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Summary: Background: Angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are widely used as a first-line therapy for the treatment of cardiovascular disease. Here, ACEI modulate the bradykinin receptor (BDKRB1 and BDKRB2) system and NO-dependent endothelial function, thus determining cardiovascular health and regenerative arteriogenesis. The current study aims at evaluating nitric oxide-dependent endothelial function, and gene expression of bradykinin receptors in peripheral blood mononuclear cells (PBMC) from patients with ACEI or ARB treatment. Patients and methods: The WalkByLab has been established to screen cardiovascular patients for peripheral artery disease and coronary artery disease. In total 177 patients from WalkByLab with heterogenous disease and risk status were randomly selected, divided according to their medication history into the following groups: 1. ACEI group, 2. ARB group or 3. non-ACE/ARB group. Total plasma nitrite/nitrate (NO) levels were measured, endothelial function was evaluated by assessing flow meditated dilation (FMD). PBMC were isolated from peripheral whole blood, and gene expression (qRT-PCR) of bradykinin receptors and angiotensin converting enzyme were assessed. Results: Plasma total NO concentration in the ACEI group (24.66±16.28, µmol/l) was increased as compared to the ARB group (18.57±11.58, µmol/l, P=0.0046) and non-ACE/ARB group (16.83±8.64, µmol/l, P=0.0127) in patients between 40 to 90 years of age. However, FMD values (%) in the ACEI group (7.07±2.40, %) were similar as compared to the ARB (6.35±2.13, %) and non-ACE/ARB group (6.51±2.15, %), but significantly negatively correlated with age. Interestingly, BDKRB1 mRNA level was significantly higher and BDKRB2 mRNA level lower in the ACEI group (BDKRB1 3.88-fold±1.05, BDKRB2 0.22-fold±0.04) as compared to the non-ACE/ARB group (BDKRB1 1.00-fold±0.39, P

We aimed to investigate the tolerability, safety and effectiveness of enhanced external counterpulsation therapy (EECP) versus individual shear rate therapy (ISRT) in patients with lower extremity atherosclerotic disease (LEAD).Eighteen patients (age: 73.1 ± 6 years) underwent EECP and ISRT, each daily over five consecutive days in a cross-over design with a one week resting period in between the two regimens. A quality of life questionnaire was used to assess the therapy experience. Oxygen saturation (SO2), relative haemoglobin amount (rHb) and blood flow (Flow) in the capillary-venous-system (microcirculation) of the skin were monitored continuously during all therapy sessions using the micro-lightguide spectrophotometer, also known as Oxygen to See (O2C). The effects of EECP and ISRT on the renal function and skeletal muscles were evaluated using serial blood and urine tests.EECP therapy had to be terminated early before the end of the 5ISRT significantly improves tolerability, safety, and effectiveness over EECP in patients with LEAD.

Background For patients treated with dual antiplatelet therapy, standardized drug-specific 3-to-7 day cessation is recommended prior to major surgery to reach sufficient platelet function recovery. Here we investigated the hypothesis that supplemental fibrinogen might mitigate the inhibitory effects of antiplatelet therapy.Methods and Results To this end blood from healthy donors was treated in vitro with platelet inhibitors, and in vitro thrombus formation and platelet activation were assessed. Ticagrelor, acetylsalicylic acid, the combination of both, and tirofiban all markedly attenuated the formation of adherent thrombi, when whole blood was perfused through collagen-coated microchannels at physiological shear rates. Addition of fibrinogen restored in vitro thrombus formation in the presence of antiplatelet drugs and heparin. However, platelet activation, as investigated in assays of P-selectin expression and calcium flux, was not altered by fibrinogen supplementation. Most importantly, fibrinogen was able to restore in vitro thrombogenesis in patients on maintenance dual antiplatelet therapy after percutaneous coronary intervention.Conclusion Thus, our in vitro data support the notion that supplementation of fibrinogen influences the perioperative hemostasis in patients undergoing surgery during antiplatelet therapy by promoting thrombogenesis without significantly interfering with platelet activation.

Individual shear rate therapy (ISRT) evolved from external counterpulsation with individual treatment pressures based on Doppler ultrasound measurements. In this study, we assessed the effect of ISRT on blood pressure (BP) in patients with coronary artery disease (CAD). Eighty-four patients with symptomatic CAD were included in the study. Forty-one patients were enrolled for 6 weeks, comprising 30 sessions of ISRT; 43 age- and sex-matched patients represented the control group. The 24-h BP was determined by measuring the pulse transit time before and after 6 weeks of ISRT or the time-matched control. Participants were divided into three groups according to the 24-h BP before treatment: BP1 130/80 mmHg (normotensive); BP2 ≥ 130-140/80 mmHg (moderate hypertensive); BP3 140/80 mmHg (hypertensive). After 30 sessions of ISRT, the 24-h BP decreased significantly, whereas no changes were observed in the controls. The BP-lowering effect correlated with the 24-h BP before therapy (systolic: r = -0.78; p 0.001; diastolic: r = -0.76; p 0.001). In BP1, the systolic BP decreased by 4.3 ± 6.4 mmHg (p = 0.011), and the diastolic BP decreased by 4.8 ± 11.0 mmHg (p = 0.032); in BP2, the systolic BP decreased by 13.3 ± 7.5 mmHg (p 0.001), and the diastolic BP decreased by 5.0 ± 7.5 mmHg (p = 0.002); and in BP3, the systolic BP decreased by 22.9 ± 11.4 mmHg (p 0.001), and the diastolic BP decreased by 9.1 ± 9.5 mmHg (p = 0.003). Our findings demonstrate that ISRT reduces BP in patients with CAD. The higher the initial BP the greater the lowering effect.

AIM Arteriogenesis constitutes the most efficient endogenous rescue mechanism in cases of cerebral ischaemia. The aim of this work was to investigate whether angiotensin-converting enzyme inhibitors (ACEi) stimulates, and angiotensin II receptor type 1 blockers (ARB) inhibits cerebral collateral growth by applying a three-vessel occlusion (3-VO) model in rat. METHODS Cerebral collateral growth was measured post 3-VO (1) by assessing blood flow using the cerebrovascular reserve capacity (CVRC) technique, and (2) by assessing vessel diameters in the posterior cerebral artery (PCA) via the evaluation of latex angiographies. A stimulatory effect on arteriogenesis was investigated for ACEi administration ± bradykinin receptor 1 (B1R) and 2 (B2R) blockers, and an inhibitory effect was analysed for ARB administration. Results were validated by immunohistochemical analysis and mechanistic data were collected by human umbilical vein endothelial cell (HUVEC) viability or scratch assay and monocyte (THP-1) migration assay. RESULTS An inhibitory effect of ARB on arteriogenesis could not be demonstrated. However, collateral growth measurements demonstrated a significantly increased CVRC and PCA diameters in the ACEi group. ACEi stimulates cell viability and migration, which could be partially reduced by additional administration of bradykinin receptor 1 inhibitor (B1Ri). ACEi inhibits the degradation of pro-arteriogenic bradykinin derivatives, but combined ACEi + B1Ri + B1Ri (BRB) treatment did not reverse the stimulatory effect. Yet, co-administration of ACEi + BRB enhances arteriogenesis and cell migration. CONCLUSION We demonstrate a potent stimulatory effect of ACEi on cerebral arteriogenesis in rats, presumable via B1R. However, results imply a pleiotropic and compensatory effect of ACEi on bradykinin receptor-stimulated arteriogenesis.

Aims: This report reviews major laws, acts and regulations of social benefits and services for individuals with disabilities, focusing on cerebral palsy in the five Nordic countries. It summarizes the available benefits and services and the re-application process and provides comparative analyses among the countries. Methods: Published reports, articles and relevant government and municipal websites were reviewed for each respective country and used to compile an overview and comparison between the countries. Results: In the Nordic countries, there are a number of laws and regulations in place to support individuals with cerebral palsy and their families. In addition, there are numerous social benefits available for which individuals with disabilities can apply. Although there are national differences, the similarities across the five countries regarding laws, social benefits offered for individuals with cerebral palsy and the application processes are clear. However, the application processes seem cumbersome and, at times, redundant. Physicians and other healthcare specialists repeatedly need to write ‘medical certificates’ describing the diagnosis and its consequences for a disability that is chronic and lifelong. Conclusions: Participation in society for individuals with cerebral palsy disabilities can be enabled by social benefits. By extension, social benefits may indirectly have implications for public health in individuals with disabilities. Although the lives of individuals with cerebral palsy – as with others – can improve in certain areas, the need for social benefits will generally increase, not decrease, over time. Although it is clearly important to have checks and balances that prevent system misuse, it might be worthwhile from a cost-benefit perspective to investigate whether the current systems could be improved to better manage time and resources and avoid emotional distress by streamlining the application process.

Objective Present bench study aimed to evaluate whether technical characteristics of Fantom Encore® bioresorbable scaffold (BRS) allow to perform proximal optimization/side branch dilation/proximal optimization (POT-SB-POT) technique, as an adequate solution for bifurcation percutaneous coronary intervention. Methods Two Fantom Encore® BRS platforms (small with 3.0 mm nominal diameter, n = 7; and large with 3.5 mm nominal diameter, n = 7) were evaluated in bench models, which were designed according to Finet-law and fitted to nominal scaffold diameter in the distal main branch (MB) and fitted to indicated maximal expansion capacity in the proximal main branch (MB). Results were evaluated by (a) fluoroscopy, (b) optical coherence tomography (OCT) and (c) micro-computed tomography (μCT). Results All procedures were performed according to the protocol. Careful review of the fluoroscopic loops by an independent operator did not reveal any strut fracture or major deformation. By OCT the overall rate of perfectly apposed struts in the bifurcation area was 15 ± 6% after SB opening, that increased significantly but remained low with 22 ± 9% after final POT (p = .001). Compared to SB ballooning alone, significant benefit of final POT was found in rate of perfect apposition in the proximal MB (15 ± 12% vs. 26 ± 15%, respectively; p = .017) and at the abostial side of polygon of confluence (7 ± 9% vs. 16 ± 13%, respectively; p = .005). μCT analysis revealed a single strut fracture in one case with the small platform, while four cases showed single or multiple strut fractures with the large platform. Conclusion The mechanical characteristics of the device are not suitable for use of Conventional techniques for bifurcation PCI such as POT-SB-POT. The use of Fantom Encore® BRS for bifurcation PCI with relevant SB should not be encouraged.

Background and aims Arteriogenesis, the positive outward remodeling and growth of pre-existent collateral vessels, holds potential as a novel treatment for ischemic vascular disease. An extracranial arteriogenesis model in a pig will allow us to study molecular changes in a complex arteriolar network in a more clinically relevant large-animal model. To increase fluid shear stress in the brain, an experimental carotid arteriovenous fistula (AVF model) in minipigs was established, providing high flow through the extracranial rete mirabile. The aim of the study was to examine whether creation of a carotid AVF can induce extracranial arteriogenesis in the pig. Methods Angiography was performed to demonstrate blood flow diversion. Animals were sacrificed after 0, 3 and 14 days post-surgery and both retia mirabilia were removed. Immunohistochemical analysis was performed to analyze cell proliferation and accumulation of mononuclear cells in the vessel wall. Results After 3 days of high-flow conditions, increases in vascular cell proliferation (approximately 1.5-fold; p = 0.143) and monocyte invasion (approximately 6-fold; p = 0.057) were observed when compared to animals sacrificed immediately after AVF formation. Quantitative PCR (RT-qPCR) analysis from rete mirabile tissue samples 3 days post-surgery revealed that monocyte chemoattractant protein (MCP)-1 and tissue inhibitor of metalloproteinases (TIMP)-1 were highly upregulated. Expression of the pro-arteriogenic marker, CD44, reached maximum expression level 14 days post-surgery. Conclusions In response to high levels of shear stress produced in the pig AVF model, the onset of the arteriogenic process can be induced. This was demonstrated by enhanced cell proliferation, monocyte invasion and vascular remodeling.

The aim of this study was to elucidate if patients with coronary artery disease (CAD), who fail to respond to revascularization procedures, can improve from individual shear rate therapy (ISRT). The ISRT is an adaptation of the external counterpulsation with lower individual treatment pressures based on Doppler-ultrasound measurements during counterpulsation. In contrast to the external counterpulsation therapy, the ISRT is based on the detection of the individual intra-arterial shear rate. Here we report about the first clinical trial of 31 patients with CAD who were enrolled for 30 sessions of ISRT. To determine the therapeutic effect of ISRT we measured the exercise capacity, the arterial stiffness, the aortic wave reflection, and the 24-hour blood pressure before and after 30 treatment sessions. After 6 weeks of accomplished ISRT the walking distance during the 6-minute walking test extended by 78 m (p = 0.007). The total exercise duration in the exercise stress electrocardiogram increased by 84 seconds (p = 0.012) but not the stress intensity (p = 0.086). The pulse wave velocity decreased by 1.2 m/s (p = 0.004) and demonstrated a decrease in arterial stiffness. Pulse wave analysis results demonstrated a progressive decrease in central blood pressure by 12 mmHg (p = 0.008), in pulse pressure by 9 mmHg (p = 0.005), and in augmentation pressure by 5.3 mmHg (p = 0.004). The 24-hour blood pressure decreased systolic by 15 mmHg (p

Aim Physical activity is a potent way to impede vascular aging. However, patients who suffer from peripheral artery disease (PAD) are often unable to exercise adequately. For those patients, we have developed individual shear rate therapy (ISRT), which is an adaptation of external counterpulsation and enhances endovascular fluid shear stress to increase collateral growth (arteriogenesis). To evaluate the effects of physical exercise and ISRT on the telomere biology of peripheral blood mononuclear cells (PBMCs), we conducted two clinical trials. Methods In the ISRT-1 study, we assessed PBMC telomerase activity in 26 young healthy volunteers upon a single (short-term) ISRT session and a single treadmill running session. In the ISRT-2 study, we investigated PBMC telomere biology of 14 aged PAD patients, who underwent 30 hours of (long-term) ISRT within a 5-week-period. Results We demonstrate that telomerase activity significantly increased from 39.84 Total Product Generated Units (TPG) ± 6.15 to 58.10 TPG ± 10.46 upon a single treadmill running session in healthy volunteers. In the ISRT-2 trial, PBMC telomerase activity and the mRNA expression of the telomere-protective factor TRF2 increased from 40.87 TPG ± 4.45 to 60.98 TPG ± 6.83 and 2.21-fold ± 0.48, respectively, upon long-term ISRT in aged PAD patients. Conclusion In summary, we show that acute exercise and long-term ISRT counterpulsation positively affect PBMC telomerase activity, which is indicative for an improved regenerative potential of immune cells and vascular tissues. Long-term ISRT also enhances the gene expression of the telomere protective factor TRF2. This article is protected by copyright. All rights reserved.

Background— Prosthetic orifice area, usually calculated by transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE), provides important information regarding the hemodynamic performance of aortic bioprostheses. However, both TTE and TEE have limitations; therefore accurate and reproducible determination of the orifice area often remains a challenge. The present study aimed to investigate the feasibility of cardiovascular magnetic resonance (CMR) to assess the orifice areas of aortic bioprostheses. Methods and Results— CMR planimetry of the orifice area was performed in 65 patients (43/22 stented/stentless prostheses; mean time since implantation, 3.1�2.8 years; mean orifice area [TTE], 1.70�0.43 cm 2 ; 62 normally functioning prostheses, 2 severe stenoses, and 1 severe regurgitation) in an imaging plane perpendicular to the transprosthetic flow using steady-state free-precession cine imaging under breath-hold conditions on a 1.5-T MR system. CMR results were compared with TTE (continuity equation, n=65) and TEE (planimetry, n=31). CMR planimetry was readily feasible in 80.0%; feasible with limitation in 15.4% because of stent, flow, and sternal wire artifacts; and impossible in 4.6% because of flow artifacts. Correlations of the orifice areas by CMR with TTE ( r =0.82) and CMR with TEE ( r =0.92) were significant. The average difference between the methods was −0.02�0.24 cm 2 (TTE) and 0.05�0.15 cm 2 (TEE). Agreement was present for stented and stentless devices and independent of orifice size. Intraobserver and interobserver variabilities of CMR planimetry were 6.7�5.4% and 11.5�7.8%. Conclusions— The assessment of aortic bioprostheses with normal orifice areas by CMR is technically feasible and provides orifice areas with a close correlation to echocardiography and low observer dependency.

Das hepatopulmonale Syndrom (HPS) ist eine Storung des pulmonalen Gasaustausches mit Hypoxamie im Zusammenhang mit einer Lebererkrankung, ohne dass eine ausreichende Erklarung durch eine kardiale oder pulmonale Erkrankung besteht [1, 2]. Die zugrunde liegende Lebererkrankung kann akut oder chronisch und von unterschiedlicher Atiologie sein, zumeist liegt aber eine Zirrhose vor. Die Pravalenz des HPS bei Patienten mit einer Lebererkrankung wird zwischen 17 und 42% angegeben [3, 4]. Die Mortalitatsrate dieser Patienten hangt mit der Hohe des intrapulmonalen Shuntvolumens und des pO2 unter Raumluft zusammen und ist gegenuber lebererkrankten Patienten ohne HPS deutlich erhoht [5].

Background— Granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently shown to increase collateral flow index in patients with coronary artery disease. Experimental models showed beneficial effects of GM-CSF on collateral artery growth in the peripheral circulation. Thus, in the present study, we evaluated the effects of GM-CSF in patients with peripheral artery disease. Methods and Results— A double-blinded, randomized, placebo-controlled study was performed in 40 patients with moderate or severe intermittent claudication. Patients were treated with placebo or subcutaneously applied GM-CSF (10 μg/kg) for a period of 14 days (total of 7 injections). GM-CSF treatment led to a strong increase in total white blood cell count and C-reactive protein. Monocyte fraction initially increased but thereafter decreased significantly as compared with baseline. Both the placebo group and the treatment group showed a significant increase in walking distance at day 14 (placebo: 127±67 versus 184±87 meters, P =0.03, GM-CSF: 126±66 versus 189±141 meters, P =0.04) and at day 90. Change in walking time, the primary end point of the study, was not different between groups. No change in ankle-brachial index was found on GM-CSF treatment at day 14 or at day 90. Laser Doppler flowmetry measurements showed a significant decrease in microcirculatory flow reserve in the control group ( P =0.03) and no change in the GM-CSF group. Conclusions— The present study does not support the use of GM-CSF for treatment of patients with moderate or severe intermittent claudication. Issues that need to be addressed are dosing, the selection of patients, and potential differences between GM-CSF effects in the coronary and the peripheral circulation.