Virendra I. Patel

Common femoral artery occlusive disease: Contemporary results following surgical endarterectomy

OBJECTIVE Proliferation of endovascular techniques with perceived reduction in treatment morbidity repetitively question the precept that surgical endarterectomy is the preferred treatment for occlusive disease of the common femoral artery (CFA). This study details a contemporary experience with common femoral endarterectomy (CFE) with and without concomitantly performed endovascular therapies. METHODS Technical, hemodynamic, and clinical success of CFE performed between 2002 and 2005 were determined according to the Society of Vascular Surgery reporting standards. Primary and assisted patencies of the CFA segment, freedom from reintervention in the ipsilateral limb, and survival were assessed using Kaplan-Meier life-table analysis. Multivariate analysis was performed to evaluate factors associated with patency and survival. RESULTS CFE was performed on 65 limbs in 58 patients (mean age 71 +/- 10; male 77%; diabetes 28%; creatinine >/= 1.5 mg/dL 19%). Forty-four cases (68%) were performed for claudication, and 21 cases (32%) for critical limb ischemia. Thirty-seven cases (57%) were performed as a hybrid procedure wherein concomitant endovascular interventions were performed. Twenty iliac (TASC II A-30%; B-35%; C-20%; D-15%) and 25 femoropopliteal (TASC II A-24%; B-60%; C-12%; D-4%) lesions were treated. Technical success was achieved in 100% of the cases. Hemodynamic success was achieved in 95% of the cases with mean postoperative increase in ankle-brachial index (ABI) of 0.24 +/- 0.24. All but one patient (98.5%) had improvement in symptoms and/or ABI. Average hospital stay was 3.2 days (range 1-12 days). There were 3 (5%) major complications requiring reintervention (early failure secondary to untreated inflow lesion, hematoma, and wound infection), six (9%) minor complications which were treated conservatively (five wound infections, one lymph leak), and no perioperative mortality. With a mean follow-up period of 27 months (range 1-58 months), 1- and 5-year primary patencies were 93% and 91%, respectively. Assisted patency was 100% at both time points. There was no difference in patencies between CFE performed alone or as a hybrid procedure. Multivariate analysis showed congestive heart failure (CHF) as the only predictor of primary failure (odds ratio [OR] 18.5 [2.6-142.9]; P = .004). Freedom from reintervention in the ipsilateral limb was 82% at 1 year and 78% at 5 years, with CHF again as the only predictor of reintervention (OR 5.3 [1.4-19.6]; P =.012). Survival was 89% at 1 year and 70% at 5 years. There were no amputations. CONCLUSIONS These data suggest CFE should remain the standard of care for occlusive disease of the CFA. Its safety and efficacy establish a standard for comparison with emerging endovascular therapies.

Genetic Engineering of a Suboptimal Islet Graft with A20 Preserves β Cell Mass and Function

Transplantation of an excessive number of islets of Langerhans (two to four pancreata per recipient) into patients with type I diabetes is required to restore euglycemia. Hypoxia, nutrient deprivation, local inflammation, and the β cell inflammatory response (up-regulation of NF-κB-dependent genes such as inos) result in β cell destruction in the early post-transplantation period. Genetic engineering of islets with anti-inflammatory and antiapoptotic genes may prevent β cell loss and primary nonfunction. We have shown in vitro that A20 inhibits NF-κB activation in islets and protects from cytokine- and death receptor-mediated apoptosis. In vivo, protection of newly transplanted islets would reduce the number of islets required for successful transplantation. Transplantation of 500 B6/AF1 mouse islets into syngeneic, diabetic recipients resulted in a cure rate of 100% within 5 days. Transplantation of 250 islets resulted in a cure rate of only 20%. Transplantation of 250 islets overexpressing A20 resulted in a cure rate of 75% with a mean time to cure of 5.2 days, comparable to that achieved with 500 islets. A20-expressing islets preserve functional β cell mass and are protected from cell death. These data demonstrate that A20 is an ideal cytoprotective gene therapy candidate for islet transplantation.

Management of diseases of the descending thoracic aorta in the endovascular era: a Medicare population study.

Objective:Prospective trials have shown improved perioperative outcomes with endovascular repair of thoracic aortic (TEVAR) pathologies compared with conventional surgery (OPEN). There are no long-term population data detailing the impact of TEVAR on practice patterns and results of treatment of descending thoracic aortic pathology (DTA), which are the goal of this study. Methods:All procedures performed on the DTA captured in the Medicare database from 2004 to 2007 were identified by ICD-9 codes and stratified into OPEN and TEVAR cohorts. Outcomes included perioperative mortality (&khgr;2) and 5-year actuarial survival. Results:There were 11,166 patients identified (4838 [43%] TEVAR vs. 6328 [57%] OPEN) with 7247 (65%) nonruptured, degenerative thoracic aortic aneurysms (TAA), 2701 (24%) descending aortic dissections, 1033 (9%) thoracic aortic ruptures, and 185 (2%) traumatic aortic tears. The distribution of cases changed significantly during the study period (P < 0.0001) with an increase in TEVAR, decrease in OPEN, and increase in total cases over time (Table 1). The perioperative mortality was lower in the TEVAR group for the entire population (360 [7.4%] TEVAR vs. 1175 [18.5%] OPEN, P < 0.0001), and for the individual pathologies: TAA (182/3529 [5%] TEVAR vs. 451/3718 [12%] OPEN, P < 0.001), dissections (76/833 [9%] TEVAR vs. 399/1868 [21%] OPEN, P < 0.001) and ruptures (87/368 [24%] TEVAR vs. 298/665 [45%] OPEN, P < 0.0001). The Kaplan–Meier curve significantly favored TEVAR for the entire cohort because of the early mortality of the OPEN cohort but the curves converged by 5 years. The 5-year survival by indication was: entire population (53.4% TEVAR vs. 53.3% OPEN, P < 0.0001), TAA (55.8% TEVAR vs. 59.7% OPEN, P = 0.84), dissection (58.2% TEVAR vs. 50.6% OPEN, P < 0.0001), ruptures (23.3% TEVAR vs. 25.3% OPEN, P = 0.001), and trauma (62.9% TEVAR vs. 50.9% OPEN, P = 0.12). Conclusion:There has been a significant increase in the use of TEVAR for management of diseases of the DTA. TEVAR offers a significant perioperative survival advantage when compared with OPEN regardless of the indication for repair. However, in the Medicare population, the 5-year survival is similar between the 2 cohorts.

Endovascular management of patients with critical limb ischemia

BACKGROUND Although percutaneous intervention (PTA) is considered first-line therapy for peripheral vascular disease in many scenarios, its role in critical limb ischemia (CLI), wherein anatomic disease is more extensive, remains unclear. In the present study, late (5-year) clinical and patency data for PTA in CLI are defined. METHODS From January 2002 to December 2007, 409 patients underwent infrainguinal PTA ± stent for CLI (Rutherford IV-VI) of 447 limbs. Primary patency, assisted patency, limb salvage, and survival were assessed using Kaplan-Meier. Predictors of patency, limb salvage, and death were determined using multivariate models. RESULTS Demographics included age (70 ± 12 years old), diabetes (65.8%), and dialysis dependence (13%). The superficial femoral artery was treated in 58% of the patients, 16% were limited to the crural vessels, 38% had multilevel treatment, and stents were placed in 26%. Eighty percent of patients received postprocedure clopidogrel. Mean follow-up was 28 months (0-83). Five-year primary and assisted patency were 31% ± 0.04 and 75% ± 0.04, respectively. Limb salvage at 5 years was 74% ± 0.038. Sixty-three patients had major amputations. Survival at 5 years was 39% ± 0.03. Multivariate analysis identified dialysis dependence (P = .0005; 2.7 [1.6-4.8]), ≤1 vessel runoff (P = .02; 1.5 [1.1-2.0]), and warfarin use (P = .001; 1.7 [1.25-2.3]) as negative predictors of primary patency, but none of these were negative predictors of assisted patency. Dialysis dependence (P = .006; 2.5 [1.3-4.8]), female gender (P = .02; 2.0 [1.1-3.7]), and ≤1 vessel run-off (P = .04; 1.8 [1.0-3.2]) predicted limb loss. Dialysis dependence (P = .0003; 2.3 [1.5-3.5]), diabetes (P = .04; 1.5 [0.5-2.1]), and poor run-off (P = .04; 1.6 [1.2-2.1]) were predictors of mortality. CONCLUSION Although primary patency is low, excellent limb salvage rates can be achieved in patients with CLI through close follow-up and secondary interventions. These data, and the 12% annual death rate, validate PTA as first-line therapy in patients with CLI.

Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia

Vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to atherosclerosis, postangioplasty restenosis, and transplant vasculopathy. Forkhead transcription factors belonging to the FoxO subfamily have been shown to inhibit growth and cell cycle progression in a variety of cell types. We hypothesized that forkhead proteins may play a role in VSMC biology. Under in vitro conditions, platelet-derived growth factor (PDGF)-BB, tumor necrosis factor-α, and insulin-like growth factor 1 stimulated phosphorylation of FoxO in human coronary artery smooth muscle cells via MEK1/2 and/or phosphatidylinositol 3-kinase-dependent signaling pathways. PDGF-BB, tumor necrosis factor-α, and insulin-like growth factor 1 treatment resulted in the nuclear exclusion of FoxO, whereas PDGF-BB alone down-regulated the FoxO target gene, p27kip1, and enhanced cell survival and progression through the cell cycle. These effects were abrogated by overexpression of a constitutively active, phosphorylation-resistant mutant of the FoxO family member, TM-FKHRL1. The anti-proliferative effect of TM-FKHRL1 was partially reversed by small interfering RNA against p27kip1. In a rat balloon carotid arterial injury model, adenovirus-mediated gene transfer of FKHRL1 caused an increase in the expression of p27kip1 in the VSMC and inhibition of neointimal hyperplasia. These data suggest that FoxO activity inhibits VSMC proliferation and activation and that this signaling axis may represent a therapeutic target in vasculopathic disease states.

A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia

A20 is a NF‐κB‐dependent gene that has dual anti‐inflammatory and antiapoptotic functions in endothelial cells (EC). The function of A20 in smooth muscle cells (SMC) is unknown. We demonstrate that A20 is induced in SMC in response to inflammatory stimuli and serves an anti‐inflammatory function via blockade of NF‐κB and NF‐κB‐dependent proteins ICAM‐1 and MCP‐1. A20 inhibits SMC proliferation via increased expression of cyclin‐dependent kinase inhibitors p21waf1 and p27kip1. Surprisingly, A20 sensitizes SMC to cytokine‐ and Fas‐mediated apoptosis through a novel NO‐dependent mechanism. In vivo, adenoviral delivery of A20 to medial rat carotid artery SMC after balloon angioplasty prevents neointimal hyperplasia by blocking SMC proliferation and accelerating re‐endothelialization, without causing apoptosis. However, expression of A20 in established neointimal lesions leads to their regression through increased apoptosis. This is the first demonstration that A20 exerts two levels of control of vascular remodeling and healing. A20 prevents neointimal hyperplasia through combined anti‐inflammatory and antiproliferative functions in medial SMC. If SMC evade this first barrier and neointima is formed, A20 has a therapeutic potential by uniquely sensitizing neointimal SMC to apoptosis. A20‐based therapies hold promise for the prevention and treatment of neointimal disease.—Patel, V. I., Daniel, S., Longo, C. R., Shrikhande, G. V., Scali, S. T., Czismadia, E., Groft, C. M., Shukri, T., Motley‐Dore, C., Ramsey, H. E., Fisher, M. D., Grey, S. T., Arvelo, M. B., Ferran, C. A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia. FASEB J. 20, 1418–1430 (2006)

Relative importance of aneurysm diameter and body size for predicting abdominal aortic aneurysm rupture in men and women

OBJECTIVE Women have been shown to have up to a fourfold higher risk of abdominal aortic aneurysm (AAA) rupture at any given aneurysm diameter compared with men, leading to recommendations to offer repair to women at lower diameter thresholds. Although this higher risk of rupture may simply reflect greater relative aortic dilatation in women who have smaller aortas to begin with, this has never been quantified. Our objective was therefore to quantify the relationship between rupture and aneurysm diameter relative to body size and determine whether a differential association between aneurysm diameter, body size, and rupture risk exists for men and women. METHODS We performed a retrospective review of all patients in the Vascular Study Group of New England (VSGNE) database who underwent endovascular or open AAA repair. Height and weight were used to calculate each patients body mass index and body surface area (BSA). Next, indices of each measure of body size (height, weight, body mass index, BSA) relative to aneurysm diameter were calculated for each patient. To generate these indices, we divided aneurysm diameter (in cm) by the measure of body size; for example, aortic size index (ASI) = aneurysm diameter (cm)/BSA (m(2)). Along with other relevant clinical variables, we used these indices to construct different age-adjusted and multivariable-adjusted logistic regression models to determine predictors of ruptured repair vs elective repair. Models for men and women were developed separately, and different models were compared using the area under the curve. RESULTS We identified 4045 patients (78% male) who underwent AAA repair (53% endovascular aortic aneurysm repairs). Women had significantly smaller diameter aneurysms, lower BSA, and higher BSA indices than men. For men, the variable that increased the odds of rupture the most was aneurysm diameter (area under the curve = 0.82). Men exhibited an increased rupture risk with increasing aneurysm diameter (<5.5 cm: odds ratio [OR], 1.0; 5.5-6.4 cm: OR, 0.9; 95% confidence interval [CI], 0.5-1.7; P = .771; 6.5-7.4 cm: OR, 3.9; 95% CI, 1.9-1.0; P < .001; ≥ 7.5 cm: OR, 11.3; 95% CI, 4.9-25.8; P < .001). In contrast, the variable most predictive of rupture in women was ASI (area under the curve = 0.81), with higher odds of rupture at a higher ASI (ASI >3.5-3.9: OR, 6.4; 95% CI, 1.7-24.1; P = .006; ASI ≥ 4.0: OR, 9.5; 95% CI, 2.3-39.4; P = .002). For women, aneurysm diameter was not a significant predictor of rupture after adjusting for ASI. CONCLUSIONS Aneurysm diameter indexed to body size is the most important determinant of rupture for women, whereas aneurysm diameter alone is most predictive of rupture for men. Women with the largest diameter aneurysms and the smallest body sizes are at the greatest risk of rupture.

Improved results using Onyx glue for the treatment of persistent type 2 endoleak after endovascular aneurysm repair.

OBJECTIVE Persistent type 2 (PT2) endoleaks (present ≥ 6 months) after endovascular aneurysm repair are associated with adverse outcomes, and selective secondary intervention is indicated in those patients with an expanding aneurysm sac. This study evaluated the outcomes of secondary intervention for PT2. METHODS From 1999 to 2007, 136 patients who underwent endovascular aneurysm repair developed PT2 and comprised the study cohort. Primary end points included PT2 resolution (secondary interventional success) and survival, and were evaluated using multiple logistic regression and Kaplan-Meier analyses, respectively. RESULTS Fifty-one patients underwent a total of 68 secondary interventions for PT2 with expanding aneurysm sacs with a median postsecondary interventional follow-up of 13.7 months. Secondary interventions included 20 inferior mesenteric artery coil embolizations, 17 Onyx glue embolizations, 11 aneurysm sac coil embolizations, 10 non-Onyx glue embolizations, 7 lumbar artery coil embolizations, 2 open lumbar ligations, and 1 graft explant. The overall secondary interventional success rate was 43% (29 of 68). Onyx glue embolization was associated with a greater success rate when used as the initial secondary intervention (odds ratio, 59.61; 95% confidence interval, 4.78-742.73; P < .001). There was no difference in success between the different techniques when multiple secondary interventions were required. Five-year survival was 72% ± 0.08% and was unrelated to any of the secondary interventional techniques. CONCLUSIONS Secondary intervention for PT2 is associated with success in less than half of all cases. Onyx glue embolization was associated with greater long-term success when used as the initial secondary intervention.

A20 Protects From CD40-CD40 Ligand-Mediated Endothelial Cell Activation and Apoptosis

Background—CD40/CD40 ligand (CD40L) signaling is a potent activator of endothelial cells (ECs) and promoter of atherosclerosis. In this study, we investigate whether A20 (a gene we have shown to be antiinflammatory and antiapoptotic in ECs) can protect from CD40/CD40L-mediated EC activation. Methods and Results—Overexpression of CD40, in a transient transfection system, activates the transcription factor NF-&kgr;B and upregulates I&kgr;B&agr;, E-selectin, and tissue factor (TF) reporter activity. Coexpression of A20 inhibits NF-&kgr;B and upregulation of I&kgr;B&agr; and E-Selectin but not TF, suggesting that CD40 induces TF in a non–NF-&kgr;B–dependent manner. In human coronary artery ECs (HCAECs), adenovirus-mediated overexpression of A20 blocks physiological, CD40-induced activation of NF-&kgr;B, upstream of I&kgr;B&agr; degradation (Western blot) and subsequently upregulation of ICAM-1, VCAM-1, and E-selectin (flow cytometry). Although A20 does not block TF transcription its expression in HCAECs inhibits TF induction (colorimetric assay and RT-PCR) by blunting CD40 upregulation. We demonstrate that CD40 signaling induces apoptosis in a proinflammatory microenvironment. A20 overexpression protects from CD40-mediated EC apoptosis (DNA content analysis and trypan blue exclusion). We also demonstrate that signaling through CD40L activates NF-&kgr;B and induces apoptosis in ECs, both of which are inhibited by A20 overexpression. Conclusion—A20 works at multiple levels to protect ECs from CD40/CD40L mediated activation and apoptosis. A20-based therapy could be beneficial for the treatment of vascular diseases such as atherosclerosis and transplant-associated vasculopathy.

Evolution of operative strategies in open thoracoabdominal aneurysm repair

OBJECTIVE During a 24-year interval, we managed >90% of thoracoabdominal aortic aneurysm (TAA) repairs with a clamp-and-sew (clamp/sew) approach supplemented with protective adjuncts, including renal hypothermia and epidural cooling with aggressive intercostal reconstruction for spinal cord protection. A finite paraplegia rate led to operative modifications using distal aortic perfusion (DAP) through atriofemoral bypass to support cord collateral circulation and selective intercostal reconstruction based on motor evoked potential (MEP) monitoring. This study evaluated the effect of DAP/MEP on perioperative outcomes. METHODS Consecutive patients undergoing repair of nonruptured Crawford extent I-III TAA using DAP/MEP were compared with propensity-matched patients treated with the clamp/sew technique. Outcomes included 30-day mortality and paraplegia. RESULTS There were 52 patients in the DAP cohort vs 127 undergoing clamp/sew. The DAP and clamp/sew cohorts differed in age (62.6 vs 69.5 years, P = .0003), presence of Marfan disease (10% vs 2%, P = .01), and chronic dissection (37% vs 8%, P = .001). Operative mortality was low (DAP, 2%; clamp/sew, 5%; P = .38). Postoperative renal insufficiency, although doubled in clamp/sew (17%) vs DAP (8%; P = .10), was not significant. DAP patients had a significantly lower incidence of intercostal reconstruction than the clamp/sew group (10% vs 34%, P < .0001), yet there was no paraplegia in the DAP cohort vs 5% in clamp/sew (P = .11). The composite death/paraplegia rate was decreased with DAP at 1 of 52 (2%) vs clamp/sew at 11 of 127 (9%; P = .01). Paraparesis with complete recovery occurred in 5 of 52 (10%) of the DAP group. CONCLUSIONS Elective TAA repair was accomplished with a low mortality in the DAP and clamp/sew cohorts. The use of MEP in the DAP cohort (despite a higher spinal cord ischemic risk due to the number of chronic dissection patients) decreased the need for intercostal reconstruction, with no paraplegia to date. DAP with MEP is the preferred operative strategy for extent I to III TAA repair.