Publications by authors named "Ahmad S Amin"

36 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

Left Axis Deviation in Brugada Syndrome: Vectorcardiographic Evaluation during Ajmaline Provocation Testing Reveals Additional Depolarization Abnormalities.

Int J Mol Sci 2021 Jan 6;22(2). Epub 2021 Jan 6.

Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Patients with Brugada syndrome (BrS) can show a leftward deviation of the frontal QRS-axis upon provocation with sodium channel blockers. The cause of this axis change is unclear. In this study, we aimed to determine (1) the prevalence of this left axis deviation and (2) to evaluate its cause, using the insights that could be derived from vectorcardiograms. Hence, from a large cohort of patients who underwent ajmaline provocation testing ( = 1430), we selected patients in whom a type-1 BrS-ECG was evoked ( = 345). Depolarization and repolarization parameters were analyzed for reconstructed vectorcardiograms and were compared between patients with and without a >30° leftward axis shift. We found (1) that the prevalence of a left axis deviation during provocation testing was 18% and (2) that this left axis deviation was not explained by terminal conduction slowing in the right ventricular outflow tract (4th QRS-loop quartile: +17 ± 14 ms versus +13 ± 15 ms, nonsignificant) but was associated with a more proximal conduction slowing (1st QRS-loop quartile: +12[8;18] ms versus +8[4;12] ms, < 0.001 and 3rd QRS-loop quartile: +12 ± 10 ms versus +5 ± 7 ms, < 0.001). There was no important heterogeneity of the action potential morphology (no difference in the ventricular gradient), but a left axis deviation did result in a discordant repolarization (spatial QRS-T angle: 122[59;147]° versus 44[25;91]°, < 0.001). Thus, although the development of the type-1 BrS-ECG is characterized by a terminal conduction delay in the right ventricle, BrS-patients with a left axis deviation upon sodium channel blocker provocation have an additional proximal conduction slowing, which is associated with a subsequent discordant repolarization. Whether this has implications for risk stratification is still undetermined.
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http://dx.doi.org/10.3390/ijms22020484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825029PMC
January 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

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 Jan 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand.

Heart Rhythm 2020 12 30;17(12):2145-2153. Epub 2020 Jun 30.

Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Pacific Rim Electrophysiology Research Institute, Bumrungrad Hospital, Bangkok, Thailand.

Background: Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model.

Objective: The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand.

Methods: We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants.

Results: Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0-11.1), but an enrichment of low-frequency (MAF<0.001 and >0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3).

Conclusion: The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci.
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http://dx.doi.org/10.1016/j.hrthm.2020.06.027DOI Listing
December 2020

SCN5a overlap syndromes-This episode: Long QT syndrome type 3 meets multifocal ectopic Purkinje-related premature contractions.

Authors:
Ahmad S Amin

Heart Rhythm 2020 10 1;17(10):1777-1778. Epub 2020 Jun 1.

Amsterdam University Medical Centers, Academic Medical Center, Heart Center, Department of Cardiology, Amsterdam, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2020.05.033DOI Listing
October 2020

An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.

Circulation 2020 02 27;141(6):418-428. Epub 2020 Jan 27.

Division of Cardiology, Toronto General Hospital and University of Toronto, Canada (A.A, M.C., M.H.G.).

Background: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.

Methods: Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.

Results: Of 17 genes reported as being causative for LQTS, 9 () were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes () were curated as definitive genes for typical LQTS. Another 4 genes () were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene () had moderate level evidence for causing LQTS.

Conclusions: More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017940PMC
February 2020

Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores.

Eur Heart J 2019 10;40(37):3097-3107

Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, Meibergdreef 9, AZ Amsterdam, The Netherlands.

Aims: Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG).

Methods And Results: In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose-response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74).

Conclusion: We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.
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http://dx.doi.org/10.1093/eurheartj/ehz435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769824PMC
October 2019

Disease Modifiers of Inherited Channelopathy.

Front Cardiovasc Med 2018 1;5:137. Epub 2018 Oct 1.

Department of Clinical and Experimental Cardiology, Heart Centre, Academic Medical Center, Amsterdam, Netherlands.

To date, a large number of mutations in , the gene encoding the pore-forming α-subunit of the primary cardiac Na channel (Na1.5), have been found in patients presenting with a wide range of ECG abnormalities and cardiac syndromes. Although these mutations all affect the same Na1.5 channel, the associated cardiac syndromes each display distinct phenotypical and biophysical characteristics. Variable disease expressivity has also been reported, where one particular mutation in may lead to either one particular symptom, a range of various clinical signs, or no symptoms at all, even within one single family. Additionally, disease severity may vary considerably between patients carrying the same mutation. The exact reasons are unknown, but evidence is increasing that various cardiac and non-cardiac conditions can influence the expressivity and severity of inherited channelopathies. In this review, we provide a summary of identified disease entities caused by mutations, and give an overview of co-morbidities and other (non)-genetic factors which may modify channelopathies. A comprehensive knowledge of these modulatory factors is not only essential for a complete understanding of the diverse clinical phenotypes associated with mutations, but also for successful development of effective risk stratification and (alternative) treatment paradigms.
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http://dx.doi.org/10.3389/fcvm.2018.00137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174200PMC
October 2018

Clinical Spectrum of SCN5A Mutations: Long QT Syndrome, Brugada Syndrome, and Cardiomyopathy.

JACC Clin Electrophysiol 2018 05 2;4(5):569-579. Epub 2018 May 2.

Heart Centre Academic Medical Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

SCN5A gene encodes the pore-forming ion-conducting α-subunit of the cardiac sodium channel (Na1.5), which is responsible for the initiation and propagation of action potentials and thereby determines cardiac excitability and conduction of electrical stimuli through the heart. The importance of Na1.5 for normal cardiac electricity is reflected by various disease entities that can be caused by mutations in SCN5A. Gain-of-function mutations in SCN5A lead to more sodium influx into cardiomyocytes through aberrant channel gating and cause long QT syndrome, a primary electrical disease of the heart. Loss-of-function mutations in SCN5A lead to lower expression levels of SCN5A or production of defective Na1.5 proteins and cause Brugada syndrome, an electrical disease with minor structural changes in the heart. In addition, both loss- and gain-of-function mutations may cause dilated cardiomyopathy, which is an arrhythmogenic disease with gross structural defects of the left ventricle (and sometimes both ventricles). Other SCN5A-related diseases are multifocal ectopic premature Purkinje-related complexes (gain-of-function mutations), isolated cardiac conduction defect (loss-of-function mutations), sick sinus syndrome (loss-of-function mutations), atrial fibrillation (loss-of-function or gain-of-function mutations), and overlap syndromes (mutations with both loss-of-function and gain-of-function effects). Growing insights into the role of SCN5A in health and disease has enabled clinicians to lay out gene-specific risk stratification schemes and mutation-specific diagnostic and therapeutic strategies in the management of patients with a SCN5A mutation. This review summarizes currently available knowledge about the pathophysiological mechanisms of SCN5A mutations and describes how this knowledge can be used to manage patients suffering from potentially lethal cardiac diseases.
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http://dx.doi.org/10.1016/j.jacep.2018.03.006DOI Listing
May 2018

Yield and Pitfalls of Ajmaline Testing in the Evaluation of Unexplained Cardiac Arrest and Sudden Unexplained Death: Single-Center Experience With 482 Families.

JACC Clin Electrophysiol 2017 12 28;3(12):1400-1408. Epub 2017 Jun 28.

Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address:

Objectives: This study evaluated the yield of ajmaline testing and assessed the occurrence of confounding responses in a large cohort of families with unexplained cardiac arrest (UCA) or sudden unexplained death (SUD).

Background: Ajmaline testing to diagnose Brugada syndrome (BrS) is routinely used in the evaluation of SUD and UCA, but its yield, limitations, and appropriate dosing have not been studied in a large cohort.

Methods: We assessed ajmaline test response and genetic testing results in 637 individuals from 482 families who underwent ajmaline testing for SUD or UCA.

Results: Overall, 89 individuals (14%) from 88 families (18%) had a positive ajmaline test result. SCN5A mutations were identified in 9 of 86 ajmaline-positive cases (10%). SCN5A mutation carriers had positive test results at significantly lower ajmaline doses than noncarriers (0.75 [range: 0.64 to 0.98] mg/kg vs. 1.03 [range: 0.95 to 1.14] mg/kg, respectively; p < 0.01). In 7 of 88 families (8%), it was concluded that the positive ajmaline response was a confounder, either in the presence of an alternative genetic diagnosis accounting for UCA/SUD (5 cases) or noncosegregation of positive ajmaline response and arrhythmia (2 cases). The rate of confounding responses was significantly higher in positive ajmaline responses obtained at >1 mg/kg than in those obtained at ≤1 mg/kg (7 of 48 vs. 0 of 41 individuals; Fisher's exact test: p = 0.014).

Conclusions: In line with previous, smaller studies, a positive ajmaline response was observed in a large proportion of UCA/SUD families. Importantly, our data emphasize the potential for confounding possibly false-positive ajmaline responses in this population, particularly at high doses, which could possibly lead to a misdiagnosis. Clinicians should consider all alternative causes in UCA/SUD and avoid ajmaline doses >1 mg/kg.
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http://dx.doi.org/10.1016/j.jacep.2017.04.005DOI Listing
December 2017

SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers.

Int J Cardiol 2018 Sep 30;266:128-132. Epub 2018 Apr 30.

Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Ventricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions (PVCs). Presence of SCN5A mutation increases the risk of PVCs upon exposure to sodium channel blockers (SCB) in patients with baseline type-1 ECG. In patients without baseline type-1 ECG, however, the effect of SCN5A mutation on the risk of SCB-induced arrhythmia is unknown. We aimed to establish whether presence/absence, type, and topology of SCN5A mutation correlates with PVC occurrence during ajmaline infusion.

Methods And Results: We investigated 416 patients without baseline type-1 ECG who underwent ajmaline testing and SCN5A mutation analysis. A SCN5A mutation was identified in 88 patients (S). Ajmaline-induced PVCs occurred more often in patients with non-missense mutations (S) or missense mutations in transmembrane or pore regions of SCN5A-encoded channel protein (S) than patients with missense mutations in intra-/extracellular channel regions (S) and patients without SCN5A mutation (S) (29%, 24%, 9%, and 3%, respectively; P<0.001). The proportion of patients with ajmaline-induced BrS was similar in different mutation groups but lower in S (71% S, 63% S, 70% S, and 34% S; P<0.001). Logistic regression indicated S and S as predictors of ajmaline-induced PVCs.

Conclusions: SCN5A mutation is associated with an increased risk of drug-induced ventricular arrhythmia in patients without baseline type-1 ECG. In particular, S and S are at high risk.
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http://dx.doi.org/10.1016/j.ijcard.2017.09.010DOI Listing
September 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 phenotype is equally important in promoting variants from benign to pathogenic as well as in demoting variants from pathogenic to benign.

Heart Rhythm 2018 04 6;15(4):562-563. Epub 2018 Jan 6.

Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2018.01.007DOI Listing
April 2018

Letter by Amin et al Regarding Article, "Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?"

Circ Cardiovasc Genet 2016 12;9(6):580

Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1161/CIRCGENETICS.116.001629DOI Listing
December 2016

Genetic Control of Potassium Channels.

Card Electrophysiol Clin 2016 06 26;8(2):285-306. Epub 2016 Mar 26.

Department of Clinical and Experimental Cardiology, Heart Centre, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; King Abdulaziz University, Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, PO Box 80200, Jeddah 21589, Kingdom of Saudi Arabia. Electronic address:

Approximately 80 genes in the human genome code for pore-forming subunits of potassium (K(+)) channels. Rare variants (mutations) in K(+) channel-encoding genes may cause heritable arrhythmia syndromes. Not all rare variants in K(+) channel-encoding genes are necessarily disease-causing mutations. Common variants in K(+) channel-encoding genes are increasingly recognized as modifiers of phenotype in heritable arrhythmia syndromes and in the general population. Although difficult, distinguishing pathogenic variants from benign variants is of utmost importance to avoid false designations of genetic variants as disease-causing mutations.
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http://dx.doi.org/10.1016/j.ccep.2016.01.003DOI Listing
June 2016

Prognostic significance of fever-induced Brugada syndrome.

Heart Rhythm 2016 07 23;13(7):1515-20. Epub 2016 Mar 23.

Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. Electronic address:

Background: In Brugada syndrome (BrS), spontaneous type 1 electrocardiogram (ECG) is an established risk marker for fatal arrhythmias whereas drug-induced type 1 ECG shows a relatively benign prognosis. No study has analyzed the prognosis of fever-induced type 1 ECG (F-type1) in a large BrS cohort.

Objectives: The objectives of this study were to assess the prognosis of F-type1 in asymptomatic BrS and to compare the effects of fever and drugs on ECG parameters.

Methods: One hundred twelve patients with BrS who developed F-type1 were retrospectively enrolled. Prognosis was evaluated in 88 asymptomatic patients. In a subgroup (n = 52), ECG parameters of multiple ECGs (at baseline, during fever, and after drug challenge) were analyzed.

Results: Eighty-eight asymptomatic patients had a mean age of 45.8 ± 18.7 years, and 71.6% (67 of 88) were men. Twenty-one percent (18 of 88) had a family history of sudden cardiac death, and 26.4% (14 of 53) carried a pathogenic SCN5A mutation. Drug challenge was positive in 29 of 36 patients tested (80.6%). The risk of ventricular fibrillation in asymptomatic patients was 0.9%/y (3 of 88; 43.6 ± 37.4 months). ST-segment elevation in lead V2 during fever and after drug challenge was not significantly different (0.41 ± 0.21 ms during fever and 0.40 ± 0.30 ms after drug challenge; P > .05). Fever shortened the PR interval compared to baseline, whereas drug challenge resulted in prolonged PR interval and QRS duration (PR interval: 169 ± 29 ms at baseline, 148 ± 45 ms during fever, and 202 ± 35 ms after drug challenge; QRS duration: 97 ± 18 ms at baseline, 92 ± 28 ms during fever, and 117 ± 21 ms after drug challenge).

Conclusion: Patients with BrS who develop F-type1 are at risk of arrhythmic events. F-type1 appears to develop through a more complex mechanism as compared with drug-induced type 1 ECG.
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http://dx.doi.org/10.1016/j.hrthm.2016.03.044DOI Listing
July 2016

Genetic screening in acquired long QT syndrome? CAUTION: proceed carefully.

Eur Heart J 2016 05 30;37(18):1465-8. Epub 2015 Dec 30.

Heart Centre AMC, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia

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http://dx.doi.org/10.1093/eurheartj/ehv620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914884PMC
May 2016

SCN5A-related dilated cardiomyopathy: what do we know?

Authors:
Ahmad S Amin

Heart Rhythm 2014 Aug 29;11(8):1454-5. Epub 2014 May 29.

Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2014.05.031DOI Listing
August 2014

Coronary ectasia and repeated myocardial infarction in a young man.

Int J Cardiol 2014 Feb 7;171(3):e74-5. Epub 2013 Dec 7.

Department of Cardiology, Tergooiziekenhuizen, Blaricum-Hilversum, The Netherlands.

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http://dx.doi.org/10.1016/j.ijcard.2013.11.102DOI Listing
February 2014

Long QT syndrome: beyond the causal mutation.

J Physiol 2013 Sep 10;591(17):4125-39. Epub 2013 Jun 10.

A. A. M. Wilde: Department of Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Congenital long QT syndrome (LQTS) is caused by single autosomal-dominant mutations in a gene encoding for a cardiac ion channel or an accessory ion channel subunit. These single mutations can cause life-threatening arrhythmias and sudden death in heterozygous mutation carriers. This recognition has been the basis for world-wide staggering numbers of subjects and families counselled for LQTS and treated based on finding (putative) disease-causing mutations. However, prophylactic treatment of patients is greatly hampered by the growing awareness that simple carriership of a mutation often fails to predict clinical outcome: many carriers never develop clinically relevant disease while others are severely affected at a young age. It is still largely elusive what determines this large variability in disease severity, where even within one pedigree, an identical mutation can cause life-threatening arrhythmias in some carriers while in other carriers no disease becomes clinically manifested. This suggests that additional factors modify the clinical manifestations of a particular disease-causing mutation. In this article, potential demographic, environmental and genetic factors are reviewed, which, in conjunction with a mutation, may modify the phenotype in LQTS, and thereby determine, at least partially, the large variability in disease severity.
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http://dx.doi.org/10.1113/jphysiol.2013.254920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779107PMC
September 2013

Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community.

Eur Heart J 2013 May 20;34(20):1506-16. Epub 2013 Feb 20.

Heart Failure Research Center, University of Amsterdam, Amsterdam, The Netherlands.

Aims: Non-cardiac drugs that impair cardiac repolarization (electrocardiographic QT prolongation) are associated with an increased sudden cardiac arrest (SCA) risk. Emerging evidence suggests that non-cardiac drugs that impair cardiac depolarization and excitability (electrocardiographic QRS prolongation) also increase the risk for SCA. Nortriptyline, which blocks the SCN5A-encoded cardiac sodium channel, may exemplify such drugs. We aimed to study whether nortriptyline increases the risk for SCA, and to establish the underlying mechanisms.

Methods And Results: We studied QRS durations during rest/exercise in an index patient who experienced ventricular tachycardia during exercise while using nortriptyline, and compared them with those of 55 controls with/without nortriptyline and 24 controls with Brugada syndrome (BrS) without nortriptyline, who carried an SCN5A mutation. We performed molecular-genetic (exon-trapping) and functional (patch-clamp) experiments to unravel the mechanisms of QRS prolongation by nortriptyline and the SCN5A mutation found in the index patient. We conducted a prospective community-based study among 944 victims of ECG-documented SCA and 4354-matched controls to determine the risk for SCA associated with nortriptyline use. Multiple mechanisms may act in concert to increase the risk for SCA during nortriptyline use. Pharmacological (nortriptyline), genetic (loss-of-function SCN5A mutation), and/or functional (sodium channel inactivation at fast heart rates) factors conspire to reduce the cardiac sodium current and increase the risk for SCA. Nortriptyline use in the community was associated with a 4.5-fold increase in the risk for SCA [adjusted OR: 4.5 (95% CI: 1.1-19.5)], particularly when other sodium channel-blocking factors were present.

Conclusions: Nortriptyline increases the risk for SCA in the general population, particularly in the presence of genetic and/or non-genetic factors that decrease cardiac excitability by blocking the cardiac sodium channel.
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http://dx.doi.org/10.1093/eurheartj/eht054DOI Listing
May 2013

Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner.

Eur Heart J 2012 Mar 23;33(6):714-23. Epub 2011 Dec 23.

Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Aims: Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1's 3' untranslated region (3'UTR).

Methods And Results: This study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1's 3'UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1's 3'UTR with the derived SNP variants was lower than the expression of the 3'UTR with the ancestral SNP variants.

Conclusion: Our data indicate that 3'UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.
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http://dx.doi.org/10.1093/eurheartj/ehr473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303714PMC
March 2012

Facilitatory and inhibitory effects of SCN5A mutations on atrial fibrillation in Brugada syndrome.

Europace 2011 Jul 26;13(7):968-75. Epub 2011 Jan 26.

Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Aims: Brugada syndrome (BrS) is associated with increased risk for atrial fibrillation (AFib). However, the role of SCN5A mutations in the occurrence of AFib remains unclear. Cardiac sodium current reduction caused by SCN5A mutations may facilitate AFib by slowing intra-atrial conduction and inducing structural changes, but also prevent it by suppressing atrial ectopic activity. Here, we examined the relation between SCN5A mutations, atrial conduction velocity, atrial structural changes, and atrial ectopic activity in BrS.

Methods And Results: Data from 214 BrS patients [78 with an SCN5A mutation (patients with an SCN5A mutation, BrSSCN5A+) and 136 without an SCN5A mutation (patients without an SCN5A mutation, BrSSCN5A-)] were collected. Intra-atrial conduction velocity was assessed by measuring P-wave durations at baseline and during sodium channel provocation testing. Atrial structural changes were assessed by measuring atrial dimensions using cardiac magnetic resonance imaging. Atrial ectopic activity was assessed by determining the incidence of atrial ectopic beats using 24 h Holter recordings. Clinical characteristics (including AFib occurrence) did not differ between BrSSCN5A+ and BrSSCN5A-. Baseline P-wave durations were longer in BrSSCN5A+ than in BrSSCN5A-, but lengthened markedly in BrSSCN5A- during provocation testing. Atrial dimensions did not differ. Atrial ectopic beats occurred more often in BrSSCN5A-, and the proportion of patients experiencing one or more atrial ectopic beats was larger in BrSSCN5A- than in BrSSCN5A+.

Conclusion: In BrS, the presence of an SCN5A mutation is associated with intra-atrial conduction slowing and suppressed atrial ectopic activity. Intra-atrial conduction slowing may provide a plausible substrate for AFib maintenance, while reduced atrial ectopic activity may constitute inhibition of the trigger for AFib initiation.
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http://dx.doi.org/10.1093/europace/eur011DOI Listing
July 2011

SCN5A mutations in atrial fibrillation.

Heart Rhythm 2010 Dec 17;7(12):1870-1. Epub 2010 Sep 17.

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http://dx.doi.org/10.1016/j.hrthm.2010.09.012DOI Listing
December 2010

Cardiac sodium channelopathies.

Pflugers Arch 2010 Jul 29;460(2):223-37. Epub 2009 Nov 29.

Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Cardiac sodium channel are protein complexes that are expressed in the sarcolemma of cardiomyocytes to carry a large inward depolarizing current (INa) during phase 0 of the cardiac action potential. The importance of INa for normal cardiac electrical activity is reflected by the high incidence of arrhythmias in cardiac sodium channelopathies, i.e., arrhythmogenic diseases in patients with mutations in SCN5A, the gene responsible for the pore-forming ion-conducting alpha-subunit, or in genes that encode the ancillary beta-subunits or regulatory proteins of the cardiac sodium channel. While clinical and genetic studies have laid the foundation for our understanding of cardiac sodium channelopathies by establishing links between arrhythmogenic diseases and mutations in genes that encode various subunits of the cardiac sodium channel, biophysical studies (particularly in heterologous expression systems and transgenic mouse models) have provided insights into the mechanisms by which INa dysfunction causes disease in such channelopathies. It is now recognized that mutations that increase INa delay cardiac repolarization, prolong action potential duration, and cause long QT syndrome, while mutations that reduce INa decrease cardiac excitability, reduce electrical conduction velocity, and induce Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, or combinations thereof. Recently, mutation-induced INa dysfunction was also linked to dilated cardiomyopathy, atrial fibrillation, and sudden infant death syndrome. This review describes the structure and function of the cardiac sodium channel and its various subunits, summarizes major cardiac sodium channelopathies and the current knowledge concerning their genetic background and underlying molecular mechanisms, and discusses recent advances in the discovery of mutation-specific therapies in the management of these channelopathies.
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http://dx.doi.org/10.1007/s00424-009-0761-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883928PMC
July 2010

Cardiac ion channels in health and disease.

Heart Rhythm 2010 Jan 5;7(1):117-26. Epub 2009 Aug 5.

Heart Failure Research Center, University of Amsterdam, Amsterdam, The Netherlands.

Cardiac electrical activity depends on the coordinated propagation of excitatory stimuli through the heart and, as a consequence, the generation of action potentials in individual cardiomyocytes. Action potential formation results from the opening and closing (gating) of ion channels that are expressed within the sarcolemma of cardiomyocytes. Ion channels possess distinct genetic, molecular, pharmacologic, and gating properties and exhibit dissimilar expression levels within different cardiac regions. By gating, ion channels permit ion currents across the sarcolemma, thereby creating the different phases of the action potential (e.g., resting phase, depolarization, repolarization). The importance of ion channels in maintaining normal heart rhythm is reflected by the increased incidence of arrhythmias in inherited diseases that are linked to mutations in genes encoding ion channels or their accessory proteins and in acquired diseases that are associated with changes in ion channel expression levels or gating properties. This review discusses ion channels that contribute to action potential formation in healthy hearts and their role in inherited and acquired diseases.
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http://dx.doi.org/10.1016/j.hrthm.2009.08.005DOI Listing
January 2010

Tubulin polymerization modifies cardiac sodium channel expression and gating.

Cardiovasc Res 2010 Mar 26;85(4):691-700. Epub 2009 Oct 26.

Department of Clinical and Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Aims: Treatment with the anticancer drug taxol (TXL), which polymerizes the cytoskeleton protein tubulin, may evoke cardiac arrhythmias based on reduced human cardiac sodium channel (Na(v)1.5) function. Therefore, we investigated whether enhanced tubulin polymerization by TXL affects Na(v)1.5 function and expression and whether these effects are beta1-subunit-mediated.

Methods And Results: Human embryonic kidney (HEK293) cells, transfected with SCN5A cDNA alone (Na(v)1.5) or together with SCN1B cDNA (Na(v)1.5 + beta1), and neonatal rat cardiomyocytes (NRCs) were incubated in the presence and in the absence of 100 microM TXL. Sodium current (I(Na)) characteristics were studied using patch-clamp techniques. Na(v)1.5 membrane expression was determined by immunocytochemistry and confocal microscopy. Pre-treatment with TXL reduced peak I(Na) amplitude nearly two-fold in both Na(v)1.5 and Na(v)1.5 + beta1, as well as in NRCs, compared with untreated cells. Accordingly, HEK293 cells and NRCs stained with anti-Na(v)1.5 antibody revealed a reduced membrane-labelling intensity in the TXL-treated groups. In addition, TXL accelerated I(Na) decay of Na(v)1.5 + beta1, whereas I(Na) decay of Na(v)1.5 remained unaltered. Finally, TXL reduced the fraction of channels that slow inactivated from 31% to 18%, and increased the time constant of slow inactivation by two-fold in Na(v)1.5. Conversely, slow inactivation properties of Na(v)1.5 + beta1 were unchanged by TXL.

Conclusion: Enhanced tubulin polymerization reduces sarcolemmal Na(v)1.5 expression and I(Na) amplitude in a beta1-subunit-independent fashion and causes I(Na) fast and slow inactivation impairment in a beta1-subunit-dependent way. These changes may underlie conduction-slowing-dependent cardiac arrhythmias under conditions of enhanced tubulin polymerization, e.g. TXL treatment and heart failure.
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http://dx.doi.org/10.1093/cvr/cvp352DOI Listing
March 2010

Exercise-induced ECG changes in Brugada syndrome.

Circ Arrhythm Electrophysiol 2009 Oct 24;2(5):531-9. Epub 2009 Aug 24.

Heart Failure Research Center and Department of Cardiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Background: Ventricular arrhythmia occurrence during exercise is reported in Brugada syndrome (BrS). Accordingly, experimental studies suggest that BrS-linked SCN5A mutations reduce sodium current more at fast heart rates. Yet, the effects of exercise on the BrS ECG phenotype have not been studied. We aimed to assess ECG responses to exercise in BrS and determine whether these responses are affected by the presence of an SCN5A mutation.

Methods And Results: ECGs at baseline, at peak exercise, and during recovery were analyzed from 35 male control subjects, 25 BrS men without SCN5A mutation (BrS(SCN5A)(-)), and 25 BrS men with SCN5A mutation (BrS(SCN5A+); 15 with missense mutation and 10 with mutation leading to premature truncation of the protein). No differences existed in clinical phenotype between BrS groups. At baseline, BrS(SCN5A)(-) and BrS(SCN5A+) patients had lower heart rates, wider QRS, shorter QT(c), and higher peak J-point amplitudes than control subjects; BrS(SCN5A+) patients also had longer PR than BrS(SCN5A)(-) and control subjects. Exercise resulted in PR shortening in all groups, more QRS widening in BrS(SCN5A+) than in BrS(SCN5A)(-) and control subjects(,) and less QT shortening in BrS(SCN5A)(-) and BrS(SCN5A+) than in control subjects. The latter resulted in QT(c) shortening in control subjects but QT(c) prolongation in BrS(SCN5A)(-) and BrS(SCN5A+). Finally, the increase in peak J-point amplitude during exercise was similar in all 3 groups but resulted in a coved-type pattern only in BrS(SCN5A)(-) and BrS(SCN5A+).

Conclusions: Exercise aggravated the ECG phenotype in BrS. The presence of an SCN5A mutation was associated with further conduction slowing at fast heart rates. Possible mechanisms that may explain the observed ECG changes are discussed.
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http://dx.doi.org/10.1161/CIRCEP.109.862441DOI Listing
October 2009