Alexandra Hammer

Exercise training increases endothelial progenitor cells and decreases asymmetric dimethylarginine in peripheral arterial disease: A randomized controlled trial

BACKGROUND Supervised exercise training (SET) is recommended as initial treatment to improve walking capacity in peripheral arterial disease (PAD) patients with intermittent claudication. Various mechanisms by which SET yields beneficial effects are postulated, however data regarding its influence on angiogenesis are scarce. Thus, we designed a prospective randomized controlled trial to study the impact of SET on markers of angiogenesis and endothelial function in PAD. METHODS Forty PAD patients were randomized to SET on top of best medical treatment (SET+BMT) for 6 months versus best medical treatment (BMT) only. Endothelial progenitor cells (EPC) were assessed by whole-blood flow cytometry (co-expression of CD34+ CD133+ KDR+) and cell culture assays (endothelial cell-colony forming units, circulating angiogenic cells, migration assay) at baseline, 3, 6 and 12-months after inclusion. Changes of plasma levels of asymmetric dimethylarginine (ADMA), vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1) and maximum walking distance were determined. RESULTS EPC - measured by flow cytometric and cell culture techniques - increased significantly upon training paralleled by a significant decrease of ADMA when compared to the BMT group (p<0.05). Six months after training cessation, the beneficial effect of SET on EPC diminished, but maximum walking distance was significantly improved compared to baseline and controls (p<0.05). No significant changes were observed for VEGF and SDF-1 plasma levels in time course. CONCLUSIONS SET increases circulating EPC counts and decreases ADMA levels reflecting enhanced angiogenesis and improved endothelial function, which might contribute to cardiovascular risk reduction.

Comparison of Midregional Pro-Atrial and B-Type Natriuretic Peptides in Chronic Heart Failure Influencing Factors, Detection of Left Ventricular Systolic Dysfunction, and Prediction of Death

OBJECTIVES Midregional pro-atrial natriuretic peptide (MR-proANP) was assessed for the importance of influencing factors, the ability to detect left ventricular systolic dysfunction, and the prognostic power compared with B-type natriuretic peptide (BNP) and amino-terminal pro-B-type natriuretic peptide (NT-proBNP) in chronic heart failure (HF). BACKGROUND MR-proANP is a biologically stable natriuretic peptide measured by a recently developed assay, with potential advantages over conventional natriuretic peptides such as BNP and NT-proBNP. METHODS We measured MR-proANP, BNP, and NT-proBNP in 797 patients with chronic HF. RESULTS All 3 natriuretic peptides were independently influenced by left ventricular ejection fraction (LVEF), glomerular filtration rate (GFR), and the presence of ankle edema. Area under receiver-operator characteristic curves for detection of an LVEF <40% were similar between MR-proANP (0.799 [95% confidence interval (CI): 0.753 to 0.844]), BNP (0.803 [95% CI: 0.757 to 0.849]), and NT-proBNP (0.730 [95% CI: 0.681 to 0.778]). During a median observation time of 68 months, 492 (62%) patients died. In multiple Cox regression analysis each natriuretic peptide was the strongest prognostic parameter among various clinical variables. Proportion of explained variation showed that NT-proANP (4.36%) was a significantly stronger predictor of death than both NT-proBNP (2.47%, p < 0.0001) and BNP (2.42%, p < 0.0001). CONCLUSIONS Despite similarities in influencing factors and detection of reduced LVEF, MR-proANP outperformed BNP and NT-proBNP in the prediction of death. A new assay technology and the high biological stability of MR-proANP are potential explanations for these findings.

Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: A double-blind, placebo-controlled, 3-arm study

BACKGROUND Supplementation with 1 g/d omega-3-polyunsaturated fatty acids (n3-PUFAs) demonstrated a small survival advantage in patients with chronic heart failure (CHF) in the GISSI-HF trial. However, a dose-efficacy relationship was postulated for the beneficial effects of n3-PUFA before. Therefore, we evaluated dose-dependent effects of n3-PUFA in patients with severe CHF. METHODS In a double-blind, randomized, controlled pilot trial, 43 patients with severe, nonischemic heart failure received 1 g/d n3-PUFA (n = 14), 4 g/d n3-PUFA (n = 13), or placebo (n = 16) for 3 months. Changes in left ventricular ejection fraction (LVEF), flow-mediated vasodilation, plasma high-sensitive interleukin 6 and high-sensitive tumor necrosis factor α, and exercise peak oxygen consumption were assessed. RESULTS Left ventricular ejection fraction increased in a dose-dependent manner (P = .01 for linear trend) in the 4 (baseline vs 3 months [mean ± SD]: 24% ± 7% vs 29% ± 8%, P = .005) and 1 g/d treatment groups (24% ± 8% vs 27% ± 8%, P = .02). Flow-mediated vasodilation increased significantly with high-dose 4 g/d n3-PUFA (8.4% ± 4.8% vs 11.6% ± 7.0%, P = .01) but only trendwise with low-dose 1 g/d (8.3% ± 5.3% vs 10.2% ± 4.3%, P = .07). Interleukin 6 significantly decreased with 4 g/d n3-PUFA (3.0 ± 2.9 pg/mL vs 0.7 ± 0.8 pg/mL, P = .03) but only trendwise with 1 g/d (4.5 ± 6.6 pg/mL to 1.6 ± 2.1 pg/mL, P = .1). High-sensitive tumor necrosis factor α decreased trendwise with 4 g/d n3-PUFA but remained unchanged with 1 g/d. In patients with maximal exercise effort, only 4 g/d increased the peak oxygen consumption. No changes in any investigated parameters were noted with placebo. CONCLUSION Treatment with n3-PUFA for 3 months exerts a dose-dependent increase of LVEF in patients with CHF. In parallel, a significant improvement of endothelial function and decrease of interleukin 6 is found with high-dose n3-PUFA intervention.

Gene therapy for therapeutic angiogenesis in peripheral arterial disease - a systematic review and meta-analysis of randomized, controlled trials

BACKGROUND Beyond pharmacological, endovascular and surgical treatment strategies for peripheral arterial disease (PAD), therapeutic angiogenesis has been advocated to relieve symptoms and support limb salvage, in particular in patients with critical limb ischemia. We aimed to systematically review randomized controlled trials (RCTs) of gene therapy in PAD. PATIENTS AND METHODS A systematic search of electronic databases was performed to identify RCTs studying local administration of pro-angiogenic growth factors (VEGF, FGF, HGF, Del-1, HIF-1alpha) using plasmid or viral gene transfer by intra-arterial or intra-muscular injections. Outcomes of interest comprised all-cause mortality, amputations, ulcer healing, walking distance and ankle-brachial index. If feasible, standard meta-analysis should be performed with subgroup analysis for claudicants and patients with critical limb ischemia (CLI). RESULTS The systematic search yielded 12 RCTs for analysis from 1163 citations. In total, 1494 patients (29 % females) were included with the majority suffering from CLI (64 %). Various endpoints were improved by single studies, but none by a majority of studies. Meta-analysis showed neither a significant benefit nor harm for gene therapy when synthesizing data for all-cause mortality (OR 0.88, 95 % CI 0.62 - 1.26) amputations (OR 0.64, 95 % CI 0.31 - 1.31) or ulcer healing (OR 1.79, 95 % CI 0.8 - 4.01). No differences were seen between patients with intermittent claudication or CLI. CONCLUSIONS Despite promising results in single studies, no clear benefit could be identified for gene therapy in PAD patients, irrespective of disease severity.

Microvascular function is impaired in children with morbid obesity

Children’s obesity is a growing problem in Western societies. We hypothesized that morbid obesity (body mass index [BMI] > 99.5th percentile) might affect microvascular function at an early stage. Therefore, we assessed the microvascular function of 41 obese children (13.2 ± 2.8 years, BMI 32.9 ± 6.6) in comparison to 91 healthy controls (12.7 ± 2.1 years, BMI 18.2 ± 2.5) by post-occlusive reactive hyperemia measured by a laser Doppler: baseline perfusion, biological zero (defined as ‘no-flow’ laser Doppler signal during suprasystolic occlusion), peak perfusion (following occlusion), time to peak perfusion and recovery time (time until resuming baseline perfusion) were recorded and compared between both groups. Peak perfusion was higher in children with morbid obesity than in controls (1.67 ± 0.76 AU [arbitrary units] vs 1.26 ± 0.5 AU, p < 0.001). Consecutively, recovery time was longer in children with morbid obesity (118.21 ± 34.64 seconds) than in healthy children (83.18 ± 35.08 seconds, p < 0.001). In conclusion, higher peak perfusion and prolonged recovery time in children with morbid obesity seem to reflect microvascular dysfunction due to an impaired vasoconstrictive ability of precapillary sphincters.

Prognostic value of sequential measurements of amino-terminal prohormone of B-type natriuretic peptide in ambulatory heart failure patients.

We evaluated the prognostic value of sequential NT‐proBNP values in ambulatory heart failure patients after discharge, investigating whether the current value or the recent percent change is more important.

Impact of exercise training on inflammation and platelet activation in patients with intermittent claudication.

BACKGROUND Serum markers of inflammation and platelet activation are related to cardiovascular risk. Cardiovascular risk reduction is a major treatment goal in patients with peripheral arterial disease (PAD). Although current guidelines recommend supervised exercise training (SET) for PAD patients with intermittent claudication, its contribution to risk reduction remains unclear. Aim of the present study was to assess the impact of SET on inflammation and platelet activation as surrogates for cardiovascular risk. METHODS Fifty-three patients with intermittent claudication were randomly assigned to SET on top of best medical treatment (BMT) for 6 months (SET-group) or to BMT only (BMT-group). High sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and fibrinogen as well as soluble P-selectin (sP-sel), prothrombin fragment 1+2 (F1.2) and monocyte-platelet aggregates (MPA) were determined at study entry, after 3, 6 and 12 months. RESULTS While clinical improvement, reflected by an increase of walking capacity, was observed upon SET, no lasting changes of markers of inflammation and platelet activation were found within the SET-group during the training period. Compared to the BMT-group no improvements of these markers were observed in response to training at any time point (all p >0.05). CONCLUSION Regular SET added no further anti-inflammatory effect and had no effect on platelet activation when provided on top of BMT in PAD patients with intermittent claudication.

Target site pharmacokinetics of linezolid after single and multiple doses in diabetic patients with soft tissue infection

The underlying pathology of diabetic wounds, i.e. impairment of macro‐ and microcirculation, might also impact target site penetration of antibacterial drugs. To compare tissue concentrations of linezolid in infected and not infected tissue 10 patients suffering from type 2 diabetes with foot infection were included in the study. Tissue penetration of linezolid was assessed using in vivo microdialysis at the site of infection as well as in non‐inflamed subcutaneous adipose tissue. All patients were investigated after receiving a single dose of linezolid and five patients in addition at steady state. After a single dose of linezolid significantly higher area under the concentration vs. time curve over 8 hours (AUC0–8) and maximum concentrations (Cmax)‐values were observed in plasma (65.5 ± 21.2 mg*h/L and 16.4 ± 4.6 mg/L) as compared to inflamed (36.3 ± 22.9  mg*h/L and 6.6 ± 3.6 mg/L) and non‐inflamed tissue (33.0 ± 17.7 mg*h/L and 6.7 ± 3.6 mg/L). Multiple administrations of linezolid led to disappearance of significant differences in Cmax and AUC0–8 between plasma, inflamed, and non‐inflamed tissue. Approximately 2‐fold increase of Cmax and AUC0–8‐values in tissue was observed at steady state as compared to the first administration. Penetration of linezolid is not impaired in diabetic foot infection but equilibrium between plasma and tissue might be delayed.

Dark chocolate and vascular function in patients with peripheral artery disease: a randomized, controlled cross-over trial.

Flavonoid-rich dark chocolate has positive effects on vascular function in healthy subjects and in patients at risk of atherosclerosis. The impact of dark chocolate on endothelial and microvascular function in patients with symptomatic peripheral artery disease (PAD) has not been investigated so far. In an investigator blinded, randomized, controlled, cross-over trial we assessed the effect of flavonoid-rich dark chocolate and cocoa-free control chocolate on flow-mediated dilatation (FMD) of the brachial artery and on microvascular function (assessed by Laser Doppler fluxmetry) in 21 patients with symptomatic (Fontaine stage II) PAD. Measurements were done in each patient on 2 single days, with an interval of 7 days, at baseline and at 2 hours after ingestion of 50 g dark chocolate or 50 g white chocolate, respectively. FMD remained unchanged after intake of dark chocolate (baseline and 2 hours after ingestion, %: 5.1 [IQR 4.4 to 7.3] and 5.5 [IQR 3.9 to 10.4]; p = 0.57, and after intake of white chocolate (baseline and 2 hours after ingestion, %: 6.4 [IQR 4.5 to 11.4] and 4.4 [IQR 2.6 to 8.7]; p = 0.14. Similarly, microcirculatory parameters were not significantly altered after intake of any chocolate compared with the respective baseline values. In conclusion, a single consumption of 50 g dark chocolate has no effect on endothelial and microvascular function in patients with symptomatic PAD.

B-Type Natriuretic Peptide Predicts Benefit From a Home-Based Nurse Care in Chronic Heart Failure

BACKGROUND Home-based nurse care (HBNC) can reduce adverse events in patients with chronic heart failure. However, which patients really benefit from such an intervention remains unclear. We investigated if B-type natriuretic peptide (BNP), a strong prognostic marker in chronic heart failure, can predict benefit from HBNC. METHODS AND RESULTS After discharge from heart failure hospitalization, 96 patients were randomized to either HBNC for 12 months or usual care. The combined endpoint of death or heart failure hospitalization was evaluated after 12 and 24 months. The median value of BNP (267 pg/mL) was used as a cutoff value to predict benefit from the HBNC. HBNC reduced the endpoint after 12 (P = .013) and 24 months (P = .033, relative risk [RR] (95% confidence intervals): 0.42 [0.20-0.78] and 0.55 [0.31-0.98], respectively). This benefit from HBNC was dependent on BNP. In patients with supramedian BNP, the endpoint was significantly reduced after 12 (P = .002) and 24 months (P = .003, RR: 0.39 [0.20-0.76] and 0.50 [0.30-0.83], respectively), whereas in patients with inframedian BNP no significant changes occurred. CONCLUSIONS A high BNP can predict benefit from HBNC in patients with chronic heart failure and may assist in selecting patients for such an intervention.