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This protocol for a Cochrane Review has been withdrawn due to lack of progress. The editorial group took the decision, authors have been informed. There are no plans to move this review forward until a priority setting in the area has been performed.

Summary Background We hypothesize that stenting of the internal carotid artery can immediately impede blood flow to the external carotid artery by either plaque shift or stent coverage of the ostium, and thereby cause ischemic symptoms like ipsilateral jaw claudication. Methods Thirty-three patients with high-grade asymptomatic stenosis of the internal carotid artery who underwent endovascular treatment were examined by ultrasound of the external carotid artery and performed an exercise test by chewing chewing gum synchronously to an electronic metronome for 3 min. Tests were performed before, the day after, and 1 week after the stenting procedure. Claudication time was defined as the timespan until occurrence of pain of the masseter muscle and/or chewing dyssynchrony to the metronome for more than 15 s. Ten patients with an isolated, atherosclerotic stenosis of the external carotid artery served as controls. Results A significantly reduced claudication time (in seconds) was recorded in patients who underwent carotid artery stenting compared to baseline values; median 89 (interquartile range, IQR, 57 to 124) vs. median 180 (IQR 153 to 180; p < 0.001). By categorization of the flow velocity at the external carotid artery into faster or slower as 200 cm/sec, the effect was even accentuated. Stenting values showed improvement 1 week after but did not return to baseline levels. No respective changes were found in controls. Conclusion Stenting of the internal carotid artery lead to ipsilateral flow deterioration at the external carotid artery resulting in temporary jaw claudication. This impairment attenuated over the time and was significantly reduced after 1 week.

Background Experimental and clinical data indicate a major influence of diabetes on atherogenesis. We aimed to assess whether the effect of diabetes on long-term mortality in asymptomatic patient with carotid stenosis is contingent upon the degree of the carotid atherosclerotic burden. Methods 1065 patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality. Results During a median of 11.8 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. Diabetes and glycohemoglobin A1c (Hba1c) levels were significantly associated with mortality. Diabetes displayed an independent risk for all-cause (adjusted HR 1.62; 95% CI 1.35–1.94) and cardiovascular death (adjusted HR 1.75, 95% CI 1.40–2.19). The adjusted hazard ratio per increase of 1% of Hba1c levels was 1.21 (P

Background and Purpose Despite extensive research in the last decade, the role of serum amyloid A (SAA) in atherogenesis remains highly controversial. The aim of this study was therefore to assess whether SAA is associated with long‐term mortality in patients with subclinical carotid artery disease. Methods One thousand sixty‐five patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause‐specific mortality. Results During a median of 11.8 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. Patients who died within the follow‐up period had significantly higher baseline SAA serum levels compared to those who survived (12.9 vs 9.5 mg/dL; P

Background and aims Von Willebrand factor (VWF) plays an important role in thrombogenesis and mediates platelet adhesion particularly under high shear stress. Such conditions are generally found in stenotic arteries and can eventually cause myocardial infarction or stroke. We aimed to study whether levels of VWF antigen (VWF:Ag) predict future major adverse cardiovascular events (MACE) in patients suffering from carotid artery stenosis. Methods Patients with atherosclerotic carotid artery disease defined by the presence of nonstenotic plaques or any degree of carotid stenosis were prospectively enrolled. Concentrations of VWF were measured by enzyme immunoassay. Results VWF:Ag levels were more stable after 4 freeze-thaw cycles, when compared to VWF activity, and we showed similar concentrations of VWF in citrated plasma and serum (±4%). Levels of VWF:Ag predicted future cardiovascular events in 811 patients with carotid stenosis independent of known cardiovascular risk factors. Patients with VWF:Ag concentrations in the 4th quartile had a 44% event rate after an average 3-year follow up and a hazard ratio of 2.15 (95% confidence interval 1.46–3.16; p Conclusions High concentrations of VWF:Ag predict major cardiovascular events in patients with carotid stenosis, and given their high event rate may be useful for risk stratification of such patients.

BACKGROUND Red cell distribution width (RDW) is associated with morbidity and mortality in chronic cardiac disease. The aim of the present study was to investigate the role of RDW as a predictor of adverse outcome in patients with carotid atherosclerosis. MATERIALS AND METHODS We prospectively studied 1065 of 1286 consecutive patients with neurological asymptomatic carotid artery stenosis as assessed by duplex Doppler sonography. The study end points were all-cause mortality and cardiovascular mortality respectively. RESULTS During a median follow-up time of 6·2 years (interquartile range 5·9-6·6), corresponding to 5551 overall person-years, 275 patients (25·8%) died. Of them, 182 patients (66·2%) died due to cardiovascular causes. RDW was significantly associated with adverse outcome. In a continuous multivariate Cox regression analysis, the adjusted hazard ratio for each per cent increase in RDW was 1·39 (95% CI 1·27-1·53; P

Background Randomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. Objectives The objective of this review was to systematically analyse the effects of perioperatively administered beta-blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia. Search methods We identified trials by searching the following databases from the date of their inception until June 2013: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Biosis Previews, CAB Abstracts, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Derwent Drug File, Science Citation Index Expanded, Life Sciences Collection, Global Health and PASCAL. In addition, we searched online resources to identify grey literature. Selection criteria We included randomized controlled trials if participants were randomly assigned to a beta-blocker group or a control group (standard care or placebo). Surgery (any type) had to be performed with all or at least a significant proportion of participants under general anaesthesia. Data collection and analysis Two review authors independently extracted data from all studies. In cases of disagreement, we reassessed the respective studies to reach consensus. We computed summary estimates in the absence of significant clinical heterogeneity. Risk ratios (RRs) were used for dichotomous outcomes, and mean differences (MDs) were used for continuous outcomes. We performed subgroup analyses for various potential effect modifiers. Main results We included 89 randomized controlled trials with 19,211 participants. Six studies (7%) met the highest methodological quality criteria (studies with overall low risk of bias: adequate sequence generation, adequate allocation concealment, double/triple-blinded design with a placebo group, intention-to-treat analysis), whereas in the remaining trials, some form of bias was present or could not be definitively excluded (studies with overall unclear or high risk of bias). Outcomes were evaluated separately for cardiac and non-cardiac surgery. CARDIAC SURGERY (53 trials) We found no clear evidence of an effect of beta-blockers on the following outcomes. • All-cause mortality: RR 0.73, 95% CI 0.35 to 1.52, 3783 participants, moderate quality of evidence. • Acute myocardial infarction (AMI): RR 1.04, 95% CI 0.71 to 1.51, 3553 participants, moderate quality of evidence. • Myocardial ischaemia: RR 0.51, 95% CI 0.25 to 1.05, 166 participants, low quality of evidence. • Cerebrovascular events: RR 1.52, 95% CI 0.58 to 4.02, 1400 participants, low quality of evidence. • Hypotension: RR 1.54, 95% CI 0.67 to 3.51, 558 participants, low quality of evidence. • Bradycardia: RR 1.61, 95% CI 0.97 to 2.66, 660 participants, low quality of evidence. • Congestive heart failure: RR 0.22, 95% CI 0.04 to 1.34, 311 participants, low quality of evidence. Beta-blockers significantly reduced the occurrence of the following endpoints. • Ventricular arrhythmias: RR 0.37, 95% CI 0.24 to 0.58, number needed to treat for an additional beneficial outcome (NNTB) 29, 2292 participants, moderate quality of evidence. • Supraventricular arrhythmias: RR 0.44, 95% CI 0.36 to 0.53, NNTB six, 6420 participants, high quality of evidence. • On average, beta-blockers reduced length of hospital stay by 0.54 days (95% CI -0.90 to -0.19, 2450 participants, low quality of evidence). NON-CARDIAC SURGERY (36 trials) We found a potential increase in the occurrence of the following outcomes with the use of beta-blockers. • All-cause mortality: RR 1.24, 95% CI 0.99 to 1.54, 11,463 participants, low quality of evidence. Whereas no clear evidence of an effect was noted when all studies were analysed, restricting the meta-analysis to low risk of bias studies revealed a significant increase in all-cause mortality with the use of beta-blockers: RR 1.27, 95% CI 1.01 to 1.59, number needed to treat for an additional harmful outcome (NNTH) 189, 10,845 participants. • Cerebrovascular events: RR 1.59, 95% CI 0.93 to 2.71, 9150 participants, low quality of evidence. Whereas no clear evidence of an effect was found when all studies were analysed, restricting the meta-analysis to low risk of bias studies revealed a significant increase in cerebrovascular events with the use of beta-blockers: RR 2.09, 95% CI 1.14 to 3.82, NNTH 255, 8648 participants. Beta-blockers significantly reduced the occurrence of the following endpoints. • AMI: RR 0.73, 95% CI 0.61 to 0.87, NNTB 72, 10,958 participants, high quality of evidence. • Myocardial ischaemia: RR 0.43, 95% CI 0.27 to 0.70, NNTB seven, 1028 participants, moderate quality of evidence. • Supraventricular arrhythmias: RR 0.72, 95% CI 0.56 to 0.92, NNTB 111, 8794 participants, high quality of evidence. Beta-blockers significantly increased the occurrence of the following adverse events. • Hypotension: RR 1.50, 95% CI 1.38 to 1.64, NNTH 15, 10,947 participants, high quality of evidence. • Bradycardia: RR 2.24, 95% CI 1.49 to 3.35, NNTH 18, 11,083 participants, moderate quality of evidence. We found no clear evidence of an effect of beta-blockers on the following outcomes. • Ventricular arrhythmias: RR 0.64, 95% CI 0.30 to 1.33, 526 participants, moderate quality of evidence. • Congestive heart failure: RR 1.17, 95% CI 0.93 to 1.47, 9223 participants, moderate quality of evidence. • Length of hospital stay: mean difference -0.27 days, 95% CI -1.29 to 0.75, 601 participants, low quality of evidence. Authors' conclusions According to our findings, perioperative application of beta-blockers still plays a pivotal role in cardiac surgery , as they can substantially reduce the high burden of supraventricular and ventricular arrhythmias in the aftermath of surgery. Their influence on mortality, AMI, stroke, congestive heart failure, hypotension and bradycardia in this setting remains unclear. In non-cardiac surgery, evidence from low risk of bias trials shows an increase in all-cause mortality and stroke with the use of beta-blockers. As the quality of evidence is still low to moderate, more evidence is needed before a definitive conclusion can be drawn. The substantial reduction in supraventricular arrhythmias and AMI in this setting seems to be offset by the potential increase in mortality and stroke.

SummaryCellular adhesion molecules also known as selectins promote recruitment of inflammatory cells into the arterial wall where they interact with lipid particles leading subsequently to plaque formation. The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the endothelial-leukocyte adhesion molecule 1 (ELAM-1) also known as E-selectin mediate the attachment of leukocytes and have been implicated in the destabilisation of atherosclerotic plaques. Therefore, we hypothesised that plasma selectin levels are associated with adverse clinical outcome. We prospectively studied 855 patients with sonographically confirmed carotid atherosclerosis. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (26 %) died. We detected a significant association between cardiovascular mortality and ICAM-1 (adjusted hazard ratio [HR]: 3.43, 95 % confidence interval [CI] 2.00–5.88, p< 0.001) as well as VCAM-1 (adjusted HR: 2.51, 95 % CI 1.45–4.34, p=0.001) when comparing the fourth with the first quartile. Comparable results were obtained for all-cause mortality. In contrast, we could not detect a significant association between E-selectin and all-cause or cardiovascular mortality. We identified the selectins ICAM-1 and VCAM-1 as strong and independent predictors of all-cause and cardiovascular mortality in patients with stable carotid atherosclerosis. These molecules are elevated in states of endothelial activation and might assist to monitor anti-atherosclerotic therapy and select those patients with carotid atherosclerosis, who are at higher risk for cardiovascular events.

Inflammation is associated with atherosclerotic disease. In this context, it has been shown that an increased neutrophil count is a risk factor for cardiovascular events in patients with coronary and peripheral artery disease. However, the impact of neutrophils on long-term mortality in patients with carotid atherosclerosis is not yet fully understood.We prospectively studied 853 of 1268 consecutive patients with neurologically asymptomatic carotid stenosis for all-cause and cardiovascular death, respectively.During a median follow-up time of 6.3 years (IQR 5.8-6.7 years) a total of 203 deaths (23.8%), including 134 cardiovascular deaths (15.7%), were recorded. An increase of 1 G/L of neutrophil count indicated an increased risk for all-cause mortality of 1.20 (CI [95%] 1.10-1.31, P0.001) and of cardiovascular death of 1.30 (CI 1.17-1.45, P0.001), respectively. For the second to the fourth quartile of the neutrophil count, adjusted hazard ratios for all-cause mortality were 1.12 (CI, 0.71-1.75), 1.46 (CI, 0.96-2.21), and 1.76 (CI, 1.15-2.69; P = 0.03 for trend); and 1.41 (CI, 0.80-2.49), 1.53 (CI, 0.88-2.68), and 2.54 (CI, 1.49-4.33; P0.01 for trend) for cardiovascular mortality, compared to the lowest quartile, respectively. Patients with baseline carotid stenosis of more than 50% and/or increased neutrophil count (≥median), had a 1.9-2.4 fold increase in risk of (CV-) death, compared to patients with carotid narrowing of less than 50% and/or neutrophil count less than the median (P0.001). After adjusting for cardiovascular risk factors, only neutrophils, but not eosinophils, basophils, monocytes, lymphocytes, or the total leukocyte count showed a significant association with long-term mortality. No significant association was found between white blood cell subtypes with either baseline degree or progression during a 6 month follow-up of carotid stenosis.The baseline neutrophil count was an independent predictor for all-cause and cardiovascular mortality in neurologically asymptomatic patients with carotid stenosis. Thus, the measurement of neutrophils could provide prognostic information on outcome in patients at risk.

Anemia is associated with the cardiovascular outcome in healthy subjects but its impact on outcome in patients with cardiovascular disease has not yet been fully understood. Therefore, we assessed the long-term influence of hemoglobin on all-cause and cardiovascular mortality in patients with atherosclerotic disease. We prospectively studied 1,065 of 1,286 consecutive patients with asymptomatic carotid narrowing. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (25.8%) died. Continuous measures of hemoglobin displayed a significant inverse effect on all-cause mortality and cardiovascular mortality (adjusted hazard ratio [HR] for increase of 1 SD of hemoglobin 0.73, 95% confidence interval [CI] 0.64 to 0.83; p0.001) and adjusted HR 0.76, 95% CI 0.64 to 0.89; p = 0.001, respectively). The cumulative 6-year survival rate was 61%, 79%, 80%, and 81% in the first, second, third, and fourth quartile of hemoglobin (log-rank p0.001). Patients within the first quartile (12.9 g/dl) had a significantly increased risk of all-cause mortality (adjusted HR 1.93, 95% CI 1.46 to 2.54, p0.001) and cardiovascular mortality (adjusted HR 1.68, 95% CI 1.19 to 2.36, p = 0.003) compared to patients with greater levels. In conclusion, our study has demonstrated a significant association with hemoglobin levels and all-cause and cardiovascular mortality in patients with carotid narrowing. Nevertheless, additional research, in terms of randomized controlled trials, is needed to warrant these findings and to evaluate potential therapeutic interventions.

Percutaneous transluminal angioplasty is a minimally invasive therapy for the treatment of patients with peripheral artery disease who suffer from intermittent claudication or critical limb ischemia. The main advantages of the endovascular approach are a low complication rate ranging between 0.5% and 4%, a high technical success rate approaching 90% even in long occlusions, and an acceptable clinical outcome.1,2 Traditionally, percutaneous transluminal angioplasty (PTA) has been the standard for revascularization in aortoiliac, femoropopliteal, and below-the-knee arteries,1 and in many interventional centers, PTA still is the first and most frequently used methodology. However, high rates of failure resulting from an unacceptable incidence of restenosis, particularly in long and complex disease, are the main limitations of PTA.3 Modern bare metal stents (BMS), nitinol self-expanding stents, and cobalt-chromium balloon-expanding stents improved the durability of endovascular interventions, particularly in certain lower-limb indications. Advantages of self-expanding nitinol stents include acceptable radial strength combined with shape-memory characteristics, crush recoverability, and reduced foreshortening, which allows precise placement. Self-expanding nitinol stents are used mainly for external iliac and femoropopliteal indications but have its limitation in ostial common iliac artery lesions. Advantages of cobalt-chromium balloon-expanding stents are high radial strength, specifically for ostial iliac lesions with reduced strut thickness, allowing smaller introducer sizes. These properties of both stents types were expected to improve patency rates compared with PTA and earlier types of stents.4,5 However, the main obstacle of these BMS remains exaggerated neointimal hyperplasia, leading to in-stent restenosis in 25% to 50% within 12 to 24 months, depending on the location of implantation.6,7 New developments over the last several years include drug-eluting balloons (DEBs), new types of stents such as drug-eluting stents (DES) and covered stent grafts, and novel atherectomy systems. These are designed to reduce restenosis and …

Background and Purpose— Inflammatory responses play a key role in atherogenesis. The aim of this study was to assess the prognostic value of hsCRP (high-sensitivity C-reactive protein) and to evaluate whether degree of carotid stenosis and serum levels of hsCRP jointly predict long-term mortality in asymptomatic patients with carotid atherosclerosis. Methods— One thousand sixty-five patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality. Results— During a median of 11.81 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. The risk of all-cause and cardiovascular mortality significantly increased in patients with elevated serum levels of hsCRP (the adjusted hazard ratio for cardiovascular mortality per increase of 1 mg/dL of hsCRP levels was 1.47; P 0.29 mg/dL (=median) had nearly twice as high a risk of cardiovascular mortality compared with patients with carotid stenosis of P P Conclusions— Measurement of hsCRP in combination with ultrasound investigations of the carotid arteries at a single time point provides additional prognostic information for patients with asymptomatic carotid atherosclerosis.

Multidetector CT angiography (CTA) is a non-invasive imaging technique for evaluation of peripheral vascular disease. CTA might be particularly useful for assessment of intermediate- and long-term morphological outcome after endovascular treatment. Validation of CTA vs. the current imaging standard, colour Doppler ultrasonography (CDUS), for quantification of native and in-stent re-stenosis in the superficial femoral artery (SFA) is required.Seventy randomized patients who underwent stent implantation (n=47) or balloon angioplasty (n=23) underwent 6-month follow-up with CDUS and CTA. CTA was compared with CDUS in both sub-groups of patients in terms of binary re-stenosis (50% lumen narrowing) and re-occlusion. Agreement between CTA and CDUS was assessed using Kappa (κ) statistics with 95% confidence intervals, and correlation coefficients.Binary re-stenosis was detected in 16/70 (22.9%) patients by CTA and 17/70 (24.3%) patients by CDUS (κ=0.88, 95% CI: 0.80-0.96). Re-stenosis rates after balloon angioplasty were 39.1% (9/23) on CTA and CDUS (κ=0.82, 95% CI: 0.66-0.98), and after stent implantation 14.9% (7/47) on CTA and 17.0% (8/47) on CDUS (κ=0.92, 95% CI: 0.84-1.00). Re-occlusions were detected in 3/70 (4.3%) patients by both CTA and CDUS (κ=0.65; 95% CI 0.54-0.76). Significant correlations (r=0.85, p0.001) were noted between degree of re-stenosis on CTA and peak velocity ratio on CDUS. The correlation coefficient was higher in patients after balloon angioplasty (r=0.94, p0.001) than in patients after stent implantation (r=0.71, p0.001).CTA and CDUS show excellent agreement for evaluation of native and in-stent re-stenosis after endovascular treatment of SFA obstructions. CTA is an appropriate non-invasive imaging modality for follow-up after endovascular therapy.

Besides its effects on glucose and lipid metabolism, the Wnt pathway has been increasingly implicated in the regulation of proliferation, migration and survival of vascular cells. In addition, defective Wnt signaling has been identified in a family with autosomal dominant early coronary artery disease. The aim of this study was to investigate whether premature coronary artery disease is associated with features of decreased Wnt signaling.We prospectively enrolled 100 consecutive young survivors of myocardial infarction (MI≤40 years of age) from two high-volume cardiac catheterization centers and 100 sex and age matched hospital controls. We determined serum levels of Wnt-1 and its antagonist Dkk-1 by ELISA. MI patients showed significantly lower Wnt-1 levels as compared to controls (151 ng/mL, IQR 38-473 ng/mL vs. 233 ng/mL, IQR 62-1756; p0.005) whereas Dkk-1 was not different at baseline. Wnt-1 levels remained stable over time, whereas Dkk-1 significantly increased at one-year follow-up from 3557, IQR 2306-5810 pg/mL to 4973, IQR 3293-7093 pg/mL (p0.001). In the stable phase of the disease, Wnt-1 levels were lower (p0.005) and Dkk-1 levels were significantly higher (p0.001) as compared to controls. Wnt-1 at follow-up was associated with glucose, HbA1c, non-HDL-, HDL-cholesterol and triglyceride levels but no other features of the metabolic syndrome.This study establishes an association between low Wnt-1 and high Dkk-1 serum levels and premature myocardial infarction. Wnt-1 is associated with markers of glucose and lipid metabolism. Further research elucidating the role of Wnt pathways in premature coronary artery disease and metabolic syndrome is warranted.

Eur J Clin Invest 2012; 42 (9): 921–926 Abstract Background Humoral mediators of inflammation, in particular the complement system, have been described to play an important role in atherogenesis. Previously, we found a single-nucleotide polymorphism (SNP) in the complement 5 gene (C5 rs17611, A>G) independently associated with stroke. Up to now, the impact of C5 rs17611 on the progression of atherosclerosis and cardiovascular outcome in patients with asymptomatic atherosclerosis was unclear. Materials and Methods We investigated C5 rs17611 in a cohort of 1065 consecutive patients with asymptomatic carotid atherosclerosis. All patients were prospectively followed for the progression of carotid atherosclerosis and the development of a first major cardiovascular event (MACE), respectively. Results Three hundred and thirty-seven patients (31·6%) experienced a MACE during a median follow-up of 3·0 years. The homozygous GG genotype of the C5 rs17611 was significantly associated with adverse cardiovascular outcome (adjusted HR: 1·36 [95% CI, 1·07–1·73]; P = 0·01). After stratification for sex, C5 rs17611 CC was found to be an independent risk factor for MACE in men (HR 1·50 [95% CI, 1·12–1·83]). No association of C5 rs17611 with progression of carotid stenosis, observed in 93 (8·7%) patients, was detectable. Performance of ELISA indicated a significant association of the C5 rs17611 variant with C5a plasma levels. Conclusion The C5 rs17611 GG genotype is associated with increased C5a plasma levels and represents a risk factor for adverse cardiovascular outcome in male patients with carotid atherosclerosis.

BACKGROUND Inflammatory responses are pivotal in the initiation and development of premature atherosclerotic lesions. Galectin-3 represents a valuable biomarker for both progression and destabilization of atherosclerotic lesions. This study aims to assess the involvement of galectin-3 in premature myocardial infarction. DESIGN In this multicentre case-control study, we assessed circulating galectin-3 levels in 144 patients comprising 72 consecutive survivors of acute myocardial infarction (≤ 40 years) and 72 hospital controls frequency matched for age, gender and centre. RESULTS Patients with acute myocardial infarction showed significantly higher galectin-3 levels as compared to controls in the acute phase of acute myocardial infarction (2552 ± 1992 vs. 1666 ± 829 pg/mL; P < 0·001) as well as in the stable phase 1 year after the index event (3692 ± 1774 vs. 1666 ± 829 pg/mL; P < 0·001). Circulating galectin-3 was significantly and independently associated with premature myocardial infarction in the logistic regression analysis (acute phase: adj. OR per 1-SD change 2·03, 95% CI 1·30-3·19; P = 0·002; stable phase: adj. OR of 6·54 (95% CI 2·56-16·68; P < 0·001). Moreover, we observed a significant correlation between circulating galectin-3 and leucocyte count (r = 0·35, P < 0·001), non-HDL cholesterol (r = 0·23, P = 0·014) and HDL cholesterol (r = -0·29, P = 0·002). CONCLUSION We demonstrated that elevated levels of circulating galectin-3 are strongly associated with premature myocardial infarction. Galectin-3 might serve as link between dyslipidaemia as driving force of plaque formation with inflammation as initiator of plaque rupture in patients with premature acute myocardial infarction.

Eur J Clin Invest 2012; 42 (6): 631–636 Abstract Background Low-density lipoprotein (LDL) cholesterol lowering has been established as one of the principal targets in preventive cardiology. Recently, assessment of LDL particle size and number as well as other lipid moieties has been presented as a more reliable method to quantify atherogenicity of the lipoprotein fractions. Thus, it was our aim to assess the influence of different lipoprotein fractions on premature myocardial infarction (≤ 40 years of age). Methods and results We enrolled 302 patients into our multicentre case–control study, including 102 patients with myocardial infarction and 200 age-, gender- and centre-matched controls. The LDL and HDL Lipoprint® System were used for lipid subfraction quantification. The lipid risk factors most strongly associated with premature acute myocardial infarction (AMI) in the adjusted model were non-HDL C (OR 5·02, 95% CI 2·75–9·15, P-value = 0·001), LDL-C (OR 4·35, 95% CI 2·5–7·57, P-value = 0·001), VLDL-C (OR 3·66, 95% CI 2·14–6·28, P-value = 0·001), large IDL-C (OR 3·15, 95% CI 1·94–5·12, P-value = 0·001), large LDL-C (OR 3·67, 95% CI 2·19–6·15, P-value = 0·001) and intermediate LDL-C (OR 1·96, 95% CI 1·25–3·06, P-value = 0·003). In contrast, small dense LDL was not significantly associated with premature myocardial infarction. Conclusion Non-HDL cholesterol is most strongly associated with premature coronary artery disease and could serve as preferred risk predictor and therapeutic target in this young patient population (≤ 40 years). Besides, VLDL, LDL-C, large LDL, intermediate LDL and large IDL were significantly associated with premature myocardial infarction. Furthermore, our data suggest that risk prediction using small dense LDL particles might not be useful in young AMI survivors.

Eur J Clin Invest 2012; 42 (5): 463–469 Abstract Background Myeloperoxidase (MPO) is involved in a multitude of inflammatory processes involving oxidative modification of soluble components and cellular surfaces. Thus, MPO plays a key role in promoting atherosclerosis via oxidative stress by modification of both high- and low-density lipoprotein and production of other bioactive molecules. A polymorphism (MPO 463G>A, rs2333227) results in different expression rates of MPO. We aimed to assess whether MPO could be of clinical use as a risk marker for vascular disease in a high-risk group. Material and methods Plasma MPO levels of 406 patients suffering from peripheral arterial disease (PAD) were measured on an Abbott Architect i2000sr and grouped into patients with high (>115 ng/mL) and low (< 115 ng/mL) MPO levels. Genotyping of rs2333227 was performed on an ABI TaqMan 7900HT RT-PCR thermocycler. Results The relative risk of major adverse cardiovascular events (MACE) for patients with high plasma MPO is 1·2 (95%CI: 1·038–1·377, P A is not an independent risk factor for MACE in patients suffering from PAD.

Background A novel self-expanding drug-eluting stent was designed to slowly release everolimus to prevent restenosis following peripheral arterial intervention. The purpose of the first-in-human Superficial Femoral Artery Treatment with Drug-Eluting Stents (STRIDES) trial was to evaluate the safety and efficacy of this device for the treatment of symptomatic superficial femoral and proximal popliteal arterial occlusive disease. Methods and Results One hundred four patients were enrolled at 11 European investigative centers in a prospective, nonrandomized, single-arm trial. The patients had severe symptomatic vascular disease, including a significant proportion of patients with critical limb ischemia (17%), diabetes (39%), and single-vessel outflow (26%). The mean lesion length was 9.0 ± 4.3 cm. Ninety-nine percent of patients were available for 12-month follow-up, including duplex imaging in 90% and arteriography in 83%. Clinical improvement, defined as a sustained decrease in Rutherford-Becker clinical category, was achieved in 80% of patients. Primary patency (freedom from ≥50% in-stent restenosis) was 94 ± 2.3% and 68 ± 4.6% at 6 and 12 months, respectively. Plain radiographic examination of 122 implanted devices at 12 months revealed no evidence for stent fracture. Conclusions The everolimus-eluting self-expanding nitinol stent can be successfully implanted in patients with severe peripheral arterial disease with favorable outcomes and clinical improvements observed in the majority of patients.

BACKGROUND: Acupuncture has been shown to influence skin perfusion and the subjective cold perception threshold. Therefore, we hypothesized that auricular electroacupuncture (EA) might reduce symptoms in primary Raynaud's phenomenon (PRP). METHODS: Twenty-six patients with PRP received 6 cycles of auricular EA. After 3, 6 and 24 weeks attack frequency and severity were reevaluated using standardized questionnaires and a visual analogue scale (VAS). Skin temperature was assessed by infrared thermography and laser Doppler perfusion imaging was used to determine skin perfusion. RESULTS: Compared to baseline we found a significant reduction of attack frequency after 3 (p = 0.001) and 6 weeks (p < 0.001) of auricular EA. This improvement sustained following cessation of EA, after 24 weeks (p < 0.001). Furthermore, attack associated pain was reduced after 3 (p = 0.003), 6 (p = 0.003) and 24 weeks (p = 0.001) of treatment, while skin temperature and skin perfusion did not change significantly throughout the study period. CONCLUSIONS: Auricular EA reduces symptoms by means of frequency and severity of attacks in PRP but has no influence on skin perfusion and skin temperature.

SummaryAcute myocardial infarction at a young age is associated with high morbidity and long-term mortality. The NADPH oxidase system as a main source of reactive oxygen species in vascular cells has been implicated in development and progression of coronary artery disease (CAD). In our study, we investigated the effect of polymorphisms in the p22-PHOX (CYBA) gene on CAD in young patients (≤ 40 years). We prospectively recruited 302 subjects into our multi-centre case control study, including 102 young myocardial infarction patients (≤ 40 years) from two high-volume cardiac catheterisation hospitals and frequency-matched them on age, gender, and center to 200 hospital controls in an approximate 2:1 ratio per case patient. The homozygote c.-930A>G promoter polymorphism was significantly more prevalent in the controls than in the infarction patients. In the adjusted logistic regression analysis, we detected a protective effect of the c.-930A>G promoter polymorphism against premature myocardial infarction. Using a logadditive/per-allele model, we detected an unadjusted odds ratio (OR) of 0.63 (95% confidence interval [CI] 0.45–0.9, p-value 0.011). In the adjusted model the association was more pronounced with an OR of 0.5 (95% CI 0.3–0.81, p-value 0.005). The C242T polymorphism and the 640A>G polymorphism did not differ significantly between the study groups. Furthermore we could not detect a significant effect for these polymorphisms in the logistic regression analysis. The present study suggests a protective association between the c.-930A>G promoter polymorphism in the p22-PHOX (CYBA) gene and the development of myocardial infarction in young individuals (≤ 40 years).

Eur J Clin Invest 2011; 41 (4): 365–371 Abstract Background A single-nucleotide polymorphism (SNP) in the palladin gene (PALLD, rs7439293) has recently been reported to be associated with coronary heart disease (CHD) in two case–control studies as well as in a large population-based cohort (Atherosclerosis Risk in Communities study, ARIC). Its clinical relevance, however, has not been evaluated prospectively. We investigated whether the risk allele (A) of PALLD rs7439293 (G>A) is associated with the occurrence of future major cardiovascular events (MACE) in a cohort of patients with prevalent carotid atherosclerosis. Materials and methods A total of 1283 consecutive patients with neurologically asymptomatic carotid atherosclerosis were included in the study and prospectively followed for a median of 3·5 years (interquartile range 3–4 years). We analysed whether the risk allele is associated with progression of carotid atherosclerosis after a 6–9-month period as measured by duplex Doppler sonography. Patients were then followed for the occurrence of a first MACE, a composite of myocardial infarction, stroke, coronary revascularization and death. Results After a median of 7·5 months (interquartile range 6–9 months), progression of carotid stenosis was observed in 103 (8·1%) patients. Cardiovascular events occurred in 337 (30%) patients after a median follow-up of 3·5 years. The risk allele of PALLD was neither associated with progressive carotid atherosclerosis (P = 0·21) nor with MACE (P = 0·58). Adjusted hazard ratios for a first MACE in heterozygous and homozygous carriers were 0·83 (95% CI 0·58–1·18) and 0·94 (95% CI 0·65–1·35) compared to wild type, respectively. Conclusions The A-allele of PALLD rs7439293 was not associated with progressive carotid atherosclerosis as measured by duplex Doppler sonography nor did it represent a risk factor for adverse cardiovascular outcome among patients with prevalent carotid atherosclerosis.

The aim of our study was to evaluate the effect of drug-eluting stents (DES) compared with bare-metal stents (BMS) on all-cause mortality and target vessel revascularization (TVR) in a “real-world” clinical setting. One thousand four hundred and ninety consecutive patients, who underwent PCI, were included in a prospective registry from January 2003 until December 2006. Patients were divided retrospectively into two groups: those who received a DES and those who received a BMS. The primary combined endpoint all-cause mortality or TVR and the individual endpoints death and TVR were evaluated during a mean follow-up period of 24.56 ± 12.5 months (range 6–52 months). In total 1,033 patients (69.3%) received BMS, while 457 patients (30.7%) received DES. With respect to clinical characteristics, significant differences between groups were found for age, hyperlipidemia, diabetes mellitus, heart failure, previous cerebral insult and presence of acute coronary syndrome (ACS) during intervention. Propensity score analysis was performed in attempt to eliminate this selection bias. With respect to the combined endpoint all-cause death or TVR, 12.9% of patients with DES and 21.3% with BMS (p = 0.015) had an event during the follow-up. 12.3% of patients with BMS but only 5.7% with DES died during the follow-up (p = 0.025). Thirty-three patients (7.2%) of the DES group and 99 patients (9.6%) of the BMS group (p = 0.1) needed TVR. Our results obtained in a “real-world” clinical setting exhibit a clinical long-term benefit for DES compared with BMS and underline the safety and efficacy of DES over BMS.

Background. Hemodialysis immediately before kidney transplant surgery has been suggested to adversely affect early graft function. On the other hand, considering its profound antiinflammatory effects, a beneficial impact of regional citrate anticoagulation on the evolution of graft function can be speculated. We sought to assess the clinical impact of preoperative hemodialysis and dialysis anticoagulation in two related randomized trials. Methods. Eligible kidney transplant candidates with a serum potassium less than or equal to 5.0 mEq/L were randomized to receive dialysis or no dialysis before deceased donor transplantation. Patients with a potassium more than 5.0 mEq/L were randomized to receive dialysis with heparin or citrate anticoagulation. The primary endpoint was the estimated glomerular filtration rate (eGFR) at posttransplant day 5. Results. The first comparison (56 vs. 54 patients) revealed no effect of dialysis on eGFR at day 5 (primary endpoint, 12 [interquartile range 5―36] vs. 13 [5―37] mL/min/1.73 m 2 , P=0.98), rates of delayed graft function (22% vs. 27%, P=0.66), cellular rejection (20% vs. 24%, P=0.65), and C4d-positive dysfunction (2% vs. 9%, P=0.11) or 1-year death-censored graft survival (89% vs. 91%, P=0.51). Comparing citrate with heparin anticoagulation (44 vs. 66 patients), no differences in eGFR at day 5 (17 [8―31] vs. 14 [6―38] ml/min/1.73 m 2 , P=0.57), delayed graft function (21% vs. 30%, P=0.28), cellular rejection (23% vs. 33%, P=0.29), and graft survival (90% vs. 88%, P=0.44) were found. For citrate anticoagulation, less C4d-positive rejection episodes (P=0.08) and higher 1-year eGFR levels (P=0.03) were observed. Conclusion. Pretransplant hemodialysis and anticoagulation may not affect early graft function in a meaningful way.

Background Patients with symptomatic peripheral artery disease (PAD) are considered cardiovascular high-risk patients. Our aim was to investigate whether incidental renal artery stenosis (RAS) increases the risk for adverse cardiovascular and renal outcomes in these patients. Materials and methods We prospectively enrolled 487 consecutive patients admitted for revascularization of symptomatic PAD and performed a renal overview angiogram categorizing RAS as absent (0–29%), moderate (30–59%) and severe (≥ 60%) respectively. Clinical follow-up was for median 15 months (IQR 12–22) for the occurrence of major adverse events [MAE: composite of death, myocardial infarction (MI), stroke, percutaneous coronary intervention, coronary bypass surgery, amputation and kidney failure]. Glomerular filtration rates (GFR) were obtained at 12 months to quantify the course of renal function. Results A severe RAS was found in 76 patients (15·6%). Overall MAE occurred in 121 patients (24·8%), the composite endpoint of MI, stroke, amputation and death occurred in 101 patients (20·7%). Patients with a severe RAS had a 1·87-fold increased adjusted risk for MAE (95% CI 1·12–3·12, P = 0·017), a 2·51-fold increased adjusted risk for occurrence of the composite endpoint of MI, stroke, amputation and death (95% CI 1·45–4·34, P = 0·001) and a 2·93-fold increased risk for death (95% CI 1·41–6·08, P = 0·004), compared to those of patients without RAS respectively. We observed a significant association between the decrease of GFR over the 12-month follow-up period and the severity of RAS by multivariable analysis (P = 0·044). Conclusion Severe RAS in patients with symptomatic PAD is an independent predictor of major adverse cardiovascular events, adverse renal outcome and mortality.

Die periphere arterielle Verschlusskrankheit (paVK) ist eine Manifestation der Atheroskleorose an den Transportarterien der unteren Extremitaten. Die Inzidenz ist altersabhangig und liegt bei der uber 70-jahrigen Bevolkerung bei 18 bis 20 Prozent, wobei eine grose Zahl der Patienten asymptomatisch ist. Die Pravalenz der Erkrankung nimmt entsprechend der sich standig nach oben verschiebenden Alterspyramide unserer Bevolkerung kontinuierlich zu.

Aims Myocardial infarction (MI) in very young individuals is a rare disease associated with an unfavourable prognosis. Familial-combined hyperlipidaemia (FCHL) increases the risk for MI in individuals below 60 years; however, its role in very young MI patients below 40 years is not as well established. We investigated the prevalence and impact of FCHL in these very young MI patients. Methods and results We prospectively enrolled 102 consecutive MI survivors (≤40 years) from two high-volume cardiac catheterization centres. Patients were frequency-matched for age, gender, and centre to 200 hospital controls free from coronary heart disease. Myocardial infarction patients were invited to send family members for FCHL screening. Overall, 37 families were screened. Familial-combined hyperlipidaemia was diagnosed using a nomogram, which takes into account total cholesterol, triglycerides, and Apo B100 levels. Thirty-eight acute myocardial infarction (AMI) patients (38%) and five controls (2.5%) displayed the FCHL phenotype, 21 of these MI patients sent family members for screening, and FCHL was confirmed in 16 families (76%). The FCHL phenotype was associated with a 24-fold increased adjusted risk for MI (95% CI 7.5–81, P < 0.001). Of all lipid parameters, VLDL-cholesterol, and non-HDL-cholesterol were most strongly associated with MI. Conclusions The present study suggests that the FCHL phenotype seems to be a major risk factor for the occurrence of MI at a very young age. It remains to be determined whether this excessively increased risk can be favourably modified by therapeutic interventions.

To investigate the safety and efficacy of the procoagulant wound dressing Neptune Pad (Biotronik, Berlin, Germany) compared with those of conventional manual compression for access site management after peripheral percutaneous interventions.The study was approved by the institutional ethics committee, and all patients gave written informed consent. Two hundred one consecutive patients were enrolled and were randomly assigned to be treated with the Neptune Pad (n = 100) or conventional manual compression (n = 101). Patients were followed up clinically until hospital discharge and with duplex ultrasonography at 24 hours after the procedure to evaluate occurrence of access site complications. Time to hemostasis and time to ambulation were recorded, and patient and physician discomfort were measured by using a visual analogue scale.The risk for access site complications was not significantly different between the Neptune Pad group and the conventional compression group (adjusted odds ratio, 1.15; 95% confidence interval: 0.47, 2.84; P = .76). Time to hemostasis was marginally reduced in the Neptune Pad group. Patient and physician discomfort were lessened with use of the device.The hemostatic device Neptune Pad does not improve the safety of access site management after peripheral percutaneous procedures. Markedly improved comfort was noted among patients in the Neptune Pad group and by the physicians obtaining hemostasis.

Carotid plaque echolucency seen at ultrasonography (US) is a potential indicator of plaque instability and may help identify patients at risk for major adverse cardiovascular events (MACEs). The authors performed this study to determine whether decreasing gray-scale median (GSM) levels at repeat carotid US examinations are associated with future MACEs.The study was approved by the institutional ethics committee and all patients provided informed consent. The authors prospectively studied 574 patients with carotid plaques of at least 30% from a group of 1268 consecutive patients who were initially asymptomatic with respect to carotid disease. GSM levels were determined with carotid US at baseline and after a median of 7.5 months (range, 6-9 months), and the mean change of the GSM was calculated. Patients were then followed up clinically for a median of 3.2 years for the occurrence of composite MACE.During the initial period, the median change in carotid GSM was 2.9 (interquartile range [IQR], -6.9 to 11.0). Of 574 study participants, 230 (40%) showed a reduction of GSM levels and 344 (60%) showed an increase. MACEs were observed in 177 (31%) of the 574 patients. Adjusted hazard ratios for the lowest quartile (GSM change less than -6.9), the second quartile (GSM change between -6.9 and 2.9), and the third quartile (GSM change between 3.0 and 11.0) were 1.71 (95% confidence interval [CI]: 1.09, 2.66), 1.36 (95% CI: 0.86, 2.16), and 1.22 (95% CI: 0.77, 1.95), respectively, compared with the highest quartile (GSM change greater than 11.0) (P = .018).Increasing echolucency of carotid artery plaques within a 6- to 9-month interval is predictive of midterm clinical adverse events of atherosclerosis.

To prospectively determine whether cutting balloon angioplasty, when compared with conventional balloon angioplasty (CBA), improves morphologic and clinical outcome in patients with femoropopliteal in-stent restenosis.Patients with symptomatic femoropopliteal in-stent restenosis were randomly assigned to undergo CBA or peripheral cutting balloon angioplasty (PCBA) for treatment of lesions up to 20 cm in length. Patients were followed up clinically and with duplex ultrasonography (US) at 1, 3, and 6 months for occurrence of a restenosis of 50% or higher. The Fisher exact test and Mann Whitney U test were used for statistical analyses.Forty patients were enrolled; one patient was lost to follow-up. In the remaining patients, CBA was performed in 22 patients; PCBA was used in 17 patients. Average lesion length was 80 mm +/- 68 (standard deviation). Restenosis rates at 6 months were 65% (11 of 17; 95% confidence interval: 42%, 88%) after PCBA versus 73% (16 of 22; 95% confidence interval: 54%, 92%) after CBA (P = .73). Ankle brachial index (0.83 vs 0.75, P = .26) and maximum walking capacity on the treadmill (117 m vs 103 m, P = .97) at 6 months were also not significantly different between the two groups.PCBA failed to prove superiority compared with CBA for treatment of femoropopliteal in-stent restenosis in this pilot study. In restenotic lesions with an average length of approximately 8 cm, both treatment modalities yielded disappointing 6-month patency rates.

Background The formation of abdominal aortic aneurysm (AAA) is caused by a destructive remodeling of the extracellular matrix in the vascular wall. Proteoglycan content and biosynthesis have been shown to be altered in AAA. Xylosyltransferase I (XT-I) is the initial and rate-limiting enzyme in the biosynthesis of the proteoglycan-linked glycosaminoglycan chains. A familial predisposition to AAA is well recognized. Thus, variations in the XT-I coding gene XYLT1 might be risk factors for AAA formation. Methods We performed genotyping of two genetic variations in the XYLT1 gene which, have been already linked to proteoglycan-associated diseases, in 129 AAA patients and 129 age- and sex-matched healthy controls. Results The T-allele of the polymorphism c.343G > T (p.A115S) was found to be significantly more frequent in AAA patients compared to the healthy control group, demonstrating that carriers of the T-allele have a 5-fold increased risk of developing AAA (odds ratio 4.87, 95%-CI 1.38–17.19; p = 0.011). Conclusions Our results show that XT-I polymorphisms potentially confer to the genetic susceptibility of AAA.

To prospectively determine, in a randomized controlled trial, whether cutting balloon angioplasty (CBA) yields superior morphologic and clinical outcomes at 6 months compared with the 6-month outcomes after conventional percutaneous transluminal angioplasty (PTA) in patients with short de novo superficial femoropopliteal artery (SFA) lesions.This study was approved by the ethics committees of the two participating centers, and informed consent was obtained from all patients. The authors randomly assigned 43 patients (26 men, 17 women; median age, 69 years) who had 5 cm or shorter de novo SFA lesions in association with intermittent claudication or chronic limb ischemia to undergo CBA or PTA. The patients were followed up clinically, and restenosis was assessed with duplex ultrasonography (US) at 6 months. chi(2) and Mann-Whitney U tests were used to compare data between the two treatment groups.The US-determined 6-month restenosis rate was 32% (seven patients) in the PTA group versus 62% (13 patients) in the CBA group (P = .048). Sixteen (73%) PTA group patients versus eight (38%) CBA group patients were asymptomatic at follow-up (P = .059). There was no significant difference in ankle-brachial index (median, 0.83 vs 0.77 for PTA vs CBA group, respectively; P = .56) or pain-free walking distance (median,1000 m vs 600 m for PTA vs CBA group, respectively; P = .17) between the two groups.CBA did not prove to be superior to conventional PTA for treatment of short de novo SFA lesions and yielded increased restenosis rates at 6 months.

There exists no systematic evaluation of liver function in renal allograft recipients undergoing C2-monitoring with Neoral [cyclosporine A (CsA)-microemulsion]. In the present cohort analysis, we compared the hepatic profiles of C2-monitored (n = 80), C0-monitored (n = 81), and non-CsA-treated renal allograft recipients (n = 29), transplanted between 1/1999 and 2/2004 in our institution. While the C2-targets were set in accordance with (n = 72) or below (n = 8) the consensus on Neoral (1500 +/- 200 ng/ml), non-CsA-patients received FK506 (n = 29), partially in combination with rapamycin (n = 13) as primary immunosuppression. Analysis of maximum hepatic laboratory parameters and also repeated measures by anova within 30 days post-transplant revealed highly significant elevations of direct, indirect and total bilirubin, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase (P0.001) in the C2-group, in comparison with the C0- and the non-CsA-group. Bilirubin-levels were by far the most affected of all hepatic parameters, and correlated with C2-levels (r2 = 0.62). Seventeen CsA-patients had excessive bilirubin-elevations (4 mg/dl) and were therefore considered to be 'CsA-sensitive' [14 C2-patients (17% of all C2-patients), 3 C0-patients (4% of all C0-patients)]. Bilirubin- and the other parameter elevations in these patients were reversible upon withdrawal or lowering of CsA. Most 'CsA-sensitive' patients (n = 12, 70%) displayed pre-transplant hepatic impairment, indicating a pre-existing liver instability. Collectively, our data emphasize the need for increased awareness toward individual predispositions for CsA-sensitivity.

Capillary C4d deposition is a valuable marker of antibody-mediated rejection (AMR). In this analysis, flow cytometric detection of alloantibody-triggered C4d deposition to HLA antigen-coated microparticles ([C4d]FlowPRA) was evaluated for its value as a marker for C4d deposition in renal allografts. For comparative analysis, 105 first renal biopsies performed for graft dysfunction and an equal number of concurrent sera were subjected to immunohistochemistry and [C4d] plus standard [IgG]FlowPRA, respectively. C4d deposition/fixation was detected in 17 biopsies and, applying [C4d]FlowPRA HLA class I and II screening, also in a small number of corresponding sera (N = 20). IgG reactivity detected by standard [IgG]FlowPRA was more frequent (49% of sera). Comparing [C4d]FlowPRA screening with capillary C4d staining, we found a high level of specificity (0.92 [95% confidence interval: 0.86-0.98]), which far exceeded that calculated for [IgG]FlowPRA (0.60 [0.50-0.70]). [IgG]FlowPRA screening, however, turned out to be superior in terms of sensitivity (0.94 [0.83-1.05] vs. 0.76 [0.56-0.97] calculated for C4d-fixing panel reactivity). Remarkably, posttransplant single antigen testing for identification of complement-fixing donor-specific alloreactivities failed to improve the predictive value of FlowPRA-based serology. In conclusion, our results suggest that detection of complement-fixing HLA panel reactivity could provide a specific tool for monitoring of C4d-positive AMR.

Aims Blood d-dimer testing has been proposed as diagnostic marker with high sensitivity for exclusion of acute aortic dissection (AAD). We performed a systematic review and validated the findings in a prospective patient cohort. Methods and results We searched MEDLINE, EMBASE, CINAHL, and BIOSIS from inception until January 2007 using a combination of search terms for aortic dissection and d-dimer. Study type, type of assay used, predefined cut-off level, result of d-dimer testing, sensitivity, and specificity were abstracted. In 16 identified studies (437 patients), the reported cut-off values ranged from 0.1 to 0.9 µg/mL. d-Dimer testing provided high sensitivity (0.97 95% CI 0.94–0.98) and negative likelihood ratio (0.06 95% CI 0.02–0.13). In our cohort of 65 patients (36 male, 55%; median age 59 years, IQR 49–67) with proven AAD, d-dimer levels scattered from 0.24 to 137.88 µg/mL (median 3.47; IQR 1.55–14.49). Mean NPV for the different cut-off levels ranged from 92 % for a cut-off level of 0.9 µg/mL to 100% for a cut-off level of 0.1 µg/mL in our study population. Conclusion Current evidence supports a routine measurement of d-dimer in excluding AAD. A d-dimer

Background and Purpose— The progression of carotid stenosis reflects the activity of atherosclerotic disease and may indicate a risk for systemic atherothrombotic complications. We investigated whether progressive carotid stenosis determined by duplex ultrasonography predicts adverse outcomes in cardiovascular high-risk patients. Methods— We prospectively studied 1065 of 1268 consecutive patients initially asymptomatic with respect to carotid disease. Carotid ultrasound investigations at baseline and after a median of 7.5 months (range, 6 to 9 months) were performed to identify patients with progressive stenosis as defined by Doppler velocity criteria. Patients were then followed up clinically for a median of 3.2 years for the occurrence of major adverse cardiovascular events (composite MACEs: myocardial infarction, percutaneous coronary or peripheral interventions, coronary or vascular surgery, amputation, stroke, and all-cause mortality). Results— We found progressive carotid stenosis in 93 patients (9%) by ultrasound and thereafter recorded 495 MACEs in 421 patients (40%) during clinical follow-up. Patients with progressive carotid stenosis had a significantly increased risk for cardiovascular events compared with patients with nonprogressive disease: adjusted hazard ratios and confidence intervals were 2.01 for composite MACEs (95% CI, 1.48 to 2.67, P P =0.044), 1.59 for any coronary event (95% CI, 1.10 to 2.28, P =0.011), 2.00 for stroke (95% CI, 1.02 to 4.11, P =0.035), 2.42 for any peripheral vascular event (95% CI, 1.61 to 3.62, P P =0.039). Conclusion— Progression of carotid stenosis within a 6- to 9-month interval detected by duplex ultrasound predicts midterm clinical adverse events of atherosclerosis in high-risk patients affecting the coronary, cerebrovascular, and peripheral circulations.

Summary Background No accurate, independent biomarker has been identified that could reliably predict neurological outcome early after cardiac arrest. We speculated that brain natriuretic peptide (BNP) measured at hospital admission may predict patient outcome. Methods BNP-levels were measured in 155 comatose cardiac arrest survivors (108 male, 58 years [IQR 49–68]) (median time to ROSC 11 min; IQR 20–30) during a 6-year study period. Cardiovascular co-morbidities and resuscitation history were assessed according to the Utstein-style and patients were followed for 6-month neurological outcome measured by cerebral performance category (CPC) and survival. Results Seventy patients (45%) suffered from unfavourable neurological outcome and 79 deaths (51%) occurred during the first 6 months. BNP was significantly associated with an adverse neurological outcome and mortality, independent of the prearrest health condition and cardiac arrest characteristics (median 60 pg/ml; IQR 10–230). Adjusted odds ratios for poor neurological outcome at 6 months were 1.14 (95% CI 0.51–2.53), 1.76 (95% CI 0.80–3.88) and 2.25 (95% CI 1.05–4.81), for increasing quartiles of BNP as compared to the lowest quartile. Adjusted odds ratios for mortality until 6 months were 1.09 (95% CI 0.35–3.40), 2.81 (0.80–9.90) and 4.7 (1.27–17.35) compared to the lowest quartile, respectively. Conclusion Brain natriuretic peptide levels on admission predict neurological outcome at 6 months and survival after cardiac arrest.

Purpose: To evaluate the agreement of duplex ultrasound (DUS) versus digital subtraction angiography (DSA) for assessment of femoropopliteal arterial disease in a real-world clinical setting. Methods: Consecutive patients with peripheral artery disease who were scheduled for a percutaneous intervention were included in this retrospective study. During an 18-month period, 491 patients (276 men; median age 73 years, interquartile range 64–81) were enrolled. A peak systolic velocity ratio (PSVR) >2.4 was the optimal cutoff for detecting a >50% stenosis by DSA. Findings of preprocedural DUS in the proximal, middle, and distal ipsilateral superficial femoral artery and in the popliteal segment were analyzed for agreement with preprocedural femoropopliteal DSA using kappa statistics. Only the target limb in each patient was analyzed, for a total of 1964 vascular segments. Results: Agreement for the degree of stenosis in 10% increments was only moderate (weighted kappa 0.67, 95% CI 0.65 to 0.69). Using the PSVR >2.4 cutoff, agreement between DUS and DSA for a >50% stenosis was good (kappa 0.79, 95% CI 0.77 to 0.81). Sensitivity, specificity, positive predictive value, and negative predictive value for correctly detecting a >50% stenosis by DUS were 0.81 (0.78 to 0.84), 0.93 (0.91 to 0.94), 0.84 (0.81 to 0.87), and 0.91 (0.87 to 0.95), respectively. Comparable findings were observed within different patient subgroups. Conclusion: Agreement between DUS and DSA in the femoropopliteal segment is only moderate with respect to the absolute degree of stenosis. However, detection of a >50% stenosis can be done with acceptable precision in routine clinical practice using PSVR >2.4 as a threshold.

Background— Primary stenting with self-expanding nitinol stents of the superficial femoral artery yielded improved morphological and clinical results compared with balloon angioplasty with optional stenting until 12 months in a randomized controlled trial. We now report 2-year data on restenosis and clinical outcomes of these patients. Methods and Results— Of 104 patients with chronic limb ischemia and superficial femoral artery obstructions, 98 (94%) could be followed up until 2 years after intervention for occurrence of restenosis (>50%) by duplex ultrasound and for clinical and hemodynamic outcome by treadmill walking distance and ankle brachial index. Restenosis rates at 2 years were 45.7% (21 of 46) versus 69.2% (36 of 52) in favor of primary stenting compared with balloon angioplasty with optional secondary stenting by an intention-to-treat analysis ( P =0.031). Consistently, stenting (whether primary or secondary; n=63) was superior to plain balloon angioplasty (n=35) with respect to the occurrence of restenosis (49.2% versus 74.3%; P =0.028) by a treatment-received analysis. Clinically, patients in the primary stent group showed a trend toward better treadmill walking capacity (average, 302 versus 196 m; P =0.12) and better ankle brachial index values (average, 0.88 versus 0.78; P =0.09) at 2 years, respectively. Reintervention rates tended to be lower after primary stenting (17 of 46 [37.0%] versus 28 of 52 [53.8%]; P =0.14). Conclusions— At 2 years, primary stenting with self-expanding nitinol stents for the treatment of superficial femoral artery obstructions yields a sustained morphological benefit and a trend toward clinical benefit compared with balloon angioplasty with optional stenting.

Background and Purpose— Atherosclerosis is a systemic inflammatory disease. We demonstrated previously that high-sensitivity C-reactive protein (hs-CRP) is associated with short-term progression of carotid atherosclerosis. We now investigated whether baseline levels of hs-CRP predict midterm clinical outcome in these patients. Methods— We prospectively studied 1065 of 1268 consecutive patients who were initially asymptomatic with respect to carotid artery disease and were investigated with serial carotid ultrasound examinations at baseline and after a 6- to 9-month interval. Patients were followed-up clinically for the occurrence of cardiovascular events, a composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, and death. Results— We recorded progression of carotid stenosis in 93 patients (9%) after 6 to 9 months, and 381 cardiovascular events in 337 patients (27%) during a median of 3 years of clinical follow-up (interquartile range, 2.5 to 3.5 years). The hs-CRP levels were significantly elevated in patients with progressive carotid stenosis ( P P Conclusion— Inflammation was associated with morphological and clinical progression of atherosclerotic disease. Patients with elevated levels of hs-CRP exhibit an increased risk for adverse cardiovascular outcome attributable to clinical adverse events of progressive atherosclerotic disease.

BACKGROUND The presence of preformed alloantibodies with the ability to activate complement may pose a particular risk for kidney allograft rejection. The aim of this study was to evaluate variables that determine the complement-fixing capability of human leukocyte antigen (HLA) sensitization. METHODS Sixty-five sensitized patients with > or =10% pretransplant panel-reactive antibody (PRA) levels uncovered by immunoglobulin G [IgG]FlowPRA HLA class I and/or class II screening were included. Applying modified FlowPRA screening, sera were evaluated for patterns of alloreactive IgG subclasses and IgM, and, in parallel, for their complement-activating ability assessed by flow cytometric detection of human complement split product deposition ([C4d]FlowPRA). RESULTS Approximately two-thirds (68%) of tested sera were found to contain complement-fixing alloreactivity (> or =10%[C4d]FlowPRA). IgG1 type panel reactivity was predominant (detectable HLA class I and II reactivity in 93% and 91% of IgG-positive sera), followed by IgG3 (49%/44%), IgG2 (44%/27%), and IgG4 (19%/11%). Applying partial correlation we found an independent correlation of both %[IgG1]FlowPRA and %[IgG3]FlowPRA with %[C4d]FlowPRA reactivities (P< or =0.01). In addition, for IgG1 a contribution of the amount of bound alloantibody to complement-fixation was observed. Complement-fixation was also favored by the simultaneous presence of alloreactive IgG1, IgG3, and IgM. Previous grafting, but not pregnancy and transfusion, was independently associated with complement-fixing sensitization (P

PURPOSE To investigate whether balloon angioplasty of the superficial femoral artery (SFA) increases serum levels of C5a and whether C5a predicts risk of restenosis. METHODS C5a antigen was measured at baseline and 8 hours after intervention in 131 consecutive patients (76 women; median age 72 years) with intermittent claudication who underwent successful primary SFA balloon angioplasty. Patients were followed for a median 10 months [interquartile range (IQR) 6 to 14] for the occurrence of >50% restenosis by duplex ultrasound. RESULTS Median C5a levels increased significantly from 39.7 ng/mL (IQR 27.8 to 55.0) at baseline to 53.8 ng/mL (IQR 35.6 to 85.1, p