Management of chronic atherosclerotic mesenteric ischemia.

Chronic mesenteric ischemia (CMI) is most likely caused by atherosclerosis and less frequently by external compression, fibromuscular dysplasia and vasculitis. Symptomatic CMI is an uncommon, potentially under-diagnosed condition caused by fixed stenoses or occlusion of in most conditions at least two visceral arteries. If only one of the three major bowel providing arteries - the celiac trunk, the superior and inferior mesenteric arteries - is affected, the patient is usually asymptomatic due to a tight collateral network. Symptoms and clinical signs of CMI may vary from the classical triad of postprandial pain, weight loss and upper abdominal bruit to nonspecific symptoms thus frequently resulting in delayed diagnosis. Established non-invasive diagnostic means are duplex ultrasound or CT- and MR-angiography offering excellent three dimensional reconstruction of the vessel pathology facilitating the decision for the appropriate revascularisation strategy. During the last decade, despite higher restenosis rates endovascular revascularization has replaced surgical revascularization as therapy of choice in most centers. If untreated CMI of atherosclerotic origin is associated with a high morbidity and mortality. This manuscript reviews the most relevant clinical aspects of the disease and the current practice of diagnosis and treatment of CMI.

Acute and long-term outcome of Silverhawk assisted atherectomy for femoro-popliteal lesions according the TASC II classification: a single-center experience.

BACKGROUND: Directional atherectomy (DA) has become popular in some centers to remove atherosclerotic plaques in femoro-popliteal lesions. Although immediate and also short - term outcome data are promising, solid long-term data are warranted to justify the widespread use in daily practice. PATIENTS AND METHODS: In this prospective study de novo and restenotic lesions of the femoro-popliteal segments were treated with the Silverhawk device. 161 consecutive patients (164 lesions) with peripheral artery disease (PAD) Rutherford classes 2 to 5 were included from June 2002 to October 2004 and October 2006 to June 2007 (59 % male, mean age 67 +/- 11 years, range 40 to 88) and the outcome analyzed according to the TASC II classification. RESULTS: DA alone was performed successfully in 28 % (n = 46), adjunctive balloon angioplasty in 65 % (n = 107) and stenting in 7 % (n = 11). The overall technical success rate was 76 % (124 / 164) and the procedural success rate 95 % (154 / 164). At 12 months primary patency rate was 61 % (85 / 140) and the secondary patency rate was 75 % (105 / 140) in the entire cohort, being less favourable in TASC D compared to TASC A to C lesions (p = 0.034 and p < 0.001, respectively). Furthermore the restenosis rate differed trendwise (p = 0.06) between de novo and restenotic lesions. Changes in the ABI and the Rutherford classes were significantly in favour of TASC A to C lesions compared to TASC D after 12 months (p = 0.004). The event free survival (MI, TIA, or restenosis) was 48 % at 12 months and 38.5 % at 24 months. Predictor for restenosis in the multivariable analysis was only male gender (p=0.04). CONCLUSIONS: The results in TASC D lesions are inferior to those in the lesser stages. DA of femoro-popliteal arteries leads shows a trend to better long-term technical and clinical outcome in de novo lesions compared to restenotic lesions.

The potential role of DES in peripheral in-stent restenosis.

In-stent restenosis (ISR) after non-coronary interventions is becoming an increasing clinical and technical problem in daily practice due to the more liberal use of stents particularly in femoro-popliteal and infra-popliteal interventions. Whereas in the coronaries the role of drug eluting stents (DES) in the treatment of ISR is already well defined, very limited data exist about the use of DES in the treatment of ISR in non-coronary arteries. So far little data is published on the potential role of DES in in-stent restenosis except in renal artery interventions. The concept of DES in femoro-popliteal lesions even excluding ISR so far failed for sirolimus and everolimus eluting self-expanding stents. In infra-popliteal lesions promising single centre reports have already been published. Own single center reports showed favorable patency rates for the treatment of renal artery ISR. So far, only one study - the Zilver(R) PTX(R) single arm study - investigates in a subcohort of 120 of 818 lesions the outcome of a paclitaxel eluting DES in treating ISR in femoro-popliteal arteries. The Zilver(R) PTX(R) stent consists of a self-expanding nitinol stent platform with a polymer free paclitaxel coating with a dose density of 3 mg/mm2. In an interim analysis the freedom from target lesion revascularization is 78% after one year. Even if not yet having data for primary and secondary patency available, these results compare favorably with alternative treatment options such as plain balloon angioplasty and cutting balloon angioplasty or even directional atherectomy. No data have been published or presented yet about the treatment of infra-popliteal ISR. Randomized comparative trials comparing dedicated DES with standard interventional techniques such as plain old balloon angioplasty for the treatment of ISR in femoro-popliteal and infra-popliteal ISR are mandatory.

Occlusion of iatrogenic pseudoaneurysms with percutaneous ultrasound guided thrombin injection.

BACKGROUND: Pseudoaneurysm is a common complication of cardiac catheterization and coronary intervention with an incidence of 2% even in experienced centers. PATIENTS AND METHODS: In a feasibility study conducted between December 2004 and February 2006 we enrolled 76 patients consecutively to receive local thrombin injection (mean 329 IU; range 100-800 IU) into the aneurysma sac. RESULTS: Ultrasound guided thrombotic occlusion of pseudoaneurysms was successful after one injection in 83% of the patients, 17% of the patients required more than one injection. The overall success rate of the procedure was 98,9%. No peripheral embolisation of thrombin was noted during any injection and we registered no other complication that needed any further intervention. CONCLUSIONS: We conclude that ultrasound guided occlusion of pseudoaneurysms using thrombin injection with a success rate of the procedure of 98,9% is feasible and safe.

Role of superoxide dismutase in in vivo and in vitro nitrate tolerance.

We assessed whether pharmacological inhibition of CuZn-superoxide dismutase (SOD) mimics the molecular mechanism of either in vitro or in vivo nitrovasodilator tolerance. In endothelium-intact aortic rings from in vivo tolerant rabbits the GTN- and acetylcholine (ACh)-induced maximal relaxation was attenuated by 36 and 23%, respectively. In vitro treatment of control rings with GTN (1 h 10 microM) similarly attenuated the vasorelaxant response to GTN, but not to ACh. Formation of superoxide radicals (*O2-) in endothelium-intact rings (lucigenin-chemiluminescence) increased 2.5 fold in in vivo tolerance, but significantly decreased in in vitro tolerance. The membrane associated NADH oxidase activity was increased 2.5 fold in homogenates of in vivo tolerant aortae, but was not changed in in vitro tolerant aorta. Conversely, SOD activity and protein expression was halved in in vivo tolerance, but SOD activity was not altered by in vitro tolerance. The *O2- scavenger tiron (10 mM) effectively restored the vasorelaxant response to GTN in in vivo tolerant aortic rings, but not the reduced response to GTN in in vitro tolerant rings. Pretreatment (1 h) of vessels with diethyldithiocarbamate (DETC; 10 mM) attenuated vasorelaxant responses to GTN and ACh, increased vascular *O2- production, and inhibited SOD activity in vessel homogenates to a similar degree as observed in in vivo tolerance. DETC-treatment of in vivo-tolerant vessels induced an additional increase in *O2- production. Increased *O2- production in in vivo nitrate tolerant aorta is associated with activation of vascular NADH oxidase and inactivation of CuZnSOD. Therefore, in vivo tolerance can be mimicked by in vitro inhibition of CuZnSOD, but not by in vitro exposure to GTN, which does not affect vascular *O2- production, NADH oxidase and CuZnSOD.

Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system.

BACKGROUND: Angiotensin II activates NAD(P)H-dependent oxidases via AT1-receptor stimulation, the most important vascular source of superoxide (O2*-). The AT1 receptor is upregulated in vitro by low-density lipoprotein. The present study was designed to test whether hypercholesterolemia is associated with increased NAD(P)H-dependent vascular O2*- production and whether AT1-receptor blockade may inhibit this oxidase and in parallel improve endothelial dysfunction. METHODS AND RESULTS: Vascular responses were determined by isometric tension studies, and relative rates of vascular O2*- production were determined by use of chemiluminescence with lucigenin, a cypridina luciferin analogue, and electron spin resonance studies. AT1-receptor mRNA was quantified by Northern analysis, and AT1-receptor density was measured by radioligand binding assays. Hypercholesterolemia was associated with impaired endothelium-dependent vasodilation and increased O2*- production in intact vessels. In vessel homogenates, we found a significant activation of NADH-driven O2*- production in both models of hyperlipidemia. Treatment of cholesterol-fed animals with the AT1-receptor antagonist Bay 10-6734 improved endothelial dysfunction, normalized vascular O2*- and NADH-oxidase activity, decreased macrophage infiltration, and reduced early plaque formation. In the setting of hypercholesterolemia, the aortic AT1 receptor mRNA was upregulated to 166+/-11%, accompanied by a comparable increase in AT1-receptor density. CONCLUSIONS: Hypercholesterolemia is associated with AT1-receptor upregulation, endothelial dysfunction, and increased NADH-dependent vascular O2*- production. The improvement of endothelial dysfunction, inhibition of the oxidase, and reduction of early plaque formation by an AT1-receptor antagonist suggests a crucial role of angiotensin II-mediated O2*- production in the early stage of atherosclerosis.

Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase C.

BACKGROUND: Angiotensin II infusion has been shown to cause hypertension and endothelial dysfunction and to increase superoxide (O-.2) production in vascular tissue, mainly via an activation of nicotinamide adenine dinucleotide (phosphate) [NAD(P)H]-dependent oxidase, the most significant O-.2 source in endothelial and/or smooth muscle cells. With these studies, we sought to determine whether endothelial dysfunction in renovascular hypertension is secondary to an activation of these oxidases. METHODS: Endothelial function in aortas from rats with two kidney-one clip (2K-1C) hypertension and age-matched controls was assessed using isometric tension studies in organ chambers. Changes in vascular O-.2 production were measured using lucigenin-enhanced chemiluminescence and electron spin resonance spectroscopy. RESULTS: In hypertensive animals, relaxation to endothelium-dependent (acetylcholine) and endothelium-independent nitrovasodilators (nitroglycerin) was impaired. Constriction to a direct activator of protein kinase C (PKC) phorbol ester 12,13 dibutyrate (PDBu) was enhanced, and vascular O-.2 was significantly increased compared with controls. Vascular O-.2 was normalized by the PKC inhibitor calphostin C, by the inhibitor of flavin-dependent oxidases, diphenylene iodonium, and recombinant heparin-binding superoxide dismutase, whereas inhibitors of the xanthine oxidase (oxypurinol), nitric oxide synthase (NG-nitro-l-arginine) and mitochondrial NADH dehydrogenase (rotenone) were ineffective. Studies of vascular homogenates demonstrated that the major source of O-.2 was a NAD(P)H-dependent oxidase. Incubation of intact tissue with PDBu markedly increased O-. 2, the increase being significantly stronger in vessels from hypertensive animals as compared with vessels from controls. Endothelial dysfunction was improved by preincubation of vascular tissue with superoxide dismutase and calphostin C. CONCLUSIONS: We therefore conclude that renovascular hypertension in 2K-1C rats is associated with increased vascular O-.2 leading to impaired vasodilator responses to endogenous and exogenous nitrovasodilators. Increased vascular O-.2 is likely secondary to a PKC-mediated activation of a membrane-associated NAD(P)H-dependent oxidase.