Michele Antonello

Adrenomedullin stimulates angiogenic response in cultured human vascular endothelial cells: Involvement of the vascular endothelial growth factor receptor 2

In recent years, evidence has accumulated that many endogenous peptides play an important regulatory role in angiogenesis by modulating endothelial cell behavior. Adrenomedullin (AM), one such factor, was previously shown to exert a clearcut proangiogenic effect in vitro when tested on specialized human endothelial cells, such as HUVECs and immortalized endothelial cell lines. In the present study we used normal adult vascular endothelial cells isolated from human saphenous vein to analyze in vitro the role of AM, related to both early (increased cell proliferation) and late (differentiation and self-organization into capillary-like structures) angiogenic events and their relationship with the vascular endothelial growth factor (VEGF) signaling cascade. The results indicated that also in this endothelial cell phenotype AM promoted cell proliferation and differentiation into cord-like structures. These actions resulted specific and were mediated by the binding of AM to its AM1 (CRLR/RAMP2) receptor. Neither the administration of a VEGF receptor 2 (VEGFR-2) antagonist nor the downregulation of VEGF production by gene silencing were able to suppress the proangiogenic effect of AM. However, when the experiments were performed in the presence of SU5416 (a selective inhibitor of the VEGFR-2 receptor at the level of the intra-cellular tyrosine kinase domain) the proangiogenic effect of AM was abolished. This result suggests that in vascular endothelial cells the binding of AM to its AM1 receptor could trigger a transactivation of the VEGFR-2 receptor, leading to a signaling cascade inducing proangiogenic events in the cells.

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.

Thoracic aorta endograft as an adjunct to resection of a locally invasive tumor: A new indication to endograft

Covered stent grafts are currently used for arterial aneurysm exclusion, aortic dissection, or peripheral occlusive disease. A new indication to endograft was applied to perform resection of the thoracic aorta for infiltration of an adjacent lung cancer into the vessel wall, avoiding a major vascular intervention for aortic graft interposition associated with tumor resection.

Suprarenal Fixation of Endograft in Abdominal Aortic Aneurysm Treatment: Focus on Renal Function

Objective:The objective of this work was to evaluate any variation of renal function detected by renal scintigraphy after the suprarenal fixation of endografts for abdominal aortic aneurysm (AAA) repair. Summary Background Data:In the few articles that have considered this problem, renal function was evaluated only by biochemical tests, which are inadequate in demonstrating small changes in renal function and in appreciating the worsening of a single kidneys function. Methods:Between April 1999 and May 2002, 47 patients with an inappropriate infrarenal proximal neck had a suprarenal fixation for AAA. To assess renal function, a technetium-99m diethylene triamine penta-acetic acid (99mTC-DTPA) perfusion scintigraphy was performed preoperatively on the third postoperative day and at 6, 12 months, and then yearly thereafter. Worsening of renal function was defined as a decrease of glomerular filtration rate (GFR) ≥20% (detected with Gates method). Serum creatinine level was tested preoperatively and at the first and third postoperative day. Results:Endograft deployment was technically successful in 44 patients (93.6%); clinical perioperative success was obtained in 46 patients (97.8%). In 12 patients (25.5%), a permanent reduction of the GFR was observed using postoperative 99mTC-DTPA perfusion scintigraphy. By 99m TC-DTPA perfusion scintigraphy, a permanent reduction of GFR was observed postoperatively in 12 patients. A slight GFR reduction (<20%) was present in 7 (14.9%) patients, due to the planned occlusion of accessory renal arteries. A more significant GFR reduction (>20%) was present unexpectedly in 5 (10.6%) patients, in 3 of these a single kidney was involved, in 5 both with an increase of the serum creatinine level >20%. Conclusions:Suprarenal fixation of endografts in AAA treatment is a safe procedure with good early and midterm procedural results and a risk of GFR impairment (>20%) of 10.6%.

Role of aneurysm sac embolization during endovascular aneurysm repair in the prevention of type II endoleak-related complications

OBJECTIVE The goal of this study was to evaluate the role of intraoperative aneurysm sac embolization during endovascular aneurysm repair (EVAR) using a standard dose of coils and fibrin glue in the prevention of type II endoleak (EII). METHODS Two groups were compared: 83 patients underwent standard EVAR during the period 2008-2009 (group A) and 79 patients underwent EVAR during the period 2010-2011 (group B). Computed tomography scans were evaluated with Osirix Pro 4.0 software to obtain aneurysm sac volume. EII rates at the first computed tomography scan follow-up, as well as midterm freedom from EII and freedom from related reintervention, were compared. Preoperative number of patent aortic side branches (inferior mesenteric artery, lumbar arteries, accessory renal arteries), sac thrombus, and sac volume were evaluated for their association with EII in the two groups using multiple logistic regressions. RESULTS Patient characteristics, Society for Vascular Surgery comorbidity scores (0.85 ± 0.44 vs 0.82 ± 0.46; P = .96), and operative time (185 ± 52 vs 179 ± 49; P = .92) were similar for groups A and B. The first computed tomography scan (≤3 months) revealed a significantly larger number of EIIs in group A than in group B (23% vs 10%; P = .02). Spontaneous EII resolution occurred in 65% of patients in group A and in 79% in group B (P = 1.0), whereas sac volume increased in 25% and 10% (P = .63) of cases, respectively. At 18 months (range, 6 months to 4.4 years), overall mean differences in sac volume shrinkage (27 ± 12 cm(3) vs 25 ± 12 cm(3); P = .19) and freedom from EII (92% vs 96%; P = .33) were similar, whereas freedom from reintervention was significantly lower in group A (93% vs 99%; P = .03) than in group B. Multivariate analysis showed preoperative aneurysm sac volume >125 cm(3) to be the only independent significant predictor of EII (odds ratio, 4.0; 95% confidence interval, 1.5-10.5; P = .005). CONCLUSIONS Although further confirmatory studies are needed, sac embolization during EVAR may be a valid approach to preventing EII and its complications during short- and midterm follow-up. More aggressive intraoperative embolization should be considered for patients with a preoperative aneurysm sac volume >125 cm(3).

Pro-angiogenic activity of Urotensin-II on different human vascular endothelial cell populations

Urotensin-II (U-II), along its receptor UT, is widely expressed in the cardiovascular system, where it exerts regulatory actions under both physiological and pathological conditions. In the present study, human vascular endothelial cells (EC) from one arterious and three venous vascular beds were used to investigate in vitro their heterogeneity in terms of expression of U-II and UT and of angiogenic response to the peptide. Real-time PCR and immunocytochemistry demonstrated the expression of UT, as mRNA and protein, in all the EC populations investigated. U-II, on the contrary, was detectable only in EC from aorta and umbilical vein. U-II did not affect the proliferation rate of adult human EC, but induced a moderate proliferative effect on EC from human umbilical vein. When tested in the Matrigel assay, however, all EC exhibited a strong angiogenic response to the peptide, comparable to that of fibroblast growth factor-2 (FGF-2) and it was not associated to an increased expression of vascular endothelial growth factor (VEGF) and/or its receptors. The angiogenic effect of U-II was abolished by the UT antagonist palosuran. Overall, these data suggest that U-II, in addition to the well known role in the regulation of cardiovascular function, also exert a specific angiogenic activity.

Expression and Functional Role of Urotensin-II and Its Receptor in the Adrenal Cortex and Medulla: Novel Insights for the Pathophysiology of Primary Aldosteronism

CONTEXT The involvement of urotensin II, a vasoactive peptide acting via the G protein-coupled urotensin II receptor, in arterial hypertension remains contentious. OBJECTIVE We investigated the expression of urotensin II and urotensin II receptor in adrenocortical and adrenomedullary tumors and the functional effects of urotensin II receptor activation. DESIGN The expression of urotensin II and urotensin II receptor was measured by real time RT-PCR in aldosterone-producing adenoma (n = 22) and pheochromocytoma (n = 10), using histologically normal adrenocortical (n = 6) and normal adrenomedullary (n = 5) tissue as control. Urotensin II peptide and urotensin II receptor protein were investigated with immunohistochemistry and immunoblotting. To identify urotensin II-related and urotensin II receptor-related pathways, a whole transcriptome analysis was used. The adrenocortical effects of urotensin II receptor activation were also assessed by urotensin II infusion with/without the urotensin II receptor antagonist palosuran in rats. RESULTS Urotensin II was more expressed in pheochromocytoma than in aldosterone-producing adenoma tissue; the opposite was seen for the urotensin II receptor expression. Urotensin II receptor activation in vivo in rats enhanced (by 182 +/- 9%; P < 0.007) the adrenocortical expression of immunoreactive aldosterone synthase. CONCLUSIONS Urotensin II is a putative mediator of the effects of the adrenal medulla and pheochromocytoma on the adrenocortical zona glomerulosa. This pathophysiological link might account for the reported causal relationship between pheochromocytoma and primary aldosteronism.

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.

Safe Resection of the Aortic Wall Infiltrated by Lung Cancer After Placement of an Endoluminal Prosthesis

BACKGROUND Few investigators have reported the results of combined resection of lung cancer infiltrating the thoracic aorta; only anecdotal accounts of off-label use of thoracic aortic endografts to facilitate resection of such tumors have been published. In this paper, we describe our experience using this innovative approach in terms of technical details and outcomes. METHODS We retrospectively reviewed data on 9 patients (6 men and 3 women, median age 61 years) with preoperatively suspected thoracic aorta neoplastic invasion, who were operated on after positioning of an endograft and underwent en bloc tumor resection including the aortic wall. RESULTS All but one cancer were non-small cell lung carcinomas; 4 patients received neoadjuvant chemotherapy, and 7 received adjuvant therapy. Aortic endografting was performed 2 to 17 days before resection of the tumor in 7 patients and as part of a one-stage procedure in 2 patients. The proximal end of the stent graft was deployed in the aortic arch (n = 1) or the descending aorta (n = 8). Lung resections were left pneumonectomies in 4 patients and left lower lobectomies in 5. Five patients underwent additional buttressing of the aortic defect using a synthetic patch (n = 2) or the omentum (n = 3). No cardiopulmonary bypass was required. At the last follow-up, 3 patients had evidence of tumor recurrence (one local and two distant). No endograft-related complications were detected. CONCLUSIONS Thoracic aortic endografting allowed safe en bloc resection of tumors invading the aortic wall, avoiding the need for extracorporeal circulatory support. Such an extended indication for thoracic aortic endografts seems promising and should be considered for selected oncologic cases.

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.