Sudden cardiac death (SCD) is an unexplained death due to cardiac causes occurring in a short time period (generally within 1 h of yhe onset of symptoms) in a person with known or unknown cardiac disease (Myeburg, 2001; Priori et al., 2015). SCD is the most common cause of death in the Western countries and, in the USA, it accounts for 250 000–400 000 cases annually (Stecker et al., 2014). The most common electrophysiologic mechanisms leading to SCD are tachyarrhythmias such as ventricular fibrillation (VF) or ventricular tachycardia (VT).
In the general population, the incidence of SCD ranges from 1/100,000 in adolescents to 1/1,000 in individuals aged 45–75 years (Stecker et al., 2014). Almost 80% of the MSC are due to life-threatening arrhythmias [most frequent ventricular fibrillation (VF)] occurring in patients with ischemic heart disease or heart failure. Another 10-15% occurs in patients with heart disease, e.g. hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy, among others; the first two of the leading causes of SCD in young athletes (Wever y Robles, 2004). Finally, in less than 5% of patients, SCD occurs in young theoretically healthy patients (under 30 years) with a structurally normal heart. In many of these patients the epidemiological studies have demonstrated that a family history of SCD is an independent risk factor. This finding strongly suggests that in these patients the arrhythmogenic episode may have a genetic basis, and therefore, we speak of primary arrhythmogenic syndromes.
In the last 20 years we have made extraordinary progress in understanding the pathophysiology of cardiac arrhythmias and molecular genetic studies have established a direct relationship between the presence of mutations in genes encoding ion channels responsible for the electrical activity of the heart and the onset and/or maintenance of certain cardiac arrhythmias which can lead to SCD in the absence of structural heart defects.
Thus, patients with primary arrhythmogenic syndromes present mutations in the genes encoding the a and β subunits of cardiac ion channels or some proteins that form part of the channelosome, i.e. they present a channelopathy leading to alterations in the electrical properties of the cardiomyocytes.From this point of view, primary arrhythmogenic syndromes are purely electrical disorders unrelated to underlying structural heart disease. However, some channelopathies may cause or can be associated with a structural heart disease. In fact, some patients with Brugada syndrome linked to mutations in the SCN5A gene encoding the α-subunit of the Na+ channel present morphological alterations in the right ventricle.
There is a variety of congenital diseases associated to mutations in the genes encoding the a (pore-forming) and “accessory” subunits of ion channels or those encoding any of the proteins that form the channelosome of the different cardiac ion channels. These mutations change sometimes only in subtle ways the functioning of ion channels altering the electrical properties of cardiac myocytes. Therefore, we talk about CHANNELOPATHIES to describe diseases caused by disturbed function of ion channel subunits or the proteins that regulate them (Priori et al., 2013). In fact, the study of inherited channelopathies comprises studies of the whole channel apparatus and the structural framework that direct and supports proteins in the cell membrane.
The channelopathies are PRIMARY ARRHYTHMOGENIC CARDIOMYOPATHIES genetically determined, i.e., they are pure electrical diseases that are not secondary to an underlying structural heart disease. However, some channelopathies may cause or can be associated with a structural heart disease. In fact, some patients with Brugada syndrome linked to mutations in the SCN5A gene encoding the α -subunit of the Na+ channel present morphological alterations in the right ventricle.
Because we are dealing with channelopathies, we must undertand what is an ion channel and the classification, topology and function of the cardiac ion chanel involved in the primary arrhythmogenic syndromes.
Myerburg RJ. Sudden cardiac death: exploring the limits of our knowledge. J Cardiovasc Electrophysiol. 2001;12:369–381.
Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–63.
Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015;36:2793-867.
Stecker EC, Reinier K, Marijon E, et al. Public health burden of sudden cardiac death in the United States. Circ Arrhythm Electrophysiol. 2014;7:212-217.
Wever EF, Robles de Medina EO. Sudden death in patients without structural heart disease. J Am Coll Cardiol 2004; 43:1137-1144.