Ventricular arrhythmias and sudden cardiac death are a leading cause of death in patients with atrial fibrillation (AF). This study investigated how AF promotes ventricular arrhythmias.Cellular electrophysiology of AF patients was characterized using human left ventricular (LV) samples from patients with sinus rhythm (n = 25) or rate-controlled AF (n = 16). In LV cardiomyocytes from AF patients, delayed afterdepolarizations and Ca2+ waves, both established triggers for ventricular arrhythmias, were significantly more frequent compared to sinus rhythm patients. In vitro AF simulation in murine LV cardiomyocytes confirmed increased ventricular proarrhythmic activity upon AF. Oxidative Ca2+/calmodulin-dependent protein kinase II activation was increased in murine LV cardiomyocytes after AF simulation. MMVV knock-in mice with genetic ablation of Ca2+/calmodulin-dependent protein kinase II oxidation did not develop ventricular proarrhythmic activity after AF simulation. This study demonstrates that AF promotes ventricular arrhythmogenesis. The findings offer new mechanistic insights into the interaction of AF and ventricular arrhythmias.

AIMS:In dyssynchronous heart failure (DHF), left bundle branch block (LBBB) causes inhomogeneous left ventricular (LV) workload and systolic dysfunction. We aimed to investigate underlying metabolic remodelling in an ovine model. METHODS AND RESULTS:Eleven sheep with dual-chamber-pacemakers for LBBB-like activation (DHF) were studied at baseline and after eight weeks. Six untreated sheep served as controls (CTRL). Regional workload was evaluated using invasive hemodynamics and echocardiography. 18F-fluorodeoxyglucose-tracer positron-emission-tomography/computed tomography visualized regional glucose-uptake. Magnetic resonance imaging assessed fibrosis (late gadolinium enhancement, LGE). Septal and lateral wall tissue was analysed with histology, confocal microscopy, ultra-high-performance liquid chromatography-high resolution mass-spectrometry (UHPLC-HRMS). Dyssynchrony induced low septal and high lateral asymmetry in workload and glucose-uptake. After eight weeks, DHF animals exhibited LV dilation and LVEF decline (31.1±5.1% vs. 59.4±3.5% at baseline, p<0.05). Septal thinning and lateral hypertrophy rebalanced workload and glucose-uptake. No fibrosis was seen on LGE or histology. DHF-animals showed enrichment of mitochondria at the intercalated discs (EMID-sign) - highest in the lateral wall (DHF septal 7.0±4.8% vs. lateral 48.4±12.3%, p<0.05). Mitochondrial redox balance in DHF shifted towards a more oxidised state without evidence of oxidative stress. Metabolomics revealed no differences between septal and lateral walls but severe energy depletion of tricarboxylic acid cycle substrates and phosphocreatine in DHF (fold change DHF/CTRL 0.01, p<0.01). CONCLUSION:Experimental DHF is characterised by non-fibrotic, dilated LV without signs of oxidative stress. Workload increase in the lateral wall leads to hypertrophy and EMID, homogenizing metabolic profiles between wall segments. However, the ventricle enters energy starvation and systolic dysfunction.

Accurate nanoscale detection of hydrogen is essential for understanding hydrogen-related phenomena in materials, yet conventional deuterium tracing is often complicated by residual background hydrogen. This study evaluates tritium as an unambiguous isotopic marker for nanoscale hydrogen analysis in metals using atom probe tomography (APT). Titanium was selected for its ability to incorporate hydrogen isotopes, providing a suitable platform for tritium detection. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and electron backscatter diffraction (EBSD) were performed prior to tritium charging to characterize the initial composition and microstructure. APT analysis in laser-mode before and after tritium charging, at three post-charging intervals, enables tracking of tritium incorporation over time. Thermal desorption analysis (TDA) confirmed the presence of tritium and complemented the SIMS measurements, highlighting the role of the surface oxide layer in modulating tritium release. This work serves as a fundamental benchmarking study for leveraging tritium and APT as a combined tool for understanding the nanoscale location of hydrogen in materials, being relevant for interpreting local processes related to e.g., hydrogen embrittlement.

Potential step chronoamperometry is often used to study the electrochemical unloading process and to determine the diffusion coefficient D of an intercalating atom species in a host material, as it is seemingly easily applicable. The present work emphasises the importance of ensuring a diffusion-controlled unloading process during the potential step chronoamperometry measurement, if determination of the diffusion coefficient is targeted. As an example, diffusion-controlled and non-diffusion-controlled hydrogen unloading series from palladium samples and the resulting diffusion coefficients are presented, for comparison. A literature review summarising the diffusion coefficients of different intercalating species determined for several different systems by this method reveals a systematic error in the results. It turned out that insufficient diffusion control is a common issue in the application of the chronoamperometry method. Based on this finding, it is suggested to verify measurements in the diffusion-controlled regime when chronoamperometry is applied. A suitable verification technique is provided.

BACKGROUND:The Treatment of sleep apnoea Early After Myocardial infarction with Adaptive Servo-Ventilation (TEAM-ASV I) trial showed that adding adaptive servo-ventilation (ASV) to treat sleep-disordered breathing (SDB) early after acute myocardial infarction (AMI) improved myocardial salvage and decreased infarct size. It is purported that ASV may mitigate the inflammatory response, cardiac congestion, or fibrosis, but evidence supporting this assertion is sparse. METHODS:This ancillary analysis of the multicentre, randomised, open-label TEAM-ASV I trial assessed patients with analysable blood samples at baseline and 12-week follow-up. Patients were randomised to early ASV treatment in addition to standard care for AMI and standard care alone (control). Changes in the levels of circulating biomarkers of inflammation (high-sensitivity C-reactive protein [hs-CRP], fibrinogen, interleukin [IL]-6, and interleukin-33 receptor [IL-33R]), fluid overload (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and antigen carbohydrate [CA]-125), and fibrosis (procollagen III type aminoterminal propeptide [PIIINP] and matrix metalloproteinase [MMP]-9) were compared between the ASV and control groups. RESULTS:Forty SDB patients were analysed. The reduction in IL-33R was greater in the control group than in the ASV group (-1.94 [-3.88, 1.56] versus -4.30 [-6.46, -2.02] ng·ml-1). However, changes in other biomarkers of inflammation (hs-CRP, fibrinogen, and IL-6), fluid overload (NT-proBNP and CA-125), and fibrosis (PIIINP and MMP-9) were similar in both groups. CONCLUSIONS:This ancillary analysis of TEAM-ASV I does not support that treatment of SDB in the early phase after AMI with ASV has a clinically relevant short-term effect on biomarkers of inflammation, fluid overload, or fibrosis. Further studies are warranted to explain how early treatment with ASV results in increased myocardial salvage after AMI beyond the effects of SDB treatment on hemodynamics and oxygen demand‒supply mismatch. CLINICAL TRIAL REGISTRATION:NCT02093377.

Testing of metals for hydrogen embrittlement is of great interest for a safe hydrogen infrastructure. However, the costs and efforts involved in in-situ tests in hydrogen pressure autoclaves are high. Simpler alternatives are ex-situ testing with hydrogen pre-charging or in-situ testing with the hollow specimen technique, in which the specimen is pressurized with hydrogen gas from the inside through a longitudinal hole. However, the comparability of the techniques has not been conclusively clarified. Slow strain rate tensile tests are carried out with the three techniques on the nickel-based alloy 718 in wrought and additive manufactured states. Experiments are performed at hydrogen gas pressures up to 200 bar. Testing in nitrogen gas is used as a reference. Hydrogen pre-charging was conducted at 350 degrees C and 100 bar pressure. The in-situ techniques show increasing hydrogen embrittlement with increasing hydrogen pressure. The most severe embrittlement could be achieved with hydrogen pre-charging. Conventional and hollow specimens agree on yield strength and tensile strength but differ in elongation to failure and reduction of area. Influencing variables such as surface qualities and multi-axial stresses in hollow specimens resulting from the internal pressure are discussed. The damage mechanisms of all techniques are analyzed by fracture surface examinations using SEM and EBSD.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide, underscoring the urgent need for novel therapeutic targets and strategies. The kinase MARK4 (MAP (microtubule-associated proteins)/microtubule affinity-regulating kinase 4) regulates microtubule-associated proteins pivotal for cell polarity, protein stability, and intracellular signaling. Animal models of heart failure revealed elevated MARK4 levels, which correlated with impaired cardiac contractility. However, the involvement of MARK4 and its potential as a molecular drug target has not yet been explored in the myocardium of cardiovascular patients. We investigated the MARK4 mRNA expression in human myocardial biopsies of 152 high-risk cardiovascular patients undergoing cardiac surgery. Comprehensive echocardiography as well as testing for sleep-disordered breathing (SDB), a critical comorbidity in heart failure, were assessed preoperatively. We observed a substantial upregulation of myocardial MARK4 expression in patients with impaired cardiac contractility, resulting in an inverse correlation with the left ventricular ejection fraction. Myocardial MARK4 expression also correlated with echocardiographic E/e’, a central parameter of diastolic dysfunction. Mechanistically, our analyses revealed that MARK4 expression increases in SDB and under hypoxic conditions, as evidenced by significant correlations between myocardial MARK4 expression and factors like mean oxygen saturation, time with oxygen saturation below 90%, and the oxygen desaturation index. Multivariable regression analysis revealed that both left ventricular ejection fraction and mean oxygen saturation were independently associated with dysregulated MARK4 levels, even when controlling for important clinical covariables as potential confounders. Taken together, our findings demonstrate that MARK4 expression is highly increased in the myocardium of cardiovascular high-risk patients, suggesting it is a potential molecular target against cardiovascular diseases.

Heart failure and cardiovascular disease represent a significant burden on healthcare systems worldwide. Recent evidence associates an increased expression of the dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) with an impaired cardiac function in mice. However, there remains a paucity of data on myocardial DYRK1B expression in patients with cardiovascular disease in the context of other comorbidities. In our study, we examined DYRK1B mRNA expression in human right atrial appendage biopsies from 159 patients undergoing elective coronary artery bypass surgery. Each patient was tested for sleep-disordered breathing the night prior to surgery. In this large representative study cohort with cardiovascular high-risk patients, we found that an impaired cardiac function as well as sleep-disordered breathing (SDB), including various oxidative stress parameters, were associated with an increased myocardial DYRK1B expression. A multivariate regression analysis revealed left ventricular ejection fraction and the presence of SDB as significant predictors of the myocardial DYRK1B expression independent of other clinical covariates. Based on these findings, DYRK1B represents a promising molecular target in patients with heart failure and reduced ejection fraction as well in patients with sleep-disordered breathing.

The understanding of cardiomyopathies is hindered by a lack of quantitative histologic data. To address this methodical gap, we wrote a MATLAB-based image analysis platform to quantify nuclear and cellular disarray. We validated its utility in an animal model of tachycardiomyopathy (T-CM), whose ultrastructural remodeling processes have only partially been characterized and differ substantially from more prevalent cardiomyopathies. Six rabbits received right ventricular pacemaker implants. Three animals were paced incrementally up to 380 bpm for 30 days to induce T-CM. In three control rabbits, the pacemaker remained inactive (SHAM). Left ventricular tissue was collected, fixed in formalin, embedded in paraffin, stained, and digitized for nuclear morphometry, texture analysis, orientation analysis, and vascular architecture evaluation. Nuclear segmentation performed by the software was highly accurate, closely matching manual counts (mean manual nuclear count per slide = 81.3 ± 3.8, mean automated nuclear count per slide = 81.9 ± 4.3, r = 0.981, p<0.001). In T-CM, nuclei were enlarged [SHAM (a.u.) = 2362, T-CM (a.u.) = 2660, p=0.0042]. Texture patterns differed between the groups with higher nuclear contrast in T-CM [SHAM (a.u.) = 0.0169, T-CM (a.u.) = 0.0247, p=0.0149], highlighting structural remodeling at the nuclear level. Median vessel size increased in T-CM [SHAM (a.u.) = 1532, T-CM (a.u.) = 2421, p<0.0001]. In conclusion, our MATLAB-based image analysis platform allows high-throughput quantification of nuclear and extracellular disarray. It identified enlargement of nuclei and increased nuclear contrast as part of ultrastructural remodeling in tachycardiomyopathy.

AIMS:Transthyretin amyloid cardiomyopathy (ATTR-CM) is marked by deposition of transthyretin amyloid in the myocardium. Patients present with symptoms of heart failure, left ventricular (LV) hypertrophy, diastolic dysfunction, and arrhythmias. Echocardiographic apical sparing, quantified via the relative apical sparing (RELAPS) pattern, is a hallmark imaging feature but its histopathological and clinical implications remain uncertain. This study investigated the association between apical sparing, myocardial amyloid load, and clinical phenotypes in newly diagnosed ATTR-CM. METHODS AND RESULTS:We prospectively enrolled 61 patients undergoing LV endomyocardial biopsy for suspected amyloidosis between May 2022 and May 2024. After histological confirmation, 56 patients with wild-type ATTR-CM were included. LV amyloid load was quantified from Congo red-stained endomyocardial biopsies. Echocardiographic parameters including global longitudinal strain (GLS) and RELAPS were assessed peri-interventionally. Clinical, laboratory, and imaging features were compared between patients with and without RELAPS. Patients with RELAPS had significantly higher LV amyloid load than those without. RELAPS was associated with elevated N-terminal pro-B-type natriuretic peptide levels, higher Perugini scores, lower GLS and atrial strain. No differences between patients with and without RELAPS were found regarding age or wall thickness. RELAPS correlated with markers of disease severity and atrial remodelling. The Perugini scores failed to distinguish intermediate levels of myocardial amyloid content in 71.1% of cases. CONCLUSIONS:Apical sparing reflects advanced myocardial involvement in ATTR-CM and correlates with increased amyloid load and biomarkers in a large endomyocardial biopsy collective. RELAPS, together with histological amyloid quantification, offers valuable insights for risk stratification and may guide therapeutic intervention in this progressive disease.

Hydrogen plays an increasingly important role in green energy technologies. For instance, proton‐conducting oxides with high performance for fuel cell components or electrolyzers need to be developed. However, this requires a fundamental understanding of hydrogen‐defects interactions. Although point defects and grain boundaries in oxides have been extensively studied, the role of dislocations as line defects remains less understood, primarily due to the challenge for effective dislocation engineering in brittle oxides. In this work, we demonstrate the impact of dislocations in bulk single‐crystal perovskite oxide SrTiO 3 on hydrogen uptake and diffusion using deuterium as tracer. Dislocations with a high density up to ∼10 14 /m 2 were mechanically introduced at room temperature. Exposing this dislocation‐rich region and the reference regions (with a dislocation density of ∼10 10 /m 2 ) to deuterium at 400°C for 1 h, followed by secondary ion mass spectrometry measurements, we observed a ∼100 times increase in deuterium incorporation in the dislocation‐rich region. The result suggests that dislocations in oxides can act as an effective reservoir for deuterium. This proof‐of‐concept brings new insights into the emerging hydrogen‐dislocation interactions in functional oxides.

Rationale: The Treatment of sleep apnea Early After Myocardial infarction with Adaptive Servo-Ventilation (TEAM-ASV I) trial showed that adding adaptive servo-ventilation (ASV) to treat sleep-disordered breathing (SDB) early after acute myocardial infarction improved myocardial salvage and decreased infarct size. It is purported that ASV may mitigate the inflammatory response, cardiac congestion, or fibrosis, but evidence supporting this assertion is sparse. Objectives: To evaluate whether treatment of SDB early after AMI with ASV affects circulating biomarkers of inflammation, fluid overload, and fibrosis. Methods: This ancillary analysis of the multicenter, randomized, open-label TEAM-ASV I trial assessed patients with first-time acute myocardial infarction (AMI) and SDB (apnea-hypopnea index [AHI] ≥15/h) and analyzable blood samples at baseline and 12-week follow-up. Patients were randomized to early ASV treatment in addition to standard care of AMI and standard care alone (control). Changes in levels of circulating biomarkers were compared between the ASV and control groups. We tested biomarkers of inflammation (high-sensitivity C-reactive protein [hs-CRP], fibrinogen, interleukin [IL]-6, interleukin-33 receptor [IL-33R]), fluid overload (N-terminal pro B-type natriuretic peptide [NT-proBNP], antigen carbohydrate [CA]-125), and fibrosis (procollagen III type aminoterminal propeptide [PIIINP], matrix metalloproteinase [MMP]-9). Results: Blood samples of SDB patients (n=40) were analyzed at baseline (3.5±0.2 days after AMI) and 12 weeks. The reduction of IL-33R was greater in the control group than in the ASV group (-1.94 [-3.88, 1.56] versus -4.30 [-6.46, -2.02]). However, changes of other biomarkers of inflammation (hs-CRP, fibrinogen, IL-6), fluid overload (NT-proBNP, CA-125), and fibrosis (PIIINP, and MMP-9) were similar in both groups. Conclusion: This ancillary analysis of TEAM-ASV I does not support that treatment of SDB in the early phase after AMI with ASV has a clinically relevant short-term effect on biomarkers of inflammation, fluid overload, or fibrosis. Further studies are warranted to explain how early treatment with ASV results in increased myocardial salvage after AMI beyond effects of SDB treatment on hemodynamics and oxygen demand-supply mismatch.

For the usage of intercalating material systems to store and convert energy of renewable sources, their phase stabilities need to be engineered to adjust to the desired operation conditions. This can, e.g., be achieved by miniaturization, leading to constraints that modify the systems thermodynamics. The experimental investigation of such systems is cumbersome, as experiments on nano-sized systems are time intensive. Numerical simulations based on chemo-mechanically coupled continuum models can serve as a tool helping to understand these systems and to study different effects of miniaturization. In this work we present a phase-field model for the example of open, constrained metal hydrogen thin film systems, that allows the prediction of the hydrogen intercalation and hydride formation. The model relies on a free energy density consisting of chemical, mechanical and interfacial parts. The first two contributions are based on measurements of the thermodynamics of open Niobium-Hydrogen thin films, that are chosen as a model. The interfacial contribution of Cahn- Hilliard-type introduces a phase-field description for both phases. To study the systems behavior a numerical implementation in the commercial Finite Element solver ABAQUS is presented. Numerical results are presented and compared to previously obtained experimental results on the open systems thermodynamics. We show, that the model is capable of reproducing experimentally observed behavior of thin films especially regarding the coexistence of alpha- and hydride-phase in thermodynamic equilibrium, where the equilibrium concentrations in both phases drastically differ from bulk values, and gradients in concentration and stresses result due to the interfacial constraint conditions.

Hydrogen plays an increasingly important role in green energy technologies. For instance, proton-conducting oxides with high performance for fuel cell components or electrolyzers need to be developed. However, this requires a fundamental understanding of hydrogen-defects interactions. Although point defects and grain boundaries in oxides have been extensively studied, the role of dislocations as line defects remains less understood, primarily due to the challenge for effective dislocation engineering in brittle oxides. In this work, we demonstrate the impact of dislocations in bulk single-crystal perovskite oxide SrTiO3 on hydrogen uptake and diffusion using deuterium as tracer. Dislocations with a high density up to similar to 1014/m2 were mechanically introduced at room temperature. Exposing this dislocation-rich region and the reference regions (with a dislocation density of similar to 1010/m2) to deuterium at 400 degrees C for 1 h, followed by secondary ion mass spectrometry measurements, we observed a similar to 100 times increase in deuterium incorporation in the dislocation-rich region. The result suggests that dislocations in oxides can act as an effective reservoir for deuterium. This proof-of-concept brings new insights into the emerging hydrogen-dislocation interactions in functional oxides.

Hydrogen embrittlement (HE) can significantly degrade the mechanical properties of steels. This phenomenon is particularly relevant for high-strength steels where large elastic stresses lead to detrimental localized concentrations of hydrogen at defects. In this study, unnotched rotating bending specimens of the bearing steel SAE 52100 (100Cr6) quenched and tempered at 180 °C and 400 °C were electrochemically charged with hydrogen. Charged and non-charged specimens then underwent rotating bending fatigue testing, either immediately after charging or after aging at room temperature up to 72 h. The hydrogen-charged specimens annealed at 180 °C showed a sizeable drop in fatigue limit and fatigue lifetime compared to the non-charged specimens with cracks mainly originating from near-surface non-metallic inclusions. In comparison, the specimens annealed at 400 °C exhibited a moderate drop in fatigue limit and lifetime due to hydrogen charging with cracks originating mostly from the surface. Aging had only insignificant effects on the fatigue lifetime. Notably, annealing of charged samples for 2 h at 180 °C restored their lifetime to that of non-charged specimens.