Search

Aims Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). It is known that AF impairs the diagnostic accuracy of NT‐proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT‐proBNP for HF and AF in stable outpatients with cardiovascular risk factors. Methods and results Data were obtained from the DIAST‐CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population‐based cohorts using the same inclusion/exclusion criteria: LIFE‐Adult (n = 2869), SHIP (n = 2013), and SHIP‐TREND (n = 2408). Serum levels of NT‐proBNP were taken once at baseline. The DIAST‐CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT‐proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT‐proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver‐operating characteristic curves of NT‐proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79–0.88]) and for HF with EF 50% was significantly lower (0.61 [0.56–0.65]) than for AF (P = 0.001). During follow‐up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT‐proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75–0.83]) than of newly diagnosed HF (0.59 [0.55–0.63]; P 50% is very limited.

BACKGROUND Data comparing remote magnetic catheter navigation (RMN) with manual catheter navigation (MCN) ablation of atrial fibrillation (AF) is lacking. The aim of the present prospective observational study was to compare the outcome of RMN versus (vs.) MCN ablation of AF with regards to AF recurrence. METHODS The study comprised 667 consecutive patients with a total of 939 procedures: 287 patients were ablated using RMN, 380 using MCN. RESULTS There was no significant difference between the groups at baseline. After 2.3 ± 2.3 years of follow-up, 23% of the patients in the MCN group remained free of AF recurrence compared to 13% in the RMN group (p

Arterial lactate is an established risk marker in patients with pulmonary embolism (PE). However, its clinical applicability is limited by the need of an arterial puncture. In contrast, venous lactate can easily be measured from blood samples obtained via routine peripheral venepuncture. We investigated the prognostic value of venous lactate with regard to in-hospital adverse outcomes and mortality in 419 consecutive PE patients enrolled in a single-center registry between 09/2008 and 09/2017. An optimised venous lactate cut-off value of 3.3 mmol/l predicted both, in-hospital adverse outcome (OR 11.0 [95% CI 4.6-26.3]) and all-cause mortality (OR 3.8 [95%CI 1.3-11.3]). The established cut-off value for arterial lactate (2.0 mmol/l) and the upper limit of normal for venous lactate (2.3 mmol/l) had lower prognostic value for adverse outcomes (OR 3.6 [95% CI 1.5-8.7] and 5.7 [95% CI 2.4-13.6], respectively) and did not predict mortality. If added to the 2019 European Society of Cardiology (ESC) algorithm, venous lactate

In der Herz-Kreislauf-Medizin als einem der umfangreichsten Leistungsbereiche des Gesundheitswesens lassen sich zahlreiche Beispiele fur Uberdiagnostik und Ubertherapie finden. Der vorliegende Beitrag greift drei davon heraus, eines aus der Kardiologie und zwei aus der Gefasmedizin. Beim Thema der chronischen koronaren Herzkrankheit geht es um den verlasslichen Ischamienachweis vor koronaren Interventionen. In den Abschnitten uber die Duplexsonographie der Halsgefase und die Thrombophiliediagnostik wird erortert, welche validen klinischen Fragestellungen uberhaupt die Durchfuhrung dieser Untersuchungen rechtfertigen. Das Schadenspotenzial der Uberdiagnostik liegt in diesen beiden Fallen sowohl beim unnotigen Ressourcenverbrauch als auch – viel bedeutsamer – in der sich anschliesenden Ubertherapie. Die wenigen angemessenen Indikationen werden konkret beschrieben.

Patients with type 2 diabetes (T2D) are threatened by excessive cardiovascular morbidity and mortality. While accelerated arterial stiffening may represent a critical mechanistic factor driving cardiovascular risk in T2D, specific therapies to contain the underlying diabetic arterial remodeling have been elusive. The present translational study investigates the role of microRNA-29b (miR-29b) as a driver and therapeutic target of diabetic aortic remodeling and stiffening. Using a murine model (db/db mice), as well as human aortic tissue samples, we find that diabetic aortic remodeling and stiffening is associated with medial fibrosis, as well as fragmentation of aortic elastic layers. miR-29b is significantly downregulated in T2D and miR-29b repression is sufficient to induce both aortic medial fibrosis and elastin breakdown through upregulation of its direct target genes COL1A1 and MMP2 thereby increasing aortic stiffness. Moreover, antioxidant treatment restores aortic miR-29b levels and counteracts diabetic aortic remodeling. Concluding, we identify miR-29b as a comprehensive—and therefore powerful—regulator of aortic remodeling and stiffening in T2D that moreover qualifies as a (redox-sensitive) target for therapeutic intervention., Graphical Abstract, Stiffening of large arteries represents a significant complication in patients with diabetes mellitus resulting in high blood pressure levels and widespread organ damage (in particular in heart, brain, and kidneys). In this study we identify microRNA-29b as a comprehensive regulator and potential therapeutical target of diabetic arterial remodeling and stiffening.

For heart failure patients with reduced ejection fraction, optimised medication improves symptom control and reduces mortality. Substances influencing the renin-angiotensin-aldosteron-system, so-called RAAS-inhibitors, are the cornerstone of heart failure treatment. This article summarises a consensus between experts in cardiology and in nephrology on a pragmatic approach to manage a drop in glomerular filtration rate and incident hyperkalaemia - the two most common reasons for reducing or discontinuing heart failure medication.Bei Patienten mit Herzinsuffizienz und reduzierter Ejektionsfraktion wird durch eine optimierte medikamentöse Therapie sowohl die Symptomkontrolle verbessert als auch die Mortalität gesenkt. Eckpfeiler der Herzinsuffizienztherapie sind dabei Medikamente mit Einfluss auf das Renin-Angiotensin-Aldosteron-System, sogenannte RAAS-Inhibitoren. Dieser Artikel stellt einen kardiologisch-nephrologischen Konsens zur praxisorientierten Hilfestellung bei abnehmender glomerulärer Filtrationsrate oder Anstieg des Serum-Kaliumspiegels vor. Dies sind die 2 häufigsten Gründe für eine Dosisreduktion oder das Absetzen von prognoseverbessernden Medikamenten bei Herzinsuffizienzpatienten.

Tachycardia is a reliable predictor of adverse outcomes in normotensive patients with acute pulmonary embolism (PE). However, different prognostic relevant heart rate thresholds have been proposed. The aim of the study was to investigate the prognostic performance of different thresholds used for defining tachycardia in normotensive PE patients.We performed a post-hoc analysis of normotensive patients with confirmed PE consecutively included in a single-centre and a multi-centre registry. An adverse outcome was defined as PE-related death, need for mechanical ventilation, cardiopulmonary resuscitation or administration of catecholamines.Of 1567 patients (median age: 72 [IQR, 59-79] years; females: 46.1%) included in the analysis, 78 patients (5.0%) had an in-hospital adverse outcome. The rate of an adverse outcome was higher in patients with a heart rate ≥100 bpm (7.6%) and ≥110 bpm (8.3%) compared to patients with a heart rate100 bpm (3.0%). A heart rate ≥100 bpm and ≥110 bpm was associated with a 2.7 (95% CI 1.7-4.3) and 2.4-fold (95% CI 1.5-3.7) increased risk for an adverse outcome, respectively. Receiver operating characteristics analysis revealed a similar area under the curve with regard to an adverse outcome for all scores and algorithm (ESC 2019 algorithm, modified FAST and Bova score) if calculated with a heart rate threshold of ≥100 bpm or of ≥110 bpm.Defining tachycardia by a heart rate ≥100 bpm is sufficient for risk stratification of normotensive patients with acute PE. The use of different heart rate thresholds for calculation of scores and algorithm does not appear necessary.

ObjectiveRight ventricular (RV) involvement complicating myocardial infarction (MI) is thought to impact prognosis, but potent RV markers for risk stratification are lacking. Therefore, the aim of this trial was to assess the frequency and prognostic implications of concomitant structural and functional RV injury in MI.MethodsCardiac magnetic resonance (CMR) was performed in 1235 patients with MI (ST-elevation myocardial infarction: n=795; non-STEMI: n=440) 3 days after reperfusion by primary percutaneous coronary intervention. Central core laboratory-masked analyses included structural (oedema representing reversible ischaemia, irreversible infarction, microvascular obstruction (MVO)) and functional (ejection fraction, global longitudinal strain (GLS)) RV alterations. The clinical end point was the 12-month rate of major adverse cardiac events (MACE).ResultsRV ischaemia and infarction were observed in 19.6% and 12.1% of patients, respectively, suggesting complete myocardial salvage in one-third of patients. RV ischaemia was associated with a significantly increased risk of MACE (10.1% vs 6.2%; p=0.035), while patients with RV infarction showed only numerically increased event rates (p=0.075). RV MVO was observed in 2.4% and not linked to outcome (p=0.894). Stratification according to median RV GLS (10.2% vs 3.8%; pConclusionsRV GLS is a predictor of postinfarction adverse events over and above established risk factors, while structural RV involvement was not independently associated with outcome.

Purpose Myocardial feature-tracking (FT) deformation imaging is superior for risk stratification compared with volumetric approaches. Because there is no clear recommendation regarding FT postprocessing, we compared different FT-strain analyses with reference standard techniques, including tagging and strain-encoded (SENC) MRI. Methods Feature-tracking software from four different vendors (TomTec, Medis, Circle [CVI], and Neosoft), tagging (Segment), and fastSENC (MyoStrain) were used to determine left ventricular global circumferential strains (GCS) and longitudinal strains (GLS) in 12 healthy volunteers and 12 patients with heart failure. Variability and agreements were assessed using intraclass correlation coefficients for absolute agreement (ICCa) and consistency (ICCc) as well as Pearson correlation coefficients. Results For FT-GCS, consistency was excellent comparing different FT vendors (ICCc = 0.84-0.97, r = 0.86-0.95) and in comparison to fast SENC (ICCc = 0.78-0.89, r = 0.73-0.81). FT-GCS consistency was excellent compared with tagging (ICCc = 0.79-0.85, r = 0.74-0.77) except for TomTec (ICCc = 0.68, r = 0.72). Absolute FT-GCS agreements among FT vendors were highest for CVI and Medis (ICCa = 0.96) and lowest for TomTec and Neosoft (ICCa = 0.32). Similarly, absolute FT-GCS agreements were excellent for CVI and Medis compared with both tagging and fast SENC (ICCa = 0.84-0.88), good to excellent for Neosoft (ICCa = 0.77 and 0.64), and lowest for TomTec (ICCa = 0.41 and 0.47). For FT-GLS, consistency was excellent (ICCc ≥ 0.86, r ≥ 0.76). Absolute agreements among FT vendors were excellent (ICCa = 0.91-0.93) or good to excellent for TomTec (ICCa = 0.69-0.85). Absolute agreements (ICCa) were good (CVI 0.70, Medis 0.60) and fair (TomTec 0.41, Neosoft 0.59) compared with tagging, but excellent compared with fast SENC (ICCa = 0.77-0.90). Conclusion Although absolute agreements differ depending on deformation assessment approaches, consistency and correlation are consistently high regardless of the method chosen, thus indicating reliable strain assessment. Further standardisation and introduction of uniform references is warranted for routine clinical implementation.

Endpoints of large-scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and - with less certainty - testosterone in highly selected patients. Erythropoiesis-stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co-morbidities such as sleep-disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state-of-the-art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co-morbidities may be important for these patient-related outcomes. Additional studies on functional capacity and quality of life in heart failure are required.

Aims Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes. Methods and results One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson’s trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF−) median percentage MF (≥11% or Conclusion Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

Sex-specific outcome data following myocardial infarction (MI) are inconclusive with some evidence suggesting association of female sex and increased major adverse cardiac events (MACE). Since mechanistic principles remain elusive, we aimed to quantify the underlying phenotype using cardiovascular magnetic resonance (CMR) quantitative deformation imaging and tissue characterisation.In total, 795 ST-elevation MI patients underwent post-interventional CMR imaging. Feature-tracking (CMR-FT) was performed in a blinded core-laboratory. Left ventricular function was quantified using ejection fraction (LVEF) and global longitudinal/circumferential/radial strains (GLS/GCS/GRS). Left atrial function was assessed by reservoir (εs), conduit (εe) and booster-pump strains (εa). Tissue characterisation included infarct size, microvascular obstruction and area at risk. Primary endpoint was the occurrence of MACE within 1 year.Female sex was associated with increased MACE (HR 1.96, 95% CI 1.13-3.42, p = 0.017) but not independently of baseline confounders (p = 0.526) with women being older, more often diabetic and hypertensive (p 0.001) and of higher Killip-class (p = 0.010). Tissue characterisation was similar between sexes. Women showed impaired atrial (εs p = 0.011, εe p 0.001) but increased systolic ventricular mechanics (GLS p = 0.001, LVEF p = 0.048). While atrial and ventricular function predicted MACE in men only LV GLS and GCS were associated with MACE in women irrespective of confounders (GLS p = 0.036, GCS p = 0.04).In men ventricular systolic contractility is impaired and volume assessments precisely stratify elevated risks. In contrast, women experience reduced atrial but increased ventricular systolic strain. This may reflect ventricular diastolic failure with systolic compensation, which is independently associated with MACE adding incremental value to sex-specific prognosis evaluation.

AIMS: The objective of this paper is to assess whether cardiac contractility modulation (via the Optimizer System) plus standard of care (SoC) is a cost-effective treatment for people with heart failure [New York Heart Association (NYHA) III, left ventricular ejection fraction of 25-45%, and narrow QRS] compared against SoC alone from the perspective of the English National Health Service. METHODS AND RESULTS: We developed a regression equation-based cost-effectiveness model, using individual patient data from three randomized control trials (FIX-HF-5 Phases 1 and 2, and FIX-HF-5C) to populate the majority of parameters. A series of regression equations predicted NYHA class over time, mortality, all-cause hospitalization rates, and health-related quality of life. We conducted the analysis in line with the National Institute for Health and Care Excellence reference case, modelling costs from an English National Health Service perspective, and considering outcomes in quality-adjusted life years (QALYs) over a patient lifetime perspective. Our base case analysis produced an incremental cost per additional QALY of GBP22 988 (€25 750) when comparing Optimizer + SoC to SoC alone. This result was not sensitive to parameter uncertainty but was sensitive to the time horizon over which costs and QALYs were captured and the duration over which a survival benefit with Optimizer + SoC can be assumed to apply. CONCLUSIONS: Cardiac contractility modulation is likely to be cost-effective in people with heart failure with reduced ejection fraction, NYHA III, and narrow QRS, provided that the treatment benefit can be maintained beyond the duration of the existing clinical trial follow-up. This analysis supports the current recommendations of the European Society of Cardiology that this therapy may be considered for such patients. peerReviewed

Aims Chronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling. Methods and results We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4−/−) vs. wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4−/− mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs. 0.27, P Conclusion Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.

Background Mutations in the splice factor RBM20 account for ∼3% of genetic cardiomyopathies. Mutations at position R634 in the hotspot RS-domain were found to cause dilative cardiomyopathy (DCM) (R634W) or left ventricular non-compaction cardiomyopathy (LVNC) (R634L), but the pathophysiological mechanisms that govern the heterogeneity in phenotype presentation remain unknown. Purpose We aimed here to identify the molecular events caused by the distinct RBM20 mutations from DCM and LVNC patients using a patient-specific induced stem cell model (iPSC) and test if the currently clinically used β-blockers (Metroprolol) are suitable for different RBM20-dependent cardiomyopathies. Methods We generated iPSC-cardiomyocytes of 2 DCM- and 2 LVNC-patients harboring the RBM20-mutations R634W (DCM) or R634L (LVNC). We investigated alternative splicing, sarcomeric regularity, cAMP-level, kinase-specific phosphorylation of Ca2+ players and Ca2+ handling. To investigate the impact of the genetic background, isogenic rescue lines were generated by CRISPR/Cas9. Different clinical drugs as Metoprolol and Verapamil were used to analyze the pharmacological improvement in vitro. Results We investigated the splicing pattern of the 2 RBM20 mutations in DCM and LVNC iPSC-CMs and observed common isoform changes in titin and a 24bp-insertion in the gene RYR2. The Ca2+ handling gene triadin is misspliced in LVNC-CMs, whereas the structural gene LDB3 is misspliced in DCM-CMs. As a possible consequence of splice defects in sarcomeric genes, both DCM and LVNC-CMs exhibited an irregular sarcomeric structure. The Ca2+ handling gene CAMK2δ was predominantly misspliced in LVNC-CMs leading to CAMK2δ-dependent hyperphosphorylation of its target PLN-Thr17 and subsequently to shortened Ca2+ elimination time and weakened response to β-adrenergic stimulation. By contrast, DCM-CMs exhibited increased Ca2+ sparks and decreased systolic and diastolic Ca2+ levels. RBM20 expression itself was decreased in LVNC-CMs, but not in DCM-CMs. This highlights that 2 distinct RBM20 mutations can lead to different pathological Ca2+ phenotypes. Isogenic CRISPR/Cas9 repair of both RBM20 mutations in LVNC and DCM demonstrated a rescue in gene missplicing, sarcomeric regularity and the Ca2+ handling aberrations and underscored the causative nature of the 2 mutations and their diverging effects. Ca2+ channel blockage with Verapamil showed a significant improvement of some of the LVNC disease characteristics compared to commonly clinically used β-blocker Metoprolol and underpins the potential clinical use of this drug in patients with LVNC. Conclusion We show the first iPSC-model of splice-defect associated RBM20-dependent LVNC and DCM. In summary, our results suggest that the molecular aberrations in alternative splicing differ depending on the distinct mutation in RBM20 and lead to shared and differential pathologies. Verapamil could be a good candidate in the treatment of RBM20-dependent LVNC. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Bunderministerium für Bildung und Forschung BMBFGerman Center for Cardiovascular Research DZHK

Atrial fibrillation (AF) is often found in patients with heart failure (HF). Clinical data indicated that the arrhythmic component of AF alone could contribute to left-ventricular (LV) dysfunction. However, the effects of non-tachycardic AF with arrhythmic excitation of the human LV, are unknown. We investigated human LV myocardium from patients with sinus rhythm (SR) or normofrequent AF (mean EF>50%, matched clinical data, derived from septal resections during AVR). In histological analysis we detected no difference between SR (n=17 patients) and AF patients (n=18) regarding the amount and distribution of fibrosis. We isolated human LV cardiomyocytes (CM) and studied cellular Ca-handling (Fura-2). Systolic Ca-transient amplitude of LV CM was reduced in patients suffering from AF (n=8 AF patients vs. 11 SR), while diastolic Ca-levels and Ca-transient kinetics were not significantly changed. These results were confirmed in LV CM from non-failing donors (NF) with AF (n=4 AF patients vs. 8 SR). For the standardized investigation of a normofrequent arrhythmia, we simulated AF in vitro by using arrhythmic (60 bpm, 40% beat-to-beat variability) or rhythmic (60 bpm) field stimulation. Human LV CM from NF SR patients (n=8) showed an impaired Ca-transient amplitude after 24h arrhythmic culture pacing without changes in diastolic Ca and Ca-transient kinetics. For studying a model suitable for more standardized chronic pacing, we utilized human iPSC cardiomyocytes (iPSC-CM) from healthy donors (n=6). After 7 days, arrhythmically paced iPSC-CM exhibited a reduced systolic Ca-transient amplitude, a trend towards a prolonged Ca-elimination time and a reduced sarcoplasmic reticulum Ca-load. Confocal line-scans of arrhythmically paced cells (Fluo-4 AM) showed an increased diastolic Ca-leak from the sarcoplasmic reticulum, possibly underlying the reduced Ca-load. Coupled with the Ca changes, cytosolic Na was elevated after arrhythmia. We found an increased late INa, which could explain the detrimentally altered Ca/Na-interplay. Accordingly, Patch-clamp experiments revealed a prolonged action potential duration after arrhythmia. We further elucidated the underlying mechanisms of this electrophysiological remodeling by showing that oxidative stress (H2O2, LPO) is increased in the LV of patients suffering from AF (n=6 AF patients vs. 6 SR), which was associated with an enhanced NOX2/-4 activity. Consecutively, Ca2+/calmodulin-dependent protein kinase IIδ (CaMKII) was found to be more oxidized (CaMKII-Met281/282) in the LV of AF patients (n=7 AF patients vs. 7 SR) leading to an increased CaMKII activity, which adversely regulated EC-coupling protein phosphorylation including RyR2 hyperphosphorylation. Normofrequent arrhythmia/AF impairs human ventricular EC-coupling via increased oxidative stress and enhanced CaMKII. Thus, this translational study provides the first mechanistic characterization and the potential negative impact of isolated AF on the human LV. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Else Kröner-Fresenius-Stiftung (EKFS) and Deutsche Gesellschaft für Innere Medizin

Aims The 2019 European Society of Cardiology (ESC) guidelines provide a revised definition of high-risk pulmonary embolism (PE) encompassing three clinical presentations: Cardiac arrest, obstructive shock, and persistent hypotension. This study investigated the prognostic implications of this new definition. Methods and results Data from 784 consecutive PE patients prospectively enrolled in a single-centre registry were analysed. Study outcomes include an in-hospital adverse outcome (PE-related death or cardiopulmonary resuscitation) and in-hospital all-cause mortality. Overall, 86 patients (11.0%) presented with high-risk PE and more often had an adverse outcome (43.0%) compared to intermediate-high-risk patients (6.1%; P, Graphical Abstract

Aortic valve calcification (AVC) in aortic stenosis patients has diagnostic and prognostic implications. Little is known about the interchangeability of AVC obtained from different multidetector computed tomography (MDCT) software solutions. Contrast-enhanced MDCT data sets of 50 randomly selected aortic stenosis patients were analysed using three different software vendors (3Mensio, CVI42, Syngo.Via). A subset of 10 patients were analysed twice for the estimation of intra-observer variability. Intra- and inter-observer variability were determined using the ICC reliability method, Bland-Altman analysis and coefficients of variation. No differences were revealed between the software solutions in the AVC calculations (3Mensio 941 ± 623, Syngo.Via 948 mm3 ± 655, CVI42 941 ± 637, p = 0.455). The best inter-vendor agreement was found between the CVI42 and the Syngo.Via (ICC 0.997 (CI 0.995–0.998)), followed by the 3Mensio and the CVI42 (ICC 0.996 (CI 0.922–0.998)), and the 3Mensio and the Syngo.Via (ICC 0.992 (CI 0.986–0.995)). There was excellent intra- (3Mensio: ICC 0.999 (0.995–1.000), CVI42: ICC 1.000 (0.999–1.000), Syngo.Via: ICC 0.998 (0.993–1.000)) and inter-observer variability (3Mensio: ICC 1.000 (0.999–1.000), CVI42: ICC 1.000 (1.000–1.000), Syngo.Via: ICC 0.996 (0.985–0.999)) for all software types. Contrast-enhanced MDCT-derived AVC scores are interchangeable between and reproducible within different commercially available software solutions. This is important since sufficient reproducibility, interchangeability and valid results represent prerequisites for accurate TAVR planning and its widespread clinical use.

Aims Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction. Methods and results We studied the effects of danicamtiv on LV and LA function in non‐clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P

© 2019 The Authors European Journal of Heart Failure © 2019 European Society of Cardiology, Recent evidence suggests comparable in‐hospital and long‐term outcomes between takotsubo syndrome (TTS) and acute coronary syndrome. Medical scoring systems are practical tools for decision making and prognostic assessment. However, TTS‐specific scoring systems for risk stratification have not yet been established. Recently, classification based on triggering conditions proved useful in predicting adverse outcomes in TTS (InterTAK Classification).1 Since clinical parameters other than triggering conditions can be associated with adverse outcomes in TTS, such as systolic blood pressure and heart rate, the present study aimed to establish a scoring system combining triggering factors with other important but easily‐ obtainable clinical parameters of daily clinical practice., C.T. has been supported by the H.H. Sheikh Khalifa bin Hamad Al-Thani Research Programme and the Swiss Heart Foundation. L.S.M. was supported by EU HORIZON 2020 (SILICOFCM ID777204). The InterTAK Registry is supported by the Biss Davies Charitable Trust.

The impact of heart failure on outcome in stroke patients is not fully understood. There is evidence for an increased mortality and morbidity, but it remains uncertain whether thrombectomy in patients with large vessel occlusion (LVO) in the anterior circulation is less effective in patients with heart failure compared to patients without. Retrospectively, we analyzed echocardiographic data of all patients in our stroke database, who underwent mechanical thrombectomy (n=668) for the presence of heart failure. Furthermore, we collected baseline characteristics and neurological and neuroradiological parameters. In the analysis, 373 of the 668 patients of our stroke database underwent echocardiography. Of these 373 patients, 90 patients (24%) suffered from heart failure with reduced left ventricular ejection fraction measured by echocardiography according to the current guidelines. After adjustment for age, the Alberta stroke program early CT score (ASPECTS), and time from symptom onset to recanalization, the analysis revealed that thrombectomy in patients with heart failure and LVO is not associated with less favorable outcome measured by the modified Rankin Scale after 90 days (3 (0-6) vs. 3 (1-5); p=0.380). Moreover, we could not find a significant difference in mortality compared to patients without heart failure (11.0% vs. 7.4%; p=0.313).

Background Inflammation and incomplete thrombus resolution leading to obstructive fibrotic remodelling are considered critical mechanisms for the development of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE). Osteopontin (OPN) is involved in a variety of biological processes including inflammation and tissue fibrosis. Methods OPN plasma concentrations were measured in 70 CTEPH and 119 PE patients. Tissue material from 6 CTEPH patients removed during pulmonary endarterectomy and murine venous thrombi induced by subtotal ligation of the inferior vena cava in C57BL/6 mice were analysed by (immuno)histochemistry. Results CTEPH patients had higher OPN plasma concentrations (median, 106.9 [interquartile range, 75.6–155.9]) compared to PE patients (90.4 [53.3–123.9] ng/mL, p = 0.001). OPN- and matrix metalloproteinase (MMP)-9-positive cells were predominantly present in myofibroblast-rich and profibrotic areas of CTEPH tissue material. Early stages of murine thrombus resolution were characterised by high numbers of OPN- and MMP-2-positive cells while OPN was almost absent in fresh thrombi of CTEPH tissue material. PE patients with OPN plasma concentrations of Conclusion The results of the present observational translational study point to a possible involvement of OPN in the pathogenesis of CTEPH by affecting early inflammatory and late fibrotic processes.

Introduction Sex-specific differences regarding risk factors, symptoms and prognosis have been reported for several cardiovascular diseases. For patients with pulmonary embolism (PE), sex-specific data are limited and inconsistent. We aimed to investigate sex-specific differences in PE. Materials and methods Over a 10-year period (01/2003–09/2013), patients with confirmed PE were enrolled in a prospective single-centre cohort study. Results We prospectively examined 569 PE patients (55.9% women). Men more often had cancer (20.7% vs. 13.5%, p = 0.024) and unprovoked PE (61.0% vs. 47.5%, p = 0.001) while women more frequently presented with risk factors for venous thromboembolism such as older age (median, 71 [IQR, 55–79] vs. 67 [53–75] years, p = 0.008), surgery/trauma/immobilisation (38.4% vs. 29.5%, p = 0.026) and sex-hormone therapy (14.8% vs. 0.8%, p Overall, 84 patients (14.8%) had an adverse 30-day outcome and 43 (7.6%) died within 30 days; outcomes did not differ between males and females and were not influenced by the patients' sex. Risk stratification markers and models such as right ventricular dysfunction on TTE/CT, cardiac troponin, sPESI, Bova score and 2014 ESC guidelines algorithm predicted adverse outcome in normotensive female patients only, while tachycardia, hypoxia, NT-proBNP and modified FAST score were able to predict an adverse outcome in both sexes. Using sex-specific biomarker cut-off values, the 2014 ESC guidelines algorithm was able to predict adverse outcome in both sexes. Conclusions The 30-day adverse outcomes did not differ between male and female PE patients and were not influenced by the patients' sex despite sex-specific differences in the prognostic performance of risk stratification markers/models.

Right ventricular (RV) function is prognostically relevant in heart failure with preserved ejection fraction (HFpEF) but data on profound assessment of RV and right atrial (RA) interaction in HFpEF are lacking. The current study characterizes RV and RA interaction using invasive pressure–volume-loop analysis and cardiac magnetic resonance imaging (CMR) data. We performed CMR and myocardial feature-tracking in 24 HFpEF patients and 12 patients without HFpEF. Invasive pressure–volume-loops were obtained to evaluate systolic and diastolic RV properties. RV early filling was determined from CMR RV volume–time curves. RV systolic function was slightly increased in HFpEF (RV EF 68 ± 8 vs. 60 ± 9%, p = 0.01), while no differences in RV stroke volume were found (45 ± 7 vs 42 ± 9 ml/m2, p = 0.32). RV early filling was decreased in HFpEF (21 ± 11 vs. 40 ± 11% of RV filling volume, p

AIMS Cardiac contractility modulation (CCM) improves symptoms and exercise tolerance and reduces heart failure (HF) hospitalizations over 6-month follow-up in patients with New York Heart Association (NYHA) class III or IV symptoms, QRS

Prevention strategies for cardiac events depend of the risk for such an event. A very high risk is defined as a risk > 10% over 10 years. For example, a patient with known coronary artery disease has such a very high risk of death. However, a patient with diabetes and severe hypertension without known coronary artery disease carries the same risk. Here, secondary preven-tion and primary prevention overlap. Prevention guidelines include a number of general recommendations, such as changes in behaviour, nutrition, body weight, and physical activity as well as smoking intervention strategies. Drug treatment-based prevention strategies address diabetes mellitus, hypercholesterolaemia, platelet aggregation, and arterial hypertension. Follow-ing hospitalisation for heart failure or acute coronary syndrome, participation in a centre-based or home-based rehabilitation programme is recommended. There are a number of new treatment options with a promising potential to reduce the rate of events in patients with cardiovascular diseases and in patients with cardiovascular risk factors. Very recent treatment strategies include the PCSK9 inhibitors for hypercholesterolaemia and the SGLT2 inhibitors for reduction of cardiovascular events in patients with diabetes mellitus and increased cardiovascular risk.

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/., Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes. Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients. Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients. Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers., Open Access funding provided by Universität Zürich. CT has been supported by the H.H. Sheikh Khalifa bin Hamad Al-Thani Research Programme and the Swiss Heart Foundation. L.S.M. has been supported by EU HORIZON 2020 (SILICOFCM ID777204). J.R.G has received a grant “Filling the gap” from the University of Zurich. The InterTAK Registry is supported by The Biss Davies Charitable Trust.

Aims Right atrial (RA) dilation and stretch provide prognostic information in patients with cardiovascular diseases. We investigated the prevalence, confounding factors and prognostic relevance of RA dilation in patients with pulmonary embolism (PE). Methods Overall, 609 PE patients were consecutively included in a prospective single-centre registry between September 2008 and August 2017. Volumetric measurements of heart chambers were performed on routine non-electrocardiographic-gated computed tomography and plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) measured on admission. An in-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration. Results Patients with an adverse outcome (11.2%) had larger RA volumes (median 120 (interquartile range 84–152) versus 102 (78–134) mL; p=0.013), RA/left atrial (LA) volume ratios (1.7 (1.2–2.4) versus 1.3 (1.1–1.7); p, RA dilation is a frequent finding but its prognostic performance appears inferior compared to other risk stratification markers. MR-proANP predicts an adverse outcome but elevation does not appear to be caused by RA dilation in a relevant proportion. https://bit.ly/3q55dqy

Background: Right heart catheterization using exercise stress is the reference standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF) but carries the risk of the invasive procedure. We hypothesized that real-time cardiac magnetic resonance (RT-CMR) exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary noninvasive alternative for diagnosing HFpEF. Methods: The HFpEF-Stress trial (CMR Exercise Stress Testing in HFpEF; URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03260621. URL: https://dzhk.de/ ; Unique identifier: DZHK-17) prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion (E/e′>8, New York Heart Association class ≥II) to undergo echocardiography, right heart catheterization, and RT-CMR at rest and during exercise stress. HFpEF was defined according to pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during exercise stress). RT-CMR functional assessments included time–volume curves for total and early (1/3) diastolic left ventricular filling, left atrial (LA) emptying, and left ventricular/LA long axis strain. Results: Patients with HFpEF (n=34; median pulmonary capillary wedge pressure at rest, 13 mm Hg; at stress, 27 mm Hg) had higher E/e′ (12.5 versus 9.15), NT-proBNP (N-terminal pro–B-type natriuretic peptide; 255 versus 75 ng/L), and LA volume index (43.8 versus 36.2 mL/m 2 ) compared with patients with noncardiac dyspnea (n=34; rest, 8 mm Hg; stress, 18 mm Hg; P ≤0.001 for all). Seven patients were excluded because of the presence of non-HFpEF cardiac disease causing dyspnea on imaging. There were no differences in RT-CMR left ventricular total and early diastolic filling at rest and during exercise stress ( P ≥0.164) between patients with HFpEF and noncardiac dyspnea. RT-CMR revealed significantly impaired LA total and early ( P P =0.001) after adjustment for clinical and imaging measures and emerged as the best predictor for HFpEF (area under the curve at rest 0.82 versus exercise stress 0.93; P =0.029). Conclusions: RT-CMR allows highly accurate identification of HFpEF during physiologic exercise and qualifies as a suitable noninvasive diagnostic alternative. These results will need to be confirmed in multicenter prospective research studies to establish widespread routine clinical use. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03260621. URL: https://dzhk.de/ ; Unique identifier: DZHK-17.

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as ‘HFrEF’ (HF with reduced LVEF), ‘HFpEF’ (HF with preserved LVEF), and more recently ‘HFmrEF’ (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

Funding Acknowledgements Type of funding sources: None. Background Cardiac magnetic resonance myocardial feature tracking (CMR-FT) derived global strain assessments provide incremental prognostic information in patients following acute myocardial infarction (AMI). Functional analyses of the remote myocardium (RM) are scarce and whether they provide an additional prognostic value in these patients is unknown. Methods 1052 patients following acute myocardial infarction were included. CMR imaging and strain analyses as well as scar size quantification were performed after reperfusion by primary percutaneous coronary intervention. The occurrence of major adverse cardiac events (MACE) within 12 months after the index event was defined as primary clinical endpoint. Results Patients with MACE had significantly lower RM circumferential strain (CS) compared to those without MACE. A cut-off value for RM CS of -25.8% best identified high-risk patients (p < 0.001 on log-rank testing) and impaired RM CS was a strong predictor of MACE (HR 1.05, 95% CI 1.07-1.14, p = 0.003). RM CS provided further risk stratification amongst patients considered at risk according to established CMR parameters for 1.) patients with reduced left ventricular ejection fraction (LVEF) ≤ 35 % (p = 0.002 on log-rank testing), 2.) patients with reduced global circumferential strain (GCS) > -18,3 % (p = 0.015 on log-rank testing), and 3.) patients with large microvascular obstruction ≥ 1.46 % (p = 0.038 on log-rank testing). Conclusion CMR-FT derived RM CS is a useful parameter to characterize the response of RM and allows improved stratification following AMI beyond commonly used parameters, especially of high-risk patients.

Funding Acknowledgements Type of funding sources: None. Background Myocardial infarct size (IS) remains one of the strongest predictors of adverse cardiac events following acute myocardial infarction (AMI). Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) can precisely quantify the extent of injury but requires manual post-processing. Whether novel user-independent artificial intelligence (AI) based fully-automated analyses may facilitate clinical workflow and deliver similar information for risk stratification is unknown. Methods 913 AMI patients from two multi-center trials (AIDA-STEMI n = 704 with ST-elevation myocardial infarction [STEMI] and TATORT-NSTEMI n = 245 with non-ST-elevation-infarction [NSTEMI]) were included in this sub-study. IS was quantified manually using conventional software (Medis, Leiden Netherlands) and fully automated AI-based software (NeoSoft). All automatically detected IS were evaluated visually and corrected if necessary. Analyzed data were tested for agreement and prediction of major adverse clinical events (MACE) within one year after AMI. Results Automated and manual IS were similarly associated with outcome in cox regression analyses (HR 1.05 [95% CI 1-02-1.07] p < 0.001 for automated IS and HR 1.04 [95% CI 1.02-1.06]; p < 0.001 for manual IS). Comparison of C-statistics derived area under the curve (AUC) resulted in equivalent MACE prediction (AUC 0.65 for automated vs. AUC 0.66 for manual, p = 0.53). Manual correction of the automated scar detection did not lead to an improved risk prediction of MACE (AUC 0.65 to 0.66, p = 0.43). There was good agreement of automated and manually derived IS (intraclass correlation coefficient [ICC] 0.75 [0.07-0.89]) which was further improved after manual correction of the underlying contours (ICC 0.98 [0.97-0.98]). Conclusion AI-based software enables automated scar quantification with similar prognostic value compared to conventional methods in patients following AMI.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is poorly understood and therapeutic strategies are lacking. This study aimed to identify plasma proteins with pathophysiological relevance in HFpEF and with respect to spironolactone-induced effects. We assessed 92 biomarkers in plasma samples from 386 HFpEF patients—belonging to the Aldo-DHF trial—before (baseline, BL) and after one-year treatment (follow up, FU) with spironolactone (verum) or a placebo. At BL, various biomarkers showed significant associations with the two Aldo-DHF primary end point parameters: 33 with E/e’ and 20 with peak VO2. Ten proteins including adrenomedullin, FGF23 and inflammatory peptides (e.g., TNFRSF11A, TRAILR2) were significantly associated with both parameters, suggesting a role in the clinical HFpEF presentation. For 13 proteins, expression changes from BL to FU were significantly different between verum and placebo. Among them were renin, growth hormone, adrenomedullin and inflammatory proteins (e.g., TNFRSF11A, IL18 and IL4RA), indicating distinct spironolactone-mediated effects. BL levels of five proteins, e.g., inflammatory markers such as CCL17, IL4RA and IL1ra, showed significantly different effects on the instantaneous risk for hospitalization between verum and placebo. This study identified plasma proteins with different implications in HFpEF and following spironolactone treatment. Future studies need to define their precise mechanistic involvement.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Research Foundation (DFG, CRC 1002, D1) Background Myocardial fibrosis is a major determinant of outcome in aortic stenosis (AS). Novel fast real-time (RT) cardiac magnetic resonance (CMR) mapping techniques allow comprehensive quantification of fibrosis but have not yet been compared against standard techniques and histology. Methods Patients with severe AS underwent CMR before (n = 110) and left ventricular (LV) endomyocardial biopsy (n = 46) at transcatheter aortic valve replacement (TAVR). Midventricular short axis (SAX) native, post-contrast T1 and extracellular volume fraction (ECV) maps were generated using commercially available MOLLI (native: 5(3)3, post-contrast: 4(1)3(1)2) and RT single-shot inversion recovery fast low-angle shot (FLASH) with radial undersampling. Focal late gadolinium enhancement was excluded from T1 and ECV regions of interest. ECV and LV mass were used to calculate LV matrix volumes. Variability and agreements were assessed between RT, MOLLI and histology using intraclass correlation coefficients, coefficients of variation and Bland Altman analyses. Results RT and MOLLI derived ECV were similar for midventricular SAX slice coverage (26.2 vs. 26.5, p = 0.073) and septal region of interest (26.2 vs. 26.5, p = 0.216). MOLLI native T1 time was in median 20 ms longer compared to RT (p 0.91), excellent for post-contrast T1 times (ICC >0.81) and good for native T1 times (ICC >0.62). Diffuse collagen volume fraction by biopsies was in median 7.8%. ECV (RT r = 0.345, p = 0.039; MOLLI r = 0.40, p = 0.010) and LV matrix volumes (RT r = 0.45, p = 0.005; MOLLI r = 0.43, p = 0.007) were the only parameters associated with histology. Conclusions RT mapping offers fast and sufficient ECV and LV matrix volume calculation in AS. ECV and LV matrix volume represent robust and universally comparable parameters with associations to histologically assessed fibrosis and may emerge as potential targets for clinical decision making.

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License., Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. Methods and results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002). Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome., C. T. has been supported by the H.H. Sheikh Khalifa binHamad Al-Thani Research Programme and the Swiss HeartFoundation. The InterTAK Registry is supported by the BissDavies Charitable Trust. L. S. M. has been supported by EUHORIZON 2020(SILICOFCM ID777204)

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Centre for Cardiovascular Research Purpose Myocardial Feature-Tracking (FT) deformation imaging is superior for risk-stratification compared to volumetric approaches. Since there is no clear recommendation regarding FT post-processing, we compared different FT-strain analyses with reference standard techniques, including tagging and strain encoded (SENC) magnetic resonance imaging. Methods FT software from 4 different vendors (TomTec/Medis/Circle(CVI)/Neosoft), tagging (Segment), and fastSENC (MyoStrain) were used to determine left ventricular global circumferential and longitudinal strains (GCS/GLS) in 12 healthy volunteers and 12 heart failure patients. Variability and agreements were assessed using intraclass correlation coefficients for absolute agreement (ICCa) and consistency (ICCc) as well as pearson correlation coefficients. Results For FT-GCS, consistency was excellent comparing different FT-vendors (ICCc = 0.84-0.97, r = 0.86-0.95) and compared to fSENC (ICCc = 0.78-0.89, r = 0.73-0.81). FT-GCS consistency was excellent compared to tagging (ICCc = 0.79-0.85, r = 0.74-0.77) except for TomTec (ICCc = 0.68, r = 0.72). Absolute FT-GCS agreements between FT-vendors were highest for CVI and Medis (ICCa = 0.96) and lowest for TomTec and Neosoft (ICCa = 0.32). Similarly, absolute FT-GCS agreements were excellent for CVI and Medis compared to both tagging and fSENC (ICCa = 0.84-0.88), good to excellent for Neosoft (ICCa = 0.77 and 0.64) and lowest for TomTec (ICCa = 0.41 and 0.47). For FT-GLS, consistency was excellent (ICCc≥0.86, r≥0.76). Absolute agreements between FT-vendors were excellent (ICCa = 0.91-0.93) or good to excellent for TomTec (ICCa = 0.69-0.85). Absolute agreements (ICCa) were good (CVI 0.70, Medis 0.60) and fair (TomTec 0.41, Neosoft 0.59) compared to tagging but excellent compared to fSENC (ICCa = 0.77-0.90). Conclusion Although absolute agreements differ depending on deformation assessment approaches, consistency and correlation are consistently high irrespective of the method chosen, thus indicating reliable strain assessment. Further standardisation and introduction of uniform references is warranted for routine clinical implementation.

Funding Acknowledgements Type of funding sources: None. Background Cardiovascular magnetic resonance (CMR) imaging is considered the reference methodology for cardiac morphology and function but requires manual post-processing. Whether novel artificial intelligence (AI) -based automated analyses deliver similar information for risk stratification is unknown. Therefore, this study aimed to investigate feasibility and prognostic implications of AI-based analyses. Methods CMR data (n = 1017 patients) from two myocardial infarction multi-center trials were included. Analyses of biventricular parameters including ejection fraction (EF) were manually and automatically assessed using conventional and AI-based software. Obtained parameters entered regression analyses for prediction of major adverse clinical events (MACE) defined as death, reinfarction or congestive heart failure within one-year after the acute event. Results Both manual and uncorrected automated volumetric assessments showed similar impact on outcome on univariate (LVEF HR 0.93, [95% CI 0.91-0.95]; p < 0.001 for manual and HR 0.94 [0.92-0.96]; p < 0.001 for automated) and multivariable analyses (LVEF HR 0.95, [0.92-0.98]; p = 0.001 for manual and HR 0.95 [CI 0.92-0.98]; p = 0.001 for automated). Manual correction of the automated contours did not lead to improved risk prediction (LVEF AUC 0.67 automated vs. 0.68 automated corrected, p = 0.49). There was acceptable agreement (bias: 2.6%, 95% limits of agreement [LOA] -9.1-14.2%, intraclass correlation coefficient [ICC] 0.88 [0.77-0.93] for LVEF) of manual and automated volumetric assessments. Conclusions User independent volumetric analyses performed by fully automated software are feasible and results are equally predictive of MACE compared with conventional analyses in patients following myocardial infarction.

Copyright © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher (P

Aims: \ud A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO ‐ heart rate and stroke volume and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses.\ud \ud Methods and Results: \ud Data from two prospective trials of HFpEF (n=108) and a study of healthy participants (n=42) with invasive hemodynamic measurements during exercise were utilized. Differences in central hemodynamic responses were analyzed with regression models.\ud \ud Chronotropic incompetence was present in 39‐56% of patients with HFpEF and 3‐56% of healthy participants depending on the definition used, but some (n=47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) [HFpEF: +4±10 ml/m2, healthy participants: +24±12 ml/m2, p

While numerous studies have confirmed the prognostic role of high-sensitivity troponin T (hsTnT) in pulmonary embolism (PE), high-sensitivity troponin I (hsTnI) is inappropriately studied. This study aimed to investigate the prognostic relevance of hsTnI in normotensive PE, establish the optimal cut-off value for risk stratification and to compare the prognostic performances of hsTnI and hsTnT. Based on data from 459 consecutive PE patients enrolled in a single-centre registry, receiver operating characteristic analysis was used to identify an optimal hsTnI cut-off value for prediction of in-hospital adverse outcomes (PE-related death, cardiopulmonary resuscitation or vasopressor treatment) and all-cause mortality. Patients who suffered an in-hospital adverse outcome (4.8%) had higher hsTnI concentrations compared with those with a favourable clinical course (57 (interquartile range (IQR) 22–197) versus 15 (IQR 10–86) pg·mL−1, p=0.03). A hsTnI cut-off value of 16 ng·mL−1 provided optimal prognostic performance and predicted in-hospital adverse outcomes (OR 6.5, 95% CI 1.9–22.4) and all-cause mortality (OR 3.7, 95% CI 1.0–13.3). Between female and male patients, no relevant differences in hsTnI concentrations (17 (IQR 10–97) versus 17 (IQR 10–92) pg·mL−1, p=0.79) or optimised cut-off values were observed. Risk stratification according to the 2019 European Society of Cardiology algorithm revealed no differences if calculated based on either hsTnI or hsTnT (p=0.68). Our findings confirm the prognostic role of hsTnI in normotensive PE. HsTnI concentrations >16 pg·mL−1 predicted in-hospital adverse outcome and all-cause mortality; sex-specific cut-off values do not seem necessary. Importantly, our results suggest that hsTnI and hsTnT can be used interchangeably for risk stratification., The study confirms the prognostic relevance of high-sensitivity troponin I in normotensive pulmonary embolism. A cut-off value of 16 pg·mL−1 can be used for risk stratification in male and female patients; sex-specific adjustments do not appear necessary. https://bit.ly/3lCECip

Introduction: Myocardial infarct size (IS) remains one of the strongest predictors of adverse cardiac events following acute myocardial infarction (AMI). Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) can precisely quantify the extent of injury but requires manual post-processing. Whether novel user-independent artificial intelligence (AI) based fully-automated analyses may facilitate clinical workflow and deliver similar information for risk stratification is unknown. Methods: 913 AMI patients from two multi-center trials (AIDA-STEMI n = 704 with ST-elevation myocardial infarction [STEMI] and TATORT-NSTEMI n = 245 with non-ST-elevation-infarction [NSTEMI]) were included in this sub-study. IS was quantified manually using conventional software (Medis, Leiden Netherlands) and fully automated AI-based software (NeoSoft). All automatically detected IS were evaluated visually and corrected if necessary. Analyzed data were tested for agreement and prediction of major adverse clinical events (MACE) within one year after AMI. Results: Automated and manual IS were similarly associated with outcome in cox regression analyses (HR 1.05 [95% CI 1-02-1.07] p < 0.001 for automated IS and HR 1.04 [95% CI 1.02-1.06]; p < 0.001 for manual IS). Comparison of C-statistics derived area under the curve (AUC) resulted in equivalent MACE prediction (AUC 0.65 for automated vs. AUC 0.66 for manual, p = 0.53). Manual correction of the automated scar detection did not lead to an improved risk prediction of MACE (AUC 0.65 to 0.66, p = 0.43). There was good agreement of automated and manually derived IS (intraclass correlation coefficient [ICC] 0.75 [0.07-0.89]) which was further improved after manual correction of the underlying contours (ICC 0.98 [0.97-0.98]). Conclusion: AI-based software enables automated scar quantification with similar prognostic value compared to conventional methods in patients following AMI.

Introduction: There is evidence to suggest that subtype of aortic stenosis (AS), degree of myocardial fibrosis (MF) and level of aortic valve calcification (AVC) are associated with adverse cardiac outcome in AS. Since little is known about their respective contribution, we sought to investigate their relative importance and interplay as well as association with adverse cardiac events. Methods: 100 consecutive patients with severe AS and indication for transfemoral transcatheter aortic valve replacement (TAVR) were prospectively enrolled between January 2017 and October 2018. Patients underwent transthoracic echocardiography, multi detector computed tomography (MDCT) and left ventricular endomyocardial biopsy at the time of TAVR. Results: The final study cohort consisted of 92 patients with completed study protocol comprising of 39 (42.4 %) normal ejection fraction high gradient (NEFHG), 13 (14.1 %) low EF high gradient (LEFHG), 25 (27.2 %) low EF (flow) low gradient (LEFLG) and 15 (16.3 %) paradoxical low flow low gradient (PLFLG) AS. The high gradient phenotype (NEFHG and LEFHG) showed the largest amount of AVC (807 ± 421; 813 ± 281 mm 3 respectively) as compared to the low gradient phenotype (LEFLG and PLFLG; 503 ± 326; 555 ± 594 mm 3 respectively, pLEFHG>PLFLG>HEFHG, pPLFLG n=4>LEFHG n=2>NEFHG n=1). Within LEFLG AS, patients with larger AVC (>476.8 mm 3 ) had larger MF (40.2%) and higher cardiovascular mortality (n=5) as compared to patients with less AVC (≤476.8 mm 3 , 17.1% MF, p=0.027, cardiovascular mortality n=2). Conclusion: MF is associated with adverse cardiovascular outcome following TAVR which is most prevalent in low ejection fraction situations. Within the low ejection fraction low gradient subtype large AVC was associated with high amounts of MF and adverse cardiovascular outcome.

Introduction: Invasive right heart catherization (RHC) using exercise-stress is the reference-standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF) but carries the risk of the procedure. Real-time cardiovascular magnetic resonance (RT-CMR) imaging allows bicycle exercise CMR with unprecedented temporal and spatial resolution and may represent a novel non-invasive alternative. Methods: The HFpEF stress trial (NCT03260621) prospectively included 75 patients with echocardiographic signs of diastolic dysfunction and dyspnoea on exertion (E/E’>8, NYHA≥II) who underwent echocardiography, RHC and RT-CMR at rest and exercise-stress. HFpEF was defined according to pulmonary capillary wedge pressure (PCWP ≥15mmHg at rest or ≥25mmHg during exercise stress). RT-CMR functional assessments included time-volume-curves for total and early (1/3) diastolic left ventricular (LV) filling or left atrial (LA) emptying and LV/LA long axis strain (LAS). Results: HFpEF patients (n=34, mean PCWP rest 13mmHg, stress 27mmHg) had higher E/e’ (12.5 vs 9.15), NT-proBNP (255 vs 75ng/l) and LA volume index (43.8 vs 36.2ml/m 2 ) compared to non-HFpEF patients (n=34, rest 8mmHg, stress 18mmHg, p≤0.001 for all). There were no differences in RT-CMR LV total and early diastolic filling at rest and during exercise-stress (p≥0.164). In contrast, RT-CMR revealed impaired stress LA total (p=0.033) and early (p Conclusions: RT-CMR allows highly accurate identification of HFpEF during physiological exercise and may establish itself as a novel non-invasive diagnostic alternative for routine clinical use.

BackgroundDefective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown.MethodsANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute pulmonary embolism (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 via osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells.ResultsCirculating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were elevated in patients with pulmonary embolism and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and transforming growth factor-β1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels.ConclusionOur findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from pulmonary embolism to CTEPH.

Background In heart failure (HF) both Ca2+/Calmodulin-dependent protein-kinase II (CaMKII) and late sodium current (INaL) are known to contribute to arrhythmogenesis as they contribute to action-potential (AP) prolongation and the occurrence of early- (EADs) and delayed afterdepolarizations (DADs). Further, augmented CaMKII and INaL maintain a vicious cycle as they both can activate each other. We recently found that the sodium channel isoform NaV1.8 is upregulated in HF and hypertrophy and that it is involved in INaL-generation. In the current study we investigated the effects of NaV1.8-knock-out (KO) on HF-progression and arrhythmogenesis in a CaMKII-overexpressing HF mouse model. Methods/Results CaMKII overexpressing mice (CaMKII+/T) were crossbred with NaV1.8-KO mice (SCN10A−/−). To our surprise knock-out of NaV1.8 in CaMKII+/T mice (SCN10A−/−/CaMKII+/T) significantly improved survival (median survival 103 days vs 74.5 CaMKII+/T, p Conclusion We found a survival benefit by selective knock-out of the neuronal sodium channel isoform NaV1.8 in a proarrhythmic HF mouse model with augmented CaMKII expression. However, in our model NaV1.8-knock-out showed no effects on HF progression, while cellular proarrhythmic triggers were attenuated. Taken together with our findings in IPS-cardiomyocytes treated with the CRSIPR/Cas9 technology NaV1.8 plays a significant role for the generation of INaL and cellular arrhythmogenic triggers in the cardiomyocyte. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Deutsche Stiftung für Herzforschung

Background/Purpose Takotsubo syndrome (TTS) is characterized by acute transient left ventricular dysfunction in the absence of obstructive coronary lesions. We identified a higher sensitivity to catecholamine-induced stress toxicity as mechanism associated with the TTS phenotype in our former study, but the pathogenesis of TTS is still not completely understood. In this study our aim was to prove the hypothesis of an altered phosphodiesterase (PDE)-dependent 3',5'-cyclic adenosine monophosphate (cAMP)-signaling in TTS in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Methods and results We generated functional TTS-iPSC-CMs and treated them with catecholamines to mimic a TTS-phenotype. To directly address the hypothesis that local cAMP dynamics might be altered in TTS, we used Förster resonance energy transfer (FRET) based cAMP sensors, which are specifically located in the cytosol or at the sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA) micro domain. We demonstrated that β-adrenergic receptor (β-AR) stimulations resulted in stronger cytosolic FRET responses in TTS-CMs compared to controls. In contrast, no differences of cAMP level were observed in the SERCA-PLN micro domain between TTS- and control-iPSC-CMs. To analyze the interplay of β-AR signaling and specific PDE contribution to the cAMP signaling in TTS, specific PDE-inhibitors were used. We were able to show in the cytosol that after β-AR stimulation, the strong effects of the PDE4 family of control cells were significantly decreased in diseased TTS CMs, which is in line with previously described reduced PDE4 activity in failing mouse hearts. In contrast, the contribution of PDE3 to cytoplasmic cAMP degradation was increased in TTS (Figure 1 A). This is in line with increased PDE3A and down-regulated PDE4D protein expression in TTS-iPSC-CMs compared to control cells. Analysis of PDE-dependent cAMP level in the SERCA micro domain show also a significantly reduced PDE4 activity. But the dynamic cytosolic PDE contribution of PDE2 and PDE3 after catecholamine treatment in TTS is lost in SERCA micro domain (Figure1B). Conclusion Our data showed for the first time alterations of local cAMP signaling in healthy and diseased TTS-iPSC-CMs. We demonstrated an isozym shift from PDE4 in control to PDE3 and PDE2 in TTS and identified PDE4 as an important player in the β-adrenergic cAMP signaling in TTS. Therefore, PDE4 activators may be a possible new therapeutic target option in the treatment of TTS. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DZHK

Background Right ventricular (RV) involvement complicating myocardial infarction (MI) is thought to impact prognosis, but potent RV markers for risk stratification are lacking. Purpose To assess the frequency and prognostic implications of concomitant structural and functional RV injury in MI. Methods Cardiac magnetic resonance (CMR) was performed in 1235 patients with MI (STEMI: n=795; NSTEMI: n=440) 3 days after reperfusion by primary percutaneous coronary intervention. Central core laboratory-masked analyses included structural (edema representing reversible ischemia, irreversible infarction, microvascular obstruction [MVO]) and functional (ejection fraction, global longitudinal strain [GLS]) RV alterations. The clinical endpoint was the 12-month rate of major adverse cardiac events (MACE). Results RV ischemia and infarction were observed in 19.6% and 12.1% of patients, respectively, suggesting complete myocardial salvage in one-third of patients. RV ischemia was associated with a significantly increased risk of MACE (10.1% versus 6.2%; p=0.035), while patients with RV infarction showed only numerically increased event rates (p=0.075). RV MVO was observed in 2.4% and not linked to outcome (p=0.894). Stratification according to median RV GLS (10.2% versus 3.8%; p Conclusions RV GLS is a predictor of post-infarction adverse events over and above established risk factors, while structural RV involvement was not independently associated with outcome. Funding Acknowledgement Type of funding source: None

Background Myocardial fibrosis is a major determinant of outcome in aortic stenosis (AS). Novel fast real-time (RT) cardiac magnetic resonance (CMR) mapping techniques allow comprehensive quantification of fibrosis but have not yet been adequately validated against standard techniques and histology. Methods Patients with severe AS underwent CMR before (n=110) and left ventricular (LV) endomyocardial biopsy (n=46) at transcatheter aortic valve replacement (TAVR). Midventricular short axis native, post-contrast T1 and extracellular volume fraction (ECV) maps were generated using commercially available 5(3)3 MOLLI and RT single-shot inversion recovery fast low-angle shot (FLASH) with radial undersampling. ECV and LV mass were used to calculate LV matrix volumes. Variability and agreements were assessed between RT, MOLLI and histology using intraclass correlation coefficients, coefficients of variation and Bland Altman analyses. Results RT and MOLLI derived ECV were similar for myocardium (26.2 vs. 26.5, p=0.073) and inter-ventricular septum (26.2 vs. 26.5, p=0.216). MOLLI native T1 time was in median 20 ms longer compared to RT (p0.91), excellent for post-contrast T1 times (ICC >0.81) and good for native T1 times (ICC >0.62). Diffuse collagen volume fraction by biopsies was in median 7.8%. ECV (RT r=0.345, p=0.039; MOLLI r=0.40, p=0.010) and LV matrix volumes (RT r=0.45, p=0.005; MOLLI r=0.43, p=0.007) were the only parameters associated with histology. Conclusions RT mapping offers precise T1 and ECV assessments with similar agreement with histology as compared to conventional MOLLI techniques. Single-shot real time techniques may be advantageous in sicker patients prone to dyspnoea or arrhythmia. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Research Foundation

In heart failure, enhanced persistent current through neuronal sodium channel NaV1.8 (INaL) may induce influx of Na+ into cardiomyocytes. This may cause Ca2+ influx via the Na+/Ca2+ exchanger leading to increased proarrhythmogenic diastolic sarcoplasmic reticulum (SR) Ca2+ leak. This Ca2+ may activate Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) which can induce INaL augmentation by phosphorylating NaV1.5 channels leading to a vicious cycle between INaL and CaMKIIδ. Here, we examined whether CaMKIIδ associates with NaV1.8 in human and mouse cardiomyocytes thereby regulating its function. Interaction and co-localisation of CaMKIIδ and NaV1.8 were confirmed by co-immunoprecipitation and immunocytochemistry. Whole-cell patch clamp showed a potent reduction of INaL after addition of novel specific Nav1.8 blockers, either A-803467 (30 nmol/L) or PF-01247324 (1 μmol/L) in failing mouse cardiomyocytes overexpressing CaMKIIδc (CaMKIIδc+/T: −109.4±10.6 vs A-803467: −56.9±11.7 and PF-01247324:−-69.9±8.6 A*ms*F-1). In failing human cardiomyocytes inhibition of either NaV1.8 or CaMKIIδ using AIP (1 μmol/L) or AIP and PF-01247324 together led to a significant and comparable decrease of INaL (control: −93.7±7.1 vs PF-01247324: −56.8±6.6; AIP: −44.2±6.6; AIP+PF-01247324: −39.8±5.4 A*ms*F-1). Furthermore, to confirm whether observed alterations in INaL after inhibition of NaV1.8 are not due to an overall reduction in peak sodium current (INa) we measured INa properties in mouse cardiomyocytes. Importantly, we observed no difference neither in the peak nor in inactivation between wild type (WT), WT with PF-01247324 and in mice lacking NaV1.8. Using confocal microscopy we investigated whether inhibition of the NaV1.8-mediated INaL could attenuate the increase of proarrhythmogenic SR Ca2+ spark frequency (CaSpF) caused by overexpression of CaMKIIδ in mice. We observed a significant reduction of CaSpF in both NaV1.8 inhibitor groups (PF-01247324: 0.51±0.08 and A-803467: 0.57±0.08 μm–1 s–1) compared to control (1.00±0.13 μm–1 s–1). Incubation of human failing cardiomyocytes with either AIP (0.35±0.06 μm–1 s–1) or PF-01247324 (0.44±0.11 μm–1 s–1), or blocking CaMKIIδ and NaV1.8 together (0.30±0.08 μm–1 s–1) resulted in significant decrease of CaSpF compared to control (0.89±0.13 μm–1 s–1). In conclusion, we show for the first time subcellular localisation of the neuronal sodium channel NaV1.8 and its interaction with CaMKIIδ in both human and mouse ventricular cardiomyocytes. Moreover, pharmacological inhibition of NaV1.8 caused a reduction of the augmented INaL and spontaneous diastolic SR-Ca2+ release in both failing human and mouse cardiomyocytes. NaV1.8 and CaMKIIδ interaction seem to play a relevant role for the generation of arrhythmogenic triggers (INaL & spontaneous diastolic SR-Ca2+ release) in both human and mouse cardiomyocytes from failing hearts. Funding Acknowledgement Type of funding source: None