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INTRODUCTION Platelet toll-like receptor 4 (TLR4) is overexpressed in patients with myocardial infarction (MI) but it remains to elucidate if it is activated and the potential trigger. METHODS Serum levels of lipopolysaccharides (LPS) and platelet aggregation (PA) by collagen alone or in combination with a TLR4 inhibitor (TLR4i) were studied ex vivo in platelets from 40 MI patients and 40 controls matched for age, sex and atherosclerotic risk factors; platelet TIR domain-containing adaptor protein (TIRAP) and TIRAP-MyD88 interaction were also investigated by western blot and co-immunoprecipitation, respectively. In vitro experiments were conducted to see if LPS triggers platelet TIRAP phosphorylation. RESULTS Serum LPS was significantly higher in patients compared to controls (29.5±7.1 vs 16.2±3.8 pg/mL; p

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors Eli Lilly and Company; Pfizer; Bayer; GlaxoSmithKline; Merck; Actelion Pharmaceuticals; Meso Scale Diagnostics; United Therapeutics Corporation; Novartis Pharma; Merck Sharp and Dohme; GlaxoSmithKline Australia; Deutsche Forschungsgemeinschaft; Grupo Ferrer Internacional, S.A The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors acknowledge the database administration by Torsten Tille, Dresden, and the project administration of Mrs Romy Hoppenz and Mrs Linda Kottke at GWT-TUD GmbH, Dresden. Medical writing services provided by Richard Murphy PhD of Adelphi Communications Ltd, Macclesfield, UK were funded by Bayer AG in accordance with Good Publication Practice (GPP3) guidelines. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Actelion, personal fees from Acceleron, personal fees from MSD, personal fees from Jansen, personal fees from Pfizer, outside the submitted work. Dr Hans Klose reports speaker and consultancy fees from Actelion, Bayer AG, GSK, Novartis, Pfizer, and United Therapeutics and research support from Actelion, Bayer AG, GSK, Pfizer, and MSD. Dr Michael Halank reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer AG, Berlin-Chemie, GSK, OMT, MSD, and Novartis. Dr George Giannakoulas reports speaker and consultancy fees from Actelion, Bayer, ELPEN Pharmaceuticals, GSK, Pfizer, Lilly, and United Therapeutics, and research support from GSK, ELPEN Pharmaceuticals, and Galenica. Dr Henning Gall has received honoraria and/or other support from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Pavel Jansa reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Prof Ekkehard Grünig reports research grants and speaker honoraria/consultancy fees from Actelion and Bayer/MSD, research grants from GSK, United Therapeutics, Bellerophon, OMT GmbH, Pfizer, Reata, and Novartis, and speaker honoraria from Bial, Medscape, and OrPha Swiss GmbH. Prof David Pittrow reports personal fees from Actelion, Bayer AG, Aspen, Boehringer Ingelheim, Sanofi, Biogen, Shire, and MSD outside the submitted work. Silvia Ulrich reports research grants and personal fees from Actelion, Bayer, MSD, and Orpha Swiss. Tobias J. Lange has received personal fees from Actelion, MSD, Pfizer, and OMT orphan. Dr Iraklis Tsangaris reports speaker and consultancy fees from Actelion, Bayer AG, ELPEN, GSK, MSD, Pfizer, and United Therapeutics. Stephan Rosenkranz reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Prof Iveta Šimková reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Dr Marc Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, and United Therapeutics. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck; and research support through his institution from Actelion, Merck, GlaxoSmithKline, and Ferrer. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GSK. Jean-Luc Vachiéry reports ongoing consultancies to Actelion, Sonnivie, Arena Pharma, Bial Portela, and Respira Therapeutics, past consultancies to AstraZeneca, BayerShering, CardioMEMS, GlaxoSmithKline, Pfizer, Merck, and United Therapeutics, and current membership of an advisory board or similar group for Actelion and GlaxoSmithKline. Jean-Luc Vachiéry's institution receives funding from Actelion Pharmaceuticals for performing clinical studies. Regina Steringer-Mascherbauer, Jens Klotsche, and Miguel-Angel Gomez Sanchez have no conflicts of interest relevant to the EXPERT study. Hossein-Ardeschir Ghofrani reports personal fees for advisory board work, and payment for lectures including service on speaker bureaus, from Actelion, Bayer, GSK, Novartis, and Pfizer; consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis, and Pfizer; and grants from Deutsche Forschungsgemeinschaft (DFG). Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, GlaxoSmithKline, and Ferrer, outside the submitted work. Gérald Simonneau reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from MSD, outside the submitted work. Douglas S. Helmersen reports industry-sponsored research with Bayer AG, United Therapeutics, and Gilead Sciences, Inc., and advisory board/speaker fees from Bayer AG and Actelion. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, Acceleron, Janssen, and United Therapeutics. Anco Boonstra reports consultancy fees from Pfizer BV and hospitality from Teva Nederland. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Evgenia Williams and Christian Meier are employees of Bayer AG.

Background Pulmonary hypertension (PH) patients show, during exercise, an excessive increase in ventilation (V E ) compared to carbon dioxide output (VCO 2 ), determining a high V E /VCO 2 slope. There are several possible causes, including an elevated dead space ventilation (V D ), V E /perfusion (Q) mismatch and/or an enhanced peripheral or central chemoreceptor activity. We evaluated the causes of exercise hyperventilation in PH patients. Methods Eighteen group I and IV PH patients underwent cardiopulmonary exercise test with blood gas analysis at every minute. V E , alveolar ventilation (V A ) and V D vs. VCO 2 relationship were calculated. Resting chemoreceptor sensitivity was analyzed through hypoxia/hypercapnia tests. Results PeakVO 2 and V E /VCO 2 slopes were 1.06±0.24l/min and 39.1±9.0, respectively. Throughout the exercise, 30% of V E was due to V D . V E /VCO 2 slope significantly correlated with V D /VCO 2 slope (r=0.82, p A /VCO 2 slope (r=0.3, p=ns). Peak exercise end-tidal CO 2 (PetCO 2 ) correlated with V D /VCO 2 slope (r=−0.79, p E /VCO 2 slope (r=−0.91, p 2 were elevated without arterial hypoxemia suggesting a high V E /Q mismatch. Chemoreceptor peripheral response to hypoxia and central CO 2 response were both enhanced being peripheral responses to hypoxia and hypercapnia 0.416±0.402 (normal ref values=0.285±0.221) l/min/O 2 Sat and 0.076±0.047 (0.066±0.430) l/min/mmHg, respectively; central hypercapnic chemosensitivity was 4.475±3.99 (2.352±0.936) l/min/mmHg. Conclusions Increased DS, V E /Q mismatch and chemorecptor response are among the main mechanisms involved in exercise hyperventilation in PH. ClinicalTrial.gov NCT02892981

AIMS Mineralocorticoid receptor antagonists (MRAs) have been demonstrated to improve outcomes in reduced ejection fraction heart failure (HFrEF) patients. However, MRAs added to conventional treatment may lead to worsening of renal function and hyperkalaemia. We investigated, in a population-based analysis, the long-term effects of MRA treatment in HFrEF patients. METHODS AND RESULTS We analysed data of 6046 patients included in the Metabolic Exercise Cardiac Kidney Index score dataset. Analysis was performed in patients treated (n = 3163) and not treated (n = 2883) with MRA. The study endpoint was a composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Ten years' survival was analysed through Kaplan-Meier, compared by log-rank test and propensity score matching. At 10 years' follow-up, the MRA-untreated group had a significantly lower number of events than the MRA-treated group (P

Cardiopulmonary exercise testing allows the assessment of the integrative cardiopulmonary response to exercise and is a useful tool to assess the underlying pathophysiologic mechanisms leading to exercise intolerance. Patients with pulmonary hypertension often face a considerable delay in diagnosis due to the rarity of the disease and nonspecific symptoms of dyspnea, fatigue, and exercise limitation. Cardiopulmonary exercise testing may be suggestive of pulmonary hypertension in patients with evidence of both circulatory impairment and ventilatory inefficiency. Other factors, such as mechanical ventilatory constraints from dynamic hyperinflation and peripheral muscle dysfunction, contribute to the profound dyspnea during exercise experienced by many patients with pulmonary hypertension. In patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension, several exercise variables, such as low peak [Formula: see text]o2, high Vd/Vt, and high [Formula: see text]e/[Formula: see text]co2, have proven to be useful in establishing the severity of functional impairment, predicting prognosis, and assessing the efficacy of interventions.

Despite recent advances in the therapeutic management of patients affected by pulmonary arterial hypertension (PAH), survival remains poor. Prompt identification of the disease, especially in subjects at increased risk of developing PAH, and prognostic stratification of patients are a necessary target of clinical practice but remain challenging. Cardiopulmonary exercise test (CPET) parameters, particularly peak oxygen uptake, end-tidal carbon dioxide tension and the minute ventilation/carbon dioxide production relationship, emerged as new prognostic tools for PAH patients. Moreover, CPET provides a comprehensive pathophysiological evaluation of patients' exercise limitation and dyspnoea, which are the main and early symptoms of the disease. This review focuses on the role of CPET in the management of PAH patients, reporting guideline recommendations for CPET and discussing the pathophysiology of exercise limitation and the most recent use of CPET in the diagnosis, prognosis and therapeutic targeting of PAH.

Aims The cardio-renal syndrome plays a critical role in acute heart failure (HF). Levosimendan, an inodilator drug, has a positive but controversial effect on kidney. Our aim was to evaluate its effects on both renal and systemic haemodynamic parameters as well as on renal function, explaining the possible mechanisms involved. Methods and results Patients with acute decompensated HF, moderate renal impairment, wedge pressure >20 mmHg and EF

In normal coronary arteries, several different mechanisms of blood flow regulation exist, acting at different levels of the coronary tree: endothelial, nervous, myogenic and metabolic regulation. In addition, physiologic blood flow regulation is also dependent on the activity of several coronary ion channels, including ATP-dependent K+ channels, voltage-gated K+ channels and others. In this context, ion channels contribute by matching demands for homeostatic maintenance. They play a primary role in rapid response of both endothelium and vascular smooth muscle cells of larger and smaller arterial vessels of the coronary bed, leading to coronary vasodilation. Consequently, an alteration in ion channel function or expression could be directly involved in coronary vasomotion dysfunction.

Background Poor diuretic response in acute heart failure is related to poor clinical outcome. The underlying mechanisms and pathophysiology behind diuretic resistance are incompletely understood. We evaluated a combined approach using clinical characteristics and biomarkers to predict diuretic response in acute heart failure (AHF). Methods and results We investigated explanatory and predictive models for diuretic response—weight loss at day 4 per 40 mg of furosemide—in 974 patients with AHF included in the PROTECT trial. Biomarkers, addressing multiple pathophysiological pathways, were determined at baseline and after 24 h. An explanatory baseline biomarker model of a poor diuretic response included low potassium, chloride, hemoglobin, myeloperoxidase, and high blood urea nitrogen, albumin, triglycerides, ST2 and neutrophil gelatinase-associated lipocalin (r2 = 0.086). Diuretic response after 24 h (early diuretic response) was a strong predictor of diuretic response (β = 0.467, P

Heart failure is a major public health problem because of its high prevalence and impact on mortality, morbidity, quality of life, and social costs. The aim of this analysis was to estimate the effects of the novel inodilator levosimendan versus standard inotropic therapy (ST) of dobutamine in acute heart failure. A study population of 292 patients with acute heart failure was derived from an observational registry of patients referred to our department. Of these, 147 patients received iv levosimendan (0.05-0.1 μg·kg·min for 24 hours), and 145 patients were treated with ST. Duration of hospitalization, survival at 1 month, and the rehospitalization rate during the year after the index hospitalization were evaluated. Cost-effectiveness analysis was performed. The mean length of hospitalization was 12.08 and 13.57 days in the levosimendan and ST groups, respectively (P < 0.05). Rehospitalization rates were lower in the levosimendan group at 6 months (1.44% vs. 2.3%; P < 0.05) and 12 months (7.6% vs. 14.3%; P < 0.05). Mortality rate at 1 month was 2.1% versus 6.9% in the levosimendan and ST groups, respectively (P < 0.05). The per-capita cost of treatment with levosimendan was €78.86 higher than that with ST during the first hospitalization but €280.22 lower when the rehospitalization rate was considered.

Background: Deregulation of microRNAs (miRNAs) may be involved in the pathogenesis of heart failure (HF) and renal disease. Our aim is to describe miRNA levels related to early worsening renal function in acute HF patients.Method and results: We studied the association between 12 circulating miRNAs and Worsening Renal Function (WRF; defined as an increase in the serum creatinine level of 0.3 mg per deciliter or more from admission to day 3), absolute change in creatinine and Neutrophil Gelatinase Associated Lipocalin (NGAL) from admission to day 3 in 98 patients hospitalized for acute HF.At baseline, circulating levels of all miRNAs were lower in patients with WRF, with statistically significant decreased levels of miR-199a-3p, miR-423-3p, and miR-let-7i-5p (p-value Conclusions: Our results show that the levels of circulating miRNAs at hospital admission for acute HF were consistently lower in patients who developed worsening of renal function. MiR-199a-3p was the best predictor of WRF in these patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Background: According to guidelines, implantable cardioverter defibrillator (ICD) is recommended in prevention of sudden cardiac death (SCD) in heart failure (HF) patients (pts). Guidelines have several limitations because ICD indication is based mainly on left ventricular ejection fraction (EF). Recent data showed that, independently from EF, 123-iodine metaiodobenzylguanidine imaging (123-I MIBG) could help to identify HF pts at high risk of SCD [heart/ mediastinum (H/M) ratio ≤1.6 and a summed score (SS) > 26], who may benefit of ICD. Aim: Our aim is to assess, in a real world registry, the role of 123-I MIBG for the prediction of ventricular tachyarrhythmia (VT) causing appropriate ICD therapy in HF pts. Methods: We consecutively enrolled 97 patients admitted to our hospital with diagnosis of HF, left ventricular ejection fraction (LVEF) ≤35% and indication to ICD. All patients underwent MIBG imaging. The patients were classified into two groups: Group 1 with H/M≤1.6 , SS> 26; Group2 with H/M>1.6, SS Results: 65 pts were included in group 1 and 32 pts in group 2. All baseline characteristics were similar in 2 groups apart from the etiology (table 1). In group 1, H/M ratio was 1.37±0.3 vs 1.8 ± 0.2 in group 2 (p=0.0002); SS was 37.5± 9.7 vs 16 ±6 in group 2 (p = 0.0001). At 1 year follow-up VTs causing appropriate ICD therapy in group 1 were 13.4% vs 1.28% in group 2(p=0.02); overall cardiac events were in group 1 16.4 % vs 1.92% in group 2 (p=0.02). Conclusion: Our results suggest that 123 I-MIBG can identify patients at increased risk for arrhythmic death and can be useful in the decision-making of ICD implantation independently from ejection fraction.