Channelopathies and sudden cardiac death: genetics and pharmacological triggers

For the podcast associated with this article, please visit https://academic. oup.com/eurheartj/pages/Podcasts. Sudden cardiac death has many causes. Most commonly individuals during or after acute myocardial infarction1 or those with heart failure2 are prone to fatal arrhythmias. Particularly in younger subjects, however, genetic cardiomyopathies and channelopathies are important causes of sudden death. Often overlooked are channelopathies such as the short3,4 or long QT and Brugada syndromes, in which mutations in the gene (SCN5A) encoding the alpha subunit of the cardiac sodium channel (NaV1.5) are known to be involved.5 Brugada syndrome is an inherited cardiac disorder predisposing to ventricular arrhythmias6 with characteristic ECG features.7 Despite considerable efforts, its genetic basis and cellular mechanisms are not fully understood. In their article entitled ‘RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome’, Flavien Charpentier and colleagues from INSERM in Nantes, France sought to identify a new susceptibility gene for Brugada syndrome.8 Whole-exome sequencing performed in a three-generation pedigree with five affected members allowed the identification of one rare non-synonymous substitution (p.R211H) in RRAD, the gene encoding the RAD GTPase, carried by all affected members of the family. Three additional rare missense variants were found in 3 out of 186 unrelated index cases. In human hearts there were higher levels of RRAD transcripts, particularly in the subepicardium, and in mice in the right ventricular outflow tract. Induced pluripotent stem cells with the p.R211H variant exhibited reduced action potential upstroke velocity, prolonged action potentials, and increased incidence of early afterdepolarizations, with decreased Na+ peak current amplitude and increased Na+ persistent current amplitude, as well as abnormal distribution of actin and fewer focal adhesions, compared with intrafamilial control induced pluripotent stem cells. Insertion of the p.R211H-RRAD variant in control induced pluripotent stem cells confirmed these results. In addition, induced pluripotent stem cells from affected patients exhibited a decreased L-type Ca2+ current amplitude. Thus, RRAD is a new susceptibility gene for Brugada syndrome. These novel findings are put into context in an Editorial by Elijah R. Behr from St George’s University of London in the UK.9 Furthermore, certain drugs may induce or unmask Brigada syndromes, such as RAF and MEK inhibitors for the treatment of melanoma,10 and sodium-channel blockers,11 among others. These may induce fatal arrhythmias, but the variability of cardiac electrical response remains unexplained. This is addressed in the article ‘Predicting cardiac electrical response to sodium channel blockade and Brugada syndrome using polygenic risk scores’ by Rafik Tadros and colleagues from the Institut De Cardiologie de Montreal in Canada.12 In 1368 patients undergoing ajmaline infusion for suspected Brugada syndrome, they investigated predictors of PR and QRS changes and type I Brugada syndrome ECG features. Higher polygenic risk scores for PR interval, baseline PR, and female sex were associated with a more pronounced PR slope, while polygenic risk scores for QRS duration and age were positively associated with QRS slope. Polygenic risk scores for Brugada syndrome, baseline QRS duration, presence of type II or III Brugada ECG features at baseline, and family history of Brugada syndrome were independently associated with the occurrence of a type I Brugada ECG. Thus, genetic factors underlie the variability of cardiac electrical response to sodium channel blockers. Polygenic risk scores for Brugada syndrome, family history, and baseline ECG can predict the development of a diagnostic drug-induced type I Brugada ECG (Figure 1). Thus, polygenic risk scores could be used in the diagnosis of Brugada syndrome and to identify those at risk for arrhythmias to sodium channel blockers. This is further discussed in an Editorial by Pedro Brugada from the Free University of Brussels (UZ Brussel) VUB in Belgium.13 (A) Bar plot representing number of individuals per PRSBrS quintile in the cohort without a known SCN5A mutation, with (red bars) and without (blue bars) ajmaline-induced Type I Brugada syndrome electrocardiogram. (B) Correlation plot of ajmaline dose required to induce a Type I Brugada syndrome electrocardiogram and PRSBrS for SCN5A mutation carriers (red markers) and non-carriers (blue markers). Line represents the linear regression in cases without a known SCN5A mutation, with the correlation coefficient (r) and test P-value (P) at the top left corner (from Tadros R, Tan HL, for the ESCAPE-NET Investigators, el Mathari S, Kors JA, Postema PG, Lahrouchi N, Beekman L, Radivojkov-Blagojevic M, Amin AS, Meitinger T, Tanck MW, Wilde AA, Bezzina CR. Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores. See pages 3097–3107). (A) Bar plot representing number of individuals per PRSBrS quintile in the cohort without a known SCN5A mutation, with (red bars) and without (blue bars) ajmaline-induced Type I Brugada syndrome electrocardiogram. (B) Correlation plot of ajmaline dose required to induce a Type I Brugada syndrome electrocardiogram and PRSBrS for SCN5A mutation carriers (red markers) and non-carriers (blue markers). Line represents the linear regression in cases without a known SCN5A mutation, with the correlation coefficient (r) and test P-value (P) at the top left corner (from Tadros R, Tan HL, for the ESCAPE-NET Investigators, el Mathari S, Kors JA, Postema PG, Lahrouchi N, Beekman L, Radivojkov-Blagojevic M, Amin AS, Meitinger T, Tanck MW, Wilde AA, Bezzina CR. Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores. See pages 3097–3107). Another important channelopathy is congenital long QT syndrome.5,14,15 Patients with that condition should avoid drugs that can cause torsades de pointes, a Class-I recommendation of the ESC guidelines.16 In their article entitled ‘Long-term proarrhythmic pharmacotherapy among patients with congenital long QT syndrome and risk of arrhythmia and mortality’, Peter Weeke and colleagues from Copenhagen University Hospital in Hellerup, Denmark determined the risk of ventricular arrhythmia and all-cause mortality induced by such drugs in congenital long QT syndrome.17 During follow-up, 167 (60%) of the 279 congenital long QT syndrome patients were treated with drugs that may induce torsades de pointes, most commonly antibiotics in 34%, proton pump inhibitors in 15%, antidepressants in 12%, and antifungals in 10%. Treatment with drugs slightly decreased 1 year after diagnosis compared with 1 year before. Five years after diagnosis, 34% had received such drugs. Risk factors for torsades de pointes drug treatment were age at diagnosis and previous treatment with such drugs. During follow-up, nine patients were admitted with ventricular arrhythmia; eight patients died. However, no significant association between the use of drugs potentially inducing torsades de pointes and ventricular arrhythmias or all-cause mortality was found. Thus, the use of drugs potentially inducing torsades de pointes is common among patients with congenital long QT syndrome. In a thought-provoking Editorial, Peter J. Schwartz from the Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico in Milan, Italy reiterates the critical need for more awareness in prescribing patterns in this high-risk patient group.18 Many genetic and inflammatory cardiomyopathies and myocardial storage diseases are prone to arrythmias. Sarcoidosis may affect the heart19 and cause conduction disorders20 and arrythmias,21 and may even phenotypically present as hypertrophic cardiomyopathy.22 In their article ‘Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries’ Kaj Ekström and colleagues from the Helsingin Yliopisto in Finland assessed sudden cardiac death as a presenting manifestation in 351 patients with cardiac sarcoidosis.23 High-grade atrioventricular block was the most common first sign of cardiac sarcoidosis in 42%, followed by heart failure in 16%, unexpected fatal sudden cardiac death in 11%, aborted sudden cardiac death in 3%, and sustained ventricular tachycardia in 14% (Figure 2). Severe coronary artery disease was found at autopsy concomitant with cardiac sarcoidosis in 11% of cases presenting with fatal sudden cardiac death. Of all sudden deaths recorded, two-thirds were unexpected. Survival from symptom onset was 85% at 5 years and 76% at 10 years. Thus, fatal and aborted sudden cardiac death constitute 14% of the presenting manifestations of cardiac sarcoidosis. Nearly two-thirds of all fatalities from cardiac sarcoidosis are caused by undiagnosed granulomas in the heart. Distribution of different presenting manifestations (bar chart) and modes of death (pie chart) in cardiac sarcoidosis in Finland from1998 through 2015 (from Ekström K, Lehtonen J, Nordenswan H-K, Mäyränpää MI, Räisänen-Sokolowski A, Kandolin R, Simonen P, Pietilä-Effati P, Alatalo A, Utriainen S, Rissanen TT, Haataja P, Kokkonen J, Vihinen T, Miettinen H, Kaikkonen K, Kerola T, Kupari M. Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries. See pages 3121–3128). Distribution of different presenting manifestations (bar chart) and modes of death (pie chart) in cardiac sarcoidosis in Finland from1998 through 2015 (from Ekström K, Lehtonen J, Nordenswan H-K, Mäyränpää MI, Räisänen-Sokolowski A, Kandolin R, Simonen P, Pietilä-Effati P, Alatalo A, Utriainen S, Rissanen TT, Haataja P, Kokkonen J, Vihinen T, Miettinen H, Kaikkonen K, Kerola T, Kupari M. Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries. See pages 3121–3128). The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.