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Background. We evaluated cerebrovascular events (CVE) after kidney transplantation (KTx) and sought to identify pre-transplant predictors of transient ischaemic attacks (TIA) and strokes post-transplantation. Methods. A total of 1617 consecutive kidney and 16 kidney–pancreas recipients transplanted between 1995 and 2005wereanalysedinthisretrospectivesingle-centrestudy. Risk factors for CVE, e.g. recipient and donor age and gender, diagnosis of chronic kidney disease, end-stage renal disease (ESRD) duration, histories of hypertension, hyperlipidaemia, smoking, atrial fibrillation (AF), diabetes mellitus (DM), ischaemic heart, peripheral- and cerebrovascular disease, as well as pre-transplant myocardial infarction or CVE (i.e. TIA/strokes) were analysed. Furthermore, the predictive value of pre-transplant screening tests, i.e. echocardiography (n = 1184) and carotid ultrasound (n = 922), was investigated. Results. During a median follow-up of 4 years, 64 CVE (54 strokes and 10 TIA) were observed. Nineteen (5.1%) of 373 deceased patients died from fatal stroke. Recipient age, history of AF and hyperlipidaemia (P = 0.00, respectively), reduced left ventricular function (LVF) (P = 0.01) andthedegreeofstenosisbycarotidultrasound(P =0.002), duration of ESRD (P = 0.03) and interstitial nephritis as renal disease cause (P = 0.04) evolved as predictors of TIA/stroke post-transplant in univariate analysis. In multivariable analysis, AF (P = 0.001) and DM (P = 0.037) were significant predictors for post-transplant CVE. Conclusions. AF and DM are independent predictors of CVE after KTx. Beyond their general ability to detect severely comorbid patients, pre-transplant screening tests (e.g. carotid ultrasound or echocardiography) were not able to identify renal transplant candidates at risk for CVE after transplantation.

Endovascular therapy is a rapidly evolving field for the treatment of patients with peripheral arterial disease, and a magnitude of studies reporting on various modern revascularization concepts have been recently published. Thus, studies assessing the efficacy of endovascular therapy of peripheral arteries do not operate with uniformly defined endpoints, rendering a direct comparison of studies difficult. The purpose of this consensus statement is to highlight differences in the terminology used in the current literature and to propose some standardized criteria that must be considered when reporting results of endovascular revascularization for chronic ischaemia of lower limb arteries.

Remnant cholesterol has been defined as the cholesterol present in triglyceride-rich remnant lipoproteins. Elevated levels of remnant cholesterol have been associated with increased cardiovascular risk. Acute myocardial infarction (AMI) in very young individuals (≤40 years) represents a rare disease with a typical risk factor profile and a lipid phenotype that is characterized by a predominance of elevated triglyceride-rich lipoproteins.The aim of this study was to investigate the role of remnant cholesterol in premature AMI.We prospectively enrolled 302 patients into our multicenter case-control study comprising 102 consecutive myocardial infarction survivors (≤40 years) and 200 hospital controls. Myocardial infarction patients were frequency matched for age, gender, and center. Remnant cholesterol was calculated from standard lipid parameters.Remnant cholesterol was 1.7-fold higher in premature AMI patients compared with controls (61.1 ± 36.8 vs 35.8 ± 16.8 mg/dL; P.001). Remnant cholesterol was the lipid fraction most strongly associated with premature myocardial infarction (odds ratio 3.87; 95% confidence interval 2.26-6.64; P.001) for an increase of 1-standard deviation. This observation was independent from clinical risk factors and plasma lipid levels.Remnant cholesterol is strongly associated with premature myocardial infarction, can be easily calculated, and might serve as a new potent risk marker in this young patient population.

Background There is growing evidence that the predictive value of HDL cholesterol levels for cardiovascular risk stratification is limited in patients with coronary artery disease (CAD). HDL function seems to be a more sensitive surrogate of cardiovascular risk estimation than simple serum levels. Therefore, we aimed to assess whether impaired antioxidant HDL function is involved in the development of premature acute myocardial infarction (AMI). Methods In this multicentre case–control study, we compared the antioxidant function of HDL, measured by the HDL inflammatory index (HII), and HDL particle size in 184 patients comprising 92 patients with AMI at a very young age (≤40 years of age) and 92 age- and gender-matched controls. Results Antioxidant capacities of HDL were significantly impaired in the acute phase of AMI (HII of 1·50 [IQR 1·10–1·74] vs. 0·56 [IQR 0·41–0·86] in controls, P

Background and Purpose— Dental and periodontal disease are potentially involved in the pathogenesis of atherosclerosis. We investigated whether dental and periodontal status is associated with the presence and future progression of carotid stenosis. Methods— We randomly selected 411 of 1268 participants from the prospective Inflammation and Carotid Artery Risk for Atherosclerosis Study and evaluated dental and periodontal status and oral hygiene at baseline measuring three World Health Organization-validated indices: DMFT (decayed, missing, filled teeth), SLI (Silness-Löe Index), and CPITN (community periodontal index for treatment needs), respectively. The degree of carotid stenosis was measured by duplex ultrasound at baseline and after median 7.5 months (range=6 to 9 months) to identify patients with progressive carotid stenosis. Results— DMFT ( P P =0.048), CPITN ( P =0.007), and edentulousness ( P =0.007) were associated with the baseline degree of carotid stenosis. Atherosclerosis progression was observed in 48 of 411 patients (11.7%). DMFT (adjusted odds ratio [OR]=1.11, 95% CI=1.01 to 1.22, P =0.032) and SLI (adjusted OR=1.77, 95% CI=1.09 to 2.79, P =0.021), but not CPITN (adjusted OR=1.51, 95% CI=0.89 to 2.45, P =0.16) were significant predictors of disease progression, irrespective of traditional cardiovascular risk factors and the baseline degree of stenosis. Edentulous patients had a significantly increased risk for disease progression as compared with patients with teeth (adjusted OR=2.10, 95% CI=1.06 to 4.16, P =0.33). Conclusion— Dental status, oral hygiene, and particularly tooth loss are associated with the degree of carotid stenosis and predict future progression of the disease.

Because stent implantation for disease of the superficial femoral artery has been associated with high rates of late clinical failure, percutaneous transluminal angioplasty is preferred for endovascular treatment, and stenting is recommended only in the event of suboptimal technical results. We evaluated whether primary implantation of a self-expanding nitinol (nickel-titanium) stent yielded anatomical and clinical benefits superior to those afforded by percutaneous transluminal angioplasty with optional secondary stenting.We randomly assigned 104 patients who had severe claudication or chronic limb ischemia due to stenosis or occlusion of the superficial femoral artery to undergo primary stent implantation (51 patients) or angioplasty (53 patients). Restenosis and clinical outcomes were assessed at 6 and 12 months.The mean (+/-SD) length of the treated segment was 132+/-71 mm in the stent group and 127+/-55 mm in the angioplasty group. Secondary stenting was performed in 17 of 53 patients (32 percent) in the angioplasty group, in most cases because of a suboptimal result after angioplasty. At 6 months, the rate of restenosis on angiography was 24 percent in the stent group and 43 percent in the angioplasty group (P=0.05); at 12 months the rates on duplex ultrasonography were 37 percent and 63 percent, respectively (P=0.01). Patients in the stent group were able to walk significantly farther on a treadmill at 6 and 12 months than those in the angioplasty group.In the intermediate term, treatment of superficial-femoral-artery disease by primary implantation of a self-expanding nitinol stent yielded results that were superior to those with the currently recommended approach of balloon angioplasty with optional secondary stenting. (ClinicalTrials.gov number, NCT00281060.).

BACKGROUND AND STUDY AIMS Strictures are a substantial cause of morbidity in patients with Crohn's disease. Endoscopic balloon dilation is a therapeutic option in limited strictures to avoid intestinal surgery, although there have been few reports regarding the long-term outcome. PATIENTS AND METHODS Balloon dilation was scheduled for 46 patients (26 women, 20 men; median age 34) with Crohn's-associated symptomatic and radiographically confirmed intestinal stenosis. The study plan envisaged up to four consecutive treatments within the first 2 months until relief of symptoms, and thereafter dilations depending on clinical requirements. RESULTS Dilation was not possible in seven of the 46 patients (15 %), due to technical problems (n = 2), internal fistulas (n = 3), or absence of a stenosis (n = 2). Thirty-nine patients received at least one treatment. The site of obstruction was the ileocolonic anastomosis in 23 of the 39 patients (59 %) and surgically untreated areas in 16 patients (41 %). After the initial dilation series (median 1, interquartile range 1-2), strictures were traversed in 37 of the 39 patients (95 %). During a median follow-up period of 21 months (range 3-98 months), 24 of the 39 patients (62 %) underwent a repeat intervention, including 12 (31 %) with repeat dilation, 11 (28 %) with surgical resection, and one patient who received an intestinal stent. The cumulative percentages of patients without a repeat intervention or surgery at 6, 12, 24, and 36 months were 68 %, 48 %, 36 %, and 31 %, and 97 %, 91 %, 84 % and 75 %, respectively. Two perforations and one case of severe bleeding were seen in the 73 dilation procedures (4 %) performed. CONCLUSIONS Endoscopic balloon dilation is a safe and effective method that allows surgery to be avoided in approximately 75 % of patients with Crohn's-associated short intestinal strictures. However, recurrent symptoms frequently make it necessary to repeat the procedure.

PURPOSE To evaluate immediate and midterm clinical outcomes after percutaneous transluminal angioplasty (PTA) of deep femoral artery stenosis in patients with chronically occluded superficial femoral arteries (SFA) and to report the results of a systematic review of the literature in this field. METHODS A retrospective analysis was conducted of 55 consecutive patients (42 men; median age 72 years, interquartile range [IQR] 63-79) with severe intermittent claudication (n = 38) or critical limb ischemia (n = 17) who underwent balloon angioplasty of deep femoral artery stenosis. Patients were followed with ankle-brachial index (ABI) measurement, estimation of maximum walking capacity, clinical staging of peripheral artery disease (PAD), and duplex ultrasound imaging for restenosis. A systematic review of the literature using MEDLINE, EMBASE, and a hand search was done. RESULTS Technical success (residual stenosis < 30%) was achieved in 85% (47/55), with 1 (2%) minor complication. The median ABI marginally increased from 0.48 at baseline to 0.53 post intervention without significant difference in the change of ABI between patients with supra- or infragenicular reconstitution of the femoropopliteal runoff. During a median 13-month (IQR 3-42) follow-up, no significant improvement in ABI or walking distance was maintained, and only 16 (29%) patients reported a sustained clinical improvement by 1 PAD stage. Cumulative patency and reintervention-free survival rates were, respectively, 71% and 61% at 1 year and 49% and 48% at 3 years. In the literature, only case series were found, but no randomized trial evaluating the efficacy of deep femoral artery PTA. CONCLUSION PTA of the deep femoral artery can be performed with high technical success rates at a low interventional risk. However, in the majority of patients, this technique yields no sustained hemodynamic or clinical benefit. Due to a high rate of late failures, it should be reserved for limb salvage in patients without a surgical alternative.

Background A functional GT dinucleotide length polymorphism in the haem oxygenase-1 (HO-1) gene promoter is thought to be involved in the pathogenesis of cardiovascular disease. Short (

To determine and compare the rates of in-stent restenosis, late clinical deterioration, and stent fractures in nitinol stents versus Wallstents implanted for suboptimal angioplasty in the superficial femoral artery (SFA).Interrogation of an angioplasty database identified 286 consecutive patients (178 men; mean age 67+/-10 years, range 44-87) with severe claudication (n=254) or critical limb ischemia (n=32) who had stents implanted after suboptimal angioplasty over a 5-year period. Wallstents with a mean stented lesion length of 107+/-71 mm were implanted in 116 patients, while nitinol stents were used in 170 patients: 45 SMART stents (mean stented lesion length 139+/-88 mm) and 125 Dynalink/Absolute stents (mean stented lesion length 125+/-84 mm). Patients were followed for in-stent restenosis (50%) by duplex ultrasound, clinical deterioration by at least 1 Fontaine stage compared to baseline, and stent fractures by biplanar radiography.In-stent restenosis rates at 1, 2, and 3 years were 46%, 66%, and 72% for Wallstents compared to 20%, 36%, and 53% for nitinol stents (p0.001), respectively, without significant difference between the 2 nitinol stent groups (p=0.59). Clinical deterioration at 1, 2, and 3 years was found in 10%, 15%, and 18% with Wallstents versus 4%, 5%, and 5% with nitinol stents (p=0.014), respectively, without difference between the 2 nitinol stent groups (p=0.47). Fracture rates were 19% for Wallstents after a mean 43+/-24 months, 28% for SMART stents after mean 32+/-16 months, and 2% for Dynalink/Absolute stents after a mean 15+/-9 months.Intermediate-term in-stent restenosis remains a major problem even with current nitinol stent technology; however, clinical deterioration seems no matter of serious concern with SMART and Dynalink/Absolute stents. Stent fractures may be lower with Dynalink/Absolute stents, but randomized head-to-head comparisons are needed to validate these data.

PURPOSE To report procedure-related complications and neurological adverse events of unprotected over-the-wire (OTW) and protected rapid exchange (RX) carotid artery stenting (CAS) in a single-center patient series during an 8-year period. METHODS Between 1997 and 2004, 651 consecutive patients (445 men; median age 72 years, interquartile range 64-77) were enrolled in a registry database of carotid stent procedures; from 1997 to 2002, 471 patients underwent unprotected CAS using an OTW technique, while the other 180 patients were treated with protected CAS using RX monorail systems from 2003 to 2004. Technical success and complications (neurological, hemodynamic instability, and access site) up to 30 days post intervention were analyzed. RESULTS Technical success improved from 95% with unprotected OTW CAS to 99% with protected RX CAS (p=0.025). Procedure-related complications occurred in 86 (18.3%) of 471 unprotected OTW CAS versus 18 (10.0%) of 180 protected RX CAS procedures (p=0.010). Transient ischemic attacks (3.2% versus 2.8%), minor stroke (1.7% versus 0.6%), and major stroke (2.1% versus 0.6%) showed a trend toward a difference between unprotected OTW and protected RX CAS (p=0.076); combined 30-day stroke/death rates were 3.8% for OTW versus 1.2% for RX CAS (p=0.073). During the 8-year period from 1997 to 2004, the annual rates of procedure-related complications (p=0.002), neurological events (p=0.040), and stroke and death (p=0.14) markedly decreased. CONCLUSIONS Carotid stenting became substantially safer in the era of protected RX technology. In addition to a reduction in neurological complications, which may be due to cerebral protection devices, the improved technical success and reduced non-neurological procedure-related complications are likely due to recent technical advances unrelated to cerebral protection.

Background and Purpose— There is considerable variability in the antiplatelet effects of the thienopyridine agent “clopidogrel.” We tested for an association of gene sequence variations in P2Y12 and occurrence of neurological adverse events in patients with symptomatic peripheral artery disease (PAD) during clopidogrel treatment. Methods— We studied 137 patients undergoing antiplatelet therapy with clopidogrel and 336 patients with aspirin for the occurrence of neurological events (ischemic stroke and/or carotid revascularization). Prevalence of 2 previously described exonic polymorphisms of the P2Y12 gene, 34C>T and 52G>T, was determined by polymerase chain reaction. Results— Genotype frequencies for mutated, heterozygous, and wild-type alleles for the 34C>T and the 52G>T polymorphisms were 9% (n=40), 44% (n=210), and 47% (n=223), and 4% (n=17), 27% (n=127), and 70% (n=329), respectively. During the median follow-up of 21 months, neurological events occurred in 8% of patients. In patients with aspirin therapy, neither polymorphism was associated with neurological events. However, in clopidogrel patients, carriers of at least one 34T allele had a 4.02-fold increased adjusted risk for neurological events compared with carriers of only 34C alleles (95% confidence interval, 1.08 to 14.9). Neither polymorphism was associated with all-cause mortality. Conclusions— In PAD patients, clopidogrel response variability exists, which may result in increased risk for cerebrovascular events. Sequence alterations of the target receptor gene represent one possible mechanism for clopidogrel failure. Whether identification of the 34C>T polymorphism as a contributor to this process could serve as risk stratification tool, an indicator for higher clopidogrel doses, or the use of alternate agents warrants further investigation.

Background: Amiloride-sensitive epithelial sodium channels (ENaCs) are important candidates in the development of hypertension, which is a major risk factor for stroke. Two single-nucleotide polymorphisms (SNPs) in the gene that encodes the ENac α-subunit (αENaC) have been identified. We evaluated those SNPs for a possible association with ischemic cerebrovascular events (ICEs). Methods and Results: We genotyped 1399 patients with ICEs [median age, 70 years; interquartile range, 58–78 years; 745 (53%) men] and 1076 control individuals without vascular disease [47 (39–58) years; 557 (52%) men] for the SNPs Trp493Arg and Ala663Thr. The SNP frequencies at nucleotide 3977 (Trp493Arg) in the αENaC gene were significantly different in patients and controls. Carriers of 493Arg had a 1.78-fold increased risk (95% confidence interval, 1.02–3.12) for ICEs compared with Trp/Trp carriers. Interaction analysis revealed that the relative risk was even higher in women in the lowest age tertile [adjusted odds ratio, 3.26 (1.10–9.72)]. Conclusions: Carriers of the 493Arg allele are at increased risk for ICEs compared with Trp/Trp carriers. The effect is independent of traditional vascular risk factors and is particularly evident in younger women. The Trp493Arg variant in αENaC may represent an important candidate genetic susceptibility factor in the development of ICEs.

Background and Purpose— Gender differences are currently becoming increasingly recognized as an important prognostic factor in patients with atherosclerotic disease. We investigated gender-related differences in vascular outcome and mortality of asymptomatic patients with high-grade internal carotid artery (ICA) stenosis. Methods— We enrolled 525 consecutive patients (325 males with a median age of 72 years and 200 females with a median age of 75 years) from a single center registry who were initially treated conservatively with respect to a neurologically asymptomatic ≥70% ICA stenosis. Patients were followed-up for a median of 38 months (interquartile range, 18 to 65) for major adverse cardiovascular, cerebral, and peripheral vascular events (MACE: combined end point including myocardial infarction, stroke, [partial] limb amputation, and death), vascular mortality, and all-cause mortality. Results— Cumulative MACE-free survival rates in males and females at 1, 3, and 5 years were 83%, 65%, 48% versus 85%, 73%, and 67% ( P =0.004), respectively. Adjusted hazard ratios for MACE, vascular mortality, and all-cause mortality for males were 1.96 ( P =0.016), 2.48 ( P P =0.007) as compared with females, irrespective of age, vascular risk factors, comorbidities, and the individual risk status estimated by the American Society of Anesthesiologists (ASA) score. Conclusion— Male patients with high-grade carotid artery stenosis are at a considerably higher risk for poor outcome than their female counterparts. In particular, the risk for fatal vascular events is substantially increased in males.

Hemodialysis patients are prone to deficiency of vitamin C, which constitutes the most abundant nonenzymatic antioxidant in blood. Because antioxidants are involved in the pathogenesis of atherosclerosis, the authors examined the association of total vitamin C plasma level with cardiovascular outcomes in such patients. One hundred thirty-eight consecutive maintenance hemodialysis patients (median age 61 yr, 90 males) were enrolled in a single-center study. At baseline, routine laboratory parameters were recorded, and predialysis total vitamin C plasma levels were measured by high-pressure liquid chromatography. Patients were prospectively followed-up for the occurrence of a primary composite endpoint consisting of fatal and nonfatal major adverse cardiovascular events (MACE) and for all-cause and cardiovascular mortality. MACE occurred in 35 patients (25%) over a period of median 30 mo, and 42 patients (30%) died [29 cardiovascular deaths (21% of total)]. Using Cox proportional hazards modeling, adjusted hazard ratios for the occurrence of MACE were 3.90 (95% confidence interval [CI]: 1.42 to 10.67; P = 0.008) and 3.03 (95% CI: 1.03 to 8.92; P = 0.044) for patients in the lower (32 micromol/L) and middle (32 to 60 micromol/L) tertile of total vitamin C levels, compared with patients in the upper tertile (60 micromol/L). Hazard ratios for cardiovascular death were 3.79 (95% CI: 1.23 to 11.66; P = 0.020) and 2.89 (95% CI: 0.89 to 9.37; P = 0.076). Total vitamin C levels were not independently associated with all-cause mortality. This study concludes that low total vitamin C plasma levels predict adverse cardiovascular outcomes among maintenance hemodialysis patients. Future studies should address the potential protective effect of an adequate vitamin C supplementation.

Aims Complement activation occurs in atherosclerotic lesions, and particularly complement component C5a exerts potent chemotactic and proinflammatory effects. However, it is yet unknown, whether plasma levels of C5a may predict cardiovascular risk. The aim of this study was to examine whether plasma levels of the complement component C5a may predict cardiovascular risk in patients with advanced atherosclerosis. Methods and results We studied 173 patients with symptomatic peripheral artery disease (median age 72, 82 male). Cardiovascular risk profile, levels of the complement factor C5a, and other non-specific inflammatory parameters [high sensitivity C-reactive protein, serum amyloid A (SAA), and fibrinogen] were obtained at baseline, and patients were followed for median 22 months [interquartile range (IQR) 13-27] for the occurrence of major adverse cardiovascular events (MACE: myocardial infarction, percutaneous coronary interventions, coronary artery bypass graft, carotid revascularization, stroke, and death). We observed 65 MACE in 49 patients (28%). Cumulative event rates (95% confidence interval (CI)) within quartiles of C5a at 24 months were 16 (5-27), 26 (13-39), 36 (21-51), and 37% (23-51), respectively (P=0.0077). Adjusted hazard ratios for the occurrence of a first MACE according to increasing quartiles of C5a were 1.81, 2.23, and 2.66, respectively, as compared to the lowest quartile (P=0.038), irrespective of the level of other inflammatory parameters. Conclusion Complement activation, indicated by the elevation of C5a, seems to be associated with increased cardiovascular risk in patients with advanced atherosclerosis. Clinically, determination of C5a may add to the predictive value of other non-specific inflammatory parameters.

On waiting lists, transplant candidates are routinely screened for potentially harmful complement-fixing alloantibodies using complement-dependent cytotoxicity (CDC) panel-reactive antibody (PRA) testing. We have recently developed a novel cell-independent assay for assessment of complement-activating panel reactivity ([C4d]FlowPRA), which is based on selective flow-cytometric detection of alloantibody-triggered C4 complement split product deposition to human leukocyte antigen (HLA)-coated FlowPRA beads. Serum specimens selected from 120 transplant candidates were evaluated by [C4d]FlowPRA (HLA class I vs II) in comparison with FlowPRA IgG alloantibody screening (HLA class I vs II), a method detecting both complement- and noncomplement-activating alloantibodies, and with CDC-PRA on separated T (T-CDC) or B cells (B-CDC, evaluation on platelet-absorbed sera). For each assay, ≥10% PRA reactivity was considered positive. Comparing complement-dependent PRA assays with standard FlowPRA, the specificity calculated for [C4d]FlowPRA (HLA class I: 92%; class II: 100%) was found to be superior to that of CDC testing (T-CDC-PRA: 79%; B-CDC-PRA: 86%). Because noncomplement-activating alloreactivities were not detected for both techniques, low sensitivities were calculated ([C4d]FlowPRA HLA class I: 61%; class II: 31%; T-CDC-PRA: 70%; B-CDC-PRA: 55%). Compared with CDC-PRA, [C4d]FlowPRA gave a high specificity (HLA class I compared with T-CDC: 89%, HLA class II compared with B-CDC: 95%) but, at least in part because of false-positive CDC results, a modest sensitivity (66% and 38%, respectively). For both HLA classes, we found a highly significant association between absolute [C4d]FlowPRA and CDC-PRA levels (p < 0.0001). Our results suggest that detection of C4 split product deposition to FlowPRA beads may represent an attractive HLA-specific and time-effective alternative to CDC-PRA screening.

OBJECTIVE: To investigate 3D-conformal external beam radiotherapy for prevention of recurrent in-stent restenosis after carotid artery angioplasty. PATIENTS AND METHODS: Between Oct 2000 and Sep 2001 five patients with recurrent carotid artery in-stent restenosis of more than 50% lumen loss diagnosed with duplex sonography were enrolled. After successful revascularization, radiotherapy treatment planning was performed, which was based on the angioplasty protocol and all images documenting the intervention. A single dose of 5 Gy was prescribed to the 100% isodose. The treatment started on day one after angioplasty. In total, 4 fractions were given within 3 days. RESULTS: All patients tolerated the treatment well. No acute radiotherapy associated side effects were observed. Two patients developed recurrence within four months after therapy. In both cases, late total occlusion of the stent was noticed. One patient died and one developed a severe stroke. The other three patients remained asymptomatic with evidence of less than 50% restenosis. CONCLUSION: 3D-conformal radiotherapy is a feasible treatment option for highly selected patients with carotid artery in-stent restenosis. These preliminary results from a very small group of patients do show some potential for radiotherapy to prevent restenosis. However, due to the risk of late stent thrombosis, radiotherapy for the prevention of recurrent carotid artery in-stent restenosis is not recommended.

ObjectiveWe hypothesized that higher neutrophil counts are associated with an increased incidence of major adverse cardiovascular events (MACE) in patients with clinically advanced atherosclerosis.MethodsWe prospectively studied 398 patients (233 men; median age, 69 years) with symptomatic peripheral artery disease who were admitted to the inpatient ward of the angiology department of a tertiary care university hospital in a cohort study. Total and differential white blood cell (WBC) counts were obtained, and patients were followed for MACE, defined as myocardial infarction, percutaneous coronary interventions, coronary artery bypass grafting, stroke, carotid revascularization, and death.ResultsDuring a median follow-up of 20 months, 140 MACE occurred in 105 patients (26%). Multivariate Cox proportional hazards analysis was used to assess the association of differential WBC count parameters (in tertiles) with MACE and their interrelation with traditional cardiovascular risk factors and other parameters of inflammation. Patients with neutrophil counts >5.8 G/L (upper tertile) exhibited an increased adjusted risk for all MACE (hazards ratio [HR], 1.83; P = .017), death (HR, 3.39; P = .010), and the composite of myocardial infarction, stroke, and death (HR, 2.20; P = .012) compared with patients in the lower tertile (5.8 G/L) indicate a substantially increased risk for major adverse cardiovascular events, adding to the prognostic information of traditional atherothrombotic risk factors and other parameters of inflammation.

BACKGROUND Kidney transplant recipients with a current positive complement-dependent cytotoxicity crossmatch (CDCXM) are at high risk for hyperacute rejection and graft loss. Immunoadsorption (IA) represents an efficient strategy to remove donor-specific alloantibodies. In this analysis, we evaluated effectiveness of peritransplant IA as an anti-humoral strategy to overcome a current positive CDCXM in presensitized renal allograft recipients. METHODS Between 1999 and 2003, 40 high risk cadaveric kidney allograft recipients (median CDC panel reactive antibody [PRA] level, 77%; number of retransplants, n = 38) were subjected to peritransplant IA with protein A (one pretransplant IA session followed by a course of repeat posttransplant IA sessions) in addition to preemptive antilymphocyte antibody therapy. RESULTS In nine of these patients, a current positive CDCXM was rendered negative by a single pretransplant IA session. Thirty-one recipients had a negative CDCXM already before pretransplant IA. No difference in graft survival was found between CDCXM-positive and CDCXM-negative recipients (3-year graft survival, 78% vs. 71%, P = 0.6). Comparable rates of immunological graft loss at 3 years were observed (11% vs. 13%, P = 0.8). Patient groups did not significantly differ with respect to median serum creatinine at 1 year (1.23 mg/dL [CDCXM-positive] vs. 1.57 mg/dl [CDCXM-negative], P = 0.07) and at the end of follow-up (median 32 months; 1.19 mg/dL vs. 1.63 mg/dL, P = 0.06). Moreover, patient groups showed similar rates of biopsy-proven cellular rejection (11% vs. 20%) or C4d-positive graft dysfunction (33% vs. 32%). CONCLUSION Our results demonstrate that peritransplant IA enables successful cadaveric kidney transplantation in the context of a positive CDCXM.

To report a retrospective cohort study of nitinol stent implantation in patients at high risk for restenosis owing to long-segment (or =10 cm) femoropopliteal disease.Sixty-five consecutive patients with peripheral artery disease underwent long-segment (or =10 cm) femoropopliteal stent implantation using self-expanding nitinol stents after initial failure of plain balloon angioplasty (i.e., residual stenosis30% or a flow-limiting dissection). Patients were followed for first occurrence of in-stent restenosis, defined as a50% lumen diameter reduction by color-coded duplex sonography, with angiographic confirmation.Cumulative median length of the stented segments was 16 cm (interquartile range [IQR] 12-25, absolute range 10-40) using up to 5 overlapping stents. During the median 8-month follow-up (IQR 6-11), no early thrombotic reocclusions occurred within 30 days, but 26 (40%) patients developed an in-stent restenosis. Cumulative freedom from restenosis at 6 and 12 months was 79% and 54% overall, respectively; at the same time periods, the rates were 84% and 71% in nondiabetic patients (n=41) versus 68% and 22% in diabetics (n=24) (adjusted hazard ratio 3.8, p=0.01). Cumulative stent length and number of implanted stents were not associated with restenosis.Midterm restenosis after long-segment femoropopliteal stenting using self-expanding nitinol stents remains a major problem, particularly in patients with diabetes mellitus. The midterm results in nondiabetics are encouraging.

Abdominal aortic aneurysm (AAA) is characterized by dilatation of arterial walls, which is accompanied by degradation of elastin and collagen molecules. Biochemical and environmental factors are known to be relevant for AAA development, and familial predisposition is well recognized. A connective tissue disorder that is also associated with fragmentation of elastic fibers is Pseudoxanthoma elasticum (PXE). PXE is caused by mutations in the ABCC6 gene and mainly affects dermal, ocular and all vascular tissues. To investigate whether variations in ABCC6 are found in AAA patients and to determine mutations in PXE patients, we analyzed seven selected ABCC6 exons of 133 AAA and 54 PXE patients subjected to mutational analysis. In our cohort of AAA patients, we found five ABCC6 alterations, which result in missense or silent amino acid variants. The allelic frequencies of these sequence variations were not significantly different between AAA patients and healthy controls. Therefore, we suggest that alterations in ABCC6 are not a genetic risk factor for AAA. Mutational screening of the PXE patients revealed 19 different ABCC6 variations, including two novel PXE-causing mutations. These results expand the ABCC6 mutation database in PXE.

SummaryInflammation is a key factor in the pathogenesis of abdominal aortic aneurysms (AAA). Interleukin 1 (IL-1), a fundamental regulator of the inflammatory cascade, has been shown to be involved in this process. Several functional polymorphisms in the IL-1 gene cluster are known. In this matched case-control study, we investigated a potential association between six genetic variants in IL-1 and IL-1 receptor antagonist (IL-1 RN) withAAA. We enrolled 405 individuals, 135 consecutive patients with AAA were individually age- and sex-matched to 270 patients with coronary artery disease (CAD). Traditional cardiovascular risk factors and IL-1 genotypes were determined, and the distribution of six single nucleotide polymorphisms were compared between patients and controls by multivariable conditional logistic regression analysis: IL-1A (-889) C>T, IL-1A (+4845) G>T, IL-1B (-511) C>T, IL-1B (-31) C>T, IL-1B (+3954) C>T and IL-1RN (+2018) C>T. IL-1A (-889) C>T and IL-1A (+4845) G>T (kappa 0.98, 95% CI 0.96 to 1.00), and IL-1B (-511) C>T and IL-1B (-31) C>T (kappa 0.98, 95% CI 0.96 to 1.00) were closely linked, therefore IL-1A (-889) C>T and IL-1B (-31) C>T were not considered for further analyses. None of the 4 remaining polymorphisms showed a significant association with AAA: IL-1RN (+2018) C>T (p=0.061), IL-1B (+3954) C>T (p=0.51), IL-1B (-511) C>T (p=0.61) and IL-1A (+4845) G>T (p=0.81). No significant first-degree interactions between the genetic variants andAAA were detected. In conclusion, these six genetic variants in the interleukin-1 gene cluster do not seem to play a clinically relevant role in the pathogenesis of AAA, although we cannot rule out the existence of higher degree gene-gene or gene-environment interactions.

Heme oxygenase (HO) seems to be a novel protective factor with potent anti-inflammatory, anti-oxidant, and anti-proliferative effects. HO-1, the inducible isoform, is expressed in various tissues and is upregulated by multiple stimuli. However, humans differ quantitatively in their ability to mount an HO-1 response, modulated by two potentially functional polymorphisms in the HO-1 gene promoter region. From several studies it seems that the ability of a patient with certain genotypes to respond strongly in terms of upregulating HO-1 may be an important endogenous protective factor. In the present article we systematically review the hitherto published evidence that promoter polymorphisms in the HO-1 gene exert functional importance by influencing the level of HO-1 expression in different organ systems.

Background. Intravenous vitamin C supplementation to haemodialysis patients might ameliorate responsiveness to recombinant human erythropoietin (rHuEpo). This study was performed to analyse the relation between vitamin C plasma concentration and response to rHuEpo. Methods. In a cross-sectional, single-centre observational study including all haemodialysis patients, pre-dialysis plasma vitamin C concentrations were measured by high-performance liquid chromatography and response to rHuEpo (haemoglobin concentration/ international units rHuEpo/kg/week) was recorded together with baseline laboratory data. Results. Univariate analysis yielded a significant correlation between vitamin C plasma levels and response to rHuEpo (n ¼ 130, r ¼ 0.25, P ¼ 0.004), which still persisted after adjustment for transferrin saturation, C-reactive protein, malondialdehyde, parathyroid hormone, route of rHuEpo administration, residual renal function and diabetes mellitus (adjusted r ¼ 0.23, P ¼ 0.014). Analysis per quartiles of vitamin C plasma level revealed a significantly lower response to rHuEpo with decreasing vitamin C values (P ¼ 0.026). Conclusions. In unselected haemodialysis patients, vitamin C plasma levels account, at least partially, for the response to rHuEpo. Larger-sized interventional studies are needed to find out whether vitamin C plasma levels may or may not appropriately reflect the potential beneficial effect of vitamin C supplements on rHuEpo responsiveness.

Background. Capillary deposition of the complement split product C4d has turned out to be a valuable marker of antibody-mediated rejection. The impact of pre- and posttransplant variables including particular immunosuppressive regimens on the frequency of C4d deposition has not yet been systematically investigated in a large multivariate analysis. Methods. In this retrospective study, the authors evaluated the incidence of C4d deposition in 388 kidney transplant recipients subjected to diagnostic biopsy within the first 6 months and analyzed the influence of potential confounders on the rate of C4d-positive graft dysfunction by applying multivariate logistic regression. Results. Sixty-six recipients (17%) developed linear C4d deposits in at least a quarter of peritubular capillaries, a finding associated with inferior 1-year allograft survival (73% vs. 88% in C4d-negative patients, P=0.0003). A 50% reduction in the odds of C4d-positive graft dysfunction was found if calcineurin inhibitor or mycophenolate mofetil (MMF) therapy was started 2 to 4 hr before transplantation when compared with initiation after surgery (adjusted odds ratio [OR], 0.5; P=0.03). No differences with respect to C4d staining results were found for the use of tacrolimus, MMF, or sirolimus, or for cyclosporine C2 monitoring. Retransplantation (OR, 3.6; P

Background: Prostanoids are in widespread use for the treatment of critical limb ischemia and are suggested to improve arterial compliance. However, dose- and time-dependency of these drug effects are indeterminate. We investigated the influence of intravenous application of prostanoids on arterial compliance parameters in patients with critical limb ischemia due to peripheral artery disease (PAD). Patients and methods: We included 82 consecutive patients with PAD Fontaine stage III and IV in a patient-blinded, randomized controlled trial. Patients were randomly assigned to either single dose intravenous treatment with 40 mug (n = 29) or 60 mug (n = 27) of Alprostadil (PGE1) in 250 ml 0.9% saline over 2 hours, or 250 ml 0.9% saline solution as a placebo group (n = 26). Large and small artery compliance was measured by peripheral pulse contour analysis at baseline, at one hour during intravenous infusion of Alprostadil, immediately after and 24 hours after the end of the infusion. For study purpose the patients received Alprostadil only once during the observation period of 2 days. Results: Large artery compliance, blood pressure, heart rate and cardiac output were unaffected by PGE1 administration irrespectively of drug-dosage or time interval. Small artery compliance increased at 1 hour during intravenous application of Alprostadil (40 mug Alprostadil p = 0.001; 60 mug Alprostadil p < 0.0001) compared to placebo and increased median +47% (IQR +5% to +100%) after administration of 40 mug Alprostadil and median +32% (IQR –11% to +88%) after 60 mug Alprostadil (p = 0.5). Immediately after the end of Alprostadil infusion small artery compliance decreased to baseline levels. Conclusions: Prostaglandin E1 causes a significant improvement of small artery compliance during the time of intravenous application. However, this effect rapidly diminishes after the end of administration and no dose-dependency between 40 mug and 60 mug Alprostadil is observed.

To evaluate, in a propensity score-adjusted analysis, the intermediate-term primary patency rates associated with nitinol versus stainless steel self-expanding stent placement for treatment of atherosclerotic lesions in femoropopliteal arteries.The authors analyzed the clinical and imaging data of 175 consecutive patients with peripheral artery disease and either intermittent claudication (n = 150) or critical limb ischemia (n = 25) who underwent femoropopliteal artery implantation of nitinol (n = 104) or stainless steel (n = 123) stents in a nonrandomized setting. The stents were placed owing to either significant residual stenosis (ie,30% lumen diameter reduction) or flow-limiting dissection after initial balloon angioplasty of the femoropopliteal artery. Patients were followed up for a median period of 9 months (mean, 13 months; range, 6-66 months) for the detection of a first in-stent restenosis, defined as a greater than 50% lumen diameter reduction that was seen at color-coded duplex ultrasonography and confirmed at angiography.Cumulative patency rates at 6, 12, and 24 months were 85%, 75%, and 69%, respectively, after nitinol stent placement versus 78%, 54%, and 34%, respectively, after stainless steel stent placement (P =.008, log-rank test). There were no statistically significant differences in associated patency among the three different nitinol stents used (P =.72, log-rank test). Multivariate Cox proportional hazard analysis, in which the effect of propensity to receive a nitinol stent was considered, revealed a significantly reduced risk of restenosis with the nitinol stents compared with the risk of restenosis with the stainless steel stents (adjusted hazard ratio, 0.44; 95% confidence interval: 0.22, 0.85; P =.014).Nitinol stents are associated with significantly improved primary patency rates in femoropopliteal arteries compared with stainless steel stents. Randomized controlled trials are needed to confirm these results.

We performed a multicenter case-control study to evaluate the impact of the glycoprotein 1b alpha (-5)T/C Kozak polymorphism on the risk of ischemic cerebrovascular events. The genetic analysis in 1399 patients (745 men; median age, 70 years; interquartile ratio, 58-78) and 1066 control subjects (549 men; median age, 47 years; interquartile ratio, 39-59) was carried out with mutagenically separated polymerase chain reaction. Homozygous C/C genotype carriers had a 3.5-fold increased risk for ischemic cerebrovascular events (95% confidence interval, 1.5-7.9, P = 0.003) over T/T or T/C genotype carriers together. The effect was independent of well-established atherosclerotic risk factors. Our findings could be explained by the reported gene dose effect of the Kozak polymorphism on the density of the glycoprotein 1b alpha/IX/V receptors on platelets. According to our data, the (-5)C Kozak allele may represent a candidate genetic susceptibility factor for ischemic cerebrovascular events.

Background: Patients with renal insufficiency tend to suffer from advanced atherosclerosis and exhibit a reduced life expectancy. We investigated the association of renal impairment, traditional cardiovascular risk factors and all-cause mortality in patients with symptomatic peripheral artery disease (PAD). Methods: We studied 515 patients with advanced PAD (intermittent claudication, n = 410; critical ischemia, n = 105). Cardiovascular risk profile and calculated glomerular filtration rate (GFR) were obtained at baseline and patients were followed for median 21 months (interquartile range 12 to 25) for mortality. Results: Sixty-five patients (13%) died. Cumulative survival rates at 6, 12, and 24 months were 97%, 95%, and 89%, respectively. Adjusted hazard ratios for mortality according to decreasing quartiles of GFR were 1.2, 2.5, and 5.9 compared to the highest quartile (P

To investigate whether smoking has an effect on recurrent lumen narrowing after percutaneous transluminal angioplasty (PTA) or stent placement in lower-limb arteries.A total of 650 patients (median age, 70 years; 389 men) with peripheral artery disease who underwent iliac artery PTA (n = 95), iliac artery stent placement (n = 83), femoropopliteal PTA (n = 406), or femoropopliteal stent placement (n = 66) were selected from a prospective database. Patients were categorized according to their preintervention smoking habits as nonsmokers (n = 352), light smokers (one to nine cigarettes daily) (n = 54), habitual smokers (10-20 cigarettes daily) (n = 82), or heavy smokers (20 cigarettes daily) (n = 162). Multivariate Cox proportional hazards analysis was used to determine whether there was an association between smoking habits and restenosis (or =50%) in the treated vessel segment within 1 year after treatment.Cumulative restenosis rates at 6 and 12 months according to patients' smoking habits were 99 and 190 nonsmokers, 18 and 22 light smokers, 16 and 29 habitual smokers, and 26 and 47 heavy smokers, respectively (P.001). Adjusted hazard ratios for restenosis in smokers compared with nonsmokers were 1.51 (95% CI: 0.92, 2.50) for light smokers, 0.49 (95% CI: 0.28, 0.87) for habitual smokers, and 0.46 (95% CI: 0.30, 0.71) for heavy smokers, indicating a reduced restenosis risk in patients who smoked 10 or more cigarettes daily. These patients had reduced restenosis rates after either iliac (P =.011) or femoropopliteal intervention (P =.009). However, endovascular treatment at a younger age, coronary artery disease, and history of myocardial or cerebrovascular infarction were more frequently found in smokers.Smoking 10 or more cigarettes daily is associated with a reduced rate of intermediate-term restenosis after lower-limb endovascular interventions.

Purpose To compare the diagnostic accuracy of contrast-enhanced magnetic resonance angiography (MRA) to that of digital subtraction angiography (DSA) in the detection, grading, and measurement of atherosclerotic stenoses involving the aortic arch arteries. Methods The MRA and DSA studies from 28 patients (16 women; mean age 61.6 years, range 24-83) being evaluated for possible aortic arch vessel disease were examined. The aortic arch vasculature was divided into 9 segments; within each segment, the presence and severity of stenotic or occlusive disease was determined based on a 5-point scale. In addition, stenosis length and distance to the branch were measured in 5-mm increments. Image quality was assessed using a 5-point scale. The accuracy, sensitivity, and specificity values, as well as the positive and negative predictive values in MRA's identification of lesions, were evaluated in comparison to DSA. Results In 28 patients, 189 segments were assessed by both methods. Of these, 173 were correctly rated by MRA, resulting in an accuracy of 91.5%. The accuracy dropped slightly to 86.5% when 11 "not assessable" lesions were included. Sensitivity and specificity for severity measurement were 88.5% and 95.6%, respectively. In 39 of 45 lesions, stenosis length measurements were identical by both methods, but there was a difference of 0.5 cm each in 6 lesions. Conclusions MRA as compared to DSA shows high accuracy in the detection and grading of lesions involving the aortic arch vessels. The noninvasive nature of this method recommends its use for screening, treatment planning, and follow-up in known or suspected arterial disease in aortic arch arteries.

ObjectivesWe investigated the association of the heme oxygenase-1 (HO-1) promoter genotype with the inflammatory response and restenosis after balloon angioplasty.BackgroundHeme oxygenase-1, which is induced by balloon angioplasty, can inhibit neointima formation and vascular remodeling. A dinucleotide repeat in the HO-1 gene promoter shows a length polymorphism that modulates HO-1 gene transcription. Short (

To investigate whether endovascular brachytherapy diminishes vascular inflammation in response to femoropopliteal percutaneous transluminal angioplasty (PTA) or stent implantation in two double-blind randomized-controlled trials.Forty-seven consecutive patients from two double-blind randomized-controlled trials were studied. Patients either underwent femoropopliteal PTA with endovascular gamma irradiation (n = 8) or placebo irradiation (n = 7) or underwent PTA and stent implantation with brachytherapy (n = 15) or placebo irradiation (n = 17). High-sensitivity C-reactive protein (CRP), serum amyloid A (SAA), and fibrinogen levels were measured at baseline and 8, 24, and 48 hours after the intervention. The change of acute phase parameters from baseline to 48 hours after intervention indicated the extent of the inflammatory response and was compared between patients undergoing brachytherapy and those undergoing placebo irradiation. Fisher exact test was used for comparison of categorical data, and nonparametric statistical methods were applied for analysis of continuous data (Mann-Whitney U tests for unpaired data and Friedman analysis for repetitive measurements).Median patient age was 70 years (interquartile range, 56-74 years); 33 (70%) patients were men and 14 (30%) were women. Clinical characteristics and baseline values of acute phase parameters were similar between groups. A statistically significant increase in CRP, SAA, and fibrinogen values was observed after PTA and stent implantation, both in the patients who underwent brachytherapy and in those who underwent placebo irradiation. Compared with placebo irradiation, however, brachytherapy did not significantly reduce any acute phase parameter from baseline to 8, 24, or 48 hours after the intervention (P.05 for all comparisons).Endovascular brachytherapy did not diminish early vascular inflammation in response to PTA or stent implantation and even induced a trend toward an increased inflammatory response.

Renal artery stenosis (RAS) leading to hypertension or ischemic nephropathy can be treated by endovascular revascularization using balloon angioplasty or stent implantation. Although high technical success rates > 95%, relatively low frequencies of complications and good long-term patency can be achieved, the indications for interventional treatment are a matter of ongoing debate. Curing hypertension by means of angioplasty rarely occurs, although the number of antihypertensive medication usually can be reduced after successful treatment. Targeting ischemic nephropathy, revascularization can stabilize or at least slow the decline of renal function. Nevertheless, angioplasty also bears the risk of inducing renal deterioration. Careful patient selection remains the most crucial point in renal interventions, however, current data are insufficient to give final recommendations on this issue. The present review focuses on the potential beneficial effects of renal artery PTA and stenting in patients with RAS.

The evaluation of patients with acute chest pain remains challenging, as it implies the risk of fatal misdiagnosis. It is well recognized that typical angina does not specifically identify patients at high risk. We investigated the predictive value of characteristics atypical for myocardial ischemia for exclusion of acute or subacute coronary events, focusing on patients' symptoms, medical history and risk factors.We prospectively studied 1288 consecutive patients presenting with acute chest pain at a non-trauma emergency department. Patients' symptoms, history and risk factors were evaluated using seven predefined criteria and assigned as typical or atypical for ischemic coronary chest pain. Positive predictive value (PPV) and 95% confidence intervals (95% CI) were calculated to predict or exclude acute myocardial infarction (AMI) and major adverse cardiac events (MACE: cardiovascular death, percutaneous coronary interventions, bypass surgery, or myocardial infarction) within six months.AMI occurred in 168 patients (13%), and 6-months MACE (including AMI) overall in 240 patients (19%). Presence of four or more criteria typical for myocardial ischemia was associated with a PPV of 0.21 (0.17 to 0.25) for predicting AMI and 0.30 (0.25 to 0.35) for 6-months MACE. Presence of four or more criteria atypical for coronary ischemia was associated with a PPV of 0.94 (0.91 to 0.96) for excluding AMI and 0.93 (0.90 to 0.96) for excluding 6-months MACE. In 165 of 476 patients under 40 years of age (35%), four or more atypical criteria excluded AMI and 6-months MACE with PPVs of 0.98 (0.96 to 1.0).Evaluation of criteria atypical for myocardial ischemia with acute chest pain may help to identify candidates for early discharge, whereas typical characteristics have very little diagnostic value.

Background. The heme oxygenase (HO) isoenzyme HO-1 has recently been suggested to protect transplants from ischemia/reperfusion and immunologic injury. Inducibility of this enzyme is modulated by a (GT)n dinucleotide length polymorphism in the HO-1 gene promoter. Short (class S) repeats are associated with greater up-regulation of HO-1 than are long repeats. In the present study we investigated the impact of the promoter polymorphism of kidney allograft donors on clinical outcomes after transplantation. Methods. We enrolled 101 recipients of cadaveric donor kidney allografts (who underwent transplantation between June 1998 and September 1999) in this retrospective study. The HO-1 genotype was assessed using genomic DNA isolated from cryopreserved donor splenocytes. Results. Fifty patients (49.5%) had received a kidney from a donor with at least one class S allele. Recipients of allografts from a class S allele carrier had significantly lower 1-year serum creatinine levels (median 1.46 mg/dL, interquartile range 1.17-1.68 mg/dL) compared with recipients of a non-class S allele donor kidney (median 1.61 mg/dL, interquartile range 1.38-2.22 mg/dL, P=0.01). After adjustment for cold ischemia time, retransplantation, donor age, delayed graft function, and HLA mismatch, recipients of a class S allele transplant had serum creatinine levels 0.81 times (95% confidence interval: 0.70-0.96, P=0.01) those of recipients of a non-class S allele transplant. The two patient groups did not differ significantly with respect to the incidence of delayed graft function, allograft rejection, or immunologic graft loss. Conclusion. Our data suggest an influence of the HO-1 gene promoter polymorphism on kidney allograft function and thus support previous studies indicating a protective effect of HO-1 induction in organ transplantation.

Heme oxygenase-1 (HO-1) has been demonstrated to exert potent anti-oxidant and anti-inflammatory effects in the context of atherosclerotic vascular disease, and therefore was referred to as a potential vascular protective factor. A (GT)n dinucleotide repeat polymorphism in the HO-1 promoter has been shown to modulate HO-1 gene expression. Short ( or =25) repeat (class L) alleles after adjustment for potentially confounding factors. Genotype distributions of S/S, S/L and L/L in patients were 9.8% (n=39), 45.1% (n=180) and 45.1% (n=180), which was similar to the distribution in controls with 11.5% (n=46), 44.5% (n=177) and 44.0% (n=175). In the presence of vascular risk factors, the HO-1 genotype became functionally relevant: in patients without hyperlipidemia the S/S genotype exerted a protective effect on the development of ischaemic cerebrovascular events (OR 0.2; 95% CI 0.1-0.6), while this effect was no longer present in hyperlipidemic patients. Short (

Background and Purpose— Magnesium (Mg) deficiency is thought to be a risk factor for cerebrovascular atherosclerosis and complications. We investigated the prognostic impact of Mg serum levels with respect to the occurrence of neurological events in patients with advanced atherosclerosis. Methods— We prospectively studied 323 patients with symptomatic peripheral artery disease and intermittent claudication (197 men; median age, 68 years). Serum Mg was determined, and patients were followed for a median of 20 months (interquartile range, 12 to 25 months) for the occurrence of neurological events, defined as ischemic stroke and/or carotid revascularization (carotid endarterectomy or carotid stenting). Multivariate Cox proportional hazards analysis was applied to assess the association of serum Mg (in tertiles) and neurological events. Results— Neurological events occurred in 35 patients (11%) (15 patients with stroke, 13 with carotid revascularization, and 7 with stroke and subsequent revascularization). Compared with patients in the highest tertile of Mg serum levels (>0.84 mmol/L), patients with Mg serum values Conclusions— Low Mg serum levels indicate an increased risk for neurological events in patients with symptomatic peripheral artery disease, favoring Mg substitution therapy in those patients with advanced atherosclerosis.

SummaryLow serum albumin is a powerful predictor of cardiovascular adverse events in healthy subjects and patients with subclinical atherosclerosis. We investigated the association between serum albumin, traditional cardiovascular risk factors, markers of inflammation and cardiovascular outcome in 515 patients with advanced atherosclerosis and severe peripheral artery disease. Cardiovascular risk profile, serum albumin, serum amyloid A (SAA) and fibrinogen were obtained at baseline, and patients were followed for median 21 months (interquartile range 12 to 25) for the occurrence of major adverse cardiac events (MACE: myocardial infarction, percutaneous coronary interventions, coronary artery bypass graft, and death). We observed 135 MACE in 109 patients (21%). Cumulative event-free survival rates at 6, 12, and 24 months were 95%, 91%, and 80%, respectively. Low albumin predicted MACE independently of SAA and fibrinogen. Adjusted hazard ratios for the occurrence of MACE, any death, and the composite of death and MI according to increasing quartiles of albumin were 2.40, 1.14 and 1.09 (p

Background— C-reactive protein (CRP) and glycohemoglobin (HbA1c) are established risk factors for the development of cardiovascular disease. We investigated the joint effects of these parameters on cardiovascular outcome of patients with advanced atherosclerosis. Methods and Results— We studied 454 patients with advanced atherosclerosis (median age, 69 years; 264 male). Cardiovascular risk profile, high-sensitivity CRP (hs-CRP), and HbA1c were obtained at baseline, and patients were followed for a median of 21 months (interquartile range, 13 to 26) for the occurrence of major adverse cardiovascular events (MACE) (myocardial infarction, percutaneous coronary interventions, coronary artery bypass graft, carotid revascularization, stroke, and death). We observed 166 MACE in 128 patients (28%). Cumulative event-free survival rates at 6, 12, and 24 months were 91%, 85%, and 73%, respectively. Adjusted hazard ratios for the occurrence of MACE according to increasing quartiles of hs-CRP and HbA1c were 1.35 ( P =0.31), 1.90 ( P =0.026) and 2.13 ( P =0.007), and 1.40 ( P =0.26), 1.81 ( P =0.059), and 2.36 ( P =0.023), respectively, compared with the lowest quartiles. Considering both parameters jointly, we found that patients with hs-CRP >0.44 mg/dL and HbA1c >6.2% (upper quartiles) were at highest risk for MACE, with each parameter adding to the prognostic information of the other. Conclusions— Inflammation, indicated by hs-CRP, and hyperglycemia, indicated by HbA1c, jointly contribute to the cardiovascular risk of patients with advanced atherosclerosis. Patients with both hs-CRP and HbA1c in the upper quartiles (>0.44 mg/dL and >6.2%, respectively) are at particularly high risk for poor cardiovascular outcome.

Purpose: To investigate the frequency of and risk factors for hypotension and bradycardia in response to elective carotid stenting and their association with neurological complications. Methods: A retrospective analysis was conducted of 471 patients (321 men; median age 72 years, interquartile range 64–77) who underwent elective carotid artery stenting without cerebral protection for high-grade (>70%) symptomatic (n = 147) or asymptomatic (n=324) internal carotid artery stenosis at a single center. Frequency and potential risk factors for severe hypotension (systolic blood pressure Results: Thirty-four (7%) patients had severe hypotension (n=23), bradycardia (n=2), or both (n=9) despite routine premedication with atropine and adequate fluid balance. Intravenous catecholamines (dopamine) were necessary in 8 patients with prolonged hypotension; none of the patients with bradycardia needed pacemaker support. Neurological complications (transient ischemic attack, minor stroke, major stroke, death) occurring in 33 (7%) patients were not significantly associated with hemodynamic instability (4/34 [12%] versus 29/437 [7%], p = 0.26). Age >77 years (fourth quartile; OR 6.40, 95% CI 1.80 to 22.78, p=0.004) and coronary artery disease (OR 2.81, 95% CI 1.29 to 6.14, p=0.010) were associated with an increased adjusted risk for hypotension or bradycardia. Conclusions: Hemodynamic instability due to hypotension and bradycardia in response to carotid artery stenting occurs in a relatively low proportion of patients. Elderly patients and those with coronary artery disease are at highest risk. Although the rate of neurological complications was not significantly increased in patients with hemodynamic instability, the higher frequencies of neurological complications in these patients admonish us to be careful.

Background and purpose: Elevated plasma levels of interleukin-6 (IL-6) are associated with an increased risk and worse outcome of acute vascular events. A common G/C promoter polymorphism at nt (−174) of the IL-6 gene has been shown to affect basal IL-6 levels. Consequently, the IL-6 genotype may be associated with risk and outcome of ischemic stroke (IS). We investigated the statistical association between this polymorphism and cerebrovascular events, as well as the clinical outcome in patients with symptoms before the age of 60. Methods: We examined 214 patients of 60 years or less with acute ischemic stroke or transient ischemic attack (TIA) and 214 age- and sex-matched healthy control subjects for the (−174) IL-6 G/C polymorphism by mutagenic separated polymerase chain reaction (MS PCR). Clinical severity of the vascular event was evaluated by validated scales at predefined points of time. Results: In the total group of patients, the genotype and allele frequencies in the patient group (38% GG, 45% GC, 17% CC; allelic frequency: 60% G, 40% C) did not differ significantly from the control group. However, individuals homozygous for the (−174)G variant had significantly worse scores on the NIH Stroke Scale (NIHSS) already on admission and 1 week after the event. Also, patients with severe disability 1 week and 3 months after the event (Rankin Scale (RS) 4 or 5; NIH Stroke Scale≥6) were significantly more often carriers of the GG genotype. In a multivariate analysis, the IL-6 (−174)GG genotype was significantly associated with severe disability after 1 week (RS 4–5; odds ratio (OR)=3.2, 95% CI: 1.5–6.6; p=0.002; NIHSS≥6; OR=4.2, 95% CI: 1.6–11.1). Conclusions: The (−174)GG-genotype of the IL-6 gene is associated with severe stroke in young patients with acute cerebrovascular events. Further studies with larger patient groups are warranted to confirm these findings.

Purpose:To investigate the association of baseline peripheral blood monocyte counts and restenosis after femoropopliteal percutaneous transluminal angioplasty (PTA) and PTA plus elective stent implantation.Methods:Three hundred thirty consecutive patients (170 men; median age 71 years, interquartile range 61–78) with peripheral artery disease underwent femoropopliteal PTA (n=258) or PTA plus elective stent implantation (n=72). Multivariate Cox regression analysis was used to determine the predictive value of baseline peripheral blood monocyte counts on the rate of restenosis (≥50% luminal reduction) in follow-up.Results:Cumulative patency at 6 and 12 months was 55% and 39% after PTA and 70% and 41% after elective stenting, respectively (p=0.19). Pretreatment monocyte counts (in tertiles) were associated with restenosis after PTA (p=0.002) and stent implantation (p=0.02). Compared to patients with monocyte counts 9/L (lower tertile, n=128), patients with monocytes from 0.3 to 0.4×109/L (middle tertile, n=91) had a 1.8-fold increased adjusted risk for restenosis (95% CI 1.1 to 2.8, p=0.01). Patients with monocytes >0.4×109/L (upper tertile, n=87) had a 2.3-fold increased adjusted risk (95% CI 1.4 to 3.5, pConclusions:Baseline monocyte counts were associated with restenosis after femoropopliteal PTA and elective stent implantation, suggesting that circulating monocytes play a pivotal role in the development of recurrent lumen narrowing.

To determine the association between pre- and postintervention serum C-reactive protein (CRP) levels and 6-month restenosis after endovascular treatment of atherosclerotic lesions in arteries below the knee.Eighty-nine patients with peripheral arterial disease underwent primary successful percutaneous transluminal angioplasty (PTA) of the distal popliteal, anterior tibial, posterior tibial, and fibular arteries. Six-month patency was evaluated with the ankle brachial index (ABI) and color-coded duplex ultrasonography (US). The association between restenosis and preintervention and 48-hour postintervention CRP levels was assessed with multiple logistic regression analysis.ABI improved from a preintervention median of 0.54 to a postintervention median of 0.75 (P.001). The primary technical success rate was 94% (100 of 106). In 50 patients, a suboptimal technical result was achieved with 30%-40% residual stenosis at the dilated segment. The median ABI at 6 months was 0.65, and it was inversely correlated with preintervention (r = -0.27, P =.009) and 48-hour postintervention (r = -0.40, P.001) CRP levels. With duplex US at 6 months, restenosis (or =50%) occurred in 36 patients. Patients with a preintervention CRP level of 0.23-0.92 mg/dL (2.3-9.2 mg/L) had a 3.7-fold increased adjusted risk for restenosis (P =.05); patients with a preintervention CRP level greater than 0.92 mg/dL (9.2 mg/L) had a 4.7-fold increased adjusted risk (P =.03). Postintervention CRP values greater than 2.42 mg/dL (24.2 mg/L) were associated with a 10.7-fold adjusted risk for restenosis (P =.002). Suboptimal PTA result was the only other parameter associated with an increased risk for restenosis (odds ratio, 3.7; P =.03).Pre- and postintervention CRP levels were associated with restenosis after PTA of the distal popliteal and tibioperoneal arteries, which indicates that inflammation plays a crucial role in the pathophysiology of this process.

SummaryPlasminogen activator inhibitor-1 (PAI-1) is suggested to be involved in the pathophysiology of early thrombosis and late restenosis after percutaneous transluminal angioplasty (PTA). The role of the PAI-1 promoter genotype in this context is indeterminate. We investigated the association of the (4G/5G) polymorphism at nucleotide position (–675) in the PAI-1 gene promoter, PAI-1 plasma levels, and postangioplasty outcome after femoropopliteal PTA.We studied 251 consecutive patients who underwent femoropopliteal PTA. In a subgroup of 86 patients PAI-1 plasma levels at baseline,8,24 and 48 hours postintervention were measured and correlated to the genotype. Patients were followed for early thrombosis and the late restenosis (≥50%) within 12 months. Multivariate Cox proportional hazards analysis was performed to assess the association between the PAI-1 genotype and PTA failure.Results show that the PAI-1 genotype was neither associated with PAI-1 plasma levels (p=0.40) nor the change of PAI-1 from baseline to 8 (p=0.39), 24 (p=0.86) and 48 hours (p=0.89). Three out of 35 homozygous (4G/4G) patients (9%) had early thrombotic reocclusions, compared to two out of 153 heterozygous (4G/5G) patients (1%) and none of the 63 homozygous (5G/5G) patients (p=0.007). Restenosis after median 5 months (interquartile range 3 to 9) was found in 117 patients (42%), without significant association between the PAI-1 genotype and late postangioplasty failure (Log Rank p=0.95).We can conclude that carriers of the 4G allele exhibited a higher frequency of early thrombotic reocclusions after percutaneous angioplasty. However, the PAI-1 gene promoter polymorphism (4G/5G) was not associated with PAI-1 plasma levels or late postangioplasty restenosis.

SummaryThe interleukin-1 system is fundamentally involved in the pathogenesis of restenosis after percutaneous transluminal angioplasty (PTA). In order to further define the clinical impact of genetic variation in this potent proinflammatory pathway we investigated the joint effects of two single nucleotide polymorphisms in the interleukin-1 beta gene [IL-1B(–511) and IL-1B(+3954)] and a variable number tandem repeat polymorphism in intron 2 of the interleukin 1 receptor antagonist gene (IL-1RN VNTR) on postintervention inflammation and occurrence of restenosis in 183 consecutive patients who underwent successful femoropopliteal PTA. C-reactive protein (CRP) and serum amyloid A (SAA) were determined pre- and 48 hours postintervention. Patients were followed up to 12 months for the occurrence of postangioplasty restenosis (≥50 %). When analyzed separately, none of the polymorphisms was associated either with inflammation or restenosis. However, when the IL-1B (–511) and the IL-1RN VNTR genotypes were combined, a highly significant relationship was observed: Non-carriers of the two repeat allele of the IL-1RN VNTR (IL-1RN*2) who were heterozygous and homozygous for the IL-1B (–511)T allele exhibited a gradually increased inflammatory response and a higher restenosis risk. In contrast, carriers of the IL-1RN*2 and the IL-1B (–511)T allele showed a significantly better outcome.This remarkable gene dose-dependent association emphasizes the advantage of considering combinations of genetic markers rather that isolated polymorphisms in the analysis of multifactorial vascular disease.

Objective: To investigate long-term clinical and morphological outcome of patients with subclavian–axillary vein thrombosis treated with systemic thrombolysis compared to anticoagulation in a retrospective, nonrandomised study. Methods: We studied 95 consecutive inpatients with subclavian–axillary vein thrombosis treated either with systemic urokinase thrombolysis and subsequent oral anticoagulation (n=33) or with anticoagulation only (n=62). Anticoagulation was performed with heparin and phenprocoumon. Patients were followed for median 40 months (IQR 14 to 94) for symptomatic upper extremity post-thrombotic syndrome and for venous recanalisation by duplex ultrasound. Results: Primary technical success rate of the systemic thrombolysis was 88% (n=29) with seven peri-intervention bleeding complications (21%). No complication was observed in patients with anticoagulation only (p