Publications by authors named "Yigal M Pinto"

161 Publications

Improving electrocardiogram-based detection of rare genetic heart disease using transfer learning: An application to phospholamban p.Arg14del mutation carriers.

Comput Biol Med 2021 Apr 11;131:104262. Epub 2021 Feb 11.

Amsterdam UMC, University of Amsterdam, Department of Biomedical Engineering and Physics, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Radiology and Nuclear Medicine, Amsterdam, the Netherlands.

The pathogenic mutation p.Arg14del in the gene encoding Phospholamban (PLN) is known to cause cardiomyopathy and leads to increased risk of sudden cardiac death. Automatic tools might improve the detection of patients with this rare disease. Deep learning is currently the state-of-the-art in signal processing but requires large amounts of data to train the algorithms. In situations with relatively small amounts of data, like PLN, transfer learning may improve accuracy. We propose an ECG-based detection of the PLN mutation using transfer learning from a model originally trained for sex identification. The sex identification model was trained with 256,278 ECGs and subsequently finetuned for PLN detection (155 ECGs of patients with PLN) with two control groups: a balanced age/sex matched group and a randomly selected imbalanced population. The data was split in 10 folds and 20% of the training data was used for validation and early stopping. The models were evaluated with the area under the receiver operating characteristic curve (AUROC) of the testing data. We used gradient activation for explanation of the prediction models. The models trained with transfer learning outperformed the models trained from scratch for both the balanced (AUROC 0.87 vs AUROC 0.71) and imbalanced (AUROC 0.0.90 vs AUROC 0.65) population. The proposed approach was able to improve the accuracy of a rare disease detection model by transfer learning information from a non-manual annotated and abundant label with only limited data available.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104262DOI Listing
April 2021

Titin Circular RNAs Create a Back-Splice Motif Essential for SRSF10 Splicing.

Circulation 2021 Apr 15;143(15):1502-1512. Epub 2021 Feb 15.

Amsterdam UMC, University of Amsterdam, Departments of Experimental Cardiology, Amsterdam Cardiovascular Sciences (A.J.T., L.C.O., Y.J.R., I.v.d.M., S.A., S.C.K., A.v.d.B., Y.M.P.), Amsterdam, The Netherlands.

Background: TTN (Titin), the largest protein in humans, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to the cardiomyocyte. Mutations that disrupt the transcript are the most frequent cause of hereditary heart failure. We showed before that produces a class of circular RNAs (circRNAs) that depend on RBM20 to be formed. In this study, we show that the back-splice junction formed by this class of circRNAs creates a unique motif that binds SRSF10 to enable it to regulate splicing. Furthermore, we show that one of these circRNAs (cTTN1) distorts both localization of and splicing by RBM20.

Methods: We calculated genetic constraint of the identified motif in 125 748 exomes collected from the gnomAD database. Furthermore, we focused on the highest expressed RBM20-dependent circRNA in the human heart, which we named cTTN1. We used shRNAs directed to the back-splice junction to induce selective loss of cTTN1 in human induced pluripotent stem cell-derived cardiomyocytes.

Results: Human genetics suggests reduced genetic tolerance of the generated motif, indicating that mutations in this motif might lead to disease. RNA immunoprecipitation confirmed binding of circRNAs with this motif to SRSF10. Selective loss of cTTN1 in human induced pluripotent stem cell-derived cardiomyocytes induced structural abnormalities, apoptosis, and reduced contractile force in engineered heart tissue. In line with its SRSF10 binding, loss of cTTN1 caused abnormal splicing of important cardiomyocyte SRSF10 targets such as and . Strikingly, loss of cTTN1 also caused abnormal splicing of itself. Mechanistically, we show that loss of cTTN1 distorts both localization of and splicing by RBM20.

Conclusions: We demonstrate that circRNAs formed from the transcript are essential for normal splicing of key muscle genes by enabling splice regulators RBM20 and SRSF10. This shows that the transcript also has regulatory roles, besides its well-known signaling and structural function. In addition, we demonstrate that the specific sequence created by the back-splice junction of these circRNAs has important functions. This highlights the existence of functionally important sequences that cannot be recognized as such in the human genome but provides an as-yet unrecognized source for functional sequence variation.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032209PMC
April 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 Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.

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

Computer versus cardiologist: Is a machine learning algorithm able to outperform an expert in diagnosing a phospholamban p.Arg14del mutation on the electrocardiogram?

Heart Rhythm 2021 Jan 8;18(1):79-87. Epub 2020 Sep 8.

Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.

Background: Phospholamban (PLN) p.Arg14del mutation carriers are known to develop dilated and/or arrhythmogenic cardiomyopathy, and typical electrocardiographic (ECG) features have been identified for diagnosis. Machine learning is a powerful tool used in ECG analysis and has shown to outperform cardiologists.

Objectives: We aimed to develop machine learning and deep learning models to diagnose PLN p.Arg14del cardiomyopathy using ECGs and evaluate their accuracy compared to an expert cardiologist.

Methods: We included 155 adult PLN mutation carriers and 155 age- and sex-matched control subjects. Twenty-one PLN mutation carriers (13.4%) were classified as symptomatic (symptoms of heart failure or malignant ventricular arrhythmias). The data set was split into training and testing sets using 4-fold cross-validation. Multiple models were developed to discriminate between PLN mutation carriers and control subjects. For comparison, expert cardiologists classified the same data set. The best performing models were validated using an external PLN p.Arg14del mutation carrier data set from Murcia, Spain (n = 50). We applied occlusion maps to visualize the most contributing ECG regions.

Results: In terms of specificity, expert cardiologists (0.99) outperformed all models (range 0.53-0.81). In terms of accuracy and sensitivity, experts (0.28 and 0.64) were outperformed by all models (sensitivity range 0.65-0.81). T-wave morphology was most important for classification of PLN p.Arg14del carriers. External validation showed comparable results, with the best model outperforming experts.

Conclusion: This study shows that machine learning can outperform experienced cardiologists in the diagnosis of PLN p.Arg14del cardiomyopathy and suggests that the shape of the T wave is of added importance to this diagnosis.
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http://dx.doi.org/10.1016/j.hrthm.2020.08.021DOI Listing
January 2021

Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease.

Am Heart J 2020 08 21;226:60-68. Epub 2020 May 21.

Department of Cardiology, Radboudumc, Nijmegen, the Netherlands.

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II-mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. METHODS: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2-infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). SUMMARY: The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2-infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally.
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http://dx.doi.org/10.1016/j.ahj.2020.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239793PMC
August 2020

The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin-angiotensin system.

Eur Heart J Cardiovasc Pharmacother 2020 09;6(5):317-325

Vascular Medicine, Amsterdam UMC, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.

The SARS-CoV-2 pandemic is a healthcare crisis caused by insufficient knowledge applicable to effectively combat the virus. Therefore, different scientific discovery strategies need to be connected, to generate a rational treatment which can be made available as rapidly as possible. This relies on a solid theoretical understanding of the mechanisms of SARS-CoV-2 infection and host responses, which is coupled to the practical experience of clinicians that are treating patients. Because SARS-CoV-2 enters the cell by binding to angiotensin-converting enzyme 2 (ACE2), targeting ACE2 to prevent such binding seems an obvious strategy to combat infection. However, ACE2 performs its functions outside the cell and was found to enter the cell only by angiotensin II type 1 receptor (AT1R)-induced endocytosis, after which ACE2 is destroyed. This means that preventing uptake of ACE2 into the cell by blocking AT1R would be a more logical approach to limit entry of SARS-CoV-2 into the cell. Since ACE2 plays an important protective role in maintaining key biological processes, treatments should not disrupt the functional capacity of ACE2, to counterbalance the negative effects of the infection. Based on known mechanisms and knowledge of the characteristics of SARS-CoV we propose the hypothesis that the immune system facilitates SARS-CoV-2 replication which disrupts immune regulatory mechanisms. The proposed mechanism by which SARS-CoV-2 causes disease immediately suggests a possible treatment, since the AT1R is a key player in this whole process. AT1R antagonists appear to be the ideal candidate for the treatment of SARS-CoV-2 infection. AT1R antagonists counterbalance the negative consequences of angiotesnin II and, in addition, they might even be involved in preventing the cellular uptake of the virus without interfering with ACE2 function. AT1R antagonists are widely available, cheap, and safe. Therefore, we propose to consider using AT1R antagonists in the treatment of SARS-CoV-2.
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http://dx.doi.org/10.1093/ehjcvp/pvaa053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314063PMC
September 2020

circRNAprofiler: an R-based computational framework for the downstream analysis of circular RNAs.

BMC Bioinformatics 2020 Apr 29;21(1):164. Epub 2020 Apr 29.

Department of Experimental Cardiology, Amsterdam UMC, location AMC, Amsterdam, The Netherlands.

Background: Circular RNAs (circRNAs) are a newly appreciated class of non-coding RNA molecules. Numerous tools have been developed for the detection of circRNAs, however computational tools to perform downstream functional analysis of circRNAs are scarce.

Results: We present circRNAprofiler, an R-based computational framework that runs after circRNAs have been identified. It allows to combine circRNAs detected by multiple publicly available annotation-based circRNA detection tools and to analyze their expression, genomic context, evolutionary conservation, biogenesis and putative functions.

Conclusions: Overall, the circRNA analysis workflow implemented by circRNAprofiler is highly automated and customizable, and the results of the analyses can be used as starting point for further investigation in the role of specific circRNAs in any physiological or pathological condition.
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http://dx.doi.org/10.1186/s12859-020-3500-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191743PMC
April 2020

Risk Prediction in Transition: MAGGIC Score Performance at Discharge and Incremental Utility of Natriuretic Peptides.

J Card Fail 2020 Jan 18;26(1):52-60. Epub 2019 Nov 18.

Heart and Vascular Institute, Henry Ford Hospital, Detroit, Michigan; Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; Center for Individualized and Genomic Medicine Research, Henry Ford Hospital, Detroit, Michigan. Electronic address:

Background: Risk stratification for hospitalized patients with heart failure (HF) remains a critical need. The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score is a robust model derived from patients with ambulatory HF. Its validity at the time of discharge and the incremental value of natriuretic peptides (NPs) in this setting is unclear.

Methods: This was a single-center study examining a total of 4138 patients with HF from 2 groups; hospital discharge patients from administrative data (n = 2503, 60.5%) and a prospective registry of patients with ambulatory HF (n = 1635, 39.5%). The ambulatory registry patients underwent N-terminal pro-B-type NP (BNP) measurement at enrollment, and in the hospitalize discharge cohort clinical BNP levels were abstracted. The primary endpoint was all-cause mortality within 1 year. MAGGIC score performance was compared between cohorts utilizing Cox regression and calibration plots. The incremental value of NPs was assessed using calculated area under the curve and net reclassification improvement (NRI).

Results: The hospitalized and ambulatory cohorts differed with respect to primary outcome (777 and 100 deaths, respectively), sex (52.1% vs 41.7% female) and race (35% vs 49.5% African American). The MAGGIC score showed poor discrimination of mortality risk in the hospital discharge (C statistic: 0.668, hazard ratio [HR]: 1.1 per point, 95% confidence interval [CI]: 0.652, 0.684) but fair discrimination in the ambulatory cohorts (C statistic: 0.784, HR: 1.16 per point, 95% CI: 0.74, 0.83), respectively, a difference that was statistically significant (P = .001 for C statistic, 0.002 for HR). Calibration assessment indicated that the slope and intercept (of MAGGIC-predicted to observed mortality) did not statistically differ from ideal in either cohort and did not differ between the cohorts (all P > .1). NP levels did not significantly improve prediction in the hospitalized cohort (P = .127) but did in the ambulatory cohort (C statistic: 0.784 [95% CI: 0.74, 0.83] vs 0.82 [95% CI: 0.78, 0.85]; P = .018) with a favorable NRI of 0.354 (95% CI: 0.202-0.469; P = .002).

Conclusion: The MAGGIC score showed poor discrimination when used in patients with HF at hospital discharge, which was inferior to its performance in patients with ambulatory HF. Discrimination within the hospital discharge group was not improved by including hospital NP levels.
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http://dx.doi.org/10.1016/j.cardfail.2019.11.016DOI Listing
January 2020

Diagnostic tools for early detection of cardiac dysfunction in childhood cancer survivors: Methodological aspects of the Dutch late effects after childhood cancer (LATER) cardiology study.

Am Heart J 2020 01 9;219:89-98. Epub 2019 Nov 9.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Amsterdam UMC, University of Amsterdam, Department of Pediatric Oncology, Amsterdam, The Netherlands.

Background: Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and electrocardiographic measurements, and/or biomarkers will allow for improved recognition of patients with cardiac dysfunction before heart failure develops, and may also identify patients at lower risk for heart failure.

Objective: To describe the methodology of the Dutch LATER cardiology study (LATER CARD).

Methods: The LATER CARD study is a cross-sectional study in long-term CCS treated with (potentially) cardiotoxic cancer therapies and sibling controls. We will evaluate 1) the prevalence and associated (treatment related) risk factors of subclinical cardiac dysfunction in CCS compared to sibling controls and 2) the diagnostic value of echocardiography including myocardial strain and diastolic function parameters, blood biomarkers for cardiomyocyte apoptosis, oxidative stress, cardiac remodeling and inflammation and ECG or combinations of them in the surveillance for cancer therapy-related cardiac dysfunction. From 2017 to 2020 we expect to include 1900 CCS and 500 siblings.

Conclusions: The LATER CARD study will provide knowledge on different surveillance modalities for detection of cardiac dysfunction in long-term CCS at risk for heart failure. The results of the study will enable us to improve long-term follow-up surveillance guidelines for CCS at risk for heart failure.
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http://dx.doi.org/10.1016/j.ahj.2019.10.010DOI Listing
January 2020

Multimodality imaging in the diagnosis, risk stratification, and management of patients with dilated cardiomyopathies: an expert consensus document from the European Association of Cardiovascular Imaging.

Eur Heart J Cardiovasc Imaging 2019 10;20(10):1075-1093

Department of Cardiology, University of Medicine and Pharmacy "Carol Davila"- Euroecolab, Emergency Institute of Cardiovascular Diseases "Prof. Dr. C. C. Iliescu", Sos. Fundeni 258, Sector 2, Bucharest, Romania.

Dilated cardiomyopathy (DCM) is defined by the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to explain these changes. This is a heterogeneous disease frequently having a genetic background. Imaging is important for the diagnosis, the prognostic assessment and for guiding therapy. A multimodality imaging approach provides a comprehensive evaluation of all the issues related to this disease. The present document aims to provide recommendations for the use of multimodality imaging according to the clinical question. Selection of one or another imaging technique should be based on the clinical condition and context. Techniques are presented with the aim to underscore what is 'clinically relevant' and what are the tools that 'can be used'. There remain some gaps in evidence on the impact of multimodality imaging on the management and the treatment of DCM patients where ongoing research is important.
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http://dx.doi.org/10.1093/ehjci/jez178DOI Listing
October 2019

External Validation of the ELAN-HF Score, Predicting 6-Month All-Cause Mortality in Patients Hospitalized for Acute Decompensated Heart Failure.

J Am Heart Assoc 2019 07 12;8(14):e010309. Epub 2019 Jul 12.

1 Heart Center Department of Clinical and Experimental Cardiology Amsterdam Cardiovascular Sciences Amsterdam University Medical Center University of Amsterdam Amsterdam the Netherlands.

Background Our aim was to calibrate and externally revalidate the ELAN-HF (European Collaboration on Acute Decompensated Heart Failure) score, to confirm and improve on a previous external validation of the risk score. Methods and Results The ELAN-HF score predicts 6-month all-cause mortality in patients hospitalized for acute decompensated heart failure using absolute and percentage change of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels in addition to clinical variables. For the external validation, we used the PRIMA II (Can NT-proBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?) trial. For both data sets, observed versus predicted mortality was compared for the 4 risk categories; and the mean predicted mortality was plotted against the observed mortality with calculation of a correlation coefficient and SEE. The model discriminant ability was determined by comparing the C-statistics for both data sets. The predicted versus actual 6-month mortality values in the derivation cohort were 3.7% versus 3.6% for the low-risk category, 9.4% versus 9.2% for the intermediate-risk category, 24.2% versus 23.5% for the high-risk category, and 54.2% versus 51.1% for the very-high-risk category. The correlation between predicted and observed mortality by deciles was 0.92, with an SEE of ±4%. In the validation cohort, predicted versus actual 6-month mortality values were 3.0% versus 2.2% for the low-risk category, 9.4% versus 8.2% for the intermediate-risk category, 25.0% versus 22.9% for the high-risk category, and 56.8% versus 53.6% for the very-high-risk category. The correlation between predicted and actual mortality by quintiles was 0.99, with an SEE of ±2%. There was no significant difference in C-statistic between the derivation cohort (0.78; 95% CI, 0.74-0.82) and the validation cohort (0.77; 95% CI, 0.69-0.84; P=0.693). Conclusions Our study confirms that the ELAN-HF score predicts accurately 6-month mortality in patients hospitalized for acute decompensated heart failure with the use of easily obtained characteristics.
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http://dx.doi.org/10.1161/JAHA.118.010309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662127PMC
July 2019

Heritability in genetic heart disease: the role of genetic background.

Open Heart 2019;6(1):e000929. Epub 2019 May 28.

Heart Center, Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Background: Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or 'modifier genes'. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins.

Methods: We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy.

Results: Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy.

Conclusions: Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.
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http://dx.doi.org/10.1136/openhrt-2018-000929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546190PMC
February 2021

Prognosis and NT-proBNP in heart failure patients with preserved versus reduced ejection fraction.

Heart 2019 08 8;105(15):1182-1189. Epub 2019 Apr 8.

Heart Centre, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amasterdam, The Netherlands.

Background: We assessed the prognostic significance of absolute and percentage change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients hospitalised for acute decompensated heart failure with preservedejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF).

Methods: Patients with left ventricular ejection fraction ≥50% were categorised as HFpEF (n=283), while those with <40% as were categorised as HFrEF (n=776). Prognostic values of absolute and percentage change in NT-proBNP levels for 6 months all-cause mortality after discharge were assessed separately in patients with HFpEF and HFrEF by multivariable adjusted Cox regression analysis. Comorbidities were compared between heart failure groups.

Results: Discharge NT-proBNP levels predicted outcome similarly in HFpEF and HFrEF: for any 2.7-factor increase in NT-proBNP levels, the HR for mortality was 2.14 for HFpEF (95% CI 1.48 to 3.09) and 1.96 for HFrEF (95% CI 1.60 to 2.40). Mortality prediction was equally possible for NT-proBNP reduction of ≤30% (HR 4.60, 95% CI 1.47 to 14.40 and HR 3.36, 95% CI 1.93 to 5.85 for HFpEF and HFrEF, respectively) and for >30%-60% (HR 3.28, 95% CI 1.07 to 10.12 and HR 1.79, 95% CI 0.99 to 3.26, respectively), compared with mortality in the reference groups of >60% reductions in NT-proBNP levels. Prognostically relevant comorbidities were more often present in patients with HFpEF than patients with HFrEF in low (≤3000 pg/mL) but not in high (>3000 pg/mL) NT-proBNP discharge categories.

Conclusions: Our study highlights-after demonstrating that NT-proBNP levels confer the same relative risk information in HFpEF as in HFrEF-the possibility that comorbidities contribute relatively more to prognosis in patients with HFpEF with lower NT-proBNP levels than in patients with HFrEF.
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http://dx.doi.org/10.1136/heartjnl-2018-314173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662953PMC
August 2019

Circular RNAs open a new chapter in cardiovascular biology.

Nat Rev Cardiol 2019 08;16(8):503-514

Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Circular RNAs (circRNAs) are emerging as a new class of non-coding RNA molecules. This unusual class of RNA species is generated by a back-splicing event of one or two exons, resulting in a covalently closed circRNA molecule. Owing to their circular form, circRNAs are protected from degradation by exonucleases and have greater stability than linear RNA. Advances in computational analysis of RNA sequencing have revealed that thousands of different circRNAs are expressed in a wide range of mammalian tissues, including the cardiovascular system. Moreover, numerous circRNAs are expressed in a disease-specific manner. A great deal of progress has been made in understanding the biogenesis and function of these circRNAs. In this Review, we discuss the current understanding of circRNA biogenesis and function, with a particular emphasis on the cardiovascular system.
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http://dx.doi.org/10.1038/s41569-019-0185-2DOI Listing
August 2019

Relevance of Titin Missense and Non-Frameshifting Insertions/Deletions Variants in Dilated Cardiomyopathy.

Sci Rep 2019 03 11;9(1):4093. Epub 2019 Mar 11.

Blueprint Genetics, Helsinki, Finland.

Recent advancements in next generation sequencing (NGS) technology have led to the identification of the giant sarcomere gene, titin (TTN), as a major human disease gene. Truncating variants of TTN (TTNtv) especially in the A-band region account for 20% of dilated cardiomyopathy (DCM) cases. Much attention has been focused on assessment and interpretation of TTNtv in human disease; however, missense and non-frameshifting insertions/deletions (NFS-INDELs) are difficult to assess and interpret in clinical diagnostic workflow. Targeted sequencing covering all exons of TTN was performed on a cohort of 530 primary DCM patients from three cardiogenetic centres across Europe. Using stringent bioinformatic filtering, twenty-nine and two rare TTN missense and NFS-INDELs variants predicted deleterious were identified in 6.98% and 0.38% of DCM patients, respectively. However, when compared with those identified in the largest available reference population database, no significant enrichment of such variants was identified in DCM patients. Moreover, DCM patients and reference individuals had comparable frequencies of splice-region missense variants with predicted splicing alteration. DCM patients and reference populations had comparable frequencies of rare predicted deleterious TTN missense variants including splice-region missense variants suggesting that these variants are not independently causative for DCM. Hence, these variants should be classified as likely benign in the clinical diagnostic workflow, although a modifier effect cannot be excluded at this stage.
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http://dx.doi.org/10.1038/s41598-019-39911-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412046PMC
March 2019

Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure.

Mol Ther 2019 03 17;27(3):584-599. Epub 2018 Nov 17.

Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands. Electronic address:

Heart failure is preceded by ventricular remodeling, changes in left ventricular mass, and myocardial volume after alterations in loading conditions. Concentric hypertrophy arises after pressure overload, involves wall thickening, and forms a substrate for diastolic dysfunction. Eccentric hypertrophy develops in volume overload conditions and leads wall thinning, chamber dilation, and reduced ejection fraction. The molecular events underlying these distinct forms of cardiac remodeling are poorly understood. Here, we demonstrate that miR-148a expression changes dynamically in distinct subtypes of heart failure: while it is elevated in concentric hypertrophy, it decreased in dilated cardiomyopathy. In line, antagomir-mediated silencing of miR-148a caused wall thinning, chamber dilation, increased left ventricle volume, and reduced ejection fraction. Additionally, adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation. Mechanistically, miR-148a targets the cytokine co-receptor glycoprotein 130 (gp130) and connects cardiomyocyte responsiveness to extracellular cytokines by modulating the Stat3 signaling. These findings show the ability of miR-148a to prevent the transition of pressure-overload induced concentric hypertrophic remodeling toward eccentric hypertrophy and dilated cardiomyopathy and provide evidence for the existence of separate molecular programs inducing distinct forms of myocardial remodeling.
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http://dx.doi.org/10.1016/j.ymthe.2018.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403487PMC
March 2019

Formins Emerge as a Cause of Hypertrophic Cardiomyopathy: New Genes for Thick Hearts.

J Am Coll Cardiol 2018 11;72(20):2468-2470

Department of Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1016/j.jacc.2018.09.026DOI Listing
November 2018

Biomarkers to diagnose ventricular dysfunction in childhood cancer survivors: a systematic review.

Heart 2019 02 29;105(3):210-216. Epub 2018 Aug 29.

Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Heart Center, Amsterdam, The Netherlands.

Objective: To systematically review the literature and assess the diagnostic value of biomarkers in detection of late-onset left ventricular (LV) dysfunction in childhood cancer survivors (CCS) treated with anthracyclines.

Methods: We systematically searched the literature for studies that evaluated the use of biomarkers for detection of LV dysfunction in CCS treated with anthracyclines more than 1 year since childhood cancer diagnosis. LV dysfunction definitions were accepted as an ejection fraction <50% or <55% and/or a fractional shortening <28%, <29% or <30%. Contingency tables were created to assess diagnostic accuracies of biomarkers for diagnosing LV dysfunction.

Results: Of 1362 original studies screened, eight heterogeneous studies evaluating four different biomarkers in mostly asymptomatic CCS were included. In four studies, an abnormal N-terminal pro-B-type natriuretic peptide (NT-proBNP, cut-off range 63-125 ng/L) had low sensitivity (maximally 22%) and a specificity of up to 97% for detection of LV dysfunction. For troponin levels, in five studies one patient had an abnormal troponin value as well as LV dysfunction, while in total 127 patients had LV dysfunction without troponin elevations above cut-off values (lowest 0.01 ng/mL). Two studies that evaluated brain natriuretic peptide and nitric oxide were underpowered to draw conclusions.

Conclusions: In individual studies, the diagnostic value of NT-proBNP for detection of LV dysfunction in CCS is limited. Troponins have no role in detecting late-onset LV dysfunction with cut-off values as low as 0.01 ng/mL. Further study on optimal NT-proBNP cut-off values for rule out or rule in of LV dysfunction is warranted.
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http://dx.doi.org/10.1136/heartjnl-2018-313634DOI Listing
February 2019

AAV9-mediated Rbm24 overexpression induces fibrosis in the mouse heart.

Sci Rep 2018 08 3;8(1):11696. Epub 2018 Aug 3.

Department of Experimental Cardiology, Academic Medical Center (AMC), Amsterdam, The Netherlands.

The RNA-binding protein Rbm24 has recently been identified as a pivotal splicing factor in the developing heart. Loss of Rbm24 in mice disrupts cardiac development by governing a large number of muscle-specific splicing events. Since Rbm24 knockout mice are embryonically lethal, the role of Rbm24 in the adult heart remained unexplored. Here, we used adeno-associated viruses (AAV9) to investigate the effect of increased Rbm24 levels in adult mouse heart. Using high-resolution microarrays, we found 893 differentially expressed genes and 1102 differential splicing events in 714 genes in hearts overexpressing Rbm24. We found splicing differences in cardiac genes, such as PDZ and Lim domain 5, Phospholamban, and Titin, but did not find splicing differences in previously identified embryonic splicing targets of Rbm24, such as skNAC, αNAC, and Coro6. Gene ontology enrichment analysis demonstrated increased expression of extracellular matrix (ECM)-related and immune response genes. Moreover, we found increased expression of Tgfβ-signaling genes, suggesting enhanced Tgfβ-signaling in these hearts. Ultimately, this increased activation of cardiac fibroblasts, as evidenced by robust expression of Periostin in the heart, and induced extensive cardiac fibrosis. These results indicate that Rbm24 may function as a regulator of cardiac fibrosis, potentially through the regulation of TgfβR1 and TgfβR2 expression.
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http://dx.doi.org/10.1038/s41598-018-29552-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076270PMC
August 2018

Additional Genetic Variants in Inherited Dilated Cardiomyopathy: Just Another Brick in the Wall?

Circ Genom Precis Med 2018 07;11(7):e002249

Department of Cardiology (Y.M.P.).

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http://dx.doi.org/10.1161/CIRCGEN.118.002249DOI Listing
July 2018

The clinical outcome of LMNA missense mutations can be associated with the amount of mutated protein in the nuclear envelope.

Eur J Heart Fail 2018 10 26;20(10):1404-1412. Epub 2018 Jun 26.

Department of Cardiology, Odense University Hospital, Odense, Denmark.

Aims: Lamin A/C mutations are generally believed to be associated with a severe prognosis. The aim of this study was to investigate disease expression in three affected families carrying different LMNA missense mutations. Furthermore, the potential molecular disease mechanisms of the mutations were investigated in fibroblasts obtained from mutation carriers.

Methods And Results: A LMNA-p.Arg216Cys missense mutation was identified in a large family with 36 mutation carriers. Disease expression was unusual with a late onset and a favourable prognosis. Two smaller families with severe disease expression were shown to carry a LMNA-p.Arg471Cys and LMNA-p.Arg471His mutation, respectively. LMNA gene and protein expression was investigated in eight different mutation carriers by quantitative reverse transcriptase polymerase chain reaction, Western blotting, immunohistochemistry, and protein mass spectrometry. The results showed that all mutation carriers incorporated mutated lamin protein into the nuclear envelope. Interestingly, the ratio of mutated to wild-type protein was only 30:70 in LMNA-p.Arg216Cys carriers with a favourable prognosis while LMNA-p.Arg471Cys and LMNA-p.Arg471His carriers with a more severe outcome expressed significantly more of the mutated protein by a ratio of 50:50.

Conclusion: The clinical findings indicated that some LMNA mutations may be associated with a favourable prognosis and a low risk of sudden death. Protein expression studies suggested that a severe outcome was associated with the expression of high amounts of mutated protein. These findings may prove to be helpful in counselling and risk assessment of LMNA families.
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http://dx.doi.org/10.1002/ejhf.1241DOI Listing
October 2018

Race and Beta-Blocker Survival Benefit in Patients With Heart Failure: An Investigation of Self-Reported Race and Proportion of African Genetic Ancestry.

J Am Heart Assoc 2018 05 8;7(10). Epub 2018 May 8.

Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI

Background: It remains unclear whether beta-blockade is similarly effective in black patients with heart failure and reduced ejection fraction as in white patients, but self-reported race is a complex social construct with both biological and environmental components. The objective of this study was to compare the reduction in mortality associated with beta-blocker exposure in heart failure and reduced ejection fraction patients by both self-reported race and by proportion African genetic ancestry.

Methods And Results: Insured patients with heart failure and reduced ejection fraction (n=1122) were included in a prospective registry at Henry Ford Health System. This included 575 self-reported blacks (129 deaths, 22%) and 547 self-reported whites (126 deaths, 23%) followed for a median 3.0 years. Beta-blocker exposure (BBexp) was calculated from pharmacy claims, and the proportion of African genetic ancestry was determined from genome-wide array data. Time-dependent Cox proportional hazards regression was used to separately test the association of BBexp with all-cause mortality by self-reported race or by proportion of African genetic ancestry. Both sets of models were evaluated unadjusted and then adjusted for baseline risk factors and beta-blocker propensity score. BBexp effect estimates were protective and of similar magnitude both by self-reported race and by African genetic ancestry (adjusted hazard ratio=0.56 in blacks and adjusted hazard ratio=0.48 in whites). The tests for interactions with BBexp for both self-reported race and for African genetic ancestry were not statistically significant in any model (>0.1 for all).

Conclusions: Among black and white patients with heart failure and reduced ejection fraction, reduction in all-cause mortality associated with BBexp was similar, regardless of self-reported race or proportion African genetic ancestry.
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http://dx.doi.org/10.1161/JAHA.117.007956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015313PMC
May 2018

RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling.

Circulation 2018 09;138(13):1330-1342

Department of Experimental Cardiology (M.M.G.v.d.H., A.B., A.S.A., I.v.d.M., S.A., M.A.F.K., C.A.S., J.A.J., C.A.R., A.o.V., A.B., Y.M.P., E.E.C.), Academic Medical Center, Amsterdam, The Netherlands.

Background: Mutations in RBM20 (RNA-binding motif protein 20) cause a clinically aggressive form of dilated cardiomyopathy, with an increased risk of malignant ventricular arrhythmias. RBM20 is a splicing factor that targets multiple pivotal cardiac genes, such as Titin (TTN) and CAMK2D (calcium/calmodulin-dependent kinase II delta). Aberrant TTN splicing is thought to be the main determinant of RBM20-induced dilated cardiomyopathy, but is not likely to explain the increased risk of arrhythmias. Here, we investigated the extent to which RBM20 mutation carriers have an increased risk of arrhythmias and explore the underlying molecular mechanism.

Methods: We compared clinical characteristics of RBM20 and TTN mutation carriers and used our previously generated Rbm20 knockout (KO) mice to investigate downstream effects of Rbm20-dependent splicing. Cellular electrophysiology and Ca measurements were performed on isolated cardiomyocytes from Rbm20 KO mice to determine the intracellular consequences of reduced Rbm20 levels.

Results: Sustained ventricular arrhythmias were more frequent in human RBM20 mutation carriers than in TTN mutation carriers (44% versus 5%, respectively, P=0.006). Splicing events that affected Ca- and ion-handling genes were enriched in Rbm20 KO mice, most notably in the genes CamkIIδ and RyR2. Aberrant splicing of CamkIIδ in Rbm20 KO mice resulted in a remarkable shift of CamkIIδ toward the δ-A isoform that is known to activate the L-type Ca current ( I). In line with this, we found an increased I, intracellular Ca overload and increased sarcoplasmic reticulum Ca content in Rbm20 KO myocytes. In addition, not only complete loss of Rbm20, but also heterozygous loss of Rbm20 increased spontaneous sarcoplasmic reticulum Ca releases, which could be attenuated by treatment with the I antagonist verapamil.

Conclusions: We show that loss of Rbm20 disturbs Ca handling and leads to more proarrhythmic Ca releases from the sarcoplasmic reticulum. Patients that carry a pathogenic RBM20 mutation have more ventricular arrhythmias despite a similar left ventricular function, in comparison with patients with a TTN mutation. Our experimental data suggest that RBM20 mutation carriers may benefit from treatment with an I blocker to reduce their arrhythmia burden.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.031947DOI Listing
September 2018

The MEF2 transcriptional target DMPK induces loss of sarcomere structure and cardiomyopathy.

Cardiovasc Res 2018 09;114(11):1474-1486

Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Academic Medical Center, Amsterdam, The Netherlands.

Aims: The pathology of heart failure is characterized by poorly contracting and dilated ventricles. At the cellular level, this is associated with lengthening of individual cardiomyocytes and loss of sarcomeres. While it is known that the transcription factor myocyte enhancer factor-2 (MEF2) is involved in this cardiomyocyte remodelling, the underlying mechanism remains to be elucidated. Here, we aim to mechanistically link MEF2 target genes with loss of sarcomeres during cardiomyocyte remodelling.

Methods And Results: Neonatal rat cardiomyocytes overexpressing MEF2 elongated and lost their sarcomeric structure. We identified myotonic dystrophy protein kinase (DMPK) as direct MEF2 target gene involved in this process. Adenoviral overexpression of DMPK E, the isoform upregulated in heart failure, resulted in severe loss of sarcomeres in vitro, and transgenic mice overexpressing DMPK E displayed disruption of sarcomere structure and cardiomyopathy in vivo. Moreover, we found a decreased expression of sarcomeric genes following DMPK E gain-of-function. These genes are targets of the transcription factor serum response factor (SRF) and we found that DMPK E acts as inhibitor of SRF transcriptional activity.

Conclusion: Our data indicate that MEF2-induced loss of sarcomeres is mediated by DMPK via a decrease in sarcomeric gene expression by interfering with SRF transcriptional activity. Together, these results demonstrate an unexpected role for DMPK as a direct mediator of adverse cardiomyocyte remodelling and heart failure.
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http://dx.doi.org/10.1093/cvr/cvy091DOI Listing
September 2018

Cardiac circRNAs arise mainly from constitutive exons rather than alternatively spliced exons.

RNA 2018 06 22;24(6):815-827. Epub 2018 Mar 22.

Department of Experimental Cardiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.

Circular RNAs (circRNAs) are a relatively new class of RNA molecules, and knowledge about their biogenesis and function is still in its infancy. It was recently shown that alternative splicing underlies the formation of circular RNAs (circRNA) arising from the Titin gene. Since the main mechanism by which circRNAs are formed is still unclear, we hypothesized that alternative splicing, and in particular exon skipping, is a major driver of circRNA production. We performed RNA sequencing on human and mouse hearts, mapped alternative splicing events, and overlaid these with expressed circRNAs at exon-level resolution. In addition, we performed RNA sequencing on hearts of Rbm20 KO mice to address how important Rbm20-mediated alternative splicing is in the production of cardiac circRNAs. In human and mouse hearts, we show that cardiac circRNAs are mostly (∼90%) produced from constitutive exons and less (∼10%) from alternatively spliced exons. In Rbm20 KO hearts, we identified 38 differentially expressed circRNAs of which 12 were produced from the gene. Even though appeared the most prominent target of Rbm20 for circularization, we also detected Rbm20-dependent circRNAs arising from other genes including , , and Interestingly, only Ttn circRNAs seemed to arise from Rbm20-mediated skipped exons. In conclusion, cardiac circRNAs are mostly derived from constitutive exons, suggesting that these circRNAs are generated at the expense of their linear counterpart and that circRNA production impacts the accumulation of the linear mRNA.
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http://dx.doi.org/10.1261/rna.064394.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959250PMC
June 2018

NT-proBNP (N-Terminal pro-B-Type Natriuretic Peptide)-Guided Therapy in Acute Decompensated Heart Failure: PRIMA II Randomized Controlled Trial (Can NT-ProBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?).

Circulation 2018 04 14;137(16):1671-1683. Epub 2017 Dec 14.

Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands (S.S., K.S., J.G.P.T., Y.M.P., W.E.K.).

Background: The concept of natriuretic peptide guidance has been extensively studied in patients with chronic heart failure (HF), with only limited success. The effect of NT-proBNP (N-terminal probrain natriuretic peptide)-guided therapy in patients with acute decompensated HF using a relative NT-proBNP target has not been investigated. This study aimed to assess whether NT-proBNP-guided therapy of patients with acute decompensated HF using a relative NT-proBNP target would lead to improved outcomes compared with conventional therapy.

Methods: We conducted a prospective randomized controlled trial to study the impact of in-hospital guidance for acute decompensated HF treatment by a predefined NT-proBNP target (>30% reduction from admission to discharge) versus conventional treatment. Patients with acute decompensated HF with NT-proBNP levels >1700 ng/L were eligible. After achieving clinical stability, 405 patients were randomized to either NT-proBNP-guided or conventional treatment (1:1). The primary end point was dual: a composite of all-cause mortality and HF readmissions in 180 days and the number of days alive out of the hospital in 180 days. Secondary end points were all-cause mortality within 180 days, HF readmissions within 180 days, and a composite of all-cause mortality and HF readmissions within 90 days.

Results: Significantly more patients in the NT-proBNP-guided therapy group were discharged with an NT-proBNP reduction of >30% (80% versus 64%, =0.001). Nonetheless, NT-proBNP-guided therapy did not significantly improve the combined event rate for all-cause mortality and HF readmissions (hazard ratio, 0.96; 95% confidence interval, 0.72-1.37; =0.99) or the median number of days alive outside of the hospital (178 versus 179 days for NT-proBNP versus conventional patients, =0.39). Guided therapy also did not significantly improve any of the secondary end points.

Conclusions: The PRIMA II trial (Can NT-ProBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?) demonstrates that the guidance of HF therapy to reach an NT-proBNP reduction of >30% after clinical stabilization did not improve 6-month outcomes.

Clinical Trial Registration: URL: http://www.trialregister.nl. Unique identifier: NTR3279.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.029882DOI Listing
April 2018

Prognostic Value of Serial Galectin-3 Measurements in Patients With Acute Heart Failure.

J Am Heart Assoc 2017 Nov 29;6(12). Epub 2017 Nov 29.

Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands.

Background: Several clinical studies have evaluated the association between galectin-3 levels and outcome in patients with heart failure (HF). However, little is known about the predictive value of repeated galectin-3 measurements. This study evaluates the prognostic value of repeated time-dependent galectin-3 measurements in acute HF patients.

Methods And Results: In the TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients with Heart Failure) clinical cohort study, 496 acute HF patients were enrolled in 14 hospitals in The Netherlands, between 2009 and 2014. Repeated blood samples (7) were drawn during 1-year follow-up. Associations between repeated biomarker measurements and the primary end point were assessed using a joint model. Median age was 74 years and 37% were women. The primary end point, composite of all-cause mortality and HF rehospitalization, was reached in 188 patients (40%), during a median follow-up of 325 days (interquartile range 85-401). The median baseline galectin-3 level was 24 ng/mL (interquartile range 18-34). The mean number of galectin-3 measurements available per patient was 4.3. After adjustment for clinical factors and N-terminal pro-brain natriuretic peptide, there was a weak association between baseline galectin-3 and risk of the primary end point. When repeated measurements were taken into account, the adjusted hazard ratio per 1 SD increase of the galectin-3 level (on the log2 scale) at any time point increased to 1.67 (95% confidence interval, 1.24-2.23, <0.001). After additional adjustment for repeated N-terminal pro-brain natriuretic peptide measurements, the association remained statistically significant.

Conclusions: Repeated galectin-3 measurements appeared to be a strong predictor of outcome in acute HF patients, independent of N-terminal pro-brain natriuretic peptide. Hence, galectin-3 may be helpful in clinical practice for prognostication and treatment monitoring.
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http://dx.doi.org/10.1161/JAHA.116.003700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778986PMC
November 2017

Prognostic Value of Serial ST2 Measurements in Patients With Acute Heart Failure.

J Am Coll Cardiol 2017 Nov;70(19):2378-2388

Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands; Cardiovascular Research School, Erasmus Medical Center (COEUR), Rotterdam, the Netherlands.

Background: Several clinical studies have evaluated the association between ST2 and outcome in patients with heart failure (HF). However, little is known about the predictive value of frequently measured ST2 levels in patients with acute HF.

Objectives: This study sought to describe the prognostic value of baseline and repeated ST2 measurements in patients with acute HF.

Methods: In the TRIUMPH (Translational Initiative on Unique and novel strategies for Management of Patients with Heart failure) clinical cohort study, 496 patients with acute HF were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Repeated blood samples (7) were drawn during 1-year follow-up. ST2 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were measured in a central laboratory. The primary endpoint was the composite of all-cause mortality and HF rehospitalization. Associations between repeated biomarker measurements and the primary endpoint were assessed using a joint model.

Results: Median age was 74 years, and 37% of patients were women. The primary endpoint was reached in 188 patients (40%) during a median follow-up of 325 days (interquartile range: 85 to 401). The median baseline ST2 level was 71 ng/ml (interquartile range: 46 to 102). After adjustment for clinical factors and NT-proBNP, baseline ST2 was associated with an increased risk of the primary endpoint, and the hazard ratio per 1 SD increase of the baseline ST2 level (on the log scale) was 1.30 (95% confidence interval: 1.08 to 1.56; p = 0.005). When repeated measurements were taken into account, the adjusted hazard ratio per 1 SD increase of the ST2 level (on the log scale) during follow-up increased to 1.85 (95% confidence interval: 1.02 to 3.33; p = 0.044), adjusted for clinical factors and repeated measurements of NT-proBNP. Furthermore, ST2 levels appeared to elevate several weeks before the time of the primary endpoint.

Conclusions: Repeated ST2 measurements appeared to be a strong predictor of outcome in patients with acute HF, independent of repeatedly measured NT-proBNP. Hence ST2 may be helpful in clinical practice for prognostication and treatment monitoring. (TRanslational Initiative on Unique and novel strategies for Management of Patients with Heart failure [TRIUMPH]; NTR1893).
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http://dx.doi.org/10.1016/j.jacc.2017.09.026DOI Listing
November 2017