Abstract
Background
Fibroblast activation protein (FAP) plays an important role in cardiac wound healing and remodelling. Although initially developed as a theranostic ligand for metastasized cancer, ...FAPI tracers have recently been used to study cardiac remodelling following myocardial infarction in small animal models. Aim of our analysis was to evaluate the activity of fibroblast activation protein via (FAPI) PET-CT scans in human hearts.
Methods
FAPI-PET-CT scans of 229 patients of two consecutive cohorts (initial cohort: n=185; confirmatory cohort: n=44) suffering from metastasized cancer were analysed using a 17-segment model of the left ventricle. Patient characteristics included age, sex, cancer entity, body mass index, renal function, thyroid stimulating hormone, cardiovascular risk factors, previous radiation to the chest, chemotherapies received, and current cardiac medication. Multivariate regression models were created using data from the initial cohort by selecting variables according to Akaike's information criterion in a step-down approach. Linear regression models were used for signal prediction to find potential outliers with unexpectedly high signal intensities. The created models were subsequently evaluated in the confirmatory cohort for reproducibility.
Results
Signal intensity were significantly higher in patients with overweight, diabetes and following radiation to the chest. Our prediction model performed well in both cohorts. A focal enrichment pattern was more frequently observed in patients with known cardiovascular risk factors.
Conclusions
FAPI-PET-CT scans represent a new imaging modality to potentially investigate active cardiac remodelling. High signal intensities are associated with cardiovascular risk factors and metabolic disease. Furthermore, high cardiac FAPI signal intensities are suggestive of an underlying cardiac disease.
Funding Acknowledgement
Type of funding source: None
The central region of the Milky Way is one of the foremost locations to look for dark matter (DM) signatures. We report the first results on a search for DM particle annihilation signals using new ...observations from an unprecedented γ -ray survey of the Galactic Center (GC) region, i.e., the Inner Galaxy Survey, at very high energies ( ≳100 GeV ) performed with the H.E.S.S. array of five ground-based Cherenkov telescopes. No significant γ -ray excess is found in the search region of the 2014–2020 dataset and a profile likelihood ratio analysis is carried out to set exclusion limits on the annihilation cross section ⟨ σv ⟩ . Assuming Einasto and Navarro-Frenk-White (NFW) DM density profiles at the GC, these constraints are the strongest obtained so far in the TeV DM mass range. For the Einasto profile, the constraints reach ⟨ σv ⟩ values of 3.7×10-26 cm3 s -1 for 1.5 TeV DM mass in the W+W- annihilation channel, and 1.2×10-26 cm3 s -1 for 0.7 TeV DM mass in the τ+τ- annihilation channel. With the H.E.S.S. Inner Galaxy Survey, ground-based γ -ray observations thus probe ⟨ σv ⟩ values expected from thermal-relic annihilating TeV DM particles.
Abstract
Background
Atrial fibrillation occurs in the context of atrial remodeling processes which are the result of an underlying atrial cardiomyopathy (AC). Insufficient understanding of the ...pathophysiological mechanisms behind AC contributes significantly to the fact that current clinical strategies for the treatment of atrial fibrillation are often ineffective. A systematic investigation of these cellular remodeling processes in the context of the various cardiac diseases underlying AC is still missing.
Purpose
The aim of this study was to characterize different subtypes of AC associated with common cardiac disease entities by systematic cellular electrophysiological characterization of the atria in combination with molecular and structural investigations.
Methods
For a comprehensive analysis of the molecular changes associated with AC, we characterized several mouse models of common heart diseases, including models for dilated cardiomyopathy (DCM), HFpEF, mitral regurgitation and immune checkpoint inhibitor (ICI-)mediated myocarditis. Patch clamp experiments were performed on isolated atrial cardiomyocytes to study atrial action potentials (aAP) and different ion currents contributing to the aAP. The cellular electrophysiological parameters of the different models were correlated to clinical parameters (ecg, echocardiography of the atria) of the mouse models and with data from RNA sequencing of the mice’ atria.
Results
Patch clamp measurements performed on isolated left and right atrial cardiomyocytes revealed distinct differences among the examined models. In all pathophysiological models, the aAP was significantly shorter than in the corresponding wild type mice. The different ion current components we measured various changes in potassium, sodium and calcium currents. The repolarizing TASK-1 potassium current was significantly increased in all models. The DCM model caused by an R636Q mutation in the RBM20 gene showed the most severe changes in cellular electrophysiology. Considering the detected atrial changes, we investigated the effects of SGLTi on atrial cardiomyocytes of the different models. When elevated concentrations of dapa-, empa- and sotagliflozin were administrated on atrial cardiomyocytes, a class-I-antiarrhythmic effect with reduced aAP inducibility and changes in the aAP duration could be observed.
Conclusion
Characterization of murine models of cardiac disease with respect to classification of AC subtypes revealed various electrical remodeling processes at the level of ion currents involved in aAP formation. A potent inductor of atrial proarrhythmogenity in the AC subtypes was an aAP shortening caused by an increase in repolarizing potassium currents, mediated especially by TASK-1. The most severe electrical remodeling in atria cardiomyocytes was observed in the RBM20-mutant model (DCM). SGLTi exhibit anti-arrhythmic effects in different murine disease models and may provide future treatment options for patients with AC.
Recurrent novae are repeating thermonuclear explosions in the outer layers of white dwarfs, due to the accretion of fresh material from a binary companion. The shock generated when ejected material ...slams into the companion star's wind can accelerate particles. We report very-high-energy (VHE; Formula: see text) gamma rays from the recurrent nova RS Ophiuchi, up to 1 month after its 2021 outburst, observed using the High Energy Stereoscopic System (H.E.S.S.). The temporal profile of VHE emission is similar to that of lower-energy giga-electron volt emission, indicating a common origin, with a 2-day delay in peak flux. These observations constrain models of time-dependent particle energization, favoring a hadronic emission scenario over the leptonic alternative. Shocks in dense winds provide favorable environments for efficient acceleration of cosmic rays to very high energies.
Context.
Young massive stellar clusters are extreme environments and potentially provide the means for efficient particle acceleration. Indeed, they are increasingly considered as being responsible ...for a significant fraction of cosmic rays (CRs) that are accelerated within the Milky Way. Westerlund 1, the most massive known young stellar cluster in our Galaxy, is a prime candidate for studying this hypothesis. While the very-high-energy
γ
-ray source HESS J1646−458 has been detected in the vicinity of Westerlund 1 in the past, its association could not be firmly identified.
Aims.
We aim to identify the physical processes responsible for the
γ
-ray emission around Westerlund 1 and thus to understand the role of massive stellar clusters in the acceleration of Galactic CRs better.
Methods.
Using 164 h of data recorded with the High Energy Stereoscopic System (H.E.S.S.), we carried out a deep spectromorphological study of the
γ
-ray emission of HESS J1646−458. We furthermore employed H I and CO observations of the region to infer the presence of gas that could serve as target material for interactions of accelerated CRs.
Results.
We detected large-scale (∼2° diameter)
γ
-ray emission with a complex morphology, exhibiting a shell-like structure and showing no significant variation with
γ
-ray energy. The combined energy spectrum of the emission extends to several tens of TeV, and it is uniform across the entire source region. We did not find a clear correlation of the
γ
-ray emission with gas clouds as identified through H I and CO observations.
Conclusions.
We conclude that, of the known objects within the region, only Westerlund 1 can explain the majority of the
γ
-ray emission. Several CR acceleration sites and mechanisms are conceivable and discussed in detail. While it seems clear that Westerlund 1 acts as a powerful particle accelerator, no firm conclusions on the contribution of massive stellar clusters to the flux of Galactic CRs in general can be drawn at this point.
Abstract
Background and purpose
Adenosine-to-Inosine (A-to-I) RNA editing is a post-transcriptional modification process that affects the secondary structure of RNAs. Changes in RNA editing have been ...associated with human diseases. We therefore aimed to analyze editing in the healthy and failing human heart.
Methods and results
Transcriptome sequencing of human heart samples of heart failure (HF) patients (n=20) and controls (n=10) revealed A-to-I editing as the major type of editing (>80%). In HF patients, RNA editing was reduced, which was primarily attributable to Alu elements in introns of protein-coding genes. We identified 166 upregulated circRNAs in HF, with the majority showing reduced RNA editing in their parental host gene (88.3%). CircRNA expression did not correlate with their corresponding host gene (R=0.07, P<0.05), suggesting that an alternative splicing mechanism gives rise to the elevated circRNA levels in HF. The RNA editing enzyme ADAR2, which binds to RNA regions that are edited from adenosine to inosine, was decreased in failing human hearts (−68.2%). In vitro, reduction of ADAR2 increased circRNA levels suggesting a causal effect of reduced ADAR2 levels on increased circRNAs in the failing human heart. To gain mechanistic insight, we examined the formation of circRNAs on one exemplary candidate. AKAP13 was among the top edited mRNAs in the human heart and gave rise to a circular transcript, which was elevated in HF. ADAR2 reduced the formation of double-stranded structures in AKAP13 pre-mRNA, thereby reducing the stability of Alu elements and the circularization of the resulting circRNA. Overexpression of circAKAP13 impaired the sarcomere regularity of human induced pluripotent stem cell-derived cardiomyocytes (−31.0%).
Conclusion
Our study shows that ADAR2 mediates A-to-I RNA editing in the human heart. We describe an alternative splicing mechanism of circRNAs in the human heart. In the healthy human heart, A-to-I RNA editing represses the formation of dsRNA structures of Alu elements thereby favoring linear mRNA splicing. Our results contribute to a better mechanistic understanding into the human-specific regulation of circRNA formation and are relevant to diseases with reduced RNA editing and increased circRNA levels.
Funding Acknowledgement
Type of funding sources: None.
Abstract Magnetic fields in galaxies and galaxy clusters are believed to be the result of the amplification of intergalactic seed fields during the formation of large-scale structures in the ...universe. However, the origin, strength, and morphology of this intergalactic magnetic field (IGMF) remain unknown. Lower limits on (or indirect detection of) the IGMF can be obtained from observations of high-energy gamma rays from distant blazars. Gamma rays interact with the extragalactic background light to produce electron−positron pairs, which can subsequently initiate electromagnetic cascades. The gamma-ray signature of the cascade depends on the IGMF since it deflects the pairs. Here we report on a new search for this cascade emission using a combined data set from the Fermi Large Area Telescope and the High Energy Stereoscopic System. Using state-of-the-art Monte Carlo predictions for the cascade signal, our results place a lower limit on the IGMF of B > 7.1 × 10 −16 G for a coherence length of 1 Mpc even when blazar duty cycles as short as 10 yr are assumed. This improves on previous lower limits by a factor of 2. For longer duty cycles of 10 4 (10 7 ) yr, IGMF strengths below 1.8 × 10 −14 G (3.9 × 10 −14 G) are excluded, which rules out specific models for IGMF generation in the early universe.
Aims. The identification of PeVatrons, hadronic particle accelerators reaching the knee of the cosmic ray spectrum (few × 10 15 eV), is crucial to understand the origin of cosmic rays in the Galaxy. ...We provide an update on the unidentified source HESS J1702-420, a promising PeVatron candidate. Methods. We present new observations of HESS J1702-420 made with the High Energy Stereoscopic System (H.E.S.S.), and processed using improved analysis techniques. The analysis configuration was optimized to enhance the collection area at the highest energies. We applied a three-dimensional likelihood analysis to model the source region and adjust non thermal radiative spectral models to the γ -ray data. We also analyzed archival Fermi Large Area Telescope data to constrain the source spectrum at γ -ray energies > 10 GeV. Results. We report the detection of γ -rays up to 100 TeV from a specific region of HESS J1702-420, which is well described by a new source component called HESS J1702-420A that was separated from the bulk of TeV emission at a 5.4 σ confidence level. The power law γ -ray spectrum of HESS J1702-420A extends with an index of Γ = 1.53 ± 0.19 stat ± 0.20 sys and without curvature up to the energy band 64−113 TeV, in which it was detected by H.E.S.S. at a 4.0 σ confidence level. This makes HESS J1702-420A a compelling candidate site for the presence of extremely high energy cosmic rays. With a flux above 2 TeV of (2.08 ± 0.49 stat ± 0.62 sys ) × 10 −13 cm −2 s −1 and a radius of (0.06 ± 0.02 stat ± 0.03 sys )°, HESS J1702-420A is outshone – below a few tens of TeV – by the companion HESS J1702-420B. The latter has a steep spectral index of Γ = 2.62 ± 0.10 stat ± 0.20 sys and an elongated shape, and it accounts for most of the low-energy HESS J1702-420 flux. Simple hadronic and leptonic emission models can be well adjusted to the spectra of both components. Remarkably, in a hadronic scenario, the cut-off energy of the particle distribution powering HESS J1702-420A is found to be higher than 0.5 PeV at a 95% confidence level. Conclusions. For the first time, H.E.S.S. resolved two components with significantly different morphologies and spectral indices, both detected at > 5 σ confidence level, whose combined emissions result in the source HESS J1702-420. We detected HESS J1702-420A at a 4.0 σ confidence level in the energy band 64−113 TeV, which brings evidence for the source emission up to 100 TeV. In a hadronic emission scenario, the hard γ -ray spectrum of HESS J1702-420A implies that the source likely harbors PeV protons, thus becoming one of the most solid PeVatron candidates detected so far in H.E.S.S. data. However, a leptonic origin of the observed TeV emission cannot be ruled out either.
Abstract
The High Altitude Water Cherenkov (HAWC) observatory and the High Energy Stereoscopic System (H.E.S.S.) are two leading instruments in the ground-based very-high-energy
γ
-ray domain. HAWC ...employs the water Cherenkov detection (WCD) technique, while H.E.S.S. is an array of Imaging Atmospheric Cherenkov Telescopes (IACTs). The two facilities therefore differ in multiple aspects, including their observation strategy, the size of their field of view, and their angular resolution, leading to different analysis approaches. Until now, it has been unclear if the results of observations by both types of instruments are consistent: several of the recently discovered HAWC sources have been followed up by IACTs, resulting in a confirmed detection only in a minority of cases. With this paper, we go further and try to resolve the tensions between previous results by performing a new analysis of the H.E.S.S. Galactic plane survey data, applying an analysis technique comparable between H.E.S.S. and HAWC. Events above 1 TeV are selected for both data sets, the point-spread function of H.E.S.S. is broadened to approach that of HAWC, and a similar background estimation method is used. This is the first detailed comparison of the Galactic plane observed by both instruments. H.E.S.S. can confirm the
γ
-ray emission of four HAWC sources among seven previously undetected by IACTs, while the three others have measured fluxes below the sensitivity of the H.E.S.S. data set. Remaining differences in the overall
γ
-ray flux can be explained by the systematic uncertainties. Therefore, we confirm a consistent view of the
γ
-ray sky between WCD and IACT techniques.
PDF
