Publications by authors named "Elham Kayvanpour"

42 Publications

Energy Metabolites as Biomarkers in Ischemic and Dilated Cardiomyopathy.

Int J Mol Sci 2021 Feb 18;22(4). Epub 2021 Feb 18.

Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany.

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 = 82 patients with Dilated Cardiomyopathy (DCM) and = 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 ( = 1.7 × 10). 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 = 52 DCM, = 39 ischemic HF and = 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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http://dx.doi.org/10.3390/ijms22041999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923201PMC
February 2021

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Nat Genet 2021 02 25;53(2):128-134. Epub 2021 Jan 25.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

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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http://dx.doi.org/10.1038/s41588-020-00762-2DOI Listing
February 2021

Generation of pluripotent stem cell lines and CRISPR/Cas9 modified isogenic controls from a patient with dilated cardiomyopathy harboring a RBM20 p.R634W mutation.

Stem Cell Res 2020 Jul 2;47:101901. Epub 2020 Jul 2.

Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; German Center of Cardiovascular Research (DZHK), Germany. Electronic address:

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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http://dx.doi.org/10.1016/j.scr.2020.101901DOI Listing
July 2020

Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy.

J Clin Med 2020 May 16;9(5). Epub 2020 May 16.

Institute for Cardiomyopathies Heidelberg (ICH), Heart Center Heidelberg, University of Heidelberg, 69121 Heidelberg, Germany.

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 ( < 2 × 10). 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 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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http://dx.doi.org/10.3390/jcm9051499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291244PMC
May 2020

Familial Recurrent Myocarditis Triggered by Exercise in Patients With a Truncating Variant of the Desmoplakin Gene.

J Am Heart Assoc 2020 05 15;9(10):e015289. Epub 2020 May 15.

German Center for Cardiovascular Research (DZHK) partner site Berlin Germany.

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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http://dx.doi.org/10.1161/JAHA.119.015289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660888PMC
May 2020

microRNA neural networks improve diagnosis of acute coronary syndrome (ACS).

J Mol Cell Cardiol 2021 02 17;151:155-162. Epub 2020 Apr 17.

Department of Internal Medicine III, Heidelberg University, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Germany; Department of Genetics, Stanford Genome Technology Center, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.yjmcc.2020.04.014DOI Listing
February 2021

Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta-analysis and systematic review.

ESC Heart Fail 2020 08 14;7(4):1430-1441. Epub 2020 Apr 14.

Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

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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http://dx.doi.org/10.1002/ehf2.12689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373946PMC
August 2020

Postcardiac injury syndrome after cardiac implantable electronic device implantation.

Herz 2020 Nov 13;45(7):696-702. Epub 2020 Mar 13.

Department of Medicine III, Universitätsklinikum Heidelberg, INF 410, 69120, Heidelberg, Germany.

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 C‑reactive 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.
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http://dx.doi.org/10.1007/s00059-020-04910-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581580PMC
November 2020

Evaluating the Use of Circulating MicroRNA Profiles for Lung Cancer Detection in Symptomatic Patients.

JAMA Oncol 2020 05;6(5):714-723

Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center and Faculty of Medicine, Saarland University, Homburg, Germany.

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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http://dx.doi.org/10.1001/jamaoncol.2020.0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059111PMC
May 2020

The chameleon of cardiology: cardiac sarcoidosis before and after heart transplantation.

ESC Heart Fail 2020 04 5;7(2):692-696. Epub 2019 Dec 5.

Department of Medicine III, University of Heidelberg, Heidelberg, Germany.

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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http://dx.doi.org/10.1002/ehf2.12581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160489PMC
April 2020

Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals.

Clin Res Cardiol 2019 Nov 12;108(11):1297-1308. Epub 2019 Apr 12.

Department of Medicine III, Institute for Cardiomyopathy, University of Heidelberg, INF 410, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1007/s00392-019-01465-3DOI Listing
November 2019

Identification and regulation of the long non-coding RNA Heat2 in heart failure.

J Mol Cell Cardiol 2019 01 13;126:13-22. Epub 2018 Nov 13.

Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Theodor Stern Kai 7, Frankfurt, Germany; German Centre for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany; Kerckhoff Heart and Thorax Center, Department of Cardiology, Bad Nauheim, Germany.

Aims: Circulating immune cells have a significant impact on progression and outcome of heart failure. Long non-coding RNAs (lncRNAs) comprise novel epigenetic regulators which control cardiovascular diseases and inflammatory disorders. We aimed to identify lncRNAs regulated in circulating immune cells of the blood of heart failure patients.

Methods And Results: Next-generation sequencing revealed 110 potentially non-coding RNA transcripts differentially expressed in peripheral blood mononuclear cells of heart failure patients with reduced ejection fraction. The up-regulated lncRNA Heat2 was further functionally characterized. Heat2 expression was detected in whole blood, PBMNCs, eosinophil and basophil granulocytes. Heat2 regulates cell division, invasion, transmigration and immune cell adhesion on endothelial cells.

Conclusion: Heat2 is an immune cell enriched lncRNA that is elevated in the blood of heart failure patients and controls cellular functions.
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http://dx.doi.org/10.1016/j.yjmcc.2018.11.004DOI Listing
January 2019

Genomic structural variations lead to dysregulation of important coding and non-coding RNA species in dilated cardiomyopathy.

EMBO Mol Med 2018 01;10(1):107-120

Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany

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 ( = 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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http://dx.doi.org/10.15252/emmm.201707838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760848PMC
January 2018

Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy.

Eur Heart J 2017 Dec;38(46):3449-3460

Department of Bioinformatics, University of Saarland, Building E2.1, 66123 Saarbrücken, Germany.

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.
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http://dx.doi.org/10.1093/eurheartj/ehx545DOI Listing
December 2017

Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: a meta-analysis on 7675 individuals.

Clin Res Cardiol 2018 Jan 24;107(1):30-41. Epub 2017 Aug 24.

Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, INF 410, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1007/s00392-017-1155-5DOI Listing
January 2018

Epigenome-Wide Association Study Identifies Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure.

Circulation 2017 Oct 24;136(16):1528-1544. Epub 2017 Aug 24.

From Department of Internal Medicine III, Institute for Cardiomyopathies, University of Heidelberg, Germany (B.M., J.H., F.S.-H., E.K., K.F., A.L., R.N., C.S., S.M., D.M.-B., A.A., H.H., D.B.H., M.M.-H., T.W., H.A.K.); Siemens Healthcare GmbH, Strategy and Innovation, Erlangen, Germany (C.D., M.W., A.E.P.); Department of Bioinformatics, University of Saarland, Saarbrücken, Germany (A.K.); German Centre for Cardiovascular Research, Berlin, Germany (B.M., J.H., F.S.-H., E.K., K.F., A.L., D.S., M.M.-H., T.W., J.B., H.A.K.); Institute for Molecular Cardiology and Epigenetics, University of Heidelberg, Germany (D.S., J.B.); Funktionelle Genomanalyse, Deutsches Krebsforschungszentrum, Heidelberg, Germany (A.B.); Department of Cardiac Surgery, University of Heidelberg, Germany (A.R.); Siemens AG, Corporate Technology, Vienna, Austria (D.P.); Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Austria (D.P.); and Division of Epigenomics and Cancer Risk Factors, Deutsches Krebsforschungszentrum, Heidelberg, Germany (D.W., C.P.).

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 ≤0.05), with 3 of them reaching epigenome-wide significance at ≤5×10. 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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027355DOI Listing
October 2017

The prognostic value of right ventricular long axis strain in non-ischaemic dilated cardiomyopathies using standard cardiac magnetic resonance imaging.

Eur Radiol 2017 Sep 10;27(9):3913-3923. Epub 2017 Feb 10.

Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, 69120, Germany.

Objective: To investigate the association of right ventricular long axis strain (RV-LAS), a parameter of longitudinal function, with outcome in patients with non-ischaemic dilated cardiomyopathy (NIDCM).

Methods: In 441 patients with NIDCM, RV-LAS was analysed retrospectively by measuring the length between the epicardial border of the left ventricular apex and the middle of a line connecting the origins of the tricuspidal valve leaflets in end-diastole and end-systole on non-contrast standard cine sequences.

Results: The primary endpoint (cardiac death or heart transplantation) occurred in 41 patients, whereas 95 reached the combined endpoint (including cardiac decompensation and sustained ventricular arrhythmias) during a median follow-up of 4.2 years. Kaplan-Meier survival curves showed a poor outcome in patients with RV-LAS values below -10% (log-rank, p < 0.0001). In a risk stratification model RV-LAS improved prediction of outcome in addition to RV ejection fraction (RVEF) and presence of late gadolinium enhancement. Assessment of RV-LAS offered incremental information compared to clinical symptoms, biomarkers and RVEF. Even in the subgroup with normal RVEF (>45%, n = 213) reduced RV-LAS was still associated with poor outcome.

Conclusion: Assessment of RV-LAS is an independent indicator of outcome in patients with NIDCM and offers incremental information beyond clinical and cardiac MR parameters.

Key Points: • Impaired right ventricular longitudinal function (RV-LAS) is associated with poorer cardiac outcomes. • Poor outcome is associated with decreased RV-LAS even in patients with RVEF >45%. • Addition of RV-LAS to known risk factors enhances the power prognostic information.
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http://dx.doi.org/10.1007/s00330-016-4729-0DOI Listing
September 2017

Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals.

Clin Res Cardiol 2017 Feb 30;106(2):127-139. Epub 2016 Aug 30.

Department of Medicine III, University of Heidelberg, INF 410, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1007/s00392-016-1033-6DOI Listing
February 2017

Personalized Computer Simulation of Diastolic Function in Heart Failure.

Genomics Proteomics Bioinformatics 2016 08 29;14(4):244-52. Epub 2016 Jul 29.

Institute for Cardiomyopathies, Department of Medicine III, University of Heidelberg, 69120 Heidelberg, Germany; German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim, Germany. Electronic address:

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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http://dx.doi.org/10.1016/j.gpb.2016.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996856PMC
August 2016

The Role of Quality Control in Targeted Next-generation Sequencing Library Preparation.

Genomics Proteomics Bioinformatics 2016 08 28;14(4):200-6. Epub 2016 Jul 28.

Institute for Cardiomyopathies, Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany; German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim, Germany. Electronic address:

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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http://dx.doi.org/10.1016/j.gpb.2016.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996852PMC
August 2016

A self-taught artificial agent for multi-physics computational model personalization.

Med Image Anal 2016 12 21;34:52-64. Epub 2016 Apr 21.

Medical Imaging Technologies, Siemens Healthcare, Princeton, USA.

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.
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http://dx.doi.org/10.1016/j.media.2016.04.003DOI Listing
December 2016

Protective effects of anti-oxidant supplementations on contrast-induced nephropathy after coronary angiography: an updated and comprehensive meta-analysis and systematic review.

Kardiol Pol 2016 18;74(7):610-26. Epub 2016 Jan 18.

Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

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.
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http://dx.doi.org/10.5603/KP.a2016.0007DOI Listing
June 2017

Biomarker changes after strenuous exercise can mimic pulmonary embolism and cardiac injury--a metaanalysis of 45 studies.

Clin Chem 2015 Oct 3;61(10):1246-55. Epub 2015 Aug 3.

Department of Medicine III, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Germany;

Background: Biomarkers are well established for diagnosis of myocardial infarction [cardiac troponins, high-sensitivity cardiac troponins (hs-cTn)], exclusion of acute and chronic heart failure [B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP)] and venous thromboembolism (d-dimers). Several studies have demonstrated acute increases in cardiac biomarkers and altered cardiac function after strenuous sports that can pretend a cardiovascular emergency and interfere with state-of-the-art clinical assessment.

Methods: We performed a systematic review and metaanalysis of biomarker and cardiovascular imaging changes after endurance exercise. We searched for observational studies published in the English language from 1997 to 2014 that assessed these biomarkers or cardiac function and morphology directly after endurance exercise. Of 1787 identified abstracts, 45 studies were included.

Results: Across all studies cardiac troponin T (cTnT) exceeded the cutoff value (0.01 ng/mL) in 51% (95% CI, 37%-64%) of participants. The measured pooled changes from baseline for high-sensitivity cTnT (hs-cTnT) were +26 ng/L (95% CI, 5.2-46.0), for cTnI +40 ng/L (95% CI, 21.4; 58.0), for BNP +10 ng/L (95% CI, 4.3; 16.6), for NT-proBNP +67 ng/L (95% CI, 49.9; 84.7), and for d-dimer +262 ng/mL (95% CI, 165.9; 358.7). Right ventricular end diastolic diameter increased and right ventricular ejection fraction as well as the ratio of the early to late transmitral flow velocities decreased after exercise, while no significant changes were observed in left ventricular ejection fraction.

Conclusions: Current cardiovascular biomarkers (cTnT, hs-cTnT, BNP, NT-proBNP, and d-dimer) that are used in clinical diagnosis of pulmonary embolism, acute coronary syndrome, and heart failure are prone to alterations due to strenuous exercise. Hence, it is necessary to take previous physical exercise into account when a cardiac emergency is suspected.
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http://dx.doi.org/10.1373/clinchem.2015.240796DOI Listing
October 2015

Determined to Fail--the Role of Genetic Mechanisms in Heart Failure.

Curr Heart Fail Rep 2015 Oct;12(5):333-8

Institute for Cardiomyopathies Heidelberg (ICH), Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Genetic variants contribute to several steps during heart failure pathophysiology. The mechanisms include frequent polymorphisms that increase the susceptibility to heart failure in the general population and rare variants as causes of an underlying cardiomyopathy. In this review, we highlight recent discoveries made by genetic approaches and provide an outlook onto the role of epigenetic modifiers of heart failure.
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http://dx.doi.org/10.1007/s11897-015-0264-6DOI Listing
October 2015

Towards Personalized Cardiology: Multi-Scale Modeling of the Failing Heart.

PLoS One 2015 31;10(7):e0134869. Epub 2015 Jul 31.

Department of Medicine III, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany; Klaus Tschira Institute for Computational Cardiology, Heidelberg, Germany.

Background: Despite 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 Results: State-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.

Conclusion: This 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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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134869PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521877PMC
April 2016

Current status of sodium bicarbonate in coronary angiography: an updated comprehensive meta-analysis and systematic review.

Cardiol Res Pract 2015 21;2015:690308. Epub 2015 Apr 21.

Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton & Harefield NHS Foundation Trust, London, UK.

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 P < 0.1 for Q test or I (2) > 50% 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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http://dx.doi.org/10.1155/2015/690308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417980PMC
May 2015

Administration of erythropoietin in patients with myocardial infarction: does it make sense? An updated and comprehensive meta-analysis and systematic review.

Cardiovasc Revasc Med 2015 Apr-May;16(3):179-89. Epub 2015 Jan 29.

Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom.

This systematic review with meta-analysis sought to determine protective effects of erythropoietin on clinical outcomes following percutaneous coronary intervention (PCI). Medline, Embase, Elsevier and Sciences online database as well as Google scholar literature were used for selecting appropriate studies with randomized controlled design. The effect sizes measured were odds ratio (OR) for categorical variables and weighted mean difference (WMD) with 95% confidence interval for calculating differences between mean values of duration of hospitalization in intervention and control groups. Values of P<0.1 for Q test or I(2)>50% indicated significant heterogeneity between the studies. The literature searches of all major databases retrieved 973 studies. After screening, a total of 15 trials that reported outcomes were identified. Pooled analysis was performed on left ventricular ejection fraction (WMD of -0.047; 95% CI: -0.912 to 0.819; P=0.9), left ventricular end diastolic volume (WMD of -0.363; 95% CI: -3.902 to 3.175; P=0.8), left ventricular end systolic volume (WMD of 0.346; 95% CI: -2.533 to 3.226; P=0.8), infarct size (WMD of -0.446; 95% CI: -2.352 to -1.460; P=0.6), stroke (OR of 2.1; 95% CI: 0.58 to 7.54; P=0.2), re-myocardial infarction (OR of 1.06; 95% CI: 0.52 to 2.185; P=0.8), heart failure (OR of 0.53; 95% CI: 0.259 to 1.105; P=0.09), mortality (OR of 0.56; 95% CI: 0.27 to 1.19; P=0.13), thrombosis (OR of 0.774; 95% CI: 0.41 to 1.45; P=0.4), major adverse cardiovascular events (OR of 0.926; 95% CI: 0.63 to 1.35; P=0.6). Short-term administration of EPO in patients with myocardial infarction (MI) undergoing PCI does not result in improvement in cardiac function, reduction of infarct size and all-cause mortality. Low dose EPO therapy may not be the choice of treatment for the patients with MI, while higher doses might be more effective.
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http://dx.doi.org/10.1016/j.carrev.2015.01.008DOI Listing
February 2016

Robust image-based estimation of cardiac tissue parameters and their uncertainty from noisy data.

Med Image Comput Comput Assist Interv 2014 ;17(Pt 2):9-16

Clinical applications of computational cardiac models require precise personalization, i.e. fitting model parameters to capture patient's physiology. However, due to parameter non-identifiability, limited data, uncertainty in the clinical measurements, and modeling assumptions, various combinations of parameter values may exist that yield the same quality of fit. Hence, there is a need for quantifying the uncertainty in estimated parameters and to ascertain the uniqueness of the found solution. This paper presents a stochastic method to estimate the parameters of an image-based electromechanical model of the heart and their uncertainty due to noise in measurements. First, Bayesian inference is applied to fully estimate the posterior probability density function (PDF) of the model. To that end, Markov Chain Monte Carlo sampling is used, which is made computationally tractable by employing a fast surrogate model based on Polynomial Chaos Expansion, instead of the true forward model. Then, we use the mean-shift algorithm to automatically find the modes of the PDF and select the most likely one while being robust to noise. The approach is used to estimate global active stress and passive stiffness from invasive pressure and image-based volume quantification. Experiments on eight patients showed that not only our approach yielded goodness of fits equivalent to a well-established deterministic method, but we could also demonstrate the non-uniqueness of the problem and report uncertainty estimates, crucial information for subsequent clinical assessments of the personalized models.
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http://dx.doi.org/10.1007/978-3-319-10470-6_2DOI Listing
January 2015

Transplantation of bone marrow stem cells during cardiac surgery.

Asian Cardiovasc Thorac Ann 2015 03 3;23(3):363-74. Epub 2014 Oct 3.

Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton & Harefield NHS Foundation Trust, London, UK.

Background: This systematic review with meta-analysis sought to determine the efficacy and safety of intramyocardial transplantation of bone marrow stem cells during coronary artery bypass graft surgery on postoperative cardiac functional parameters such as left ventricular ejection fraction and left ventricular end-diastolic volume.

Methods: Medline/PubMed, Embase, Elsevier, Sciences online database, and Google Scholar literature search were searched. The effect sizes measured were risk ratio for categorical variables and weighted mean difference with 95% confidence interval for calculating differences between mean values of baseline and follow-up cardiac functional parameters. A value of p < 0.1 for Q test, or I(2 )> 50%, indicated significant heterogeneity among studies. The literature search retrieved 2900 studies from screened databases, of which 2866 (98.6%) were excluded and 34 (619 patients) were included for scoping review. The final analysis included 9 studies (335 patients).

Results: Pooled effects estimates of left ventricular ejection fraction and left ventricular end-diastolic volume showed that bone marrow stem cell transplantation had a weighted mean difference of 4.06 (95% confidence interval: 0.41-7.72; p = 0.02) and 7.06 (95% confidence interval: -8.58-22.7; p = 0.3), respectively.

Conclusions: Intramyocardial transplantation of bone marrow stem cells improves cardiac functional parameters, significantly increasing left ventricular ejection fraction with a nonsignificant reduction in left ventricular end-diastolic volume. Also, this therapeutic method has no life-threatening complications and was therefore found to be an effective and safe method.
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http://dx.doi.org/10.1177/0218492314553251DOI Listing
March 2015