Dangerous encounters: triggers of fatal ventricular arrhythmias and safety of interventional treatment strategies

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Arrhythmias can be a nuisance or a cause of syncope and deadly events.2–4 Sudden cardiac death is still a highly unresolved issue in cardiology. While environmental factors are important for those associated with myocardial infarction, others are mainly due to a genetic disposition, as outlined in a clinical review entitled ‘Modifier genes in sudden cardiac death’ authored by Peter J. Schwartz and colleagues from the IRCCS Istituto Auxologico Italiano in Milan, Italy.5 Of note, genetic conditions, even those due to identical gene mutations, can lead to variable clinical manifestations, possibly due to modifier genes. Here, this is addressed for cardiac arrhythmia. In two important clinical conditions, this is associated with the risk for sudden cardiac death, i.e. in a monogenic disorder such as congenital long QT syndrome and in life-threatening arrhythmias in acute myocardial infarction for which the search for genetic modifiers of arrhythmic risk is still challenging. Advances in understanding the contribution of modifier genes to a higher or lower propensity toward sudden death will improve patient-specific risk stratification and be a major step toward precision medicine. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of life-threatening ventricular arrhythmias.6–8 Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging.9 Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. In a FAST TRACK clinical research paper entitled ‘An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis’, Robert Murray Hamilton and colleagues from the Hospital for Sick Children in Toronto, Canada sought to determine if anti-desmosome antibodies are present in ARVC.10 They identified anti-DSG2 antibodies in all subjects with definite ARVC and in most borderline subjects (Figure 1). Antibodies were mainly absent in two control cohorts. The level of anti-DSG2 antibodies correlated with the burden of premature ventricular beats and they caused gap junction dysfunction in vitro. Thus, anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. Anti-DSG2 antibodies probably explain the cardiac inflammation that is common in ARVC and may represent a new therapeutic target. These findings are further discussed in a thought-provoking Editorial by Hugh Calkins from the John Hopkins Hospital in Baltimore, Maryland, USA.11 Purified IgG antibodies from the serum of two patients with arrhythmogenic right ventricular cardiomyopathy, as well as commercial anti-DSG-2 IgG demonstrate reduced cell-to-cell dye transfer distance compared with cells exposed to IgG from normal human serum (P ≤ 0.0001 and P = 0.0025, respectively). The two-tailed P-values between the indicated groups are exact values calculated using a MannWhitney U-test. Error bars indicate standard deviation (from Chatterjee D, Fatah M, Akdis D, Spears DA, Koopmann TT, Mittal K, Rafiq MA, Cattanach BM, Zhao Q, Healey JS, Ackerman MJ, Bos JM, Sun Y, Maynes JT, Brunckhorst C, Medeiros-Domingo A, Duru F, Saguner AM, Hamilton RM. An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis. See pages 3932–3944). Atrial fibrillation and atrial flutter are common arrhythmias with increased use of invasive procedures.12–14 A steady re-evaluation of relevant safety endpoints is recommended, and both quality management and pay-for-performance programmes are evolving. In a FAST TRACK entitled ‘In-hospital mortality of patients with atrial arrhythmias: insights from the German-wide Helios hospital network of 161 502 patients and 34 025 arrhythmia-related procedures’, Sebastian König and colleagues from the Herzzentrum Leipzig Universitatsklinik in Leipzig, Germany report overall in-hospital mortality and mortality of invasive arrhythmia-related procedures as well as mortality predictors in a German-wide hospital network.15 In 161 502 patients, in-hospital mortality was 0.6%, with a significant decrease from 0.75% to 0.5% (P < 0.01) during the observation period. In multivariable analysis, age, high centre volume, emergency hospital admission, and the Charlson Comorbidity Index were independent predictors of in-hospital mortality. Mortality rates were 0.05% for left atrial catheter ablation, 0.3% for right atrial procedures, and 0.56% for implantation of a left atrial appendage occluder, respectively. These real-world findings are put into context in an Editorial by William Stevenson from Vanderbilt University Medical Center in Nashville, Tennessee (USA).16 Sudden cardiac arrest accounts for 10% of adult mortality in Western populations.17 Such an event affects not only cardiac patients, but also younger indiviuals with a genetic predispoisition18,19 and athletes.20,21 In their article ‘A comprehensive evaluation of the genetic architecture of sudden cardiac arrest’ Dan E. Arking and colleagues from the SCD working group of the CHARGE Consortium identified loci associated with sudden cardiac arrest and risk factors associated with it.22 In a large genome-wide association study for sudden cardiac arrest involving 3939 cases and 25 989 controls, no variants were associated with sudden cardiac arrest at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with sudden cardiac arrest at nominal significance. Using cross-trait genetic risk score associations, they established a genetic correlation between sudden cardiac arrest and coronary artery disease and traditional risk factors for it, as well as height, body mass index, and electrical instability traits, suggesting aetiological roles for these traits in sudden cardiac arrest risk. Thus, a comprehensive approach to the genetic architecture of sudden cardiac arrest can shed light on the determinants of such events. The clinical implications of these findings are outlined in an Editorial by Peter J. Schwartz from the IRCCS Istituto Auxologico Italiano in Milano, Italy.23 Pacemakers and implantable cardioverter defibrillators24,25 are established tools to treat bradycardic and tachycardic arrythmias. Often patients scheduled for the implantation of such devices are taking anticoagulants for different indications. Guidelines recommend warfarin continuation rather than heparin bridging for pacemaker and defibrillator surgery, after the BRUISE CONTROL trial demonstrated a huge reduction in pocket haematomas with such an approach. However, today direct oral anticoagulants or DOACs are used to treat the majority of such patients.26–28 In their article ‘Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thrombo-embolic events (BRUISE CONTROL-2)’, David H. Birnie and his colleagues the BRUISE CONTROL-2 Investigators sought to understand the best strategy to manage the DOACs in such a situation.29 They randomly assigned patients with atrial fibrillation and CHA2DS2-VASc score ≥2 to continued vs. interrupted DOACs. In the continued arm, the median time between pre- and post-operative DOACs doses was 12 h and in the interrupted arm it was 72 h (Figure 2). Clinically significant haematoma occurred in of 2.1% in the continued DOAC arm and in 2.1% in the interrupted arm. Thus, depending on the clinical situation, either management strategy might be reasonable. Main results of Bruise Control 2 (from Birnie DH, Healey JS, Wells GA, Ayala-Paredes F, Coutu B, Sumner GL, Becker G, Verma A, Philippon F, Kalfon E, Eikelboom J, Sandhu RK, Nery PB, Lellouche N, Connolly SJ, Sapp J, Essebag V, for the BRUISE CONTROL-2 Investigators. Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thrombo-embolic events (BRUISE CONTROL-2). See pages 3973–3979). The editors hope that this issue of the European Heart Journal will be of interest to its readers.