ABC | Volume 112, Nº3, March 2019

Updated The Brazilian Society of Cardiology and Brazilian Society of Exercise and Sports Medicine Updated Guidelines for Sports and Exercise Cardiology - 2019 Arq Bras Cardiol. 2019; 112(3):326-368 5. Channelopathies 5.1. Introduction Channelopathies are inherited arrhythmogenic heart diseases that do not involve structural impairment and are caused by genetic changes that result in dysfunction of the cardiac ion channels, which leads to risk of SD. 163 The most commonly known channelopathies are long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPTV) 75 Sinus node disease and Lenegre disease or conduction system disease are also examples of channelopathies. Ion channels, the ion currents moving through these channels, proteins that attach to the membrane structure of myocardial cells, and the junctions between these structures are involved in electrical impulse formation and the synchronous transmission of these impulses throughout the heart, which generates cardiac action potential. 164,165 The performance of each of these functions is determined by different genes. Mutations in related genes cause specific dysfunctions and cause channelopathies. 166,167 The ion channels in the cell membrane allow ions to enter and exit following a voltage gradient. Genetic mutation in these channels can lead to gain or loss of function. With the recent increases in knowledge about these entities, defibrillator use and easier access to genetic evaluation, decisions shared between the medical team and the family have allowed a more permissive stance toward exercise in individuals with channelopathies. 168 Detailed recommendations on the most prevalent syndromes are described below. 5.2. Long QT Syndrome Long QT syndrome (LQTS) is the prototype channelopathy. First describedmore than 50 years ago as an autosomal recessive disease, Jervell and Lange-Nielsen syndrome 169,170 includes congenital deafness, increased QTc intervals, and syncope or SD. Subsequently, an autosomal dominant form called Roman-Ward syndrome (prolonged QTc without deafness) was discovered. Several types of LQTS are currently known, which are determined by gene mutations that cause distinct changes in ventricular depolarization and repolarization. The typical clinical features of LQTS include syncope or SD associated with increased QTc intervals and ventricular tachyarrhythmias such as torsade de pointes. 171 Typically, certain factors trigger syncope in LQTS, which are related by subtype and genotype. The most common triggers are: adrenergic activity in SQTL1, sudden awakening and an acute auditory stimulus in SQTL2 and sleeping/resting in SQTL3. However, phenotypic presentations vary widely. Carriers can be asymptomatic, have no increase in QTc interval or have syncope or SD in the first days of life. Thus, diagnostic criteria were developed to score alterations, which are divided into three main groups: clinical history, family history and ECG. 163 5.2.1. Genetic Alterations in Long QT Syndrome Genetic alterations are known in approximately 60% of the clinical cases of LQTS, and at least 17 genes have been associated with this clinical entity. Generally, patients have mutations in three specific genes: KCNQ1, KCNH2 or SCN5A. 172 Hundreds of mutations have already been described, with the most prevalent type being cardiac. 173 The most common mutation occurs in the KCNQ1 gene, which is responsible for more than 30% of the genetic variants and pathological mutations identified in LQTS and causes SQTL1. 173 This type of mutation causes a loss of function in the IKs potassium current, 166 which plays an important role in cell repolarization and QT interval adaptation to heart rate. SQTL5, a mutation caused by the KCNE1 gene, is much less frequent (considered rare) and is responsible for IKs loss-of- function. 166 The KCNH2 (HERG) gene, which encodes the alpha subunit of the fast potassium channels, and KCNE2, which encodes the beta subunit, are responsible for the rapid entry of potassium during phase 3 of the action potential. 174 Loss of alpha subunit function accounts for 40% of genotyped LQTS and is responsible for SQTL2. 175 SQTL3 accounts for approximately 10% of all mutations diagnosed in LQTS, due to changes in the SCN5A gene, whose functional gain produces a continuous sodium input during the plateau phase, which facilitates early depolarization in cardiac cells. Although hundreds of other mutations have been described, treatment and follow-up of LQTS patients and families are restricted to the most known forms. 176 5.2.2. Risk Stratification in Long QT Syndrome Genetic analysis has been widely used for risk stratification and determining specific therapeutic interventions in LQTS patients and their relatives. Since LQTS is an uncommon clinical condition and data have only been obtained through cohort studies, the evidence level for recommendations about risk stratification and treatment strategies has been limited to B. The most robust risk marker of LQTS is a previous episode of aborted SD, and its most common cause is polymorphic ventricular tachycardia, degenerating or not into ventricular fibrillation. Patients who have experienced such a condition have a 13-fold increased risk of new SD episodes. Previous syncope is also an extremely unfavorable risk marker, which could double the risk. 177 However, the risk of having an arrhythmic event is not the same for all patients. Evidence shows that individuals with SQTL2 and SQTL3 have a higher risk of events than those with the mutations that cause SQTL1. In addition, individuals with a QTc duration > 500 ms are at higher risk than those with shorter QTc durations. 172 Mutations involving the gene segment that encodes the channel pore are also related to poorer prognosis. Therefore, once again, the value of genotyping in patients with this syndrome is clear. A family history of SD did not prove to be a higher risk marker for events. 178 5.2.3. Recommendations for Athletes with Long QT Syndrome A few years ago, LQTS patients were advised not to participate in competitive sports based on the understanding that they were exposed to an increased risk of SD. In 2015, Aziz et al. 179 studied more than 100 patients with a positive LQTS genotype, all engaged in some type of sports program. 345