Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 39
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
ESC Heart Fail ; 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32285648

RESUMO

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.

2.
J Mol Cell Cardiol ; 2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32305360

RESUMO

BACKGROUND: Cardiac troponins are the preferred biomarkers of acute myocardial infarction. Despite superior sensitivity, serial testing of Troponins to identify patients suffering acute coronary syndromes is still required in many cases to overcome limited specificity. Moreover, unstable angina pectoris relies on reported symptoms in the troponin-negative group. In this study, we investigated genome-wide miRNA levels in a prospective cohort of patients with clinically suspected ACS and determined their diagnostic value by applying an in silico neural network. METHODS: PAXgene blood and serum samples were drawn and hsTnT was measured in patients at initial presentation to our Chest-Pain Unit. After clinical and diagnostic workup, patients were adjudicated by senior cardiologists in duty to their final diagnosis: STEMI, NSTEMI, unstable angina pectoris and non-ACS patients. ACS patients and a cohort of healthy controls underwent deep transcriptome sequencing. Machine learning was implemented to construct diagnostic miRNA classifiers. RESULTS: We developed a neural network model which incorporates 34 validated ACS miRNAs, showing excellent classification results. By further developing additional machine learning models and selecting the best miRNAs, we achieved an accuracy of 0.96 (95% CI 0.96-0.97), sensitivity of 0.95, specificity of 0.96 and AUC of 0.99. The one-point hsTnT value reached an accuracy of 0.89, sensitivity of 0.82, specificity of 0.96, and AUC of 0.96. CONCLUSIONS: Here we show the concept of neural network based biomarkers for ACS. This approach also opens the possibility to include multi-modal data points to further increase precision and perform classification of other ACS differential diagnoses.

3.
Herz ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170340

RESUMO

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 < 0.001 in RA lead implantation). Dyspnea, chest pain, dry cough, and fever were the most frequently reported symptoms in patients with PCIS. Pericardial and pleura effusion as well as elevated C­reactive protein (CRP), increased erythrocyte sedimentation rate (ESR), and leukocytosis were the most common findings. 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.

4.
ESC Heart Fail ; 7(2): 692-696, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31802644

RESUMO

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.

5.
Biochem Biophys Res Commun ; 519(1): 141-147, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31481236

RESUMO

Atrial fibrillation (AF) is the most frequent sustained arrhythmia and can lead to structural cardiac changes, known as tachycardia-induced cardiomyopathy (TIC). HCN4 is implicated in spontaneous excitation of the sinoatrial node, while channel dysfunction has been associated with sinus bradycardia, AF and structural heart disease. We here asked whether HCN4 mutations may contribute to the development of TIC, as well. Mutation scanning of HCN4 in 60 independent patients with AF and suspected TIC followed by panel sequencing in carriers of HCN4 variants identified the HCN4 variant P883R [minor allele frequency (MAF): 0,88%], together with the KCNE1 variant S38G (MAF: 65%) in three unrelated patients. Family histories revealed additional cases of AF, sudden cardiac death and cardiomyopathy. Patch-clamp recordings of HCN4-P883R channels expressed in HEK293 cells showed remarkable alterations of channel properties shifting the half-maximal activation voltage to more depolarized potentials, while channel deactivation was faster compared to wild-type (WT). Co-transfection of WT and mutant subunits, resembling the heterozygous cellular situation of our patients, revealed significantly higher current densities compared to WT. In conclusion HCN4-P883R may increase ectopic trigger and maintenance of AF by shifting the activation voltage of If to more positive potentials and producing higher current density. Together with the common KCNE1 variant S38G, previously proposed as a genetic modifier of AF, HCN4-P883R may provide a substrate for the development of AF and TIC.

6.
Clin Res Cardiol ; 108(11): 1297-1308, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30980206

RESUMO

BACKGROUND: Left ventricular non-compaction has been increasingly diagnosed in recent years. However, it is still debated whether non-compaction is a pathological condition or a physiological trait. In this meta-analysis and systematic review, we compare studies, which investigated these two different perspectives. Furthermore, we provide a comprehensive overview on the clinical outcome as well as genetic background of left ventricular non-compaction cardiomyopathy in adult patients. METHODS AND RESULTS: We retrieved PubMed/Medline literatures in English language from 2000 to 19/09/2018 on clinical outcome and genotype of patients with non-compaction. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Altogether, 35 studies with 2271 non-compaction patients were included in our meta-analysis. The mean age at diagnosis was the mid of their fifth decade. Two-thirds of patients were male. Congenital heart diseases including atrial or ventricular septum defect or Ebstein anomaly were reported in 7% of patients. Twenty-four percent presented with family history of cardiomyopathy. The mean frequency of neuromuscular diseases was 5%. Heart rhythm abnormalities were reported frequently: conduction disease in 26%, supraventricular tachycardia in 17%, and sustained or non-sustained ventricular tachycardia in 18% of patients. Three important outcome measures were reported including systemic thromboembolic events with a mean frequency of 9%, heart transplantation with 4%, and adequate ICD therapy with 15%. Nine studies investigated the genetics of non-compaction cardiomyopathy. The most frequently mutated gene was TTN with a pooled frequency of 11%. The average frequency of MYH7 mutations was 9%, for MYBPC3 mutations 5%, and for CASQ2 and LDB3 3% each. TPM1, MIB1, ACTC1, and LMNA mutations had an average frequency of 2% each. Mutations in PLN, HCN4, TAZ, DTNA, TNNT2, and RBM20 were reported with a frequency of 1% each. We also summarized the results of eight studies investigating the non-compaction in altogether 5327 athletes, pregnant women, patients with sickle cell disease, as well as individuals from population-based cohorts, in which the presence of left ventricular hypertrabeculation ranged from 1.3 to 37%. CONCLUSION: The summarized data indicate that non-compaction may lead to unfavorable outcome in different cardiomyopathy entities. The presence of key features in a multimodal diagnostic approach could distinguish between benign morphological trait and manifest cardiomyopathy.


Assuntos
Miocárdio Ventricular não Compactado Isolado/genética , Humanos , Miocárdio Ventricular não Compactado Isolado/diagnóstico , Miocárdio Ventricular não Compactado Isolado/terapia
7.
Circ Heart Fail ; 12(3): e005371, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30871351

RESUMO

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.


Assuntos
Arritmias Cardíacas/genética , Cardiomiopatias/genética , Proteínas de Ligação a RNA/genética , Morte Súbita Cardíaca/etiologia , Humanos , Mutação , Sistema de Registros
9.
EMBO Mol Med ; 10(1): 107-120, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29138229

RESUMO

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.


Assuntos
Cardiomiopatia Dilatada/genética , Regulação da Expressão Gênica , Variação Estrutural do Genoma , RNA/genética , Transcriptoma , Animais , Estudos de Coortes , Humanos , Masculino , Camundongos , MicroRNAs/genética , Miocárdio/metabolismo , Locos de Características Quantitativas , RNA Longo não Codificante/genética , RNA Mensageiro/genética
10.
Clin Res Cardiol ; 107(1): 30-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28840316

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, which goes along with increased risk for sudden cardiac death (SCD). Despite the knowledge about the different causal genes, the relationship between individual genotypes and phenotypes is incomplete. METHODS AND RESULTS: We retrieved PubMed/Medline literatures on genotype-phenotype associations in patients with HCM and mutations in MYBPC3, MYH7, TNNT2, and TNNI3. Altogether, 51 studies with 7675 HCM patients were included in our meta-analysis. The average frequency of mutations in MYBPC3 (20%) and MYH7 (14%) was higher than TNNT2 and TNNI3 (2% each). The mean age of HCM onset for MYH7 mutation positive patients was the beginning of the fourth decade, significantly earlier than patients without sarcomeric mutations. A high male proportion was observed in TNNT2 (69%), MYBPC3 (62%) and mutation negative group (64%). Cardiac conduction disease, ventricular arrhythmia and heart transplantation (HTx) rate were higher in HCM patients with MYH7 mutations in comparison to MYBPC3 (p < 0.05). Furthermore, SCD was significantly higher in patients with sarcomeric mutations (p < 0.01). CONCLUSION: A pooled dataset and a comprehensive genotype-phenotype analysis show that the age at disease onset of HCM patients with MYH7 is earlier and leads to a more severe phenotype than in patient without such mutations. Furthermore, patients with sarcomeric mutations are more susceptible to SCD. The present study further supports the clinical interpretation of sarcomeric mutations in HCM patients.


Assuntos
Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/genética , Morte Súbita Cardíaca/prevenção & controle , Mutação , Cadeias Pesadas de Miosina/genética , Adulto , Idade de Início , Idoso , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Cardiomiopatia Hipertrófica/terapia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Morte Súbita Cardíaca/etiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Transplante de Coração , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Resultado do Tratamento , Troponina I/genética , Troponina T/genética , Adulto Jovem
11.
Eur Heart J ; 38(46): 3449-3460, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29029073

RESUMO

Aims: In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. Methods and results: In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays. Conclusion: Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome.


Assuntos
Hipertrofia Ventricular Esquerda/genética , Mutação/genética , Adulto , Arritmias Cardíacas/genética , Cardiomiopatia Dilatada/genética , Conectina/genética , Morte Súbita Cardíaca/etiologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Lamina Tipo A/genética , Masculino , Linhagem , Proteínas de Ligação a RNA/genética
12.
Circulation ; 136(16): 1528-1544, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-28838933

RESUMO

BACKGROUND: Biochemical DNA modification resembles a crucial regulatory layer among genetic information, environmental factors, and the transcriptome. To identify epigenetic susceptibility regions and novel biomarkers linked to myocardial dysfunction and heart failure, we performed the first multi-omics study in myocardial tissue and blood of patients with dilated cardiomyopathy and controls. METHODS: Infinium human methylation 450 was used for high-density epigenome-wide mapping of DNA methylation in left-ventricular biopsies and whole peripheral blood of living probands. RNA deep sequencing was performed on the same samples in parallel. Whole-genome sequencing of all patients allowed exclusion of promiscuous genotype-induced methylation calls. RESULTS: In the screening stage, we detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy (false discovery corrected P≤0.05), with 3 of them reaching epigenome-wide significance at P≤5×10-8. Twenty-seven (46%) of these loci could be replicated in independent cohorts, underlining the role of epigenetic regulation of key cardiac transcription regulators. Using a staged multi-omics study design, we link a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression. Furthermore, we identified distinct epigenetic methylation patterns that are conserved across tissues, rendering these CpGs novel epigenetic biomarkers for heart failure. CONCLUSIONS: The present study provides to our knowledge the first epigenome-wide association study in living patients with heart failure using a multi-omics approach.


Assuntos
Cardiomiopatia Dilatada/genética , Metilação de DNA , Epigênese Genética , Epigenômica/métodos , Loci Gênicos , Insuficiência Cardíaca/genética , Ventrículos do Coração/química , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/diagnóstico , Estudos de Casos e Controles , Ilhas de CpG , Perfilação da Expressão Gênica , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , RNA Mensageiro/genética , Análise de Sequência de RNA
13.
Clin Res Cardiol ; 106(2): 127-139, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27576561

RESUMO

AIMS: Routine genetic testing in Dilated Cardiomyopathy (DCM) has recently become reality using Next-Generation Sequencing. Several studies have explored the relationship between genotypes and clinical phenotypes to support risk estimation and therapeutic decisions, however, most studies are small or restricted to a few genes. This study provides to our knowledge the first systematic meta-analysis on genotype-phenotype associations in DCM. METHODS AND RESULTS: We retrieved PubMed/Medline literature on genotype-phenotype associations in patients with DCM and mutations in LMNA, PLN, RBM20, MYBPC3, MYH7, TNNT2 and TNNI3. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Together, 48 studies with 8097 patients were included. Furthermore, we reviewed recent studies investigating genotype-phenotype associations in DCM patients with TTN mutations. The average frequency of mutations in the investigated genes was between 1 and 5 %. The mean age of DCM onset was the beginning of the fifth decade for all genes. Heart transplantation (HTx) rate was highest in LMNA mutation carriers (27 %), while RBM20 mutation carriers were transplanted at a markedly younger age (mean 28.5 years). While 73 % of DCM patients with LMNA mutations showed cardiac conduction diseases, low voltage was the reported ECG hallmark in PLN mutation carriers. The frequency of ventricular arrhythmia in DCM patients with LMNA (50 %) and PLN (43 %) mutations was significantly higher. The penetrance of DCM phenotype in subjects with TTN truncating variants increased with age and reached 100 % by age of 70. CONCLUSION: A pooled analysis of available genotype-phenotype data shows a higher prevalence of sudden cardiac death (SCD), cardiac transplantation, or ventricular arrhythmias in LMNA and PLN mutation carriers compared to sarcomeric gene mutations. This study will further support the clinical interpretation of genetic findings.


Assuntos
Cardiomiopatia Dilatada/genética , Mutação , Adulto , Fatores Etários , Arritmias Cardíacas/genética , Arritmias Cardíacas/mortalidade , Arritmias Cardíacas/fisiopatologia , Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/cirurgia , Morte Súbita Cardíaca/etiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Transplante de Coração , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Medição de Risco , Fatores de Risco , Fatores Sexuais
15.
Genomics Proteomics Bioinformatics ; 14(4): 244-52, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27477449

RESUMO

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.


Assuntos
Simulação por Computador , Insuficiência Cardíaca/fisiopatologia , Adulto , Idoso , Fator Natriurético Atrial/análise , Biomarcadores/análise , Pressão Sanguínea , Cateterismo Cardíaco , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/metabolismo , Ecocardiografia , Feminino , Insuficiência Cardíaca/metabolismo , Frequência Cardíaca , Hemodinâmica , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Precursores de Proteínas/análise
16.
Genomics Proteomics Bioinformatics ; 14(4): 200-6, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27475404

RESUMO

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.


Assuntos
DNA/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/normas , DNA/química , DNA/genética , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Controle de Qualidade , Análise de Sequência de DNA/métodos , Análise de Sequência de DNA/normas
17.
J Transl Med ; 14(1): 219, 2016 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-27456854

RESUMO

BACKGROUND: The dependency of miRNA abundance from physiological processes such as exercises remains partially understood. We set out to analyze the effect of physical exercises on miRNA profiles in blood and plasma of endurance and strength athletes in a systematic manner and correlated differentially abundant miRNAs in athletes to disease miRNAs biomarkers towards a better understanding of how physical exercise may confound disease diagnosis by miRNAs. METHODS: We profiled blood and plasma of 29 athletes before and after exercise. With four samples analyzed for each individual we analyzed 116 full miRNomes. The study set-up enabled paired analyses of individuals. Affected miRNAs were investigated for known disease associations using network analysis. RESULTS: MiRNA patterns in blood and plasma of endurance and strength athletes vary significantly with differences in blood outreaching variations in plasma. We found only moderate differences between the miRNA levels before training and the RNA levels after training as compared to the more obvious variations found between strength athletes and endurance athletes. We observed significant variations in the abundance of miR-140-3p that is a known circulating disease markers (raw and adjusted p value of 5 × 10(-12) and 4 × 10(-7)). Similarly, the levels of miR-140-5p and miR-650, both of which have been reported as makers for a wide range of human pathologies significantly depend on the training mode. Among the most affected disease categories we found acute myocardial infarction. MiRNAs, which are up-regulated in endurance athletes inhibit VEGFA as shown by systems biology analysis of experimentally validated target genes. CONCLUSION: We provide evidence that the mode and the extent of training are important confounding factors for a miRNA based disease diagnosis.


Assuntos
Exercício Físico/fisiologia , MicroRNAs/genética , Esportes , Análise por Conglomerados , Fatores de Confusão Epidemiológicos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , MicroRNAs/sangue , Análise de Componente Principal , Treinamento de Resistência
18.
Med Image Anal ; 34: 52-64, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27133269

RESUMO

Personalization is the process of fitting a model to patient data, a critical step towards application of multi-physics computational models in clinical practice. Designing robust personalization algorithms is often a tedious, time-consuming, model- and data-specific process. We propose to use artificial intelligence concepts to learn this task, inspired by how human experts manually perform it. The problem is reformulated in terms of reinforcement learning. In an off-line phase, Vito, our self-taught artificial agent, learns a representative decision process model through exploration of the computational model: it learns how the model behaves under change of parameters. The agent then automatically learns an optimal strategy for on-line personalization. The algorithm is model-independent; applying it to a new model requires only adjusting few hyper-parameters of the agent and defining the observations to match. The full knowledge of the model itself is not required. Vito was tested in a synthetic scenario, showing that it could learn how to optimize cost functions generically. Then Vito was applied to the inverse problem of cardiac electrophysiology and the personalization of a whole-body circulation model. The obtained results suggested that Vito could achieve equivalent, if not better goodness of fit than standard methods, while being more robust (up to 11% higher success rates) and with faster (up to seven times) convergence rate. Our artificial intelligence approach could thus make personalization algorithms generalizable and self-adaptable to any patient and any model.


Assuntos
Inteligência Artificial , Simulação por Computador , Medicina de Precisão/métodos , Humanos , Física , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Anal Chem ; 88(4): 2088-95, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26760198

RESUMO

A certain degree of bias in high-throughput molecular technologies including microarrays and next-generation sequencing (NGS) is known. To quantify the actual impact of the biomarker discovery platform on miRNA profiles, we first performed a meta-analysis: raw data of 1 539 microarrays and 705 NGS blood-borne miRNomes were statistically evaluated, suggesting a substantial influence of the technology on biomarker profiles. We observed highly significant dependency of the miRNA nucleotide composition on the expression level. Higher expression in NGS was discovered for uracil-rich miRNAs (p = 7 × 10(-37)), while high expression in microarrays was found predominantly for guanine-rich miRNAs (p = 3 × 10(-33)). To verify the findings, 10 identical replicates of one individual were measured using NGS and microarrays (2 525 miRNAs from miRBase version 21). Overall, we calculated a correlation coefficient of 0.414 for both technologies. Detailed analysis however revealed that the correlation was observed only for miRNAs in the early miRBase versions (<8). The majority of miRNAs (2 013 from miRBase version 8 onward) was not correlated between microarray and NGS. Specifically, we observed 67 miRNAs with a median read count above 10 in NGS, while they were not detected in any of the 10 replicated array experiments. In contrast, 234 miRNAs were discovered in all 10 replicated array measurements but were not found in any of the NGS experiments of the same individual. While the first group had average guanine content of 22%, the latter group consisted of 41% of this nucleotide. Selected concordant and discordant miRNAs were tested in quantitative real-time-polymerase chain reaction (RT-qPCR) experiments again of the same individual, providing further evidence for the substantial bias depending on the base composition. As a consequence, biomarkers that have been discovered by specific high-throughout technologies have to be carefully considered. Especially for validation of the platform, the selection of reasonable candidates is essential.


Assuntos
Biomarcadores/análise , Sequenciamento de Nucleotídeos em Larga Escala , MicroRNAs/análise , Humanos , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA
20.
Kardiol Pol ; 74(7): 610-26, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26779856

RESUMO

BACKGROUND AND AIM: This systematic review with meta-analysis sought to determine the strength of evidence for effects of antioxidants (AO) such as N-acetyl cysteine (NAC), vitamin C, vitamin E, and alpha-lipoic acid on the incidence of contrast-in-duced nephropathy (CIN), requirement for haemodialysis, level of serum creatinine, and mortality after coronary angiography. METHODS AND RESULTS: After Medline, Embase, Elsevier, Sciences online database, and Google Scholar literature searches, studies with randomised controlled design were selected for the meta-analysis. The effect sizes measured were odds ratio (OR) for categorical variables and standard mean difference (SMD) with 95% confidence interval (CI) for calculating differences between mean changes of serum creatinine in intervention and control groups. A value of p < 0.1 for Q test or I2 > 50% indicated significant heterogeneity between the studies. Literature search of all major databases retrieved 2350 studies. After screening, a total of 49 trials were identified that reported outcomes. Pooled treatment effect analysis revealed that NAC (OR of 0.79; 95% CI 0.69-0.9; p = 0.000), vitamin C (0.63; 95% CI 0.45-0.89; p = 0.000), and vitamin E (OR of 0.5; 95% CI 0.27-0.92; p = 0.026) could significantly reduce the incidence of CIN. NAC (SMD of -0.119; 95% CI -0.191 - 0.046; p = 0.000), but not vitamin C (SMD of -0.08; 95% CI -0.22-0.04; p = 0.1) and vitamin E (-0.25; 95% CI -0.46-0.05; p = 0.1), could significantly reduce mean levels of serum creatinine. Nevertheless, AO could not reduce the incidence of mortality, with an OR of 0.94 (95% CI 0.69-1.28; p = 0.7). CONCLUSIONS: Overall, antioxidants such as NAC, vitamin C, and vitamin E can reduce the incidence of CIN, while only NAC might be able to significantly lower serum creatinine levels. There is no impact of AO supplementation on mortality.


Assuntos
Antioxidantes/uso terapêutico , Meios de Contraste/efeitos adversos , Angiografia Coronária/efeitos adversos , Suplementos Nutricionais , Nefropatias/prevenção & controle , Idoso , Antioxidantes/farmacologia , Feminino , Humanos , Incidência , Nefropatias/induzido quimicamente , Nefropatias/epidemiologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA