Showing papers by "Benjamin Meder published in 2021"
Montreal Heart Institute1, University of Amsterdam2, National Institutes of Health3, National Health Service4, Imperial College London5, University of Oxford6, Erasmus University Medical Center7, University Medical Center Groningen8, Utrecht University9, Heidelberg University10, Tohoku University11, Francis Crick Institute12, University of Paris13, Technische Universität München14, University of Western Ontario15, University College London16
TL;DR: In this paper, the authors conducted genome-wide association studies and multi-trait analyses in hypertrophic (HCM) and dilated (DCM) cardiomyopathies.
Abstract: The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
124 citations
University of Michigan1, Unica Corporation2, Mayo Clinic3, Charité4, Brigham and Women's Hospital5, Oregon Health & Science University6, University of Pennsylvania7, University of Virginia Health System8, University of Göttingen9, Durham University10, Heidelberg University11, Tel Aviv University12, Yale University13
TL;DR: Sara Saberi, MD Nuno Cardim, MD Mohamad Yamani, MD Jeanette Schulz-Menger Wanying Li, PhD Victoria Florea, MD Amy J. Kwong, MD, MPH Michael Jerosch-Herold, PhD Ahmad Masri, MD Anjali Owens, MD Neal K. Lakdawala, MD
Abstract: Sara Saberi , MD Nuno Cardim, MD Mohamad Yamani, MD Jeanette Schulz-Menger Wanying Li, PhD Victoria Florea, MD Amy J. Sehnert, MD Raymond Y. Kwong, MD, MPH Michael Jerosch-Herold, PhD Ahmad Masri , MD Anjali Owens, MD Neal K. Lakdawala , MD Christopher M. Kramer , MD Mark Sherrid , MD Tim Seidler, MD Andrew Wang , MD Farbod SedaghatHamedani, MD Benjamin Meder , MD Ofer Havakuk, MD Daniel Jacoby , MD
89 citations
TL;DR: In this article, the main objective of the diagnostic algorithm outlined in this position statement is to detect cardiac amyloidosis as reliably and early as possible, to accurately determine its extent, and to reliably identify the underlying subtype of amyloids, thereby enabling subsequent targeted treatment.
Abstract: Systemic forms of amyloidosis affecting the heart are mostly light-chain (AL) and transthyretin (ATTR) amyloidoses. The latter is caused by deposition of misfolded transthyretin, either in wild-type (ATTRwt) or mutant (ATTRv) conformation. For diagnostics, specific serum biomarkers and modern non-invasive imaging techniques, such as cardiovascular magnetic resonance imaging (CMR) and scintigraphic methods, are available today. These imaging techniques do not only complement conventional echocardiography, but also allow for accurate assessment of the extent of cardiac involvement, in addition to diagnosing cardiac amyloidosis. Endomyocardial biopsy still plays a major role in the histopathological diagnosis and subtyping of cardiac amyloidosis. The main objective of the diagnostic algorithm outlined in this position statement is to detect cardiac amyloidosis as reliably and early as possible, to accurately determine its extent, and to reliably identify the underlying subtype of amyloidosis, thereby enabling subsequent targeted treatment.
42 citations
University of Paris1, Institute of Chartered Accountants of Nigeria2, Utrecht University3, Greifswald University Hospital4, Charité5, Medical University of Vienna6, University of Regensburg7, University of Pennsylvania8, National University of Singapore9, National Institutes of Health10, Children's Hospital of Philadelphia11, Imperial College London12, Ludwig Maximilian University of Munich13, Technische Universität München14, University of Mainz15, Brigham and Women's Hospital16, Harvard University17, University of Iceland18, Heidelberg University19, Stanford University20, French Institute of Health and Medical Research21, University of Lübeck22, Centre national de la recherche scientifique23, University of Nantes24, Université Paris-Saclay25, Swedish University of Agricultural Sciences26, Paris Descartes University27, University College London28
TL;DR: In this article, the authors conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population, and identified and replicated two new DCM-associated loci on chromosome 3p25.1 and chromosome 22q11.23.
Abstract: Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
38 citations
TL;DR: A new set of metabolomic biomarkers for HF was identified by identifying underlying biological cascades that potentially represent suitable intervention targets by using a multi-OMICS approach.
Abstract: With more than 25 million people affected, heart failure (HF) is a global threat. As energy production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM (p = 1.7 × 10-6). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting enzymes of these pathways could also be found and validated in our second stage of metabolite assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades that potentially represent suitable intervention targets.
19 citations
Heidelberg University1, University of Bremen2, University Hospital Heidelberg3, Gdańsk Medical University4, Luther University5, University of Turin6, Charité7, University of California, San Francisco8, University of Southern California9, HealthPartners10, University of Cologne11, Ludwig Maximilian University of Munich12, Winterthur Museum, Garden and Library13, Turku University Hospital14, Hannover Medical School15, Medical University of Warsaw16, University of Cambridge17, University Hospital of Basel18, Christchurch Hospital19, Greifswald University Hospital20, Charles University in Prague21, University of Florida22, University Hospital Regensburg23, Chiba University24, Mayo Clinic25, University of Iowa26, Schiller International University27, Kantonsspital St. Gallen28, Otto-von-Guericke University Magdeburg29, University of Göttingen30, Leipzig University31, Leiden University32, University of Zurich33, Imperial College London34
TL;DR: In this article, the authors investigated the prevalence, clinical correlates, and prognostic impact of atrial fibrillation (AF) in patients with TTS and found that AF on admission is significantly associated with increased in-hospital and long-term mortality rates.
Abstract: 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<0.001), and there were fewer women (P=0.046) in the AF than in the non-AF group. Left ventricular ejection fraction was significantly lower (P=0.001), and cardiogenic shock was more often observed (P<0.001) in the AF group. Both in-hospital (P<0.001) and long-term mortality (P<0.001) were higher in the AF group. Multivariable Cox regression analysis revealed that AF was independently associated with higher long-term mortality (hazard ratio, 2.31; 95% CI, 1.50-3.55; P<0.001). Among patients with AF on admission, 42% had no known history of AF before the acute TTS event, and such patients had comparable in-hospital and long-term outcomes compared with those with a history of AF. Conclusions In patients presenting with TTS, AF on admission is significantly associated with increased in-hospital and long-term mortality rates. Whether antiarrhythmics and/or cardioversion are beneficial in TTS with AF should thus be tested in a future trial. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01947621.
15 citations
TL;DR: In this article, a searchable, quantitative human transcriptome annotation with 31,025 known and 5,740 novel transcript isoforms is presented. But this method is limited to the presence of RBM20 mutations associated with aggressive dilated cardiomyopathy (DCM).
Abstract: Alternative splicing generates differing RNA isoforms that govern phenotypic complexity of eukaryotes. Its malfunction underlies many diseases, including cancer and cardiovascular diseases. Comparative analysis of RNA isoforms at the genome-wide scale has been difficult. Here, we establish an experimental and computational pipeline that performs de novo transcript annotation and accurately quantifies transcript isoforms from cDNA sequences with a full-length isoform detection accuracy of 97.6%. We generate a searchable, quantitative human transcriptome annotation with 31,025 known and 5,740 novel transcript isoforms ( http://steinmetzlab.embl.de/iBrowser/ ). By analyzing the isoforms in the presence of RNA Binding Motif Protein 20 (RBM20) mutations associated with aggressive dilated cardiomyopathy (DCM), we identify 121 differentially expressed transcript isoforms in 107 cardiac genes. Our approach enables quantitative dissection of complex transcript architecture instead of mere identification of inclusion or exclusion of individual exons, as exemplified by the discovery of IMMT isoforms mis-spliced by RBM20 mutations. Thereby we achieve a path to direct differential expression testing independent of an existing annotation of transcript isoforms, providing more immediate biological interpretation and higher resolution transcriptome comparisons.
13 citations
TL;DR: In this paper, a position papier is presented, einen Uberblick zur aktuellen Datenlage und zum Einsatz der Wearables bei der Detektion von symptomatischen and asymptomatische Arrhythmien zu geben.
Abstract: Der technische Fortschritt in der Medizin hat dazu gefuhrt, dass Herzfrequenz und Herzrhythmus nicht nur mittels professioneller Gerate aufgezeichnet werden konnen, sondern dies inzwischen auch vom Laien durch von jedermann erwerbbare sog. Wearables moglich ist. Unter Wearables versteht man direkt am Korper oder der Kleidung getragene elektronische Gerate, die in der Lage sind, biophysikalische Daten zu erheben. Zu den bekanntesten Wearables zahlen Smartwatches, Armbander und Brustgurte. Wearables sind in der Lage, Herzfrequenz, Pulskurven und das EKG zu erfassen. So konnen Wearables als Eventrekorder mit Symptom-getriggerter Aufzeichnung von Arrhythmien oder zum aktiven oder passiven Screening auf Vorhofflimmern genutzt werden. Dazu stehen prinzipiell 2 Verfahren zur Verfugung: die Elektrokardiographie und die Photoplethysmographie. Mit beiden Verfahren ist es inzwischen moglich, Software-unterstutzt mit einer hohen Sensitivitat und Spezifitat Vorhofflimmern zu identifizieren. Ziel dieses Positionspapiers ist es, einen Uberblick zur aktuellen Datenlage und zum Einsatz der Wearables bei der Detektion von symptomatischen und asymptomatischen Arrhythmien zu geben. Zusatzlich werden gesundheitsokonomische und auch rechtliche Aspekte im Umgang mit Wearables beleuchtet.
11 citations
TL;DR: In this paper, the authors characterized the transcriptional changes of ICIM myocardial biopsies and their possible implications and concluded that interferon-gamma and inflammasome-regulating proteins, such as GBP5, may be of unrecognized significance in the pathophysiology of ICI.
Abstract: Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcriptional changes of ICIM myocardial biopsies and their possible implications. Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n = 9) with samples from dilated cardiomyopathy (DCM, n = 11), virus-induced myocarditis (VIM, n = 5), and with samples of patients receiving ICIs without any evidence of myocarditis (n = 4). Patients with ICIM (n = 19) showed an inconsistent clinical presentation, e.g., asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), a drop in left ventricular ejection fraction, or late gadolinium enhancement in cMRI. We found 3784 upregulated genes in ICIM (FDR < 0.05). In the overrepresented pathway 'response to interferon-gamma', we found guanylate binding protein 5 and 6 (compared with VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37)) to be significantly increased in ICIM on RNA- and protein-level. We conclude that interferon-gamma and inflammasome-regulating proteins, such as GBP5, may be of unrecognized significance in the pathophysiology of ICIM.
10 citations
TL;DR: Machine learning has the potential to improve patient selection and risk management of interventional cardiovascular procedures, as it is capable of making superior predictions compared to current logistic risk scores.
Abstract: Currently, patient selection in TAVI is based upon a multidisciplinary heart team assessment of patient comorbidities and surgical risk stratification. In an era of increasing need for precision medicine and quickly expanding TAVI indications, machine learning has shown promise in making accurate predictions of clinical outcomes. This study aims to predict different intrahospital clinical outcomes in patients undergoing TAVI using a machine learning-based approach. The main clinical outcomes include all-cause mortality, stroke, major vascular complications, paravalvular leakage, and new pacemaker implantations. The dataset consists of 451 consecutive patients undergoing elective TAVI between February 2014 and June 2016. The applied machine learning methods were neural networks, support vector machines, and random forests. Their performance was evaluated using five-fold nested cross-validation. Considering all 83 features, the performance of all machine learning models in predicting all-cause intrahospital mortality (AUC 0.94–0.97) was significantly higher than both the STS risk score (AUC 0.64), the STS/ACC TAVR score (AUC 0.65), and all machine learning models using baseline characteristics only (AUC 0.72–0.82). Using an extreme boosting gradient, baseline troponin T was found to be the most important feature among all input variables. Overall, after feature selection, there was a slightly inferior performance. Stroke, major vascular complications, paravalvular leakage, and new pacemaker implantations could not be accurately predicted. Machine learning has the potential to improve patient selection and risk management of interventional cardiovascular procedures, as it is capable of making superior predictions compared to current logistic risk scores.
9 citations
TL;DR: In this article, a review article highlights some of the recent advances in the field, ranging from aspects of granule formation to 3D genome architectures underlying RBM20-related cardiomyopathy.
Abstract: Splice regulators play an essential role in the transcriptomic diversity of all eukaryotic cell types and organ systems. Recent evidence suggests a contribution of splice-regulatory networks in many diseases, such as cardiomyopathies. Adaptive splice regulators, such as RNA-binding motif protein 20 (RBM20) determine the physiological mRNA landscape formation, and rare variants in the RBM20 gene explain up to 6% of genetic dilated cardiomyopathy (DCM) cases. With ample knowledge from RBM20-deficient mice, rats, swine and induced pluripotent stem cells (iPSCs), the downstream targets and quantitative effects on splicing are now well-defined and the prerequisites for corrective therapeutic approaches are set. This review article highlights some of the recent advances in the field, ranging from aspects of granule formation to 3D genome architectures underlying RBM20-related cardiomyopathy. Promising therapeutic strategies are presented and put into context with the pathophysiological characteristics of RBM20-related diseases.
Paris Descartes University1, Seconda Università degli Studi di Napoli2, Sheba Medical Center3, University of Barcelona4, Odense University Hospital5, St Bartholomew's Hospital6, University College London7, Aarhus University Hospital8, University Hospital Heidelberg9, Autonomous University of Barcelona10, Utrecht University11, Maastricht University12, Boston Children's Hospital13, University of Girona14, Stanford University15
TL;DR: In this article, the authors describe the phenotype and prognosis of dystrophin gene associated dilated cardiomyopathy in DMD mutation carriers without severe skeletal myopathy and conclude that the onset of DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletalmyopathy.
Abstract: Aims Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy. Methods and results At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5-311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up. Conclusions DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.
TL;DR: APopt/PRIMA-1Met (APR-246) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent.
Abstract: APR-246 (Eprenetapopt/PRIMA-1Met) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.
TL;DR: The concept of neural network based biomarkers for ACS are shown and this approach also opens the possibility to include multi-modal data points to further increase precision and perform classification of other ACS differential diagnoses.
TL;DR: The results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.
Abstract: lncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNAs structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their down-stream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs we demonstrate first the significant association of a SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of suboptimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.
TL;DR: In this article, the diagnostic value of microRNAs (miRNAs) for the detection of non-ST-segment elevation myocardial infarction (NSTEMI) using high-sensitivity troponin T (hs-cTnT) was assessed.
Abstract: Aims To assess the diagnostic value of microRNAs (miRNAs) for the detection of non-ST-segment elevation myocardial infarction (NSTEMI). Methods and results A total of 1042 patients presenting between August 2014 and April 2017 to the emergency department with the suspected acute coronary syndrome were included. Non-ST-segment elevation myocardial infarction was diagnosed per criteria of the fourth Universal definition of myocardial infarction (UDMI) using high-sensitivity troponin T (hs-cTnT). Expression levels of eleven microRNAs (miR-21, miR-22, miR-29a, miR-92a, miR-122, miR-126, miR-132, miR-133, miR-134, miR-191, and miR-423) were determined using RT-qPCR. Discrimination of NSTEMI was assessed for individual and a panel of miRNAs compared to the hs-cTnT reference using C-statistics and reclassification analysis. NSTEMI was diagnosed in 137 (13.1%) patients. The area under the curve (AUC) of the hs-cTnT based reference was 0.937. In a multivariate model, three miRNAs (miR-122, miR-133, and miR-134) were found to be associated with NSTEMI with AUCs between 0.506 and 0.656. A panel consisting of these miRNAs revealed an AUC of 0.662 for the diagnosis of NSTEMI. The AUC of the combination of the miRNA panel and troponin reference was significantly lower than the reference standard (AUC: 0.897 vs. 0.937, P = 0.006). Despite a significant improvement of NSTEMI reclassification measured by IDI and NRI, miRNAs did not improve the specificity of hs-cTnT kinetic changes for the diagnosis of NSTEMI (ΔAUC: 0.04). Conclusion Although single miRNAs are significantly associated with the diagnosis of NSTEMI a miRNA panel does not add diagnostic accuracy to the hs-cTnT reference considering baseline values and kinetic changes as recommended by the fourth version of UDMI. Clinical trials identifier NCT02116153.
TL;DR: In this paper, the authors developed a risk model for non-ischemic dilated cardiomyopathy (DCM) patients with SVA and sudden cardiac death (SCD) using Cox proportional hazards and internally validated using cross validation.
TL;DR: In this paper, the effect of single nucleotide polymorphisms (SNPs) on the structure of lncRNAs was investigated in the context of dilated cardiomyopathy and showed that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies.
Abstract: lncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNA structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their downstream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs, we demonstrate first the significant association of an SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.
TL;DR: In dem vorliegenden Konsensuspapier werden Expertenempfehlungen zur derzeitigen Notwendigkeit, Indikation and Durchfuhrung einer molekularen Autopsie formuliert as mentioned in this paper.
Abstract: Obduktionen (Sektionen oder Leichenoffnungen) aus klinischer oder forensischer Indikation bei unklaren, fruhzeitigen (in der Regel <40. Lebensjahr, im Einzelfall auch spater) oder kardiovaskularen Todesfallen dienen neben der definitiven Ursachenklarung auch der Erkennung bzw. der Abgrenzung von genetischen Ursachen. Diese sind besonders in praventiver Hinsicht fur biologisch verwandte Familienmitglieder relevant, v. a. nach umfanglichen Obduktionen ohne Feststellung der Todesursache („mors sine materia“). Eine molekulare Autopsie zielt auf eine postmortale Aufklarung der Todesursache durch die Identifizierung bzw. Bestatigung einer erblichen kardiovaskularen Erkrankung. In dem vorliegenden Konsensuspapier werden Expertenempfehlungen zur derzeitigen Notwendigkeit, Indikation und Durchfuhrung einer molekularen Autopsie formuliert. Zusatzlich sollte bei dem Verdacht auf eine genetisch bedingte kardiovaskulare Erkrankung eine systematische klinische (und ggf. genetische) Untersuchung von Familienmitgliedern durchgefuhrt werden.
University of Zurich1, Hannover Medical School2, University of Bremen3, University Hospital Heidelberg4, Gdańsk Medical University5, Martin Luther University of Halle-Wittenberg6, University of Turin7, Charité8, University of California, San Francisco9, University of Southern California10, HealthPartners11, University of Cologne12, University of Göttingen13, Technische Universität München14, University of Ulm15, John Radcliffe Hospital16, Winterthur Museum, Garden and Library17, Turku University Hospital18, Medical University of Warsaw19, University of Cambridge20, University Hospital of Basel21, Christchurch Hospital22, Greifswald University Hospital23, Heidelberg University24, Charles University in Prague25, University of Florida26, University of Lisbon27, University of Regensburg28, Chiba University29, Mayo Clinic30, University of Iowa31, University of Jena32, Kantonsspital St. Gallen33, University of Adelaide34, Otto-von-Guericke University Magdeburg35, Leipzig University36, Leiden University37, Imperial College London38
TL;DR: Investigation of prevalence of acute pulmonary triggers in patients with takotsubo syndrome and their impact on outcomes found that acute pulmonary disorders are known physical triggers of TTS.
Abstract: 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.
TL;DR: In this article, the authors identified upregulation of Sam68-like Mammalian Protein 2 (SLM2) in the left ventricle of dilated cardiomyopathy (DCM) patients.
TL;DR: The PROMISE system as mentioned in this paper was developed for research purposes to evaluate the concept in a pilot study with nineteen cardiomyopathy patients undergoing genotyping, questionnaires, and longitudinal follow-up.
Abstract: BACKGROUND The development of Precision Medicine strategies requires high-dimensional phenotypic and genomic data, both of which are highly privacy-sensitive data types. Conventional data management systems lack the capabilities to sufficiently handle the expected large quantities of such sensitive data in a secure manner. PROMISE is a genetic data management concept that implements a highly secure platform for data exchange while preserving patient interests, privacy, and autonomy. METHODS The concept of PROMISE to democratize genetic data was developed by an interdisciplinary team. It integrates a sophisticated cryptographic concept that allows only the patient to grant selective access to defined parts of his genetic information with single DNA base-pair resolution cryptography. The PROMISE system was developed for research purposes to evaluate the concept in a pilot study with nineteen cardiomyopathy patients undergoing genotyping, questionnaires, and longitudinal follow-up. RESULTS The safety of genetic data was very important to 79%, and patients generally regarded the data as highly sensitive. More than half the patients reported that their attitude towards the handling of genetic data has changed after using the PROMISE app for 4 months (median). The patients reported higher confidence in data security and willingness to share their data with commercial third parties, including pharmaceutical companies (increase from 5 to 32%). CONCLUSION PROMISE democratizes genomic data by a transparent, secure, and patient-centric approach. This clinical pilot study evaluating a genetic data infrastructure is unique and shows that patient's acceptance of data sharing can be increased by patient-centric decision-making.
TL;DR: In this article, the effects of the broad-spectrum histone deacetylases (HDACi) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autoophagy transcription factor activity (Transcription factor EB, TFEB, forkhead boxO) and autophagic flux in neuroblastoma cells were analyzed.
Abstract: Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze the effects of the broad-spectrum HDAC inhibitors (HDACi) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity (Transcription factor EB—TFEB, forkhead boxO—FOXO) and autophagic flux in neuroblastoma cells. In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma.
TL;DR: The e-Patient erhalt damit in Zukunft durch Smart Devices and Direct-to-Consumer-Technologien einen erleichterten Zugang zu seinen eigenen Gesundheitsdaten, die bisher in Datensilos aufbewahrt und nur eingeschrankt an ihn weitergegeben werden as mentioned in this paper.
Abstract: Neue digitale Technologien bieten groses Potenzial, die Gesundheitsversorgung in den kommenden Jahrzehnten grundlegend zu verandern. Die „Digital Health“ umfasst dabei nahezu alle Bereiche im Gesundheitssystem und nimmt – nicht nur wegen der aktuellen COVID-19-Pandemie – erheblich an Bedeutung zu. In Zukunft sollen nicht nur bekannte Prozesse digitalisiert werden, sondern neue digitale Masnahmen eine Beteiligung des Patienten gezielt fordern und ihn aktiv in Diagnose- sowie Behandlungsprozess einbinden. Der „e-Patient“ erhalt damit in Zukunft durch Smart Devices und Direct-to-Consumer-Technologien einen erleichterten Zugang zu seinen eigenen Gesundheitsdaten, die bisher in Datensilos aufbewahrt und nur eingeschrankt an ihn weitergegeben werden. Fortschritte in der Sensortechnologie und bei sog. Wearables ermoglichen nicht nur ein kontinuierliches Monitoring und einen Beitrag zu diesen patientenzentrierten Gesundheitsdaten, sondern ermoglichen neue Diagnoseverfahren und Therapien auserhalb des Krankenhauses. Die Digitalisierung liefert also zahlreiche Ansatze fur eine effizientere und kostengunstigere Krankenversorgung und Pravention.
TL;DR: In this paper, a searchable, quantitative human transcriptome annotation with 31,025 known and 5,740 novel transcript isoforms (http://steinmetzlab.embl.de/iBrowser/).
Abstract: Alternative splicing generates differing RNA isoforms that govern phenotypic complexity of eukaryotes. Its malfunction underlies many diseases, including cancer and cardiovascular diseases. Comparative analysis of RNA isoforms at the genome-wide scale has been difficult. Here, we established an experimental and computational pipeline that performs de novo transcript annotation and accurately quantifies transcript isoforms from cDNA sequences with a full-length isoform detection accuracy of 97.6%. We generated a searchable, quantitative human transcriptome annotation with 31,025 known and 5,740 novel transcript isoforms (http://steinmetzlab.embl.de/iBrowser/). By analyzing the isoforms in the presence of RNA Binding Motif Protein 20 (RBM20) mutations associated with aggressive dilated cardiomyopathy (DCM), we identified 121 differentially expressed transcript isoforms in 107 cardiac genes. Our approach enables quantitative dissection of complex transcript architecture instead of mere identification of inclusion or exclusion of individual exons, as exemplified by novel IMMT isoforms. Thereby we achieve a path to direct differential expression testing independent of an existing annotation of transcript isoforms as the functional unit, instead of genes or exons, providing more immediate biological interpretation and higher resolution transcriptome comparisons.
04 May 2021
TL;DR: The experience during a total blackout of all computer systems at a large-scale medical university centre lasting for almost 2 days, affecting not only the hospital information system but also all picture archieving systems, access to laboratory data, office, and email software and even the personnel’s ability to log into their accounts is reported.
Abstract:
We report here our experience during a total blackout of all computer systems at a large-scale medical university centre lasting for almost 2 days, affecting not only the hospital information system but also all picture archieving systems, access to laboratory data, office, and email software and even the personnel’s ability to log into their accounts. While initially threatening, staff quickly adapted to the situation and the promise of ‘digital health’ to enable more time for the patient and improve communication, was essentially fulfilled when our computer system was totally down. Based on our experience, we recommend an involvement of health professionals and their medical societies in every step of the digital transformation to accomplish this mission in a responsible, safe, and human-centred way.
TL;DR: The case of a female patient presented with typical angina, as well as dizziness, trembling, and repeated vomiting, after accidental poisoning with sodium selenite is illustrated and guidance for cardiovascular management is provided.
Abstract: A female patient presented with typical angina, as well as dizziness, trembling, and repeated vomiting, after accidental poisoning with sodium selenite. Our case illustrates the role of se...