Author + information
- Received October 16, 2017
- Revision received March 2, 2018
- Accepted March 8, 2018
- Published online May 21, 2018.
- aHeart Centre Academic Medical Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- bPrincess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia
- cDepartment of Medicine, Columbia University Irving Medical Centre, New York, New York
- ↵∗Address for correspondence:
Dr. Arthur A.M. Wilde, Department of Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
SCN5A gene encodes the pore-forming ion-conducting α-subunit of the cardiac sodium channel (Nav1.5), which is responsible for the initiation and propagation of action potentials and thereby determines cardiac excitability and conduction of electrical stimuli through the heart. The importance of Nav1.5 for normal cardiac electricity is reflected by various disease entities that can be caused by mutations in SCN5A. Gain-of-function mutations in SCN5A lead to more sodium influx into cardiomyocytes through aberrant channel gating and cause long QT syndrome, a primary electrical disease of the heart. Loss-of-function mutations in SCN5A lead to lower expression levels of SCN5A or production of defective Nav1.5 proteins and cause Brugada syndrome, an electrical disease with minor structural changes in the heart. In addition, both loss- and gain-of-function mutations may cause dilated cardiomyopathy, which is an arrhythmogenic disease with gross structural defects of the left ventricle (and sometimes both ventricles). Other SCN5A-related diseases are multifocal ectopic premature Purkinje-related complexes (gain-of-function mutations), isolated cardiac conduction defect (loss-of-function mutations), sick sinus syndrome (loss-of-function mutations), atrial fibrillation (loss-of-function or gain-of-function mutations), and overlap syndromes (mutations with both loss-of-function and gain-of-function effects). Growing insights into the role of SCN5A in health and disease has enabled clinicians to lay out gene-specific risk stratification schemes and mutation-specific diagnostic and therapeutic strategies in the management of patients with a SCN5A mutation. This review summarizes currently available knowledge about the pathophysiological mechanisms of SCN5A mutations and describes how this knowledge can be used to manage patients suffering from potentially lethal cardiac diseases.
Supported by the Netherlands CardioVascular Research Initiative, the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (PREDICT; to Drs. Wilde and Amin). The funding sources had no role in the preparation of the manuscript and in the decision to submit the manuscript for publication. Dr. Wilde has served on the scientific advisory board of LilaNova. Dr. Amin has reported that he has no relationships relevant to the contents of this paper to disclose. The authors are members of the European Reference Network for rare, low prevalence, and complex diseases of the heart (Expertise Reference Network GUARD-Heart).
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Received October 16, 2017.
- Revision received March 2, 2018.
- Accepted March 8, 2018.
- 2018 American College of Cardiology Foundation