Publications by authors named "Paul G A Volders"

72 Publications

Familial Evaluation in Idiopathic Ventricular Fibrillation: Diagnostic Yield and Significance of J Wave Syndromes.

Circ Arrhythm Electrophysiol 2021 Mar 7;14(3):e009089. Epub 2021 Feb 7.

Cardiovascular Clinical Academic Group, Molecular & Clinical Sciences Rsrch Inst, St. George's, University of London and St. George's University Hospitals NHS Foundation Trust, London, United Kingdom (B.E., C.S., E.R.B.).

[Figure: see text].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.120.009089DOI Listing
March 2021

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

Authors:
Roddy Walsh Najim Lahrouchi Rafik Tadros Florence Kyndt Charlotte Glinge Pieter G Postema Ahmad S Amin Eline A Nannenberg James S Ware Nicola Whiffin Francesco Mazzarotto Doris Škorić-Milosavljević Christian Krijger Elena Arbelo Dominique Babuty Hector Barajas-Martinez Britt M Beckmann Stéphane Bézieau J Martijn Bos Jeroen Breckpot Oscar Campuzano Silvia Castelletti Candan Celen Sebastian Clauss Anniek Corveleyn Lia Crotti Federica Dagradi Carlo de Asmundis Isabelle Denjoy Sven Dittmann Patrick T Ellinor Cristina Gil Ortuño Carla Giustetto Jean-Baptiste Gourraud Daisuke Hazeki Minoru Horie Taisuke Ishikawa Hideki Itoh Yoshiaki Kaneko Jørgen K Kanters Hiroki Kimoto Maria-Christina Kotta Ingrid P C Krapels Masahiko Kurabayashi Julieta Lazarte Antoine Leenhardt Bart L Loeys Catarina Lundin Takeru Makiyama Jacques Mansourati Raphaël P Martins Andrea Mazzanti Stellan Mörner Carlo Napolitano Kimie Ohkubo Michael Papadakis Boris Rudic Maria Sabater Molina Frédéric Sacher Hatice Sahin Georgia Sarquella-Brugada Regina Sebastiano Sanjay Sharma Mary N Sheppard Keiko Shimamoto M Benjamin Shoemaker Birgit Stallmeyer Johannes Steinfurt Yuji Tanaka David J Tester Keisuke Usuda Paul A van der Zwaag Sonia Van Dooren Lut Van Laer Annika Winbo Bo G Winkel Kenichiro Yamagata Sven Zumhagen Paul G A Volders Steven A Lubitz Charles Antzelevitch Pyotr G Platonov Katja E Odening Dan M Roden Jason D Roberts Jonathan R Skinner Jacob Tfelt-Hansen Maarten P van den Berg Morten S Olesen Pier D Lambiase Martin Borggrefe Kenshi Hayashi Annika Rydberg Tadashi Nakajima Masao Yoshinaga Johan B Saenen Stefan Kääb Pedro Brugada Tomas Robyns Daniela F Giachino Michael J Ackerman Ramon Brugada Josep Brugada Juan R Gimeno Can Hasdemir Pascale Guicheney Silvia G Priori Eric Schulze-Bahr Naomasa Makita Peter J Schwartz Wataru Shimizu Takeshi Aiba Jean-Jacques Schott Richard Redon Seiko Ohno Vincent Probst Elijah R Behr Julien Barc Connie R Bezzina

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

Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Dr Hein Wellens MD PhD.

Eur Heart J 2020 08;41(30):2832-2834

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehaa615DOI Listing
August 2020

Repolarization instability and arrhythmia by IKr block in single human-induced pluripotent stem cell-derived cardiomyocytes and 2D monolayers.

Europace 2020 09;22(9):1431-1441

Department of Cardiology, CARIM, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

Aims: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have proven valuable for studies in drug discovery and safety, although limitations regarding their structural and electrophysiological characteristics persist. In this study, we investigated the electrophysiological properties of Pluricyte® CMs, a commercially available hiPSC-CMs line with a ventricular phenotype, and assessed arrhythmia incidence by IKr block at the single-cell and 2D monolayer level.

Methods And Results: Action potentials were measured at different pacing frequencies, using dynamic clamp. Through voltage-clamp experiments, we determined the properties of INa, IKr, and ICaL. Intracellular Ca2+ measurements included Ca2+-transients at baseline and during caffeine perfusion. Effects of IKr block were assessed in single hiPSC-CMs and 2D monolayers (multi-electrode arrays). Action-potential duration (APD) and its rate dependence in Pluricyte® CMs were comparable to those reported for native human CMs. INa, IKr, and ICaL revealed amplitudes, kinetics, and voltage dependence of activation/inactivation similar to other hiPSC-CM lines and, to some extent, to native CMs. Near-physiological Ca2+-induced Ca2+ release, response to caffeine and excitation-contraction coupling gain characterized the cellular Ca2+-handling. Dofetilide prolonged the APD and field-potential duration, and induced early afterdepolarizations. Beat-to-beat variability of repolarization duration increased significantly before the first arrhythmic events in single Pluricyte® CMs and 2D monolayers, and predicted pending arrhythmias better than action-potential prolongation.

Conclusion: Taking their ion-current characteristics and Ca2+ handling into account, Pluricyte® CMs are suitable for in vitro studies on action potentials and field potentials. Beat-to-beat variability of repolarization duration proved useful to evaluate the dynamics of repolarization instability and demonstrated its significance as proarrhythmic marker in hiPSC-CMs during IKr block.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euaa111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478319PMC
September 2020

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses.

J Mol Cell Cardiol 2020 09 22;146:69-83. Epub 2020 Jul 22.

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

Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular- and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models: reduced I, I, I, I and I, dual effects on I and I (inhibition at low and augmentation at high concentrations), and increased I and SR Ca leak. Multiscale simulations in the absence or presence of preexistent atrial fibrillation or heart-failure-related remodeling demonstrated that low ethanol concentrations prolonged atrial action-potential duration (APD) without effects on ventricular APD. Conversely, high ethanol concentrations abbreviated atrial APD and prolonged ventricular APD. High ethanol concentrations promoted reentry in tissue simulations, but the extent of reentry promotion was dependent on the presence of altered intercellular coupling, and the degree, type, and pattern of fibrosis. Taken together, these data provide novel mechanistic insight into the potential proarrhythmic interactions between a preexisting substrate and acute changes in cardiac electrophysiology. In particular, acute ethanol exposure has concentration-dependent electrophysiological effects that differ between atria and ventricles, and between healthy and diseased hearts. Low concentrations of ethanol can have anti-fibrillatory effects in atria, whereas high concentrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2020.07.007DOI Listing
September 2020

INSPIRE: A European training network to foster research and training in cardiovascular safety pharmacology.

J Pharmacol Toxicol Methods 2020 Sep 18;105:106889. Epub 2020 Jun 18.

UCB Biopharma SRL, Early Solutions, Development Science, Non-Clinical Safety Evaluation, Braine-l'Alleud, Belgium.

Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vascn.2020.106889DOI Listing
September 2020

Haloperidol and sudden death in first acute myocardial infarction.

Int J Cardiol Heart Vasc 2020 Feb 13;26:100482. Epub 2020 Feb 13.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2020.100482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046527PMC
February 2020

Incidence and predictors of implantable cardioverter-defibrillator therapy and its complications in idiopathic ventricular fibrillation patients.

Europace 2019 Oct;21(10):1519-1526

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Aims: Idiopathic ventricular fibrillation (IVF) is a rare cause of sudden cardiac arrest. Implantable cardioverter-defibrillator (ICD) implantation is currently the only treatment option. Limited data are available on the prevalence and complications of ICD therapy in these patients. We sought to investigate ICD therapy and its complications in patients with IVF.

Methods And Results: Patients were selected from a national registry of IVF patients. Patients in whom no underlying diagnosis was found during follow-up were eligible for inclusion. Recurrence of ventricular arrhythmia (VA) was derived from medical and ICD records, electrogram records of ICD therapies were used to differentiate between appropriate or inappropriate interventions. Independent predictors for appropriate ICD shock were calculated using cox regression. In 217 IVF patients, recurrence of sustained VAs occurred in 66 patients (30%) during a median follow-up period of 6.1 years. Ten patients died (4.6%). Thirty-eight patients (17.5%) experienced inappropriate ICD therapy, and 32 patients (14.7%) had device-related complications. Symptoms before cardiac arrest [hazard ratio (HR): 2.51, 95% confidence interval (CI): 1.48-4.24], signs of conduction disease (HR: 2.27, 95% CI: 1.15-4.47), and carrier of the DPP6 risk haplotype (HR: 3.24, 1.70-6.17) were identified as independent predictors of appropriate shock occurrence.

Conclusion: Implantable cardioverter-defibrillator therapy is an effective treatment in IVF, treating recurrences of potentially lethal VAs in approximately one-third of patients during long-term follow-up. However, device-related complications and inappropriate shocks were also frequent. We found significant predictors for appropriate ICD therapy. This may imply that these patients require additional management to prevent recurrent events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euz151DOI Listing
October 2019

To the Editor- Interpretation of electrograms is key to understand the clinical potential of ECGI.

Heart Rhythm 2019 06 27;16(6):e51-e52. Epub 2019 Feb 27.

Department of Cardiology, Maastricht University, Maastricht, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2019.02.030DOI Listing
June 2019

Proarrhythmic proclivity of left-stellate ganglion stimulation in a canine model of drug-induced long-QT syndrome type 1.

Int J Cardiol 2019 07 31;286:66-72. Epub 2019 Jan 31.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands. Electronic address:

Background: Left-stellate ganglion stimulation (LSGS) can modify regional dispersion of ventricular refractoriness, promote triggered activity, and reduce the threshold for ventricular fibrillation (VF). Sympathetic hyperactivity precipitates torsades de pointes (TdP) and VF in susceptible patients with long-QT syndrome type 1 (LQT1). We investigated the electromechanical effects of LSGS in a canine model of drug-induced LQT1, gaining novel arrhythmogenic insights.

Methods: In nine mongrel dogs, the left and right stellate ganglia were exposed for electrical stimulation. ECG, left- and right-ventricular endocardial monophasic action potentials (MAPs) and pressures (LVP, RVP) were recorded. The electromechanical window (EMW; Q to LVP at 90% relaxation minus QT interval) was calculated. LQT1 was mimicked by infusion of the KCNQ1/I blocker HMR1556.

Results: At baseline, LSGS and right-stellate ganglion stimulation (RSGS) caused similar heart-rate acceleration and QT shortening. Positive inotropic and lusitropic effects were more pronounced under LSGS than RSGS. I blockade prolonged QTc, triggered MAP-early afterdepolarizations (EADs) and rendered the EMW negative, but no ventricular tachyarrhythmias occurred. Superimposed LSGS exaggerated EMW negativity and evoked TdP in 5/9 dogs within 30 s. Preceding extrasystoles originated mostly from the outflow-tracts region. TdP deteriorated into therapy-refractory VF in 4/5 animals. RSGS did not provoke TdP/VF.

Conclusions: In this model of drug-induced LQT1, LSGS readily induced TdP and VF during repolarization prolongation and MAP-EAD generation, but only if EMW turned from positive to very negative. We postulate that altered mechano-electric coupling can exaggerate regional dispersion of refractoriness and facilitates ventricular ectopy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2019.01.098DOI Listing
July 2019

Integration of cardiac magnetic resonance imaging, electrocardiographic imaging, and coronary venous computed tomography angiography for guidance of left ventricular lead positioning.

Europace 2019 Apr;21(4):626-635

Department of Cardiology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.

Aims: An appropriate left ventricular (LV) lead position is a pre-requisite for response to cardiac resynchronization therapy (CRT) and is highly patient-specific. The purpose of this study was to develop a non-invasive pre-procedural CRT-roadmap to guide LV lead placement to a coronary vein in late-activated myocardium remote from scar.

Methods And Results: Sixteen CRT candidates were prospectively included. Electrocardiographic imaging (ECGI), computed tomography angiography (CTA), and delayed enhancement cardiac magnetic resonance imaging (DE-CMR) were integrated into a 3D cardiac model (CRT-roadmap) using anatomic landmarks from CTA and DE-CMR. Electrocardiographic imaging was performed using 184 electrodes and a CT-based heart-torso geometry. Coronary venous anatomy was visualized using a designated CTA protocol. Focal scar was assessed from DE-CMR. Cardiac resynchronization therapy-roadmaps were constructed for all 16 patients [left bundle branch block: n = 6; intraventricular conduction disturbance: n = 8; narrow-QRS (ablate and pace strategy); n = 1; right bundle branch block: n = 1]. The number of coronary veins ranged between 3 and 4 per patient. The CRT-roadmaps showed no (n = 5), 1 (n = 6), or 2 (n = 5) veins per patient located outside scar in late-activated myocardium [≥50% QRS duration (QRSd)]. Final LV lead position was outside scar in late-activated myocardium in 11 out of 14 implanted patients, while a LV lead in scar was unavoidable in the remaining three patients.

Conclusion: A non-invasive pre-implantation CRT-roadmap was feasible to develop in a case series by integration of coronary venous anatomy, myocardial-scar localization, and epicardial electrical activation patterns, anticipating on clinically relevant features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euy292DOI Listing
April 2019

Late complications of an atrial septal occluder provoked by anticoagulant therapy.

J Cardiol Cases 2018 Feb 7;17(2):68-71. Epub 2017 Nov 7.

Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands.

Late complications of an atrial septal occluder device (ASO) are rare but may be serious. We report a case with extensive hemopericardium five years after ASO implantation most likely triggered by anticoagulant therapy. Although not surgically confirmed, indirect clues for erosion of the atrial wall by the device were the exclusion of other etiologies, lack of recurrence after pericardial drainage and withdrawal of anticoagulants. In addition, multimodality imaging using echocardiography, computed tomography, and cardiac magnetic resonance imaging were helpful to elucidate this unusual cause. Initiation of anticoagulant treatment in patients with an ASO should be carefully balanced and may warrant more frequent echocardiographic follow-up. < Late complications of an atrial septal occlude device (ASO) are rare. Initiation of anticoagulant therapy in patients with an ASO may lead to late hemopericardium, suggesting that more frequent echocardiographic follow-up is warranted.>.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jccase.2017.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149637PMC
February 2018

Beauty and the beat: A complicated case of multifocal ectopic Purkinje-related premature contractions.

HeartRhythm Case Rep 2018 Sep 22;4(9):429-433. Epub 2018 Jun 22.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrcr.2018.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140614PMC
September 2018

Predicting changes to I from missense mutations in human SCN5A.

Sci Rep 2018 08 24;8(1):12797. Epub 2018 Aug 24.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, 6202 AZ, The Netherlands.

Mutations in SCN5A can alter the cardiac sodium current I and increase the risk of potentially lethal conditions such as Brugada and long-QT syndromes. The relation between mutations and their clinical phenotypes is complex, and systems to predict clinical severity of unclassified SCN5A variants perform poorly. We investigated if instead we could predict changes to I, leaving the link from I to clinical phenotype for mechanistic simulation studies. An exhaustive list of nonsynonymous missense mutations and resulting changes to I was compiled. We then applied machine-learning methods to this dataset, and found that changes to I could be predicted with higher sensitivity and specificity than most existing predictors of clinical significance. The substituted residues' location on the protein correlated with channel function and strongly contributed to predictions, while conservedness and physico-chemical properties did not. However, predictions were not sufficiently accurate to form a basis for mechanistic studies. These results show that changes to I, the mechanism through which SCN5A mutations create cardiac risk, are already difficult to predict using purely in-silico methods. This partly explains the limited success of systems to predict clinical significance of SCN5A variants, and underscores the need for functional studies of I in risk assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-30577-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109095PMC
August 2018

Concealed abnormal atrial phenotype in patients with Brugada syndrome and no history of atrial fibrillation.

Int J Cardiol 2018 02;253:66-70

Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland; Centre for Computational Medicine in Cardiology, Faculty of Informatics, Università della Svizzera Italiana, Lugano, Switzerland.

Objectives: The electrocardiogram (ECG) of patients with BrS in sinus rhythm might reflect intrinsic atrial electrical abnormalities independent from any previous atrial fibrillation (AF). Aim of this study is to investigate the presence of P-wave abnormalities in patients with BrS and no history of AF, and to compare them with those displayed by patients with documented paroxysmal AF and by healthy subjects.

Methods: Continuous 5-min 16-lead ECG recordings in sinus rhythm were obtained from 72 participants: 32 patients with a type 1 Brugada ECG, 20 patients with a history of paroxysmal AF and 20 age-matched healthy subjects. Different ECG-based features were computed on the P-wave first principal component representing the predominant morphology across leads and containing the maximal information on atrial depolarization: duration, full width half maximum (FWHM), area under the curve and number of peaks in the wave.

Results: Patients with BrS and no history of AF (mean age: 53±12years; males: 28 pts., spontaneous type 1 ECG: 20 pts., SCN5A mutation: 10 pts) presented with longer P-wave duration, higher FWHM and wider area under the curve in comparison with the other two groups. Although P-wave features were abnormal in BrS patients, no significant difference was found between patients with spontaneous type 1 ECG and ajmaline-induced type 1 ECG, symptomatic and asymptomatic ones, and between patients with a pathogenic SCNA5 mutation and patients without a known gene mutation.

Conclusions: Patients with BrS without previous occurrence of AF present with a concealed abnormal atrial phenotype. In these patients atrial electrical abnormalities can be detected even in the absence of an overt ECG ventricular phenotype, symptoms and a SCN5A mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2017.09.214DOI Listing
February 2018

Heritability in a SCN5A-mutation founder population with increased female susceptibility to non-nocturnal ventricular tachyarrhythmia and sudden cardiac death.

Heart Rhythm 2017 12 3;14(12):1873-1881. Epub 2017 Aug 3.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address:

Background: Heritable cardiac-sodium channel dysfunction is associated with various arrhythmia syndromes, some predisposing to ventricular fibrillation. Phenotypic diversity among carriers of identical-by-descent mutations is often remarkable, suggesting influences of genetic modifiers.

Objective: The purpose of this study was to identify a unique SCN5A-mutation founder population with mixed clinical phenotypes and sudden cardiac death, and to investigate the heritability of electromechanical traits besides the SCN5A-mutation effect.

Methods: The 16-generation founder population segregating SCN5A c.4850_4852delTCT, p.(Phe1617del), was comprehensively phenotyped. Variance component analysis was used to evaluate the mutation's effects and assess heritability.

Results: In 45 p.(Phe1617del) positives, the mutation associated strongly with QTc prolongation (472 ± 60 ms vs 423 ± 35 ms in 26 mutation negatives; P <.001; odds ratio for long-QT syndrome 22.4; 95% confidence interval 4.5-224.2; P <.001) and electromechanical window (EMW) negativity (-29 ± 47 ms vs 34 ± 26 ms; P <.001). Overlapping phenotypes including conduction delay and Brugada syndrome were noted in 19. Polymorphic ventricular tachyarrhythmias occurred mostly in the daytime, after arousal-evoked heart-rate acceleration and repolarization prolongation. Cox proportional hazards regression analysis revealed female gender as an independent risk factor for cardiac events (hazard ratio 5.1; 95% confidence interval 1.6-16.3; P = .006). p.(Phe1617del) was an important determinant of QTc, QTc, and EMW, explaining 18%, 28%, and 37%, respectively, of the trait's variance. Significant heritability was observed for PQ interval (P = .003) after accounting for the p.(Phe1617del) effect.

Conclusion: This SCN5A-p.(Phe1617del) founder population with phenotypic divergence and overlap reveals long-QT syndrome-related and arousal-evoked ventricular tachyarrhythmias with a female preponderance. Variance component analysis indicates additional genetic variance for PQ interval hidden in the genome, besides a dominant p.(Phe1617del) effect on QTc and EMW.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2017.07.036DOI Listing
December 2017

In Vivo Validation of Electrocardiographic Imaging.

JACC Clin Electrophysiol 2017 03 1;3(3):232-242. Epub 2017 Feb 1.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands. Electronic address:

Objectives: The purpose of this study was to evaluate the accuracy of noninvasive reconstructions of epicardial potentials, electrograms, activation and recovery isochrones, and beat origins by simultaneously performing electrocardiographic imaging (ECGI) and invasive epicardial electrography in intact animals.

Background: Noninvasive imaging of electrical potentials at the epicardium, known as ECGI, is increasingly applied in patients to assess normal and abnormal cardiac electrical activity.

Methods: Body-surface potentials and epicardial potentials were recorded in normal anesthetized dogs. Computed tomography scanning provided a torso-heart geometry that was used to reconstruct epicardial potentials from body-surface potentials.

Results: Electrogram reconstructions attained a moderate accuracy compared with epicardial recordings (median correlation coefficient: 0.71), but with considerable variation (interquartile range: 0.36 to 0.86). This variation could be explained by a spatial mismatch (overall resolution was <20 mm) that was most apparent in regions with electrographic transition. More accurate derivation of activation times (Pearson R: 0.82), recovery times (R: 0.73), and the origin of paced beats (median error: 10 mm; interquartile range: 7 to 17 mm) was achieved by a spatiotemporal approach that incorporates the characteristics of the respective electrogram and neighboring electrograms. Reconstruction of beats from repeated single-site pacing showed a stable localization of origin. Cardiac motion, currently ignored in ECGI, correlates negatively with reconstruction accuracy.

Conclusions: ECGI shows a decent median accuracy, but variability in electrogram reconstruction can be sizable. At present, therefore, clinical interpretations of ECGI should not be made on the basis of single electrograms only. Incorporating local spatiotemporal characteristics allows for accurate reconstruction of epicardial activation and recovery patterns, and beat origin localization to a 10-mm precision. Even more reliable interpretations are expected when the influences of cardiac motion are accounted for in ECGI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacep.2016.11.012DOI Listing
March 2017

Physiology-based regularization of the electrocardiographic inverse problem.

Med Biol Eng Comput 2017 Aug 21;55(8):1353-1365. Epub 2016 Nov 21.

Department of Data Science and Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.

The inverse problem of electrocardiography aims at noninvasively reconstructing electrical activity of the heart from recorded body-surface electrocardiograms. A crucial step is regularization, which deals with ill-posedness of the problem by imposing constraints on the possible solutions. We developed a regularization method that includes electrophysiological input. Body-surface potentials are recorded and a computed tomography scan is performed to obtain the torso-heart geometry. Propagating waveforms originating from several positions at the heart are simulated and used to generate a set of basis vectors representing spatial distributions of potentials on the heart surface. The real heart-surface potentials are then reconstructed from the recorded body-surface potentials by finding a sparse representation in terms of this basis. This method, which we named 'physiology-based regularization' (PBR), was compared to traditional Tikhonov regularization and validated using in vivo recordings in dogs. PBR recovered details of heart-surface electrograms that were lost with traditional regularization, attained higher correlation coefficients and led to improved estimation of recovery times. The best results were obtained by including approximate knowledge about the beat origin in the PBR basis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11517-016-1595-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544815PMC
August 2017

QT interval variability in body surface ECG: measurement, physiological basis, and clinical value: position statement and consensus guidance endorsed by the European Heart Rhythm Association jointly with the ESC Working Group on Cardiac Cellular Electrophysiology.

Europace 2016 Jun 27;18(6):925-44. Epub 2016 Jan 27.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.

This consensus guideline discusses the electrocardiographic phenomenon of beat-to-beat QT interval variability (QTV) on surface electrocardiograms. The text covers measurement principles, physiological basis, and clinical value of QTV. Technical considerations include QT interval measurement and the relation between QTV and heart rate variability. Research frontiers of QTV include understanding of QTV physiology, systematic evaluation of the link between QTV and direct measures of neural activity, modelling of the QTV dependence on the variability of other physiological variables, distinction between QTV and general T wave shape variability, and assessing of the QTV utility for guiding therapy. Increased QTV appears to be a risk marker of arrhythmic and cardiovascular death. It remains to be established whether it can guide therapy alone or in combination with other risk factors. QT interval variability has a possible role in non-invasive assessment of tonic sympathetic activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euv405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905605PMC
June 2016

Myokit: A simple interface to cardiac cellular electrophysiology.

Prog Biophys Mol Biol 2016 Jan 23;120(1-3):100-14. Epub 2015 Dec 23.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, PO Box 5800, 6202 AZ, Maastricht, The Netherlands. Electronic address:

Myokit is a new powerful and versatile software tool for modeling and simulation of cardiac cellular electrophysiology. Myokit consists of an easy-to-read modeling language, a graphical user interface, single and multi-cell simulation engines and a library of advanced analysis tools accessible through a Python interface. Models can be loaded from Myokit's native file format or imported from CellML. Model export is provided to C, MATLAB, CellML, CUDA and OpenCL. Patch-clamp data can be imported and used to estimate model parameters. In this paper, we review existing tools to simulate the cardiac cellular action potential to find that current tools do not cater specifically to model development and that there is a gap between easy-to-use but limited software and powerful tools that require strong programming skills from their users. We then describe Myokit's capabilities, focusing on its model description language, simulation engines and import/export facilities in detail. Using three examples, we show how Myokit can be used for clinically relevant investigations, multi-model testing and parameter estimation in Markov models, all with minimal programming effort from the user. This way, Myokit bridges a gap between performance, versatility and user-friendliness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbiomolbio.2015.12.008DOI Listing
January 2016

Detailed characterization of familial idiopathic ventricular fibrillation linked to the DPP6 locus.

Heart Rhythm 2016 Apr 8;13(4):905-12. Epub 2015 Dec 8.

Heart Center, 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:

Background: Familial idiopathic ventricular fibrillation (IVF) is a severe disease entity and is notoriously difficult to manage because there are no clinical risk indicators for premature cardiac arrest. Previously, we identified a link between familial IVF and a risk haplotype on chromosome 7q36 (involving the arrhythmia gene DPP6).

Objective: The purpose of this study was to expand our knowledge of familial IVF and to discuss its (extended) clinical characteristics.

Methods: We studied 601 family members and probands: 286 DPP6 risk-haplotype positive (haplotype-positive) and 315 DPP6 risk-haplotype negative (haplotype-negative) individuals. Clinical parameters, a combination of all-cause mortality and (aborted) cardiac arrest and differences between haplotype-positives and haplotype-negatives, were evaluated.

Results: There were no differences in electrocardiographic indices between haplotype-positives and haplotype-negatives, or between haplotype-positives with or without events. Cardiac magnetic resonance documented slightly larger ventricular volumes in haplotype-positives compared to controls (P <.05), but these were not clinically useful. Mortality and/or cardiac arrest occurred in 85 haplotype-positives (30%) and 18 haplotype-negatives (6%). Twenty-four haplotype-positives (8% male) were resuscitated from ventricular fibrillation (VF). Documented VF was always elicited by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall. Median survival in risk-haplotype haplotype-positives was 70 vs. 93 years for haplotype-negatives (P < .01), with a worse phenotype in males (median survival 63 vs. 83 years in females, P < .01). Implantable cardioverter-defibrillators were implanted in 99 patients (76 [77%] for primary prevention). Two arrhythmic events occurred in the primary prevention group during follow-up (5 ± 3 years).

Conclusion: Despite our extensive analysis, the complexity in identifying asymptomatic IVF family members at risk for future arrhythmias based on clinical parameters is once more demonstrated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2015.12.006DOI Listing
April 2016

Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers.

Eur Heart J 2016 06 24;37(23):1815-22. Epub 2015 Oct 24.

Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.

Aims: Phenotypic heterogeneity and incomplete penetrance are common in patients with hypertrophic cardiomyopathy (HCM). We aim to improve the understanding in genotype-phenotype correlations in HCM, particularly the contribution of an MYL2 founder mutation and risk factors to left ventricular hypertrophic remodelling.

Methods And Results: We analysed 14 HCM families of whom 38 family members share the MYL2 c.64G > A [p.(Glu22Lys)] mutation and a common founder haplotype. In this unique cohort, we investigated factors influencing phenotypic outcome in addition to the primary mutation. The mutation alone showed benign disease manifestation with low penetrance. The co-presence of additional risk factors for hypertrophy such as hypertension, obesity, or other sarcomeric gene mutation increased disease penetrance substantially and caused HCM in 89% of MYL2 mutation carriers (P = 0.0005). The most prominent risk factor was hypertension, observed in 71% of mutation carriers with HCM and an additional risk factor.

Conclusion: The MYL2 mutation c.64G > A on its own is incapable of triggering clinical HCM in most carriers. However, the presence of an additional risk factor for hypertrophy, particularly hypertension, adds to the development of HCM. Early diagnosis of risk factors is important for early treatment of MYL2 mutation carriers and close monitoring should be guaranteed in this case. Our findings also suggest that the presence of hypertension or another risk factor for hypertrophy should not be an exclusion criterion for genetic studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehv522DOI Listing
June 2016

Opportunities and challenges of current electrophysiology research: a plea to establish 'translational electrophysiology' curricula.

Europace 2015 May 17;17(5):825-33. Epub 2015 Feb 17.

Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands

Cardiac electrophysiology has evolved into an important subspecialty in cardiovascular medicine. This is in part due to the significant advances made in our understanding and treatment of heart rhythm disorders following more than a century of scientific discoveries and research. More recently, the rapid development of technology in cellular electrophysiology, molecular biology, genetics, computer modelling, and imaging have led to the exponential growth of knowledge in basic cardiac electrophysiology. The paradigm of evidence-based medicine has led to a more comprehensive decision-making process and most likely to improved outcomes in many patients. However, implementing relevant basic research knowledge in a system of evidence-based medicine appears to be challenging. Furthermore, the current economic climate and the restricted nature of research funding call for improved efficiency of translation from basic discoveries to healthcare delivery. Here, we aim to (i) appraise the broad challenges of translational research in cardiac electrophysiology, (ii) highlight the need for improved strategies in the training of translational electrophysiologists, and (iii) discuss steps towards building a favourable translational research environment and culture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euu301DOI Listing
May 2015

Electromechanical window negativity in genotyped long-QT syndrome patients: relation to arrhythmia risk.

Eur Heart J 2015 Jan 8;36(3):179-86. Epub 2014 Sep 8.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands

Aim: Prolonged and dispersed left-ventricular (LV) contraction is present in patients with long-QT syndrome (LQTS). Electrical and mechanical abnormalities appear most pronounced in symptomatic individuals. We focus on the 'electromechanical window' (EMW; duration of LV-mechanical systole minus QT interval) in patients with genotyped LQTS. Profound EMW negativity heralds torsades de pointes in animal models of drug-induced LQTS.

Methods And Results: We included 244 LQTS patients from three centres, of whom 97 had experienced arrhythmic events. Seventy-six matched healthy individuals served as controls. QT interval was subtracted from the duration of Q-onset to aortic-valve closure (QAoC) midline assessed non-invasively by continuous-wave echocardiography, measured in the same beat. Electromechanical window was positive in controls but negative in LQTS patients (22 ± 19 vs. -43 ± 46 ms; P < 0.0001), being even more negative in symptomatic than event-free patients (-67 ± 42 vs. -27 ± 41 ms; P < 0.0001). QT, QTc, and QAoC were longer in LQTS subjects (451 ± 57, 465 ± 50, and 408 ± 37 ms, P < 0.0001). Electromechanical window was a better discriminator of patients with previous arrhythmic events than resting QTc (AUC 0.77 (95% CI, 0.71-0.83) and 0.71 (95% CI, 0.65-0.78); P = 0.03). In multivariate analysis, EMW predicted arrhythmic events independently of QTc (odds ratio 1.25; 95% CI, 1.11-1.40; P = 0.001). Adding EMW to QTc for risk assessment led to a net reclassification improvement of 13.3% (P = 0.03). No EMW differences were found between the three major LQTS genotypes.

Conclusions: Patients with genotype-positive LQTS express EMW negativity, which is most pronounced in patients with documented arrhythmic events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehu370DOI Listing
January 2015

Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of IKs, but preserved cAMP-dependent up-regulation.

Cardiovasc Res 2014 Oct 18;104(1):216-25. Epub 2014 Aug 18.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, PO Box 5800, Maastricht 6202 AZ, The Netherlands

Aims: Mutations in KCNQ1, encoding for Kv7.1, the α-subunit of the IKs channel, cause long-QT syndrome type 1, potentially predisposing patients to ventricular tachyarrhythmias and sudden cardiac death, in particular, during elevated sympathetic tone. Here, we aim at characterizing the p.Lys557Glu (K557E) Kv7.1 mutation, identified in a Dutch kindred, at baseline and during (mimicked) increased adrenergic tone.

Methods And Results: K557E carriers had moderate QTc prolongation that augmented significantly during exercise. IKs characteristics were determined after co-expressing Kv7.1-wild-type (WT) and/or K557E with minK and Yotiao in Chinese hamster ovary cells. K557E caused IKs loss of function with slowing of the activation kinetics, acceleration of deactivation kinetics, and a rightward shift of voltage-dependent activation. Together, these contributed to a dominant-negative reduction in IKs density. Confocal microscopy and western blot indicated that trafficking of K557E channels was not impaired. Stimulation of WT IKs by 3'-5'-cyclic adenosine monophosphate (cAMP) generated strong current up-regulation that was preserved for K557E in both hetero- and homozygosis. Accumulation of IKs at fast rates occurred both in WT and in K557E, but was blunted in the latter. In a computational model, K557E showed a loss of action potential shortening during β-adrenergic stimulation, in accordance with the lack of QT shortening during exercise in patients.

Conclusion: K557E causes IKs loss of function with reduced fast rate-dependent current accumulation. cAMP-dependent stimulation of mutant IKs is preserved, but incapable of fully compensating for the baseline current reduction, explaining the long QT intervals at baseline and the abnormal QT accommodation during exercise in affected patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvu191DOI Listing
October 2014

Interventricular differences in β-adrenergic responses in the canine heart: role of phosphodiesterases.

J Am Heart Assoc 2014 Jun 5;3(3):e000858. Epub 2014 Jun 5.

INSERM UMR-S 769, LabEx LERMIT, DHU TORINO, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.) Université Paris-Sud, Châtenay-Malabry, France (C.E.M., H.M., D.M., V.A., Z.H.S., P.L., L., R.F., G.V.).

Background: RV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in β-adrenergic (β-AR) responsiveness is unknown. In this study, we examine whether β-AR response and signaling differ in right (RV) versus left (LV) ventricles.

Methods And Results: Sarcomere shortening, Ca(2+) transients, ICa,L and IKs currents were recorded in isolated dog LV and RV midmyocytes. Intracellular [cAMP] and PKA activity were measured by live cell imaging using FRET-based sensors. Isoproterenol increased sarcomere shortening ≈10-fold and Ca(2+)-transient amplitude ≈2-fold in LV midmyocytes (LVMs) versus ≈25-fold and ≈3-fold in RVMs. FRET imaging using targeted Epac2camps sensors revealed no change in subsarcolemmal [cAMP], but a 2-fold higher β-AR stimulation of cytoplasmic [cAMP] in RVMs versus LVMs. Accordingly, β-AR regulation of ICa,L and IKs were similar between LVMs and RVMs, whereas cytoplasmic PKA activity was increased in RVMs. Both PDE3 and PDE4 contributed to the β-AR regulation of cytoplasmic [cAMP], and the difference between LVMs and RVMs was abolished by PDE3 inhibition and attenuated by PDE4 inhibition. Finally LV and RV intracavitary pressures were recorded in anesthetized beagle dogs. A bolus injection of isoproterenol increased RV dP/dtmax≈5-fold versus 3-fold in LV.

Conclusion: Canine RV and LV differ in their β-AR response due to intrinsic differences in myocyte β-AR downstream signaling. Enhanced β-AR responsiveness of the RV results from higher cAMP elevation in the cytoplasm, due to a decreased degradation by PDE3 and PDE4 in the RV compared to the LV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.114.000858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309082PMC
June 2014

Successful treatment of a patient with symptomatic long QT syndrome type 3 using ranolazine combined with a beta-blocker.

Int J Cardiol 2014 Jan 4;171(1):90-2. Epub 2013 Dec 4.

University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2013.11.066DOI Listing
January 2014

Right-ventricular enlargement in arrhythmogenic right-ventricular cardiomyopathy is associated with decreased QRS amplitudes and T-wave negativity.

Ann Noninvasive Electrocardiol 2013 Nov 9;18(6):555-63. Epub 2013 Sep 9.

Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) can lead to RV dilatation. We hypothesized that electrocardiographic characteristics including QRS amplitudes in the extremity- and precordial leads, the S amplitude in lead V1 , and extent of T-wave negativity over the precordial leads are related to RV dilatation in this condition.

Methods: In 42 ARVC patients and 42 controls, we correlated total QRS amplitude in the extremity leads (∑QRSext ), precordial leads (∑QRSprec ) and in all leads (∑QRStot : summation of ∑QRSext and ∑QRSprec ), S amplitude in lead V1 and the extent of T-wave inversion in the precordial leads (V1 vs. beyond V1 ) with RV end diastolic diameter (RVEDD) by echocardiography.

Results: In the ARVC group, the mean age was 46 ± 14 years, 31 patients were male, 28 had an implantable cardioverter defibrillator (ICD), and 7 had a LV ejection fraction (EF) < 55%. The control group was age- and gender matched to the ARVC cohort. In contrast to controls, the ∑QRSext (regression coefficient (RC), -0.29; P = 0.020), ∑QRSprec (RC, -0.20; P = 0.015), and ∑QRStot (RC, -0.14; P = 0.009) were lower with RV dilatation in ARVC. S amplitude in lead V1 was not related to RV diameter (RC, -0.98; P = 0.088). Precordial T-wave inversion beyond lead V1 (V2 -V6 ) was associated with a larger RV diameter (RC, 8.58; P = 0.012).

Conclusions: Summed QRS amplitudes in the extremity and precordial leads, and T-wave inversion beyond lead V1 are associated with RV dilatation in patients with ARVC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/anec.12080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931952PMC
November 2013

Sudden death by stress: how far under the nerves should we dig to find out why LQT1 patients die?

J Am Coll Cardiol 2014 Mar 30;63(8):828-30. Epub 2013 Oct 30.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2013.09.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988421PMC
March 2014