Past and future of channelopathies and a focus on cardiac arrest

Abstract

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on arrhythmias contains a Special Article contribution entitled ‘1970–2020: 50 years of research on the long QT syndrome—from almost zero knowledge to precision medicine’, authored by Peter Schwartz from the IRCCS in Milan, Italy.1 A lot has been written about the long QT syndrome (LQTS) and there is a wealth of traditional reviews summarizing the existing knowledge on epidemiology, pathogenesis, clinical presentation, and the state of genetic testing.2,3 However, this Special Article is very special indeed. Professor Schwartz notes that those involved in clinical research rarely begin working on a rather obscure disease, still largely unexplored, following its ripening into a medical entity of great interest to clinicians and basic scientists alike, and to do so for exactly 50 years. This is what has been Professor Schwartz’s privilege in the relentless pursuit of the intriguing disease known as LQTS. This essay begins with the encounter with his first patient affected by LQTS when just a handful of cardiologists had seen similar cases, and continues with the series of efforts which eventually led—together with many brilliant partners and associates—to the description and understanding of the natural history of the disease and the most effective therapies. It then touches on how the International Registry for LQTS, with its well-documented family trees, constituted the necessary springboard for the major genetic discoveries of the 1990s. From the explosion of genetic data, his own interest focused first on the intriguing genotype–phenotype correlation and then on ‘modifier genes’, in an attempt to understand why family members with the same disease-causing mutation may have an opposite clinical history; and from there on to induced pluripotent stem cell (iPS)-derived cardiomyocytes, used for unravelling the specific mechanisms of action of modifier genes and for exploring novel therapeutic strategies. This long, and highly rewarding, journey continues because the fascination with and the attraction of the unknown is irresistible. Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to sudden cardiac death (SCD) by the Brugada brothers, although its eponymous title was only bestowed 4 years later. Eight patients had demonstrated an electrocardiogram (ECG) pattern of ‘right bundle branch block, normal QT interval and persistent ST-segment elevation in precordial leads V1 to V2–V3 not explainable by electrolyte disturbances, ischaemia or structural heart disease’.4 In a State of the Art Review article entitled ‘Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?’, Elijah Behr from St George’s University of London in the UK, and colleagues5 note that BrS was first described as a primary electrical disorder predisposing to the risk of SCD and characterized by right precordial lead ST elevation. Then, early descriptions of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. The authors propose that the final common pathway for BrS could be viewed as a disease of ‘reduced RVOT conduction reserve’ (Figure 1). Brugada syndrome (BrS) as a disease of impaired right ventricular outflow tract (RVOT) conduction reserve. Normally, intrinsic RVOT conduction reserve may be affected by a patient’s age and gender. In BrS, cellular and tissue abnormalities cause a reduction in RVOT conduction reserve: genetic abnormalities, whether mediated by a pathogenic SCN5A variant, an increased BrS-PRS, and/or additional genetic insults, may have direct effects on Nav1.5, as well as tissue effects causing RVOT inflammation, fibrosis, and gap junction abnormalities. Decreased Nav1.5 current, together with electrical discontinuity caused by RVOT structural changes, converges to disrupt normal depolarization, with or without secondary repolarization effects, leading to impairment of the conduction reserve of the RVOT. In this framework, the marginal conduction reserve can be exposed by acute modulators such as fever, drugs, and altered vagal tone which further impair conduction and expose the Brugada phenotype (from Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM. Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway? See pages 1073–1081). Brugada syndrome (BrS) as a disease of impaired right ventricular outflow tract (RVOT) conduction reserve. Normally, intrinsic RVOT conduction reserve may be affected by a patient’s age and gender. In BrS, cellular and tissue abnormalities cause a reduction in RVOT conduction reserve: genetic abnormalities, whether mediated by a pathogenic SCN5A variant, an increased BrS-PRS, and/or additional genetic insults, may have direct effects on Nav1.5, as well as tissue effects causing RVOT inflammation, fibrosis, and gap junction abnormalities. Decreased Nav1.5 current, together with electrical discontinuity caused by RVOT structural changes, converges to disrupt normal depolarization, with or without secondary repolarization effects, leading to impairment of the conduction reserve of the RVOT. In this framework, the marginal conduction reserve can be exposed by acute modulators such as fever, drugs, and altered vagal tone which further impair conduction and expose the Brugada phenotype (from Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM. Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway? See pages 1073–1081). Since its description, BrS has been the subject of increased scientific interest as a cause of SCD due to ventricular tachycardia/fibrillation in young and otherwise healthy individuals. BrS is believed to be a genetic disease, although the majority of clinically confirmed cases lack molecular validation, due to our current shortfall of understanding of the genetics of this syndrome.6,7 Despite SCN5A being the most commonly known mutated gene to date, the genotype–phenotype relationship is poorly understood and remains uncertain. In a clinical research article entitled ‘Brugada syndrome genetics is associated with phenotype severity’, Giuseppe Ciconte from the IRCCS Policlinico San Donato in Italy, and colleagues aimed to elucidate the genotype–phenotype correlation in BrS.8 BrS probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by means of epicardial arrhythmogenic substrate mapping and were allocated to two groups according to the presence or absence of the SCN5A mutation. Two hundred probands (mean age 43 years) were included in this study. SCN5A-positive patients exhibited a larger epicardial arrhythmogenic substrate area, more prolonged ECGs, and more frequently late potentials at non-invasive testing (Figure 2). The presence of an SCN5A mutation explained >26% of the variation in the epicardial arrhythmogenic substrate area and was the strongest predictor of a larger epicardial arrhythmogenic area. Brugada syndrome phenotypic expression predictors. (A) Large Brugada syndrome epicardial substrate in a male patient with spontaneous type 1 electrocardiogram pattern experiencing appropriate implantable cardioverter-defibrillator therapy. (B) Specific contribution of each variable (SCN5A mutations, spontaneous type 1 electrocardiogram pattern, and gender), in explaining the variance of the arrhythmogenic substrate. (C) Receiver-operating characteristic curve analysis demonstrating the accuracy of the model for the prediction of a large arrhythmogenic substrate (≥6.3 cm2) (from Ciconte G, Monasky MM, Santinelli V, Micaglio E, Vicedomini G, Anastasia L, Negro G, Borrelli V, Giannelli L, Santini F, de Innocentiis C, Rondine R, Locati ET, Bernardini A, Mazza BC, Mecarocci V, Calović Ž, Ghiroldi A, D’Imperio S, Benedetti S, Di Resta C, Rivolta I, Casari G, Petretto E, Pappone C. Brugada syndrome genetics is associated with phenotype severity. See pages 1082–1090). Brugada syndrome phenotypic expression predictors. (A) Large Brugada syndrome epicardial substrate in a male patient with spontaneous type 1 electrocardiogram pattern experiencing appropriate implantable cardioverter-defibrillator therapy. (B) Specific contribution of each variable (SCN5A mutations, spontaneous type 1 electrocardiogram pattern, and gender), in explaining the variance of the arrhythmogenic substrate. (C) Receiver-operating characteristic curve analysis demonstrating the accuracy of the model for the prediction of a large arrhythmogenic substrate (≥6.3 cm2) (from Ciconte G, Monasky MM, Santinelli V, Micaglio E, Vicedomini G, Anastasia L, Negro G, Borrelli V, Giannelli L, Santini F, de Innocentiis C, Rondine R, Locati ET, Bernardini A, Mazza BC, Mecarocci V, Calović Ž, Ghiroldi A, D’Imperio S, Benedetti S, Di Resta C, Rivolta I, Casari G, Petretto E, Pappone C. Brugada syndrome genetics is associated with phenotype severity. See pages 1082–1090). The authors conclude that in BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the phenotypic expression of BrS and provide possible explanations for the varying degrees of disease expression. The manuscript is accompanied by an Editorial by Connie R. Bezzina from the AMC Heart Center in Amsterdam, the Netherlands, and colleagues.9 The authors note that while we are still at the early stages of being able to offer individualized prognosis for BrS patients, studies like that of Ciconte and colleagues are beginning to illuminate the path between genetic risk factors and clinical outcomes. Although COVID-19 manifests primarily as a severe respiratory infection, numerous studies demonstrate that cardiovascular complications are common, and pre-existing cardiovascular conditions are predictors of survival in COVID-19.10–12 The first cases of COVID-19 in Sweden were reported in early February 2020. The Swedish Public Health Authority declared community spread in Sweden on 16 March. As a consequence, updated guidelines from the European Resuscitation Council (ERC) and the Swedish Resuscitation Council recommended that bystanders should avoid ventilation and focus their resuscitation attempts on chest compressions only in the case of suspected COVID-19.13 In a clinical research article entitled ‘Cardiac arrest in COVID-19: characteristics and outcomes of in- and out-of-hospital cardiac arrest. A report from the Swedish Registry for Cardiopulmonary Resuscitation’, Pedram Sultanian from the University of Gothenburg in Sweden, and colleagues investigated characteristics and outcomes among cardiac arrest cases with COVID-19 and differences between the pre-pandemic and the pandemic period in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA).14 The authors included all patients reported to the Swedish Registry for Cardiopulmonary Resuscitation from anuary to July 2020. Sultanian et al. enrolled ∼2000 cases of OHCA and 1000 cases of IHCA. During the pandemic, 10.0% of OHCAs and 16.1% of IHCAs had ongoing COVID-19 with regards to OHCA. Adjusted 30-day survival was 4.7% for patients with COVID-19, 9.8% for patients without COVID-19, and 7.6% in the pre-pandemic period (P = 0.03) with regards to IHCA. Adjusted 30-day survival was 23.1% in COVID-19-positive cases, 39.5% in patients without COVID-19, and 36.4% in the pre-pandemic period (P = 0.04). The authors conclude that this is, to the best of their knowledge, the most detailed report on characteristics and outcome in COVID-19 patients suffering cardiac arrest within and beyond the hospital perimeter, and that they report a number of unexpected findings, many of which highlight the severity of COVID-19 and the potential shift in the epidemiology of cardiac arrest brought about by this pandemic. The manuscript is accompanied by an Editorial by Xavier Jouven from the Université de Paris in France, and colleagues.15 The authors note that these findings highlight the importance of anticipation and planning in the management of healthcare crises. The observations with respect to the COVID-19 pandemic and cardiac arrest should serve as an important wake-up call for healthcare systems worldwide to develop blueprints and contingency plans for preparedness in the case of such eventualities. With improvements in pharmacological and device therapy, earlier and more aggressive cardiovascular prevention, and prompt coronary intervention, there has been a gradual and substantial reduction in SCD risk over the last two decades in patients with heart failure. Thus, one may even reasonably speculate whether the results of randomized trials on implantable cardioverter-defibrillators (ICDs) would be the same if conducted in the current era of heart failure management,16,17 as the evidence supporting guideline recommendations for ICDs dates from the late 1990s and early 2000s.18 There is a particular need to revisit the current status of routine primary prevention ICD implantation in women. This issue contains a Viewpoint article entitled ‘Time to revisit implantable cardioverter-defibrillator implantation criteria in women’ by Sérgio Barra from the Hospital da Luz Arrábida in Portugal, and colleagues.19 The authors note that the low level of participation of female patients in ICD trials is a long-standing problem, but physicians and guidelines continue to extrapolate from results derived mainly from men to recommend routine ICD implantation in women despite lack of clear proof of a reduction in mortality. Conversely, the benefit of an ICD in men may have been relatively underestimated when looking at the data in total. It is evident that the data being used for decision-making are both outdated and also weak with respect to potential benefit in women. Hence it can be strongly argued that true equipoise exists for new, well-designed randomized trials assessing the efficacy of primary prevention ICDs, particularly in female patients, in conjunction with current heart failure therapies. The issue is also complemented by two Discussion Forum contributions. In an article entitled ‘Prognostication after out-of-hospital cardiac arrest: biases and caveats’, Andrew Williams from the King’s College Hospital in London, UK and colleagues comment on the recent publication entitled ‘A practical risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest: MIRACLE2’ by Nilesh Pareek from the King’s College Hospital NHS Foundation Trust in the UK, and colleagues.20,21 Pareek and colleagues respond in a separate contribution.22 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.