Commentary: raised c-troponin levels as a sign of myocardial injury after COVID-19 vaccination in healthy individuals are worrying.

BACKGROUND: Recently, Buergin et al. (Eur J Heart Fail 25(10):1871-1881, 2023 doi:10.1002/ejhf.2978) thoroughly measured a frequency of 2.8% elevated high-sensitivity cardiac troponin T levels, a sign of myocardial damage, after mRNA-1273 (Moderna) booster vaccinations. In their discussion, they claim that before vaccinations were available, the incidence and extent of myocardial damage associated with COVID-19 infection would have been much higher. We here scrutinize this claim based on empirical data. MAIN BODY: Burgin et al. have only cited papers in support of their claim which considered hospitalized COVID-19 patients. After extracting COVID-19 infection data from Germany and Switzerland and the expected frequency of elevated troponin levels after COVID-19 infection in both hospitalized and non-hospitalized individuals, we find that the extent of myocardial damage after vaccinating a considerable proportion of the general population is expected to be much higher than after natural infections. CONCLUSIONS: The claim that the extent of myocardial injury after COVID-19 infection would be higher than after vaccination is not supported by empirical evidence and therefore wrong. We conclude that cross-national systematic observational studies should be conducted that allow a more precise estimation of the risk-benefit ratio of COVID-19 mRNA vaccinations.

MsQuality: an interoperable open-source package for the calculation of standardized quality metrics of mass spectrometry data.

MOTIVATION: Multiple factors can impact accuracy and reproducibility of mass spectrometry data. There is a need to integrate quality assessment and control into data analytic workflows. RESULTS: The MsQuality package calculates 43 low-level quality metrics based on the controlled mzQC vocabulary defined by the HUPO-PSI on a single mass spectrometry-based measurement of a sample. It helps to identify low-quality measurements and track data quality. Its use of community-standard quality metrics facilitates comparability of quality assessment and control (QA/QC) criteria across datasets. AVAILABILITY AND IMPLEMENTATION: The R package MsQuality is available through Bioconductor at https://bioconductor.org/packages/MsQuality.

Elevated Temperature, Nitrate and Diesel Oil Enhance the Distribution of the Opportunistic Pathogens Scedosporium spp.

Scedosporium infections mainly occur after aspiration of contaminated water or inoculation with polluted environmental materials. Scedosporium spp. have been isolated from anthropogenic environments frequently. To understand their propagation and routes of infection, possible reservoirs of Scedosporium spp. should be explored. In this study, the impact of temperature, diesel and nitrate on Scedosporium populations in soil is described. Soil was treated with diesel and KNO3 and incubated for nine weeks at 18 and 25 °C. Isolation of Scedosporium strains was done using SceSel+. For the identification of 600 isolated strains, RFLP and rDNA sequencing were used. Scedosporium apiospermum, S. aurantiacum, S. boydii and S. dehoogii were isolated at the beginning and/or the end of incubation. Temperature alone had a minor effect on the Scedosporium population. The combination of 25 °C and nitrate resulted in higher Scedosporium numbers. Treatment with 10 g diesel/kg soil and incubation at 25 °C resulted in even higher abundance, and favored S. apiospermum and S. dehoogii. The results of this study show that diesel-polluted soils favor dispersal of Scedosporium strains, especially S. apiospermum and S. dehoogii. Higher temperature force the effect of supplementations.

Modeling incomplete penetrance in arrhythmogenic cardiomyopathy by human induced pluripotent stem cell derived cardiomyocytes.

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are commonly used to model arrhythmogenic cardiomyopathy (ACM), a heritable cardiac disease characterized by severe ventricular arrhythmias, fibrofatty myocardial replacement and progressive ventricular dysfunction. Although ACM is inherited as an autosomal dominant disease, incomplete penetrance and variable expressivity are extremely common, resulting in different clinical manifestations. Here, we propose hiPSC-CMs as a powerful in vitro model to study incomplete penetrance in ACM. Six hiPSC lines were generated from blood samples of three ACM patients carrying a heterozygous deletion of exon 4 in the PKP2 gene, two asymptomatic (ASY) carriers of the same mutation and one healthy control (CTR), all belonging to the same family. Whole exome sequencing was performed in all family members and hiPSC-CMs were examined by ddPCR, western blot, Wes™ immunoassay system, patch clamp, immunofluorescence and RNASeq. Our results show molecular and functional differences between ACM and ASY hiPSC-CMs, including a higher amount of mutated PKP2 mRNA, a lower expression of the connexin-43 protein, a lower overall density of sodium current, a higher intracellular lipid accumulation and sarcomere disorganization in ACM compared to ASY hiPSC-CMs. Differentially expressed genes were also found, supporting a predisposition for a fatty phenotype in ACM hiPSC-CMs. These data indicate that hiPSC-CMs are a suitable model to study incomplete penetrance in ACM.

VAMS-Based Blood Capillary Sampling for Mass Spectrometry-Based Human Metabolomics Studies.

Volumetric absorptive microsampling (VAMS) is a recently developed sample collection method that enables single-drop blood collection in a minimally invasive manner. Blood biomolecules can then be extracted and processed for analysis using several analytical platforms. The integration of VAMS with conventional mass spectrometry (MS)-based metabolomics approaches is an attractive solution for human studies representing a less-invasive procedure compared to phlebotomy with the additional potential for remote sample collection. However, as we recently demonstrated, VAMS samples require long-term storage at -80 °C. This study investigated the stability of VAMS samples during short-term storage and compared the metabolome obtained from capillary blood collected from the fingertip to those of plasma and venous blood from 22 healthy volunteers. Our results suggest that the blood metabolome collected by VAMS samples is stable at room temperature only for up to 6 h requiring subsequent storage at -80 °C to avoid significant changes in the metabolome. We also demonstrated that capillary blood provides better coverage of the metabolome compared to plasma enabling the analysis of several intracellular metabolites presented in red blood cells. Finally, this work demonstrates that with the appropriate pre-analytical protocol capillary blood can be successfully used for untargeted metabolomics studies.

Effects of Viktor Philippi's Bioenergetic Meditation on Anxiety, Burnout, and Depression: An Analysis of Four Feasibility Studies.

INTRODUCTION: Anxiety, burnout, and depression cause a substantial psychological and social burden. Bioenergetic meditation (BM) was developed by Viktor Philippi as a method to strengthen psychological and physical health. This work presents the results of four feasibility studies investigating the effects of BM developed by Viktor Philippi as a support for people suffering from these psychological disorders. MATERIALS AND METHODS: A total of four prospective, non-randomized feasibility studies were conducted (N1 = 185, N2 = 140, N3 = 33, N4 = 32). Studies 1 and 2 were multicentric studies with a pre-post comparison consisting of 10 BMs within 10 weeks with individual study start and end points. Studies 3 and 4 consisted of 7 BMs within 3 days with a pre-post evaluation and follow-up measurements at 6, 12, and 18 months. The Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II), and Hamburg Burnout Inventory (HBI) were used to measure symptoms of anxiety, depression, and burnout, respectively. RESULTS: After 10 BMs within 10 weeks, highly reliable decreases in symptoms of depression occurred in 58-73% of cases (p < 0.005). The median BDI-II score declined significantly by 60% (p < 0.0001) after 10 weeks of BM. Symptoms of anxiety were highly reliably reduced in roughly one-third of cases after 10 weekly BMs, with the average total BAI score declining from a severe to a moderate anxiety (p < 0.0001). The HBI showed significant improvement in all subscales. Psychological symptoms also improved significantly after 7 BMs, and symptom reductions classified as highly reliable were maintained until 18-months follow-up in more than 50% of participants. CONCLUSION: BM results in significant and lasting improvements in clinical symptoms of anxiety, depression, and burnout. Further studies including control groups are necessary to confirm these findings and determine any BM-specific effects.

Association of dietary proteins with serum creatinine and estimated glomerular filtration rate in a general population sample: the CHRIS study.

BACKGROUND: Diet is known to affect kidney function. However, population-based studies provide contrasting evidence, resulting in a poor understanding of the effect of proteins from specific foods on kidney health. METHODS: We analyzed the effect of total daily protein intake (TDPI) and source-specific daily protein intake (DPI) on fasting serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) in the Cooperative Health Research In South Tyrol (CHRIS) cross-sectional study (n = 5889), using the GA2LEN food frequency questionnaire for TDPI and DPI estimation. We fitted multivariable adjusted mixed models of SCr and eGFR on TDPI and DPI quartiles (Q1-Q4) in the overall sample, and after removing individuals with known hypertension, diabetes or chronic kidney disease (CKD). RESULTS: Higher TDPI as well as DPI from overall animal sources, fish, and poultry, were associated with higher SCr (trend test p, ptrend < 0.01), with larger effect after excluding individuals with known hypertension, diabetes or CKD. The eGFR was lower at higher TDPI (Q4 vs Q1: - 1.6 ml/min/1.73 m2; 95% CI - 2.5, - 0.7; ptrend = 3e-4) and DPI from fish (Q4 vs Q1: - 2.1 ml/min/1.73 m2; 95% CI - 2.9, - 1.20; ptrend = 4.3e-6), overall animal source (Q4 vs Q1: - 1.6 ml/min/1.73 m2; 95% CI -2.5, - 0.8), processed meat (Q4 vs Q1: - 1.4 ml/min/1.73 m2; ptrend = 0.027), red meat, offal and processed meat (Q4 vs Q1: - 1.4 ml/min/1.73 m2; ptrend = 0.015) and poultry (Q4 vs Q1: - 0.9 ml/min/1.73 m2; ptrend = 0.015). CONCLUSIONS: TDPI and DPI from specific animal sources were positively associated with SCr and negatively associated with eGFR. Lacking an alternative marker of kidney function, confounding involving muscle mass metabolism cannot be fully excluded.

Identifying factors associated with COVID-19 related deaths during the first wave of the pandemic in Europe.

Aim: To clarify the high variability in COVID-19-related deaths during the first wave of the pandemic, we conducted a modeling study using publicly available data. Materials and methods: We used 13 population- and country-specific variables to predict the number of population-standardized COVID-19-related deaths in 43 European countries using generalized linear models: the test-standardized number of SARS-CoV-2-cases, population density, life expectancy, severity of governmental responses, influenza-vaccination coverage in the elderly, vitamin D status, smoking and diabetes prevalence, cardiovascular disease death rate, number of hospital beds, gross domestic product, human development index and percentage of people older than 65 years. Results: We found that test-standardized number of SARS-CoV-2-cases and flu vaccination coverage in the elderly were the most important predictors, together with vitamin D status, gross domestic product, population density and government response severity explaining roughly two-thirds of the variation in COVID-19 related deaths. The latter variable was positively, but only weakly associated with the outcome, i.e., deaths were higher in countries with more severe government response. Higher flu vaccination coverage and low vitamin D status were associated with more COVID-19 related deaths. Most other predictors appeared to be negligible. Conclusion: Adequate vitamin D levels are important, while flu-vaccination in the elderly and stronger government response were putative aggravating factors of COVID-19 related deaths. These results may inform protection strategies against future infectious disease outbreaks.

Why do people consent to receiving SARS-CoV-2 vaccinations? A representative survey in Germany.

OBJECTIVE: To answer the question: Why do people consent to being vaccinated with novel vaccines against SARS-CoV-2? DESIGN: Representative survey. SETTING: Online panel. PARTICIPANTS: 1032 respondents of the general German population. METHOD: A representative survey among German citizens in November/December 2021 that resulted in 1032 complete responses on vaccination status, sociodemographic parameters and opinions about the COVID-19 situation. RESULTS: Almost 83% of the respondents were vaccinated. The major motivation was fear of medical consequences of an infection and the wish to lead a normal life again. The major motivation to be not vaccinated was the fear of side effects and scepticism about long-term effectiveness and safety. Sixteen per cent of vaccinated respondents reported some serious side effect, while more than 30% reported health improvements, mostly due to the relief of psychological stress and social reintegration. We also validated a 'Corona Orthodoxy Score-COS' consisting of seven items reflecting opinions on COVID-19. The scale is reliable (alpha=0.76) and unidimensional. The COS was a highly significant predictor of vaccination status and readiness to be vaccinated in a multivariable logistic regression model. Those who were vaccinated were more likely to live in smaller households (OR=0.82, p=0.024), had a higher income (OR=1.27, p<0.001), a higher COS score (OR 1.4, p<0.0001) and used less alternative media (OR=0.44, p=0.0024) and scientific publications (OR=0.42, p=0.011) as information sources. CONCLUSIONS: The major motives for being vaccinated are fear of medical symptoms and the wish to lead a normal life. Those not wanting to be vaccinated cite a lack of knowledge regarding long-term safety and side effects as reasons. This can likely only be overcome by careful and active long-term efficacy and safety monitoring.

Whole Exome Sequencing Enhanced Imputation Identifies 85 Metabolite Associations in the Alpine CHRIS Cohort.

Metabolites are intermediates or end products of biochemical processes involved in both health and disease. Here, we take advantage of the well-characterized Cooperative Health Research in South Tyrol (CHRIS) study to perform an exome-wide association study (ExWAS) on absolute concentrations of 175 metabolites in 3294 individuals. To increase power, we imputed the identified variants into an additional 2211 genotyped individuals of CHRIS. In the resulting dataset of 5505 individuals, we identified 85 single-variant genetic associations, of which 39 have not been reported previously. Fifteen associations emerged at ten variants with >5-fold enrichment in CHRIS compared to non-Finnish Europeans reported in the gnomAD database. For example, the CHRIS-enriched ETFDH stop gain variant p.Trp286Ter (rs1235904433-hexanoylcarnitine) and the MCCC2 stop lost variant p.Ter564GlnextTer3 (rs751970792-carnitine) have been found in patients with glutaric acidemia type II and 3-methylcrotonylglycinuria, respectively, but the loci have not been associated with the respective metabolites in a genome-wide association study (GWAS) previously. We further identified three gene-trait associations, where multiple rare variants contribute to the signal. These results not only provide further evidence for previously described associations, but also describe novel genes and mechanisms for diseases and disease-related traits.

GCN5 contributes to intracellular lipid accumulation in human primary cardiac stromal cells from patients affected by Arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease associated with sudden cardiac death and cardiac fibro-fatty replacement. Over the last years, several works have demonstrated that different epigenetic enzymes can affect not only gene expression changes in cardiac diseases but also cellular metabolism. Specifically, the histone acetyltransferase GCN5 is known to facilitate adipogenesis and modulate cardiac metabolism in heart failure. Our group previously demonstrated that human primary cardiac stromal cells (CStCs) contribute to adipogenesis in the ACM pathology. Thus, this study aims to evaluate the role of GCN5 in ACM intracellular lipid accumulation. To do so, CStCs were obtained from right ventricle biopsies of ACM patients and from samples of healthy cadaveric donors (CTR). GCN5 expression was increased both in ex vivo and in vitro ACM samples compared to CTR. When GCN5 expression was silenced or pharmacologically inhibited by the administration of MB-3, we observed a reduction in lipid accumulation and a mitigation of reactive oxygen species (ROS) production in ACM CStCs. In agreement, transcriptome analysis revealed that the presence of MB-3 modified the expression of pathways related to cellular redox balance. Altogether, our findings suggest that GCN5 inhibition reduces fat accumulation in ACM CStCs, partially by modulating intracellular redox balance pathways.

Age, Sex, Body Mass Index, Diet and Menopause Related Metabolites in a Large Homogeneous Alpine Cohort.

Metabolomics in human serum samples provide a snapshot of the current metabolic state of an individuum. Metabolite concentrations are influenced by both genetic and environmental factors. Concentrations of certain metabolites can further depend on age, sex, menopause, and diet of study participants. A better understanding of these relationships is pivotal for the planning of metabolomics studies involving human subjects and interpretation of their results. We generated one of the largest single-site targeted metabolomics data sets consisting of 175 quantified metabolites in 6872 study participants. We identified metabolites significantly associated with age, sex, body mass index, diet, and menopausal status. While most of our results agree with previous large-scale studies, we also found novel associations including serotonin as a sex and BMI-related metabolite and sarcosine and C2 carnitine showing significantly higher concentrations in post-menopausal women. Finally, we observed strong associations between higher consumption of food items and certain metabolites, mostly phosphatidylcholines and lysophosphatidylcholines. Most, and the strongest, relationships were found for habitual meat intake while no significant relationships were found for most fruits, vegetables, and grain products. Summarizing, our results reconfirm findings from previous population-based studies on an independent cohort. Together, these findings will ultimately enable the consolidation of sets of metabolites which are related to age, sex, BMI, and menopause as well as to participants' diet.

Comprehensive Peak Characterization (CPC) in Untargeted LC-MS Analysis.

LC-MS-based untargeted metabolomics is heavily dependent on algorithms for automated peak detection and data preprocessing due to the complexity and size of the raw data generated. These algorithms are generally designed to be as inclusive as possible in order to minimize the number of missed peaks. This is known to result in an abundance of false positive peaks that further complicate downstream data processing and analysis. As a consequence, considerable effort is spent identifying features of interest that might represent peak detection artifacts. Here, we present the CPC algorithm, which allows automated characterization of detected peaks with subsequent filtering of low quality peaks using quality criteria familiar to analytical chemists. We provide a thorough description of the methods in addition to applying the algorithms to authentic metabolomics data. In the example presented, the algorithm removed about 35% of the peaks detected by XCMS, a majority of which exhibited a low signal-to-noise ratio. The algorithm is made available as an R-package and can be fully integrated into a standard XCMS workflow.

A Modular and Expandable Ecosystem for Metabolomics Data Annotation in R.

Liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics experiments have become increasingly popular because of the wide range of metabolites that can be analyzed and the possibility to measure novel compounds. LC-MS instrumentation and analysis conditions can differ substantially among laboratories and experiments, thus resulting in non-standardized datasets demanding customized annotation workflows. We present an ecosystem of R packages, centered around the MetaboCoreUtils, MetaboAnnotation and CompoundDb packages that together provide a modular infrastructure for the annotation of untargeted metabolomics data. Initial annotation can be performed based on MS1 properties such as m/z and retention times, followed by an MS2-based annotation in which experimental fragment spectra are compared against a reference library. Such reference databases can be created and managed with the CompoundDb package. The ecosystem supports data from a variety of formats, including, but not limited to, MSP, MGF, mzML, mzXML, netCDF as well as MassBank text files and SQL databases. Through its highly customizable functionality, the presented infrastructure allows to build reproducible annotation workflows tailored for and adapted to most untargeted LC-MS-based datasets. All core functionality, which supports base R data types, is exported, also facilitating its re-use in other R packages. Finally, all packages are thoroughly unit-tested and documented and are available on GitHub and through Bioconductor.

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study.

Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value < 5 × 10-8) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies.

Ion identity molecular networking for mass spectrometry-based metabolomics in the GNPS environment.

Molecular networking connects mass spectra of molecules based on the similarity of their fragmentation patterns. However, during ionization, molecules commonly form multiple ion species with different fragmentation behavior. As a result, the fragmentation spectra of these ion species often remain unconnected in tandem mass spectrometry-based molecular networks, leading to redundant and disconnected sub-networks of the same compound classes. To overcome this bottleneck, we develop Ion Identity Molecular Networking (IIMN) that integrates chromatographic peak shape correlation analysis into molecular networks to connect and collapse different ion species of the same molecule. The new feature relationships improve network connectivity for structurally related molecules, can be used to reveal unknown ion-ligand complexes, enhance annotation within molecular networks, and facilitate the expansion of spectral reference libraries. IIMN is integrated into various open source feature finding tools and the GNPS environment. Moreover, IIMN-based spectral libraries with a broad coverage of ion species are publicly available.

Oxidant therapy improves adipogenic differentiation of adipose-derived stem cells in human wound healing.

BACKGROUND: Adipose-derived stem cells (ASC) and adipocytes are involved in numerous physiological and pathophysiological conditions, which have been extensively described in subcutaneous and visceral fat depots over the past two decades. However, much less is known about ASC and adipocytes outside classical fat tissue depots and their necessity in tissue remodeling after injury. Therefore, we investigated the etiology of adipocytes in human granulation tissue and define their possible role wound healing. METHODS: Identification of human wound tissue adipocytes was determined by immunohistochemical staining of granulation tissue sections from patients undergoing surgical debridement. Stromal cell fractions from granulation tissue and subcutaneous fat tissue were generated by collagenase type II-based protocols. Pro- and anti-inflammatory wound bed conditions were mimicked by THP1- and CD14+ monocyte-derived macrophage models in vitro. Effects of macrophage secretome on ASC differentiation and metabolism were determined by immunoblotting, flow cytometry, and microscopy assessing early and late adipocyte differentiation states. Functional rescuing experiments were conducted by lentiviral transduction of wildtype PPARG, IL1RA, and N-chlorotaurine (NCT) treatment. RESULTS: Single and clustered adipocyte populations were detected in 11 out of 13 granulation tissue specimens and single-cell suspensions from granulation tissue showed adipogenic differentiation potential. Pro-inflammatory signaling by IFNG/LPS-stimulated macrophages (M (IFNG/LPS)) inhibited the maturation of lipid droplets in differentiated ASC. In contrast, anti-inflammatory IL4/IL13-activated macrophages (M (IL4/IL13)) revealed minor effects on adipocyte development. The M (IFNG/LPS)-induced phenotype was associated with a switch from endogenous fatty acid synthesis to glycolysis-dominated cell metabolism and increased pro-inflammatory cytokine production. Impaired adipogenesis was associated with increased, but seemingly non-functional, CEBPB levels, which failed to induce downstream PPARG and CEBPA. Neither transgenic PPARG overexpression, nor inhibition of IL1B was sufficient to rescue the anti-adipogenic effects induced by IFNG/LPS-activated macrophages. Instead, macrophage co-treatment during stimulation with NCT, a mild oxidant produced by activated granulocytes present in human wounds in vivo, significantly attenuated the anti-adipogenic effects. CONCLUSIONS: In conclusion, the appearance of adipocytes in wound tissue indicates a prevailing anti-inflammatory environment that could be promoted by NCT treatment and may be associated with improved healing outcomes.

Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol.

Vitamin D3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)2D3 (calcitriol). 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases. In this context, the latest research has revealed clinical benefits of high dose vitamin D3 therapy in autoimmune diseases. The necessity of high doses of vitamin D3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis. We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D3 per kg body weight can be administered safely. Parathyroid hormone levels in serum thereby provide the key information for finding the right dose. We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D3 therapy.

Metabolic Signature of Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a genetic-based cardiac disease accompanied by severe ventricular arrhythmias and a progressive substitution of the myocardium with fibro-fatty tissue. ACM is often associated with sudden cardiac death. Due to the reduced penetrance and variable expressivity, the presence of a genetic defect is not conclusive, thus complicating the diagnosis of ACM. Recent studies on human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) obtained from ACM individuals showed a dysregulated metabolic status, leading to the hypothesis that ACM pathology is characterized by an impairment in the energy metabolism. However, despite efforts having been made for the identification of ACM specific biomarkers, there is still a substantial lack of information regarding the whole metabolomic profile of ACM patients. The aim of the present study was to investigate the metabolic profiles of ACM patients compared to healthy controls (CTRLs). The targeted Biocrates AbsoluteIDQ® p180 assay was used on plasma samples. Our analysis showed that ACM patients have a different metabolome compared to CTRLs, and that the pathways mainly affected include tryptophan metabolism, arginine and proline metabolism and beta oxidation of fatty acids. Altogether, our data indicated that the plasma metabolomes of arrhythmogenic cardiomyopathy patients show signs of endothelium damage and impaired nitric oxide (NO), fat, and energy metabolism.