Jean-Paul P.M. de Vries

Time-Dependent Changes in Atherosclerotic Plaque Composition in Patients Undergoing Carotid Surgery

Background— Time-dependent trends in the incidence of cardiovascular disease have been reported in high-income countries. Because atherosclerosis underlies the majority of cardiovascular diseases, we investigated temporal changes in the composition of atherosclerotic plaques removed from patients undergoing carotid endarterectomy. Methods and Results— The Athero-Express study is an ongoing, longitudinal, vascular biobank study that includes the collection of atherosclerotic plaques of patients undergoing primary carotid endarterectomy in the province of Utrecht from 2002 to 2011. Histopathologic features of plaques of 1583 patients were analyzed in intervals of 2 years. The analysis included quantification of collagen, calcifications, lipid cores, plaque thrombosis, macrophages, smooth muscle cells, and microvessels. Large atheroma, plaque thrombosis, macrophages, and calcifications were less frequently observed over time, with adjusted odds ratios of 0.72 (95% confidence interval, 0.650-0.789), 0.62 (95% confidence interval, 0.569-0.679), 0.87 (95% confidence interval, 0.800-0.940), and 0.75 (95% confidence interval, 0.692-0.816) per 2-year increase in time, respectively. These changes in plaque characteristics were consistently observed in patient subgroups presenting with stroke, transient ischemic attack, ocular symptoms, and asymptomatic patients. Concomitantly, risk factor management and secondary prevention strategies among vascular patients scheduled for carotid endarterectomy significantly improved over the past decade. Conclusions— In conclusion, over the past decade, atherosclerotic plaques harvested during carotid endarterectomy show a time-dependent change in plaque composition characterized by a decrease in features currently believed to be causal for plaque instability. This appears to go hand in hand with improvements in risk factor management.

Intraluminal abdominal aortic aneurysm thrombus is associated with disruption of wall integrity

OBJECTIVE An association of intraluminal thrombus (ILT) with abdominal aortic aneurysm (AAA) growth has been suggested. Previous in vitro experiments have demonstrated that aneurysm-associated thrombus may secrete proteolytic enzymes and may develop local hypoxia that might lead to the formation of tissue-damaging reactive oxygen species. In this study, we assessed the hypothesis that ventral ILT thickness is associated with markers of proteolysis and with lipid oxidation in the underlying AAA vessel wall. METHODS Ventral AAA tissue was collected from asymptomatic patients at the site of maximal diameter during open aneurysm repair. Segments were divided, one part for biochemical measurements and one for histologic analyses. We measured total cathepsin B, cathepsin S levels, and matrix metalloproteinase (MMP)-2 and MMP-9 activity. Myeloperoxidase and thiobarbituric acid reactive substances were determined as measures of lipid oxidation. Histologic segments were analyzed semiquantitatively for the presence of collagen, elastin, vascular smooth muscle cells (VSMCs), and inflammatory cells. Preoperative computed tomography angiography scans of 83 consecutive patients were analyzed. A three-dimensional reconstruction was obtained, and a center lumen line of the aorta was constructed. Ventral ILT thickness was measured in the anteroposterior direction at the level of maximal aneurysm diameter on the orthogonal slices. RESULTS Ventral ILT thickness was positively correlated with aortic diameter (r=0.25; P=.02) and with MMP-2 levels (r=0.27; P=.02). No biochemical correlations were observed with MMP-9 activity or cathepsin B and S expression. No correlation between ventral ILT thickness and myeloperoxidase or thiobarbituric acid reactive substances was observed. Ventral ILT thickness was negatively correlated with VSMCs (no staining, 18.5 [interquartile range, 12.0-25.5] mm; minor, 17.6 [10.7-22.1] mm; moderate, 14.5 [4.6-21.7] mm; and heavy, 8.0 [0.0-12.3] mm, respectively; P=.01) and the amount of elastin (no staining, 18.6 [12.2-30.0] mm; minor, 16.5 [9.0-22.1] mm; moderate, 11.7 [2.5-15.3] mm; and heavy 7.7 [0.0-7.7] mm, respectively; P=.01) in the medial aortic layer. CONCLUSIONS ILT thickness appeared to be associated with VSMCs apoptosis and elastin degradation and was positively associated with MMP-2 concentrations in the underlying wall. This suggests that ILT thickness affects AAA wall stability and might contribute to AAA growth and rupture. ILT thickness was not correlated with markers of lipid oxidation.

Outcome-based anatomic criteria for defining the hostile aortic neck

OBJECTIVE There is abundant evidence linking hostile proximal aortic neck anatomy to poor outcome after endovascular aortic aneurysm repair (EVAR), yet the definition of hostile anatomy varies from study to study. This current analysis was undertaken to identify anatomic criteria that are most predictive of success or failure at the aortic neck after EVAR. METHODS The study group comprised 221 patients in the Aneurysm Treatment using the Heli-FX Aortic Securement System Global Registry (ANCHOR) clinical trial, a population enriched with patients with challenging aortic neck anatomy and failure of sealing. Imaging protocols were not protocol specified but were performed according to the institutions standard of care. Core laboratory analysis assessed the three-dimensional centerline-reformatted computed tomography scans. Failure at the aortic neck was defined by type Ia endoleak occurring at the time of the initial endograft implantation or during follow-up. Receiver operating characteristic curve analysis was used to assess the value of each anatomic measure in the classification of aortic neck success and failure and to identify optimal thresholds of discrimination. Binary logistic regression was performed after excluding highly intercorrelated variables, creating a final model with significant predictors of outcome after EVAR. RESULTS Among the 221 patients, 121 (54.8%) remained free of type Ia endoleak and 100 (45.2%) did not. Type Ia endoleaks presented immediately after endograft deployment in 58 (58.0%) or during follow-up in 42 (42.0%). Receiver operating characteristic curve analysis identified 12 variables where the classification of patients with type Ia endoleak was significantly more accurate than chance alone. Increased aortic neck diameter at the lowest renal artery (P = .013) and at 5 mm (P = .008), 10 mm (P = .008), and 15 mm (P = .010) distally; aneurysm sac diameter (P = .001), common iliac artery diameters (right, P = .012; left, P = .032), and a conical (P = .049) neck configuration were predictive of endoleak. By contrast, increased aortic neck length (P = .050), a funnel-shaped aortic neck (P = .036), and neck mural thrombus content, as measured by average thickness (P = .044) or degrees of circumferential coverage (P = .029), were protective against endoleak. Binary logistic regression identified three variables independently predictive of type Ia endoleak. Neck diameter at the lowest renal artery (P = .002, cutpoint 26 mm) and neck length (P = .017, cutpoint 17 mm) were associated with endoleak, whereas some mural neck thrombus content was protective (P = .001, cutpoint 11° of circumferential coverage). CONCLUSIONS A limited number of independent anatomic variables are predictive of type Ia endoleak after EVAR, including aortic neck diameter and aortic neck length, whereas mural thrombus in the neck is protective. This study suggests that anatomic measures with identifiable threshold cutpoints should be considered when defining the hostile aortic neck and assessing the risk of complications after EVAR.

The durability of endovascular repair of para-anastomotic aneurysms after previous open aortic reconstruction

INTRODUCTION Anastomotic pseudoaneurysms and true para-anastomotic aneurysms after initial open abdominal aortic prosthetic reconstruction often need reintervention because they are at risk for rupture. However, open surgical reinterventions are technically challenging procedures with high mortality and morbidity rates. In the present multicenter study, we describe the long-term clinical course in an expanded number of patients who underwent endovascular repair of para-anastomotic aneurysms after previous open reconstruction. METHODS The study included all patients who were treated with an endovascular stent graft between July 1999 and July 2009 for an aortoiliac anastomotic pseudoaneurysm or a true para-anastomotic aneurysm after previous aortic prosthetic reconstruction for aneurysmal or occlusive disease in one of the four participating centers. Main outcomes were long-term complications, reinterventions and conversion rate, mortality, and hospital length of stay. RESULTS An endovascular stent graft was used to treat 58 patients (53 men; mean age, 71 ± 9 years), with 80 aortic or iliac pseudoaneurysms or true para-anastomotic aneurysm, or both. Bifurcated stent grafts were used in 32 patients, endovascular tube grafts in eight, aortouniiliac stent grafts in seven, and iliac extension grafts in 11. Stent graft deployment was successful in 55 patients, for a technical success rate of 95%. Median hospital admission was 3 days (range, 1-122 days). The 30-day and in-hospital mortality rates were 3.4% (n = 2) and 6.9% (n = 4), respectively. The 30-day clinical success rate was 91% (n = 53). Median follow-up was 41 months (range, 0-106 months). The cumulative and procedural-related mortality during follow-up was 19% (n = 11) and 10% (n = 6), respectively. Follow-up computed tomography angiography revealed nine endoleaks (three type I; six type II) in eight patients and endotension in two patients. The overall reintervention and conversion rate during follow-up was 26.9% (n = 15) and 6.9% (n = 4), respectively. Life-table analysis showed reduced freedom from reintervention for aortouniiliac and tube stent grafts. Type I endoleaks were observed in 25% of patients with endovascular aortic tube grafts for proximal anastomotic aneurysms. CONCLUSIONS The present study demonstrates that endovascular repair of para-anastomotic aortic and iliac aneurysms after initial prosthetic aortic surgery is safe and durable in patients with an appropriate anatomy. The long-term follow-up showed fewer complications occurred after procedures with bifurcated stent grafts compared with procedures with tube grafts, aortouniiliac, or iliac extension stent grafts.

Primary EndoAnchoring in the Endovascular Repair of Abdominal Aortic Aneurysms With an Unfavorable Neck

Purpose To investigate the feasibility and early results of endoanchoring (endostapling) using a new commercially available device as an adjunctive procedure during endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAAs) with an unfavorable proximal neck. Methods Between June 2010 and May 2012, 13 consecutive patients (all men; median age 73 years, range 62–82) were prospectively enrolled in a 2-center registry to follow outcomes of adjunctive primary endoanchoring (Aptus HeliFX Aortic Securement System) of the proximal endograft to enhance proximal graft fixation and sealing during EVAR. Indications for proximal neck endoanchoring included at least one of the following: neck angulation 45° to 90°, length 8 to 15 mm, diameter 29 to 33 mm, conical neck configuration, or an irregularly shaped neck. The median AAA diameter was 56 mm (range 50–98). The Endurant stent-graft was implanted in 4 patients and the Zenith device in 9. Results A median of 4 endoanchors were implanted per patient (range 3–10) in adjunctive procedures that required a median 12 minutes (range 7–20). Intraoperatively, 2 proximal type I endoleaks were present following endoanchor implantation (85% primary technical success); a cuff was deployed in 1 case, which successfully sealed the endoleak (92% assisted primary technical success). The second proximal type I endoleak was minute and sealed spontaneously within 30 days. No further major device-related complications occurred intraoperatively. In the 30-day perioperative period, the only procedure-related complications were 2 type II endoleaks, which required no intervention. Over a median follow-up of 7 months (range 2–17), no further complications occurred apart from an asymptomatic internal iliac artery occlusion and a non-lethal myocardial infarction at 9 months. The type II endoleaks spontaneously sealed. No endograft migration was noticed nor loss of endoanchor integrity. No deaths occurred throughout follow-up. Conclusion Primary endoanchoring using the HeliFX aortic securement system is feasible, and early results were promising in this series.

Age and coumarin-type anticoagulation are associated with the occurrence of intraplaque hemorrhage, while statins are associated less with intraplaque hemorrhage: a large histopathological study in carotid and femoral plaques.

INTRODUCTION Intraplaque hemorrhage (IPH) is an important determinant of progression and destabilization of atherosclerotic plaque. We recently demonstrated that IPH is an independent predictor of future cardiovascular events after carotid endarterectomy. Thus far, it is unknown whether clinical patient characteristics, such as medication use, are associated with the occurrence of IPH. The purpose of this study was to examine the association of IPH with clinical patient characteristics. METHODS AND RESULTS 1070 consecutive patients who underwent a carotid (n=794) or femoral (n=276) endarterectomy were included. Endarterectomy specimens were subjected to histopathological examination. IPH was observed in 644/794 (81%) carotid and 175/276 (63%) femoral plaques. Carotid IPH was positively correlated with advanced age (69 years [IQR: 62-75] vs. 65 years [IQR: 57-73]; P=0.002) and coumarin-type anticoagulation use prior to operation (104/116 [90%] with coumarin derivatives vs. 540/678 [80%] without coumarin derivatives; P=0.01). Carotid IPH was less frequently observed in patients that used statins prior to endarterectomy (468/595 [79%] with statin vs. 176/199 [88%] without statin; P=0.002). In multivariate analysis, age, coumarin-type anticoagulation use and statin use were independently correlated with carotid IPH. No association was observed between femoral IPH and clinical patient characteristics. CONCLUSION Advanced age and coumarin-type anticoagulation use are associated with the occurrence of IPH, while statin use is associated with less IPH.

Different stages of intraplaque hemorrhage are associated with different plaque phenotypes: a large histopathological study in 794 carotid and 276 femoral endarterectomy specimens.

BACKGROUND AND PURPOSE Intraplaque hemorrhage (IPH) is an important determinant of progression and destabilization of atherosclerotic plaque. We recently demonstrated that IPH is an independent predictor of cardiovascular events. IPH has become more clinically relevant since magnetic resonance imaging (MRI) technique is able to visualize IPH in vivo. Different stages of IPH have been described. However, etiology of the different stages is not known and it is unclear if these detected different stages are all associated with the vulnerable plaque phenotype. METHODS AND RESULTS 1070 patients who underwent a carotid (n=794) or femoral (n=276) endarterectomy were included. Histopathological presence of IPH was determined and divided into 3 types: recent, organized and amorphous IPH. Carotid IPH was observed in 644/794 (81%) plaques, divided into 14 (2%) recent, 70 (11%) organized and 560 (87%) amorphous. Femoral IPH was observed in 175/276 (63%) plaques, divided into 2 (1%) recent, 89 (51%) organized and 84 amorphous (48%). Overall presence of carotid IPH was associated with a large lipid core, no or minor staining of smooth muscle cells, no or minor calcification and high microvessel density. Overall presence of femoral IPH was associated with moderate to heavy staining of macrophages. Plaques with organized IPHs revealed more macrophages, a larger lipid core, less smooth muscle cells, less calcification and higher microvessel density than plaques with amorphous IPHs. CONCLUSIONS IPH is a significant characteristic of carotid and femoral atherosclerotic plaque and can be classified into different types. Organized IPH is associated with unstable and amorphous IPH with stable plaque characteristics.

Contrast-induced acute kidney injury and clinical outcomes after intra-arterial and intravenous contrast administration: risk comparison adjusted for patient characteristics by design.

BACKGROUND Direct comparisons between risk of contrast induced acute kidney injury (CI-AKI) after intra-arterial versus intravenous contrast administration are scarce. We estimated and compared the risk of CI-AKI and its clinical course after both modes of contrast administration in patients who underwent both. METHODS One hundred seventy patients who received both intra-arterial and intravenous contrast injections within one year between 2001 and 2010 were included. Primary outcome was occurrence of CI-AKI. Secondary outcomes were duration of hospital stay, the need for dialysis, recovery of renal function, and mortality. RESULTS The risk of CI-AKI was 24/170 (14.0%, 95% CI 9.6-20.2) after intra-arterial contrast injection versus 20/170 (11.7%, 95% CI 7.7-17.5) after intravenous contrast administration, which led to a relative risk of 1.2 (95% CI 0.7-2.1). None of the patients had a need for dialysis. Median duration of hospital stay in CI-AKI patients was 15.0 days (2.5-97.5, percentile 1-92) after intra-arterial and 15.5 days (2.5-97.5, percentile 0-38) after intravenous contrast procedures. Renal function recovered after CI-AKI in 13/24 after intra-arterial and in 10/20 patients after intravenous contrast administration. Mortality risks in CI-AKI patients were slightly higher than in non-CI-AKI patients, hazard ratios 1.6 (95% CI 0.7-3.7) for intra-arterial and 1.7 (95% CI 0.7-4.4) for intravenous contrast administration, adjusted for confounders. CONCLUSION The risk of CI-AKI, and its clinical course was similar after intra-arterial and intravenous contrast media administration, after adjustment by design for patient-related risk factors.

A randomized comparison of 1-h sodium bicarbonate hydration versus standard peri-procedural saline hydration in patients with chronic kidney disease undergoing intravenous contrast-enhanced computerized tomography

BACKGROUND Guidelines recommend saline hydration for prophylaxis of contrast-induced acute kidney injury (CI-AKI) in patients with chronic kidney disease (CKD) undergoing intravenous contrast media-enhanced CT (CE-CT). The safety and efficacy of a brief hydration protocol using sodium bicarbonate in this population is unknown. We analysed whether 1-h sodium bicarbonate hydration prior to CE-CT is non-inferior to saline hydration prior to and after CE-CT in CKD patients. METHODS We performed an open-label multicentre randomized trial. Patients were randomized to 250 mL of 1.4% sodium bicarbonate hydration prior to CE-CT or 1000 mL of 0.9% saline hydration prior to and, once again, after CE-CT. Primary outcome was the relative increase in serum creatinine 48-96 h post-CE-CT. Secondary outcomes were incidence of CI-AKI [serum creatinine increase >25%/>44 µmol/L (0.5 mg/dL)], recovery of renal function, the need for dialysis and 2-month hospital costs. RESULTS Five hundred and seventy adult CKD patients undergoing CE-CT were randomized between 2010 and 2012, of whom 548 were included in the intention-to-treat population. Mean relative serum creatinine increase was 1.2% for sodium bicarbonate and 1.5% for saline (mean difference -0.3%; 95% confidence interval -2.7 to 2.1, P-value for non-inferiority <0.0001). CI-AKI occurred in 22 patients (4.1%); 8 (3.0%) randomized to sodium bicarbonate versus 14 (5.1%) to saline (P = 0.23). Renal function recovered in 75 and 69% of CI-AKI patients, respectively (P = 0.81). No patients developed a need for dialysis. Mean hydration costs per patient were €224 for the sodium bicarbonate and €683 for the saline regime (P < 0.001). Other healthcare costs were similar. CONCLUSIONS Short hydration with sodium bicarbonate prior to CE-CT was non-inferior to peri-procedural saline hydration with respect to renal safety and may result in healthcare savings. [Netherlands Trial Register (http://www.trialregister.nl/trialreg/index.asp), Nr 2149, date of registration 23 December 2009.].

Sex Is Associated With the Presence of Atherosclerotic Plaque Hemorrhage and Modifies the Relation Between Plaque Hemorrhage and Cardiovascular Outcome

Background and Purpose— Plaque hemorrhage (PH) may lead to accelerated progression of atherosclerotic disease. The presence of local PH in the carotid plaque predicts future cardiovascular events in any vascular territory. We investigated the prevalence of local PH and the predictive value of PH for the occurrence of cardiovascular events in men and women separately. Methods— Atherosclerotic plaques from 1422 patients (969 men, 453 women) who underwent carotid endarterectomy were analyzed histologically for the presence of PH. Patients were monitored for 3 years for cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, vascular death, and vascular intervention). Results— Plaques from men showed a significantly higher prevalence of PH compared with women (67% versus 54%; P<0.001). In 1353 patients with available follow-up data, with a median duration of 2.9 years, 270 events had occurred in men (29%) and 94 in women (22%). Stratified by presence of PH, the event rate was 32% in men with PH versus 23% in men without PH, and 23% in women with PH versus 21% in women without PH. A multivariable Cox proportional hazards model found a significant interaction between sex and PH. PH was significantly associated with events in men (adjusted hazard ratio, 1.9; 95% CI, 1.2–2.8) but not in women (adjusted hazard ratio, 1.0; 95% CI, 0.6–1.7). Conclusions— Atherosclerotic carotid plaques obtained from men reveal a higher prevalence of PH compared with women. Local PH is strongly related to secondary manifestations of cardiovascular disease in men but not in women.