Markus Haumer

A Proinflammatory State Is Detectable in Obese Children and Is Accompanied by Functional and Morphological Vascular Changes

Background—Obesity is generally accepted as a risk factor for premature atherosclerosis. Subclinical inflammation as quantified by blood levels of C-reactive protein (CRP) contributes to the development and progression of atherosclerosis. We hypothesized that inflammation in obese children is related to functional and early morphological vascular changes. Methods and Results—Blood levels of high sensitivity (hs) CRP, hsIL-6, the soluble intercellular adhesion molecule1 (ICAM-1), vascular cell adhesion molecule (VCAM)-1, and E-selectin were measured in 145 severely obese (body mass index [BMI], 32.2±5.8 kg/m2) and 54 lean (BMI, 18.9±3.2 kg/m2) children 12±4 years old. Flow-mediated dilation (FMD) of the brachial artery and carotid intima-media thickness (IMT) measured by high-resolution ultrasound as markers of early vascular changes were assessed in 92 (77 obese and 15 lean) and 59 (50 obese and 9 lean) children, respectively. Obese children had significantly higher levels of hsCRP, hsIL-6, and E-selectin than healthy controls (4.1±4.8 versus 0.9±1.5 mg/L, P<0.001 for hsCRP; 1.99±1.30 versus 1.42±1.01 pg/mL, P=0.05 for hsIL-6; and 78±38 versus 59±29 ng/mL, P=0.01 for E-selectin). There were no differences in the levels of ICAM-1 and VCAM-1 between groups. Obese children had lower peak FMD response (7.70±6.14 versus 11.06±3.07%, P=0.006) and increased IMT (0.37±0.04 versus 0.34±0.03 mm, P=0.03) compared with controls. Morbidly obese children (n=14, BMI 44.1±3.9 kg/m2) had highest levels of hsCRP (8.7±0.7 mg/L), hsIL-6 (3.32±1.1 pg/mL), and E-selectin (83±40 ng/mL). Conclusions—A proinflammatory state is detectable in obese children, which is accompanied by impaired vascular endothelial function and early structural changes of arteries, even in young subjects at risk. It remains to be determined whether high hsCRP in obese children predicts cardiovascular events.

Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with restenosis after percutaneous transluminal angioplasty.

Purpose: To determine if an association exists between postdilation restenosis and heme oxygenase-1 (HO-1), which is induced by balloon injury and inhibits neointimal formation through the action of endogenous carbon monoxide. A dinucleotide repeat in the promoter region of the HO-1 gene shows a length polymorphism that modulates the level of gene transcription. Methods: This cohort study included 96 consecutive patients (64 men; median age 69 years, interquartile range 60–75) who underwent successful balloon dilation in the femoropopliteal segment. Six-month patency was evaluated using oscillography, ankle-brachial index, and duplex sonography. The association of patency and the length of (GT) repeats in the HO-1 gene promoter was assessed in univariate and multivariate analyses. Results: Restenosis was found in 23 (24%) patients within the first 6 months. Patients with short (<25 GT) dinucleotide repeats in the HO-1 gene promoter on either allele had restenosis significantly less often than patients with longer (≥25 GT) dinucleotide repeats (p = 0.01). Multivariate analysis revealed a significantly reduced risk for restenosis in these patients compared to patients without the short allele (odds ratio 0.2, 95% CI 0.06 to 0.70, p = 0.007). Conclusions: Genetic risk factors for restenosis after percutaneous transluminal angioplasty have not been investigated. In this patient population, short repeat alleles of the heme oxygenase-1 gene promoter polymorphism were associated with reduced postdilation restenosis at 6 months. Upregulation of HO-1 may be an important protective factor after balloon angioplasty by inhibition of vascular smooth muscle cell proliferation.

PTA Versus Carbofilm-Coated Stents in Infrapopliteal Arteries: Pilot Study

Purpose:To determine the primary success and short-term patency of stent application as a primary treatment modality for high-grade lesions of the infrapopliteal arteries compared with treatment with percutaneous transluminal angioplasty (PTA) in critical limb ischemia in a randomized prospective study.Methods:Endovascular therapy was performed on 95 lesions in 51 patients (mean age 72.0 years, range 47–80 years) who presented clinically with Fontaine stages III and IV. One patient underwent treatment in both limbs. After angiographic lesion identification, patients were randomized for treatment by PTA (53 lesions in 27 patients) or stent application (42 lesions in 24 patients). Follow-up by clinical investigation and conventional angiography or spiral CT angiography was performed in 37 patients (57 lesions) 6 to 12 months after the procedure, or when clinically indicated. Evaluation was performed by two observers, double-blinded, with thresholds for lesion restenosis of 50% and 70%. Statistical evaluation was performed on a lesion basis by Kaplan–Meier estimated probability rates, and log-rank and Wilcoxon tests. The primary endpoint was the angiographic patency rate of treated lesions.Results:The inter-reader agreement was high (κ = 0.82). For the stent group the cumulative primary patency at 6 months was 83.7% at the 70% restenosis threshold, and 79.7% at the 50% restenosis threshold. For PTA, the primary patency at 6 months was 61.1% at the 70% restenosis threshold and 45.6% at the 50% restenosis threshold. Both results were statistically significant (p < 0.05).Conclusion:Infrapopliteal stent application is an effective treatment modality for high-grade lesions in chronic critical limb ischemia. Compared with PTA, higher patency rates can be expected after 6 months.

Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias

Objective To compare the rate-lowering effect of diltiazem and two amiodarone regimens in critically ill patients with recent-onset atrial tachyarrhythmias. Design Prospective, randomized, controlled study. Setting Medical cardiologic intensive care unit in a university hospital. Patients Sixty critically ill patients (Acute Physiology and Chronic Health Evaluation [APACHE] III score 70 ± 30, age 67 ± 10 yrs). Interventions Patients with atrial fibrillation (n = 57), atrial flutter (n = 2), or atrial tachycardia (n = 1, and a heart rate consistently >120 beats/min over 30 mins were randomly assigned to one of three intravenous treatment regimens. Group 1 received diltiazem in a 25-mg bolus followed by a continuous infusion of 20 mg/hr for 24 hrs, group 2 received amiodarone in a 300-mg bolus, and group 3 received amiodarone in a 300-mg bolus followed by 45 mg/hr for 24 hrs. Measurements and Main Results The primary study end point was a >30% rate reduction within 4 hrs. The secondary study end point was a heart rate <120 beats/min (a patient was considered to have uncontrolled tachycardia if heart rate was >120 beats/min 4 hrs after study drug). The primary study end point was achieved in 14/20 (70%), 11/20 (55%), and 15/20 (75%) of patients in groups 1, 2, and 3, respectively (&khgr;2 = 1.95, p = .38). Uncontrolled tachycardia was more frequently observed in group 2 (0/20, 9/29 [55%], and 1/20 [5%] of patients in groups 1, 2, and 3, respectively; &khgr;2 = 17, p = .00016). In patients achieving tachycardia control, diltiazem showed a significantly better rate reduction (p = .0001 group 1 vs. group 3, p = .0001 over time;p = .0001 group 1 vs. group 2, p = .001 over time) when compared with the amiodarone groups. Premature drug discontinuation due to hypotension was required significantly more often in group 1 (6/20 [30%], 0/20, and 1/20 [5%] for groups 1, 2, and 3, respectively; &khgr;2 = 10, p = .01). Conclusion Sufficient rate control can be achieved in critically ill patients with atrial tachyarrhythmias using either diltiazem or amiodarone. Although diltiazem allowed for significantly better 24-hr heart rate control, this effect was offset by a significantly higher incidence of hypotension requiring discontinuation of the drug. Amiodarone may be an alternative in patients with severe hemodynamic compromise.

Carotid artery stenting: effect of learning curve and intermediate-term morphological outcome.

Purpose: To assess the impact of learning on the rate of success and complications of carotid stenting in a single-center, one-operator series and prospectively follow a patient cohort with regard to restenosis. Methods: In 303 patients (mean age 70 ± 8.8 years), 320 internal carotid arteries (ICA) were treated with carotid stenting for stenoses ≥70%. Four groups of 80 consecutive interventions were compared with regard to primary technical success and periprocedural complications. Stent patency in follow-up was assessed using duplex scanning. Results: Stenting was successful in 298 (93%) arteries. The combined neurological complications (transient ischemic attacks and all strokes) and 30-day death rate was 8.2% (n = 25), but the all stroke and 30-day death rate was 3.0% (n = 9). A significant reduction in the frequency of neurological complications after the initial 80 interventions was observed (p = 0.03), but technical success was not appreciably improved with increasing experience thereafter. Over a median 12 months (interquartile range 6 to 24), cumulative patency rates were 91%, 90%, and 91% at 6, 12, and 36 months, respectively. Conclusions: Elective carotid stenting can be performed with excellent technical success, an acceptable frequency of periprocedural complications, and good intermediate-term patency. However, our findings suggest that a larger number of interventions should be performed to overcome the negative effects of the initial learning phase.

Risk Stratification for Subclavian Artery Angioplasty: Is There an Increased Rate of Restenosis after Stent Implantation?

Purpose:To compare long-term patency after balloon angioplasty of stenotic or occluded subclavian arteries with and without adjunctive stenting and to identify independent risk factors for restenos...

Conventional balloon angioplasty versus peripheral cutting balloon angioplasty for treatment of femoropopliteal artery in-stent restenosis: initial experience.

PURPOSE 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Treatment of subclavian–axillary vein thrombosis: long-term outcome of anticoagulation versus systemic thrombolysis

OBJECTIVE To investigate long-term clinical and morphological outcome of patients with subclavian-axillary vein thrombosis treated with systemic thrombolysis compared to anticoagulation in a retrospective, nonrandomised study. METHODS We studied 95 consecutive inpatients with subclavian-axillary vein thrombosis treated either with systemic urokinase thrombolysis and subsequent oral anticoagulation (n=33) or with anticoagulation only (n=62). Anticoagulation was performed with heparin and phenprocoumon. Patients were followed for median 40 months (IQR 14 to 94) for symptomatic upper extremity post-thrombotic syndrome and for venous recanalisation by duplex ultrasound. RESULTS Primary technical success rate of the systemic thrombolysis was 88% (n=29) with seven peri-intervention bleeding complications (21%). No complication was observed in patients with anticoagulation only (p<0.0001). At the time of follow-up, duplex sonography showed a thrombotic subclavian vein in 40 of 83 patients (48%), but only 9 of 95 patients (10%) had a symptomatic upper extremity post-thrombotic syndrome. Patients with systemic thrombolysis exhibited a 60% adjusted reduced risk for a thrombotic subclavian vein at the time of follow-up compared to patients with anticoagulation only (95% CI: 0.2 to 0.9, p=0.03). However, the frequency of symptomatic post-thrombotic syndrome after thrombolysis and anticoagulation was similar (adjusted p=0.6). CONCLUSION Systemic thrombolysis of subclavian-axillary vein thrombosis has an acceptable primary technical success rate and improves venous recanalisation rates compared to anticoagulation. However, the high rate of complications during thrombolysis and the lack of clinical benefit suggest that conservative treatment may be favoured.

Restenosis after Percutaneous Transluminal Angioplasty in the Femoropopliteal Segment: The Role of Inflammation

Purpose: To determine the value of baseline C-reactive protein (CPR), fibrinogen, and white blood cell (WBC) counts in predicting 1-year patency after percutaneous transluminal angioplasty (PTA) in the femoropopliteal segment. Methods: In a retrospective cohort study, 168 consecutive patients (103 men; median age 70 years, interquartile range 61–77) who underwent successful PTA of the femoral and/or popliteal arteries were analyzed. Twelve-month patency was evaluated using oscillography, ankle brachial index, duplex sonography, and angiography. The predictive value of inflammatory markers was assessed in a multivariate model controlling for cardiovascular risk factors, technical success, and hemodynamic factors. Results: Transient WBC elevation was found 6 hours after PTA, but this returned to baseline after 24 hours. Fibrinogen was elevated at 24 hours. Duplex scanning disclosed restenosis in 66 (39%) patients within the first 12 months after PTA. Only residual postdilation stenosis (≥30%) in the target segment (odds ratio 3.6, p=0.001) and baseline CRP levels (odds ratio 4.2, p=0.02) were independent predictors of outcome; neither WBC counts nor fibrinogen levels at any time point was associated with restenosis. Conclusions: Primary technical success and postinterventional hemodynamic flow at the dilated segment seem to be more important for intermediate-term patency than atherogenic risk factors. The predictive value of preprocedural serum CRP levels on restenosis should be further investigated.

Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor-related protein/α2-macroglobulin receptor and transport to endosomes

LDL receptor related protein (LRP) is a ubiquitously expressed cell surface receptor that binds, at least in vitro, a plethora of ligands among them α 2‐macroglobulin and lactoferrin (Lf). The function of LRP in internalisation and distribution of ligands within cellular metabolism is still unclear. We here investigated by combined ligand‐ and immunoblotting the participation of LRP/α 2MR and its associated protein (RAP) in receptor mediated endocytosis of Lf into rat liver. We found LRP highly enriched in sucrose density gradient fractions around density 1.10 g/ml, previously characterised as endosomal fractions. RAP was concentrated in distinct fractions around density 1.14 g/ml. This separation of RAP from LRP/α 2MR is physiologically meaningful as RAP avidly binds to LRP/α 2MR and by that shuts off all ligand binding function. In endosomal fractions we found one single binding protein for 125I‐labelled Lf. With a specific anti LRP/α 2MR antibody and ligand blotting with 125I‐labelled RAP this endosomal Lf binding site was verified to be LRP/α 2MR. Endosomes did not bind labelled Lf when prepared from rats that received an intravenous injection of Lf (20 mg per animal) 20 min prior to preparation. Surprisingly we immunodetected Lf in these endosomes at a position around 600 kDa, comigrating with LRP/α 2MR. We determined Lf binding to be optimal at pH 5.8, what led us to suggest the existence of a very stable LF‐LRP/α 2MR complex in endosomes. These data support the idea of effective binding of Lf at pH as found in inflamed tissue environment where Lf is reported to be involved in leukocyte mediated inflammation regulation.