89 research outputs found
Multi-omics assessment of dilated cardiomyopathy using non-negative matrix factorization
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 nonnegative 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 (P<0.05). Characterization of top 10% features driving each latent factor showed a
significant enrichment of biological processes known to be involved in DCM pathogenesis,
including immune response (P = 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, multiomics 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
Exercise-induced release of troponin.
It is well established that regular physical activity reduces cardiovascular disease risk; however, numerous studies have demonstrated postexercise elevations in cardiac troponin (cTn), indicative of cardiac injury in apparently healthy individuals. The prevalence of these findings in different exercise settings and population groups, as well as potential underlying mechanisms and clinical significance of exercise-induced cTn release are not yet quite determined. The present review will discuss the cTn response to exercise in light of developing cTn assays and the correlation between postexercise cTn release and cardiac function. Additionally, recent data regarding the potential link between strenuous endurance exercise and its relationship with unfavorable cardiac effects in athletes, as well as the management of patients presenting at emergency care after sport events will be briefly reviewed
Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy
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 Ă 10â16).
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
genomeâenvironment interaction in DCM besides simple gene expression regulation
Marathon-Induced Cardiac Strain as Model for the Evaluation of Diagnostic microRNAs for Acute Myocardial Infarction
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 compre hensive 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 lim ited. 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
Marathon-Induced Cardiac Strain as Model for the Evaluation of Diagnostic microRNAs for Acute Myocardial Infarction
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
Energy Metabolites as Biomarkers in Ischemic and Dilated Cardiomyopathy
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 Ă 10â6
). 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
Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy
Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level
Genomic structural variations lead to dysregulation of important coding and non-coding RNA species in dilated cardiomyopathy
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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