysms is a safe procedure with good long-term results. The risk of a permanent, perioperative cerebral neurological deficit is low, but there is a considerable risk of cranial nerve injury.