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Jyh-Ming Jimmy Juang, Minoru Horie
In 1992, the Brugada syndrome (BrS) was recognized as a disease responsible for sudden cardiac death, characterized by a right bundle-branch block with ST segment elevation in the leads V1 and V2. This syndrome is highly associated with sudden cardiac death, especially in young males. BrS is currently diagnosed in patients with ST-segment elevation showing type 1 morphology ≥ 2 mm in ≥1 leads among the right precordial leads V1 or V2 positioned in the 2nd, 3rd, or 4th intercostal space, and occurring either spontaneously or after a provocative drug test by the intravenous administration of Class I antiarrhythmic drugs...
October 2016: Journal of Arrhythmia
Maria Cecilia Gonzalez Corcia, Juan Sieira, Andrea Sarkozy, Carlo de Asmundis, Gian-Battista Chierchia, Jaime Hernandez Ojeda, Gudrun Pappaert, Pedro Brugada
AIMS: To investigate the clinical characteristics, prognoses, and presence of risk factors in young patients with Brugada syndrome (BS). METHODS AND RESULTS: A consecutive cohort of 128 young BS patients (≤25 years old at diagnosis) was analysed. Eighty-eight patients (69%) were asymptomatic, whereas 40 (31%) presented with clinical manifestations of BS. Markers of prognosis and risk were identified upon comparison of these two groups. A history of malignant syncope was strong predictors of ventricular arrhythmic events...
October 13, 2016: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
Ehud Chorin, Dan Hu, Charles Antzelevitch, Aviram Hochstadt, Luiz Belardinelli, David Zeltser, Hector Barajas-Martinez, Uri Rozovski, Raphael Rosso, Arnon Adler, Jesaia Benhorin, Sami Viskin
BACKGROUND: The basic defect in long-QT syndrome type III (LQT3) is an excessive inflow of sodium current during phase 3 of the action potential caused by mutations in the SCN5A gene. Most sodium channel blockers reduce the early (peak) and late components of the sodium current (INa and INaL), but ranolazine preferentially reduces INaL. We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A. METHODS AND RESULTS: We performed an experimental study of ranolazine in TSA201 cells expressing the D1790G mutation...
October 2016: Circulation. Arrhythmia and Electrophysiology
Liyong Zhang, David J Tester, Di Lang, Yili Chen, Jinxiang Zheng, Rui Gao, Robert F Corliss, Shuangbo Tang, John W Kyle, Chao Liu, Michael J Ackerman, Jonathan C Makielski, Jianding Cheng
OBJECTIVE: To look for previously unrecognized cardiac structural abnormalities and address the genetic cause for sudden unexplained nocturnal death syndrome (SUNDS). METHODS: Data for 148 SUNDS victims and 444 controls (matched 1:3 on sex, race, and age of death within 1 year) were collected from Sun Yat-sen University from January 1, 1998, to December 31, 2014, to search morphological changes. An additional 17 patients with Brugada syndrome (BrS) collected from January 1, 2006, to December 31, 2014, served as a comparative disease cohort...
October 1, 2016: Mayo Clinic Proceedings
Aditi Khandekar, Steven Springer, Wei Wang, Stephanie Hicks, Carla J Weinheimer, Ramon Diaz-Trelles, Jeanne M Nerbonne, Stacey Rentschler
RATIONALE: Ventricular arrhythmias often arise from the Purkinje-myocyte junction and are a leading cause of sudden cardiac death. Notch activation reprograms cardiac myocytes to an "induced Purkinje-like" state characterized by prolonged action potential duration and expression of Purkinje enriched genes. OBJECTIVE: To understand the mechanism by which canonical Notch signaling causes action potential prolongation. METHODS AND RESULTS: We find that endogenous Purkinje cells have reduced peak K(+) current, Ito and IK,slow when compared with ventricular myocytes...
October 3, 2016: Circulation Research
Huan Wang, Hong-Fei Wang, Hao Zhang, Chen Wang, Yu-Fang Chen, Rong Ma, Ji-Zhou Xiang, Xin-Ling Du, Qiang Tang
AIM: Voltage-gated sodium channels composed of a pore-forming α subunit and auxiliary β subunits are responsible for the upstroke of the action potential in cardiac myocytes. The pore-forming subunit of the cardiac sodium channel Nav1.5, which is encoded by SCN5A, is the main ion channel that conducts the voltage-gated cardiac sodium current (INa) in cardiac cells. The current study sought to investigate the inhibitory effects of hesperetin (HSP) on human cardiac Nav1.5 channels stably expressed in human embryonic kidney 293 (HEK 293) cells and on the voltage-gated cardiac sodium current (INa) in human atrial myocytes...
October 3, 2016: Acta Pharmacologica Sinica
Irene Mademont-Soler, Mel Lina Pinsach-Abuin, Helena Riuró, Jesus Mates, Alexandra Pérez-Serra, Mònica Coll, José Manuel Porres, Bernat Del Olmo, Anna Iglesias, Elisabet Selga, Ferran Picó, Sara Pagans, Carles Ferrer-Costa, Geòrgia Sarquella-Brugada, Elena Arbelo, Sergi Cesar, Josep Brugada, Óscar Campuzano, Ramon Brugada
PURPOSE: Brugada syndrome (BrS) is a form of cardiac arrhythmia which may lead to sudden cardiac death. The recommended genetic testing (direct sequencing of SCN5A) uncovers disease-causing SNVs and/or indels in ~20% of cases. Limited information exists about the frequency of copy number variants (CNVs) in SCN5A in BrS patients, and the role of CNVs in BrS-minor genes is a completely unexplored field. METHODS: 220 BrS patients with negative genetic results were studied to detect CNVs in SCN5A...
2016: PloS One
James Rush Priest, Charles Gawad, Kristopher M Kahlig, Joseph K Yu, Thomas O'Hara, Patrick M Boyle, Sridharan Rajamani, Michael J Clark, Sarah T K Garcia, Scott Ceresnak, Jason Harris, Sean Boyle, Frederick E Dewey, Lindsey Malloy-Walton, Kyla Dunn, Megan Grove, Marco V Perez, Norma F Neff, Richard Chen, Katsuhide Maeda, Anne Dubin, Luiz Belardinelli, John West, Christian Antolik, Daniela Macaya, Thomas Quertermous, Natalia A Trayanova, Stephen R Quake, Euan A Ashley
Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Shinichiro Okata, Shinsuke Yuasa, Tomoyuki Suzuki, Shogo Ito, Naomasa Makita, Tetsu Yoshida, Min Li, Junko Kurokawa, Tomohisa Seki, Toru Egashira, Yoshiyasu Aizawa, Masaki Kodaira, Chikaaki Motoda, Gakuto Yozu, Masaya Shimojima, Nozomi Hayashiji, Hisayuki Hashimoto, Yusuke Kuroda, Atsushi Tanaka, Mitsushige Murata, Takeshi Aiba, Wataru Shimizu, Minoru Horie, Kaichiro Kamiya, Tetsushi Furukawa, Keiichi Fukuda
SCN5A is abundant in heart and has a major role in INa. Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation...
September 28, 2016: Scientific Reports
U Lakshmanadoss, A Mertens, M Gallagher, I Kutinsky, B Williamson
Inherited arrhythmia syndromes are a known, albeit rare, cause of sudden cardiac arrest which may present with characteristic electrocardiogram changes in patients with structurally normal heart. There are a variety of distinct arrhythmogenic syndromes that arise from mutations in voltage gated sodium channels, resulting in either gain or loss of function. We describe a patient with a primary inherited arrhythmia syndrome which presented as sudden cardiac arrest. Further workup revealed that her arrest was due to a combination of Brugada syndrome and Long QT3 syndrome secondary to a deleterious mutation of voltage-gated, sodium channel, type V alpha subunit (SCN5A Thr1709Met)...
March 2016: Indian Pacing and Electrophysiology Journal
A L M J van der Knijff-van Dortmont, M Dirckx, J J Duvekot, J W Roos-Hesselink, A Gonzalez Candel, C D van der Marel, G P Scoones, V F R Adriaens, I J J Dons-Sinke
SCN5A gene mutations can lead to ion channel defects which can cause cardiac conduction disturbances. In the presence of specific ECG characteristics, this mutation is called Brugada syndrome. Many drugs are associated with adverse events, making anesthesia in patients with SCN5A gene mutations or Brugada syndrome challenging. In this case report, we describe a pregnant patient with this mutation who received epidural analgesia using low dose ropivacaine and sufentanil during labour.
2016: Case Reports in Anesthesiology
Pim van der Harst, Jessica van Setten, Niek Verweij, Georg Vogler, Lude Franke, Matthew T Maurano, Xinchen Wang, Irene Mateo Leach, Mark Eijgelsheim, Nona Sotoodehnia, Caroline Hayward, Rossella Sorice, Osorio Meirelles, Leo-Pekka Lyytikäinen, Ozren Polašek, Toshiko Tanaka, Dan E Arking, Sheila Ulivi, Stella Trompet, Martina Müller-Nurasyid, Albert V Smith, Marcus Dörr, Kathleen F Kerr, Jared W Magnani, Fabiola Del Greco M, Weihua Zhang, Ilja M Nolte, Claudia T Silva, Sandosh Padmanabhan, Vinicius Tragante, Tõnu Esko, Gonçalo R Abecasis, Michiel E Adriaens, Karl Andersen, Phil Barnett, Joshua C Bis, Rolf Bodmer, Brendan M Buckley, Harry Campbell, Megan V Cannon, Aravinda Chakravarti, Lin Y Chen, Alessandro Delitala, Richard B Devereux, Pieter A Doevendans, Anna F Dominiczak, Luigi Ferrucci, Ian Ford, Christian Gieger, Tamara B Harris, Eric Haugen, Matthias Heinig, Dena G Hernandez, Hans L Hillege, Joel N Hirschhorn, Albert Hofman, Norbert Hubner, Shih-Jen Hwang, Annamaria Iorio, Mika Kähönen, Manolis Kellis, Ivana Kolcic, Ishminder K Kooner, Jaspal S Kooner, Jan A Kors, Edward G Lakatta, Kasper Lage, Lenore J Launer, Daniel Levy, Alicia Lundby, Peter W Macfarlane, Dalit May, Thomas Meitinger, Andres Metspalu, Stefania Nappo, Silvia Naitza, Shane Neph, Alex S Nord, Teresa Nutile, Peter M Okin, Jesper V Olsen, Ben A Oostra, Josef M Penninger, Len A Pennacchio, Tune H Pers, Siegfried Perz, Annette Peters, Yigal M Pinto, Arne Pfeufer, Maria Grazia Pilia, Peter P Pramstaller, Bram P Prins, Olli T Raitakari, Soumya Raychaudhuri, Ken M Rice, Elizabeth J Rossin, Jerome I Rotter, Sebastian Schafer, David Schlessinger, Carsten O Schmidt, Jobanpreet Sehmi, Herman H W Silljé, Gianfranco Sinagra, Moritz F Sinner, Kamil Slowikowski, Elsayed Z Soliman, Timothy D Spector, Wilko Spiering, John A Stamatoyannopoulos, Ronald P Stolk, Konstantin Strauch, Sian-Tsung Tan, Kirill V Tarasov, Bosco Trinh, Andre G Uitterlinden, Malou van den Boogaard, Cornelia M van Duijn, Wiek H van Gilst, Jorma S Viikari, Peter M Visscher, Veronique Vitart, Uwe Völker, Melanie Waldenberger, Christian X Weichenberger, Harm-Jan Westra, Cisca Wijmenga, Bruce H Wolffenbuttel, Jian Yang, Connie R Bezzina, Patricia B Munroe, Harold Snieder, Alan F Wright, Igor Rudan, Laurie A Boyer, Folkert W Asselbergs, Dirk J van Veldhuisen, Bruno H Stricker, Bruce M Psaty, Marina Ciullo, Serena Sanna, Terho Lehtimäki, James F Wilson, Stefania Bandinelli, Alvaro Alonso, Paolo Gasparini, J Wouter Jukema, Stefan Kääb, Vilmundur Gudnason, Stephan B Felix, Susan R Heckbert, Rudolf A de Boer, Christopher Newton-Cheh, Andrew A Hicks, John C Chambers, Yalda Jamshidi, Axel Visel, Vincent M Christoffels, Aaron Isaacs, Nilesh J Samani, Paul I W de Bakker
BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass...
September 27, 2016: Journal of the American College of Cardiology
Qin Xu, Dakshesh Patel, Xian Zhang, Richard D Veenstra
Histone deacetylase (HDAC) inhibitors are small molecule anti-cancer therapeutics that exhibit limiting cardiotoxicities including QT interval prolongation and life-threatening cardiac arrhythmias. Because the molecular mechanisms for HDAC inhibitor-induced cardiotoxicity are poorly understood, we performed whole cell patch voltage clamp experiments to measure cardiac sodium currents (INa) from wild-type neonatal mouse ventricular or human induced pluripotent stem cell derived cardiomyocytes treated with trichostatin A (TSA), vorinostat (VOR), or romidepsin (FK228)...
September 16, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Christian Steinberg, Gareth J Padfield, Jean Champagne, Shubhayan Sanatani, Paul Angaran, Jason G Andrade, Jason D Roberts, Jeffrey S Healey, Vijay S Chauhan, David H Birnie, Mikyla Janzen, Brenda Gerull, George J Klein, Richard Leather, Christopher S Simpson, Colette Seifer, Mario Talajic, Martin Gardner, Andrew D Krahn
BACKGROUND: Unexplained cardiac arrest (UCA) may be explained by inherited arrhythmia syndromes. The Cardiac Arrest Survivors With Preserved Ejection Fraction Registry prospectively assessed first-degree relatives of UCA or sudden unexplained death victims to screen for cardiac abnormalities. METHODS AND RESULTS: Around 398 first-degree family members (186 UCA, 212 sudden unexplained death victims' relatives; mean age, 44±17 years) underwent extensive cardiac workup, including ECG, signal averaged ECG, exercise testing, cardiac imaging, Holter-monitoring, and selective provocative drug testing with epinephrine or procainamide...
September 2016: Circulation. Arrhythmia and Electrophysiology
Nobue Yagihara, Hiroshi Watanabe, Phil Barnett, Laetitia Duboscq-Bidot, Atack C Thomas, Ping Yang, Seiko Ohno, Kanae Hasegawa, Ryozo Kuwano, Stéphanie Chatel, Richard Redon, Jean-Jacques Schott, Vincent Probst, Tamara T Koopmann, Connie R Bezzina, Arthur A M Wilde, Yukiko Nakano, Takeshi Aiba, Yoshihiro Miyamoto, Shiro Kamakura, Dawood Darbar, Brian S Donahue, Daichi Shigemizu, Toshihiro Tanaka, Tatsuhiko Tsunoda, Masayoshi Suda, Akinori Sato, Tohru Minamino, Naoto Endo, Wataru Shimizu, Minoru Horie, Dan M Roden, Naomasa Makita
BACKGROUND: Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias. METHODS AND RESULTS: We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89)...
September 2016: Journal of the American Heart Association
Edelmann J, Dobosz T, Sobieszczanska M, Kawecka-Negrusz M, Dreßler J, Nastainczyk-Wulf M
Congenital long QT-syndrome (LQTS) is an inherited cardiac arrhythmia, which is characterized by a prolonged QT interval which predisposes to sudden cardiac death due to ventricular arrhythmias. The altered functions are based on different mutations in LQTS-associated genes. In this study, we performed a mutation analysis for the detection of 125 LQTS-associated single nucleotide polymorphisms (SNPs) focused on the genes KCNQ1, KCNH2, and SCN5A by using the SNaPshot multiplex minisequencing technique. Furthermore, we investigated 152 autopsy-negative cases from younger adults and infants, as well as samples from patients with clinically suspicion for LQTS, in which we found two types of variations...
September 9, 2016: International Journal of Legal Medicine
Rangarajan D Nadadur, Michael T Broman, Bastiaan Boukens, Stefan R Mazurek, Xinan Yang, Malou van den Boogaard, Jenna Bekeny, Margaret Gadek, Tarsha Ward, Min Zhang, Yun Qiao, James F Martin, Christine E Seidman, Jon Seidman, Vincent Christoffels, Igor R Efimov, Elizabeth M McNally, Christopher R Weber, Ivan P Moskowitz
Cardiac rhythm is extremely robust, generating 2 billion contraction cycles during the average human life span. Transcriptional control of cardiac rhythm is poorly understood. We found that removal of the transcription factor gene Tbx5 from the adult mouse caused primary spontaneous and sustained atrial fibrillation (AF). Atrial cardiomyocytes from the Tbx5-mutant mice exhibited action potential abnormalities, including spontaneous depolarizations, which were rescued by chelating free calcium. We identified a multitiered transcriptional network that linked seven previously defined AF risk loci: TBX5 directly activated PITX2, and TBX5 and PITX2 antagonistically regulated membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2 In addition, reduced Tbx5 dose by adult-specific haploinsufficiency caused decreased target gene expression, myocardial automaticity, and AF inducibility, which were all rescued by Pitx2 haploinsufficiency in mice...
August 31, 2016: Science Translational Medicine
Daniel S Evans, Christy L Avery, Mike A Nalls, Guo Li, John Barnard, Erin N Smith, Toshiko Tanaka, Anne M Butler, Sarah G Buxbaum, Alvaro Alonso, Dan E Arking, Gerald S Berenson, Joshua C Bis, Steven Buyske, Cara L Carty, Wei Chen, Mina K Chung, Steven R Cummings, Rajat Deo, Charles B Eaton, Ervin R Fox, Susan R Heckbert, Gerardo Heiss, Lucia A Hindorff, Wen-Chi Hsueh, Aaron Isaacs, Yalda Jamshidi, Kathleen F Kerr, Felix Liu, Yongmei Liu, Kurt K Lohman, Jared W Magnani, Joseph F Maher, Reena Mehra, Yan A Meng, Solomon K Musani, Christopher Newton-Cheh, Kari E North, Bruce M Psaty, Susan Redline, Jerome I Rotter, Renate B Schnabel, Nicholas J Schork, Ralph V Shohet, Andrew B Singleton, Jonathan D Smith, Elsayed Z Soliman, Sathanur R Srinivasan, Herman A Taylor, David R Van Wagoner, James G Wilson, Taylor Young, Zhu-Ming Zhang, Alan B Zonderman, Michele K Evans, Luigi Ferrucci, Sarah S Murray, Gregory J Tranah, Eric A Whitsel, Alex P Reiner, Nona Sotoodehnia
The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with QRS duration at 22 loci among those of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a GWAS meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent...
August 29, 2016: Human Molecular Genetics
Isik Turker, Takeru Makiyama, Matteo Vatta, Hideki Itoh, Takeshi Ueyama, Akihiko Shimizu, Tomohiko Ai, Minoru Horie
BACKGROUND: Class IC antiarrhythmic agents may induce acquired forms of Brugada Syndrome. We have identified a novel mutation in SCN5A, the gene that encodes the α-subunit of the human cardiac sodium channel (hNav1.5), in a patient who exhibited Brugada- type ECG changes during pharmacotherapy of atrial arrhythmias. OBJECTIVE: To assess whether the novel mutation p.V1328M can cause drug induced Brugada Syndrome. METHODS: Administration of pilsicainide, a class IC antiarrhythmic agent, caused Brugada- type ST elevation in a 66-year-old Japanese male who presented with paroxysmal atrial fibrillation (PAF), type I atrial flutter and inducible ventricular fibrillation (VF) during electrophysiological study...
2016: PloS One
Mariana Priganc, Michaela Zigová, Iveta Boroňová, Jarmila Bernasovská, Dana Dojčáková, Viktória Szabadosová, Marta Mydlárová Blaščáková, Iveta Tóthová, Ján Kmec, Ivan Bernasovský
OBJECTIVE: Mutations in ion channels genes are potential cause of cardiomyopathy. The SCN5A gene (sodium channel, voltage gated, type V alpha subunit gene; 3p21) belongs to the family of cardiac sodium channel genes. Mutations in SCN5A gene lead to decreased Na+ current and ion unbalance. The SCN5A gene mutations are found in approximately 2% of patients with dilated cardiomyopathy (DCM), and they may be potential phenotype modifiers in hypertrophic cardiomyopathy (HCM). The role of SCN5A gene mutations in cardiomyopathy is not fully elucidated...
August 24, 2016: Journal of Clinical Laboratory Analysis
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