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Heart Rhythm. Author manuscript; available in PMC Mar 1, 2009.
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PMCID: PMC2515863

Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation

Lasse S. Ravn, MD,* Yoshiyasu Aizawa, MD,§ Guido D. Pollevick, PhD,§ Jacob Hofman-Bang, PhD,* Jonathan M. Cordeiro, PhD,§ Ulrik Dixen, PhD, Gorm Jensen, DMSc, Yuesheng Wu, MS,§ Elena Burashnikov, BS,§ Stig Haunso, DMSc, Alejandra Guerchicoff, PhD,§ Dan Hu, MD, PhD,§ Jesper H. Svendsen, DMSc, Michael Christiansen, MD,* and Charles Antzelevitch, PhD, FHRS§



Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of cardiovascular morbidity and mortality. Among the gene defects previously associated with AF is a gain of function of the slowly activating delayed rectifier potassium current IKs, secondary to mutations in KCNQ1. Coexpression of KCNE5, the gene encoding the MiRP4 β-subunit, has been shown to reduce IKs.


The purpose of this study was to test the hypothesis that mutations in KCNE5 are associated with AF in a large cohort of patients with AF.


One-hundred fifty-eight patients with AF were screened for mutations in the coding region of KCNE5.


A missense mutation involving substitution of a phenylalanine for leucine at position 65 (L65F) was identified in one patient. This patient did not have a history of familial AF, and neither KCNQ1 nor KCNE2 mutations were found. Transient transfection of Chinese hamster ovary (CHO) cells expressing IKs (KCNQ1+KCNE1) with KCNE5 suppressed the developing and tail currents of IKs in a concentration-dependent manner. Transient transfection with KCNE5-L65F failed to suppress IKs, yielding a current indistinguishable from that recorded in the absence of KCNE5. Developing currents recorded during a test pulse to +60 mV and tail currents recorded upon repolarization to -40 mV both showed a significant concentration-dependent gain of function in IKs with expression of KCNE5-L65F vs KCNE5-WT.


The results of this study suggest that a missense mutation in KCNE5 may be associated with nonfamilial or acquired forms of AF. The arrhythmogenic mechanism most likely is a gain of function of IKs.

Keywords: Electrophysiology, Arrhythmias, Genetics, Delayed rectifier potassium current


Atrial fibrillation (AF) is the most common form of clinical arrhythmia, affecting more than 5% of the population older than 65 years. The incidence of AF has increased progressively over the past 20 years.1,2 In approximately 12% of patients with AF, no concomitant disease is observed (“lone AF”). AF is a potentially serious disease due to thromboembolic complications3 and heart failure.4

AF has long been known to cluster in families,5 and a nationwide Icelandic study has shown strong heritability of the disease.6 The Framingham Heart Study revealed that parental AF is a risk factor for AF in offspring.7 Interestingly, maternal AF confers a higher risk to though AF is more prevalent among the male participants in the Framingham study.7

Genetic linkage analyses have identified AF loci on chromosome 10q22-24,8 chromosome 6q14-16,9 5p13,10 and 11p15.5.11 In the case of 11p15.5, the genetic defect was identified and found to involve heterozygous missense mutations in KCNQ1, resulting in gain of function of the KCNQ1-KCNE1 and KCNQ1-KCNE2 ion channels conducting the slowly activating delayed rectifier current IKs.11 Using a candidate gene approach, gain-of-function mutations in KCNE212 and KCNJ2,13 coding for the ion channel conducting the inward rectifier potassium current IK1, have been found associated with familial AF in two Chinese kindreds. However, despite identification of other KCNQ1 mutations associated with AF,14 the prevalence of KCNQ1 mutations probably is low,15 in accordance with the finding that AF is genetically heterogeneous.5 Studies have also associated GJA5 and KCNA5 with human AF.16,17 KCNA5 encodes the α-subunit of the Kv1.5 channel responsible for IKur, whereas GJA5 encodes the gap junctional protein connexin40. Olson et al16 identified loss of function of Kv1.5 channels due to a mutation in KCNA5 as a cause of AF. Interestingly, Gollob et al17 reported that somatic mutations in GJA5 predispose patients to idiopathic AF by impairing gap junction assembly.

The KCNE proteins KCNE1-KCNE5 constitute a homologous group of regulators of voltage-gated (Kv) potassium channels, and several are involved in cardiac arrhythmia.18 Thus, mutations in KCNE1 may cause Jervell and Lange-Nielsen disease,19 and mutations in KCNE2, coding for minK-related peptide 1 (MiRP1), have been associated with drug-induced arrhythmia,20,21 long QT syndrome (loss-of-function phenotype),22 and AF (gain-of-function phenotype).12 A controversial relationship exists between hypokalemic paralysis and a mutation/polymorphism in KCNE3.23,24 The KCNE proteins are single polypeptide chains of 100 to 200 amino acids. They contain an extracellular N-terminus, a single putative transmembrane segment, and an intracellular C-terminus.18 They modify the function of the different repolarizing K+ channels.18,25,26 Thus, the KCNE1 protein minK confers the characteristic slow activation of IKs.25 The interaction between individual KCNE proteins and K+ ion channel α-subunits is not specific.10 Thus, minK interacts with both KCNQ1 and HERG, and KCNE1-3 proteins interact with Kv3.1 and Kv3.2 causing diversification of channel gating.26 Other channels also interact with KCNE proteins, but the functional significance of such interactions in vivo has not been clarified.18 All KCNE genes are expressed in the heart but at varying levels20,23,27 and, for KCNE1 and KCNE3, with several splice transcripts.27 The balance between different KCNE proteins with varying effects on Kv channels may enable variable modulation of IKs and other K+ currents.28

KCNE5 is expressed in both right and left atria and ventricles.27,28 The relative amount of KCNE5 mRNA is thought to be greater than that of KCNE2.28 The KCNE5 gene product29 MiRP4 suppresses the IKs current in heterologous systems and is suggested to function as a down-regulating β-subunit to the KCNQ1 α-subunit in competition with the stimulating KCNE1 β-subunit.30 This action of KCNE5 suggests that it may be a candidate gene for AF. We examined this hypothesis by screening a cohort of AF patients for mutations in the coding region of KCNE5.

The familial form of AF is relatively uncommon, accounting for 5% of all cases of AF and up to 15% of cases of lone AF.5 The majority of cases of AF are acquired and related to structural abnormalities. However, not all individuals with the same cardiac pathology develop AF, suggesting that genetic factors predispose to the development of acquired AF.31 Little is known about the genetic predisposition to acquired AF. This report presents evidence in support of this hypothesis.

Materials and methods


The study consisted of 158 patients from the Copenhagen SAFIR (Signal Averaged ECG as a prognostic factor in atrial FIbRillation) investigation.32 Patients were recruited at the 3-year follow-up of an initial group of 244 patients (20 had died and 66 did not want to participate) with ECG-documented AF who, at the time of inclusion, were in sinus rhythm by spontaneous, pharmacologic, or electrical cardioversion. Demographic and clinical data of the patients are given in Table 1.

Table 1
Demographic and clinical characteristics of the 158 patients with atrial fibrillation


The mRNA and protein sequences of the intronless human KCNE5 (accession number NM012282), KCNE1 (NM000219), KCNE2 (NM172201), KCNE3 (NM005472), and KCNE4 (NM080671) genes, the mouse KCNE5 gene (NM021487), and the Xenopus laevis KCNE5.1 gene (AF545502) were obtained from the NCBI Entrez Nucleotide database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi).

KCNE5 protein sequences were retrieved by basic local alignment search tool (BLAST) searching the genomes via http://www.ncbi.nlm.nih.gov/Genomes/ against the human KCNE5 mRNA sequence. The open reading frame was located, translated to protein, and aligned with the clustalW algorithm using DNASTAR software (DNASTAR, Inc, Madison, WI) and parameters—gap penalty: 10, gap length penalty: 0.2, delay divergent sequences: 30, protein weight matrix: Gonnet series. Visualization of the alignment was performed using BIOEDIT software (http://www.mbio.ncsu.edu/BioEdit/bioedit.html). KCNE1-4 protein sequences were retrieved via http://genome.ucsc.edu/cgi-bin/hgGateway.


Collection of clinical data and analysis of samples was approved by the ethics committees of Copenhagen and Frederiksberg counties (KF01-147/02).

Mutation screening

Mutation screening was performed as described previously.33 Briefly, genomic DNA was extracted using QIAamp DNA Blood Mini Kit (QIAGEN, Hilden, Germany). Polymerase chain reaction (PCR) was used to amplify the DNA fragment corresponding to the single exon of the gene. Reactions containing 50 ng genomic DNA and 10 pmol of the appropriate primers were prepared and underwent PCR through 33 cycles at an annealing temperature of 60°C. The PCR product was cleaved by incubating overnight with BstEII in order to obtain two fragments of an appropriate size. Single-strand conformation polymorphism (SSCP) electrophoresis of the fragments was performed using GeneGel Excel 12.5/24 kits (Amersham Biosciences AB, Uppsala, Sweden). Aberrant conformers were directly sequenced on a 3100-Avant Genetic analyzer (Applied Biosystems, Foster City, CA, USA) using big dye chemistry. Mutation screening of KCNQ1 and KCNE2 was performed as described previously.34,35

Wild-type and mutant KCNE5 constructs

The complete coding region of KCNE5 was amplified from both patient and control human genomic DNA using PCR. The following primers were designed from KCNE5 GenBank sequence (accession number: BC035330): forward: 5′-GGAAGATCT GCTAGCGCCG-CCATGAACTGCAGCGAGAGCCAGC-3′ and reverse 5′-CCGCTCGAGGGATCCTTAGACCCGCT CAGCGCCCTGG-3 having additional 5′ sequences specifying NheI/BglII or XhoI/BamHI restriction sites used for cloning. Each gene was amplified beginning at the respective ATG start codon and included a modified translation initiation sequence (GCCGCCATG). KCNE5 PCR products from wild-type (WT) and mutant (L65F) were subcloned into the NheI (5′) and BamHI (3′) sites of the plasmid pIRES2-AcGFP1 or pIRES2-DsRed-Express (BD Biosciences-Clontech, Mountain View, CA, USA), sequenced in their entirety, and the mutation confirmed. High-quality plasmid DNA for transfections was prepared using a QIAGEN Plasmid Maxi Kit (QIAGEN, Valencia, CA, USA).

Cell culture and transient transfection

A Chinese hamster ovary (CHO) cell line stably expressing IKs (KCNQ1+KCNE1 cDNAs in a bicistronic vector; kind gift of Dr. Alfred L. George, Vanderbilt University) was cultured in F-12 nutrient mixture (Ham) medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum and penicillin (100 units/mL)-streptomycin (100 μg/mL), and 600 μg/mL hygromycin in a humidified 5% CO2 incubator at 37°C. Cultured cells were seeded in 35-mm dishes 1 day before transfection and transiently transfected with various plasmids by FuGENE6 lipid-based transfection reagent (Roche, Basel, Switzerland). In the electrophysiologic experiments, 1.5, 0.75, 0.3, or 0.15 μg of WT KCNE5 and 1.5, 0.75, or 0.3 μg of mutant KCNE5 was transfected into IKs/CHO cells. Cells displaying green fluorescence 24 to 48 hours after transfection were studied electrophysiologically.

To visualize CHO cells expressing green fluorescent protein, cells were excited at 480 nm using a 100-W mercury bulb, and fluorescence emission was detected using a 520-nm band-pass filter. To visualize cells expressing red fluorescent protein, cells were excited at 540 nm, and the fluorescence emission was detected using a 605-nm band-pass filter.

Electrophysiologic recordings

To investigate the effects of the L65F mutation on channel function, we performed whole-cell patch clamp experiments on IKs/CHO cells transfected with WT or mutant KCNE5 channels. Briefly, cells were placed in a perfusion chamber (PDMI-2, Medical Systems Corp., Greenvale, NY, USA), mounted on the stage of an inverted microscope with epi-fluorescence capabilities (TE2000, Nikon, EL Segundo, CA, USA). Cells were superfused with normal external solution of the following composition (in mmol/L): 132 NaCl, 4.8 KCl, 2 CaCl2, 1.2 MgCl2, 5 glucose, and 10 HEPES-Na (pH 7.4 adjusted with NaOH). Patch pipettes were fabricated from borosilicate glass capillaries (1.5-mm outer diameter; Fisher Scientific, Pittsburgh, PA, USA). The pipettes were pulled using a gravity puller (Narishige Corp., Greenvale, NY, USA) and filled with pipette solution of the following composition (in mmol/L): 110 aspartic acid, 5 ATP-K2, 11 EGTA, 5 HEPES, and 1 MgCl2 (pH 7.35 adjusted with KOH). Pipette resistance ranged from 1 to 4 MΩ when filled with the internal solution.

After a gigaseal was formed, the cell membrane was ruptured by applying negative pressure. Current signals were recorded using an Axopatch 200A amplifier (Axon Instruments, Foster City, CA, USA), and series resistance errors were reduced by approximately 60% to 70% with electronic compensation. All signals were acquired at 0.5 to 5 kHz (Digidata 1322, Axon Instruments) with a microcomputer running Clampex 9 software (Axon Instruments) and filtered at 5 kHz with a four-pole Bessel low-pass filter. Membrane currents were analyzed with Clampfit 9 software (Axon Instruments). Peak developing current (measured at the end of the depolarizing test pulse) and peak tail current (measured immediately following repolarization to -40 mV) were quantitated.

Data analysis

Results are expressed as mean ± SEM. Difference between groups were tested by one-way analysis of variance, followed by Scheffe modified F-test for multiple comparisons. P <.05 was considered significant.


Mutation screening

Aberrant conformers were found on SSCP analysis for mutations in KCNE5 in one patient, a 66-year-old woman with persistent AF but no family history. DNA sequencing revealed a heterozygous substitution of T for C in nucleotide 193 predicting substitution of phenylalanine (TTC) for leucine (CTC) in codon 65 (L65F; Figure 1A and B). The mutation is located in a highly conserved transmembrane domain of the protein. Table 2 shows an alignment of the three known KCNE5 homologues in humans, monkey, dog, cattle, mouse, chicken, and frog as well as the other human KCNE proteins. The L-to-F substitution changes the residue from the one conserved in the different KCNE5 proteins to the F residue specific for KCNE3. The mutation was not found in 200 normal random controls, and it was not registered as a Caucasian variant in PharmGKB (www.pharmgkb.com). No mutations were found in KCNQ1 or KCNE2.

Figure 1
Mutation screening of KCNE5. A: DNA sequence chromatogram showing the wild type (WT) and the corresponding amino acid sequence. B: DNA sequence chromatogram showing the heterozygous mutation (in bold) and the corresponding amino acid sequence. A heterozygous ...
Table 2
Alignment of amino acid sequence of KCNE5 in various species and comparison with human KCNE1-4

The family of the proband was small, and both parents were dead. None of the first-degree relatives had AF. The family had no history of sudden death or sudden infant death syndrome. The patient, who was 66 years old at the time of evaluation, had a history of AF, first documented at age 59 years. The ECG of the proband recorded during sinus rhythm showed normal PR and QT intervals and no signs of hypertrophy (Figure 1C). The patient had ischemic heart disease and mild hypertension, with a blood pressure of 155/85 mmHg at the time of presentation. Echocardiography revealed a normal left ventricular ejection fraction and a slightly dilated left atrium, with a left atrial diameter of 44 mm. The patient was treated with a statin, aspirin, diuretics, sotalol, and an angiotensin-converting enzyme inhibitor.

Electrophysiologic impact of WT and mutant KCNE5 on IKs currents

Patch clamp experiments were conducted on cells transiently transfected with WT or mutant KCNE5. IKs/CHO cells exhibited slowly activating outward current compatible with IKs recorded in native cardiac myocytes (Figure 2A). Transient transfection with increasing amounts of KCNE5 resulted in marked suppression of IKs (Figure 2B-D).

Figure 2
Representative current trace recorded from IKs/CHO cells transiently transfected with KCNE5-WT. A: Current from stable cell line of IKs/CHO. B: Current from IKs/CHO transfected with 0.15 μg KCNE5-WT. C: Current from IKs/CHO transfected with 0.3 ...

Figure 3 shows the summarized current-voltage relation for IKs in the absence and presence of various amounts of KCNE5. Addition of KCNE5 suppressed both developing (Figure 3A) and tail (Figure 3B) currents. At a voltage of +60 mV, the amplitude of the peak developing (Figure 3C) and tail currents (Figure 3D) in the cells transiently transfected with 0.15, 0.3 and 1.5 μg KCNE5-WT were significantly reduced in a concentration-dependent manner.

Figure 3
Current-voltage relationship of developing and tail currents in the absence and presence of 0.15 to 1.5 μg KCNE5-WT. A: Current-voltage relationship of peak developing current. B: Current-voltage relationship of tail current measured upon repolarization ...

Transient transfection with the KCNE5-L65F mutant gene failed to suppress the current, yielding an IKs current indistinguishable from that recorded in the absence of KCNE5 (Figure 4A and B). Figure 4C and D shows the average current-voltage relation for the effect of KCNE5-L65F mutant on IKs. Cells transfected with KCNE5-L65F showed significantly larger developing (Figure 4C) and tail (Figure 4D) currents relative to cells transfected with KCNE5-WT.

Figure 4
Current-voltage relationship of developing and tail currents in the absence and presence of 1.5 μg KCNE5-WT or KCNE5-L65F. A: Representative current trace of IKs/CHO cells transfected with 1.5 μg WT KCNE5. B: Representative current trace ...

The effects of 0.3 and 1.5 μg KCNE5-WT or KCNE5-L65F on IKs recorded at +60 mV are summarized in Figure 5. Suppression of IKs developing and tail currents by 1.5 μg KCNE5-WT was not observed with the mutant (1.5 μg KCNE5-L65F). At the lower concentration of KCNE5, suppression of developing and tail currents tended to be smaller. A statistically significant gain of function was observed at both concentrations of the β-subunit when current recorded after transfection with the KCNE5 mutant was compared to WT.

Figure 5
Effect of 0.3 and 1.5 μg KCNE5-WT or KCNE5-L65F on IKs. A: Bar graph showing density of peak developing current recorded during a test pulse to +60 mV. B: Bar graph showing density of tail currents recorded during repolarization to -40 mV following ...

The effects of equal amounts of KCNE5-WT and KCNE5-L65F on IKs were determined next. IKs/CHO cells were cotransfected with either 0.75 μg KCNE5-WT and KCNE5-L65F (Figure 6A) or 1.5 μg KCNE5-WT and KCNE5-L65F (Figure 6B). No suppression of IKs developing or tail currents by KCNE5-WT in the presence of the KCNE5-L65F mutation was observed, indicating a dominant positive effect of the mutant. Similar results were obtained when either 0.75 μg or 1.5 μg KCNE5-WT and KCNE5-L65F were cotransfected (Figure 6E and F).

Figure 6
Current-voltage relationship of developing and tail currents in cells cotransfected with equal amounts of KCNE5-WT and KCNE5-L65F. A: Representative current trace of IKs/CHO cells transfected with 0.75 μg WT KCNE5 and 0.75 μg L65F KCNE5. ...


This is the first demonstration of a mutation in KCNE5 associated with AF. Thus, KCNE5 is the 10th AF gene identified following KCNE1 in 2002,36 KCNQ1 and ANK2 in 2003,11,37 KCNH2 and KNCE2 in 2004,12,38,39 KCNJ2 in 2005,13 and KCNA516 and GJA5 in 2006,17 and ABCC9 in 2007.40 In contrast to some of the genes for which mutations were found in three large kindreds,11-13 our mutation in KCNE5 was found in one of 158 patients attending a cardiology clinic. There was no selection for familial occurrence of AF and no family history in the index family. Our findings suggest that KCNE5 mutations are a relatively rare cause (<1%) of sporadic AF. Of note, a polymorphism (97C) in KCNE533 has been associated with increased propensity for AF.36,41

Functional analysis of the L65F mutant demonstrates concentration-dependent suppression of IKs by KCNE5-WT, consistent with previously published results,28,30,42 and reversal of this suppression by the L65F mutation in KCNE5. Thus, the L65F missense mutation in KCNE5 produces an important gain of function in IKs (or KCNQ1+KCNE1+KCNE5 current).

A gain of function in IKs secondary to a KCNE1 deletion in mice43 or KCNQ1 mutation in humans11,14,15 has been associated with the development of AF. Our results suggest that a gain of function in IKs secondary to a missense mutation in KCNE5 likely contributes to the manifestation of AF in our patient. Of interest is that the expected gain of function in IKs was not accompanied by an abbreviation of QTc in our patient. This apparent discrepancy may be explained by much higher expression of KCNE5 in atria than in ventricles demonstrated by Lundquist et al.28 Accordingly, a loss-of-function mutation in KCNE5 would be expected to cause a much greater change in IKs in atria than in ventricles and thus produce little, if any change, in QTc.

The alignment in Table 2 shows that the L65F mutation is located in the transmembrane region known to be decisive for proper function.27,28 When a phylogenetic tree was constructed based on the sequences shown in Table 2 (data not shown), KCNE3 and KCNE5 were seen to more closely related than the other genes, so we used available knowledge on the KCNE3 structure-function relationship to model the tentative functional consequences of the L65F mutation. Using a series of chimeras of KCNE1 and KCNE3,44,45 it has been possible to define the particular gating characteristics of KCNE3. Based on this structural modeling, a mutation in which a small aliphatic amino acid (Leu) is substituted by a large hydrophobic amino acid (Phe) is expected to interfere with function. The suggested role of the KCNE5 subunit under physiologically relevant conditions is suppression of IKs via a positive shift of KCNQ1 activation by >140 mV so that only strong and sustained voltage depolarizations activate the channel.30 Therefore, a mutation in KCNE5 can result in a gain of function of KCNQ1. The abbreviated refractoriness that develops as a consequence can render the myocardium more vulnerable to the development of reentrant tachyarrhythmias. Interestingly, coexpression of WT and mutant KCNE5 demonstrated a dominant-positive effect as suppression of IKs current by WT KCNE5 was eliminated in the presence of the mutant KCNE5.

Study limitations

The results of this study suggest that a gain of function of IKs produced by the L65F mutation in KCNE5 is associated with AF. However, translation of these findings to the clinic must be approached with caution. Although we evaluated the modulatory effect of KCNE5 over a wide range of concentrations, the amount of KNCE5 used in our expression studies may not accurately reflect the amount present in the human heart. The precise stoichiometry of KCNQ1/KCNE1 and KCNE5 subunits present in the human heart is not clearly defined. Bendahhou et al42 reported that KCNE5 mRNA was virtually absent in human left atrial tissue. In contrast, Lundquist et al28 found that KCNE5 expression levels were comparable to both KCNE1a and KCNE1b expression levels in human left atrium. Although our results suggest that the L65F mutation contributes to AF in this setting, a definitive mechanistic link cannot be made because only a single patient with this mutation was identified.

It can be argued that at age 66 years, our patient might be better categorized as a case of acquired AF, as blood pressure was mildly elevated and this trait has been shown to be associated with development of AF. Of note, all patients with high blood pressure develop AF; the majority remain in sinus rhythm. Although it is possible that individuals who do not develop the arrhythmia are genetically protected, it is equally probable that those who develop AF are genetically predisposed. Thus, genetics may play a role in older individuals with one or more acquired risk factors. The degree to which “environmental” or acquired risk factors vs genetic factors contributes to the development of arrhythmia ultimately will distinguish between what we term acquired vs familial or congenital AF. Our results suggest that, in the case of our patient, who was identified in a study population of nonselected patients consecutively recruited based on presentation with AF, a genetic predisposition likely contributes to the clinical phenotype.

KCNE5 has been reported to modulate the function of Kv4.3.46 It is possible that the L65F mutant contributes other changes to the balance of current responsible for the characteristics of repolarization of the atrial action potential via its interaction with Kv4.3 or other channels. Additional studies are required to address this issue.


The data from this study suggest that AF in this patient is associated with L65F mutation. Whether the mutation merely functions as a predisposing factor or as an initiator can only be addressed with larger studies involving selected patients with hereditary AF as well as a larger population of unselected AF patients. Our data provide support for the hypothesis that a genetic defect in an auxiliary subunit composing the IKs channel is associated with AF, which potentially could lead to new therapeutic strategies.


We thank Ryan Pfeiffer and Jette Rasmussen for excellent technical assistance.

Supported by Grant HL47678 from the National Heart, Lung, and Blood Institute to Dr. Antzelevitch; the American Health Assistance Foundation to Dr. Cordeiro; the NYS, Florida Grand Lodges F.&A.M, The John and Birthe Meyer Foundation to Drs. Haunso and Christiansen; and The Danish National Research Foundation Centre for Cardiac Arrhythmia and The Danish Cardiovascular Research Academy to Dr. Ravn.


The first two authors contributed equally to this study.


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