Mirko Menegolo

Number and Function of Endothelial Progenitor Cells as a Marker of Severity for Diabetic Vasculopathy

Objective—Peripheral arterial disease (PAD) is a threatening complication of diabetes. As endothelial progenitor cells (EPCs) are involved in neovasculogenesis and maintenance of vascular homeostasis, their impairment may have a role in the pathogenesis of diabetic vasculopathy. This study aimed to establish whether number and function of EPCs correlate with PAD severity in type 2 diabetic patients. Methods and Results—EPCs were defined by the expression of CD34, CD133 and KDR, and quantified by flow cytometry in 127 diabetic patients with and without PAD. PAD severity has been assessed as carotid atherosclerosis and clinical stage of leg atherosclerosis obliterans. Diabetic patients with PAD displayed a significant 53% reduction in circulating EPCs versus non-PAD patients, and EPC levels were negatively correlated with the degree of carotid stenosis and the stage of leg claudication. Moreover, the clonogenic and adhesion capacity of cultured EPCs were significantly lower in diabetic patients with PAD versus patients without. Conclusions—This study demonstrates that EPC decrease is related to PAD severity and that EPC function is altered in diabetic subjects with PAD, strengthening the pathogenetic role of EPC dysregulation in diabetic vasculopathy. EPC count may be considered a novel biological marker of peripheral atherosclerosis in diabetes.

Widespread Increase in Myeloid Calcifying Cells Contributes to Ectopic Vascular Calcification in Type 2 Diabetes

Rationale: Acquisition of a procalcific phenotype by resident or circulating cells is important for calcification of atherosclerotic plaques, which is common in diabetes. Objective: We aim to identify and characterize circulating calcifying cells, and to delineate a pathophysiological role for these cells in type 2 diabetes. Methods and Results: We demonstrate for the first time that a distinct subpopulation of circulating cells expressing osteocalcin and bone alkaline phosphatase (OC+BAP+) has procalcific activity in vitro and in vivo. The study of naïve patients with chronic myeloid leukemia indicated that OC+BAP+ cells have a myeloid origin. Myeloid calcifying OC+BAP+ cells (MCCs) could be differentiated from peripheral blood mononuclear cells, and generation of MCCs was closely associated with expression of the osteogenic transcription factor Runx2. In gender-mismatched bone marrow–transplanted humans, circulating MCCs had a much longer half-life compared with OC−BAP− cells, suggesting they belong to a stable cell repertoire. The percentage of MCCs was higher in peripheral blood and bone marrow of type 2 diabetic patients compared with controls but was lowered toward normal levels by optimization of glycemic control. Furthermore, diabetic carotid endoarterectomy specimens showed higher degree of calcification and amounts of cells expressing OC and BAP in the &agr;-smooth muscle actin–negative areas surrounding calcified nodules, where CD68+ macrophages colocalize. High glucose increased calcification by MCCs in vitro, and hypoxia may regulate MCC generation in vitro and in vivo. Conclusions: These data identify a novel type of blood-derived procalcific cells potentially involved in atherosclerotic calcification of diabetic patients.

Outcomes of endovascular aneurysm repair on renal function compared with open repair

OBJECTIVE Recent studies have shown that progressive renal dysfunction may develop in patients after endovascular aneurysm repair (EVAR). Data are conflicting about the effect of EVAR on renal function compared with open repair (OR). The purpose of this study was to compare the effects of EVAR, both with transrenal fixation (TRF) and infrarenal fixation (IRF), vs OR on renal function detected with renal perfusion scintigraphy (RPS). METHODS A prospective study was carried out from January 2003 to December 2007. Exclusion criteria included factors that could influence post-procedural renal function as: preoperative creatinine clearance level <65 mL/min for men and 60 mL/min for women, renal artery stenosis >60%, renal accessory artery planned to be covered by the endograft, single functioning kidney, hemodialysis, and kidney transplant. To evaluate renal function, an RPS was performed preoperatively, at 30 days, at 6 and 12 months, and then yearly. The glomerular filtration rate (GFR) was estimated with the Gates method. RESULTS During the study period, 403 patients were enrolled; 243 (60%) had OR and 160 (40%) EVAR; among these, 83 (51%) had a TRF and 77 (48%) an IRF; 55 patients were excluded from the study. No statistical differences were observed between groups for demographics and risk factors. Statistically significant differences emerged between OR and EVAR for early postoperative death (4% vs 0%; P = .01). Follow-up ranged from 54 to 126 months (mean, 76 months) for OR and from 54 to 124 months (mean, 74 months) for EVAR (P = NS). Kaplan-Meier analysis survival rate at 9 years was 70% for OR and 58% for EVAR with a risk of secondary procedure of 9% and 34%, respectively (P < .0001). A deterioration of the GFR was observed during the follow-up in both groups with a decrease after 9 years of 11% in the EVAR group and 3% in the OR group respective to baseline (P < .001). A remarkable difference emerged on renal function between EVAR patients who required a secondary procedure compared with the other EVAR patients (P < .005). No significant differences emerged between TFR and IRF for GFR decline during the follow-up period. CONCLUSIONS After EVAR, there is a continuous decline in renal function with respect to OR, regardless of fixation level and independently of pre-existing renal insufficiency. The risk of GFR impairment after EVAR should be taken into consideration in selecting patients with preoperative renal insufficiency.

Intentional coverage of the left subclavian artery during endovascular repair of traumatic descending thoracic aortic transection

OBJECTIVE This single-center, prospective study aimed to investigate the technical success and outcome of intentional coverage of the left subclavian artery (LSA) in patients undergoing thoracic endovascular aortic repair (TEVAR) for traumatic rupture of the aortic isthmus at a tertiary care medical center. METHODS From January 2005 to June 2011, patients who presented with traumatic aortic transection underwent TEVAR with coverage of the LSA when the distance between the artery and the rupture was <2 cm. At 12, 24, and 72 hours postoperatively, clinical and neurologic evaluation including transcranial Doppler insonation of the brachial artery was performed. A decrease in peak systolic velocity (PSV) >60% with respect to the contralateral one was considered relevant. Functional status of the left arm was evaluated using a provocative test. Thoracoabdominal computerized tomographic angiography was performed postoperatively at 3-, 6-, and 12-month follow-up. RESULTS Thirty-one patients (mean age 35 years) underwent emergency TEVAR for traumatic aortic transection with intentional LSA coverage during the study period. In four cases (12.9%) coverage was partial. Two patients (6.4%) died during the postoperative period due to associated lesions. No signs of vertebrobasilar insufficiency, stroke, or paraplegia were observed in any of the patients. Nine patients (36%) had severe arm claudication (ischemic pain within 60 seconds of beginning arm exercise and decrease of PSV between 50% and 60%). Risk factors for the condition were left vertebral artery diameter <3 mm (P < .0001). A significant correlation was found between the degree of PSV reduction and left arm symptoms (P < .0001). There was an improvement in ischemic arm symptoms (P < .0001) during mean follow-up of 36 months (range, 6-65 months), with only one patient (4.2%) presenting with severe claudication. Freedom from reintervention at 48 months was 93.5%. No signs of endoleaks or graft migrations were detected on computerized tomographic angiography control scans. CONCLUSIONS Coverage of the LSA during TEVAR for traumatic aortic injuries appears to be a feasible, safe method for extending the endograft landing zone without increasing the risk of paraplegia, stroke, or left arm ischemia. Left vertebral artery diameter can be used to identify patients at risk for postoperative left arm ischemia.

Long Term Outcomes and Sac Volume Shrinkage After Endovascular Popliteal Artery Aneurysm Repair

OBJECTIVES The aim was to evaluate long-term outcomes and sac volume shrinkage after endovascular popliteal artery aneurysm repair (EVPAR). METHODS This study was a retrospective review of all EVPAR cases between 1999 and 2012. Sac volume shrinkage, long-term patency, limb salvage, and survival were evaluated using Kaplan-Meier estimates. The association of anatomical and clinical characteristics with patency was evaluated using multivariate analysis. RESULTS Forty-six EVPAR were carried out in 42 patients (mean age 78 years, 86% male; mean sac volume 45.5 ± 3.5 mL). In 93% of cases (n = 43) the procedure was elective, while in 7% of cases it was for rupture (n = 2) or acute thrombosis (n = 1). Of the 43 patients who underwent elective repair, 58% were asymptomatic and 42% symptomatic (14 claudication, 3 rest pain, and 1 compression symptoms). Technical success was 98%. Mean duration of follow-up was 56 ± 21 months. Primary patency at 1, 3, and 5 years was 82% (SE 2), 79% (SE 4), and 76% (SE 4), while secondary patency was 90% (SE 5), 85% (SE 4), and 82% (SE 1) respectively; at 5 years there was 98% limb salvage and an 84% survival rate. During follow-up 11 limbs had stent graft failure: six required conversion, one underwent amputation, and four continued with mild claudication. Of those with graft failure, 63% (7/11) occurred within the first year of follow-up. The mean aneurysm sac volume shrinkage between preoperative and 5-year post-procedure measurement was significant (45.5 ± 3.5 mL vs. 23.0 ± 5.0 mL; p < .001). Segment coverage >20 cm was a negative predictor for patency (HR 2.76; 95% CI 0.23; p = .032). CONCLUSIONS EVPAR provides successful aneurysm exclusion with good long-term patency, excellent limb salvage, and survival rates. Close surveillance is nevertheless required, particularly during the first postoperative year. Patients requiring long segment coverage (>20 cm) may be at increased risk for failure.

Parallel Endografts in the Treatment of Distal Aortic and Common Iliac Aneurysms

OBJECTIVES Endovascular treatment of distal abdominal aortic aneurysms (D-AAA) and bilateral common iliac artery aneurysms (BCIAA) may present technical challenges for standard EVAR. Parallel iliac leg endografts (ILEs) of standard aortic devices and covered stents have been successfully employed to treat patients with D-AAA and BCIAA. The perioperative and long-term results of this straightforward endovascular technique are presented. METHODS Beginning in 2009, patients deemed unfit for open surgery underwent parallel endografts D-AAA and BCIAA exclusion. Avoiding the use of a main body, ILEs are simultaneously delivered from both femoral arteries, landing parallel into the aortic neck (parallel grafts: PG). Distal landing zones including external iliac arteries (EIAs) are reached using appropriate ILEs. A third parallel covered stent graft (Viabahn, Gore) is delivered from a left brachial approach to maintain prograde blood flow to one internal iliac artery (IIA) when needed. RESULTS Eighteen patients were successfully treated using parallel endografts, nine for BCIAA and nine for D-AAA. All D-AAA presented an irregular saccular shape, including three penetrating aortic ulcers and two pseudoaneurysms of previous aortic grafts. Prograde flow to one IIA was successfully maintained using a Viabahn graft in five patients with BCIAA. Mean aneurysm size was 50 mm in D-AAA and 43 mm in BCIAA. One patient required a perioperative ILE extension to treat a type Ib endoleak. One patient suffered a minor stroke 24 hours after the procedure. Two type II endoleaks were observed postoperatively. Five patients died of non-aneurysm related causes during follow-up. No new endoleaks, graft displacements or occlusions were observed during follow-up (median: 26 months, range 12-42 months). CONCLUSIONS Successful exclusion of D-AAA and BCIAA was achieved in high-risk patients using parallel endografts, allowing antegrade blood flow to one IIA when needed. Commercially available endografts were used in a simple and effective approach, with excellent follow-up results.

Outcomes of endovascular aneurysm repair with contemporary volume-dependent sac embolization in patients at risk for type II endoleak

OBJECTIVE The aim of this study was to evaluate outcomes of intraoperative aneurysm sac embolization during endovascular aneurysm repair (EVAR) in patients considered at risk for type II endoleak (EII), using a sac volume-dependent dose of fibrin glue and coils. METHODS Between January 2012 and December 2014, 126 patients underwent EVAR. Based on preoperative computed tomography evaluation of anatomic criteria, 107 patients (85%) were defined as at risk for EII and assigned to randomization for standard EVAR (group A; n = 55, 44%) or EVAR with intraoperative sac embolization (group B; n = 52, 42%); the remaining 19 patients (15%) were defined as at low risk for EII and excluded from the randomization (group C). Computed tomography scans were evaluated with OsiriX Pro 4.0 software to obtain aneurysm sac volume. Freedom from EII, freedom from EII-related reintervention, and aneurysm sac volume shrinkage at 6, 12, and 24 months were compared by Kaplan-Meier estimates. Patients in group C underwent the same follow-up protocol as groups A and B. RESULTS Patient characteristics, Society for Vascular Surgery comorbidity scores (0.99 ± 0.50 vs 0.95 ± 0.55; P = .70), and operative time (149 ± 50 minutes vs 157 ± 39 minutes; P = .63) were similar for groups A and B. Freedom from EII was significantly lower for group A compared with group B at 3 months (58% vs 80%; P = .002), 6 months (68% vs 85%; P = .04), and 12 months (70% vs 87%; P = .04) but not statistically significant at 24 months (85% vs 87%; P = .57). Freedom from EII-related reintervention at 24 months was significantly lower for group A compared with group B (82% vs 96%; P = .04). Patients in group B showed a significantly overall mean difference in aneurysm sac volume shrinkage compared with group A at 6 months (-11 ± 17 cm(3) vs -2 ± 14 cm(3); P < .01), 12 months (-18 ± 26 cm(3) vs -3 ± 32 cm(3); P = .02), and 24 months (-27 ± 25 cm(3) vs -5 ± 26 cm(3); P < .01). Patients in group C had the lowest EII rate compared with groups A and B (6 months, 5%; 12 months, 6%; 24 months, 0%) and no EII-related reintervention. CONCLUSIONS This randomized study confirms that sac embolization during EVAR, using a sac volume-dependent dose of fibrin glue and coils, is a valid method to significantly reduce EII and its complications during early and midterm follow-up in patients considered at risk. Although further confirmatory studies are needed, the faster aneurysm sac volume shrinkage over time in patients who underwent embolization compared with standard EVAR may be a positive aspect influencing the lower EII rate also during long-term follow-up.

Diabetes modifies the relationships among carotid plaque calcification, composition and inflammation

BACKGROUND AND AIMS Diabetes is traditionally associated with vascular calcification, but the molecular mechanisms are largely unknown. We herein explored the relationships among carotid plaque calcification, composition and gene expression, and how these are modified by diabetes. METHODS We collected carotid endoarterectomy specimen from 59 patients, of whom 23 had diabetes. We analysed histology with pentachromic staining, calcification with Alizarin red and Von Kossas staining, chemical calcium extraction and quantification, as well as gene expression by quantitative PCR. RESULTS We detected no differences in the extent of plaque calcification and in plaque composition between diabetic and non-diabetic patients. In non-diabetic plaques, calcium content was directly correlated with the area occupied by muscle/fibrinoid tissue and inversely correlated with collagen, but such correlations were not seen in plaques from diabetic patients. While consistent correlations were found between calcium content and RUNX2 (direct), as well as Osteopontin (inverse), diabetes modified the association between plaque calcification and inflammatory gene expression. Only in diabetic plaques, calcium content was inversely correlated with MCP1 and IL1b, whereas the direct correlation with TNF-alpha expression seen in non-diabetic plaques was lost in diabetes. CONCLUSIONS Though plaque composition and calcification were not quantitatively affected, diabetes modified the relationships between plaque calcium, composition and inflammation. These results suggest that the mechanisms and the clinical significance of atherosclerotic calcification in diabetic may be different than in non-diabetic patients.

Arterio-venous gradients of endothelial progenitor cells reveal a complex kinetics in human limb ischemia

Ischemic recruitment of endothelial progenitor cells (EPCs) in involved in compensatory angiogenic in animal models, but this still needs to be substantiated in humans. We enrolled 12 patients, who underwent surgical correction of abdominal aortic aneurysm without atherosclerosis of leg arteries (n = 4) or lower limb atherosclerosis obliterans (AO; n = 8). We measured VEGF, SDF-1, lactate and CD34+ KDR+ EPCs in the arterial and venous circulation of lower limbs. We found that, irrespectively of AO stage and lactate production, there was no consistent arterio-venous gradient of EPC, VEGF and SDF-1. Notably, in 4/8 patients, EPCs were more abundant in the vein than in the artery. EPC gradient was directly correlated with VEGF gradient and inversely correlated with SDF-1 gradient. In conclusion, we failed to show any consistent gradient of EPCs across ischemic limbs in relation to severity of atherosclerosis obliterans, but we speculatively suggest that a bidirectional traffic of EPCs in and out the ischemic tissue might be regulated by VEGF and SDF-1.

Stent graft exclusion of a renal artery aneurysm at hilum in a case with complex anatomy.

A left renal artery aneurysm (RAA) was incidentally discovered in a 50-year-old hypertensive woman at renal artery duplex scan. The computed tomography angiography scan confirmed an eccentric, 2-cm large aneurysm localized on a prehilar branch with a very twisted and coiled main renal artery. The selective digital subtraction angiography allowed a better understanding of the local complex anatomy; a covered stent was placed with the complete exclusion of the aneurysm. Even if open surgery still represents the treatment of choice, endoluminal approach has been reported as an effective procedure especially in consideration of its low invasiveness. The exclusion by covered stent can be a safe alternative to coil embolization in case of distal RAAs as well.