Pascal Desgranges

Overexpression of Transforming Growth Factor-β1 Stabilizes Already-Formed Aortic Aneurysms A First Approach to Induction of Functional Healing by Endovascular Gene Therapy

Background—The cell response to transforming growth factor-&bgr;1 (TGF-&bgr;1), a multipotent cytokine with healing potential, varies according to tissue context. We have evaluated the ability of TGF-&bgr;1 overexpression by endovascular gene therapy to stabilize abdominal aortic aneurysms (AAAs) already injured by inflammation and proteolysis. Methods and Results—Active TGF-&bgr;1 overexpression was obtained in already-developed experimental AAAs in rats after endovascular delivery of an adenoviral construct encoding for a mutated form of active simian TGF-&bgr;1 and in an explant model using human atherosclerotic AAA fragments incubated with recombinant active TGF-&bgr;1. Transient exogenous TGF-&bgr;1 overexpression by endovascular gene delivery was followed by induction of endogenous rat TGF-&bgr;1. Overexpression of active TGF-&bgr;1 in experimental AAAs was associated with diameter stabilization, preservation of medial elastin, decreased infiltration of monocyte-macrophages and T lymphocytes, and a decrease in matrix metalloproteinase-2 and -9, which was also observed in the explant model, in both thrombus and wall. In parallel with downregulation of the destructive process, active TGF-&bgr;1 overexpression triggered endoluminal reconstruction, replacing the thrombus by a vascular smooth muscle cell–, collagen-, and elastin-rich intima. Conclusions—Local TGF-&bgr;1 self-induction after transient exogenous overexpression reprograms dilated aortas altered by inflammation and proteolysis and restores their ability to withstand arterial pressure without further dilation. This first demonstration of stabilization of expanding AAAs by delivery of a single multipotent self-promoting gene supports the view that endovascular gene therapy should be considered for treatment of aneurysms.

Is Hypogastric Artery Embolization during Endovascular Aortoiliac Aneurysm Repair (EVAR) Innocuous and Useful

INTRODUCTION We hypothesized that the coverage of the hypogastric artery with a stent-graft causes an occlusion of the artery in its proximal segment, allowing collateral network formation in distal segments of the artery. In contrast, hypogastric embolisation may cause the formation of microthrombi that tend to disseminate leading to embolic occlusion of secondary branches and collaterals. This phenomenon worsens pelvic ischemia. To answer this question we compared two groups of patients with aortoiliac aneurysms treated with or without coil embolization to assess 1) The occurrence and evolution of buttock ischemia and 2) the effect on endoleak. MATERIALS/METHODS Between October 1995 and January 2007, 147 out of 598 EVAR patients (24.6%) required occlusion of one or both hypogastric arteries. 101 were available for over one year of follow-up. Group A included 76 patients (75%) who underwent coil embolization before EVAR and group B 25 patients (25%) who had their hypogastric artery covered by the sole limb of the stent. Patient demographics, aneurysm characteristics, operative details, immediate and long term clinical outcomes, and CT-scan evaluation were stored prospectively in a specific data base and analyzed retrospectively. RESULTS They were 96 males (95%). Mean age was 72.1+/-9.5 years. One month postoperatively, 51 patients (50.0%) suffered from buttock claudication. After six months, 34 patients were still disabled (34%), 32 in Group A (42%) and 2 in Group B (8%) (p=0.001). Post-operative sexual dysfunction occurred in 19 (19.6%) without statistical difference between the two groups. Type 2 endoleaks occurred in 12 patients (16.0%) in group A and 4 patients (16.0%) in group B (p=1). Endoleak from the hypogastric artery occurred in one patient in each group. Univariate analysis showed that predictive factors of long term (over six months) buttock claudication were embolization (p<0.001), younger age (p<0.03), coronary disease (p=0.06) and left ventricular dysfunction (p<0.01). The logistic regression analysis showed that buttock claudication was independently associated with embolization OR=9.1[95%CI=1.9-44] and left ventricular dysfunction OR=4.1[95%CI=1.3-12.7]. CONCLUSIONS Coil embolization of hypogastric artery during EVAR is not an innocuous procedure and may not reduce the rate of type II endoleak.

Mitogenic and in vitro angiogenic activity of human recombinant heparin affin regulatory peptide.

We have previously described the purification of a heparin binding growth factor from adult bovine brain named heparin affin regulatory peptide (HARP), which was identical to an uterus derived growth factor named pleiotrophin and to a developmentally regulated neurite promoting factor named heparin-binding growth associated molecule. However, for yet unclear reasons, the mitogenic activity of this purified polypeptide following isolation from animal tissue extracts is a subject of controversy, due to conflicting and irreproducible data when produced by recombinant DNA technologies in E. coli or insect cells. The purified protein was inactive in mitogenic assays but the natural molecule was active in assay of neurite outgrowth. In order to clarify these conflicting results and to obtain a recombinant protein free from other contaminating heparin-binding growth factors, we have cloned human cDNA encoding human HARP, engineered its expression in NIH 3T3 cells and characterised the resulting recombinant polypeptide. Purified recombinant HARP displayed mitogenic activity for capillary endothelial cells with half-maximal stimulation at approximately 1 ng/ml (55 pM) and induced angiogenesis in an in vitro model. Interestingly, while the NH2 terminal sequence of tissue purified HARP was NH2-GKKEKPEKK, the NH2 terminal sequence of the biologically active recombinant protein was NH2-AEAGKKEKPEKK, corresponding to a three amino acid extended form.

Factors favoring stent-graft collapse after thoracic endovascular aortic repair.

OBJECTIVE Our objective was to assess potential causative factors of stent-graft collapse after thoracic endovascular aortic repair. METHODS We retrospectively reviewed clinical data and preoperative and postoperative computed tomographic scans of patients with thoracic stent-graft collapse in 2 French departments of vascular surgery. Aortic arch angulation, length of the lack of device wall apposition, proximal aortic diameter, and percentage of oversizing were assessed. RESULTS We report 4 cases of stent-graft collapse among 285 patients treated by thoracic endovascular aortic repair. All 4 patients were treated with the TAG stent graft. Only one of the patients had a symptomatic collapse: he was treated by stent-graft explantation and open repair. Endovascular management was performed in 3 of the 4 patients. None of the patients died. Lack of device wall apposition and acute aortic arch angle (range 92 degrees-118 degrees ) were observed in all 4 patients. Oversizing over 20% was observed in 3 patients. CONCLUSION This stent-graft-related complication seems related to poor apposition of the stent grafts in the highly angulated aortic arch. Excessive stent-graft oversizing could be an additional causative factor. Accurate assessment of aortic arch anatomic features, as well as the choice and sizing of the device, may prevent this complication.

Image Guidance for Endovascular Repair of Complex Aortic Aneurysms: Comparison of Two-dimensional and Three-dimensional Angiography and Image Fusion

PURPOSE To evaluate the feasibility of image fusion (IF) of preprocedural arterial-phase computed tomography with intraprocedural fluoroscopy for roadmapping in endovascular repair of complex aortic aneurysms, and to compare this approach versus current roadmapping methods (ie, two-dimensional [2D] and three-dimensional [3D] angiography). MATERIALS AND METHODS Thirty-seven consecutive patients with complex aortic aneurysms treated with endovascular techniques were retrospectively reviewed; these included aneurysms of digestive and/or renal arteries and pararenal and juxtarenal aortic aneurysms. All interventions were performed with the same angiographic system. According to the availability of different roadmapping software, patients were successively placed into three intraprocedural image guidance groups: (i) 2D angiography (n = 9), (ii) 3D rotational angiography (n = 14), and (iii) IF (n = 14). X-ray exposure (dose-area product [DAP]), injected contrast medium volume, and procedure time were recorded. RESULTS Patient characteristics were similar among groups, with no statistically significant differences (P ≥ .05). There was no statistical difference in endograft deployment success between groups (2D angiography, eight of nine patients [89%]; 3D angiography and IF, 14 of 14 patients each [100%]). The IF group showed significant reduction (P < .0001) in injected contrast medium volume versus other groups (2D, 235 mL ± 145; 3D, 225 mL ± 119; IF, 65 mL ± 28). Mean DAP values showed no significant difference between groups (2D, 1,188 Gy · cm(2) ± 1,067; 3D, 984 Gy · cm(2) ± 581; IF, 655 Gy · cm(2) ± 457; P = .18); nor did procedure times (2D, 233 min ± 123; 3D, 181 min ± 53; IF, 189 min ± 60; P = .59). CONCLUSIONS The use of IF-based roadmapping is a feasible technique for endovascular complex aneurysm repair associated with significant reduction of injected contrast agent volume and similar x-ray exposure and procedure time.

Assessment of Critical Limb Ischemia in Patients with Diabetes: Comparison of MR Angiography and Digital Subtraction Angiography

OBJECTIVE The purpose of our study was to evaluate the diagnostic accuracy of hybrid MR angiography by comparison with digital subtraction angiography (DSA) in diabetic patients with critical limb ischemia. SUBJECTS AND METHODS Thirty-one patients prospectively underwent both hybrid MR angiography and DSA. The hybrid MR angiography study consisted of high-resolution MR angiography of a single calf and foot using a contrast-enhanced 3D gradient-echo volumetric interpolated breath-hold examination with surface coils, followed by three-station bolus chase MR angiography with a dedicated peripheral vascular coil. Two blinded reviewers separately analyzed maximum-intensity-projection hybrid MR angiograms and DSA images. The peripheral vessels were divided into 10 anatomic segments for review. The status of each segment was graded as normal, stenosis less than 50% in diameter, stenosis greater than 50%, or occluded. The sensitivity and specificity of hybrid MR angiography were determined using DSA as the gold standard. Treatment options were considered separately from the results of each examination. RESULTS Among 310 analyzed segments, the sensitivities of hybrid MR angiography for stenosis and occlusion were, respectively, 95% and 95% for reviewer 1 and 96% and 90% for reviewer 2. The specificities of hybrid MR angiography for stenosis and occlusion were, respectively, 98% and 98% for reviewer 1 and 98% and 99% for reviewer 2. In 25 patients (81%), the quality of bolus chase MR angiography images was insufficient to assess runoff arteries. All treatments proposed on the basis of DSA findings were endorsed by hybrid MR angiography findings. Eleven more treatments were formulated on the basis of hybrid MR angiography findings. Of these, four were due to overestimation of stenosis on MR angiography and seven were due to the detection of patent infrageniculate arteries on hybrid MR angiography that were not detected on DSA. CONCLUSION Hybrid MR angiography depicts runoff arteries not seen on DSA. Hybrid MR angiography may be useful for treatment planning in selected diabetic patients with critical limb ischemia.

A substituted dextran enhances muscle fiber survival and regeneration in ischemic and denervated rat EDL muscle

Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration surrounded by a thin zone of peripheral surviving muscle fibers. Muscle regeneration is a complex phenomenon in which many agents interact, such as growth factors and heparan sulfate components of the extracellular matrix. We have shown that synthetic polymers, called RGTA (as regenerating agents), which imitate the heparan sulfates, are able to stimulate tissue repair when applied at the site of injury. In crushed muscles, RGTA were found to accelerate both regeneration and reinnervation. In vitro, RGTA act as protectors and potentiators of various heparin binding growth factors (HBGF). It was postulated that in vivo their tissue repair properties were due in part to an increase of bioavailability of endogenously released HBGF. In the present work, we show that ischemic and denervated EDL muscle treated by a unique injection of RGTA differs from the control after 1 wk in several aspects: 1) the epimysial postinflammatory reaction is inhibited and the area of fibrotic tissue among fibers is reduced; 2) the peripheral zone, as measured by the number of intact muscle fibers, was increased by more than twofold; and 3) In the central zone, RGTA enhances the regeneration of the muscle fibers as well as muscle revascularization. These results suggest that RGTA both protects muscle fibers from degeneration and preserves the differentiated state of the surviving fibers. For the first time it is demonstrated that a functionalized polymeric compound can prevent some of the damage resulting from muscle ischemia. RGTA may therefore open a new therapeutic approach for muscle fibrosis and other postischemic muscle pathologies.—Desgranges, P., Barbaud, C., Caruelle, J.‐P., Barritaoult, D., Gautron, J. A substituted dextran enhances muscle fiber survival and regeneration in ischemic and denervated rat EDL muscle. FASEB J. 13, 761–766 (1999)

Surgical transluminal iliac angioplasty with selective stenting: long-term results assessed by means of duplex scanning.

PURPOSE The safety of iliac angioplasty and selective stenting performed in the operating room by vascular surgeons was evaluated, and the short- and long-term results were assessed by means of serial duplex scanning. METHODS Between 1989 and 1996, 281 iliac stenotic or occlusive lesions in 235 consecutive patients with chronic limb ischemia were treated by means of percutaneous transluminal angioplasty (PTA) alone (n = 214) or PTA with stent (n = 67, 23.8%). There were 260 primary lesions and 21 restenosis after a first PTA, which were analyzed separately. Stents were implanted in selected cases, either primarily in totally occluded arteries or after suboptimum results of PTA (ie, residual stenosis or a dissection). Data were collected prospectively and analyzed retrospectively. Results were reported in an intention-to-treat basis. Clinical results and patency were evaluated by means of symptom assessment, ankle brachial pressure index, and duplex scanning at discharge and 1, 3, 6, and every 12 months after angioplasty. To identify factors that may affect outcome, 12 clinical and radiological variables, including the four categories of lesions defined by the Standards of Practice Committee of the Society of Cardiovascular and Interventional Radiology, were analyzed separately. The statistical significances of life-table analysis of patency were determined by means of the log-rank test. RESULTS There were no postoperative deaths or amputations. Local, general, and vascular complications occurred in 2.1%, 1.3% and 4.7% of cases, respectively (total, 8.1%). The mean follow-up period was 29.6 months. The cumulative patency rates +/- SE of the 260 PTAs (including 55 PTAs plus stents) were 92.9% +/- 1.5% at 1 month, 86. 5% +/- 1.7% at 1 year, 81.2% +/- 2.3% at 2 years, 78.8% +/- 2.9% at 3 years, and 75.4% +/- 3.5% at 5 and 6 years. The two-year patency rate of 21 redo PTAs (including 11 PTAs plus stents) was 79.1% +/- 18.2%. Of 12 predictable variables studied in the first PTA group, only the category of the lesion was predictive of long-term patency. The two-year patency rate was 84% +/- 3% for 199 category 1 lesions and 69.7% +/- 6.5% for 61 category 2, 3, and 4 lesions together (P =. 02). There was no difference of patency in the stented and nonstented group. CONCLUSION Iliac PTA alone or with the use of a stent (in cases of occlusion and/or suboptimal results of PTA) offers an excellent long-term patency rate. Categorization of lesions remains useful in predicting long-term outcome. PTA can be performed safely by vascular surgeons in the operating room and should be considered to be the primary treatment for localized iliac occlusive disease.

A propensity-matched comparison of outcomes for fenestrated endovascular aneurysm repair and open surgical repair of complex abdominal aortic aneurysms

OBJECTIVE The benefit of fenestrated endovascular aortic aneurysm repair (FEVAR) compared with open surgical repair (OSR) of complex abdominal aortic aneurysms (CAAAs) is unknown. This study compares 30-day outcomes of these procedures from two high-volume centers where FEVAR was undertaken for high-risk patients. METHODS Patients undergoing FEVAR with commercially available devices and OSR of CAAAs (total suprarenal/supravisceral clamp position) were propensity matched by demographic, clinical, and anatomic criteria to identify similar patient cohorts. Perioperative outcomes were evaluated using univariate and multivariate methods. RESULTS From July 2001 to August 2012, 59 FEVAR and 324 OSR patients were identified. After 1:4 propensity matching for age, gender, hypertension, congestive heart failure, coronary disease, chronic obstructive pulmonary disease, stroke, diabetes, preoperative creatinine, and anticipated/actual aortic clamp site, the study cohort consisted of 42 FEVARs and 147 OSRs. The most frequent FEVAR construct was two renal fenestrations, with or without a single mesenteric scallop, in 50% of cases. An average of 2.9 vessels were treated per patient. Univariate analysis demonstrated FEVAR had higher rates of 30-day mortality (9.5% vs. 2%; P = .05), any complication (41% vs. 23%; P = .01), procedural complications (24% vs. 7%; P < .01), and graft complications (30% vs. 2%; P < .01). Multivariable analysis showed FEVAR was associated with an increased risk of 30-day mortality (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.1-24; P = .04), any complication (OR, 2.3; 95% CI, 1.1-4.9; P = .01), and graft complications (OR, 24; 95% CI, 4.8-66; P < .01). CONCLUSIONS FEVAR, in this two-center study, was associated with a significantly higher risk of perioperative mortality and morbidity compared with OSR for management of CAAAs. These data suggest that extension of the paradigm shift comparing EVAR with OSR for routine AAAs to patients with CAAAs is not appropriate. Further study to establish proper patient selection for FEVAR instead of OSR is warranted before widespread use should be considered.

The Endovasculaire vs Chirurgie dans les Anévrysmes Rompus PROTOCOL trial update

Endovascular aortic repair (EVAR) treatment for ruptured aortoiliac aneurysms (rAIA) avoids the additional surgical insult to physiology that comes with laparotomy and open repair (OR). In systematic reviews, the pooled mortality rate from rAIA after EVAR is around 20% and morbidity around 40%. The proportion of patients with rAIA treated by EVAR is steadily increasing, as most centers are adopting an EVAR as a first line therapy. However, two trials, one randomized (n = 32) and one nonrandomized, failed to demonstrate any benefit of EVAR to OR. The multicentric randomized study named ECAR (for Endosvasculaire vs Chirurgie dans les Anévrysmes Rompus) was setup on 160 patients to compare the EVAR vs OR in rAIA. The primary outcome is mortality at 1 month. The study started in January 2008 and is still in progress.