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Permanent pacemaker implantation (PPI) is a widely recognized complication associated with TAVI (incidence up to 20%). Smaller registries have identified several variables associated with PPI. The objective was to validate patient- and transcatheter aortic valve implantation (TAVI)-related procedural variables associated with PPI. We performed a retrospective analysis of patients from six European centers undergoing TAVI with the Edwards SAPIEN 3 prosthesis. Baseline variables and pre-procedural ECG characteristics and CT-scans were taken into account. Data for 1745 patients were collected; 191 (10.9%) required PPI after TAVI. The baseline variables pulmonary hypertension (OR 1.64; 95% CI 1.01–2.59), QRS duration > 117 ms (OR 2.58; 95% CI 1.73–3.84), right bundle branch block (RBBB; OR 5.14; 95% CI 3.39–7.72), left anterior hemi block (OR 1.92; 95% CI 1.19–3.02) and first-degree atrioventricular block (AVB, OR 1.63; 95%CI 1.05–2.46) were significantly associated with PPI. RBBB (OR 8.11; 95% CI 3.19–21.86) and first-degree AVB (OR 2.39; 95% CI 1.18–4.66) remained significantly associated in a multivariate analysis. Procedure-related variables included access site (TF; OR 1.97; 95% CI 1.07–4.05), implanted valve size (29 mm; OR 1.88; 95% CI 1.35–2.59), mean TAVI valve implantation depth below the annulus > 30% (OR 3.75; 95% CI 2.01–6.98). Patients receiving PPI had longer ICU stays and later discharges. Acute kidney injury stage 2/3 was more common in patients with PPI until discharge (15.2 vs. 3.1%; p = 0.007), but was not statistically significant thereafter. Further differences in outcomes at 30 days did not reach significance. The data will aid pre- and post-procedural patient management and prevent adverse long-term outcomes. Clinical Trial: NCT03497611. [ABSTRACT FROM AUTHOR]

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 75 mg (n = 23) or prasugrel 10 mg (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 3 months. Results Baseline patient demographics were well matched between treatment groups. Prasugrel led to a significant improvement of FMD after 3 months (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). [ABSTRACT FROM AUTHOR]

Aim Atrial fibrosis, one of the most striking features in the pathology of atrial fibrillation (AF), is promoted by local and systemic inflammation. Electrophilic fatty acid nitroalkenes, endogenously generated by both metabolic and inflammatory reactions, are anti-inflammatory mediators that in synthetic form may be useful as drug candidates. Herein we investigate whether an exemplary nitro-fatty acid can limit atrial fibrosis and AF.Methods and results Wild-type C57BL6/J mice were treated for 2 weeks with angiotensin II (AngII) and vehicle or nitro-oleic acid (10-nitro-octadec-9-enoic acid, OA-NO2, 6 mg/kg body weight) via subcutaneous osmotic minipumps. OA-NO2 significantly inhibited atrial fibrosis and depressed vulnerability for AF during right atrial electrophysiological stimulation to levels observed for AngII-naive animals. Left atrial epicardial mapping studies demonstrated preservation of conduction homogeneity by OA-NO2. The protection from fibrotic remodelling was mediated by suppression of Smad2-dependent myofibroblast transdifferentiation and inhibition of Nox2-dependent atrial superoxide formation.Conclusion OA-NO2 potently inhibits atrial fibrosis and subsequent AF. Nitro-fatty acids and possibly other lipid electrophiles thus emerge as potential therapeutic agents for AF, either by increasing endogenous levels through dietary modulation or by administration as synthetic drugs. [ABSTRACT FROM AUTHOR]

Randomized trials suggest benefits for fractional flow reserve (FFR)-guided vs. angiography-guided treatment strategies in well-defined and selected patient cohorts with acute coronary syndromes (ACS). The long-term prognostic value of FFR measurement in unselected all-comer ACS patients, however, remains unknown. This subanalysis of the Fractional FLOw Reserve In cardiovascular DiseAses (FLORIDA) study sought to investigate the long-term effects of FFR in the management of lesions in patients with acute coronary syndrome (ACS). FLORIDA was an observational all-comer cohort study performed in Germany, that was population-based and unselected. Patients enrolled into the anonymized InGef Research Database presenting with ACS and undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Patients were stratified into either the FFR-guided or the angiography-guided treatment arm, based on the treatment received. A matched cohort study design was used. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiovascular events (MACE), a composite of death, non-fatal myocardial infarction (MI), and repeat revascularization. Follow-up time was 3 years. Rates of 3-year mortality were 10.2 and 14.0% in the FFR-guided and the angiography-guided treatment arms (p = 0.04), corresponding to a 27% relative risk reduction for FFR in ACS patients. Rates of MACE were similar in both arms (47.7 vs. 51.5%, p = 0.14), including similar rates of non-fatal MI (27.7 vs. 25.4%, p = 0.47) and revascularization (9.9 vs. 12.1%, p = 0.17). In this large, all-comer observational study of ACS patients, FFR-guided revascularization was associated with a lower mortality at 3 years. This finding encourages the routine use of FFR to guide lesion revascularization in patients presenting with ACS. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Myeloperoxidase (MPO) has emerged as an important pathophysiological determinant of inflammatory vascular artery disease. It is appreciated that vessel immobilized, rather than circulating, MPO is critical for the progression of atherosclerotic lesions. The objective of this study was to investigate whether vessel-immobilized MPO is associated with the extent of coronary plaque burden. Methods: MPO plasma levels were determined by ELISA before and after heparin-release of vessel-bound MPO, to study the relation between vascular MPO deposition and densitometrically assessed coronary plaque burden in 77 patients with stable coronary artery disease. Results: Patients with a low increase in MPO plasma levels upon heparinization had a significantly smaller total plaque area and volume (12.1[IR:6.2–19.4]mm2 vs. 19.8[IR:11.3–31.5]mm2, p < 0.01; 27.8[IR:12.3–44.8]mm3 vs. 55.2[IR:24.2–87.5]mm3, p < 0.05). Multivariable linear regression revealed that ΔMPO was independently associated with plaque area, and that ΔMPO increased with the number of affected vessels. Selective sampling confirmed the predominant role of coronary MPO deposition. Conclusion: Our data demonstrate that heparin-induced mobilization of vessel-bound MPO is closely linked to coronary plaque burden and thus further corroborate the evidence for the intimate involvement of this enzyme in vascular pathophysiology, as well as the importance of inflammation in atherosclerosis. [Copyright &y& Elsevier]

Abstract: Redox-sensitive posttranslational modification emerged as important signaling mechanisms. Besides other posttranslational modifications nitroalkylation by nitrated fatty acids mediate favorable anti-inflammatory effects. This review gives an overview of the generation and the reactivity of nitrated fatty acids. Additionally, it provides insights into the so far described pathways regulated by nitrated fatty acids. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation. [Copyright &y& Elsevier]

Abstract: Background: 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. Methods and results: 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; p <0.001) 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, p <0.001). Discussion: 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). [Copyright &y& Elsevier]

Aims: Nitrated fatty acids (NO2-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO2) and nitro-linoleic acid (LNO2) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO2 on I/R injury was evaluated. [ABSTRACT FROM PUBLISHER]

Abstract: Circulating levels of myeloperoxidase (MPO), a heme enzyme released upon activation of polymorphonuclear neutrophils, predict adverse outcome in patients with impaired left ventricular (LV) function. The MPO −463 G/A promoter polymorphism (rs 2333227) regulates MPO transcription, with the G allele being linked to increased protein expression. The aim of this study was to assess the prognostic information derived from the −463 G/A MPO polymorphism on outcomes of patients with impaired LV function. The −463 G/A promoter MPO genotype as well as MPO plasma levels were determined in 116 patients with impaired LV function. Patients were prospectively followed for a median of 1050 days. The GG genotype was associated with a decrease in overall survival (χ2 5.80; p =0.016). This association remained after multivariate adjustment for plasma levels of NT-proBNP, creatinine, hsCRP, and MPO; leukocyte count; and LV function (hazard ratio 3.16 (95% CI 1.17–8.53), p =0.024) and for classical cardiovascular risk factors (hazard ratio 2.88 (95% CI 1.13–7.33), p =0.026). Interestingly, we observed no association of the MPO polymorphism with total MPO protein concentration or MPO activity in plasma. The −463 G/A MPO polymorphism is linked to adverse clinical outcome of patients with impaired LV function. Further studies are needed to elucidate the value of this polymorphism for risk stratification. [Copyright &y& Elsevier]

Abstract: Activation of leukocytes and in particular polymorphonuclear neutrophils (PMN) has emerged as a critical confounder in the pathophysiology of cardiovascular disease: Myeloperoxidase (MPO), one of the principal proteins hosted in and secreted by activated PMN, has been mechanistically linked to endothelial and left ventricular (LV) dysfunction in rodent models of sepsis and ischemic cardiomyopathy. Whether PMN activation is also overt in patients with LV dysfunction of ischemic and nonischemic origin, however, remains elusive. Prospectively, 447 consecutive, stable outpatients were included in this single-center study. In 113 patients with impaired left ventricular function (ejection fraction <50%; nonischemic cardiomyopathy, n =52; ischemic cardiomyopathy, n =61), MPO plasma levels were elevated (24.5 [IR:15.8–54.0] vs 15.5 [IR:8.9–39.2] ng/ml in controls, P <0.01) as was elastase (111.5 [IR:63.8–233.3] vs 70.5 [IR:45.0–129.0] ng/ml, P <0.01) and NT-proBNP plasma levels (747.4 [IR:216.3–1958.3] vs 264.1 [IR:82.5–671.8] ng/L, P <0.01). Elevation of circulating MPO was irrespective of the etiology of heart failure and independent of traditional confounding variables. No association was observed between MPO −463 promoter polymorphism genotype and LV dysfunction. MPO plasma levels correlated with ejection fraction (P <0.01) and left ventricular end-diastolic diameter (P <0.01), respectively. Myeloperoxidase mRNA expression levels obtained from circulating leukocytes were significantly increased in patients with LV dysfunction. Systemic leukocyte activation with increased transcription of MPO mRNA and augmented release of MPO appears to represent a so far underrecognized characteristic in LV dysfunction, which was revealed to be irrespective of the underlying pathology. Given its potent proinflammatory properties, MPO may represent an important mechanistic link to LV dysfunction and deserves to be evaluated as both marker and therapeutic target in this disease. [Copyright &y& Elsevier]

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 < 0.01). In subjects with low ADMA, simvastatin improved endothelial function when given alone (9.5 ± 3.2% vs. 6.1 ± 3.8%; p < 0.001) or in combination with L-arginine (9.0 ± 3.1% vs. 6.3 ± 3.3%; p = 0.001). L-arginine alone improved endothelial function in both groups. Endothelium-independent vasodilation was not affected. 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. [Copyright &y& Elsevier]

• We report the step by step approach for JenaValve TAVR and early use of non-dedicated THV devices for severe pure native AR • This is the first report on videodensitometry quantification of AR before and after JenaValve TAVR for severe pure native AR. • Videodensitometry shows decrease of AR regurgitation fraction from 55% to 0% after JenaValve TAVR. [ABSTRACT FROM AUTHOR]

Aims: While invasively determined congestion holds mechanistic and prognostic significance in acute heart failure (HF), its role in patients with tricuspid regurgitation (TR)‐related right‐ heart failure (HF) undergoing transcatheter tricuspid valve intervention (TTVI) is less well established. A comprehensive understanding of congestion patterns might aid in procedural planning, risk stratification, and the identification of patients who may benefit from adjunctive therapies before undergoing TTVI. The aim of this study was to investigate the role of congestion patterns in patients with severe TR and its implications for TTVI. Methods and results: Within a multicentre, international TTVI registry, 813 patients underwent right heart catheterization (RHC) prior to TTVI and were followed up to 24 months. The median age was 80 (interquartile range 76–83) years and 54% were women. Both mean right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) were associated with 2‐year mortality on Cox regression analyses with Youden index‐derived cut‐offs of 17 mmHg and 19 mmHg, respectively (p < 0.01 for all). However, RAP emerged as an independent predictor of outcomes following multivariable adjustments. Pre‐interventionally, 42% of patients were classified as euvolaemic (RAP <17 mmHg, PCWP <19 mmHg), 23% as having left‐sided congestion (RAP <17 mmHg, PCWP ≥19 mmHg), 8% as right‐sided congestion (RAP ≥17 mmHg, PCWP <19 mmHg), and 27% as bilateral congestion (RAP ≥17 mmHg, PCWP ≥19 mmHg). Patients with right‐sided or bilateral congestion had the lowest procedural success rates and shortest survival times. Congestion patterns allowed for discerning specific patient's physiology and specifying prognostic implications of right ventricular to pulmonary artery coupling surrogates. Conclusion: In this large cohort of invasively characterized patients undergoing TTVI, congestion patterns involving right‐sided congestion were associated with low procedural success and higher mortality rates after TTVI. Whether pre‐interventional reduction of right‐sided congestion can improve outcomes after TTVI should be established in dedicated studies. [ABSTRACT FROM AUTHOR]

Baseline right ventricular (RV) function derived from 3-dimensional analyses has been demonstrated to be predictive in patients undergoing transcatheter tricuspid valve repair (TTVR). The complex nature of these cumbersome analyses makes patient selection based on established imaging methods challenging. Artificial intelligence (AI)-driven computed tomography (CT) segmentation of the RV might serve as a fast and predictive tool for evaluating patients prior to TTVR. Patients suffering from severe tricuspid regurgitation underwent full cycle cardiac CT. AI-driven analyses were compared to conventional CT analyses. Outcome measures were correlated with survival free of rehospitalization for heart-failure or death after TTVR as the primary endpoint. Automated AI-based image CT-analysis from 100 patients (mean age 77 ± 8 years, 63% female) showed excellent correlation for chamber quantification compared to conventional, core-lab evaluated CT analysis (R 0.963–0.966; p < 0.001). At 1 year (mean follow-up 229 ± 134 days) the primary endpoint occurred significantly more frequently in patients with reduced RV ejection fraction (EF) <50% (36.6% vs. 13.7%; HR 2.864, CI 1.212–6.763; p = 0.016). Furthermore, patients with dysfunctional RVs defined as end-diastolic RV volume > 210 ml and RV EF <50% demonstrated worse outcome than patients with functional RVs (43.7% vs. 12.2%; HR 3.753, CI 1.621–8.693; p = 0.002). Derived RVEF and dysfunctional RV were predictors for death and hospitalization after TTVR. AI-facilitated CT analysis serves as an inter- and intra-observer independent and time-effective tool which may thus aid in optimizing patient selection prior to TTVR in clinical routine and in trials. • AI-based CT analysis is inter- and intra-observer-independent and can be a time-effective tool for daily clinical practice. • AI analyses demonstrated excellent agreement and correlation with manual CT data segmentation. • Reduced RVEF and dysfunctional RV were predictors for death and hospitalization after TTVR. [ABSTRACT FROM AUTHOR]

Aims: Interventional transcatheter edge-to-edge mitral valve repair (TMVR) is an established treatment option for patients with severe mitral regurgitation (MR) and high operative risk. Cognitive impairment is one of the most common conditions among often extensive comorbidities in these patients. The specific patterns of cognitive decline and particularly the effect of TMVR are not well described. Thus, this study aimed to investigate into the impact of TMVR on cognitive impairment, exercise capacity, and quality of life. Methods: Cognitive function (executive, naming, memory, attention, language, abstraction, and orientation) was assessed with the standardized Montreal Cognitive Assessment test (MoCA; range between 0 and 30 points) before and 3 months after TMVR in 72 consecutive patients alongside echocardiographic examination and assessment of exercise capacity (six-minute walk test) as well as quality-of-life questionnaires (Minnesota living with heart failure questionnaire, MLHF-Q). Results: Patients' median age was 81 [76.0; 84.5] years, 39.7% were female with a median EuroScore II of 4.4% [2.9; 7.7]. The assessment of cognitive function showed a significant improvement of the cumulative MoCA-Test result (from 22.0 [19.0; 24.5] to 24 [22.0; 26.0]; p < 0.001) with significant changes in the subcategories executive (p < 0.001), attention (p < 0.001), abstraction (p < 0.001), and memory (p < 0.001). In addition, quality of life (from 47.5 [25.0; 69.3] to 24.0 [12.0; 40.0]; p < 0.001) and exercise capacity (from 220.0 m [160.0; 320.0] to 280.0 m [200.0; 380.0]; p = 0.003) increased significantly 3 months after the TMVR procedure. Conclusions: TMVR leads to a significant improvement of cognitive function, exercise capacity, and quality of life in patients with chronic heart failure in 3 months follow up and again highlights the benefit of the evermore established TMVR procedure for patients with high operative risk. [ABSTRACT FROM AUTHOR]

Management of patients with severe aortic stenosis (AS) may differ according to the patient sex. This study aimed to describe patterns of aortic valve replacement (AVR) for severe AS across Europe, including stratification by sex. Procedure volume data for surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI) for six years (2015–2020) were extracted from national databases for Austria, Czech Republic, Denmark, England, Finland, France, Germany, Norway, Poland, Spain, Sweden, and Switzerland and stratified by sex. Patients per million population (PPM) undergoing AVR per year were calculated using population estimates from Eurostat. Between 2015 and 2019, AVR procedures grew at an average annual rate of 3.9%. In 2020, the average total PPM undergoing AVR across all countries was 339, with 51% of procedures being TAVI and 49% SAVR. AVR PPM varied widely between countries, with the highest and lowest in Germany and Poland, respectively. The average total PPM was higher for men than women (423 vs. 258), but a higher proportion of women (62%) than men (44%) received TAVI. The proportion of TAVI among total AVR procedures increased with age, with an overall average of 96% of men and 98% of women aged ≥85 years receiving TAVI; however, adoption of TAVI varied by country. The analysis of temporal trends in the adoption of TAVI vs. SAVR across Europe showed significant variations. Despite the higher use of TAVI vs. SAVR in women, overall rates of AV intervention in women were lower compared to men. [Display omitted] • The incidence of aortic stenosis (AS) is increasing in Europe, with men and women appearing to be managed differently. • Across Europe, the overall rates of aortic valve interventions were lower in women than men with TAVI being common in women. • The findings of this study should prompt clinicians to develop sex-based strategies to treat men and women with AS equally. [ABSTRACT FROM AUTHOR]

Aims: Transcatheter mitral valve implantation (TMVI) is a new treatment option for patients with symptomatic mitral valve (MV) disease. Real‐world data have not yet been reported. This study aimed to assess procedural and 30‐day outcomes of TMVI in a real‐world patient cohort. Method and results: All consecutive patients undergoing implantation of a transapically delivered self‐expanding valve at 26 European centres from January 2020 to April 2021 were included in this retrospective observational registry. Among 108 surgical high‐risk patients included (43% female, mean age 75 ± 7 years, mean STS‐PROM 7.2 ± 5.3%), 25% was treated for an off‐label indication (e.g. previous MV intervention or surgery, mitral stenosis, mitral annular calcification). Patients were highly symptomatic (New York Heart Association [NYHA] functional class III/IV in 86%) and mitral regurgitation (MR) was graded 3+/4+ in 95% (38% primary, 37% secondary, and 25% mixed aetiology). Technical success rate was 96%, and MR reduction to ≤1+ was achieved in all patients with successful implantation. There were two procedural deaths and 30‐day all‐cause mortality was 12%. At early clinical follow‐up, MR reduction was sustained and there were significant reductions of pulmonary pressure (systolic pulmonary artery pressure 52 vs. 42 mmHg, p < 0.001), and tricuspid regurgitation severity (p = 0.013). Heart failure symptoms improved significantly (73% in NYHA class I/II, p < 0.001). Procedural success rate according to MVARC criteria was 80% and was not different in patients treated for an off‐label indication (74% vs. 81% for off‐ vs. on‐label, p = 0.41). Conclusion: In a real‐world patient population, TMVI has a high technical and procedural success rate with efficient and durable MR reduction and symptomatic improvement. [ABSTRACT FROM AUTHOR]

Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Limited data exists about the effectiveness of the coronary sinus reducer (CSR) device in patients with angina pectoris and atrial fibrillation (AF). This case demonstrates beneficial effects of AF ablation in a patient with CSR. We report four major findings: Rhythm control has a relevant effect on angina pectoris symptoms in patients with coronary artery disease and AF. In these patients, AF ablation should be considered at an early stage. Patients with persistent angina pectoris and CSR may require sinus rhythm for an optimal effect of the device. Selected coronary sinus (CS) interventions can still be performed through the mesh of the CSR device. [ABSTRACT FROM AUTHOR]

ACURATE neo2 (Neo2) implantation is performed after systematic Balloon Aortic Valvuloplasty (BAV) in most patients. No reports exist about the feasibility and safety of direct Neo2 transcatheter aortic valve implantation (TAVI) in comparison to the standard practice. We aimed to identify the patients' baseline anatomical characteristics, procedural, and early post-procedural outcomes in patients treated using Neo2 with and without BAV. This is a retrospective multicentre analysis of 499 patients with severe aortic stenosis who underwent TAVI using Neo2. The comparison was done according to the performance or omission of BAV. Echocardiography and computed tomography were analysed by an independent Core Lab. Propensity score matching (PSM) was performed based on the annular diameter and AV calcium volume, which identified 84 matched pairs. Among the cohort included, 391 (78%) patients received BAV (BAV-yes) and 108 (22%) were not attempted (BAV-no or Direct TAVI). Patients in BAV-no cohort had smaller annular diameter (22.6 vs 23.4 mm; p < 0.001) and lower calcium volume (163 vs 581 mm3; p < 0.001) compared to BAV-yes cohort. In the matched cohort, VARC-3 device technical success was similar (95%) and all other outcome measures were statistically comparable between cohorts. Direct TAVI using ACURATEneo2 without pre-TAVI balloon aortic valvuloplasty in patients with mild or less valve calcifications might be feasible and associated with comparable early outcomes compared to patients with similar anatomical features undergoing systematic balloon valvuloplasty. • ACURATEneo2 implantation is performed after systematic balloon aortic valvuloplasty with a rate higher than the contemporary devices • Implantation of ACURATEneo2 without balloon aortic valvuloplasty is not investigated yet. • Direct implantation of ACURATEneo2 in patients with aortic stenosis and mild valve calcifications showed a high rate of technical success • Procedural, in-hospital clinical outcomes and hemodynamic outcomes were comparable between the two study cohorts [ABSTRACT FROM AUTHOR]

Many diseases accompanied by chronic inflammation are connected with dysregulated activation of macrophage subpopulations. Recently, we reported that nitro-fatty acids (NO 2 -FAs), products of metabolic and inflammatory reactions of nitric oxide and nitrite, modulate macrophage and other immune cell functions. Bone marrow cell suspensions were isolated from mice and supplemented with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with NO 2 -OA for different times. RAW 264.7 macrophages were used for short-term (1–5 min) experiments. We discovered that NO 2 -OA reduces cell numbers, cell colony formation, and proliferation of macrophages differentiated with colony-stimulating factors (CSFs), all in the absence of toxicity. In a case of GM-CSF-induced bone marrow-derived macrophages (BMMs), NO 2 -OA acts via downregulation of signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) activation. In the case of M-CSF-induced BMMs, NO 2 -OA decreases activation of M-CSFR and activation of related PI3K and ERK. Additionally, NO 2 -OA also attenuates activation of BMMs. In aggregate, we demonstrate that NO 2 -OA regulates the process of macrophage differentiation and that NO 2 -FAs represent a promising therapeutic tool in the treatment of inflammatory pathologies linked with increased accumulation of macrophages in inflamed tissues. [ABSTRACT FROM AUTHOR]

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-NO 2 ) 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-NO 2 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-NO 2 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-NO 2 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-NO 2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO 2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. General significance These findings propose the OA-NO 2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response. [ABSTRACT FROM AUTHOR]

Inflammation is an immune response triggered by microbial invasion and/or tissue injury. While acute inflammation is directed toward invading pathogens and injured cells, thus enabling tissue regeneration, chronic inflammation can lead to severe pathologies and tissue dysfunction. These processes are linked with macrophage polarization into specific inflammatory “M1-like” or regulatory “M2-like” subsets. Nitro-fatty acids (NO 2 -FAs), produced endogenously as byproducts of metabolism and oxidative inflammatory conditions, may be useful for treating diseases associated with dysregulated immune homeostasis. The goal of this study was to characterize the role of nitro-oleic acid (OA-NO 2 ) in regulating the functional specialization of macrophages induced by bacterial lipopolysaccharide or interleukin-4, and to reveal specific signaling mechanisms which can account for OA-NO 2 -dependent modulation of inflammation and fibrotic responses. Our results show that OA-NO 2 inhibits lipopolysaccharide-stimulated production of both pro-inflammatory and immunoregulatory cytokines (including transforming growth factor-β) and inhibits nitric oxide and superoxide anion production. OA-NO 2 also decreases interleukin-4-induced macrophage responses by inhibiting arginase-I expression and transforming growth factor-β production. These effects are mediated via downregulation of signal transducers and activators of transcription, mitogen-activated protein kinase and nuclear factor-кB signaling responses. Finally, OA-NO 2 inhibits fibrotic processes in an in vivo model of angiotensin II-induced myocardial fibrosis by attenuating expression of α-smooth muscle actin, systemic transforming growth factor-β levels and infiltration of both “M1-” and “M2-like” macrophage subsets into afflicted tissue. Overall, the electrophilic fatty acid derivative OA-NO 2 modulates a broad range of “M1-” and “M2-like” macrophage functions and represents a potential therapeutic approach to target diseases associated with dysregulated macrophage subsets. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Recent observational clinical and ex-vivo studies suggest that inflammation and in particular leukocyte activation predisposes to atrial fibrillation (AF). However, whether local binding and extravasation of leukocytes into atrial myocardium is an essential prerequisite for the initiation and propagation of AF remains elusive. Here we investigated the role of atrial CD11b/CD18 mediated infiltration of polymorphonuclear neutrophils (PMN) for the susceptibility to AF. Methods and Results: C57bl/6J wildtype (WT) and CD11b/CD18 knock-out (CD11b−/−) mice were treated for 14 days with subcutaneous infusion of angiotensin II (Ang II), a known stimulus for PMN activation. Atria of Ang II-treated WT mice were characterized by increased PMN infiltration assessed in immunohistochemically stained sections. In contrast, atrial sections of CD11b−/− mice lacked a significant increase in PMN infiltration upon Ang II infusion. PMN infiltration was accompanied by profoundly enhanced atrial fibrosis in Ang II treated WT as compared to CD11b−/− mice. Upon in-vivo electrophysiological investigation, Ang II treatment significantly elevated the susceptibility for AF in WT mice if compared to vehicle treated animals given an increased number and increased duration of AF episodes. In contrast, animals deficient of CD11b/CD18 were entirely protected from AF induction. Likewise, epicardial activation mapping revealed decreased electrical conduction velocity in atria of Ang II treated WT mice, which was preserved in CD11b−/− mice. In addition, atrial PMN infiltration was enhanced in atrial appendage sections of patients with persistent AF as compared to patients without AF. Conclusions: The current data critically link CD11b-integrin mediated atrial PMN infiltration to the formation of fibrosis, which promotes the initiation and propagation of AF. These findings not only reveal a mechanistic role of leukocytes in AF but also point towards a potential novel avenue of treatment in AF. [ABSTRACT FROM AUTHOR]

Abstract: Two major effector systems are frequently implicated in the immune and endothelial cell alternations associated with inflammation. They include the enhanced production of reactive oxygen species and diminished bioavailability of nitric oxide (NO). Importantly, these processes can be regulated by endogenously produced methylarginines, inhibitors for NO derived from macrophages and endothelial cells. Therefore, the aim of this study was to show the potential pharmacological intervention of methylarginines (NG-methyl-L-arginine, L-NMMA; NG, NG′-dimethyl-L-arginine—symmetric dimethylarginine, SDMA; and NG, NG-dimethyl-L-arginine—asymmetric dimethylarginine, ADMA) in activation of murine peritoneal (RAW 264.7) and alveolar (MHS) macrophages with lipopolysaccharide from Gram-negative bacteria (LPS). The data presented in this study clearly declare that L-NMMA (1–50μM) and ADMA (10–50μM) significantly inhibited the LPS-induced NO production from macrophages in a concentration-dependent manner. It was demonstrated, for the first time, that the ADMA- and L-NMMA-induced down regulation of NO production was accompanied by reduced expression of mRNA and protein for inducible NO synthase as well as decreased activation of nuclear factor-κB. Importantly, we found a negative correlation between the ADMA-dependent reduction of NO production and ADMA-increased superoxide formation, which indicates that ADMA can negatively affect the balance in LPS-induced macrophage-derived production of reactive mediators. The only effect of SDMA was observed for LPS-triggered superoxide production, which was significantly decreased in its highest concentration (50μM). In summary, L-NMMA and ADMA can mediate their effects on macrophage activation via regulation of intracellular signaling pathways, which can affect critical functions in activated macrophages. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Nitro-fatty acids (NO2-FA) are electrophilic signaling mediators formed by reactions of nitric oxide and nitrite. NO2-FA exert anti-inflammatory signaling actions through post-translational protein modifications. We report that nitro-oleic acid (OA-NO2) stimulates proMMP-7 and proMMP-9 proteolytic activity via adduction of the conserved cysteine switch domain thiolate. Biotin-labeled OA-NO2 showed this adduction occurs preferentially with latent forms of MMP, confirming a role for thiol alkylation by OA-NO2 in MMP activation. In addition to regulating pro-MMP activation, MMP expression was modulated by OA-NO2 via activation of peroxisome proliferator-activated receptor-γ. MMP-9 transcription was decreased in phorbol 12-myristate 13-acetate-stimulated THP-1 macrophages to an extent similar to that induced by the peroxisome proliferator-activated receptor-γ agonist Rosiglitazone. This was affirmed using a murine model of atherosclerosis, ApoE-/- mice, where in vivo OA-NO2 administration suppressed MMP expression in atherosclerotic lesions. These findings reveal that electrophilic fatty acid derivatives can serve as effectors during inflammation, first by activating pro-MMP proteolytic activity via alkylation of the cysteine switch domain, and then by transcriptionally inhibiting MMP expression, thereby limiting the further progression of inflammatory processes. [ABSTRACT FROM AUTHOR]

Electrophilic fatty acids are generated during inflammation by non-enzymatic reactions and can modulate inflammatory responses. We used a new mass spectrometry–based electrophile capture strategy to reveal the formation of electrophilic oxo-derivatives (EFOX) from the omega-3 fatty acids docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). These EFOX were generated by a cyclooxygenase-2 (COX-2)-catalyzed mechanism in activated macrophages. Modulation of COX-2 activity by aspirin increased the rate of EFOX production and their intracellular levels. Owing to their electrophilic nature, EFOX adducted to cysteine and histidine residues of proteins and activated Nrf2-dependent anti-oxidant gene expression. We confirmed the anti-inflammatory nature of DHA- and DPA-derived EFOX by showing that they can act as peroxisome proliferator-activated receptor-γ (PPARγ) agonists and inhibit pro-inflammatory cytokine and nitric oxide production, all within biological concentration ranges. These data support the idea that EFOX are signaling mediators that transduce the beneficial clinical effects of omega-3 fatty acids, COX-2 and aspirin. [ABSTRACT FROM AUTHOR]

Nitrated derivatives of fatty acids (NO[sub2]-FA) are pluripotent cell-signaling mediators that display anti-inflammatory properties. Current understanding of NO[sub2]-FA signal transduction lacks insight into how or if NO[sub2]-FA are modified or metabolized upon formation or administration in vivo. Here the disposition and metabolism of nitro-9-cis-octadecenoic (18:1-NO[sub2]) acid was investigated in plasma and liver after intravenous injection in mice. High performance liquid chromatography-tandem mass spectrometry analysis showed that no 18:1-NO[sub2] or metabolites were detected under basal conditions, whereas administered 18:1-NO[sub2] is rapidly adducted to plasma thiol-containing proteins and glutathione. NO[sub2]-FA are also metabolized via β-oxidation, with high performance liquid chromatographytandem mass spectrometry analysis of liver lipid extracts of treated mice revealing nitro-7-cis-hexadecenoic acid, nitro-5-cis-tetradecenoic acid, and nitro-3-cis-dodecenoic acid and corresponding coenzyme A derivatives of 18:1-NO[sub2] as metabolites. Additionally, a significant proportion of 18:1-NO[sub2] and its metabolites are converted to nitroalkane derivatives by saturation of the double bond, and to a lesser extent are desaturated to diene derivatives. There was no evidence of the formation of nitrohydroxyl or conjugated ketone derivatives in organs of interest, metabolites expected upon 18:1-NO[sub2] hydration or nitric oxide (∙NO) release. Plasma samples from treated mice had significant extents of protein-adducted 18:1-NO[sub2] detected by exchange to added β-mercaptoethanol. This, coupled with the observation of 18:1-NO[sub2] release from glutathione-18:1-NO[sub2] adducts, supports that reversible and exchangeable NO[sub2]-FAthiol adducts occur under biological conditions. After administration of [3H]18:1-NO[sub2], 64% of net radiolabel was recovered 90 min later in plasma (0.2%), liver (18%), kidney (2%), adipose tissue (2%), muscle (31%), urine (6%), and other tissue compartments, and may include metabolites not yet identified. In aggregate, these findings show that electrophilic FA nitroalkene derivatives (a) acquire an extended half-life by undergoing reversible and exchangeable electrophilic reactions with nucleophilic targets and (b) are metabolized predominantly via saturation of the double bond and β-oxidation reactions that terminate at the site of acyl-chain nitration. [ABSTRACT FROM AUTHOR]

Background: Right ventricular (RV) dysfunction has been linked to worse outcomes in patients undergoing TAVI. Assessment of RV function is challenging due to its complex morphology. RV longitudinal strain (LS) assessed by speckle-tracking echocardiography (STE) is a novel measure that may overcome most of the limitations of conventional echocardiographic parameters of RV function. The aim of current study was to assess the prognostic value of RV LS in patients undergoing TAVI and to assess echocardiographic predictors of long-term mortality. Methods and results: A retrospective analysis of all consecutive patients who underwent TAVI at our hospital between 1 January 2015 and 1 June 2016. Indication for TAVI was approved by a local heart-team. Echocardiographic data at baseline and after TAVI were re-analyzed and RV LS was measured in all patients with adequate image quality. A total of 229 patients were included in our study (mean age 83.8 ± 5 years, 62% women, mean EuroSCORE II 5.7 ± 5%). All-cause mortality occurred in 17.3% over a mean follow-up of 929 ± 373 days. In multivariate analysis, only baseline average RV free-wall LS (HR 1.05, 95% CI (1.01 to 1.10), p = 0.049) and more than mild tricuspid valve regurgitation (TR) after TAVI (HR 4.39, 95% CI (2.22 to 8.70), p < 0.001) independently increased the risk of all-cause mortality at long- term follow-up (2.5 years), while conventional echocardiographic parameters of RV function did not predict mortality. Conclusion: Pre-procedural RV LS and post-procedural tricuspid regurgitation significantly predicted long-term all-cause mortality in patients undergoing TAVI while conventional echocardiographic parameters of RV function failed in predicting long-term outcome. RV longitudinal strain by STE should be considered in the routine echocardiographic assessments of patients with severe AS. [ABSTRACT FROM AUTHOR]

Abstract: 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<0.01) whereas MPO levels in the coronary sinus decreased (240.8±74.4 vs 205.4±60.1 pg/mg protein; P<0.01) in the absence of elevated serum markers for myocardial necrosis. Following PCI, patients revealed impaired vascular NO bioavailability as reflected by reduced brachial flow-mediated dilation (FMD; 6.25±3.03 to 4.90±2.70%; P<0.01), whereas FMD increased in the angiography group. Coronary plaque injury provokes rapid activation of PMN in the absence of myocardial necrosis; the coronary circulation emerges as a primary site for deposition of MPO following injury of the coronary vessel wall. Activation of PMN with release of MPO is not only restricted to the target site, but can be assessed systemically and may represent a critical mechanistic link for impaired systemic vascular NO bioavailability in patients suffering unstable coronary disease. [Copyright &y& Elsevier]

Treatment of decompensated heart failure often includes administration of levosimendan. Myeloperoxidase (MPO) is released during polymorphonuclear neutrophil (PMN) degranulation, and mediates dysregulation of vascular tone in heart failure. We evaluated the effects of levosimendan-treatment on MPO in patients with acute decompensation of chronic heart failure over a one week course. Plasma MPO levels were significantly decreased after levosimendan treatment (from 252.1 ± 31.1 pmol/l at baseline to 215.02 ± 27.96 pmol/l at 6 h, p < 0.05). Ex vivo incubation of whole blood with levosimendan decreased MPO release after PMN-stimulation (8.2 ± 1.4-fold increase at baseline vs. 6.0 ± 1.1-fold increase with levosimendan). MPO levels also significantly correlated with diastolic blood pressure over the time course. In a multivariate linear model, the main contributor to systolic, diastolic and mean blood pressure was level of PMN elastase. MPO contributed only in heparin-treated patients, suggesting a more significant role for endothelial-bound MPO than for circulating MPO or elastase with respect to blood pressure regulation. We here provide the first evidence that levosimendan treatment inhibits MPO release by PMNs in decompensated heart failure patients. This mechanism may regulate endothelial function and vascular tone in heart failure patients. [ABSTRACT FROM AUTHOR]