SCN5A Mutations in Brugada Syndrome Are Associated with Increased Cardiac Dimensions and Reduced Contractility

Background The cardiac sodium channel (Nav1.5) controls cardiac excitability. Accordingly, SCN5A mutations that result in loss-of-function of Nav1.5 are associated with various inherited arrhythmia syndromes that revolve around reduced cardiac excitability, most notably Brugada syndrome (BrS). Experimental studies have indicated that Nav1.5 interacts with the cytoskeleton and may also be involved in maintaining structural integrity of the heart. We aimed to determine whether clinical evidence may be obtained that Nav1.5 is involved in maintaining cardiac structural integrity. Methods Using cardiac magnetic resonance (CMR) imaging, we compared right ventricular (RV) and left ventricular (LV) dimensions and ejection fractions between 40 BrS patients with SCN5A mutations (SCN5a-mut-positive) and 98 BrS patients without SCN5A mutations (SCN5a-mut-negative). We also studied 18 age/sex-matched healthy volunteers. Results SCN5a-mut-positive patients had significantly larger end-diastolic and end-systolic RV and LV volumes, and lower LV ejection fractions, than SCN5a-mut-negative patients or volunteers. Conclusions Loss-of-function SCN5A mutations are associated with dilatation and impairment in contractile function of both ventricles that can be detected by CMR analysis.

[1]  H. Tan,et al.  Right ventricular pacing improves haemodynamics in right ventricular failure from pressure overload: an open observational proof-of-principle study in patients with chronic thromboembolic pulmonary hypertension. , 2011, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[2]  Tachapong Ngarmukos,et al.  Prevention of Ventricular Fibrillation Episodes in Brugada Syndrome by Catheter Ablation Over the Anterior Right Ventricular Outflow Tract Epicardium , 2011, Circulation.

[3]  John L Sapp,et al.  Cardiac-resynchronization therapy for mild-to-moderate heart failure. , 2010, The New England journal of medicine.

[4]  S. Schoenberg,et al.  Spontaneous type 1 electrocardiographic pattern is associated with cardiovascular magnetic resonance imaging changes in Brugada syndrome. , 2010, Heart rhythm.

[5]  J. Ruijter,et al.  Tubulin polymerization modifies cardiac sodium channel expression and gating. , 2010, Cardiovascular research.

[6]  A. Wilde,et al.  Local depolarization abnormalities are the dominant pathophysiologic mechanism for type 1 electrocardiogram in brugada syndrome a study of electrocardiograms, vectorcardiograms, and body surface potential maps during ajmaline provocation. , 2010, Journal of the American College of Cardiology.

[7]  Mark Potse,et al.  UvA-DARE ( Digital Academic Repository ) Pathophysiological mechanisms of arrhythmogenic right ventricular disorders , 2013 .

[8]  H. Tan,et al.  Cardiac sodium channelopathies , 2009, Pflügers Archiv - European Journal of Physiology.

[9]  S. Priori,et al.  Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities. , 2009, European Heart Journal.

[10]  A. Wilde,et al.  SCN5A Mutations and the Role of Genetic Background in the Pathophysiology of Brugada Syndrome , 2009, Circulation: Cardiovascular Genetics.

[11]  G. Breithardt,et al.  Absence of Pathognomonic or Inflammatory Patterns in Cardiac Biopsies From Patients With Brugada Syndrome , 2008, Circulation: Arrhythmia and Electrophysiology.

[12]  Ruben Coronel,et al.  Slow and Discontinuous Conduction Conspire in Brugada Syndrome: A Right Ventricular Mapping and Stimulation Study , 2008, Circulation. Arrhythmia and electrophysiology.

[13]  D. Tester,et al.  Syntrophin mutation associated with long QT syndrome through activation of the nNOS–SCN5A macromolecular complex , 2008, Proceedings of the National Academy of Sciences.

[14]  H. Wichmann,et al.  Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. , 2008, The Journal of clinical investigation.

[15]  P. C. Viswanathan,et al.  Mutation in Glycerol-3-Phosphate Dehydrogenase 1–Like Gene (GPD1-L) Decreases Cardiac Na+ Current and Causes Inherited Arrhythmias , 2007, Circulation.

[16]  Michel Haïssaguerre,et al.  Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death , 2007, Circulation.

[17]  P. Carmeliet,et al.  Overlap Syndrome of Cardiac Sodium Channel Disease in Mice Carrying the Equivalent Mutation of Human SCN5A-1795insD , 2006, Circulation.

[18]  Patrick Ruchat,et al.  Cardiac Sodium Channel Nav1.5 Is Regulated by a Multiprotein Complex Composed of Syntrophins and Dystrophin , 2006, Circulation research.

[19]  S. Priori,et al.  Cardiac Histological Substrate in Patients With Clinical Phenotype of Brugada Syndrome , 2005, Circulation.

[20]  Simona Casini,et al.  Sodium channel dysfunction in inherited and acquired cardiac diseases , 2008 .

[21]  A. Wilde,et al.  A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. , 2005, Journal of molecular and cellular cardiology.

[22]  D. Gros,et al.  Mouse Model of SCN5A-Linked Hereditary Lenègre’s Disease: Age-Related Conduction Slowing and Myocardial Fibrosis , 2005, Circulation.

[23]  J. Brugada,et al.  Brugada syndrome: report of the second consensus conference. , 2005, Heart rhythm.

[24]  Jeffrey L. Anderson,et al.  Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. , 2005, JAMA.

[25]  R. Razmi Magnetic Resonance Imaging Findings in Patients with Brugada Syndrome , 2004, Journal of cardiovascular electrophysiology.

[26]  A. Wilde,et al.  Delay in Right Ventricular Activation Contributes to Brugada Syndrome , 2004, Circulation.

[27]  A. Moorman,et al.  Cardiac chamber formation: development, genes, and evolution. , 2003, Physiological reviews.

[28]  A. George,et al.  Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). , 2003, The Journal of clinical investigation.

[29]  S. Plein,et al.  Comparison of right ventricular volume measurements between axial and short axis orientation using steady‐state free precession magnetic resonance imaging , 2003, Journal of magnetic resonance imaging : JMRI.

[30]  Lucas J Herfst,et al.  Compound Heterozygosity for Mutations (W156X and R225W) in SCN5A Associated With Severe Cardiac Conduction Disturbances and Degenerative Changes in the Conduction System , 2003, Circulation research.

[31]  T. Kurita,et al.  Abnormal response to sodium channel blockers in patients with Brugada syndrome: augmented localised wall motion abnormalities in the right ventricular outflow tract region detected by electron beam computed tomography , 2003, Heart.

[32]  H. Jongsma,et al.  A Cardiac Sodium Channel Mutation Cosegregates With a Rare Connexin40 Genotype in Familial Atrial Standstill , 2003, Circulation research.

[33]  R. Hauer,et al.  Proposed diagnostic criteria for the Brugada syndrome: consensus report. , 2002, Circulation.

[34]  P. C. Viswanathan,et al.  Clinical, Genetic, and Biophysical Characterization of SCN5A Mutations Associated With Atrioventricular Conduction Block , 2002, Circulation.

[35]  E. Stevens,et al.  The sodium channel β‐subunit SCN3b modulates the kinetics of SCN5a and is expressed heterogeneously in sheep heart , 2001, The Journal of physiology.

[36]  P. C. Viswanathan,et al.  A sodium-channel mutation causes isolated cardiac conduction disease , 2001, Nature.

[37]  A. Wilde,et al.  A single Na(+) channel mutation causing both long-QT and Brugada syndromes. , 1999, Circulation research.

[38]  M. T. Case,et al.  Chronic oral toxicity and oncogenicity studies of flecainide, an antiarrhythmic, in rats and mice. , 1984, Toxicology and applied pharmacology.

[39]  Hugues Abriel,et al.  Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology. , 2010, Journal of molecular and cellular cardiology.