Ischaemic and genetic causes of fatal arrhythmias and sudden death

For the podcast associated with this article, please visit https://academic. oup.com/eurheartj/pages/Podcasts. Fatal arrhythmias have a variety of causes and are associated with a number of cardiac conditions including coronary artery disease,1 cardiomyopathies,2,3 heart failure,4 Takotsubo syndrome,5 channelopathies such as long QT6,7 or Brugada syndromes,8,9 as well as congenital heart disease (e.g. Ebstein anomaly10). Most commonly, however, they are triggered by ischaemia, typically in the context of an acute coronary syndrome (ACS). The annual incidence of sudden cardiac death averages 0.6–1% in post-myocardial infarction patients with normal or near normal left ventricular ejection fraction (LVEF). This latter aspect is further pursued in an article entitled ‘Arrhythmic risk stratification in post-myocardial infarction patients with preserved ejection fraction: the PRESERVE EF study’ by Konstantinos A. Gatzoulis and colleagues from the University of Athens Medical School in Greece.11 In a multicentre, prospective, observational cohort study they tested a combined non-invasive/invasive risk stratification approach in 575 post-myocardial infarction ischaemia-free patients with LVEF ≥40%. Patients with either premature ventricular complexes, non-sustained ventricular tachycardia, late potentials, prolonged QTc, T-wave alternans, reduced heart rate variability, or abnormal deceleration capacity with turbulence on ECG were referred for programmed ventricular stimulation, with implantable cardioverter defibrillators (ICDs) offered to those who were inducible (Figure 1). Overall, 35.5% of the patients had at least one ECG feature. Of all patients, 27% of those undergoing programmed ventricular stimulation were inducible; 90% of them received an ICD. Within 32 months no sudden deaths were observed, but nine ICDs (1.6% of screened patients) were appropriately activated. Thus, the two-step approach of the PRESERVE EF study detects a small post-myocardial infarction subpopulation at risk of major arrhythmic events in spite of a maintained LVEF that benefits from an ICD. This conclusion is critically discussed in an Editorial by Jeffrey J. Goldberger from the University of Miami School of Medicine in Florida, USA.12 Outline of study design and findings. Starting with a cohort exhibiting a prevalence of major arrhythmic events at the 1.5% level (after a 32-month follow-up), the two-step, programmed ventricular stimulation-inclusive approach allowed for the identification of a high arrhythmic risk subgroup with a major arrhythmic event prevalence reaching 22% (almost 15-fold higher than baseline). LP, late potentials; MAE, major arrhythmic event; NIRF, non-invasive risk factors; nsVT, non-sustained ventricular tachycardia; PVC, premature ventricular complex (from Gatzoulis KA, Tsiachris D, Arsenos P, Antoniou C-K, Dilaveris P, Sideris S, Kanoupakis E, Simantirakis E, Korantzopoulos P, Goudevenos I, Flevari P, Iliodromitis E, Sideris A, Vassilikos V, Fragakis N, Trachanas K, Vernardos M, Konstantinou I, Tsimos K, Xenogiannis I, Vlachos K, Saplaouras A, Triantafyllou K, Kallikazaros I, Tousoulis D. Arrhythmic risk stratification in post-myocardial infarction patients with preserved ejection fraction: the PRESERVE EF study. See pages 2940–2949). Catecholaminergic polymorphic ventricular tachycardia is an inherited genetic disorder involving cardiac proteins regulating calcium haemostasis,13 most commonly due to a mutation in the ryanodine receptor gene.14 The condition predisposes those affected to potentially life-threatening arrhythmias and sudden death. Importantly, in patients with catecholaminergic polymorphic ventricular tachycardia, ICDs are sometimes ineffective and may even trigger fatal electrical storms. In a clinical research article entitled ‘Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest’, Christian van der Werf and colleagues from the Academic Medical Center in Amsterdam, the Netherlands assessed the efficacy and complications of ICDs placed in 136 previously untreated patients who presented with a first event of sudden cardiac arrest.15 After diagnoses, a guideline-based therapy,16 including beta-blockers, flecainide, and/or left cardiac sympathetic denervation, was initiated, and an ICD was implanted in 58% of patients. After 4.8 years, sudden death had occurred in 3.8% with an ICD and in none of those without one. Sudden death or cardiac arrest, or appropriate ICD shocks, occurred in 47% with an ICD and in 16% without one. Inappropriate ICD shocks occurred in 25% and other device-related complications in 29%. Thus, in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia who presented with sudden cardiac arrest, an ICD is not associated with improved survival. Instead, ICDs are associated with a high rate of appropriate and inappropriate shocks along with other device-related complications. Strict adherence to guideline-based medical therapy without an ICD may provide better protection, a clinically highly relevant conclusion that is put into context in an Editorial by Sami Viskin from the Tel Aviv Medical Center in Israel.17 Calmodulinopathies are rare life-threatening arrhythmia syndromes, caused by mutations in any of the three genes (CALM1–CALM3) that encode identical calmodulin isoforms. The genetic disorder affects mostly young individuals. In a clinical research manuscript entitled ‘Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry’, Peter J. Schwartz and colleagues from the Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico in Milan, Italy established the International Calmodulinopathy Registry that so far has enrolled 74 subjects with a variant of one of the three genes to understand the natural history, clinical features, and response to therapy of such patients.18 The vast majority, i.e. 87%, were symptomatic, and the 10-year mortality was 27%. The two prevalent phenotypes were long QT syndrome in 49% and catecholaminergic polymorphic ventricular tachycardia in 28%. Those with a long QT syndrome had prolonged QTc intervals to 594 ms, a high prevalence (78%) of life-threatening arrhythmias, and poor response to therapies. All patients with catecholaminergic polymorphic ventricular tachycardia were symptomatic, with the ECG frequently showing prominent U waves. Other phenotypes were idiopathic ventricular fibrillation, sudden unexplained death, overlapping syndromes, and one neurological phenotype. Thus, calmodulinopathies are largely characterized by adrenergically induced life-threatening arrhythmias. Available therapies are disquietingly ineffective, especially in those with a long QT phenotype. The clinical implications are further discussed in an enlightening Editorial by Mette Nyegaard from Aarhus University in Denmark.19 Cardiac resynchronization therapy or CRT has markedly advanced the management of patients with heart failure and wide QRS complexes as it prolongs life and reduces sudden cardiac death.20 However, CRT is not effective in all patients.21 In their article ‘Cardiac resynchronization therapy non-responder to responder conversion rate in the more response to cardiac resynchronization therapy with MultiPoint Pacing (MORE-CRT MPP) study: results from Phase I’, Christophe Leclercq and colleagues from the Hopital Pontchaillou CHU in Rennes Cedex, France assess in a randomized trial the impact of MultiPoint™ Pacing (MPP) or continued biventricular pacing in 1921 non-responders to standard biventricular pacing.22 No difference was observed in non-responder to responder conversion rate between MultiPoint™ Pacing or continued biventricular pacing (Figure 2). In the MultiPoint™ Pacing arm, 29% received MultiPoint™ Pacing programmed with a wide LV electrode anatomical separation of ≥30 mm and shortest LV1–LV2 and LV2–RV timing delays, while 71% received MultiPoint™ Pacing programmed with other settings (MPP-Other). The former pacing mode elicited a significantly higher non-responder conversion rate compared with the latter of 46% vs. 26.2% and a trend to a higher conversion rate of 46% compared with biventricular pacing (34%). Thus, after 6 months, the investigator-discretionary MultiPoint™ Pacing programming did not significantly increase the echocardiographic response compared with biventricular pacing in CRT non-responders. Non-responder to responder conversion rate: study primary endpoint The graph displays the proportion of patients converted from non-responders at 6 months to responders at 12 months between the two arms (MultiPointTM pacing and biventricular) (from Leclercq C, Burri H, Curnis A, Delnoy PP, Rinaldi CA, Sperzel J, Lee K, Calò L, Vicentini A, Concha JF, Thibault B, on behalf of the MORE-CRT MPP Investigators. Cardiac resynchronization therapy non-responder to responder conversion rate in the more response to cardiac resynchronization therapy with MultiPoint Pacing (MORE-CRT MPP) study: results from Phase I. See pages 2979--2987). This issue is complemented by various Discussion Forum contributions. In the first one ‘How to assess nocturnal hypoxaemic burden in cardiology?’ Dominik Linz and Mathias Baumert from the University of Adelaide in Australia comment on the recently published article entitled ‘The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study’ by Ali Azarbarzin and colleagues from Harvard Medical School in Boston, Massachusetts (USA).23,24 The second Discussion Forum ‘The hypoxic burden: also known as the desaturation severity parameter’ by Timo Leppänen and colleagues from the University of Eastern Finland in Kuopio, Finland also refers to this contribution.25 Azarbarzin et al. respond to both comments in separate responses.26,27 In another Discussion Forum contribution entitled ‘Reduction in mortality from implantable cardioverterdefibrillators in non-ischaemic cardiomyopathy patients is dependent on the presence of left ventricular scar’, Simon Martin Frey and colleagues from the Universitätsspital Basel in Switzerland comment on the recently published article ‘Reduction in mortality from implantable cardioverter-defibrillators in non-ischaemic cardiomyopathy patients is dependent on the presence of left ventricular scar’ by Andrew J Taylor and colleagues from the Alfred Heart Centre and Baker IDI Heart and Diabetes Research Institute in Melbourne, Australia.28,29 Taylor et al. respond to this contribution in their own manuscript.30 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.