George Oreopoulos

Regulation of Toll-Like Receptor 4 Expression in the Lung Following Hemorrhagic Shock and Lipopolysaccharide

The Toll-like receptor 4 (TLR4) has recently been shown to function as the major upstream sensor for LPS. In this study, a rodent model of lung injury following resuscitated hemorrhagic shock was used to examine the regulation of TLR4 gene and protein expression in vivo and in vitro. Intratracheal LPS alone induced a rapid reduction in whole lung TLR4 mRNA, an effect which is also observed in recovered alveolar macrophages. This effect appeared to be due to a lowering of TLR4 mRNA stability by ∼69%. By contrast, while shock/resuscitation alone had no effect on TLR4 mRNA levels, it markedly altered the response to LPS. Specifically, antecedent shock prevented the LPS-induced reduction in TLR4 mRNA levels. This reversal was explained by the ability of prior resuscitated shock both to prevent the destabilization of TLR4 mRNA by LPS and also to augment LPS-stimulated TLR4 gene transcription compared with LPS alone. Oxidant stress related to shock/resuscitation appeared to contribute to the regulation of TLR4 mRNA, because supplementation of the resuscitation fluid with the antioxidant N-acetylcysteine reversed the ability of shock/resuscitation to preserve TLR4 mRNA levels following LPS. TLR4 protein levels in whole lung mirrored the changes seen for TLR4 mRNA. Considered in aggregate, these data suggest that levels of tlr4 expression are controlled both transcriptionally as well as posttranscriptionally through altered mRNA stability and that antecedent shock/resuscitation, a form of global ischemia/reperfusion, might influence regulation of this gene.

In vivo and in vitro modulation of intercellular adhesion molecule (ICAM)-1 expression by hypertonicity.

Hepatic ischemia-reperfusion (I/R) is an important cause of organ dysfunction in the critically ill. With reperfusion, Kupffer cells release pro-inflammatory cytokines that promote endothelial cell (EC) expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1, facilitating neutrophil (PMN) infiltration. Studies suggest hypertonic saline (HTS) might exert beneficial effects on development of organ injury following shock on the basis of reduced PMN-EC interactions. We hypothesized that HTS alters expression of EC ICAM-1 and thus minimizes PMN-mediated injury. To test our hypothesis, we used an in vivo model of hepatic I/R and an in vitro model of activated EC. Rats underwent 30 min of hepatic ischemia after pretreatment with HTS (7.5% NaCl, 4cc/kg ia) or normal saline (NS). At 4 h reperfusion, plasma was taken for aspartate aminotransferase (AST) and liver tissue was harvested for assessment of hepatic ICAM-1 mRNA by Northern blot analysis. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) and exposed to hypertonic medium (350-500 mOsM). HUVEC ICAM-1 protein was measured by cell ELISA and ICAM-1 mRNA by Northern blot analysis. HTS prevented hepatic I/R injury as measured by AST. AST of shams was 282.6+/-38.1 IU/L. I/R following NS pretreatment caused significant injury (AST 973.8+/-110.9 IU/L) compared to sham (SM) (P < 0.001). Pretreatment with HTS exerted significant protection following I/R with an AST of 450.9+/-56.3 IU/L (P < 0.05). There was no significant difference in AST levels between SM and HTS groups. Reduced hepatic injury after HTS and I/R was accompanied by inhibition of I/R-induced hepatic ICAM-1 mRNA expression compared to NS treated animals (P < 0.01). Similarly, hypertonicity inhibited HUVEC LPS-induced ICAM-1 protein (LPS: 1.86+/-0.19 absorbance units; 400 mOsM +/- LPS: 1.45+/-0.14 absorbance units; 450 mOsM + LPS: 1.02+/-0.19 absorbance units, P < 0.001) and mRNA expression. Thus, hypertonicity modulates endothelial ICAM-1 expression as one possible protective mechanism against I/R injury.

Hypertonic preconditioning prevents hepatocellular injury following ischemia/reperfusion in mice: A role for interleukin 10

Ischemia/reperfusion (I/R) of the liver occurs in many clinical scenarios including trauma, elective surgery, and transplantation. Events initiated by this process can lead to inflammation in the liver, culminating in local injury as well as distant organ dysfunction. Recent studies have suggested that hypertonic saline exerts anti‐inflammatory effects, which may be beneficial in preventing organ injury. In the present study, we examine the effect of hypertonic saline on the development of liver inflammation following I/R in both rat and mouse models. Hypertonic pretreatment was shown to prevent liver enzyme release concomitant with a reduction in liver neutrophil sequestration. Hypertonic saline appeared to exert this effect by inhibiting liver tumor necrosis factor α (TNF‐α) generation, an effect that culminated in reduced liver adhesion molecule expression. Hypertonic saline pretreatment was shown to augment liver interleukin 10 (IL‐10) expression following I/R, as a potential mechanism underlying its anti‐inflammatory effect. To examine the role of IL‐10 in the protective effect of hypertonic saline on liver I/R injury, we used a murine model of I/R. In wild type mice, hypertonic pretreatment similarly prevented liver injury induced by I/R. However, in IL‐10 knockout animals, hypertonic pretreatment was unable to prevent the liver enzyme release, TNF‐α generation, or neutrophil sequestration induced by I/R. In conclusion, these findings define a novel mechanism responsible for the anti‐inflammatory effects of hypertonic saline and also suggest a potential clinical role for hyperosmolar solutions in the prevention of liver injury associated with I/R. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2004;40:211–220.)

Peripheral vascular disease: who gets it and why? A histomorphological analysis of 261 arterial segments from 58 cases.

Aims: This retrospective study aimed to document and illustrate the histomorphological changes underlying peripheral vascular disease (PVD). More specifically, it aimed to analyse and quantify those changes that lead to lower limb amputations. Histological changes were assessed in relation to various clinical pathologies, and significant correlations were sought thereafter. Methods: A total of 1305 arterial segments were examined from 58 consecutive patients undergoing a lower limb amputation from January 2002 to December 2003. Serial arterial segments were taken from the femoral, popliteal, anterior tibial, posterior tibial, peroneal, and dorsalis pedis arteries, and the degrees of atherosclerotic stenosis and medial calcification were histologically quantified. Results: Atherosclerosis was associated with severe arterial stenosis. An increased occurrence of severe atherosclerotic narrowing coincided with increasing patient age (p = 0.0166), hypertension (p = 0.0019), and diabetes mellitus (p = 0.0036). The presence of medial calcification was an important pathological feature in patients under 70 years of age (p = 0.0308) and significantly more severe in those with diabetes mellitus (p <0.001). Conclusion: Atherosclerosis and medial calcification are significant underlying lesions in diabetic patients undergoing lower limb amputation. Medial calcification can cause significant stiffening of the arterial wall and a reduction in its ability to respond to vasodilator stimuli.

Radiofrequency In Situ Fenestration for Aortic Arch Vessels During Thoracic Endovascular Repair

Purpose: To report the first clinical application of a novel technique using radiofrequency puncture to create retrograde in situ fenestrations during thoracic endovascular aortic repair (TEVAR). Methods: Between June 2011 and December 2013, 40 TEVAR procedures were performed in our facility, including 10 cases in which in situ fenestration was planned. Two thoracic stent-graft models were deployed: the Valiant (n=5) and the Zenith TX2 (n=5). A 0.035-inch PowerWire radiofrequency guidewire delivered from a brachial approach was used to fenestrate the grafts covering a left subclavian artery (LSA) in 9 cases and a left common carotid artery in one. The fenestrations were serially dilated to 6 mm, and self-expanding Advanta V12 covered stents were positioned in the target arteries. Results: Technical success was achieved in 6 of the 10 planned cases. Of the remaining 4 cases, stent-grafts were deployed in zone 3 in 2 cases (one received a chimney to the LSA). Another stent-graft was deployed in zone 2 without endoleak after fenestration was abandoned (the LSA had good filling via the vertebral artery). In the last case, the fenestration was unsuccessful in double-layered (proximal extension overlap) stent-grafts; a carotid-axillary bypass was required. There were no fenestration-related complications, but overall surgical complications included a case of paraparesis that resolved following spinal drainage and a death from a preexisting aortoesophageal fistula. There were no postoperative strokes. All fenestrations remained patent, and there were no endoleaks at a mean 12-month follow-up (range 1–33). Conclusion: Radiofrequency puncture is a viable alternative to needle or laser punctures for in situ fenestration during TEVAR. Early clinical results suggest technical feasibility and acceptable early outcomes.

Iliac branch graft in the treatment of complex aortoiliac aneurysms: early results from a North American institution.

PURPOSE To describe early experience with the use of iliac branch grafts (IBGs) in aortoiliac aneurysm repair. MATERIALS AND METHODS From July 2007 to August 2009 (25 months), 14 patients (13 men, one woman) with a mean age of 70.1 years (range, 59.3-80.0 y) were treated with IBGs. Indications were abdominal aneurysm with common iliac artery (CIA) involvement (n = 11), juxtarenal aortic aneurysm with CIA involvement (n = 1), and bilateral CIA and internal iliac artery (IIA) aneurysms (n = 1). Postoperative endoleaks and patency rate were determined with computed tomography within 1 month of implantation and 1 year thereafter, with concurrent clinical evaluation for pelvic ischemia. Mean follow-up period was 18.7 months (range, 6-35 mo). RESULTS Technical success rate, as defined by successful implantation of IBG with no intraprocedural type I or type III endoleak, was 86% (12 of 14). A total of 14 IBGs were successfully deployed in 12 patients. Two cases of technical failure were related to excessive iliac tortuosity. The mean hospitalization duration was 6.5 days (range, 3-14 d), with zero mortality at 30 days. There were two cases of type II endoleak treated conservatively and a single case of IBG-related type III endoleak that required repeat intervention. The rest of the stent-implanted aortic and iliac aneurysms remained stable in size, with no aneurysm rupture or death recorded. All stent-implanted iliac branches remained patent on follow-up. None of the patients who received IBGs had new symptoms of pelvic ischemia. CONCLUSIONS Iliac branch graft placement is a feasible technique with excellent short-term results in the treatment of aortoiliac aneurysms.

Acute thrombosis of an abdominal aortic aneurysm presenting as cauda equina syndrome

Acute aortic occlusion is an uncommon vascular emergency that can present with predominantly neurologic symptoms owing to spinal cord ischemia. We describe a 62-year-old woman who experienced acute thrombosis of an abdominal aortic aneurysm that initially presented as cauda equina syndrome. She was treated operatively with an axillary bifemoral bypass. Our case report is followed by a discussion of acute aortic occlusion.

Neoadjuvant Aortic Endografting

The advent and success of endovascular repair of abdominal aneurysms led to the development of catheter-based techniques to treat thoracic aortic pathology. Such diseases, including thoracic aortic aneurysms, acute and chronic type B dissections, penetrating aortic ulcers, and traumatic aortic transection, challenge surgeons to perform complex open operative repairs in high-risk patients. The minimally invasive nature of thoracic endografting provides an attractive alternative therapy. We present two cases of covered stent grafts deployed in the thoracic aorta to perform resection of the aortic wall infiltrated by malignancy in order to avoid a major vascular intervention and a traditional vascular graft interposition. This may become a potential new utility for aortic endografts.

Popliteal vein aneurysm.

Although popliteal venous aneurysms are uncommon, they are also potentially fatal because they can cause a pulmonary embolism. The authors report a case of a popliteal vein aneurysm in a healthy, asymptomatic 32-year-old patient as well as a review of the literature. Popliteal venous aneurysms are a rare but treatable cause of recurrent pulmonary embolism, with their true incidence probably being underestimated. Whenever possible, we recommend early surgical repair of both symptomatic and asymptomatic popliteal venous aneurysms because they are associated with an ill-defined risk of pulmonary embolism and death if left untreated.

Internal Iliac Aneurysm Repair Outcomes Using a Modification of the Iliac Branch Graft

OBJECTIVES Iliac branch grafts (IBGs) are a validated option for the treatment of aorto-iliac aneurysms preserving internal iliac artery (IIA) flow. IIA aneurysm (IIAA) is a relative contraindication to IBG placement. The goal of this study was to review experience in managing aorto-iliac aneurysms with concomitant IIAAs with extension of the IIA branch stent graft into the superior gluteal artery (SGA). METHODS This retrospective study between May 2009 and November 2014 includes consecutive patients who underwent placement of an IBG (Cook, Bloomington, IN, USA) with extension of the internal iliac component of the branch stent graft into the SGA because of aneurysmal IIA (>15 mm). The stent grafts used were Viabahn (Gore, Karlsruhe, Germany), Fluency (Bard, Flagstaff, AZ, USA), or iCast (Atrium, Hudson, NH, USA) proximally. Imaging follow up was with computed tomography angiography (CTA) within 30 days of device insertion and then annually. RESULTS The procedure was performed on 15 patients with a mean age of 76.8 years (SD 6.1 years). Twenty IIAAs were treated with a mean IIA and common iliac artery (CIA) diameter of 33 mm (SD 13 mm) and 35 mm (SD 11 mm) respectively. Technical success rate was 100%. One patient who underwent simultaneous IBG and three vessel fenestrated endovascular aneurysm repair died of mesenteric ischemia 2 days after the procedure. Mean imaging follow up with CTA was 18.3 months (SD 15.1 months). Primary patency of the SGA stent grafts was 100%. There was one case of type II endoleak. All patients were free from buttock claudication at follow up (mean: 19.7 months). Two patients who had IIA embolization contralateral to the IBG placement suffered from unilateral lower limb monoparesis. CONCLUSIONS Extension of the internal iliac component of IBGs into the SGA for distal seal is feasible and safe in the endovascular treatment of aorto-iliac aneurysms with concomitant IIAs. Long-term results are needed to further validate this technique.