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Background Many patients with severe aortic stenosis are referred late with advanced symptoms or inappropriately denied intervention. The objective was to investigate whether a structured communication to referring physicians (facilitated data relay) might improve the rate and timeliness of intervention. Methods and Results A prospective registry of consecutive patients with severe aortic stenosis at 23 centers in 9 European countries with transcatheter as well as surgical aortic valve replacement being available was performed. The study included a 3‐month documentation of the status quo (phase A), a 6‐month intervention phase (implementing facilitated data relay), and a 3‐month documentation of a legacy effect (phase‐B). Two thousand one hundred seventy‐one patients with severe aortic stenoses were enrolled (phase A: 759; intervention: 905; phase‐B: 507). Mean age was 77.9±10.0 years, and 80% were symptomatic, including 52% with severe symptoms. During phase A, intervention was planned in 464/696 (67%), 138 (20%) were assigned to watchful waiting, 8 (1%) to balloon aortic valvuloplasty, 60 (9%) were listed as not for active treatment, and in 26 (4%), no decision was made. Three hundred sixty‐three of 464 (78%) patients received the planned intervention within 3 months. Timeliness of the intervention improved as shown by the higher number of aortic valve replacements performed within 3 months (59% versus 51%, P =0.002) and a significant decrease in the time to intervention (36±38 versus 30±33 days, P =0.002). Conclusions A simple, low‐cost, facilitated data relay improves timeliness of treatment for patients diagnosed with severe aortic stenosis, resulting in a shorter time to transcatheter aortic valve replacement. This effect was mainly driven by a significant improvement in timeliness of intervention in transcatheter aortic valve replacement but not surgical aortic valve replacement. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 02241447.

BackgroundPredilation of the native valve has long been deemed necessary in transfemoral transcatheter aortic valve implantation (TF-TAVI), despite little trial evidence to support its clinical use. As most evidence is derived from retrospective analyses of observational studies, we conducted a two-armed, prospective multicentre registry.MethodsPatients undergoing TF-TAVI with the Edwards SAPIEN 3 valve, with or without balloon aortic valvuloplasty (BAV), were included and their procedural characteristics, short-term safety and short-term efficacy outcomes compared. We hypothesised that BAV may be safely omitted in many patients and omission could be associated with procedural benefits.ResultsOverall, 196 consecutive patients underwent TF-TAVI, 56 with BAV and 140 without. The mean age was 81.2±6.2 years, and the mean logistic EuroSCORE I was 17.1±13.6. Device success according to Valve Academic Research Consortium-2 (VARC-2) was achieved in 96.4%. The median procedural duration was shorter without BAV (56 min vs 90 min; p=0.001), as was fluoroscopy time (10 min vs 13 min; p=0.001). The need for balloon postdilation was less frequent in patients without BAV (15.7% vs 30.4%, p=0.029). There was no difference in the proportion of patients meeting the VARC-2 defined composite safety endpoint at 30 days (9.3% without vs 8.9% with BAV; adjusted OR (adjOR) 2.55; 95% CI 0.56 to 18.84) and at 6 months (15.2% without vs 16.4% with BAV; adjOR 1.66; 95% CI 0.49 to 6.55).ConclusionsIn the majority of patients, BAV can be safely omitted from the TAVI procedure without adverse effects. The omission of BAV is associated with shorter procedural duration and could be advantageous for the majority of patients.Trial registration numberNCT02760771.

BACKGROUND Approximately 800 000 coronary angiography procedures are per- formed in Germany each year, mainly in order to identify coronary artery stenoses. As a rule, revascularization is indicated only when coronary artery stenoses cause relevant ischemia, but this cannot be determined unequivocally by angiography alone. Pressure wire measurement and the measurement of fractional flow reserve (FFR) enable direct evaluation of the hemodynamic relevance of coronary artery stenoses during diagnostic coronary angiography. METHODS This review is based on publications retrieved by a selective search in PubMed focusing especially on large randomized trials, registry studies, and meta- analyses on either pressure wire measurement or FFR. RESULTS According to a registry study from France, the hemodynamic evaluation of a stenosis during coronary angiography affected decisions about revascularization in 43% of cases. Randomized multicenter trials have shown that a combined end- point consisting of death, myocardial infarction, or revascularization arose signifi- cantly less commonly in the FFR group than in the group receiving angiography without FFR (13.2% versus 18.3%; p = 0.02), and that patients with one or more hemodynamically significant coronary artery stenoses (FFR ≤ 0.80) benefited more from revascularization than from medical management alone (event rate, 8.1% versus 19.5%; p

The aim of this study was to assess the safety and performance of a newly introduced transfemoral self-expanding supra-annular transcatheter heart valve.Transcatheter aortic valve replacement has become an established procedure, and newer transcatheter heart valves aim to supplement the current armamentarium.BIOVALVE-I is a prospective, single-center feasibility study enrolling 13 high-risk patients with severe aortic stenosis, and BIOVALVE-II is a multicenter pilot study enrolling a further 55 patients under the same protocol.Patients' mean age was 82.4 ± 5.3 years, 57.4% had concomitant coronary artery disease, 50.0% had renal insufficiency stage ≥3, 32.4% had diabetes mellitus, 29.4% had current anemia, 19.1% had chronic obstructive pulmonary disease, 19.1% were frail, and 17.6% had prior cerebrovascular events. The primary endpoint, early safety according to the Valve Academic Research Consortium-2 guidelines, was observed in 13 patients (19.1%). One patient (1.5%) died through 30 days of a noncardiac cause, and 4 patients (7.8%) died through 180 days. Disabling stroke occurred at 30 days in 1 patient (1.5%) and at 180 days in 2 patients (3.2%). New permanent pacemakers up to 30 days were implanted in 9 patients (13.4%). Two patients (3.8%) had moderate or severe paravalvular leakage at 30 days and 4 (9.1%) at 6 months, mean effective orifice area was 2.0 ± 0.4 cmClinical outcomes with the Biovalve self-expanding transcatheter heart valve were similar to those seen in other first-in-human studies with first-generation devices for severe aortic stenosis.

AimsThere is an increasing awareness of gender-related differences in patients with severe aortic stenosis and their outcomes after surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI).MethodsData from the IMPULSE registry were analysed. Patients with severe aortic stenosis (AS) were enrolled between March 2015 and April 2017 and stratified by gender. A subgroup analysis was performed to assess the impact of age.ResultsOverall, 2171 patients were enrolled, and 48.0% were female. Women were characterised by a higher rate of renal impairment (31.7 vs 23.3%; pConclusionsThe present data show that female patients with severe AS have a distinct patient profile and are managed in a different way to males. Gender-based differences in the management of patients with severe AS need to be taken into account more systematically to improve outcomes, especially for women.

The aim of this study was to identify predictors of permanent pacemaker implantation (PPMI) following transcatheter aortic valve replacement (TAVR) with a balloon-expandable transcatheter valve (Edwards SAPIEN 3).New-onset conduction disturbances requiring PPMI remain a major concern following TAVR. Predictors are not yet well defined.The influence of angiographic implantation depth, device landing zone calcium volume, oversizing, pre- and post-dilation, and baseline conduction disturbances on PPMI rate was analyzed in 229 patients undergoing TAVR with the SAPIEN 3 device.PPMI was performed in 14.4% of patients. Patients requiring PPMI had higher left ventricular outflow tract (LVOT) calcium volume in the area below the left coronary cusp (LVOTLVOT

Transcatheter aortic valve implantation (TAVI) has become an established treatment for symptomatic aortic valve stenosis in inoperable patients and high-risk patients. In Germany the TAVI procedure has now surpassed the annual numbers of isolated surgical aortic valve replacement with a recent trend towards treatment of intermediate-risk patients; however, before TAVI can also be used in patients with lower surgical risk, studies are required to demonstrate the safety and efficacy of this method for this patient population.

We report the case of an 88-year-old man who developed a mid–left-ventricular (LV) obstruction caused by apical pacing to manage third-degree atrioventricular block. The flow generated by the obstruction was directed toward the LV apex and appeared from late systole to early diastole. The obstruction appeared to result from earlier contraction at the apex compared with the midventricular portion of the LV, which was followed by an also earlier apical relaxation. The obstruction was eliminated by using a second right-ventricular mid-septally attached electrode combined with a sequential septo-apical pacing (septal stimulation 40 ms before apical pacing).

Aims Peri-procedural transcatheter valve embolization and migration (TVEM) is a rare but potentially devastating complication of transcatheter aortic valve implantation (TAVI). We sought to assess the incidence, causes, and outcome of TVEM in a large multicentre cohort. Methods and results We recorded cases of peri-procedural TVEM in patients undergoing TAVI between January 2010 and December 2017 from 26 international sites. Peri-procedural TVEM occurred in 273/29 636 (0.92%) TAVI cases (age 80.8 ± 7.3 years; 53.8% female), of which 217 were to the ascending aorta and 56 to the left ventricle. The use of self-expanding or first-generation prostheses and presence of a bicuspid aortic valve were independent predictors of TVEM. Bail-out measures included repositioning attempts using snares or miscellaneous tools (41.0%), multiple valve implantations (83.2%), and conversion to surgery (19.0%). Using 1:4-propensity matching, we identified a cohort of 235 patients with TVEM (TVEMPS) and 932 patients without TVEM (non-TVEMPS). In the matched cohort, all-cause mortality was higher in TVEMPS than in non-TVEMPS at 30 days (18.6% vs. 4.9%; P Conclusion Transcatheter valve embolization and migration occurred in approximately 1% and was associated with increased morbidity and mortality.

Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.

Introduction Many patients with severe AS are inappropriately denied intervention and continue to present late with advanced symptoms. IMPULSE is a prospective, multicentre registry conduced in 23 centres across 9 European countries, investigating the efficacy of facilitated data transfer (FDT) in improving time to intervention in severe AS. Results from the 3 large UK centres were compared to those of other large centres in the rest of Europe. Methods Hospitals with all treatment options (sAVR, TAVI, BAV) on site were asked to document, over a 1 year period, patients with severe AS that presented with or without symptoms. A 3 months purely observational phase A was followed by a 6 months interventional phase (FDT), and a 3 months observational phase B to investigate a legacy effect. Results: A total of 2171 pts were enrolled of which 515 were recruited in the UK. Patients in the UK had a mean age of 78.1±11.0 years, 46.8% were female, the mean log EuroScore I was 17.1±13.3 and 77.9% of the patients were considered symptomatic based on the presence of chest pain, shortness of breath, dizziness on exertion. These baseline characteristics did not differ between the UK and the rest of Europe. Concomitant valve disease aortic (17.4 vs 5.1%), mitral (18.6 vs 8.3%) and tricuspid (16.2 vs 5.3%) regurgitation was more frequently diagnosed in the UK than the rest of Europe (all p Conclusions Management practices differ in the UK compared to Europe in patients with severe AS, with more frequent selection of watchful waiting and medical management. FTD increased the number of patients going for intervention, although rates remained low given that the study recruited only patients with severe aortic stenosis confirmed on echo and almost 4/5ths were symptomatic. In addition, there is a significant delay in the UK compared to Europe between decision making and actual performance of TAVI.

Fractional flow reserve (FFR) measurements can determine the haemodynamic relevance of coronary artery stenoses. Current guidelines recommend their use in lesions in the absence of non-invasive proof of ischaemia. The prognostic impact of FFR has been evaluated in randomised trials, and it has been shown that revascularisation can be safely deferred if FFR is >0.80, while revascularisation of stenoses with FFR values ≤0.80 results in significantly lower event rates compared to medical treatment. Left main stenoses, aorto-ostial lesions, as well as patients with left ventricular hypertrophy and severely-impaired ejection fraction, have been excluded from large, randomised trials. While FFR measurements are relatively straightforward to perform, uncertainty about procedural logistics, as well as data acquisition and interpretation in specific situations, could explain why they are not widely used in clinical practice. We summarise the clinical data in support of FFR measurements, and provide recommendations for performing and interpreting the procedure.

To identify predictors of paravalvular regurgitation (PVR) and permanent pacemaker implantation (PPI) following TAVR with a next-generation self-expanding device. Device landing zone (DLZ) calcification, angiographic implantation depth, and baseline and procedural characteristics were analyzed in 212 patients being treated with the ACURATE neo aortic bioprosthesis. PVR was none/trace in 57.1% and ≥ mild in 42.9% (37% mild, 6% moderate). DLZ calcification (705 (IQR 240–624) vs. 382 (IQR 240–624) mm3; P 410.6 mm3 was independently associated with PVR ≥ mild. PPI rate was 10.3% (n = 20). Patients with and without need for PPI had similar total DLZ calcium volume (740 (IQR 378–920) vs. 536 (IQR 315–822) mm3; P = 0.263), but exhibited different calcium distribution patterns: LVOT calcium > 41.4 mm3 in the sector below the left coronary cusp (LVOTLC) was associated with increased PPI risk (26.9 vs. 7.7%; P = 0.008). The quantity of AVC calcium predicts residual PVR. Multivariable analysis identified LVOTLC calcium, pre-existing RBBB, and age > 82.7 years as independent predictors of PPI. Based on these risk factors, a patient’s individual PPI risk can be stratified ranging from 3.8 to 100%.

Ziel Die Bedeutung des vermutlich neu aufgetretenen Linksschenkelblocks (LSB) als Aquivalent eines ST-Hebungsinfarktes ist fur die heutige Herzinfarktversorgung mit sofortiger Koronarangiographie nicht hinreichend belegt. Daher wurde der pradiktive Wert des LSB fur die Diagnose eines akuten transmuralen Myokardinfarktes (AMI) untersucht.

Background The latest generation of balloon-expandable valve, the Edwards Sapien 3 valve (S3V), was designed to reduce paravalvular regurgitation (PVR). We retrospectively compared S3V with Edwards Sapien XT valve (SXTV) with regard to postprocedural transvalvular pressure gradients (PGs). Methods Analysis of 152 patients receiving SXTV and 125 patients receiving S3V between February 2009 and April 2015 was performed. Transvalvular PGs and the incidence and extent of aortic regurgitation (AR) were compared postprocedurally by echocardiography for each valve size. Results Postprocedurally, mean PGs for the 23 mm valves were 10.9 ± 5.3 versus 13.9 ± 5.1 (p = 0.017), whereas maximum PGs were 19.9 ± 8.3 versus 26.1 ± 10.4 mm Hg (p = 0.005) in SXTV and S3V patients, respectively. For the 26 mm valves, gradients were also significantly higher in S3V patients (mean PG: 11.6 ± 4.9 vs. 9.2 ± 4.2 [p = 0.004]; maximum PG: 23.0 ± 10.1 vs. 17.2 ± 7.4 mm Hg [p Conclusion S3V shows lower incidence of PVR; however, it is associated with significantly higher postprocedural transvalvular PGs for 23 and 26 mm valve sizes. These data might contribute to the scientific discussion, especially with respect to prosthesis selection in individual patients with small annular dimension.

BACKGROUND We investigated the application and feasibility of a novel software tool designed for the visualization of the aortic root during transcatheter aortic valve implantation (TAVI). The final positioning of the device prior deployment remains the most critical phase during TAVI. METHODS Philips "Vascular Outlining" prototype application was used during balloon expandable Edwards Lifesciences SapienXT valve deployment. It processes any angiographic sequences, extracting the static outline of vessels and projecting the two-dimensional vessel margins as a roadmap on live fluoroscopy. Preoperational planning, sizing and anatomical assessment of access routes were performed using computed tomography scans and the Philips "HeartNavigator" software. RESULTS Fifteen high-risk aortic stenosis patients (mean age 82.0±6.6 years) underwent TAVI via transfemoral (N.=8), transapical (N.=4), and transaortic (N.=3) access routes. Mean logistic EuroSCOREs and STS-scores were 19.7±4.3% and 7.9±3.1%, respectively, mean aortic gradient was 66.3±18.3 mmHg. All valves were implanted successfully with none or trivial paravalvular regurgitation in 11 patients, mild in 3 patients, and moderate in 1 patient. TAVI was performed in all cases with only one aortic root contrast media injection during valve deployment. No major stroke or cardiovascular death occurred within 30 days. CONCLUSIONS "Vascular Outlining"-guided implantation of the SapienXT valve is feasible. This new feature might increase the accuracy of valve placement and also may reduce the need for extra contrast media use during valve deployment. However, the lack of real-time motion compensation limits its wide application, as the overlay does not move together with respiratory and cardiac motion.

The aim of this study was to determine whether the association of small label size of the surgical valve with increased mortality after transcatheter valve-in-valve (ViV) implantation is, at least in part, related to pre-existing prosthesis-patient mismatch (PPM) (i.e., a bioprosthesis that is too small in relation to body size).Transcatheter ViV implantation is an alternative for the treatment of patients with degenerated bioprostheses. Small label size of the surgical valve has been associated with increased mortality after ViV implantation.Data from 1,168 patients included in the VIVID (Valve-in-Valve International Data) registry were analyzed. Pre-existing PPM of the surgical valve was determined using a reference value of effective orifice area for each given model and size of implanted prosthetic valve indexed for body surface area. Severe PPM was defined according to the criteria proposed by the Valve Academic Research Consortium 2: indexed effective orifice area 0.65 cmAmong the 1,168 patients included in the registry, 89 (7.6%) had pre-existing severe PPM. Patients with severe PPM had higher 30-day (10.3%, p = 0.01) and 1-year (unadjusted: 28.6%, p 0.001; adjusted: 19.3%, p = 0.03) mortality rates compared with patients with no severe PPM (4.3%, 11.9%, and 10.9%, respectively). After adjusting for surgical valve label size, Society of Thoracic Surgeons score, renal failure, diabetes, and stentless surgical valves, presence of pre-existing severe PPM was associated with increased risk for 1-year mortality (odds ratio: 1.88; 95% confidence interval: 1.07 to 3.28; p = 0.03). Patients with severe PPM also more frequently harbored high post-procedural gradients (mean gradient ≥20 mm Hg).Pre-existing PPM of the failed surgical valve is strongly and independently associated with increased risk for mortality following ViV implantation.

Rationale: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling. Objective: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias. Methods and Results: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin–deficient (CD11b −/− ) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo −/− ) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wild-type mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo −/− mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H 2 O 2 incubation. Mapping of induced pluripotent stem cell–derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo −/− mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter–defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction >35% undergoing elective diagnostic cardiac evaluation. Conclusions: Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia.

Background Platelet inhibition has been linked to improved endothelial function, a prognostic factor in coronary artery disease. Whether prasugrel, a potent platelet inhibitor, affects endothelial function remains unknown. Methods This was a double-blind, randomized, active-controlled, parallel trial. Patients with unstable angina pectoris undergoing percutaneous coronary intervention (PCI) received either a daily dose of clopidogrel 75mg (n=23) or prasugrel 10mg (n=22). Flow-mediated dilation (FMD), circulating nitrate and nitrite, inflammatory markers and platelet-leukocyte aggregates (PLAs) were assessed the day after PCI and after 3months. Results Baseline patient demographics were well matched between treatment groups. Prasugrel led to a significant improvement of FMD after 3months (9.01±3.64% vs. 6.65±3.24%, p=0.001). In contrast, no significant change was observed in the clopidogrel group (7.21±2.84% vs. 6.30±2.97%, p=0.187). Adjusted for baseline FMD, hyperlipidemia and statin use, the treatment effect on change in FMD favoured prasugrel by an absolute 1.97% (95% CI 0.29% to 3.66%, p=0.023). A significant reduction of plasma hsCRP, myeloperoxidase and neutrophil elastase and an increase of nitrate levels were noted in both treatment arms. Interestingly, only prasugrel significantly reduced sCD40 ligand and RANTES and increased nitrite levels. Prasugrel reduced the ADP-stimulated increase in PLAs by 40% (IR: 82 to 13), whereas clopidogrel revealed no such effect (1% increase (IR: 13 to 50) (p=0.01). Conclusion Prasugrel exhibits beneficial mid-term effects on endothelial nitric oxide bioavailability and inflammatory markers. (EudraCT number: 2009-015406-19).

Background Pulmonary arterial hypertension (PAH) is a progressive condition harboring a poor prognosis. Iron deficiency in PAH correlates with disease severity and mortality. While replacement therapy may be beneficial, dietary iron absorption is impaired in PAH patients by hepcidin, a key regulatory protein of iron homoeostasis. We therefore assessed the therapeutic potential and safety of intravenous iron supplementation in patients with PAH and iron deficiency. Methods 20 patients with PAH and iron deficiency, who were on stable targeted PAH therapy, received a single infusion of ≤1000mg ferric carboxymaltose. All patients were assessed at baseline and two months after iron treatment. Exercise capacity was evaluated based on the 6-minute-walking distance (6MWD), and quality of life (QoL) was assessed by the SF-36 questionnaire (100 point scale). The effects were compared to 20 matched patients with stable PAH without iron deficiency who did not receive ferric carboxymaltose. Results In iron deficient patients, iron supplementation led to a marked improvement of iron status (serum iron 5.7±0.4 to 11.1±1.1μmol/L, ferritin 29.3±6.3 to 145.2±25.4μg/L, transferrin saturation 7.5±0.7 to 19.3±2.3%, all p ≤0.001). Iron-deficient patients receiving ferric carboxymaltose showed a significant increase of the 6MWD from 346.5±28.3 to 374.0±25.5m ( p =0.007), whereas no significant changes were found in the control group not receiving iron supplementation (6MWD 389.9±25.3 to 379.6±26.2m; n.s.), resulting in a net increase in the 6MWD of 37.8m ( p =0.003). This was associated with an improvement in QoL (SF-36 score from 44.3±3.7 to 50.6±3.6; p =0.01). Only minimal side-effects were reported. Conclusions These data indicate that parenteral iron supplementation with ferric carboxymaltose significantly improves exercise capacity and QoL and is well tolerated in patients with PAH and iron deficiency, and when administered in addition to targeted PAH therapies. Our results provide proof of concept for further studies evaluating the potential of iron as an adjunct in PAH treatment on a larger scale.

BackgroundSevere aortic stenosis (AS) is one of the most common and most serious valve diseases. Without timely intervention with surgical aortic valve replacement or transcatheter aortic valve replacement, patients have an estimated survival of 2–3 years. Guidelines for the treatment of AS have been developed, but studies suggest that as many as 42% of patients with AS are not treated according to these recommendations.The aims of this registry are to delineate the caseload of patients with AS, outline the management of these patients and determine appropriateness of treatments in participating centres with and without onsite access to surgery and percutaneous treatments.Methods/designThe IMPULSE enhanced registry is an international, multicentre, prospective, observational cohort registry conducted at four central full access centres (tertiary care hospitals) and at least two satellite centres per hub (primary/secondary care hospitals). An estimated 800 patients will be enrolled in the registry and patient follow-up will last for 12 months.DiscussionIn addition to the primary aims determining the caseload management and outcome of patients with AS in primary, secondary and tertiary care settings, the registry will also determine a time course for the transition from asymptomatic to symptomatic status and the diagnostic steps, treatment decisions and the identification of decision-makers in tertiary versus primary/secondary care hospitals. The last patient will be enrolled in the registry in 2018 and results of the registry are anticipated in 2019.Registration numberNCT03112629.

The opioid epidemic has brought attention to the pain relieving effect of exercise, but exercise prescription for pain relief may be quite different from that typically recommended for cardiovascular and other health benefits. Exercise induced hypoalgesia (EIH) is complex and not entirely understood but possible mechanisms include the opioid and non-opioid systems. Hypoalgesia is also known to occur in response to pain itself. Conditioned pain modulation (CPM) is the inhibition of pain from a test stimulus by a painful conditioning stimulus. Studies of EIH often involve exercise paradigms in which long duration muscle contractions are used. Long duration muscle contractions are often painful so it raises the question, “Is it exercise or the pain associated with exercise that leads to EIH?” Nine individuals underwent pain testing on the right and left knees and middle finger before and after three conditions: 10 voluntary isometric contractions, 10 contractions elicited by neuromuscular electrical stimulation (NMES) and 10 bursts of noxious electrical stimulation without muscle contraction all on the right quadriceps muscles. The contractions or stimuli lasted 10 s separated by 50 s off. The average pain rating (0-100 VAS) during the noxious stimulation (84.4 +/- 12.1) was higher than during the NMES elicited contractions (61.4 +/- 18.9; p=0.001). Subjects reported no pain during the volitional contractions. The force of the contractions is reported in % maximum voluntary contraction (%MVIC) and the volitional contraction force averaged 59.6 (+/- 18.0) % MVIC while the NMES elicited contraction force averaged 52.0 (+/-14.5) % MVIC. Hypoalgesia was observed in the right and left knees response to the noxious stimulation and NMES elicited contractions but not the volitional contractions. The results suggest that the hypoalgesia associated with the NMES elicited contractions was due to the noxious nature of the contractions and that the mechanism involves spinal mechanisms.

Pulmonary hypertension (PH) represents a serious health complication accompanied with hypoxic conditions, elevated levels of asymmetric dimethylarginine (ADMA), and overall dysfunction of pulmonary vascular endothelium. Since the prevention strategies for treatment of PH remain largely unknown, our study aimed to explore the effect of nitro-oleic acid (OA-NO2), an exemplary nitro-fatty acid (NO2-FA), in human pulmonary artery endothelial cells (HPAEC) under the influence of hypoxia or ADMA. HPAEC were treated with OA-NO2 in the absence or presence of hypoxia and ADMA. The production of nitric oxide (NO) and interleukin-6 (IL-6) was monitored using the Griess method and ELISA, respectively. The expression or activation of different proteins (signal transducer and activator of transcription 3, STAT3; hypoxia inducible factor 1α, HIF-1α; endothelial nitric oxide synthase, eNOS; intercellular adhesion molecule-1, ICAM-1) was assessed by the Western blot technique. We discovered that OA-NO2 prevents development of endothelial dysfunction induced by either hypoxia or ADMA. OA-NO2 preserves normal cellular functions in HPAEC by increasing NO production and eNOS expression. Additionally, OA-NO2 inhibits IL-6 production as well as ICAM-1 expression, elevated by hypoxia and ADMA. Importantly, the effect of OA-NO2 is accompanied by prevention of STAT3 activation and HIF-1α stabilization. In summary, OA-NO2 eliminates the manifestation of hypoxia- and ADMA-mediated endothelial dysfunction in HPAEC via the STAT3/HIF-1α cascade. Importantly, our study is bringing a new perspective on molecular mechanisms of NO2-FAs action in pulmonary endothelial dysfunction, which represents a causal link in progression of PH.

Background Transcatheter aortic valve implantation via the transfemoral route (TF-TAVI) is commonly performed as a treatment for severe aortic stenosis (AS) in patients at high surgical risk. Pre-deployment balloon aortic valvuloplasty (BAV) has generally been considered an essential step for preparing the valve landing zone for receipt of the prosthesis. However, there is little evidence supporting the clinical value of BAV, while several associated complications have been documented. This has provoked several groups to evaluate the feasibility and safety of omitting BAV form the TF-TAVI procedure (direct TF-TAVI), with encouraging results. However, studies comparing the clinical outcomes of direct TF-TAVI to standard TF-TAVI are lacking. Methods EASE-IT TF is a prospective, observational, two-armed, multicentre registry designed to gather data on procedural aspects, adverse events and survival rates associated with direct TF-TAVI using the Edwards SAPIEN 3 balloon-expandable prosthesis. Discussion EASE-IT-TF data will be analysed firstly to determine the risks and benefits associated with direct TF-TAVI vs. standard TF-TAVI, and secondly to identify associations between patient variables and specific outcomes. This may assist identification of patients who stand to benefit from direct TF-TAVI, therefore contributing to clinical reductions in TF-TAVI-associated morbidity and mortality rates in high-risk AS patients. Trial registrations Clinictrials.gov: NCT02760771 peerReviewed

Background Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. Methods The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. Results OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. Conclusions The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. General significance These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response.

Background Besides its well-established role in atherosclerosis, myeloperoxidase (MPO) has gained attention as a prognostic indicator in cardiovascular disease. Previous studies assessed MPO retrospectively and at a single time point. The current study aimed to evaluate the prognostic information of MPO prospectively and in consecutive measurements in patients presenting with chest pain. Methods MPO plasma levels were determined in 274 consecutive chest pain patients admitted to the emergency room. Results A total of 100 patients (36.5%) were finally diagnosed for acute myocardial infarction (AMI). Patients with AMI had significantly higher MPO levels than patients without AMI. Importantly, MPO levels were elevated in patients finally diagnosed for AMI even when troponin I (TNI) was negative (cutoff: 0.032ng/ml). Overall, MPO yielded a negative predictive value (NPV) of 85.5% (95% confidence interval (CI): 82.6–88.4) and a sensitivity for diagnosing AMI of 80.0% (95% CI: 75.8–84.2) compared to a NPV of 91.7% (95% CI: 89.5–94.0) and a sensitivity of 85.9% (95% CI: 82.3–89.5) for TNI. For patients with a symptom onset of ≤2h the sensitivity of MPO increased to 95.8% (95% CI: 93.7–97.9) whereas the sensitivity of TNI dropped to 50.0% (95% CI: 44.8–55.2). The negative predictive value of MPO for this group of patients was 95.6% (95% CI: 94.0–97.3) compared to 73.3% (95% CI: 69.8–76.9) for TNI. Discussion The current data underscore the role of MPO as diagnostic marker in acute coronary disease; however the additive information derived from MPO is restricted to patients presenting in the early phase of symptom onset.

Aims Observational studies have suggested a mechanistic link between the leucocyte-derived enzyme myeloperoxidase (MPO) and vasomotor function. Here, we tested whether MPO is systemically affecting vascular tone in humans. Methods and results A total of 12 135 patients were screened for leucocyte peroxidase activity. We identified 15 individuals with low MPO expression and activity (MPOlow), who were matched with 30 participants exhibiting normal MPO protein content and activity (control). Nicotine-dependent activation of leucocytes caused attenuation of endothelial nitric oxide (NO) bioavailability in the control group ( P < 0.01), but not in MPOlow individuals ( P = 0.12); here the MPO burden of leucocytes correlated with the degree of vasomotor dysfunction ( P = 0.008). To directly test the vasoactive properties of free circulating MPO, the enzyme was injected into the left atrium of anaesthetized, open-chest pigs. Myeloperoxidase plasma levels peaked within minutes and rapidly declined thereafter, reflecting vascular binding of MPO. Blood flow in the left anterior descending artery and the internal mammary artery (IMA) as well as myocardial perfusion decreased following MPO injection when compared with albumin-treated animals ( P < 0.001). Isolated IMA-rings from animals subjected to MPO revealed markedly diminished relaxation in response to acetylcholine ( P < 0.01) and nitroglycerine as opposed to controls ( P < 0.001). Conclusion Myeloperoxidase elicits profound effects on vascular tone of conductance and resistance vessels in vivo . These findings not only call for revisiting the biological functions of leucocytes as systemic and mobile effectors of vascular tone, but also identify MPO as a critical systemic regulator of vasomotion in humans and thus a potential therapeutic target.

Recruitment of polymorphonuclear neutrophils (PMNs) remains a paramount prerequisite in innate immune defense and a critical cofounder in inflammatory vascular disease. Neutrophil recruitment comprises a cascade of concerted events allowing for capture, adhesion and extravasation of the leukocyte. Whereas PMN rolling, binding, and diapedesis are well characterized, receptor-mediated processes, mechanisms attenuating the electrostatic repulsion between the negatively charged glycocalyx of leukocyte and endothelium remain poorly understood. We provide evidence for myeloperoxidase (MPO), an abundant PMN-derived heme protein, facilitating PMN recruitment by its positive surface charge. In vitro, MPO evoked highly directed PMN motility, which was solely dependent on electrostatic interactions with the leukocyte's surface. In vivo, PMN recruitment was shown to be MPO-dependent in a model of hepatic ischemia and reperfusion, upon intraportal delivery of MPO and in the cremaster muscle exposed to local inflammation or to intraarterial MPO application. Given MPO's affinity to both the endothelial and the leukocyte's surface, MPO evolves as a mediator of PMN recruitment because of its positive surface charge. This electrostatic MPO effect not only displays a so far unrecognized, catalysis-independent function of the enzyme, but also highlights a principal mechanism of PMN attraction driven by physical forces.

Objective-: Inflammatory processes and foam cell formation are key determinants in the initiation and progression of atherosclerosis. Electrophilic nitro-fatty acids, byproducts of nitric oxide-and nitrite-dependent redox reactions of unsaturated fatty acids, exhibit antiinflammatory signaling actions in inflammatory and vascular cell model systems. The in vivo action of nitro-fatty acids in chronic inflammatory processes such as atherosclerosis remains to be elucidated.Methods and results-: Herein, we demonstrate that subcutaneously administered 9-and 10-nitro-octadecenoic acid (nitro-oleic acid) potently reduced atherosclerotic lesion formation in apolipoprotein E-deficient mice. Nitro-fatty acids did not modulate serum lipoprotein profiles. Immunostaining and gene expression analyses revealed that nitro-oleic acid attenuated lesion formation by suppressing tissue oxidant generation, inhibiting adhesion molecule expression, and decreasing vessel wall infiltration of inflammatory cells. In addition, nitro-oleic acid reduced foam cell formation by attenuating oxidized low-density lipoprotein-induced phosphorylation of signal transducer and activator of transcription-1, a transcription factor linked to foam cell formation in atherosclerotic plaques. Atherosclerotic lesions of nitro-oleic acid-treated animals also showed an increased content of collagen and α-smooth muscle actin, suggesting conferral of higher plaque stability. Conclusion-: These results reveal the antiatherogenic actions of electrophilic nitro-fatty acids in a murine model of atherosclerosis. Fil: Rudolph, Tanja K.. University of Pittsburgh; Estados Unidos. University Heart Center Hamburg; Alemania Fil: Rudolph, Volker. University of Pittsburgh; Estados Unidos. University Heart Center Hamburg; Alemania Fil: Edreira, Martin Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pittsburgh; Estados Unidos Fil: Cole, Marsha P.. University of Pittsburgh; Estados Unidos Fil: Bonacci, Gustavo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pittsburgh; Estados Unidos Fil: Schopfer, Francisco J.. University of Pittsburgh; Estados Unidos Fil: Woodcock, Steven R.. University of Pittsburgh; Estados Unidos Fil: Franek, Andreas. University Heart Center Hamburg; Alemania Fil: Pekarova, Michaela. Biology Centre of the Academy of Sciences of the Czech Republic; República Checa Fil: Khoo, Nicholas K. H.. University of Pittsburgh; Estados Unidos Fil: Hasty, Alyssa H.. Vanderbilt University Medical Center; Estados Unidos Fil: Baldus, Stephan. University Heart Center Hamburg; Alemania Fil: Freeman, Bruce A.. University of Pittsburgh; Estados Unidos

Myeloperoxidase (MPO), a leukocyte-derived heme enzyme binds to the endothelium and depletes vascular nitric oxide (NO) bioavailability in animal models. Unfractionated heparins release vessel-bound MPO and increase endothelial NO bioavailability. Whether low molecular weight heparins also affect circulating MPO levels and NO dependent vasoreactivity however remains elusive.In a randomized, double-blind, placebo-controlled trial patients with stable coronary artery disease received either 1 mg/kg enoxaparin or an equivalent volume of sodium chloride (NaCl) subcutaneously. Enoxaparin led to a significant improvement of FMD (5.51+/-0.53% vs. 6.55+/-0.58%, p=0.01) accompanied by a significant increase in plasma MPO levels (2.51 [IR: 2.04-3.62] ng/ml vs. 3.70 [IR: 2.80-5.50] ng/ml; p0.001) whereas NaCl revealed neither a change in FMD (5.56+/-0.67% vs. 5.34+/-0.61%, p=ns) nor in plasma MPO levels (3.04 [IR: 2.22-4.67] ng/ml vs. 2.90 [IR: 1.95-4.32] ng/ml; p=ns). The extent of enoxaparin-induced MPO release and the improvement in endothelial function showed a good correlation (r=0.67, p0.001).This study confirms the concept that heparins improve endothelial function, an established read-out of vascular NO bioavailability, by mobilizing vessel bound MPO. These data not only support the notion of extracoagulant, anti-inflammatory properties of heparins but reinforce the concept of MPO-dependent NO oxidation as a central mechanism for regulation of vascular tone in inflammatory vascular disease. (Eudra-CT number: 2005-006113-40).

The peroxisome proliferator-activated receptor-γ (PPARγ) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPARγ include lipids and anti-hyperglycemic drugs such as thiazolidinediones (TZDs). Recently, TZDs have raised concern after being linked with increased risk of peripheral edema, weight gain, and adverse cardiovascular events. Most reported endogenous PPARγ ligands are intermediates of lipid metabolism and oxidation that bind PPARγ with very low affinity. In contrast, nitro derivatives of unsaturated fatty acids (NO2-FA) are endogenous products of nitric oxide (•NO) and nitrite (NO2−)-mediated redox reactions that activate PPARγ at nanomolar concentrations. We report that NO2-FA act as partial agonists of PPARγ and covalently bind PPARγ at Cys-285 via Michael addition. NO2-FA show selective PPARγ modulator characteristics by inducing coregulator protein interactions, PPARγ-dependent expression of key target genes, and lipid accumulation is distinctively different from responses induced by the TZD rosiglitazone. Administration of this class of signaling mediators to ob/ob mice revealed that NO2-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs.

Rationale : Fatty acid nitroalkenes are endogenously generated electrophilic byproducts of nitric oxide and nitrite-dependent oxidative inflammatory reactions. Existing evidence indicates nitroalkenes support posttranslational protein modifications and transcriptional activation that promote the resolution of inflammation. Objective : The aim of this study was to assess whether in vivo administration of a synthetic nitroalkene could elicit antiinflammatory actions in vivo using a murine model of vascular injury. Methods and Results : The in vivo administration (21 days) of nitro-oleic acid (OA-NO 2 ) inhibited neointimal hyperplasia after wire injury of the femoral artery in a murine model (OA-NO 2 treatment resulted in reduced intimal area and intima to media ratio versus vehicle- or oleic acid (OA)-treated animals, P 2 in both cultured aortic smooth muscle cells and in vivo. Inhibition of HO by Sn(IV)-protoporphyrin or HO-1 small interfering RNA reversed OA-NO 2 –induced inhibition of platelet-derived growth factor-stimulated rat aortic smooth muscle cell migration. The upregulation of HO-1 expression also accounted for the antistenotic actions of OA-NO 2 in vivo, because inhibition of neointimal hyperplasia following femoral artery injury was abolished in HO-1 −/− mice (OA-NO 2 –treated wild-type versus HO-1 −/− mice, P =0.016). Conclusions : In summary, electrophilic nitro-fatty acids induce salutary gene expression and cell functional responses that are manifested by a clinically significant outcome, inhibition of neointimal hyperplasia induced by arterial injury.

Myeloperoxidase (MPO), a heme protein abundantly expressed and secreted by polymorphonuclear neutrophils (PMN), has emerged as a critical mediator in coronary atherosclerosis. Retrospective analyses have suggested that free plasma levels of MPO predict adverse outcome in patients with low troponin T (TnT) levels who subsequently experience myocardial injury. The aim of this study was to evaluate the time course of MPO plasma levels in the early stages of acute myocardial infarction (AMI). Of 155 consecutive patients hospitalized for acute coronary syndromes, 38 presenting within 2 h of the onset of symptoms and subsequently diagnosed for AMI were included in the study. Serial blood samples taken between 1 and 24 h after the onset of chest pain were analyzed for MPO, TnT, creatine kinase MB, myoglobin, and high sensitive C-reactive protein. Fifty patients with angiographically proven but stable coronary artery disease (CAD) served as controls. In contrast to all other investigated markers, MPO was markedly elevated within 2 h of symptom onset in patients with AMI. Heparin, which is known to increase MPO plasma levels in patients with stable CAD, had no effect on MPO plasma levels in AMI patients. High levels of MPO plasma levels at the time of admission and the rapid peak of free plasma MPO levels after the onset of symptoms suggests that PMN activation is an early event in AMI and potentially precedes myocardial injury.

Myeloperoxidase (MPO), a heme protein abundantly expressed by neutrophils, monocytes and macrophages, has been suggested to critically accelerate the course of vascular inflammatory disease: Myeloperoxidase not only has been localized to atherosclerotic plaques, it also binds to and transcytopses endothelial cells to accumulate in the subendothelial space. Here, MPO remains catalytically active and is capable of oxidizing lipoproteins, matrix proteins and nitric oxide, thereby adversely affecting endothelial function. Multiple clinical trials suggest that circulating MPO levels identify patients with stable and unstable coronary artery disease as well as those with heart failure and peripheral vascular disease, who are at risk for adverse cardiovascular events. Given the powerful proinflammatory properties of this enzyme, MPO suggests to be both marker and mediator of cardiovascular pathology and emerges as both marker and potential target of treatment.

Objective: Lapatinib (Tykerb(®), GW572016), a potent inhibitor of the catalytic activities of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (ErbB2), inhibits population growth of selected EGFR and HER2 overexpressing cell lines. Previous studies with a small number of cell lines suggest a correlation between overexpression of EGFR and/or HER2 and sensitivity to growth inhibition by lapatinib; however, the precise determinants of lapatinib selectivity for tumour and/or other cells remain unclear. Materials and methods: To clarify the determinants of its selectivity in cultured cells, lapatinib‐induced cell population growth inhibition and relative EGFR and HER2 protein expression were quantified in 61 different human tumour cell lines from 12 tumour types, two oncogene transformed human cell lines and two normal human cell cultures. Using statistical tools to analyse the data, a model describing the relationship between lapatinib IC(50) (the response variable) and EGFR and HER2 expression and tissue type (explanatory variables) was derived. Conclusion: The results suggest that simultaneous consideration of EGFR and HER2 expression, as well as tissue type yields the best determinant of lapatinib selectivity in cultured cells.

BACKGROUND High-fat meals have negative effects on endothelial function, but vitamin-rich side orders may prevent these negative effects. OBJECTIVE The acute effects of conventional and alternative fast-food meals on vascular function and various cardiovascular biomarkers were investigated. DESIGN In a crossover study, flow-mediated endothelium-dependent dilatation (FMD) and cardiovascular disease risk markers were investigated in 24 healthy volunteers before and 2 and 4 h after 3 fast-food meals: a conventional beef burger with French fries, ketchup, and carbonated lemon-flavored soda (meal 1); a vegetarian burger with French fries, ketchup, and carbonated lemon-flavored soda (meal 2); and a vegetarian burger with salad, fruit, yogurt, and orange juice (meal 3). RESULTS FMD decreased after all 3 fast-food meals: the values were 9.7 +/- 2.5%, 7.5 +/- 3.5%, and 6.2 +/- 3.3% for meal 1; 9.2 +/- 3.4%, 7.1 +/- 3.4%, and 6.3 +/- 4.0% for meal 2; and 8.8 +/- 3.3%, 6.2 +/- 4.0%, and 6.8 +/- 4.3% for meal 3 at baseline, 2 h, and 4 h, respectively. There were significant intraindividual differences for time (P < 0.001) but not for type of meal (P = 0.677). A postprandial increase in baseline diameter of the brachial artery was significant for time (P < 0.001) but not for type of meal (P = 0.148). CONCLUSIONS Against common expectations, a conventional beef burger meal and presumably healthier alternatives with or without vitamin-rich side orders did not differ significantly in their acute effects on vascular reactivity. The frequently reported postprandial decline in FMD may be attributed in part to a postprandial increase in baseline arterial diameter.

Objectives We hypothesized that the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase (eNOS), might determine the endothelial effects of statins. Background Endothelial NO synthase is up-regulated by statins. However, statins failed to improve endothelial function in some studies. Asymmetric dimethylarginine inhibits eNOS by a mechanism that is reversible by L-arginine. Methods Ninety-eight clinically asymptomatic elderly subjects had their plasma ADMA levels screened. Those in the highest (high ADMA, n = 15) and lowest quartiles of the ADMA distribution (low ADMA, n = 13) were eligible to receive, in a randomized order, simvastatin (40 mg/day), L-arginine (3 g/day), or a combination of both, each for 3 weeks. Endothelium-dependent vasodilation (EDD) was assessed by brachial artery ultrasound. Results Simvastatin had no effect on EDD in subjects with high ADMA (6.2 ± 1.2% vs. 6.1 ± 0.9%), whereas simvastatin plus L-arginine significantly improved EDD (9.8 ± 1.5% vs. 5.3 ± 0.8%; p Conclusions Simvastatin does not enhance endothelial function in subjects with elevated ADMA, whereas it does so in patients with low ADMA. Combination of simvastatin with oral L-arginine improves endothelial function in subjects with high ADMA, but has no additional effect in subjects with low ADMA. As NO-mediated effects may play a major role in the therapeutic effects of statins, ADMA concentration is an important factor that influences the “pleiotropic” effects of simvastatin.

Activation of leukocytes, in particular polymorphonuclear neutrophils (PMN), is considered an early event in unstable coronary disease. Upon activation PMN liberate myeloperoxidase (MPO), an enzyme which binds to the vessel wall and depletes vascular NO bioavailability. Using coronary balloon angioplasty as a trigger to provoke coronary plaque injury, we assessed the time course of neutrophil activation, local and peripheral levels of myeloperoxidase, and systemic vascular NO bioavailability in patients with stable coronary artery disease. Twenty-four patients with stable CAD were enrolled prior to undergoing percutaneous interventions (PCI, n=14) and diagnostic coronary angiography (n=10), respectively. Following angioplasty arterial MPO plasma levels increased (231.5+/-67.6 to 273.8+/-80.4 pg/mg protein; P