Attenuation of myocardial injury by HMGB1 blockade during ischemia/reperfusion is toll-like receptor 2-dependent.

Genetic or pharmacological ablation of toll-like receptor 2 (TLR2) protects against myocardial ischemia/reperfusion injury (MI/R). However, the endogenous ligand responsible for TLR2 activation has not yet been detected. The objective of this study was to identify HMGB1 as an activator of TLR2 signalling during MI/R. C57BL/6 wild-type (WT) or TLR2(-/-)-mice were injected with vehicle, HMGB1, or HMGB1 BoxA one hour before myocardial ischemia (30 min) and reperfusion (24 hrs). Infarct size, cardiac troponin T, leukocyte infiltration, HMGB1 release, TLR4-, TLR9-, and RAGE-expression were quantified. HMGB1 plasma levels were measured in patients undergoing coronary artery bypass graft (CABG) surgery. HMGB1 antagonist BoxA reduced cardiomyocyte necrosis during MI/R in WT mice, accompanied by reduced leukocyte infiltration. Injection of HMGB1 did, however, not increase infarct size in WT animals. In TLR2(-/-)-hearts, neither BoxA nor HMGB1 affected infarct size. No differences in RAGE and TLR9 expression could be detected, while TLR2(-/-)-mice display increased TLR4 and HMGB1 expression. Plasma levels of HMGB1 were increased MI/R in TLR2(-/-)-mice after CABG surgery in patients carrying a TLR2 polymorphism (Arg753Gln). We here provide evidence that absence of TLR2 signalling abrogates infarct-sparing effects of HMGB1 blockade.

Median arcuate ligament syndrome: vascular surgical therapy and follow-up of 18 patients.

INTRODUCTION: The median arcuate ligament syndrome (MALS) or celiac artery compression syndrome is a rare vascular disorder caused by an extrinsic compression of the celiac artery from the median arcuate ligament, prominent fibrous bands, and ganglionic periaortic tissue. Clinical symptoms are postprandial abdominal pain, nausea, vomiting, unintentional weight loss, and sometimes, abdominal pain during body exercise caused by an intermittent visceral ischemia. The aim of this study was to evaluate the operative management of patients with MALS in our institution, especially in consideration of various vascular reconstructive techniques. PATIENTS AND METHODS: Between June 2000 and January 2009, a total of 341 patients were treated in our department for vascular pathologies of the visceral arteries (225 chronic visceral ischaemia, 84 acute visceral ischaemia, and 14 visceral artery aneurysms). In a retrospective study of 18 patients with MALS, the records, clinical symptoms, diagnostic evaluation, and surgical procedures were compiled. This was completed by a reassessment for a follow-up. RESULTS: A MALS was diagnosed in 15 female (83.3%) and three male (16.7%) patients. The mean patient age was 46.2 years (range 20-68 years). The diagnosis of MALS was based on a radiological analysis in all patients by a digitally subtracted angiogram, but duplex ultrasound was used lately more frequently to study the influence of respiration on the stenotic degree of the celiac trunk. All 18 patients were treated with open surgery in an elective situation. Due to the local and specific pathology of the celiac trunk with a fixed stricture or stenosis, out of 18 cases beside decompression, 11 (primary, seven; secondary, four patients) further procedures were performed on the celiac artery (aorto-celiac vein interposition n = 6, aorto-hepatic vein interposition n = 1, resection of the celiac artery and end-to-end anastomosis n = 2, patchplasty of the celiac artery with vein n = 1, and transaortic removal of a stent of the celiac artery n = 1) Follow-up was obtained in 15 patients (83.33%) with a mean duration after surgery of about three and a half years (40.68 months, range from 2 to 102 months). Eleven of the 15 patients (73.33%) were completely free of abdominal symptoms, and nine of them had gained between 3 and 10 kg in weight after surgery. The weight of two patients remained stable. Of the 11 patients with a successful outcome in the follow-up, six of them had undergone decompression solely. In the other five patients, vascular co-procedures on the celiac trunk had been performed. CONCLUSIONS: The MALS is a rare vascular disorder caused by an extrinsic compression of the celiac artery and induces upper abdominal, mostly, postprandial pain. A definite diagnosis of MALS can be achieved by lateral aortography of the visceral aorta and its branches during inspiration and expiration. Open surgical therapy is a safe and reliable procedure with no mortality and low morbidity. As to the local and specific pathology of the celiac trunk after decompression with fixed stricture or stenosis, further vascular procedures are necessary. The long-time follow-up seemed adequate. The laparoscopic approach reduces the procedure of decompression only, something which seemed inadequate for most cases. Endovascular treatment with percutaneous transluminal angioplasty and insertion of a stent does not solve the underlying problem of extrinsic compression of the celiac trunk and often requires open procedures during the long-term course. Due to the low incidence of MALS, no guidelines will do justice to all the patients sufficiently, and the choice of treatment must depend on the specific clinical situation for each patient.

Visceral artery aneurysms--follow-up of 23 patients with 31 aneurysms after surgical or interventional therapy.

PURPOSE: Visceral artery aneurysms (VAA) are rare forms of vascular pathology, with an incidence of 0.1% to 0.2% in routine autopsies. They frequently present as a life-threatening, often fatal, emergency, if associated with rupture and intra- or retroperitoneal bleeding. The clinical symptoms, natural history, and mortality of VAAs vary depending on the vessels involved. The mortality rates range from 8.5% up to 25% and, in pregnant women, up to 75%. A retrospective analysis of all VAAs diagnosed at our institution from 1991 to 2006 was performed. The presentation, management, and outcome of therapy was evaluated for each patient. MATERIALS AND METHODS: Twenty-three patients (12 men, 11 women, mean age 55.8 years) with 31 VAAs were identified. The anatomical involvement concerned seven regions: celiac (CT) nine, superior mesenteric (SMA) seven, splenic (SA) five, hepatic (HA) six, gastroduodenal (GDA) two, pancreatoduodenal (PDA) one, and one branch of the superior mesenteric artery. Fourteen patients presented symptoms attributable to their aneurysms, which included a total of four ruptures. Nine patients had no symptoms. The etiology of VAAs was atherosclerosis (67.8%), mycotic embolization (12.9%), trauma (9.7%), Marfan Syndrome (3.2%), Klippel-Trenaunay-Weber syndrome (3.2%), and giant cell arteritis (3.2%). Open surgery was performed for 29 aneurysm in 21 patients: partial resection and tailoring in 13 cases (41.9%), resection of the aneurysm with additional autologous vein graft interposition in nine cases and prosthetic graft interposition in 2 cases (35.5%), aneurysm exclusion by ligation in three cases (9.6%) and aneurysm ligation combined with additional autologous bypass procedure in two cases (6.5%). Two patients (6.5%) were treated interventionally with embolization, in one case each with a right hepatic artery aneurysm and in the other with splenic artery aneurysm. RESULTS: No deaths were observed. The morbidity rate associated with surgical treatment was low. After treatment, a total of 17 patients were followed up for a period ranging from 3 to 154 months (mean 54.6 months). Fifteen patients required no additional procedures. The patency rate of the reconstructed visceral arteries was 90.4%. Six patients were lost for follow-up. CONCLUSIONS: Surgical and interventional therapy of VAAs can be life-saving treatments for the patient with a low periprocedural morbidity. The success rate, defined as the exclusion of VAA rupture and the absence of abdominal discomfort, in our material was 88.2% after a mean follow-up of 54.6 months.

Akt or phosphoinositide-3-kinase inhibition reverses cardio-protection in Toll-like receptor 2 deficient mice.

AIM: Absence or inhibition of Toll-like receptor 2 (TLR2) signalling during murine myocardial ischaemia/reperfusion (MI/R) decreases myocardial necrosis and inflammation, thereby ameliorating cardiac dysfunction and improving survival. In the present study, we provide evidence for the involvement of the phosphoinositide-3-kinase/Akt pathway in TLR2-dependent reperfusion injury. METHODS: Adult male wild-type (WT) and TLR2(-/-) mice were subjected to myocardial ischaemia (30min) and reperfusion (4h). Animals were treated with phosphoinositide-3-kinase inhibitor wortmannin, Akt inhibitor V (triciribine), or vehicle 1h prior to MI/R. Protein expression levels of Akt1 and phosphoinositide-3-kinase and their respective phosphorylated forms were determined by Western blot analysis. Myocardial necrosis was quantified after staining with the tetrazolium method and by troponin T plasma levels. RESULTS: TLR2(-/-) mice displayed significantly increased Akt and phospho-Akt levels compared to WT mice, whilst no significant difference in phosphoinositide-3-kinase expression and phosphorylation could be observed. TLR2(-/-) mice also showed a blunted myocardial necrosis, the extent of which inversely correlated with Akt expression and degree of phosphorylation. Pharmacological inhibition of both, phosphoinositide-3-kinase or Akt, reversed the cardioprotection observed in TLR2(-/-) mice, whilst no effect could be observed in WT mice. CONCLUSION: Akt is an important mediator of cardioprotection in TLR2(-/-) animals during MI/R. The effect is, however, likely mediated by its genomic overexpression in the heart of TLR2(-/-) animals whilst Akt activation by phosphoinositide-3-kinase is unaltered.