Towards precision medicine in the prediction of sudden cardiac death

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Atrial fibrillation (AF) is the most common arrhythmia and affects > 35 million individuals worldwide. It is an important cause of stroke, which leads to an increased risk of death in AF patients. Chronic kidney disease (CKD) is another major comorbidity in modern medicine, with increasing prevalence and substantial socioeconomic impact. As CKD and AF are highly prevalent in elderly individuals and share common metabolic risk factors, the two comorbidities frequently co-exist. Previous observational studies suggested that the two diseases are risk factors for each other, suggesting a bidirectional relationship. This Focus Issue on arrhythmias contains a clinical research article entitled ‘Atrial fibrillation and kidney function: a bidirectional Mendelian randomization study’. Sehoon Park from Seoul National University College of Medicine in South Korea, and colleagues investigated the causal effects between AF and kidney function.1 The authors performed a bidirectional summary-level Mendelian randomization (MR) analysis implementing the results from a large-scale genome-wide association study (GWAS) for estimated glomerular filtration rate (eGFR). The inverse variance weighted method was the main MR method used. For replication, an allele score-based MR was performed using individual-level data within a UK Biobank cohort of white British ancestry individuals. A genetic predisposition to AF was significantly associated with decreased eGFR (P < 0.001) and increased risk of CKD (P < 0.001). The significance remained in MR sensitivity analyses, and the causal estimates were consistent when the authors limited the analysis to individuals of European ancestry. In sharp contrast, genetically predicted eGFR did not show a significant association with the risk of AF (P = 0.183). The results were similar in allele score-based MR, as the allele score for AF was significantly associated with reduced eGFR (P < 0.001), while the allele score for eGFR did not show a significant association with risk of AF (P = 0.530). The authors conclude that their study supports that AF is a causal risk factor for kidney function impairment. However, an effect of kidney function on AF was not identified in this study. The contribution is accompanied by an Editorial by Marianne Benn from the University of Copenhagen in Denmark,2 who concludes that these findings reinforce the recommendations in the 2020 ESC Guidelines for the early diagnosis and management of AF by both opportunistic and systematic screening for AF.3 They also support lifestyle interventions aimed at reducing risk of developing AF. Most importantly, rhythm control intervention to eliminate AF may prevent or postpone kidney disease. The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained arrhythmic cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing.4 Previous reports have described a subset of IVF individuals with ventricular arrhythmia (VA) initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled VF (SCVF) has been proposed. In a clinical research article entitled ‘Short-coupled ventricular fibrillation represents a distinct phenotype among latent causes of unexplained cardiac arrest: a report from the CASPER registry’, Christian Steinberg from the Laval University in Quebec, Canada, and colleagues established the phenotype and frequency of SCVF in a large cohort of UCA survivors.5 The authors performed a multicentre study including consecutive UCA survivors from the CASPER registry. SCVF was defined as otherwise unexplained VF initiated by a trigger PVC with a coupling interval of <350 ms. Among 364 UCA survivors, 24/364 (6.6%) met diagnostic criteria for SCVF. Of note, in 19 of the 24 patients, the diagnosis of SCVF was obtained by documented VF during follow-up. VA was initiated by a mean PVC coupling interval of 274 ± 32 ms. Electrical storm occurred in 21% of SCVF probands but not in any UCA proband (P < 0.001). The median time to recurrent VA in SCVF was 31 months. Recurrent VF resulted in quinidine administration in 12/24 of those with SCVF (50%), with excellent arrhythmia control. Steinberg et al. conclude that short-coupled VF is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of VF onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF still remains unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes. The contribution is accompanied by an Editorial by Pieter Postema and Martijn van der Ree from the University of Amsterdam in the Netherlands.6 The two point out that the discovery of the DPP6 risk haplotype allowed screening of pre-symptomatic family members, preventing sudden cardiac death in these high-risk patients. Undoubtedly, more (genetic) subsets of SCVF can be identified by multicentre initiatives, which may lead to further optimization of our patient care. Hereditary cardiomyopathies are a leading cause of sudden cardiac death (SCD) in young adults. In the past years, substantial progress has been made in elucidating the genetic variants that contribute to the development of cardiomyopathy. Predominantly, alterations in genes coding for cytoskeletal, sarcomeric, desmosomal, and Z-disk proteins were found to be associated with the development of cardiomyopathy. Furthermore, variants in genes encoding calcium modulators are known to be associated with cardiomyopathies, including the gene encoding phospholamban (PLN), a protein essential for calcium homeostasis. The pathogenic variant in PLN which has been studied most extensively is p.Arg14del which leads to a deletion of Arg14 in the coding region of PLN and is associated with both dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. In a clinical research article entitled ‘Prediction of ventricular arrhythmia in phospholamban p. Arg14del mutation carriers: reaching the frontiers of individual risk prediction’, Tom Verstraelen from the University of Amsterdam in the Netherlands, and colleagues note that their study aims to improve risk stratification for a primary prevention implantable cardioverter defibrillator (ICD) by developing a new mutation-specific prediction model for malignant VA in p. Arg14del carriers.7 The proposed model was compared with existing PLN risk models. Data were collected from PLN p. Arg14del carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) SCD. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p. Arg14del carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years (interquartile range 27–55). During a median follow-up of 4.3 years, 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction (LVEF), premature ventricular complex count/24 h, amount of negative T waves, and the presence of low-voltage ECG. The multivariable model had an excellent discriminative ability with a C-statistic of 0.83 (0.78–0.88). Applying the existing PLN models in the complete current cohort yielded a C-statistic of 0.68 (0.61–0.75). The authors conclude that they present a new mutation-specific model to predict individual VA risk in PLN p. Arg14del carriers which is superior to the existing PLN and arrhythmogenic right ventricular cardiomyopathy risk models. Thus, this is a demonstration that risk prediction using the mutation-specific phenotypic features can improve accuracy compared with a more generic approach. The manuscript is accompanied by an Editorial by Domenico Corrado from the University of Padova in Italy, and colleagues.8 They conclude that future development of the PLN mutation-specific risk prediction model should include LV myocardial fibrosis assessed by cardiac magnetic resonance that appears to be the most robust predictor of arrhythmic outcome. Brugada syndrome (BrS) is a rare heritable arrhythmia characterized by coved-type ST segment elevation in the right pre-cordial leads and an increased risk of SCD due to lethal VA.9–12 Mutations in the SCN5A gene, encoding the cardiac sodium channel Nav1.5, are identified in ∼20% of cases; however, the predictive value of SCN5A mutations for subsequent lethal arrhythmic events (LAEs) remains controversial. In a Translational Research article entitled ‘Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome’, Naomasa Makita from the National Cerebral and Cardiovascular Center in Suita, Japan, and colleagues investigated whether the functional curation of SCN5A variations improves the prognostic predictability.13 Using a heterologous expression system and whole-cell patch clamp, they functionally characterized 22 variants of unknown significance (VUS) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly more severe ECG conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that LOF-SCN5A mutations only and a history of aborted cardiac arrest were significant predictors of LAE. The authors conclude that in vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAE. Functionally proven LOF-SCN5A mutations are genetic burdens of SCD in BrS, while the evidence for other BrS-associated genes is elusive. The contribution is accompanied by an Editorial by Arthur Wilde and Cheng-I Wu from the Academic Medical Centre in Amsterdam, the Netherlands.14 who conclude that this study provides strong evidence that a pathogenic SCN5A variant may contribute to the severity of the phenotype but that functional studies are needed to define their clinical relevance. Thus, in earlier studies where the presence of a ‘pathogenic SCN5A variant’ did not contribute to risk, a substantial subset of SCN5A variants were probably not functionally relevant and therefore diluted the prognostic effect. The issue is also complemented by a Discussion Forum contribution. In a commentary entitled ‘Uninterrupted vs. interrupted non-vitamin K antagonist oral anticoagulant during atrial fibrillation catheter ablation: expert opinion or true evidence?’, Patrizio Pascale from the Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland and Christelle Haddad from the Louis Pradel Cardiovascular Hospital in Lyon, France comment on the recent ‘2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS)’.3,15 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.