Anders Gottsäter

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 × 10−12) and intracranial aneurysm (OR = 1.29, P = 2.5 × 10−6), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.

Chronic iliac vein occlusion: midterm results of endovascular recanalization.

Purpose: To evaluate patency and clinical outcome in patients treated with endovascular recanalization and stent placement for chronic iliac vein occlusions. Methods: During a 14-year period (1994–2008), 59 (38 women; median age 39 years) of 62 patients with chronic occlusion of the iliac vein segment in 66 limbs were successfully treated with endovascular recanalization and stent placement. A prospectively maintained database was analyzed retrospectively to obtain information on clinical details, endovascular techniques, and outcome. Results: Three (5%) procedures failed for technical reasons. Three (5%) complications occurred, 2 (3%) of which were perforations requiring transfusion and procedure termination. Initial clinical success after 6 months was achieved in 49 (83%) of the 59 patients successfully treated initially. Primary patency after a median imaging follow-up of 25 months was 67% (44/66), assisted primary patency was 75% (49/66), and secondary patency was 79% (52/66). Fifteen (23%) of 66 limbs were asymptomatic after a median clinical follow-up of 32 months, 34 (52%) limbs were improved, 13 (20%) were unchanged, and 4 (6%) were worse compared to before intervention. Actuarial primary, assisted primary, and secondary patency rates using Kaplan-Meier survival analysis were 70%, 73%, and 80%, respectively, at 5 years. Conclusion: Endovascular recanalization and stent placement is a safe and effective treatment for occluded iliac veins and adjacent segments. Clinical midterm results are encouraging. Recanalized and stented segments remain patent in the majority of patients after 2 years. Endovascular treatment can ease symptoms and prevent further deterioration of patients with post-thrombotic syndrome.

Thrombus Embolization Into IVC Filters During Catheter-Directed Thrombolysis for Proximal Deep Venous Thrombosis

Purpose: To assess the frequency of embolization into retrievable inferior vena cava (IVC) filters during catheter-directed thrombolysis (CDT) and stent placement for acute iliocaval deep venous thrombosis (DVT). Methods: Serial phlebograms from 40 patients (28 women; median age 32 years) consecutively treated with CDT for DVT during a 12-year period were retrospectively evaluated for visible emboli in the IVC filter. Clinical and procedural data extracted from a prospectively maintained database were evaluated to identify predictors for embolization into the filter. Results: Visible emboli were found in 18 (45%) patients. Visible embolization to the IVC filter was less frequent in patients with a hypercoagulable disorder (n=29, 31%) than in patients without a hypercoagulable disorder (n=11, 69%; OR 0.1, 95% CI 0.02 to 0.56, p=0.006). No patient developed clinical symptomatic pulmonary embolism or a complication related to the placement or retrieval of the IVC filter. Conclusion: Thrombus embolization during CDT is a common phenomenon in patients with proximal DVT. Placement of a retrievable IVC filter during thrombolytic therapy can prevent silent and symptomatic pulmonary embolism.

Plasma concentrations of growth arrest specific protein 6 and the soluble form of its tyrosine kinase receptor Axl as markers of large abdominal aortic aneurysms

OBJECTIVEnThe tyrosine kinase receptor Axl is expressed in the vasculature and Gas6 is the ligand. The extracellular part of Axl (sAxl) can be found in circulation. The aim of this study was to determine plasma concentrations of Gas6 and sAxl in patients with abdominal aortic aneurysms (AAA) and to evaluate if Gas6 and sAxl can be used as biomarkers.nnnDESIGN AND METHODSnImmunoassays for sAxl and Gas6 were used to investigate plasma from AAA patients. Patients with large (n=123) or small AAA (n=122) were compared with healthy controls (n=141).nnnRESULTSnGas6 correlated positively and sAxl correlated negatively with AAA size. As a consequence, the calculated Gas6/sAxl ratios correlated even better to AAA size. Forty percent of all patients with a large AAA had higher Gas6/sAxl ratio than any in the control group.nnnDISCUSSIONnThe Gas6/Axl system might be involved in AAA pathogenesis, and the Gas6/sAxl ratio may be useful as a biomarker.

Plasma concentrations of apolipoproteins A-I, B and M in patients with abdominal aortic aneurysms.

OBJECTIVESnApolipoproteins play important roles in the development of atherosclerosis but their involvement in the pathogenesis of abdominal aortic aneurysm (AAA) is poorly understood. The aim was to investigate whether apoA-I, apoB and apoM are independently associated with AAA.nnnDESIGN AND METHODSnPlasma apoA-I, apoB and apoM were measured in 343 patients with AAA and in 214 elderly apparently healthy control individuals from the background population.nnnRESULTSnAAA patients had lower apolipoprotein levels, as compared to healthy individuals: apoA-I, 1.62 vs. 2.08 g/L; apoB, 0.91 vs. 1.04 g/L; apoM, 0.72 vs. 0.91 mumol/L (p<0.0001 for all three). In multivariate analyses, apoA-I and apoB were associated with AAA, odds ratios (95% confidence intervals) being 0.53 (0.43-0.64) and 0.86 (0.75-0.998), respectively.nnnCONCLUSIONSnApoA-I, apoB and apoM levels were significantly lower in patients with AAA than in the control individuals, but only apoA-I and apoB were independently associated to AAA.

Complement activation and plasma levels of C4b-binding protein in critical limb ischemia patients.

OBJECTIVEnCritical limb ischemia (CLI) is a peripheral arterial disease manifested by drastically diminished blood flow to the legs, pain at rest, nonhealing wounds, and gangrene caused by atherosclerosis. Significant tissue necrosis is associated with late stage CLI and the patients have a poor prognosis. Necrotic and apoptotic cells activate complement and bind complement inhibitor C4b-binding protein (C4BP). The major isoform of C4BP is composed of seven identical alpha-chains and one beta-chain, here termed C4BP(beta), whereas upon inflammation a normally less abundant isoform is upregulated that is exclusively composed of alpha-chains. Measuring the alpha-chains of C4BP includes both isoforms and is termed total C4BP (C4BP(tot)). The hypothesis of this study was that levels of complement activation and C4BP are predictive for the severity of the disease and that their measurement might be of clinical advantage.nnnMETHODSnThis was a prospective, single-center study of 259 consecutive patients with CLI admitted to a secondary referral center for vascular diseases. Interventions included evaluation of soluble terminal complement complexes (C5b-9), C4BP(tot) and C4BP(beta), lipid levels, the inflammatory mediators tumor necrosis factor-alpha, interleukin-6, 8-iso-prostaglandin F(2alpha), high-sensitivity C-reactive protein, neopterin, plasma homocysteine, and plasma endothelin-1 in plasma as well as resistance to activated protein C and ankle blood pressure. All data were compared with an age-matched population based control group of 219 currently healthy individuals.nnnRESULTSnThe data are presented as mean +/- SEM/median. CLI patients showed systemic complement activation (1.17 +/- 0.06/1.13 AU/mL vs 0.69 +/- 0.07/0.59 AU/mL in healthy controls, P < .0001), which was even higher in patients with gangrene (1.33 +/- 0.11/1.28 AU/mL vs 1.1 +/- 0.08/1.0 AU/mL, P = .0264), who also showed increased C4BP levels (421 +/- 28.6/386 microg/mL vs 341 +/- 10.8/318 microg/mL for C4BP(tot), P = .0248; 374 +/- 25.4/332 microg/mL vs 305 +/- 9.5/285 microg/mL for C4BP(beta), P = .0581). C4BP plasma levels were significantly elevated in CLI patients in comparison to healthy controls (351 +/- 8.1/322 microg/mL vs 297 +/- 8.0/288 microg/mL for C4BP(tot), P = .0001; 314 +/- 7.0/287 microg/mL vs 265 +/- 7.0/263 microg/mL for C4BP(beta), P = .0004) and correlated to levels of interleukin-6 (P(tot/beta) = .0048/.0019), high-sensitivity C-reactive protein (P < .0001), leukocyte (P(tot/beta) = .0086/.0043) and platelet count (P = .0001), LDL/HDL ratio (P(tot) = .0151) and HDL (P(tot/beta) = .0047/.0177), but not to tumor necrosis factor-alpha.nnnCONCLUSIONSnIncreased complement activation and C4BP plasma levels are related to the degree of tissue necrosis and disease severity of critical limb ischemia. This knowledge in combination with the found correlations to other biomarkers is useful for understanding the pathophysiology of the disease.

Coagulation activation and ultrasound characteristics in patients with carotid artery disease

INTRODUCTIONnElevated levels of markers for thrombin activation are associated with plaque echogenicity and degree of stenosis in patients with carotid artery stenosis. The Activated Protein C-Protein C Inhibitor (APC-PCI) complex reflects activation of the Protein C system and is a measure of thrombin generation. The aim of the present study was to examine APC-PCI complex in patients undergoing thrombendartherectomy for carotid artery stenosis, and to relate the findings to clinical characteristics and plaque morphology as determined by ultrasound.nnnMATERIALS AND METHODSnBlood was obtained from 125 patients (39 female, median age 71 years) with carotid artery stenosis admitted from September 2005 to May 2007. The APC-PCI complex was measured using a sandwich immunofluorometric method and compared to an age- and sex-matched healthy control-group. Clinical and demographic characteristics, routine laboratory markers and ultrasound characteristics were analysed using univariate and multivariate analysis.nnnRESULTSnAPC-PCI complex concentration was significantly increased in patients with carotid artery stenosis (median 0.21 microg/L; 10th to 90th percentile 0.15-0.36) compared to a healthy control-group (0.19 microg/L; 0.11-0.31; P=.009). There was no significant difference in APC-PCI-values between asymptomatic (n=48) and symptomatic (n=77) patients with carotid artery stenosis (0.22 vs. 0.20 microg/L; p=0.626). Patients with minor stroke (n=31) had a higher median APC-PCI-concentration (0.27 microg/L; 0.15-0.63) than patients with amaurosis fugax (0.19 microg/L; 0.15-0.36) or transient ischemic attack (0.21 microg/L; 0.12-0.36) (p=0.016). No association was found between APC-PCI-values and the degrees of carotid artery stenosis or the time from the latest neurological symptoms to blood sampling. Patients with echolucent plaques had significantly lower APC-PCI concentrations (0.20 microg/L; 0.14-0.35 vs. 0.24 microg/L; 0.15-0.60; p=0.043), according to the Gray-Weale classification.nnnCONCLUSIONSnPatients with carotid artery disease exhibit increased concentrations of APC-PCI compared to a healthy control-group, particularly those patients with echogenic plaques, who have significantly higher APC-PCI levels than patients with echolucent plaques.

Endovascular Treatment of Venous Occlusive Disease

Endovascular treatment of acute and chronic iliac vein occlusions has proven to be safe and effective. Recanalization of chronic occlusions with balloon angioplasty and stenting can re-establish normal venous flow in the iliac veins and the IVC and relieve symptoms in the majority of treated patients. CDT with recanalization and stenting of underlying chronically obstructed iliofemoral segments is becoming the treatment of choice for patients with acute iliofemoral thrombosis, as anticoagulation and compression therapy alone are not satisfactory in preventing PTS. The new treatment modalities offer stimulating options for a patient group that is not adequately treated, neither by medical nor open surgical therapy. The substantial effort and additional costs of endovascular treatment appear to be justified by the encouraging mid-term results both for patients with acute and chronic occlusive iliofemoral disease. However, multi-center randomized prospective studies are required to further validate the role of these techniques.