Novel mechanistic insights into ventricular arrhythmias and sudden death

With thanks to Amelia Meier-Batschelet, Johanna Hugger, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on arrhythmias contains ‘The year in cardiovascular medicine 2021: arrhythmias’ by Harry Crijns from the Maastricht University Medical Centre in the Netherlands, and colleagues.1 Crijns et al. note that the year 2021 yielded remarkable societal impact arrhythmia papers reporting on important public health issues, the latest ESC 2021 pacing guidelines, randomized trials on atrial fibrillation (AF) and cardiac pacing, and intriguing multidisciplinary aspects of AF, with progress in ventricular arrhythmias, in particular an outstanding series of Brugada syndrome studies. Sudden cardiac death (SCD) is a tragic incident accountable for up to 50% of deaths from cardiovascular disease.2–8 In a State of the Art Review article entitled ‘Risk of sports-related sudden cardiac death in women’, Deepthi Rajan from Copenhagen University Hospital in Denmark, and colleagues note that sports-related SCD (SrSCD) is a phenomenon which has previously been associated with both competitive and recreational sport activities.9 SrSCD has been found to occur 5- to 33-fold less frequently in women than in men, and the sex difference persists despite a rapid increase in female participation in sports. Establishing the reasons behind this difference could pinpoint targets for improved prevention of SrSCD. Therefore, this review summarizes existing knowledge on epidemiology, characteristics, and causes of SrSCD in females, and elaborates on proposed mechanisms behind the sex differences. Although literature concerning the aetiology of SrSCD in females is limited, proposed mechanisms include sex-specific variations in hormones, blood pressure, autonomic tone, and the presentation of acute coronary syndromes. Consequently, these biological differences impact the degree of cardiac hypertrophy, dilation, right ventricular remodelling, myocardial fibrosis, and coronary atherosclerosis, and thereby the occurrence of ventricular arrhythmias in male and female athletes associated with short- and long-term exercise. Finally, cardiac examinations such as electrocardiograms and echocardiography are useful tools allowing easy differentiation between physiological and pathological cardiac adaptations following exercise in women. However, as a significant proportion of SrSCD causes in women are non-structural or unexplained after autopsy, channelopathies may play an important role, encouraging attention to prodromal symptoms and family history. These findings will aid in the identification of females at high risk of SrSCD and development of targeted prevention for female sport participants. Clinical trials have demonstrated the safety and efficacy of the Micra leadless VVI pacemaker; however, longer term outcomes in a large, real-world population with a contemporaneous comparison with transvenous VVI pacemakers have not been examined. In a Fast Track Clinical Research article entitled ‘Leadless vs. transvenous single-chamber ventricular pacing in the Micra CED study: 2-year follow-up’, Mikhael El-Chami from the Emory University School of Medicine in Atlanta, GA, USA, and colleagues compared reinterventions, chronic complications, and all-cause mortality at 2 years between leadless VVI and transvenous VVI-implanted patients.10 The Micra Coverage with Evidence Development study is a continuously enrolling, observational, cohort study of leadless VVI pacemakers in the US Medicare fee-for-service population. Patients implanted with a leadless VVI pacemaker between 9 March 2017 and 31 December 2018 were identified (n = 6219) and compared with all patients implanted with transvenous VVI during the study period (n = 10 212). Compared with transvenous VVI, patients with leadless VVI had more end-stage renal disease and a higher Charlson comorbidity index. Leadless VVI patients had significantly fewer reinterventions [adjusted hazard ratio (HR) 0.62, P = 0.003] and chronic complications (adjusted HR 0.69, 95% CI 0.60–0.81, P < 0.0001) compared with transvenous VVI patients. Adjusted all-cause mortality at 2 years was not different between the two groups (Figure 1). Adjusted time to event plots for device reinterventions, chronic complications, and mortality out to 2 years of follow-up in patients treated with leadless VVI vs. transvenous VVI pacing. (A) Hazard ratio and cumulative incidence function for 2-year device reintervention based on the Fine–Gray competing risk model. (B) Hazard ratio and cumulative incidence function for 2-year chronic complications based on the Fine–Gray competing risk model. (C) Hazard ratio and patient mortality rates based on the Cox proportional hazards model. CI, confidence interval.10 The authors conclude that in a real-world study of US Medicare patients, the Micra leadless VVI pacemaker is associated with a 38% lower adjusted rate of reinterventions and a 31% lower adjusted rate of chronic complications compared with transvenous VVI pacing without any difference in adjusted all-cause mortality at 2 years. The contribution is accompanied by an Editorial by Haran Burri from the University Hospital of Geneva in Switzerland.11 Burri notes that although the Medicare database is not monitored and does not disclose details such as cause of death, it is likely that important endpoints such as complications are well captured, due to the financial incentive for the facilities to do so in order to gain reimbursement. Data mining from sources such as health insurance programmes and telemedicine provides an opportunity to conduct large, siteless, pragmatic studies, at a low cost. Although such studies cannot replace randomized controlled trials for providing scientific evidence, they do offer new perspectives in the setting of increasing economical and administrative challenges for conducting ‘conventional’ clinical research. The choice between rhythm control and rate control in AF is still debated.12 Clinical practice guidelines restrict rhythm control therapy to patients with symptomatic atrial fibrillation (AF).13,14 In a second Fast Track Clinical Research article entitled ‘Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial’, Stephan Willems from the Semmelweis University Campus Hamburg in Germany, and colleagues noted that the EAST-AFNET 4 trial demonstrated that early, systematic rhythm control improves clinical outcomes compared with symptom-directed rhythm control.15 This pre-specified EAST-AFNET 4 analysis compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) with that in symptomatic patients. The primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, examined in a time-to-event analysis. At baseline, 30% of patients were asymptomatic (mean age 71 years, 37% women, mean CHA2DS2-VASc score 3.4, 21% heart failure) Asymptomatic patients randomized to early rhythm control received similar rhythm control therapies compared with symptomatic patients (e.g. AF ablation at 24 months: 19% in asymptomatic patients and 19.3% in symptomatic patients). Anticoagulation and treatment of concomitant cardiovascular conditions also were similar between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomized to early rhythm control and in 97/406 patients randomized to usual care (HR 0.76, 95% confidence interval 0.6–1.03), almost identical to symptomatic patients (Figure 2). Aalen–Johansen cumulative incidence curves for the first primary outcome: (A) for patients with asymptomatic atrial fibrillation at baseline and (B) for patients with symptomatic atrial fibrillation at baseline. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome. The effect of early rhythm control on this outcome was almost identical in symptomatic and asymptomatic patients.15 The authors conclude that the clinical benefit of early, systematic rhythm control is not different between asymptomatic and symptomatic patients in EAST-AFNET 4. This manuscript is accompanied by an Editorial by Robert Hatala from the National Cardiovascular Institute and Slovak Medical University in Bratislava, Slovakia.16 Hatala concludes that the EAST-AFNET 4 results demonstrate that applying a systematic holistic therapeutic approach based on anticoagulation, rate control, and upstream therapy very early after diagnosis—irrespective of arrhythmia symptoms—creates a more favourable milieu for an effective concomitant rhythm control strategy with, possibly, an increasing role for catheter ablation. However, at least two important questions remain to be resolved to implement this approach in clinical practice. (i) Are the benefits of early rhythm control limited only to ‘early’ AF (i.e. diagnosed within the previous 4–6 weeks) or can they be extrapolated to AF of longer duration? This is of utmost practical importance since most countries do not have the capacity to offer specialized care (including catheter ablation) to patients with incident AF within 4–6 weeks after initial diagnosis. (ii) Which feature of the proposed strategy of rhythm control is the decisive one: the systematic medical treatment, the early rhythm control, the systematic ablation if antiarrhythmic drugs fail, or all of them? Even with such unresolved issues, Sir Thomas Lewis would probably be pleased to see that we can further improve the outcome of ‘auricular fibrillation’ but we must implement all appropriate evidence-based therapies speedily and regardless of symptoms. The mechanisms of ventricular fibrillation (VF) are complex and still poorly known.17–20 In a Clinical Research article entitled ‘Purkinje network and myocardial substrate at the onset of human ventricular fibrillation: implications for catheter ablation’, Michel Haissaguerre from the Centre Hospitalier Universitaire de Bordeaux in France, and colleagues performed detailed mapping of the activities underlying the onset of VF and targeted ablation in patients with structural cardiac abnormalities.21 The authors evaluated 54 patients (50 ± 16 years) with VF in the setting of ischaemic (n = 15), hypertrophic (n = 8), or dilated cardiomyopathy (n = 12), or Brugada syndrome (n = 19). VF was mapped using body surface mapping to identify driver (re-entrant and focal) areas and invasive Purkinje mapping. Purkinje drivers were defined as Purkinje activities faster than the local ventricular rate. Structural substrate was delineated by electrogram criteria and by imaging. Catheter ablation was performed in 41 patients with recurrent VF. Sixty-one episodes of spontaneous or induced VF were mapped. VF was organized for the initial 5.0 ± 3.4 s, exhibiting large wavefronts with similar cycle lengths (CLs) across both ventricles. Most drivers (81%) originated from areas associated with the structural substrate. The Purkinje system was implicated as a trigger or driver in 43% of patients with cardiomyopathy. The transition to disorganized VF was associated with the acceleration of initial re-entrant activities (CL shortening from 187 ± 17 to 175 ± 20 ms, P < 0.001), then spatial dissemination of drivers. Purkinje and substrate ablation resulted in the reduction of VF recurrences from a pre-procedural median of seven episodes to 0 episode at 56 ± 30 months. The authors conclude that the onset of human VF is sustained by activities originating from Purkinje and structural substrate, before spreading throughout the ventricles to establish disorganized VF. Targeted ablation results in effective reduction of VF burden. The contribution is accompanied by an Editorial by Peter Taggart from the University College London in the UK, and colleagues.22 They note that these findings shed light on strategies to identify triggers and target the substrate—key elements enabling the development of VF—and present a coherent case for the efficacy of combining myocardial substrate characterization, Purkinje mapping, and VF mapping to optimize ablation therapy. The mapping of abnormal substrate during induced VF is an important further contribution, as this aids optimization of ablation when ectopy is not present. Taggart et al. conclude that the authors of this study should be congratulated on an outstanding contribution to clinical electrophysiology research, which adds to our understanding of VF, and will no doubt contribute to future therapeutic strategies for its management. Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown.23–25 In a Translational Research article entitled ‘Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study’, Marina Cerrone from the New York University Grossmann School of Medicine in New York, USA, and colleagues investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation commonly mutated in ARVC, as compared with normal animals.26 Exercise caused transcriptional down-regulation of genes coding for intercalated disk proteins. PKP2 loss caused cardiac contractile deficit, decreased muscle mass, and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction; an effect dampened by pre-training animals prior to PKP2 knockout. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared with matched controls. The authors speculate that exercise challenges a cardiomyocyte ‘desmosomal reserve’ which, if impaired genetically (e.g. PKP2 loss), accelerates progression of cardiomyopathy. The manuscript is accompanied by an Editorial by Kristina H. Haugaa from the Karolinska University Hospital in Stockholm, Sweden, and Christine Rootwelt-Norberg from the Oslo University Hospital in Norway.27 The authors conclude that this contribution launches a novel and interesting concept. Indeed, the hypothesis of impaired desmosomal reserve represents a supplementary explanation to the exercise-induced increased wall stress theory as causes of accelerated desmosomal dysfunction in ARVC athletes. Importantly, it provides a new and interesting step forward in the intriguing topic of exercise-induced ARVC. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘The association of atrial fibrillation with mortality in patients with breast cancer’, Jean Jacques Noubiap from the University of Adelaide in South Australia comments on the recent publication ‘Incidence, risk factors, and mortality of atrial fibrillation in breast cancer: a SEER-Medicare analysis’ by Avirup Guha from Case Western Reserve University in Cleveland, OH, USA.28,29 Guha et al. respond in a separate comment.30 The editors hope that readers of this issue of the European Heart Journal will find it of interest.