Causes and prevention of sudden cardiac death: ECG, electroanatomical mapping, fibrosis, and channelopathies

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Sudden cardiac death is a devastating event for those involved and their families, and an ongoing challenge for physicians. While implantable cardioverter defibrillators have proven effective for those at high risk,1–3 many of those receiving one never have an event. On the other hand, many die suddenly without being considered for such an intervention. Obviously the currently available risk assessment is not sensitive and specific enough. This applies in particular to those with non-ischaemic cardiomyopathies. While current guidelines recommend implantable cardioverter defibrillators in symptomatic patients with a left ventricular ejection fraction ≤35%,1 the recent Danish trial did not show benefit of prophylactic implantable cardioverter defibrillator implantation,4 although sudden cardiac death accounts for about one-third of all deaths among such patients. This dilemma is further discussed in a review entitled ‘Primary prevention implantable cardioverter-defibrillator and opportunities for sudden cardiac death risk assessment in non-ischaemic cardiomyopathy’ by Rajat Deo and colleagues from the University of Pennsylvania in Philadelphia, Pennsylvania, USA.5 They remind us that recommendations of current guidelines are based on meta-analyses of multiple trials that span three decades and include the recent DANISH trial.6 These pooled analyses report a significant reduction in all-cause mortality with implantable cardioverter defibrillator implantation compared with medical therapy alone. A refined approach of risk stratification selecting those at highest risk for sudden cardiac death may lead to an improvement in implantable cardioverter defibrillator efficacy. The authors highlight key markers of arrhythmia risk that hold promise in personalizing risk stratification for sudden cardiac death. For further risk assessment for sudden cardiac death and mortality, the amount of fibrosis within the myocardium as assessed by cardiac magentic resonance imaging (MRI) has been suggested.7,8 However, electroanatomical voltage mapping might be a better diagnostic tool for fibrosis identification. In their article entitled ‘Whole human heart histology to validate electroanatomical voltage mapping in patients with non-ischaemic cardiomyopathy and ventricular tachycardia’, Katja Zeppenfeld and colleagues from the Leiden University Medical Center in the Netherlands evaluated electroanatomical voltage mapping to detect fibrosis in non-ischaemic cardiomyopathy patients with ventricular tachycardias.9 Eight patients with non-ischaemic cardiomyopathy and ventricular tachycardias underwent electroanatomical voltage mapping prior to death or heart transplantation, with mapping data being projected onto slices of the heart (Figure 1). Pattern, architecture, and amount of fibrosis were assessed in transmural biopsies corresponding to electroanatomical voltage mapping sites. The fibrosis pattern in 507 non-ischaemic cardiomyopathy biopsies was highly variable and not limited to mid-wall/subepicardium. Fibrosis architecture was rarely compact, but typically patchy or diffuse. In non-ischaemic cardiomyopathy biopsies without abnormal fibrosis, unipolar and bipolar voltages showed a linear association with wall thickness. The amount of viable myocardium showed a linear association with both unipolar voltages and bipolar voltages. Accordingly, any cut-off to delineate fibrosis performed poorly. Th fibrosis pattern and architecture are different from those of ischaemic cardiomyopathy, and findings on ischaemic substrates may not be applicable to non-ischaemic cardiomyopathy. The implications of these findings are further discussed in an Editorial by Ardan Muammer Saguner from the University Heart Center Zurich, Switzerland.10 Voltage mapping has been integrated with full human heart histology in non-ischaemic cardiomyopathy. The histological substrate has been described, and the relationship between the amount of fibrosis as well as wall thickness and both bipolar and unipolar voltages demonstrated (from Glashan CA, Androulakis AFA, Tao Q, Glashan RN, Wisse LJ, Ebert M, de Ruiter MC, van Meer BJ, de Bakker JMT, de Riva M, Piers SRD, Zeppenfeld K. Whole human heart histology to validate electroanatomical voltage mapping in patients with non-ischaemic cardiomyopathy and ventricular tachycardia. See pages 2867–2875). Cardiac conduction disorders are an important cause of sudden cardiac death.11–13 In their article, ‘SCN5A mutations in 442 neonates and children: genotype–phenotype correlation and identification of higher-risk subgroups’, Alban-Elouen Baruteau and colleagues from the Evelina London Children’s Healthcare in the UK investigated characteristics and outcomes of 442 children ≤16 years of age with a genetically confirmed SCN5A mutation.14 Phenotypes included isolated progressive cardiac conduction disorders, overlap phenotype, long-QT syndrome type 3, and Brugada syndrome type 1, while 44% had a negative ECG. During 6 years, 272 cardiac events occurred in a third of the patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, and age ≤1 year at diagnosis were independent predictors of a cardiac event. There is an almost endless controversy regarding the choice of the QT correction formula to be used in ECGs in neonates for screening for long QT syndrome.15–17 In their article ‘For neonatal ECG screening there is no reason to relinquish old Bazett’s correction’ Peter J. Schwartz and colleagues from the IRCCS Istituto Auxologico Italiano in Milan, Italy compared the performance of four commonly used formulae (i.e. Bazett’s, QTcB; Fridericia’s, QTcF; Framingham, QTcL; and Hodges, QTcH) and a new formula in 44 596 healthy neonates studied prospectively.18 The new neonate-specific exponential correction (QTcNeo) was derived using randomly selected ECGs and externally validated. Bazett’s provided the most heart rate-independent correction with a slope closest to zero, followed by Fridericia’s, Framingham, and Hodges. The QTc–heart rate slope of neonate-specific exponential correction was similar to Bazett’s (Figure 2). The ability to identify neonates with long QT syndrome correctly was best with Bazett’s, Fridericia’s, and neonate-specific exponential correction. Cut-off values were 460 ms for Bazett’s, 394 ms for Fridericia’s, and 446 ms for neonate-specific exponential correction. These practically important findings are put into context in an Editorial by John D. Fisher from the Montefiore Medical Center and the Albert Einstein College of Medicine in New York, USA.19 Individual QT/QTc values plotted vs. heart rate. The linear regression lines fitting the relationship between QT/QTc and heart rate are shown, along with the regression equation. The slope of QTcB was 0.086, which was the closest to zero (from Stramba-Badiale M, Karnad DR, Goulene KM, Panicker GK, Dagradi F, Spazzolini C, Kothari S, Lokhandwala YY, Schwartz PJ. For neonatal ECG screening there is no reason to relinquish old Bazett's correction. See pages 2888–2895). Management of patients with inherited cardiac ion channelopathy is complex and hindered by variability in disease severity and sudden cardiac death risk.20–22 In their article entitled ‘A common co-morbidity modulates disease expression and treatment efficacy in inherited cardiac sodium channelopathy’, Carol Ann Remme and colleagues from the Academic Medical Center at the University of Amsterdam in the Netherlands investigated the modulatory role of hypertrophy, a known risk factor for arrhythmias and sudden cardiac death,23 in 164 individuals with the SCN5A-1795insD founder mutation and 247 mutation-negative relatives.24 Thirty-eight mutation-positive patients died suddenly or suffered life-threatening ventricular arrhythmias. Almost half of them were aged >40 years, many with hypertension and/or cardiac hypertrophy. While pacemaker implantation was protective for bradycardia-related sudden cardiac death in young mutation-positive patients, some of those aged >40 experienced life-threatening arrhythmias despite pacemakers. Most of them had hypertension or hypertrophy, pointing to a modulatory role for this co-morbidity. Induction of hypertrophy in adult mice carrying the homologous mutation (Scn5a1798insD/+) caused sudden cardiac death and excessive conduction disturbances, confirming a modulatory effect of hypertrophy in the setting of the mutation. The deleterious effects of the interaction between hypertrophy and the mutation were prevented by genetically impairing the pro-hypertrophic response and by pharmacological inhibition of the enhanced late sodium current associated with the mutation. This study provides the clinical and experimental evidence for a modulatory effect of cardiac hypertrophy on arrhythmia risk and treatment efficacy in inherited sodium channelopathy. The clinical implications of these findings are explored in an Editorial by Iacopo Olivotto from the Referral Center for Cardiomyopathies in Firenze, Italy.25 The editors hope that readers of this issue of the European Heart Journal will find it of interest to them. With thanks to Amelia Meier-Batschelet for help with compilation of this article.