TREM2 protects from atherosclerosis by limiting necrotic core formation.

Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, and its main complications, myocardial infarction and stroke, are the leading cause of mortality worldwide [1], [2]. Recent studies have identified Triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating myeloid cell functions [3], to be highly expressed in macrophage foam cells in experimental and human atherosclerosis [4]. However, the role of TREM2 in atherosclerosis is not fully known. Here, we show that hematopoietic or global TREM2 deficiency increased, whereas TREM2 agonism decreased necrotic core formation in early atherosclerosis. We demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages, and to the survival of lipid-laden macrophages, indicating a crucial role of TREM2 in maintaining the balance between foam cell death and clearance of dead cells in atherosclerotic lesions, thereby controlling plaque necrosis.

Von Willebrand factor antigen levels predict major adverse cardiovascular events in patients with carotid stenosis of the ICARAS study.

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 < 0.001). 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.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

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 88 randomized controlled trials with 19,161 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 evidence.• Acute myocardial infarction (AMI): RR 1.04, 95% CI 0.71 to 1.51, 3553 participants, moderate quality evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.25 to 1.05, 166 participants, low quality evidence.• Cerebrovascular events: RR 1.52, 95% CI 0.58 to 4.02, 1400 participants, low quality evidence.• Hypotension: RR 1.54, 95% CI 0.67 to 3.51, 558 participants, low quality evidence.• Bradycardia: RR 1.61, 95% CI 0.97 to 2.66, 660 participants, low quality evidence.• Congestive heart failure: RR 0.22, 95% CI 0.04 to 1.34, 311 participants, low quality 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 evidence.• Supraventricular arrhythmias: RR 0.44, 95% CI 0.36 to 0.53, NNTB five, 6420 participants, high quality 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 evidence).NON-CARDIAC SURGERY (35 trials)Beta-blockers significantly increased the occurrence of the following adverse events.• All-cause mortality: RR 1.25, 95% CI 1.00 to 1.57, 11,413 participants, low quality of evidence, number needed to treat for an additional harmful outcome (NNTH) 167.• Hypotension: RR 1.50, 95% CI 1.38 to 1.64, NNTH 16, 10,947 participants, high quality evidence.• Bradycardia: RR 2.23, 95% CI 1.48 to 3.36, NNTH 21, 11,033 participants, moderate quality evidence.We found a potential increase in the occurrence of the following outcomes with the use of beta-blockers.• Cerebrovascular events: RR 1.59, 95% CI 0.93 to 2.71, 9150 participants, low quality 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 265, 8648 participants.Beta-blockers significantly reduced the occurrence of the following endpoints.• AMI: RR 0.73, 95% CI 0.61 to 0.87, NNTB 76, 10,958 participants, high quality evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.34 to 0.77, NNTB nine, 978 participants, moderate quality evidence.• Supraventricular arrhythmias: RR 0.73, 95% CI 0.57 to 0.94, NNTB 112, 8744 participants, high quality evidence.We found no clear evidence of an effect of beta-blockers on the following outcomes.• Ventricular arrhythmias: RR 0.68, 95% CI 0.31 to 1.49, 476 participants, moderate quality evidence.• Congestive heart failure: RR 1.18, 95% CI 0.94 to 1.48, 9173 participants, moderate quality evidence.• Length of hospital stay: mean difference -0.45 days, 95% CI -1.75 to 0.84, 551 participants, low quality 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 shows an association of beta-blockers with increased all-cause mortality. Data from low risk of bias trials further suggests an increase in stroke rate 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.

Soluble galectin-3 is associated with premature myocardial infarction.

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.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

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.

Mean platelet volume predicts outcome in patients with asymptomatic carotid artery disease.

BACKGROUND AND OBJECTIVE: Platelets play a pivotal role in atherothrombosis and are potentially involved in the pathogenesis of atherosclerosis. We investigated whether mean platelet volume (MPV) predicts clinical outcome and progression of atherosclerosis in patients with asymptomatic carotid artery disease. METHODS: We studied 1006 of 1268 prospectively collected consecutive patients with asymptomatic carotid atherosclerosis who were evaluated by duplex sonography. Patients were followed up clinically for the occurrence of a major adverse cardiovascular event (MACE), a composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke and death. RESULTS: During a median follow-up of 3.1 years (interquartile range, 2.5-3.5), a total of 316 (31.5%) MACEs were recorded. Increased levels of MPV were significantly associated with increased risk of the occurrence of MACEs (adjusted hazard ratio [HR] for an increase in one standard deviation [SD] of MPV 1.22, confidence interval [CI] 1.05-1.35, P < 0.01). Patients with MPV levels above 11.8 femtolitre (= fifth quintile) had a significantly higher event rate (41.3% vs. 29.3%, P < 0.001) with an adjusted HR for MACEs of 1.65 (95% CI 1.26-2.16, P < 0.001) compared with patients with MPV levels in the first to fourth quintile. No significant association was found between baseline MPV levels with either baseline degree or progression during a 6-month follow-up of carotid stenosis. CONCLUSION: Mean platelet volume was independently and significantly associated with adverse cardiovascular outcome in patients with asymptomatic carotid atherosclerosis.

Premature myocardial infarction is associated with low serum levels of Wnt-1.

OBJECTIVE: 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. METHODS AND RESULTS: 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; p<0.005) 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 (p<0.001). In the stable phase of the disease, Wnt-1 levels were lower (p<0.005) and Dkk-1 levels were significantly higher (p<0.001) 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. CONCLUSION: 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.

Renal function and long-term mortality in patients with asymptomatic carotid atherosclerosis.

Renal dysfunction is a risk factor for mortality in patients with atherosclerosis. Estimated glomerular filtration rate (eGFR), cystatin C (CysC) and beta-2-microglobulin (B2M) are measures of renal function. It remains unclear, which of these parameters is the strongest predictor of outcome in patients with atherosclerosis. All-cause and cardiovascular mortality were prospectively investigated in 1,065 consecutive patients with asymptomatic carotid atherosclerosis. During a median follow-up of 6.3 years 275 patients died (25.8%), including 182 (66.2%) from cardiovascular causes. Estimated GFR, CysC and B2M were all significantly and independently associated with mortality. Inclusion of the renal parameters CysC and B2M but not of eGFR into a model with established cardiovascular risk factors improved the C-statistics significantly (p=0.0035 and 0.036, respectively; p=0.182 for eGFR). The net reclassification improvement (NRI) was 32.4% (p<0.0001) for CysC, 29% (p<0.0001) for B2M, and 16.5% (p=0.019) for eGFR. The integrated discrimination improvement (IDI) was 0.014 (p=0.0009) for CysC and 0.011 (p=0.005) for B2M while it was not significant for eGFR. Results were consistent for various subgroups with different extent of atherosclerosis. In summary, CysC and B2M were found to be independent predictors for mortality and had superior predictive value compared to eGFR in patients with asymptomatic carotid atherosclerosis. The clinical importance of these findings has to be validated in larger studies with a community-based approach.

Claudication: treatment options for femoropopliteal disease.

Intermittent claudication due to chronic femoropopliteal obstruction is a common disease, and patients are potentially severely disabled by the painful limitation of walking capacity. Despite major advances in pharmacological therapy of atherosclerosis, effective medication specifically for treatment of intermittent claudication is still not available. Training programs work well for patients with mild to moderate symptoms but frequently fail in patients with very compromised walking capacity. Patients with severe symptoms and markedly reduced quality of life therefore are candidates for revascularization. The preferred method of revascularization is endovascular treatment; this includes simple balloon angioplasty, debulking techniques, stent implantation, and, more recently, drug eluting technologies. Selected patients are candidates for surgery which encompasses endarterectomy of focal common femoral lesions as well as femoropopliteal bypass surgery in patients with very extensive disease or after failed endovascular approaches. The following article reviews current aspects of the management of femoropopliteal disease in patients with intermittent claudication.

The prognostic impact of soluble apoptosis-stimulating fragment on mortality in patients with carotid atherosclerosis.

BACKGROUND AND PURPOSE: Markers of apoptosis are associated with cardiovascular disease. The soluble apoptosis-stimulating fragment (sFAS) was found to be a predictor for outcome in patients with heart failure, but its importance in patients with atherosclerotic disease has not been fully understood as yet. The aim of the present study was to investigate the impact of sFAS on all-cause and cardiovascular mortality in patients with atherosclerosis in the carotid arteries. METHODS: We studied 981 of 1286 consecutive patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex Doppler sonography. Patients were prospectively followed for long-term all-cause and cardiovascular mortality. RESULTS: During a median follow-up of 6.2 years (interquartile range, 5.9 to 6.6 years), a total of 250 deaths (25.5%), including 165 (66%) cardiovascular deaths, were recorded. The risk for all-cause and for cardiovascular mortality, respectively, increased significantly with sFAS concentrations (P<0.001). The hazard ratio for all-cause death was elevated by 2.3-fold (P<0.001) and for cardiovascular death by 2.4-fold (P<0.001) in patients within the highest quintile of sFAS compared with patients within the lowest quintile, respectively. Results remained significant after adjustment for potential confounders and established cardiovascular risk factors, including high-sensitivity C-reactive protein. Patients with high sFAS but low high-sensitivity C-reactive protein had a comparable survival rate with those with elevated high-sensitivity C-reactive protein only (P=0.50). CONCLUSIONS: Markers of apoptosis, as measured by sFAS, were found to be independent risk predictors for death in patients with atherosclerotic disease in the carotid arteries.

First clinical trial of nitinol self-expanding everolimus-eluting stent implantation for peripheral arterial occlusive disease.

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.

Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML.

The second generation BCR/ABL kinase inhibitor nilotinib is increasingly used for the treatment of imatinib-resistant chronic myeloid leukemia (CML). So far, nilotinib is considered a well-tolerated drug with little if any side effects, although an increase in the fasting glucose level has been reported. We examined a series of 24 consecutive CML patients treated with nilotinib in our center for the development of non-hematologic adverse events. Three of these 24 CML patients developed a rapidly progressive peripheral arterial occlusive disease (PAOD) during treatment with nilotinib. In all three cases, PAOD required repeated angioplasty and/or multiple surgeries within a few months. No PAOD was known before nilotinib-therapy in these patients, although all three had received imatinib. In two patients, pre-existing risk factors predisposing for PAOD were known, and one of them had developed diabetes mellitus during nilotinib. In the other 21 patients treated with nilotinib in our center, one less severe PAOD, one myocardial infarction, one spinal infarction, one subdural hematoma, and one sudden death of unknown etiology were recorded. In summary, treatment with nilotinib may be associated with an increased risk of vascular adverse events, including PAOD development. In a subgroup of patients, these events are severe or even life-threatening. Although the exact mechanisms remain unknown, we recommend screening for pre-existing PAOD and for vascular risk factors such as diabetes mellitus in all patients before starting nilotinib and in the follow up during nilotinib-therapy.

Prognostic value of plasma d-dimer levels in patients with glioblastoma multiforme - Results from a pilot study.

Glioblastoma multiforme (GBM), the most common primary tumor of the central nervous system, is associated with a state of hypercoagulability. We hypothesized that tumor activity is displayed by elevated d-dimer plasma levels and that d-dimer might be used as a predictor of survival in patients with glioblastoma multiforme. We studied effects on clinical outcomes of d-dimer levels obtained two to three weeks following histologic confirmation of the diagnosis of GBM at surgery or needle biopsy, but prior to chemotherapy or radiation therapy, in 23 patients. During a median follow-up of 7.3 months (interquartile range 3.5 to 22 months), we observed a total of 21 deaths (91.3%). Elevated d-dimer levels were significantly associated with mortality compared to normal values (log rank p = 0.002). The adjusted hazard ratio for death in patients with elevated d-dimer levels was 10.8 (95% confidence interval, 1.3 to 93.1; p = 0.03), compared to controls. Similar effect sizes were revealed when analyzing the association between progression-free survival and d-dimer levels (log rank p = 0.002). Additionally, patients with elevated d-dimer levels were more likely to suffer from venous thromboembolism compared to patients with normal values (log rank p = 0.025). Our data support the assumption that d-dimer levels are related to adverse outcome in patients with GBM. However, our results need to be confirmed by a large, prospective cohort study.

D-dimer testing in the diagnosis of transfemoral pseudoaneurysm after percutaneous transluminal procedures.

OBJECTIVE: Pseudoaneurysms are characterized by extravascular circulation and therefore may lead to an activation of the coagulation cascade. We investigated d-dimer levels in patients with and without postcatheterization femoral pseudoaneurysms and hypothesized that d-dimer levels correlate with the presence of pseudoaneurysms at the vascular access site. METHODS: Patients with clinical suspected groin pseudoaneurysms after transluminal procedures were eligible. We compared prospectively-collected laboratory values of quantitative d-dimer testing in patients with and without pseudoaneurysms as assessed by color-coded duplex sonography. Furthermore, we measured the peak systolic velocity at the arterial fistula of each pseudoaneurysm. RESULTS: In 48 (40%) of 120 consecutive patients, a pseudoaneurysm was found. The level of d-dimer values was significantly higher in patients with postcatheterization femoral pseudoaneurysms compared with controls (1.9 microg/mL [interquartile range (IQR), 1.34-2.78 microg/mL] vs 0.8 microg/mL [IQR, 0.53-1.14 microg/mL]; P < .001). Values of d-dimer below 0.67 microg/mL have been calculated with a sensitivity of 94% (87%-100%), a specificity of 38% (27%-50%), a positive predictive value of 50% (40%-60%), a negative predictive value of 90% (82%-99%), and a likelihood ratio of 1.52 (1.25-1.85) with regard to the presence of pseudoaneurysms. We also found a significant correlation of the peak systolic velocity at the arterial fistula and increasing d-dimer levels (r = 0.98, P < .0001). CONCLUSION: We found a significantly higher level of d-dimer values in patients with femoral pseudoaneurysms at the vascular access site. Therefore, d-dimer levels could be a potential serological marker in the diagnosis of pseudoaneurysms. A confirmation is warranted in a larger patient sample.

Cystatin C and the risk for cardiovascular events in patients with asymptomatic carotid atherosclerosis.

BACKGROUND AND PURPOSE: Renal dysfunction is a risk factor for cardiovascular events in patients with atherosclerosis. Unlike serum creatinine or estimated glomerular filtration rate, cystatin C reflects renal dysfunction independent of factors such as sex, weight, and race. We investigated whether baseline serum levels of cystatin C predict major cardiovascular events in patients with asymptomatic carotid atherosclerosis and compared the predictive value of cystatin C to these established markers of renal function. METHODS: We prospectively studied 1004 of 1286 consecutive patients with carotid ultrasound scanning. Patients were followed for the occurrence of major cardiovascular events, a composite of myocardial infarction, percutaneous coronary intervention, coronary bypass graft, stroke, and death. RESULTS: During a median of 3 years of follow-up, we recorded 346 major cardiovascular events in 311 patients. The risk for a first major cardiovascular event increased significantly with increasing quintiles of cystatin C; hazard ratios ranged from 1.18 to 1.94 for the highest versus the lowest quintile (P<0.001 for trend). Creatinine levels showed no significant association with major cardiovascular events, and for glomerular filtration rate, only the lowest quintile was moderately associated with adverse cardiovascular outcome. CONCLUSIONS: Cystatin C was significantly and gradually associated with future cardiovascular events in patients with carotid atherosclerosis. In contrast, neither serum creatinine nor estimated glomerular filtration rate were significant predictors of adverse cardiovascular outcomes.

Effect of hemodialysis before transplant surgery on renal allograft function--a pair of randomized controlled trials.

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 m2, 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 m2, 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.

Beta endovascular brachytherapy using CO2-filled centering catheter for treatment of recurrent superficial femoropopliteal artery disease.

BACKGROUND: Recurrent disease (restenosis) after endovascular treatment of the superficial femoral artery (SFA) remains a major problem. We evaluated the efficacy of beta-endovascular brachytherapy using the CORONA centering catheter in patients with SFA restenosis in a single-arm Phase II trial. METHODS AND RESULTS: A total of 28 patients (mean age 70 years; 16 female, 12 male) with recurrent SFA stenosis were treated, and in-stent restenosis was present in 17 patients (61%). Brachytherapy was performed with strontium-90 beta source using a 7-French CO(2)-filled one-segment centering catheter. New stents had to be applied in two cases. Mean interventional length was 129 mm (range 20-240 mm). A dose of 14 Gy in vessel radius (postinterventional) plus 2 mm was applied in 24 patients and 18.4 Gy in four patients. Treatment time was 7 min 32 s per radiation segment. No major adverse events occurred. Patients were followed by ankle-brachial index and duplex sonography for a median of 42 months. Cumulative restenosis rates at 1, 2, and 3 years were 9%, 28%, and 40%, respectively. Target vessel revascularization was performed in seven cases (25%). CONCLUSIONS: In comparison to literature data, the treatment of SFA restenosis with beta brachytherapy may improve long-term patency.

Non-conventional markers of atherosclerosis before and after gastric banding surgery.

AIMS: Obesity and type 2 diabetes are associated with increased cardiovascular risk and elevation of traditional and non-traditional risk markers. As bariatric surgery reduces overweight and improves metabolic derangement, we examined a cluster of established and emerging cardiovascular risk factors, such as soluble CD40 ligand (sCD40L) and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), which might improve prediction of future cardiovascular events because of their more direct involvement in plaque destabilization. METHODS AND RESULTS: Obese patients [n = 32, body mass index (BMI) 46.1 +/- 5.9 kg/m(2)] underwent clinical examinations and blood sampling for measurement of glucose and lipid parameters as well as non-traditional cardiovascular risk markers, i.e. high-sensitivity C-reactive protein, plasminogen activator inhibitor-1 (PAI-1), soluble cellular adhesion molecules (CAM), MMP-2, MMP-9, CD40L, and Lp-PLA(2) before and after 1 year following laparoscopic adjustable gastric banding (LAGB), respectively. In patients undergoing LAGB, blood pressure (P < 0.0001) and blood glucose (P = 0.02) were significantly lowered by approximately 16% as well as triglyceride levels by approximately 29% (P = 0.002). In addition to a decrease of the inflammatory and pro-thrombotic marker PAI-1 (P = 0.001), CAMs, and MMP-9 (P = 0.004) were reduced, whereas no change was observed for plasma levels of MMP-2, sCD40L, and Lp-PLA(2) after LAGB, respectively. Individual changes in (ICAM-1) intercellular adhesion molecule-1 (DeltaICAM-1) were related to changes in insulin (Deltafasting insulin) before and after LAGB (r = 0.36 and r = 0.38; both P = 0.04). E-selectin correlated positively with changes in BMI (r = 0.38; P = 0.04 and r = 0.36; P = 0.05), while Lp-PLA(2) concentration was negatively correlated with BMI (r =-0.41; P = 0.02) after 1 year. Changes were comparable in both overweight diabetic and non-diabetic subjects. CONCLUSION: LAGB not only induced weight loss but also an improvement in the subclinical pro-inflammatory state. However, concentrations of most of the non-traditional risk factors for plaque instability, i.e. MMP-9, sCD40L, and Lp-PLA(2) remained unchanged.