Henner Hanssen

oxLDL uptake by dendritic cells induces upregulation of scavenger-receptors, maturation and differentiation

BACKGROUND Several studies have proposed a pathogenic role for oxidized LDL (oxLDL) in atherosclerosis. We tested the hypothesis whether oxLDL modulates dendritic cells (DCs), since these important antigen-presenting cells have been implicated in atherogenesis. We investigated the uptake of oxLDL by DCs, the scavenger-receptors involved and the resulting changes in phenotype and cytokine-spectra. In addition, we analyzed the impact of oxLDL on the nuclear transcription factor-kappa B (NF-kappaB)-pathway. METHODS AND RESULTS oxLDL (10microg/ml) increased the expression of the scavenger-receptors CD205 and CD36 and decreased the mannose-receptor expression. The lectin-like oxLDL-receptor (LOX-1)-expression was not affected. The endocytotic capacity of dextran and lucifer-yellow was moderately decreased by oxLDL. Blockage of the scavenger-receptors CD36, LOX-1 and CD205 reduced oxLDL uptake. Furthermore, oxLDL induced DC-maturation and triggered differentiation of DCs in myeloid and plasmacytoid DCs. oxLDL decreased IL-10 secretion and increased IL-6 release. Finally, oxLDL induced an activation of the NF-kappaB-pathway. Inhibition of IkappaBalpha-phosphorylation diminished the oxLDL-induced DC-maturation and -differentiation. CONCLUSION oxLDL uptake by DCs is mediated by the scavenger-receptors LOX-1, CD36, and CD205. oxLDL induces a proinflammatory cytokine profile in human DCs leading to DC-maturation and -differentiation which can, in part, be explained by an activation of the NF-kappaB-pathway. These results support the hypothesis that vascular inflammation may be aggravated by oxLDL induced DC-activation.

Accelerometer-based quantification of 6-minute walk test performance in patients with chronic heart failure : applicability in telemedicine

BACKGROUND Distance walked in the 6-minute walk test (6MWT) is an important prognostic parameter used clinically to assess functional status in patients with chronic heart failure (CHF). In this study, we investigated if alternative performance parameters with similar prognostic value can be gained from accelerometers. METHODS AND RESULTS Fifty CHF patients (age, 60.9 +/- 14.0 years) were asked to perform a 6MWT while wearing 2 accelerometers and 1 pedometer. Total 6MWT step frequency (SF) and activity counts (VMU) were correlated to 6MWT distance. The accelerometer was highly accurate at quantifying SF (detected vs. observed: r = 0.99; P < .001), whereas the pedometer was unreliable below 50 m/min. VMU increased linearly with walking speed (r = 0.99), and both SF and VMU correlated strongly with 6MWT distance (VMU: r = 0.91; SF: r = 0.87, respectively; P < .001) and each other (r = 0.80, P < .001). CONCLUSIONS Accelerometers are reliable in measuring physical performance during the 6MWT in CHF patients. Besides the simple acquisition of 6MWT distance currently used for patient assessment, accelerometers provide new data that might be useful to evaluate exercise performance during the 6MWT. This allows for routine assessment of exercise capacity in a home-based setting in the context of telemedicine.

Daily walking performance as an independent predictor of advanced heart failure : Prediction of exercise capacity in chronic heart failure

PURPOSE The purpose of this study was to use an accelerometer to measure daily walking performance in patients with chronic heart failure (CHF) to investigate if this parameter is a determinant of New York Heart Association class and indicative of maximal and functional exercise capacity. METHODS Fifty patients with CHF were instructed to wear an accelerometer for 7 consecutive days while going about their daily business. Maximal and functional exercise capacity was assessed by cardiopulmonary (VO(2peak)) and 6-minute walk testing, respectively. RESULTS Patients in New York Heart Association I, II, and III reached an average total walking time (TWT) of 160.6 +/- 35.8 minutes, 133.9 +/- 59.0 minutes, and 76.1 +/- 22.5 minutes per day of which 19%, 19%, and 9% where spent in the fast walking mode (>83 m/minute), respectively. The TWT correlated strongly with VO(2peak) (r = 0.72; P <.001) and 6-minute walk testing distance (r = 0.68; P <.001). The TWT and time spent in fast walking mode were the strongest determinants in discriminating moderate CHF. CONCLUSION Daily walking performance is a clear determinant of maximal and functional exercise capacities in patients with CHF. Walking intensity in particular is an independent predictor in discriminating patients with advanced heart failure. Monitoring of daily walking performance might aid in detecting disease progression and improve clinical outcome.

Retinal vessel diameter, obesity and metabolic risk factors in school children (JuvenTUM 3)

BACKGROUND The prevalence of childhood obesity is high and its association with future cardiovascular disease in adulthood is well established. The cross-sectional data presented analyze the prevalence of obesity and the association between metabolic risk factors, physical inactivity and retinal vessel diameter in young school children. METHODS The examination included 578 school children aged 11.1±0.6 years from secondary schools in the District of Munich, Germany. Anthropometric measurements and blood sampling were conducted using standard protocols for children. Physical activity was evaluated by use of a questionnaire. Retinal microvascular diameters and the arteriolar to venular ratio (AVR) were assessed with a non-mydriatic vessel analyser (SVA-T) using a computer-based program. RESULTS In our population, 128 (22.2%) children were overweight (ow) or obese (ob). The mean retinal arteriolar and venular calibres were 208.0±15.6 μm and 236.2±16.2 μm, respectively, with a mean AVR of 0.88±0.01. Girls had significantly wider arteriolar and venular diameters compared to boys (p<0.001). ow and ob children had a lower AVR compared to normal weight (nw) children (mean(95% CI); nw: 0.89(0.88-0.89); ow: 0.87(0.86-0.88); ob: 0.85(0.83-0.87); p≤0.05). Wider venular diameters were independently associated with higher BMI and higher hsCRP. Blood pressure was associated with retinal vessel constriction. Higher physical inactivity and BMI were independently associated with a reduced AVR (p=0.032 and p<0.001, respectively). CONCLUSIONS Cardiometabolic risk factors and physical inactivity are associated with retinal microvascular alterations in young children, comparable to associations in adults. Retinal vessel imaging seems to be a feasible assessment for the detection of microvascular impairments in children at risk of developing cardiovascular disease in adulthood.

Exercise-induced alterations of retinal vessel diameters and cardiovascular risk reduction in obesity

BACKGROUND The retinal microcirculation is affected early in the process of atherosclerosis and retinal vessel caliber is an emerging cardiovascular risk factor. Obesity is associated with vascular dysfunction. Here, we investigate the effect of regular exercise on retinal vessel diameters in lean and obese runners. We analyze a possible link to alterations of the nitric oxide (NO)-asymmetric dimethylarginine (ADMA) pathway. METHODS Retinal vessel diameters were assessed by means of a static vessel analyzer (SVA-T) in 15 obese athletes (OA), 14 lean amateur athletes (AA) and 17 lean elite athletes (EA) following a 10 week training program. ADMA serum levels were detected by ELISA and dimethylarginine dimethylaminohydrolase (DDAH) -1/-2 mRNA-expression in peripheral mononuclear cells (PBMC) was analyzed by real time PCR. RESULTS At baseline, the mean (±SD) arteriolar to venular diameter ratio (AVR) was impaired in obese (OA: 0.81±0.05) compared to lean subjects (AA: 0.87±0.07; EA: 0.94±0.05). The individual fitness levels correlated with AVR (rho=+0.66; P<0.001) and the training program improved AVR in all groups (P<0.001), normalising AVR in the obese (OA: 0.86±0.1). A training-induced arteriolar dilatation was found in OA (P=0.01), which was accompanied by a significant decrease of ADMA levels (0.56±0.12-0.46±0.12 μmoll(-1); P<0.028). DDAH-1 mRNA levels in PBMC increased in all groups (P<0.01). CONCLUSIONS Cardiovascular fitness and body composition affect retinal vessel diameters. Regular exercise reverses the subclinical impairment of the retinal microvasculature in obesity by inducing retinal arteriolar dilatation. The NO/ADMA pathway may play a key role in the training-induced improvement of microvascular function, which has the potential to counteract progression of small vessel disease.

Aerobic, resistance and combined exercise training on arterial stiffness in normotensive and hypertensive adults: A review

Abstract Exercise training has different effects on arterial stiffness according to training modalities. The optimal exercise modality for improvement of arterial function in normotensive and hypertensive individuals has not been well established. In this review, we aim to evaluate the effects of aerobic, resistance and combined aerobic and resistance training on arterial stiffness in individuals with and without hypertension. We systematically searched the Pubmed and Web of Science database from 1985 until December 2013 for relevant randomised controlled trials (RCTs). The data were extracted by one investigator and checked by a second investigator. The training effects on arterial stiffness were estimated using weighted mean differences of the relative changes (%) with 95% confidence intervals (CIs). We finally reviewed the results from 17 RCTs. The available evidence indicates that aerobic exercise tends to have a beneficial effect on arterial stiffness in normotensive and hypertensive patients, but does not affect arterial stiffness in patients with isolated systolic hypertension. Resistance exercise has differing effects on arterial stiffness depending on type and intensity. Vigorous resistance training is associated with an increase in arterial stiffness. There seem to be no unfavourable effects on arterial stiffness if the training is of low intensity, in a slow eccentric manner or with lower limb in healthy individuals. Combined training has neutral or even a beneficial effect on arterial stiffness. In conclusion, our review shows that exercise training has varying effects on arterial stiffness depending on the exercise modalities.

Immunomodulatory Effects of Aerobic Training in Obesity

Introduction. Physical inactivity and obesity are independent risk factors for atherosclerosis. We analyzed the immunomodulatory capacity of 10-week intensified exercise training (ET) in obese and lean athletes. Markers of the innate immune response were investigated in obese (ONE: ET≤40 km/week) and lean athletes (LNE: ET≤40 km/week and LE: ET≥55 km/week). Methods. Circulating dendritic cells (DC) were analyzed by flow-cytometry for BDCA-1/-2-expression. TLR-2/-4/-7 and MyD88 were analyzed by RT-PCR and Western blot. Circulating oxLDL levels were analyzed by ELISA. Results. BDCA-1 expression at baseline was lower in ONE compared to both other groups (ONE 0.15%; LNE 0.27%; LE 0.33%; P < .05), but significantly increased in ONE after training (+50%; P < .05). In contrast, BDCA-2 expression at baseline was higher in ONE (ONE 0.25%; LNE 0.11%; LE 0.09%; P < .05) and decreased in ONE after the 10-week training period (−27%; P < .05). Gene activations of TLR-4 and TLR-7 with corresponding protein increase were found for all three groups (P < .01/P < .05) compared to pre training. A reduction of oxLDL levels was seen in ONE (−61%; P < .05). Conclusions. Intensified exercise induces an increase of BDCA-1+ DCs and TLR-4/-7 in obese athletes. We hereby describe new immune modulatory effects, which—through regular aerobic exercise—modulate innate immunity and pro-inflammatory cytokines in obesity.

Pedometer accuracy in patients with chronic heart failure.

This study assesses the accuracy of the Omron HJ-720ITC pedometer at low walking intensities in patients with chronic heart failure. Step accuracy was assessed by visual observation on the treadmill and during free walking at 40, 50, 60, 70, 80 m/min, as well as during self paced walking using the 6 min walk test. A total of ninety-seven patients with heart failure (mean age: 61+/-13, NYHA I, N=30; NYHA II, N=32; NYHA III, N=35) participated in the study. At predefined walking speeds, a statistically significant % error in pedometer accuracy was evident at 60 m/min (p=0.039), and% error increased markedly below this threshold. Highest% error in pedometer accuracy was seen at 40 m/min (mean bias (% error): 28.3+/-9.0%; 95% CI: 21.8-34.7; p<0.001). During self paced walking (6MWT) the absolute% error in pedometer readings was largest in patients with strongest functional limitations and 6 MWT distances <400 m (mean bias (% error): 10.7+/-13.6%; CI 5.6-15.4, p<0.001). The Omron HJ-720ITC pedometer is accurate for monitoring activity in individuals with normal walking behaviour, but seems unsuitable for chronically ill patients characterised by slow walking gaits.

Modification of endothelial biology by acute and chronic stress hormones

OBJECTIVE An increasing number of studies have examined the role of emotional stress and coronary heart disease; the underlying pathophysiology is still poorly understood. The present study was designed to evaluate the relationship between acute (epi- and norepinephrine) and chronic stress hormones (dexamethasone, beta-endorphin, corticotropin releasing hormone) and endothelial dysfunction. METHODS Human microvascular endothelial cells were incubated with stress hormones for 6 and 24 h. ET-1 release and ADMA were quantified via ELISA, NO release by using cell permeable 4.5-diaminofluorescein diacetate (DAF2-DA), oxidative stress fluometrically by the ROS-sensitive carboxy-H2-DCFDA method, mitochondrial metabolic activity by using the colorimetric assay WST-1, ET-1 receptor type A (ET(A)R) protein expression by Western blot, and cell proliferation activity was assessed by the colorimetric assay BrdU. RESULTS With respect to analysed acute and chronic stress hormones, ET-1 release was significantly increased. Likewise, protein expression was enhanced after long term incubation (24 h) with norepinephrine and dexamethasone. In contrast, endothelial NO-levels were only influenced by short term stimulation of dexamethasone (upregulation of NO release) and norepinephrine (downregulation of NO release), whereas modified NO concentration mimics altered mitochondrial metabolic activity. Unexpectedly, both oxidative stress and cell proliferation were not modified by stress hormones. CONCLUSION Results suggest that acute and chronic stress hormones induce a significant ET-1 release whereas NO release remained mainly unchanged. The imbalance of pro- and antiatherosclerotic factors may play a pivotal role in the initiation of stress-related endothelial dysfunction up to myocardial infarction.

MicroRNAs as Biomarkers for Acute Atrial Remodeling in Marathon Runners (The miRathon Study – A Sub-Study of the Munich Marathon Study)

Introduction Physical activity is beneficial for individual health, but endurance sport is associated with the development of arrhythmias like atrial fibrillation. The underlying mechanisms leading to this increased risk are still not fully understood. MicroRNAs are important mediators of proarrhythmogenic remodeling and have potential value as biomarkers in cardiovascular diseases. Therefore, the objective of our study was to determine the value of circulating microRNAs as potential biomarkers for atrial remodeling in marathon runners (miRathon study). Methods 30 marathon runners were recruited into our study and were divided into two age-matched groups depending on the training status: elite (ER, ≥55 km/week, n = 15) and non-elite runners (NER, ≤40 km/week, n = 15). All runners participated in a 10 week training program before the marathon. MiRNA plasma levels were measured at 4 time points: at baseline (V1), after a 10 week training period (V2), immediately after the marathon (V3) and 24h later (V4). Additionally, we obtained clinical data including serum chemistry and echocardiography at each time point. Results MiRNA plasma levels were similar in both groups over time with more pronounced changes in ER. After the marathon miR-30a plasma levels increased significantly in both groups. MiR-1 and miR-133a plasma levels also increased but showed significant changes in ER only. 24h after the marathon plasma levels returned to baseline. MiR-26a decreased significantly after the marathon in elite runners only and miR-29b showed a non-significant decrease over time in both groups. In ER miRNA plasma levels showed a significant correlation with LA diameter, in NER miRNA plasma levels did not correlate with echocardiographic parameters. Conclusion MiRNAs were differentially expressed in the plasma of marathon runners with more pronounced changes in ER. Plasma levels in ER correlate with left atrial diameter suggesting that circulating miRNAs could potentially serve as biomarkers of atrial remodeling in athletes.