109 results on '"Elham Kayvanpour"'
Search Results
2. Assessing the Applicability of Cardiac Myosin Inhibitors for Hypertrophic Cardiomyopathy Management in a Large Single Center Cohort
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Ali Amr, Elham Kayvanpour, Christoph Reich, Jan Koelemen, Shamily Asokan, Norbert Frey, Benjamin Meder, and Farbod Sedaghat-Hamedani
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hypertrophic cardiomyopathy ,cardiac myosin inhibitors ,aficamten ,mavacamten ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background: Cardiac myosin inhibitors (CMIs), including Mavacamten and Aficamten, have emerged as a groundbreaking treatment for hypertrophic cardiomyopathy (HCM). The results from phase 2 and 3 randomized clinical trials for both drugs have showed promising outcomes. However, the highly selective patient recruitment for these trials raises questions about the generalizability of the observed positive effects across broader patient populations suffering from HCM. Methods: A retrospective cohort study at University Hospital Heidelberg included 404 HCM patients. Baseline assessments included family history, electrocardiograms (ECGs), and advanced cardiac imaging, to ensure the exclusion of secondary causes of left ventricular hypertrophy. Results: Among the HCM patients evaluated, only a small percentage met the inclusion criteria for recent CMI trials: 10.4% for EXPLORER-HCM and 4.7% for SEQUOIA-HCM. The predominant exclusion factor was the stringent left ventricular outflow tract (LVOT) gradient requirement. Conclusions: This study highlights a significant discrepancy between patient demographics in clinical trials and those encountered in routine HCM clinical practice. Despite promising results from the initial randomized clinical trials that led to the approval of Mavacamten, the selected patient population only represents a small part of the HCM patient cohort seen in routine clinics. This study advocates for further expanded randomized clinical trials with broader inclusion criteria to represent diverse primary HCM patient populations.
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- 2024
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3. Comparative Assessment of Percutaneous Left-Atrial Appendage Occlusion (LAAO) Devices—A Single Center Cohort Study
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Elham Kayvanpour, Max Kothe, Ziya Kaya, Sven Pleger, Norbert Frey, Benjamin Meder, and Farbod Sedaghat-Hamedani
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left atrial appendage closure ,atrial fibrillation ,oral anticoagulation ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background: Percutaneous left-atrial appendage closure (LAAC) is an established method for preventing strokes in patients with atrial fibrillation, offering an alternative to oral anticoagulation. Various occluder devices have been developed to cater to individual anatomical needs and ensure a safe and effective procedure. In this retrospective, monocentric cohort study, we compare different LAAO devices with respect to clinical outcomes, LAA sealing properties, and device-related complications. Methods: We conducted a retrospective analysis of 270 patients who underwent percutaneous LAA closure in our center between 2009 and 2023. Patient data were extracted from medical records, including gender, age at implantation, indication, device type and size, laboratory values, LAA anatomy, periprocedural complications, ECG parameters, transthoracic and transesophageal echocardiography parameters (TTE and TEE), as well as medication at discharge. Moreover, fluoroscopy time and implantation duration, as well as post-implantation clinical events up to 1 year, were collected. Endpoints were bleeding events, recurrent stroke, thrombi on devices, and death. Results: The implanted devices were the Watchman 2.5, Watchman FLX, Amplatzer Cardiac Plug (ACP), and Amulet. The procedural success rate was 95.7% (n = 265), with cactus anatomy posing the most challenges across all devices. The mean patient age was 75.5 ± 7.7 years, with 64.5% being male. The median CHA2DS2-VASc score was 4.8 ± 1.5 and the median HAS-BLED score was 3.8 ± 1.0. Indications for LAA closure included past bleeding events and elevated bleeding risk. Periprocedural complications were most commonly bleeding at the puncture site, particularly after ACP implantation (p = 0.014). Significant peridevice leaks (PDL) were observed in 21.4% of simple sealing mechanism devices versus 0% in double sealing mechanism devices (p = 0.004). Thrombi were detected on devices in six patients, with no subsequent ischemic stroke or thromboembolic event. Comparative analysis revealed no significant differences in the occurrence of stroke, transient ischemic attack (TIA), thromboembolic events, device-related thrombi, or mortality among different device types. A 62.3% relative risk reduction in thromboembolic events and 38.6% in major bleedings could be observed over 568.2 patient years. Conclusions: In summary, our study highlights the efficacy and safety of LAA closure using various occluder devices despite anatomical challenges. Our long-term follow-up findings support LAA closure as a promising option for stroke prevention in selected patient cohorts. Further research is needed to refine patient selection criteria and optimize outcomes in LAA closure procedures.
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- 2024
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4. NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart
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Marion Müller, Rose Eghbalian, Jes-Niels Boeckel, Karen S. Frese, Jan Haas, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Maximilian K. Lackner, Oguz F. Tugrul, Thomas Ruppert, Rewati Tappu, Diana Martins Bordalo, Jasmin M. Kneuer, Annika Piekarek, Sabine Herch, Sarah Schudy, Andreas Keller, Nadja Grammes, Cornelius Bischof, Anna Klinke, Margarida Cardoso-Moreira, Henrik Kaessmann, Hugo A. Katus, Norbert Frey, Lars M. Steinmetz, and Benjamin Meder
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Science - Abstract
Phosphorylation of the essential myosin light chain (ELC) influence actin-myosin crossbridge cycling in the heart. Here, the authors show upregulated ELC-phosphorylation in systolic heart failure and identify NIMArelated kinase 9 to bind to ELC mediating its calcium-dependent phosphorylation.
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- 2022
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5. Multi-omics assessment of dilated cardiomyopathy using non-negative matrix factorization.
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Rewati Tappu, Jan Haas, David H Lehmann, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Andreas Keller, Hugo A Katus, Norbert Frey, and Benjamin Meder
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Medicine ,Science - Abstract
Dilated cardiomyopathy (DCM), a myocardial disease, is heterogeneous and often results in heart failure and sudden cardiac death. Unavailability of cardiac tissue has hindered the comprehensive exploration of gene regulatory networks and nodal players in DCM. In this study, we carried out integrated analysis of transcriptome and methylome data using non-negative matrix factorization from a cohort of DCM patients to uncover underlying latent factors and covarying features between whole-transcriptome and epigenome omics datasets from tissue biopsies of living patients. DNA methylation data from Infinium HM450 and mRNA Illumina sequencing of n = 33 DCM and n = 24 control probands were filtered, analyzed and used as input for matrix factorization using R NMF package. Mann-Whitney U test showed 4 out of 5 latent factors are significantly different between DCM and control probands (P0.7. Using matrix factorization, multi-omics data derived from human tissue samples can be integrated and novel interactions can be identified. Hypothesis generating nature of such analysis could help to better understand the pathophysiology of complex traits such as DCM.
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- 2022
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6. Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta‐analysis and systematic review
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Arjan Sammani, Elham Kayvanpour, Laurens P. Bosman, Farbod Sedaghat‐Hamedani, Tanja Proctor, Weng‐Tein Gi, Alicia Broezel, Katrin Jensen, Hugo A. Katus, Anneline S.J.M. teRiele, Benjamin Meder, and Folkert W. Asselbergs
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Dilated cardiomyopathy ,Sudden cardiac death ,Implantable cardiac‐defibrillator ,Prognosis ,Risk ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Aims Patients with non‐ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter‐defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM. Methods and results We searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow‐up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74–1.00)], hypertension [HR 1.95; 95% CI (1.26–3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32–13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19–1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02–7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non‐sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin‐C (FLNC)] were associated with arrhythmic outcome in non‐pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high. Conclusions In patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non‐)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter‐defibrillator implantation.
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- 2020
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7. The chameleon of cardiology: cardiac sarcoidosis before and after heart transplantation
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Farbod Sedaghat‐Hamedani, Elham Kayvanpour, Sonja Hamed, Lutz Frankenstein, Johannes Riffel, Weng‐Tein Gi, Ali Amr, Omid Shirvani Samani, Jan Haas, Tobias Miersch, Esther Herpel, Michael M. Kreusser, Philipp Ehlermann, Hugo A. Katus, and Benjamin Meder
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Cardiac sarcoidosis ,Arrhythmogenic right ventricular cardiomyopathy (ARVC) ,Heart transplantation ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Cardiac sarcoidosis is a chronic inflammatory disease with a large spectrum of symptoms that can mimic diseases such as dilated, hypertrophic, or arrhythmogenic cardiomyopathies. It can be asymptomatic but can also present with ventricular arrhythmias, conduction disease, and heart failure (HF) or even sudden cardiac death (SCD). We present here the case of a patient transplanted due to end‐stage arrhythmogenic right ventricular cardiomyopathy (ARVC), fulfilling the task force criteria. A few years after successful heart transplantation (HTX), the patient developed similar symptoms and morphofunctional changes of the heart, which led to critical re‐evaluation of his primary diagnosis.
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- 2020
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8. Cardiac Myxoma in a Patient With Hypertrophic Cardiomyopathy
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Weng-Tein Gi, MD, MSc, Farbod Sedaghat-Hamedani, MD, Omid Shirvani Samani, MD, Elham Kayvanpour, MD, Esther Herpel, MD, Rawa Arif, MD, Johannes Riffel, MD, Derliz Mereles, MD, Hugo A. Katus, MD, and Benjamin Meder, MD
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cardiac myxoma ,echocardiography ,hypertrophic cardiomyopathy ,imaging ,LEOPARD syndrome ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
We report a rare case of concomitant hypertrophic cardiomyopathy and cardiac myxoma without LEOPARD syndrome. Additionally, 6 similar cases were systemically reviewed, and the characteristics of this first-ever studied patient group were summarized. (Level of Difficulty: Beginner.)
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- 2020
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9. Two Hearts at Risk
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Weng-Tein Gi, MD, MSc, Ali Amr, MD, Farbod Sedaghat-Hamedani, MD, Elham Kayvanpour, MD, Isabell Mohr, BSc, Manuela Meder, MD, Omid Shirvani Samani, MD, Herbert Fluhr, MD, Hugo A. Katus, MD, and Benjamin Meder, MD
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alcohol septal ablation ,decompensation ,hypertrophic obstructive cardiomyopathy ,pregnancy ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Hypertrophic obstructive cardiomyopathy (HOCM) increases the risk for mother and fetus during pregnancy. Alcohol septal ablation (ASA) is an established procedure in nonpregnant patients with HOCM. In this report, we present a case of a 29-year-old woman in her 29th gestational week with decompensated HOCM undergoing a successful ASA. (Level of Difficulty: Advanced.)
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- 2020
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10. Genotype Complements the Phenotype: Identification of the Pathogenicity of an LMNA Splice Variant by Nanopore Long-Read Sequencing in a Large DCM Family
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Farbod Sedaghat-Hamedani, Sabine Rebs, Elham Kayvanpour, Chenchen Zhu, Ali Amr, Marion Müller, Jan Haas, Jingyan Wu, Lars M. Steinmetz, Philipp Ehlermann, Katrin Streckfuss-Bömeke, Norbert Frey, and Benjamin Meder
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familial DCM ,laminopathy ,long-read sequencing ,nanopore ,induced pluripotent stem cell cardiomyocytes ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is of familial origin in 20–40% of cases. Genetic testing by next-generation sequencing (NGS) has yielded a definite diagnosis in many cases; however, some remain elusive. In this study, we used a combination of NGS, human-induced pluripotent-stem-cell-derived cardiomyocytes (iPSC-CMs) and nanopore long-read sequencing to identify the causal variant in a multi-generational pedigree of DCM. A four-generation family with familial DCM was investigated. Next-generation sequencing (NGS) was performed on 22 family members. Skin biopsies from two affected family members were used to generate iPSCs, which were then differentiated into iPSC-CMs. Short-read RNA sequencing was used for the evaluation of the target gene expression, and long-read RNA nanopore sequencing was used to evaluate the relevance of the splice variants. The pedigree suggested a highly penetrant, autosomal dominant mode of inheritance. The phenotype of the family was suggestive of laminopathy, but previous genetic testing using both Sanger and panel sequencing only yielded conflicting evidence for LMNA p.R644C (rs142000963), which was not fully segregated. By re-sequencing four additional affected family members, further non-coding LMNA variants could be detected: rs149339264, rs199686967, rs201379016, and rs794728589. To explore the roles of these variants, iPSC-CMs were generated. RNA sequencing showed the LMNA expression levels to be significantly lower in the iPSC-CMs of the LMNA variant carriers. We demonstrated a dysregulated sarcomeric structure and altered calcium homeostasis in the iPSC-CMs of the LMNA variant carriers. Using targeted nanopore long-read sequencing, we revealed the biological significance of the variant c.356+1G>A, which generates a novel 5′ splice site in exon 1 of the cardiac isomer of LMNA, causing a nonsense mRNA product with almost complete RNA decay and haploinsufficiency. Using novel molecular analysis and nanopore technology, we demonstrated the pathogenesis of the rs794728589 (c.356+1G>A) splice variant in LMNA. This study highlights the importance of precise diagnostics in the clinical management and workup of cardiomyopathies.
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- 2022
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11. VARS2 Depletion Leads to Activation of the Integrated Stress Response and Disruptions in Mitochondrial Fatty Acid Oxidation
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Elham Kayvanpour, Michael Wisdom, Maximilian K. Lackner, Farbod Sedaghat-Hamedani, Jes-Niels Boeckel, Marion Müller, Rose Eghbalian, Jan Dudek, Shirin Doroudgar, Christoph Maack, Norbert Frey, and Benjamin Meder
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VARS2 ,heart failure ,integrated stress response ,mitochondrial FAO ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Mutations in mitochondrial aminoacyl-tRNA synthetases (mtARSs) have been reported in patients with mitochondriopathies: most commonly encephalopathy, but also cardiomyopathy. Through a GWAS, we showed possible associations between mitochondrial valyl-tRNA synthetase (VARS2) dysregulations and non-ischemic cardiomyopathy. We aimed to investigate the possible consequences of VARS2 depletion in zebrafish and cultured HEK293A cells. Transient VARS2 loss-of-function was induced in zebrafish embryos using Morpholinos. The enzymatic activity of VARS2 was measured in VARS2-depleted cells via northern blot. Heterozygous VARS2 knockout was established in HEK293A cells using CRISPR/Cas9 technology. BN-PAGE and SDS-PAGE were used to investigate electron transport chain (ETC) complexes, and the oxygen consumption rate and extracellular acidification rate were measured using a Seahorse XFe96 Analyzer. The activation of the integrated stress response (ISR) and possible disruptions in mitochondrial fatty acid oxidation (FAO) were explored using RT-qPCR and western blot. Zebrafish embryos with transient VARS2 loss-of-function showed features of heart failure as well as indications of CNS and skeletal muscle involvements. The enzymatic activity of VARS2 was significantly reduced in VARS2-depleted cells. Heterozygous VARS2-knockout cells showed a rearrangement of ETC complexes in favor of complexes III2, III2 + IV, and supercomplexes without significant respiratory chain deficiencies. These cells also showed the enhanced activation of the ISR, as indicated by increased eIF-2α phosphorylation and a significant increase in the transcript levels of ATF4, ATF5, and DDIT3 (CHOP), as well as disruptions in FAO. The activation of the ISR and disruptions in mitochondrial FAO may underlie the adaptive changes in VARS2-depleted cells.
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- 2022
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12. Generation of pluripotent stem cell lines and CRISPR/Cas9 modified isogenic controls from a patient with dilated cardiomyopathy harboring a RBM20 p.R634W mutation
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Sabine Rebs, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Benjamin Meder, and Katrin Streckfuss-Bömeke
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Biology (General) ,QH301-705.5 - Abstract
RNA binding motif protein 20 (RBM20) is an alternative splicing factor and highly expressed in cardiac tissue. Mutations in the RS domain of RBM20 have been shown to cause different cardiomyopathies. Here, we generated induced pluripotent stem cells (iPSCs) from a dilated cardiomyopathy patient harboring the heterozygous RBM20 mutation p.R634W and consecutively produced isogenic control line using CRISPR/Cas9 genome editing. Patient-specific RBM20 iPSCs and isogenic control line maintained full pluripotency, genomic integrity, and in vitro differentiation capacity. All iPSC-lines were able to differentiate into pure cardiomyocytes, thus providing a valuable tool for studying the pathogenesis of human RBM20-mediated cardiac disease.
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- 2020
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13. Familial Recurrent Myocarditis Triggered by Exercise in Patients With a Truncating Variant of the Desmoplakin Gene
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Wolfgang Poller, Jan Haas, Karin Klingel, Jirko Kühnisch, Martina Gast, Ziya Kaya, Felicitas Escher, Elham Kayvanpour, Franziska Degener, Bernd Opgen‐Rhein, Felix Berger, Hans‐Christian Mochmann, Carsten Skurk, Bettina Heidecker, Heinz‐Peter Schultheiss, Lorenzo Monserrat, Benjamin Meder, Ulf Landmesser, and Sabine Klaassen
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arrhythmogenic cardiomyopathy ,cardiovascular genetics ,desmoplakin ,genome‐environment interactions ,myocarditis ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Variants of the desmosomal protein desmoplakin are associated with arrhythmogenic cardiomyopathy, an important cause of ventricular arrhythmias in children and young adults. Disease penetrance of desmoplakin variants is incomplete and variant carriers may display noncardiac, dermatologic phenotypes. We describe a novel cardiac phenotype associated with a truncating desmoplakin variant, likely causing mechanical instability of myocardial desmosomes. Methods and Results In 2 young brothers with recurrent myocarditis triggered by physical exercise, screening of 218 cardiomyopathy‐related genes identified the heterozygous truncating variant p.Arg1458Ter in desmoplakin. Screening for infections yielded no evidence of viral or nonviral infections. Myosin and troponin I autoantibodies were detected at high titers. Immunohistology failed to detect any residual DSP protein in endomyocardial biopsies, and none of the histologic criteria of arrhythmogenic cardiomyopathy were fulfilled. Cardiac magnetic resonance imaging revealed no features associated with right ventricular arrhythmogenic cardiomyopathy, but multifocal subepicardial late gadolinium enhancement was present in the left ventricles of both brothers. Screening of adult cardiomyopathy cohorts for truncating variants identified the rare genetic variants p.Gln307Ter, p.Tyr1391Ter, and p.Tyr1512Ter, suggesting that over subsequent decades critical genetic/exogenous modifiers drive pathogenesis from desmoplakin truncations toward different end points. Conclusions The described novel phenotype of familial recurrent myocarditis associated with a desmoplakin truncation in adolescents likely represents a serendipitously revealed subtype of arrhythmogenic cardiomyopathy. It may be caused by a distinctive adverse effect of the variant desmoplakin upon the mechanical stability of myocardial desmosomes. Variant screening is advisable to allow early detection of patients with similar phenotypes.
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- 2020
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14. Genomic structural variations lead to dysregulation of important coding and non‐coding RNA species in dilated cardiomyopathy
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Jan Haas, Stefan Mester, Alan Lai, Karen S Frese, Farbod Sedaghat‐Hamedani, Elham Kayvanpour, Tobias Rausch, Rouven Nietsch, Jes‐Niels Boeckel, Avisha Carstensen, Mirko Völkers, Carsten Dietrich, Dietmar Pils, Ali Amr, Daniel B Holzer, Diana Martins Bordalo, Daniel Oehler, Tanja Weis, Derliz Mereles, Sebastian Buss, Eva Riechert, Emil Wirsz, Maximilian Wuerstle, Jan O Korbel, Andreas Keller, Hugo A Katus, Andreas E Posch, and Benjamin Meder
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cardiac transcriptome ,dilated cardiomyopathy ,expression quantitative trait locus ,genomic structural variation ,heart failure ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as non‐coding RNAs. Besides this dynamic regulation, a large part of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome‐wide structural genomic variants (SVs) and their association with gene expression in the human heart. We detected 3,898 individual SVs affecting all classes of gene transcripts (e.g., mRNA, miRNA, lncRNA) and regulatory genomic regions (e.g., enhancer or TFBS). In a cohort of patients (n = 50) with dilated cardiomyopathy (DCM), 80,635 non‐protein‐coding elements of the genome are deleted or duplicated by SVs, containing 3,758 long non‐coding RNAs and 1,756 protein‐coding transcripts. 65.3% of the SV‐eQTLs do not harbor a significant SNV‐eQTL, and for the regions with both classes of association, we find similar effect sizes. In case of deleted protein‐coding exons, we find downregulation of the associated transcripts, duplication events, however, do not show significant changes over all events. In summary, we are first to describe the genomic variability associated with SVs in heart failure due to DCM and dissect their impact on the transcriptome. Overall, SVs explain up to 7.5% of the variation of cardiac gene expression, underlining the importance to study human myocardial gene expression in the context of the individual genome. This has immediate implications for studies on basic mechanisms of cardiac maladaptation, biomarkers, and (gene) therapeutic studies alike.
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- 2018
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15. Marathon-Induced Cardiac Strain as Model for the Evaluation of Diagnostic microRNAs for Acute Myocardial Infarction
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Omid Shirvani Samani, Johannes Scherr, Elham Kayvanpour, Jan Haas, David H. Lehmann, Weng-Tein Gi, Karen S. Frese, Rouven Nietsch, Tobias Fehlmann, Steffi Sandke, Tanja Weis, Andreas Keller, Hugo A. Katus, Martin Halle, Norbert Frey, Benjamin Meder, and Farbod Sedaghat-Hamedani
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biomarker ,troponin ,marathon running ,microRNAs ,myocardial infarction ,exercise ,Medicine - Abstract
Background: The current gold standard biomarker for myocardial infarction (MI), cardiac troponin (cTn), is recognized for its high sensitivity and organ specificity; however, it lacks diagnostic specificity. Numerous studies have introduced circulating microRNAs as potential biomarkers for MI. This study investigates the MI-specificity of these serum microRNAs by investigating myocardial stress/injury due to strenuous exercise. Methods: MicroRNA biomarkers were retrieved by comprehensive review of 109 publications on diagnostic serum microRNAs for MI. MicroRNA levels were first measured by next-generation sequencing in pooled sera from runners (n = 46) before and after conducting a full competitive marathon. Hereafter, reverse transcription quantitative real-time PCR (qPCR) of 10 selected serum microRNAs in 210 marathon runners was performed (>10,000 qPCR measurements). Results: 27 potential diagnostic microRNA for MI were retrieved by the literature review. Eight microRNAs (miR-1-3p, miR-21-5p, miR-26a-5p, miR-122-5p, miR-133a-3p, miR-142-5p, miR-191-5p, miR-486-3p) showed positive correlations with cTnT in marathon runners, whereas two miRNAs (miR-134-5p and miR-499a-5p) showed no correlations. Upregulation of miR-133a-3p (p = 0.03) and miR-142-5p (p = 0.01) went along with elevated cTnT after marathon. Conclusion: Some MI-associated microRNAs (e.g., miR-133a-3p and miR-142-5p) have similar kinetics under strenuous exercise and MI as compared to cTnT, which suggests that their diagnostic specificity could be limited. In contrast, several MI-associated microRNAs (miR-26a-5p, miR-134-5p, miR-191-5p) showed different release behavior; hence, combining cTnT with these microRNAs within a multi-marker strategy may add diagnostic accuracy in MI.
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- 2021
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16. Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease
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Farbod Sedaghat-Hamedani, Sabine Rebs, Ibrahim El-Battrawy, Safak Chasan, Tobias Krause, Jan Haas, Rujia Zhong, Zhenxing Liao, Qiang Xu, Xiaobo Zhou, Ibrahim Akin, Edgar Zitron, Norbert Frey, Katrin Streckfuss-Bömeke, and Elham Kayvanpour
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familial DCM ,SCN5a ,conduction disease ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na+ channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype.
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- 2021
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17. Energy Metabolites as Biomarkers in Ischemic and Dilated Cardiomyopathy
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Jan Haas, Karen S. Frese, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Rewati Tappu, Rouven Nietsch, Oguz Firat Tugrul, Michael Wisdom, Carsten Dietrich, Ali Amr, Tanja Weis, Torsten Niederdränk, Michael P. Murphy, Thomas Krieg, Marcus Dörr, Uwe Völker, Jens Fielitz, Norbert Frey, Stephan B. Felix, Andreas Keller, Hugo A. Katus, and Benjamin Meder
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cardiomyopathy ,energy metabolism ,heart failure ,multi-omics ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - 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.
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- 2021
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18. [Untitled]
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Ali Amr, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Tiziano Passerini, Viorel Mihalef, Alan Lai, Dominik Neumann, Bogdan Georgescu, Sebastian Buss, Derliz Mereles, Edgar Zitron, Andreas E. Posch, Maximilian Würstle, Tommaso Mansi, Hugo A. Katus, and Benjamin Meder
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Dilated cardiomyopathy ,Tau ,Myocardial stiffness ,Computer-based 3D model ,Personalized medicine ,Diastolic function ,Biology (General) ,QH301-705.5 ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
The search for a parameter representing left ventricular relaxation from non-invasive and invasive diagnostic tools has been extensive, since heart failure (HF) with preserved ejection fraction (HF-pEF) is a global health problem. We explore here the feasibility using patient-specific cardiac computer modeling to capture diastolic parameters in patients suffering from different degrees of systolic HF. Fifty eight patients with idiopathic dilated cardiomyopathy have undergone thorough clinical evaluation, including cardiac magnetic resonance imaging (MRI), heart catheterization, echocardiography, and cardiac biomarker assessment. A previously-introduced framework for creating multi-scale patient-specific cardiac models has been applied on all these patients. Novel parameters, such as global stiffness factor and maximum left ventricular active stress, representing cardiac active and passive tissue properties have been computed for all patients. Invasive pressure measurements from heart catheterization were then used to evaluate ventricular relaxation using the time constant of isovolumic relaxation Tau (τ). Parameters from heart catheterization and the multi-scale model have been evaluated and compared to patient clinical presentation. The model parameter global stiffness factor, representing diastolic passive tissue properties, is correlated significantly across the patient population with τ. This study shows that multi-modal cardiac models can successfully capture diastolic (dys) function, a prerequisite for future clinical trials on HF-pEF.
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- 2016
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19. The Role of Quality Control in Targeted Next-generation Sequencing Library Preparation
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Rouven Nietsch, Jan Haas, Alan Lai, Daniel Oehler, Stefan Mester, Karen S. Frese, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Andreas Keller, and Benjamin Meder
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Next-generation sequencing ,Quality control ,Library preparation ,Target enrichment ,Sequence variants ,Biology (General) ,QH301-705.5 ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
Next-generation sequencing (NGS) is getting routinely used in the diagnosis of hereditary diseases, such as human cardiomyopathies. Hence, it is of utter importance to secure high quality sequencing data, enabling the identification of disease-relevant mutations or the conclusion of negative test results. During the process of sample preparation, each protocol for target enrichment library preparation has its own requirements for quality control (QC); however, there is little evidence on the actual impact of these guidelines on resulting data quality. In this study, we analyzed the impact of QC during the diverse library preparation steps of Agilent SureSelect XT target enrichment and Illumina sequencing. We quantified the parameters for a cohort of around 600 samples, which include starting amount of DNA, amount of sheared DNA, smallest and largest fragment size of the starting DNA; amount of DNA after the pre-PCR, and smallest and largest fragment size of the resulting DNA; as well as the amount of the final library, the corresponding smallest and largest fragment size, and the number of detected variants. Intriguingly, there is a high tolerance for variations in all QC steps, meaning that within the boundaries proposed in the current study, a considerable variance at each step of QC can be well tolerated without compromising NGS quality.
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- 2016
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20. Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy
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Weng-Tein Gi, Jan Haas, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Rewati Tappu, David Hermann Lehmann, Omid Shirvani Samani, Michael Wisdom, Andreas Keller, Hugo A. Katus, and Benjamin Meder
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dilated cardiomyopathy ,DNA methylation ,alternative splicing ,epigenetics ,Medicine - Abstract
In recent years, the genetic architecture of dilated cardiomyopathy (DCM) has been more thoroughly elucidated. However, there is still insufficient knowledge on the modifiers and regulatory principles that lead to the failure of myocardial function. The current study investigates the association of epigenome-wide DNA methylation and alternative splicing, both of which are important regulatory principles in DCM. We analyzed screening and replication cohorts of cases and controls and identified distinct transcriptomic patterns in the myocardium that differ significantly, and we identified a strong association of intronic DNA methylation and flanking exons usage (p < 2 × 10−16). By combining differential exon usage (DEU) and differential methylation regions (DMR), we found a significant change of regulation in important sarcomeric and other DCM-associated pathways. Interestingly, inverse regulation of Titin antisense non-coding RNA transcript splicing and DNA methylation of a locus reciprocal to TTN substantiate these findings and indicate an additional role for non-protein-coding transcripts. In summary, this study highlights for the first time the close interrelationship between genetic imprinting by DNA methylation and the transport of this epigenetic information towards the dynamic mRNA splicing landscape. This expands our knowledge of the genome–environment interaction in DCM besides simple gene expression regulation.
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- 2020
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21. Corrigendum to 'Current Status of Sodium Bicarbonate in Coronary Angiography: An Updated Comprehensive Meta-Analysis and Systematic Review'
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Sadeq Ali-Hasan-Al-Saegh, Seyed Jalil Mirhosseini, Elham Rahimizadeh, Zahra Ghodratipour, Zahra Sarrafan-Chaharsoughi, Ali Mohammad Dehghan, Mohammad Reza Lotfaliani, Mohammad Rezaeisadrabadi, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Mohamed Zeriouh, Alexander Weymann, Anton Sabashnikov, and Aron-Frederik Popov
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Published
- 2018
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22. Towards Personalized Cardiology: Multi-Scale Modeling of the Failing Heart.
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Elham Kayvanpour, Tommaso Mansi, Farbod Sedaghat-Hamedani, Ali Amr, Dominik Neumann, Bogdan Georgescu, Philipp Seegerer, Ali Kamen, Jan Haas, Karen S Frese, Maria Irawati, Emil Wirsz, Vanessa King, Sebastian Buss, Derliz Mereles, Edgar Zitron, Andreas Keller, Hugo A Katus, Dorin Comaniciu, and Benjamin Meder
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Medicine ,Science - Abstract
BackgroundDespite modern pharmacotherapy and advanced implantable cardiac devices, overall prognosis and quality of life of HF patients remain poor. This is in part due to insufficient patient stratification and lack of individualized therapy planning, resulting in less effective treatments and a significant number of non-responders.Methods and resultsState-of-the-art clinical phenotyping was acquired, including magnetic resonance imaging (MRI) and biomarker assessment. An individualized, multi-scale model of heart function covering cardiac anatomy, electrophysiology, biomechanics and hemodynamics was estimated using a robust framework. The model was computed on n=46 HF patients, showing for the first time that advanced multi-scale models can be fitted consistently on large cohorts. Novel multi-scale parameters derived from the model of all cases were analyzed and compared against clinical parameters, cardiac imaging, lab tests and survival scores to evaluate the explicative power of the model and its potential for better patient stratification. Model validation was pursued by comparing clinical parameters that were not used in the fitting process against model parameters.ConclusionThis paper illustrates how advanced multi-scale models can complement cardiovascular imaging and how they could be applied in patient care. Based on obtained results, it becomes conceivable that, after thorough validation, such heart failure models could be applied for patient management and therapy planning in the future, as we illustrate in one patient of our cohort who received CRT-D implantation.
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- 2015
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23. Current Status of Sodium Bicarbonate in Coronary Angiography: An Updated Comprehensive Meta-Analysis and Systematic Review
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Sadegh Ali-Hassan-Sayegh, Seyed Jalil Mirhosseini, Elham Rahimizadeh, Zahra Ghodratipour, Zahra Sarrafan-Chaharsoughi, Ali Mohammad Dehghan, Mohammad Reza Lotfaliani, Mohammad Rezaeisadrabadi, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Mohamed Zeriouh, Alexander Weymann, Anton Sabashnikov, and Aron-Frederik Popov
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
This systematic review with meta-analysis sought to determine comparison of efficacy and safety of hydration with sodium bicarbonate versus sodium chloride on contrast induced nephropathy and clinical outcomes. We searched major electronic databases for studies in randomized controlled trials. A value of P50% indicated significant heterogeneity between the studies. Literature search of all databases retrieved 650 studies. 29 studies enrolled in meta-analysis. Pooled analysis indicated about the incidence of CIN (OR of 0.718; 95% CI: 0.60 to 0.85; P=0.000), requirement of hemodialysis (OR of 1.00; 95% CI: 0.49 to 2.01; P=0.9), mean changes of serum creatinine (WMD of 2.321; 95% CI: 1.995 to 2.648; P=0.000), length of hospital stays (WMD of −0.774; 95% CI: −1.65 to 0.10; P=0.08), major adverse cardiovascular events (OR = 1.075, 95% CI: 0.59 to 1.95; P=0.8), and mortality (OR of 0.73; 95% CI: 0.42 to 1.26; P=0.2). Overall, hydration with sodium bicarbonate could significantly reduce CIN and the length of hospital stay compared to sodium chloride. In addition NAC added as a supplement to sodium bicarbonate could increase prophylactic effects against nephropathy.
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- 2015
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24. A Bulking Agent May Lead to Adrenal Insufficiency Crisis: A Case Report
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Salma Ahi, Majid Esmaeilzadeh, Elham Kayvanpour, Farbod Sedaghat-Hamedani, and Seyed Hossein Samadanifard
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Adrenal insufficiency ,Psyllium ,Hydrocortisone ,Hormone replacement therapy ,Medicine (General) ,R5-920 - Abstract
Adrenal insufficiency is a life-threatening disorder which must be treated with glucocorticoid replacement and needs permanent dose adjustment during patient's different somatic situations. Insufficient glucocorticoid doses result in adrenal crisis and must be treated with intravenous hydrocortisone. The patient was known with Adrenal insufficiency and was treated optimally with fludrocortisone and prednisolone since seven years with no history of adrenal crisis. The patient was admitted with abdominal pain, weakness, fatigue and nausea developed 3-4 days after taking psyllium, a bulking agent, prescribed by a surgeon to diagnose anal fissure. Detailed medical history, physical examinations, laboratory and imaging examinations did not approve any other cause of adrenal crisis. Psyllium may interfere with gastrointestinal absorption of prednisolone and/or fludrocortisone and trigger acute adrenal crisis in patients with adrenal insufficiency.
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- 2011
25. A Bulking Agent May Lead to Adrenal Insufficiency Crisis: A Case Report
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Seyed Hossein Samadanifard, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Majid Esmaeilzadeh, and Salma Ahi
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Adrenal Insufficiency ,Psyllium ,Hydrocortisone ,Hormone Replacement Therapy ,Medicine (General) ,R5-920 - Abstract
Adrenal insufficiency is a life-threatening disorder which must be treated with glucocorticoid replacement and needs permanent dose adjustment during patient's different somatic situations. Insufficient glucocorticoid doses result in adrenal crisis and must be treated with intravenous hydrocortisone. The patient was known with Adrenal insufficiency and was treated optimally with fludrocortisone and prednisolone since seven years with no history of adrenal crisis. The patient was admitted with abdominal pain, weakness, fatigue and nausea developed 3-4 days after taking psyllium, a bulking agent, prescribed by a surgeon to diagnose anal fissure. Detailed medical history, physical examinations, laboratory and imaging examinations did not approve any other cause of adrenal crisis. Psyllium may interfere with gastrointestinal absorption of prednisolone and/or fludrocortisone and trigger acute adrenal crisis in patients with adrenal insufficiency.
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- 2011
26. Vito - A Generic Agent for Multi-physics Model Personalization: Application to Heart Modeling.
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Dominik Neumann, Tommaso Mansi, Lucian Mihai Itu, Bogdan Georgescu, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Jan Haas, Hugo A. Katus, Benjamin Meder, Stefan Steidl, Joachim Hornegger, and Dorin Comaniciu
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- 2015
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27. Multi-omics assessment of dilated cardiomyopathy using non-negative matrix factorization
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Rewati Tappu, Jan Haas, David H. Lehmann, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Andreas Keller, Hugo A. Katus, Norbert Frey, and Benjamin Meder
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Cardiomyopathy, Dilated ,Sarcomeres ,Multidisciplinary ,High-Throughput Nucleotide Sequencing ,Humans ,Heart ,DNA Methylation - Abstract
Dilated cardiomyopathy (DCM), a myocardial disease, is heterogeneous and often results in heart failure and sudden cardiac death. Unavailability of cardiac tissue has hindered the comprehensive exploration of gene regulatory networks and nodal players in DCM. In this study, we carried out integrated analysis of transcriptome and methylome data using non-negative matrix factorization from a cohort of DCM patients to uncover underlying latent factors and covarying features between whole-transcriptome and epigenome omics datasets from tissue biopsies of living patients. DNA methylation data from Infinium HM450 and mRNA Illumina sequencing of n = 33 DCM and n = 24 control probands were filtered, analyzed and used as input for matrix factorization using R NMF package. Mann-Whitney U test showed 4 out of 5 latent factors are significantly different between DCM and control probands (PP = 3.97E-21), nucleic acid binding (P = 1.42E-18), extracellular matrix (P = 9.23E-14) and myofibrillar structure (P = 8.46E-12). Correlation network analysis revealed interaction of important sarcomeric genes like Nebulin, Tropomyosin alpha-3 and ERC-protein 2 with CpG methylation of ATPase Phospholipid Transporting 11A0, Solute Carrier Family 12 Member 7 and Leucine Rich Repeat Containing 14B, all with significant P values associated with correlation coefficients >0.7. Using matrix factorization, multi-omics data derived from human tissue samples can be integrated and novel interactions can be identified. Hypothesis generating nature of such analysis could help to better understand the pathophysiology of complex traits such as DCM.
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- 2023
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28. Personalized Computer Simulation of Diastolic Function in Heart Failure.
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Ali Amr, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Tiziano Passerini, Viorel Mihalef, Alan Lai, Dominik Neumann, Bogdan Georgescu, Sebastian Buss, Derliz Mereles, Edgar Zitron, Andreas E. Posch, Maximilian Würstle, Tommaso Mansi, Hugo A. Katus, and Benjamin Meder
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- 2016
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29. A self-taught artificial agent for multi-physics computational model personalization.
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Dominik Neumann, Tommaso Mansi, Lucian Mihai Itu, Bogdan Georgescu, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Ali Amr, Jan Haas, Hugo A. Katus, Benjamin Meder, Stefan Steidl, Joachim Hornegger, and Dorin Comaniciu
- Published
- 2016
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30. Automatic image-to-model framework for patient-specific electromechanical modeling of the heart.
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Dominik Neumann, Tommaso Mansi, Sasa Grbic, Ingmar Voigt, Bogdan Georgescu, Elham Kayvanpour, Ali Amr, Farbod Sedaghat-Hamedani, Jan Haas, Hugo A. Katus, Benjamin Meder, Joachim Hornegger, Ali Kamen, and Dorin Comaniciu
- Published
- 2014
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31. Estimation of Regional Electrical Properties of the Heart from 12-Lead ECG and Images.
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Philipp Seegerer, Tommaso Mansi, Marie-Pierre Jolly, Dominik Neumann, Bogdan Georgescu, Ali Kamen, Elham Kayvanpour, Ali Amr, Farbod Sedaghat-Hamedani, Jan Haas, Hugo A. Katus, Benjamin Meder, and Dorin Comaniciu
- Published
- 2014
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32. Robust Image-Based Estimation of Cardiac Tissue Parameters and Their Uncertainty from Noisy Data.
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Dominik Neumann, Tommaso Mansi, Bogdan Georgescu, Ali Kamen, Elham Kayvanpour, Ali Amr, Farbod Sedaghat-Hamedani, Jan Haas, Hugo A. Katus, Benjamin Meder, Joachim Hornegger, and Dorin Comaniciu
- Published
- 2014
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33. Deep phenotyping of two preclinical mouse models and a cohort of RBM20 mutation carriers reveals no sex-dependent disease severity in
- Author
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David C, Lennermann, Mark E, Pepin, Markus, Grosch, Laura, Konrad, Elena, Kemmling, Joshua, Hartmann, Janica L, Nolte, Sandra, Clauder-Münster, Elham, Kayvanpour, Farbod, Sedaghat-Hamedani, Jan, Haas, Benjamin, Meder, Malou, van den Boogaard, Ahmad S, Amin, Matthias, Dewenter, Marcus, Krüger, Lars M, Steinmetz, Johannes, Backs, and Maarten M G, van den Hoogenhof
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Male ,Mice, Knockout ,Mice ,Mutation ,Animals ,RNA-Binding Proteins ,Female ,Arrhythmias, Cardiac ,Cardiomyopathies ,Severity of Illness Index - Published
- 2022
34. From Medical Images to Fast Computational Models of Heart Electromechanics: An Integrated Framework towards Clinical Use.
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Oliver Zettinig, Tommaso Mansi, Bogdan Georgescu, Saikiran Rapaka, Ali Kamen, Jan Haas, Karen S. Frese, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Ali Amr, Stefan Hardt, Derliz Mereles, Henning Steen, Andreas Keller, Hugo A. Katus, Benjamin Meder, Nassir Navab, and Dorin Comaniciu
- Published
- 2013
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35. Fast Data-Driven Calibration of a Cardiac Electrophysiology Model from Images and ECG.
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Oliver Zettinig, Tommaso Mansi, Bogdan Georgescu, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Ali Amr, Jan Haas, Henning Steen, Benjamin Meder, Hugo A. Katus, Nassir Navab, Ali Kamen, and Dorin Comaniciu
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- 2013
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36. A novel risk model for predicting potentially life-threatening arrhythmias in non-ischemic dilated cardiomyopathy (DCM-SVA risk)
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Philippe Charron, Benjamin Meder, Jan Haas, Grażyna Truszkowska, Mateusz Śpiewak, Hugo A. Katus, Pierre Socie, Eric Villard, Pascale Richard, Jan Koelemenoglu, Małgorzata Stępień-Wojno, Farbod Sedaghat-Hamedani, Bogna Foss-Nieradko, Weng-Tein Gi, Joanna Zakrzewska-Koperska, Elham Kayvanpour, Arjan Sammani, Ewa Michalak, Anneline S.J.M. te Riele, Folkert W. Asselbergs, Tobias Miersch, Tomasz Zieliński, Zofia T. Bilińska, Norbert Frey, Annette F. Baas, Alicia Broezel, Przemysław Chmielewski, Angelique Curjol, Rafał Płoski, David H. Lehmann, and Cardiology
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Cardiomyopathy, Dilated ,Adult ,Cardiac/diagnosis ,Male ,medicine.medical_specialty ,Cardiomyopathy ,Left ,Arrhythmias ,Ventricular tachycardia ,Ventricular Function, Left ,Sudden cardiac death ,QRS complex ,Risk Factors ,Internal medicine ,Medicine ,Humans ,Ventricular Function ,cardiovascular diseases ,Death, Sudden, Cardiac/epidemiology ,Aged ,Ejection fraction ,business.industry ,Proportional hazards model ,Arrhythmias, Cardiac/diagnosis ,Arrhythmias, Cardiac ,Dilated cardiomyopathy ,Atrial fibrillation ,Dilated/diagnosis ,Stroke Volume ,Middle Aged ,medicine.disease ,Sudden ,Defibrillators, Implantable ,Death ,Death, Sudden, Cardiac ,Cardiomyopathy, Dilated/diagnosis ,cardiovascular system ,Cardiology ,Female ,Implantable ,Cardiology and Cardiovascular Medicine ,business ,Cardiac/epidemiology ,Defibrillators - Abstract
Background Non-ischemic dilated cardiomyopathy (DCM) can be complicated by sustained ventricular arrhythmias (SVA) and sudden cardiac death (SCD). By now, left-ventricular ejection fraction (LV-EF) is the main guideline criterion for primary prophylactic ICD implantation, potentially leading either to overtreatment or failed detection of patients at risk without severely impaired LV-EF. The aim of the European multi-center study DETECTIN-HF was to establish a clinical risk calculator for individualized risk stratification of DCM patients. Methods 1393 patients (68% male, mean age 50.7 ± 14.3y) from four European countries were included. The outcome was occurrence of first potentially life-threatening ventricular arrhythmia. The model was developed using Cox proportional hazards, and internally validated using cross validation. The model included seven independent and easily accessible clinical parameters sex, history of non-sustained ventricular tachycardia, history of syncope, family history of cardiomyopathy, QRS duration, LV-EF, and history of atrial fibrillation. The model was also expanded to account for presence of LGE as the eight8h parameter for cases with available cMRI and scar information. Results During a mean follow-up period of 57.0 months, 193 (13.8%) patients experienced an arrhythmic event. The calibration slope of the developed model was 00.97 (95% CI 0.90–1.03) and the C-index was 0.72 (95% CI 0.71–0.73). Compared to current guidelines, the model was able to protect the same number of patients (5-year risk ≥8.5%) with 15% fewer ICD implantations. Conclusions This DCM-SVA risk model could improve decision making in primary prevention of SCD in non-ischemic DCM using easily accessible clinical information and will likely reduce overtreatment.
- Published
- 2021
37. Data-driven estimation of cardiac electrical diffusivity from 12-lead ECG signals.
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Oliver Zettinig, Tommaso Mansi, Dominik Neumann, Bogdan Georgescu, Saikiran Rapaka, Philipp Seegerer, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Ali Amr, Jan Haas, Henning Steen, Hugo A. Katus, Benjamin Meder, Nassir Navab, Ali Kamen, and Dorin Comaniciu
- Published
- 2014
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38. Controlling my genome with my smartphone: first clinical experiences of the PROMISE system
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Annika Krämer, Ali Amr, Michael Backes, Karen S. Frese, Hans-Ulrich Prokosch, Dominique Schröder, Hugo A. Katus, Benjamin Meder, Christoph Egger, Ninja Marnau, Norbert Frey, Andreas Keller, Dominic Deuber, Claudia Durand, Farbod Sedaghat-Hamedani, Marc Schweig, Marc Hinderer, Lena Griebel, Jan Haas, Florian Battke, Elham Kayvanpour, and Daniel Huhn
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medicine.medical_specialty ,business.industry ,Information Dissemination ,Data management ,Data security ,Cryptography ,Pilot Projects ,General Medicine ,Precision medicine ,Data science ,Data type ,Digital health ,Data sharing ,Data exchange ,Privacy ,Internal medicine ,Cardiology ,Medicine ,Humans ,Smartphone ,ddc:610 ,Cardiology and Cardiovascular Medicine ,business ,Computer Security - 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. Graphic abstract
- Published
- 2022
39. Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta‐analysis and systematic review
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Tanja Proctor, Arjan Sammani, Hugo A. Katus, Weng-Tein Gi, Laurens P Bosman, Farbod Sedaghat-Hamedani, Benjamin Meder, Alicia Broezel, Folkert W. Asselbergs, Anneline S.J.M. te Riele, Katrin Jensen, and Elham Kayvanpour
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Risk ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,Implantable cardiac‐defibrillator ,Dilated cardiomyopathy ,030204 cardiovascular system & hematology ,Sudden cardiac death ,LMNA ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,cardiovascular diseases ,030212 general & internal medicine ,FLNC ,Ejection fraction ,business.industry ,Hazard ratio ,Prognosis ,medicine.disease ,lcsh:RC666-701 ,Meta-analysis ,Heart failure ,cardiovascular system ,Cardiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims Patients with non‐ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter‐defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM. Methods and results We searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow‐up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74–1.00)], hypertension [HR 1.95; 95% CI (1.26–3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32–13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19–1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02–7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non‐sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin‐C (FLNC)] were associated with arrhythmic outcome in non‐pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high. Conclusions In patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non‐)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter‐defibrillator implantation.
- Published
- 2020
40. Postcardiac injury syndrome after cardiac implantable electronic device implantation
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Benjamin Meder, Hugo A. Katus, Panagiotis Xynogalos, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Edgar Zitron, Kevin Filbey, and Daniel Scherer
- Subjects
Kardiale Resynchronisationstherapiegeräte ,medicine.medical_specialty ,Heart Diseases ,Dilatative Kardiomyopathie ,medicine.medical_treatment ,Dilated cardiomyopathy ,Pericardial effusion ,Chest pain ,Right atrial lead implantation ,Pericarditis ,Risk Factors ,Internal medicine ,medicine ,Humans ,Perikarditis ,Myocardial infarction ,Cardiac Surgical Procedures ,business.industry ,Incidence ,Percutaneous coronary intervention ,Original Articles ,medicine.disease ,Cardiac resynchronization therapy devices ,Rechtsatriale Elektrodenimplantation ,Defibrillators, Implantable ,Cardiac surgery ,Heart Injuries ,cardiovascular system ,Cardiology ,Perikarderguss ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Complication ,business - Abstract
Background Postcardiac injury syndrome (PCIS) is an inflammatory complication that derives from injury to the epicardium, myocardium, or endocardium. It occurs after trauma, myocardial infarction, percutaneous coronary intervention, cardiac surgery, intracardiac ablation, and implantation of cardiac implantable electronic device (CIED). In this study we assessed the incidence of PCIS after CIED implantation and its possible risk factors. Material and methods All patients who received CIED implantation at Heidelberg University Hospital between 2000 and 2014 were evaluated (n = 4989 patients). Clinical data including age, sex, underlying cardiac disease, type of implanted CIED, location of electrode implantation, clinical symptoms, time of symptom onset of PCIS, therapy, and outcome were extracted and analyzed. Results We identified 19 cases of PCIS in 4989 patients, yielding an incidence of 0.38%. The age of patients with PCIS ranged from 39 to 86 years. Dilated cardiomyopathy (DCM) as underlying cardiac disease and right atrial (RA) lead implantation had a significant association with occurrence of PCIS (p = 0.045 in DCM and p Conclusion To the best of our knowledge, this is the largest cohort evaluating the incidence of PCIS after CIED implantation. The data show that PCIS is a rare complication after CIED implantation and occurs more frequently in patients with DCM and those with RA lead implantation. Although rare and mostly benign, PCIS can lead to potentially lethal complications and physicians must be aware of its symptoms.
- Published
- 2020
41. Cardiac Myxoma in a Patient With Hypertrophic Cardiomyopathy
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Omid Shirvani Samani, Hugo A. Katus, Benjamin Meder, Esther Herpel, Johannes Riffel, Farbod Sedaghat-Hamedani, Weng-Tein Gi, Rawa Arif, Derliz Mereles, and Elham Kayvanpour
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0301 basic medicine ,FO, fossa ovalis ,medicine.medical_specialty ,HCM, hypertrophic cardiomyopathy ,hs-cTnT, high-sensitivity cardiac troponin T ,030105 genetics & heredity ,HCM - Hypertrophic cardiomyopathy ,LEOPARD Syndrome ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Rare case ,medicine ,LVOT, left ventricular outflow tract ,echocardiography ,Diseases of the circulatory (Cardiovascular) system ,LEOPARD syndrome ,Mini-Focus Issue on Cardiomyopathies and Genetic Counseling ,LGE, late gadolinium enhancement ,business.industry ,Hypertrophic cardiomyopathy ,imaging ,Myxoma ,hypertrophic cardiomyopathy ,medicine.disease ,SCD, sudden cardiac death ,RC666-701 ,Concomitant ,cardiovascular system ,Cardiology ,ECG, electrocardiogram ,NT-proBNP, N-terminal pro–B-type natriuretic peptide ,Case Report: Clinical Case ,Cardiology and Cardiovascular Medicine ,business ,cardiac myxoma ,030217 neurology & neurosurgery - Abstract
We report a rare case of concomitant hypertrophic cardiomyopathy and cardiac myxoma without LEOPARD syndrome. Additionally, 6 similar cases were systemically reviewed, and the characteristics of this first-ever studied patient group were summarized. (Level of Difficulty: Beginner.), Graphical abstract, This article reports a rare case of concomitant hypertrophic cardiomyopathy and cardiac myxoma without LEOPARD syndrome. Six similar cases were reviewed…
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- 2020
42. Two Hearts at Risk
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Benjamin Meder, Herbert Fluhr, Isabell Mohr, Omid Shirvani Samani, Ali Amr, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Hugo A. Katus, Manuela Meder, and Weng-Tein Gi
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0301 basic medicine ,medicine.medical_specialty ,Alcohol septal ablation ,HOCM, hypertrophic obstructive cardiomyopathy ,LVOTO, left ventricular outflow tract obstruction ,alcohol septal ablation ,HCM, hypertrophic cardiomyopathy ,IVS, interventricular septum ,030105 genetics & heredity ,HCM - Hypertrophic cardiomyopathy ,Obstructive cardiomyopathy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,hypertrophic obstructive cardiomyopathy ,Diseases of the circulatory (Cardiovascular) system ,Medicine ,LVOT, left ventricular outflow tract ,Decompensation ,Peripartum Cardiovascular Disease Mini-Focus Issue ,Fetus ,Pregnancy ,decompensation ,business.industry ,SAM, systolic anterior motion ,ASA, alcohol septal ablation / transcoronary ablation of septal hypertrophy ,HOCM - Hypertrophic obstructive cardiomyopathy ,medicine.disease ,LV, left ventricle ,RC666-701 ,Cardiology ,Gestation ,Case Report: Clinical Case ,pregnancy ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery - Abstract
Hypertrophic obstructive cardiomyopathy (HOCM) increases the risk for mother and fetus during pregnancy. Alcohol septal ablation (ASA) is an established procedure in nonpregnant patients with HOCM. In this report, we present a case of a 29-year-old woman in her 29th gestational week with decompensated HOCM undergoing a successful ASA. (Level of Difficulty: Advanced.), Graphical abstract, Hypertrophic obstructive cardiomyopathy (HOCM) increases the risk for mother and fetus during pregnancy…
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- 2020
43. The chameleon of cardiology: cardiac sarcoidosis before and after heart transplantation
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Ali Amr, Weng-Tein Gi, Sonja Hamed, Elham Kayvanpour, Omid Shirvani Samani, Jan Haas, Philipp Ehlermann, Benjamin Meder, Farbod Sedaghat-Hamedani, Esther Herpel, Johannes Riffel, Tobias Miersch, Hugo A. Katus, Lutz Frankenstein, and Michael M. Kreusser
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medicine.medical_specialty ,Sarcoidosis ,medicine.medical_treatment ,Cardiology ,Case Report ,Cardiac sarcoidosis ,030204 cardiovascular system & hematology ,Chronic inflammatory disease ,Asymptomatic ,Right ventricular cardiomyopathy ,Sudden cardiac death ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Arrhythmogenic right ventricular cardiomyopathy (ARVC) ,medicine ,Diseases of the circulatory (Cardiovascular) system ,Humans ,030212 general & internal medicine ,Arrhythmogenic Right Ventricular Dysplasia ,Heart transplantation ,Task force ,business.industry ,food and beverages ,medicine.disease ,Death, Sudden, Cardiac ,Heart failure ,RC666-701 ,cardiovascular system ,Heart Transplantation ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Cardiac sarcoidosis is a chronic inflammatory disease with a large spectrum of symptoms that can mimic diseases such as dilated, hypertrophic, or arrhythmogenic cardiomyopathies. It can be asymptomatic but can also present with ventricular arrhythmias, conduction disease, and heart failure (HF) or even sudden cardiac death (SCD). We present here the case of a patient transplanted due to end‐stage arrhythmogenic right ventricular cardiomyopathy (ARVC), fulfilling the task force criteria. A few years after successful heart transplantation (HTX), the patient developed similar symptoms and morphofunctional changes of the heart, which led to critical re‐evaluation of his primary diagnosis.
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- 2019
44. RBM20-mutations induce disturbed splicing of calcium relevant genes and guides clinically therapy in different cardiomyopathies
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Benjamin Meder, A Wagdi, D Huebscher, Elham Kayvanpour, Sabine Rebs, Farbod Sedaghat-Hamedani, K Streckfuss-Boemeke, and Gerd Hasenfuss
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business.industry ,chemistry.chemical_element ,030229 sport sciences ,030204 cardiovascular system & hematology ,Calcium ,03 medical and health sciences ,0302 clinical medicine ,chemistry ,RNA splicing ,Cancer research ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Gene - Abstract
Background Mutations in the splice factor RBM20 account for ∼3% of genetic cardiomyopathies. Mutations at position R634 in the hotspot RS-domain were found to cause dilative cardiomyopathy (DCM) (R634W) or left ventricular non-compaction cardiomyopathy (LVNC) (R634L), but the pathophysiological mechanisms that govern the heterogeneity in phenotype presentation remain unknown. Purpose We aimed here to identify the molecular events caused by the distinct RBM20 mutations from DCM and LVNC patients using a patient-specific induced stem cell model (iPSC) and test if the currently clinically used β-blockers (Metroprolol) are suitable for different RBM20-dependent cardiomyopathies. Methods We generated iPSC-cardiomyocytes of 2 DCM- and 2 LVNC-patients harboring the RBM20-mutations R634W (DCM) or R634L (LVNC). We investigated alternative splicing, sarcomeric regularity, cAMP-level, kinase-specific phosphorylation of Ca2+ players and Ca2+ handling. To investigate the impact of the genetic background, isogenic rescue lines were generated by CRISPR/Cas9. Different clinical drugs as Metoprolol and Verapamil were used to analyze the pharmacological improvement in vitro. Results We investigated the splicing pattern of the 2 RBM20 mutations in DCM and LVNC iPSC-CMs and observed common isoform changes in titin and a 24bp-insertion in the gene RYR2. The Ca2+ handling gene triadin is misspliced in LVNC-CMs, whereas the structural gene LDB3 is misspliced in DCM-CMs. As a possible consequence of splice defects in sarcomeric genes, both DCM and LVNC-CMs exhibited an irregular sarcomeric structure. The Ca2+ handling gene CAMK2δ was predominantly misspliced in LVNC-CMs leading to CAMK2δ-dependent hyperphosphorylation of its target PLN-Thr17 and subsequently to shortened Ca2+ elimination time and weakened response to β-adrenergic stimulation. By contrast, DCM-CMs exhibited increased Ca2+ sparks and decreased systolic and diastolic Ca2+ levels. RBM20 expression itself was decreased in LVNC-CMs, but not in DCM-CMs. This highlights that 2 distinct RBM20 mutations can lead to different pathological Ca2+ phenotypes. Isogenic CRISPR/Cas9 repair of both RBM20 mutations in LVNC and DCM demonstrated a rescue in gene missplicing, sarcomeric regularity and the Ca2+ handling aberrations and underscored the causative nature of the 2 mutations and their diverging effects. Ca2+ channel blockage with Verapamil showed a significant improvement of some of the LVNC disease characteristics compared to commonly clinically used β-blocker Metoprolol and underpins the potential clinical use of this drug in patients with LVNC. Conclusion We show the first iPSC-model of splice-defect associated RBM20-dependent LVNC and DCM. In summary, our results suggest that the molecular aberrations in alternative splicing differ depending on the distinct mutation in RBM20 and lead to shared and differential pathologies. Verapamil could be a good candidate in the treatment of RBM20-dependent LVNC. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Bunderministerium für Bildung und Forschung BMBFGerman Center for Cardiovascular Research DZHK
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- 2021
45. Evaluating the Use of Circulating MicroRNA Profiles for Lung Cancer Detection in Symptomatic Patients
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Walter Maetzler, Verena Keller, Rudi Balling, Sebastian F M Haeusler, Eckart Meese, Benjamin Meder, Tanja Weis, Lars Geffers, Valentina Galata, Anne Hecksteden, Nathaniel D. Mercaldo, Anna-Katharina von Thaler, Tobias Fehlmann, Heinrich V. Groesdonk, Claus Vogelmeier, Hans-Peter Lenhof, Andreas Meiser, Masood Abu-Halima, Tim Meyer, Ingo Stehle, Daniela Hornung, Claudia Schulte, Christina Backes, Ulrike Suenkel, Florian Metzger, Rejko Krüger, Hanno Huwer, Mustafa Kahraman, Hashim Abdul-Khaliq, Pedro Guimarães, Robert Bals, Christian Deuschle, Nicole Ludwig, Sebastian Fähndrich, Stephanie Deutscher, Christian Herr, Hugo A. Katus, Andreas Keller, Elham Kayvanpour, Thomas Volk, and Caroline Diener
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Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,genetics [Lung Neoplasms] ,Internal medicine ,Biopsy ,medicine ,Humans ,030212 general & internal medicine ,Circulating MicroRNA ,ddc:610 ,Liquid biopsy ,Lung cancer ,Survival rate ,Original Investigation ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Survival Rate ,genetics [Circulating MicroRNA] ,mortality [Lung Neoplasms] ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Cancer biomarkers ,Female ,business ,Cohort study - Abstract
Importance The overall low survival rate of patients with lung cancer calls for improved detection tools to enable better treatment options and improved patient outcomes. Multivariable molecular signatures, such as blood-borne microRNA (miRNA) signatures, may have high rates of sensitivity and specificity but require additional studies with large cohorts and standardized measurements to confirm the generalizability of miRNA signatures. Objective To investigate the use of blood-borne miRNAs as potential circulating markers for detecting lung cancer in an extended cohort of symptomatic patients and control participants. Design, Setting, and Participants This multicenter, cohort study included patients from case-control and cohort studies (TREND and COSYCONET) with 3102 patients being enrolled by convenience sampling between March 3, 2009, and March 19, 2018. For the cohort study TREND, population sampling was performed. Clinical diagnoses were obtained for 3046 patients (606 patients with non–small cell and small cell lung cancer, 593 patients with nontumor lung diseases, 883 patients with diseases not affecting the lung, and 964 unaffected control participants). No samples were removed because of experimental issues. The collected data were analyzed between April 2018 and November 2019. Main Outcomes and Measures Sensitivity and specificity of liquid biopsy using miRNA signatures for detection of lung cancer. Results A total of 3102 patients with a mean (SD) age of 61.1 (16.2) years were enrolled. Data on the sex of the participants were available for 2856 participants; 1727 (60.5%) were men. Genome-wide miRNA profiles of blood samples from 3046 individuals were evaluated by machine-learning methods. Three classification scenarios were investigated by splitting the samples equally into training and validation sets. First, a 15-miRNA signature from the training set was used to distinguish patients diagnosed with lung cancer from all other individuals in the validation set with an accuracy of 91.4% (95% CI, 91.0%-91.9%), a sensitivity of 82.8% (95% CI, 81.5%-84.1%), and a specificity of 93.5% (95% CI, 93.2%-93.8%). Second, a 14-miRNA signature from the training set was used to distinguish patients with lung cancer from patients with nontumor lung diseases in the validation set with an accuracy of 92.5% (95% CI, 92.1%-92.9%), sensitivity of 96.4% (95% CI, 95.9%-96.9%), and specificity of 88.6% (95% CI, 88.1%-89.2%). Third, a 14-miRNA signature from the training set was used to distinguish patients with early-stage lung cancer from all individuals without lung cancer in the validation set with an accuracy of 95.9% (95% CI, 95.7%-96.2%), sensitivity of 76.3% (95% CI, 74.5%-78.0%), and specificity of 97.5% (95% CI, 97.2%-97.7%). Conclusions and Relevance The findings of the study suggest that the identified patterns of miRNAs may be used as a component of a minimally invasive lung cancer test, complementing imaging, sputum cytology, and biopsy tests.
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- 2021
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46. Energy metabolites as biomarkers in ischemic and dilated cardiomyopathy
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Benjamin Meder, Oguz Firat Tugrul, Michael P. Murphy, Ali Amr, Michael Wisdom, Stephan B. Felix, Jens Fielitz, Rouven Nietsch, Norbert Frey, Marcus Dörr, Uwe Völker, Elham Kayvanpour, Rewati Tappu, Karen S. Frese, Andreas Keller, Jan Haas, Torsten Dr. Niederdränk, Hugo A. Katus, Carsten Dietrich, Tanja Weis, Farbod Sedaghat-Hamedani, Thomas Krieg, Sedaghat-Hamedani, Farbod [0000-0002-3266-0527], Tappu, Rewati [0000-0003-0902-7114], Niederdränk, Torsten [0000-0002-3803-2679], Krieg, Thomas [0000-0002-5192-580X], Dörr, Marcus [0000-0001-7471-475X], Völker, Uwe [0000-0002-5689-3448], Keller, Andreas [0000-0002-5361-0895], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Epigenomics ,Male ,Metabolite ,Cardiomyopathy ,heart failure ,030204 cardiovascular system & hematology ,Pharmacology ,Epigenesis, Genetic ,lcsh:Chemistry ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,energy metabolism ,Glycolysis ,lcsh:QH301-705.5 ,Spectroscopy ,Principal Component Analysis ,Dilated cardiomyopathy ,General Medicine ,Middle Aged ,Computer Science Applications ,DNA methylation ,Female ,Adult ,Cardiomyopathy, Dilated ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Metabolomics ,medicine ,Humans ,Epigenetics ,Physical and Theoretical Chemistry ,Molecular Biology ,Aged ,business.industry ,Gene Expression Profiling ,Organic Chemistry ,multi-omics ,medicine.disease ,030104 developmental biology ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cardiovascular and Metabolic Diseases ,Heart failure ,business ,cardiomyopathy ,Biomarkers - 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.
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- 2021
47. Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect
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Antonio de Marvao, Roddy Walsh, Jean-Claude Tardif, R. Thomas Lumbers, Eric Villard, Rafik Tadros, Peter Lichtner, Catherine Francis, Julie Amyot, Michelle Michels, Hugh Watkins, Julia Cadrin-Tourigny, Najim Lahrouchi, Rudolf A. de Boer, Patrick Garceau, Karin J. H. Verweij, Paul M. Matthews, Paul Elliott, S. Matthijs Boekholdt, Folkert W. Asselbergs, Declan P. O'Regan, Benjamin Meder, Joost A. Offerhaus, Nicola Whiffin, Jacco C. Karper, Jason D. Roberts, Marie-Pierre Dubé, Hideaki Suzuki, James S. Ware, Yigal M. Pinto, Thomas Meitinger, Guillaume Lettre, Hannah G. van Velzen, Arthur A.M. Wilde, Marjon van Slegtenhorst, Francesco Mazzarotto, Wouter P. te Rijdt, Paul J.R. Barton, Sanjay K Prasad, A. John Baksi, Michael W.T. Tanck, Mario Talajic, Roy Huurman, J. Peter van Tintelen, Connie R. Bezzina, Antonis Pantazis, Robert A. Hegele, Jentien M Vermeulen, Rachel Buchan, Imke Christiaans, Jan H. Veldink, Edgar T. Hoorntje, Elham Kayvanpour, Pascale Richard, Geneviève Giraldeau, Flavie Ader, Andrew Thain, Philippe L. L’Allier, Xiao Xu, Leander Beekman, David McCarty, Alexa M.C. Vermeer, Geraldine Sloane, Wenjia Bai, Andrew R. Harper, Jolanda van der Velden, Stuart A. Cook, Ken Kelu Bisabu, Philippe Charron, Deborah Schneider-Luftman, Human Genetics, ACS - Heart failure & arrhythmias, Cardiology, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Compulsivity, Impulsivity & Attention, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, ACS - Amsterdam Cardiovascular Sciences, Epidemiology and Data Science, APH - Methodology, ACS - Atherosclerosis & ischemic syndromes, Human genetics, Physiology, Cardiovascular Centre (CVC), Clinical Genetics, Wellcome Trust, Department of Health, British Heart Foundation, Engineering & Physical Science Research Council (EPSRC), UK DRI Ltd, The Academy of Medical Sciences, and Imperial College Healthcare NHS Trust- BRC Funding
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Linkage disequilibrium ,Cardiomyopathy, Dilated/genetics ,Left ,Cardiomyopathy ,Genome-wide association study ,Kaplan-Meier Estimate ,VARIANTS ,Ventricular Function, Left ,Linkage Disequilibrium ,0302 clinical medicine ,Gene Frequency ,Dilated ,Ventricular Function ,11 Medical and Health Sciences ,Cardiomyopathy, Hypertrophic/genetics ,Genetics & Heredity ,0303 health sciences ,HERITABILITY ,Single Nucleotide ,MENDELIAN RANDOMIZATION ,Cardiology ,cardiovascular system ,HEART ,Life Sciences & Biomedicine ,Ventricular Function, Left/genetics ,Cardiomyopathy, Dilated ,medicine.medical_specialty ,Heart Ventricles ,Quantitative Trait Loci ,Biology ,Quantitative trait locus ,Sudden death ,Polymorphism, Single Nucleotide ,Article ,Heart Ventricles/physiopathology ,03 medical and health sciences ,Internal medicine ,Mendelian randomization ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,GENOME-WIDE ASSOCIATION ,Polymorphism ,030304 developmental biology ,Genetic association ,Science & Technology ,Hypertrophic/genetics ,Left/genetics ,Case-control study ,CONTRACTILITY ,06 Biological Sciences ,Cardiomyopathy, Hypertrophic ,medicine.disease ,Hypertrophic ,Dilated/genetics ,Case-Control Studies ,Genome-Wide Association Study ,030217 neurology & neurosurgery ,Developmental Biology - 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.
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- 2021
48. The clinical atlas of cardiomyopathies: data from the prospective DZHK TORCH study
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K. Weitmann, S Sluka, Benjamin Meder, J Trebing, A Kindermann, Hugo A. Katus, Thomas Eschenhagen, Elham Kayvanpour, S Preussler, Christoph Dieterich, W T Gi, Wolfgang Hoffmann, K Tan, and Farbod Sedaghat-Hamedani
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medicine.medical_specialty ,medicine.anatomical_structure ,Torch ,business.industry ,Atlas (anatomy) ,law ,Medicine ,Medical physics ,Cardiology and Cardiovascular Medicine ,business ,law.invention - Abstract
Introduction Cardiomyopathies (CMPs) are leading causes of heart failure (HF) and sudden cardiac death (SCD). Comparative data of the multiple cardiomyopathy forms are largely missing. The TranslatiOnal Registry for CardiomyopatHies (TORCH) is the largest prospective multicentre CMP registry world-wide. Enrolled patients are comprehensively phenotyped by clinical examinations, state-of-the-art imaging, and molecular investigations. In this study, we present the baseline and 1-year follow-up data. Methods TORCH is a national, prospective, multicentre registry within the German Centre for Cardiovascular Research (DZHK) and includes 2300 patients with non-ischemic (primary and secondary) CMP from 20 centres. The minimum follow up was one year. The DZHK-wide harmonization of datasets and SOPs ensure a high level of data quality and comparability across different CMP forms. Results Dilated cardiomyopathy (DCM) has the highest prevalence with 64% of all enrolled patients, followed by hypertrophic cardiomyopathy (HCM) with 16%. At baseline, patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) were treated more often with ICD implantation and showed high rates of adequate ICD therapies (65.8%, p15% and 12% receiving heart transplantation. In DCM, reverse remodelling with improvement of functional parameters and biomarkers was more often observed in idiopathic and inflammatory cases compared to familial ones. HCM patients had the most favourable outcome. Conclusion and outlook TORCH is the largest prospective study focusing on CMPs. We provided for the first time prospectively the clinical data of patients with diverse cardiomyopathies with outcome. Furthermore, comparing the different CMP forms on the clinical and molecular level will be an important step to enable translational research projects. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Centre for Cardiovascular Research (DZHK)
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- 2020
49. RBM20-mutations induce disturbed splicing of calcium relevant genes in patient-specific stem cell models of cardiomyopathies
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Benjamin Meder, Elham Kayvanpour, Farbod Sedaghat-Hamedani, K Streckfuss-Boemeke, D Huebscher, Hugo A. Katus, Gerd Hasenfuss, and Sabine Rebs
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business.industry ,chemistry.chemical_element ,030204 cardiovascular system & hematology ,Calcium ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,chemistry ,RNA splicing ,Medicine ,In patient ,Stem cell ,Cardiology and Cardiovascular Medicine ,business ,Gene - Abstract
Background and aim Mutations in the splice factor RBM20 have been identified to account for ∼3% of cardiomyopathies. In particular, the highly conserved RS-domain is a hotspot for disease-associated mutations. Distinct mutations at position 634 in the RS-domain were already described to be associated to dilative cardiomyopathy (DCM) (R634W) or to left ventricular non-compaction cardiomyopathy (LVNC) (R634L), but the molecular mechanisms that govern the heterogenic entity of DCM and LVNC remain largely unknown. We aimed to analyze the molecular driver behind the RBM20 mutation-based DCM and LVNC in a patient-specific stem cell model. Methods Human somatic cells from 2 DCM- and 2 LVNC-patients harboring the RBM20-mutations R634W (DCM) or R634L (LVNC) were reprogrammed into induced pluripotent stem cells (iPSC) and differentiated into functional cardiomyocytes (CM). Gene expression, alternative splicing activity, sarcomeric regularity, cAMP level, kinase-specific phosphorylation of important Ca2+ players, and physiological cardiac functions as Ca2+ homeostasis were analyzed (Fluo3 and Fura4). Isogenic rescue lines were generated by CRISPR/Cas9 technology to analyze the direct impact of the RBM20 mutations to the cardiac phenotype. Results We investigated the role of RBM20 mutations in DCM and LVNC-iPSC-CMs RBM20-splicing and observed common splice defects in titin-isoform-switch or a 24bp insertion in the gene ryanodine receptor 2 (RYR2).. In contrast, the calcium-handling gene Camk2δ was predominantly mis-spliced in LVNC-CMs, whereas the structural gene LDB3 was mis-spliced in DCM-CMs. As a possible consequence of splice defects in sarcomeric genes both DCM and LVNC-CMs exhibited an irregular sarcomeric structure at the Z-disk and M-line. Interestingly, the LVNC-CMs showed faster Ca2+ transient decay time and weakened response to β-adrenergic stimulation. In contrast, the DCM-CMs did exhibit increased Ca2+-sparks and decreased systolic and diastolic Ca2+ highlighting that two distinct missense mutations can lead to different pathological Ca2+ phenotypes. Ca2+ kinetic defects in LVNC-iPSC-CMs were independent of cAMP, but in line with Camk2δ-dependent hyperphosphorylation of the specific target PLN. Isogenic WT-iPSC lines were generated using CRISPR/Cas9 technology and underscored the role of RBM20-mutations in cardiomyopathies as the sarcomeric defects, Ca2+ cycling and leakage were rescued for both LVNC-CMs and DCM-CMs. Conclusion We show the first iPSC-model of splice-defect-associated RBM20-dependent LVNC and DCM. Our data demonstrate that RBM20-R634L induce mis-splicing of Camk2δ leading to hyperphosphorylation of PLN-Thr17 along with increased Ca2+ kinetics in LVNC, whereas RBM20-R634W induced RYR2-dependent Ca2+ leak with disturbed systolic and diastolic Ca2+in DCM. Taken together these results suggest that the molecular aberrations in alternative splicing differ depending on the distinct missense mutation in RBM20. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): BMBF, DZHK German Center for Cardiovascular research
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- 2020
50. Precision medicine: myocardial fibrosis burden and genotype predict outcome in non-ischemic dilated cardiomyopathy (DCM)
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W T Gi, Bernd Lahrmann, Benjamin Meder, Farbod Sedaghat-Hamedani, Julio Saez-Rodriguez, Hugo A. Katus, Lutz Frankenstein, Rebecca T. Levinson, Lorenz Uhlmann, T. Taeger, Esther Herpel, Daniel Tian Li, T Miersch, Niels Grabe, and Elham Kayvanpour
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medicine.medical_specialty ,business.industry ,Internal medicine ,Genotype ,Cardiology ,medicine ,Myocardial fibrosis ,Dilated cardiomyopathy ,Non ischemic ,Cardiology and Cardiovascular Medicine ,Precision medicine ,medicine.disease ,business - Abstract
Introduction Myocardial fibrosis occurs during pathological remodeling of the heart and can be associated with worse outcome in affected patients. Genetic background is also known to affect patients' survival. In this study we sought to estimate patients' overall fibrosis burden by combining independent modalities including left ventricular endomyocardial biopsy (LV-EMB), circulating biomarkers, and cMRI. We also aimed to use patients' genetics information to predict outcome. Furthermore, we investigated the correlation between cardiac fibrosis and genetic variations to detect novel susceptibility loci for fibrosis in DCM. Methods A total number of 542 DCM patients were included. Collagen volume fraction (CVF) was automatically estimated from biopsies. 13 circulating fibrosis biomarkers were measured using Human Magnetic Luminex Screening Assays, and the cMRIs were screened for presence of LGE. Whole exome sequencing (WES) was performed in 410 patients of the cohort using illumina HiSeq 2000. Common (MAF ≥0.05 in the study population OR gnomAD NFE AF ≥0.01) and non-common missense variants (MAF Results The median follow-up time was 43.2 months (2084 patient-years). Sixty-two patients reached the composite end point and 55 died. LV-EMB proved to be a safe procedure with a total complication rate of 2.3%. Machine learning based characterization of biopsies was highly accurate. Although the 3 different modalities did not significantly correlate with one another, the extent of CVF, levels of MMP-2, TIMP-1, OPN, and GDF-15, and presence of LGE were each significantly associated with worse outcome. Four possible susceptibility loci for cardiac fibrosis in DCM were introduced and underwent eQTL analyses. Rare missense variants in a list of 11 DCM-related genes showed to be associated with the 2 outcome measures or fibrosis burden. Conclusions LV-EMB, fibrosis biomarkers, and cMRI likely capture different aspects of a detrimental fibrosis process and may be combined to estimate patients' prognosis and monitor therapeutic success. Phenotype-genotype association studies help elucidate novel disease pathomechanisms and individualize patients' treatment. Funding Acknowledgement Type of funding source: Other. Main funding source(s): German Centre for Cardiovascular Research: DZHK
- Published
- 2020
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