Arrhythmias and sudden cardiac death: substrates, monitoring, and prevention

Arrhythmias may originate for the atria and ventricles of the heart. While supraventricular arrhythmias are much more common, particularly atrial fibrillation, they rarely are life threatening,1 whereas ventricular arrhythmias can be lethal.2 However, supraventricular arrhythmias such as atrial fibrillation are associated with embolic stroke,3 particularly in those at high risk.4 Importantly, however, such complications can be effectively prevented by anticoagulants, in particular non-vitamin K antagonist oral anticoagulants or NOACs.5,6 However, the use of NOACs is limited by the lack of effective antagonization in the case of life-threatening bleeding or emergency surgery requiring improved haemostasis. To address this issue, the Working Group on Cardiovascular Pharmacotherapy and the Working Group on Thrombosis of the European Society of Cardiology provide a position paper entitled ‘Reversal strategies for non-vitamin K antagonist oral anticoagulants (NOACs):a critical appraisal of available evidence and recommendations for clinical management—ajoint position paper of the ESC Working Group on Cardiovascular Pharmacotherapy and ESC Working Group on Thrombosis’.7 The experts assessed available strategies to antagonize the anticoagulant effects of NOACs. Apart from a possible effect of coagulation factor concentrates, the potential of emerging specific antidotes for NOACs was explored. In healthy volunteers, reversal of anti-coagulation with either a monoclonal antibody fragment binding to the thrombin inhibitor dabigatran, a truncated inactive recombinant FXa, or a synthetic, peptide-like, small molecule has been shown to be effective. Phase III studies addressing the effectiveness of these antidotes in critically ill patients are emerging. A first interim analysis of critically ill patients has shown successful reversal of the effect of dabigatran with the specific antibody fragment idarucizumab, leading to approval by the European Medicines Agency and the US Food and Drug Administration. This position paper gives practical advice on how to handle life-threatening bleeding or emergency surgery in patients on NOAC treatment. The paper also analyses clinical conditions where immediate antagonization of the effect of NOACs is assumed to be beneficial for the patient. Arrhythmias are triggered by a variety of factors. For instance, atrial fibrillation is known to occur in the context of an infection, acute inflammation, during wound healing, and after excessive alcohol consumption, among other situations. Rheumatoid arthritis is a chronic immuno-mediated disease primarily affecting the joints, characterized by persistent high-grade systemic inflammation that appears to worsen coronary artery8 and microvascular disease.9 In their review ‘Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis’, Pietro Enea Lazzerini and colleagues from the University of Siena in Italy stress again the fact that cardiovascular morbidity and mortality are increased in rheumatoid arthritis, with >50% of premature deaths attributable to cardiovascular disease.10 Of note, rheumatoid arthritis patients are twice as likely to experience sudden cardiac death compared with those without this condition, suggesting an increased risk of developing malignant ventricular arrhythmias. Indeed, alterations in ventricular repolarization as assessed by the length of the QT interval and of the autonomic nervous system represent risk factors for life-threatening ventricular arrhythmias in the general population and are commonly observed in rheumatoid arthritis. Moreover, large population-based studies indicate that the prevalence of atrial fibrillation is also significantly higher in rheumatoid arthritis than in the general population. Although the underlying mechanisms accounting for the pro-arrhythmogenic substrate in rheumatoid arthritis are probably intricate, chronic systemic inflammation is likely to play a pivotal role. Indeed, inflammation may promote arrhythmias both indirectly, by accelerating the development of ischaemic heart disease and congestive heart failure, and directly, by affecting cardiac electrophysiology. Thus, lowering the inflammatory burden through an increasingly tight control of disease activity may represent the most effective intervention to reduce arrhythmic risk in these patients. Intriguingly, these considerations could be more generally applicable to all the diseases characterized by chronic systemic inflammation such as inflammatory bowel disease and psoriasis, among others, and could help elucidate the link between low-grade chronic inflammation and arrhythmic risk in the general population. Sudden cardiac death is the most devastating complication of hypertrophic cardiomyopathy.11 In the second clinical review article entitled ‘Prevention of sudden death in hypertrophic cardiomyopathy:bridging the gaps in knowledge’, Harry Rakowski and colleagues from the Toronto General Hospital in Canada note that although the annual rate of sudden cardiac death in patients with hypertrophic cardiomyopathy averages overall below 1%/year, there is still a small subset of patients who are at increased risk of sudden cardiac death.12 The greatest challenge in the management of hypertrophic cardiomyopathy is identifying those at increased risk, as an implantable cardioverter defibrillator is potentially lifesaving in these patients. In their review, the authors summarize the available data on sudden cardiac death in hypertrophic cardiomyopathy and provide a clinical perspective on the current differing and somewhat conflicting European and American recommendations on risk stratification, with balanced guidance with regards to rational clinical decision-making. Similarly, patients with chronic heart failure are at increased risk of sudden cardiac death.13–15 Implantable cardioverter defibrillators for primary prevention of such an event are therefore an established approach to reduce mortality in patients with underlying ischaemic heart disease, while their efficacy in heart failure due to other causes is less clear. Indeed, the recent large randomized DANISH trial in patients with non-ischaemic heart failure showed no significant benefit,16 leading to calls to abandon implantable cardioverter defibrillators in this group. In a first FAST TRACK entitled ‘Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in11 trials’ Matthew Shun-Shin and colleagues from the Imperial College London in the UK undertook a meta-analysis of the totality of the evidence.17 They identified 11 randomized trials enrolling 8567 participants with heart failure, comprising 3128 patients without and 5439 patients with ischaemic heart disease that assessed the effectiveness of implantable cardioverter defibrillators. In patients without ischaemic heart disease, implantable cardioverter defibrillators reduced mortality by 24%. Thus, it appears that the DANISH study, rather than refuting the use implantable cardioverter defibrillators in patients with non-ischaemic heart failure, fits well with the existing data. Indeed, most physicians may not have been aware that patients with non-ischaemic heart disease in COMPANION gained survival benefit from an implantable cardioverter defibrillator on the background of cardiac resynchronization therapy. Furthermore, mortality was reduced in all randomized controlled trials except in the DANISH trial. The manuscript is accompanied by a critical Editorial by Jens Jakob Thune and Lars Kober, authors of the DANISH trial, from the University of Copenhagen in Denmark.18 Remote monitoring of implantable cardioverter defibrillators may improve clinical outcome. An initial meta-analysis of three randomized controlled trials, i.e. TRUST,19 ECOST,20 and IN-TIME,21 suggested improved survival of a specific remote monitoring system with daily transmissions, i.e. the Biotronik Home Monitoring system. In their manuscript entitled ‘Impact of home monitoring on outcomes in implantable cardioverter-defibrillator patients:ameta-analysis on individual patient data’, Gerhard Hindricks and colleagues from the University Heart Center Leipzig in Germany performed a patient-level analysis to verify this preliminary analysis with appropriate time-to-event statistics and to investigate further clinical endpoints.22 To that end, individual data of the TRUST, ECOST, and IN-TIME patients were pooled to calculate absolute risks of endpoints at 1-year follow-up for home monitoring vs. conventional follow-up. All-cause mortality analysis involved 2405 patients of all three trials, while other endpoints involved 1078 patients of only two trials, i.e. ECOST and IN-TIME, in which an independent blinded endpoint committee adjudicated the causes of hospitalizations and deaths. Based on this analysis, home monitoring reduced the absolute risk of death at 1 year by 1.9%, equivalent to a hazard ratio of 0.62. Also, the combined endpoint of all-cause mortality or hospitalization for worsening heart failure was reduced by 5.6% with a hazard ratio of 0.64. The composite endpoint of all-cause mortality or cardiovascular hospitalization showed only a non-siginfcant trend to a reduction by 4.1%. Thus, in a pooled patient-level analysis of three trials, home monitoring reduced all-cause mortality and the composite endpoint of all-cause mortality or worsening heart failure hospitalization. The similar magnitudes of absolute risk reductions for worsening heart failure and cardiovascular endpoints suggest that the benefit of home monitoring is driven by the prevention of heart failure exacerbation. Sudden cardiac death may further be caused by channelopathies such as long QT23 and short QT syndrome,24 catecholaminergic ventricular tachycardia, and the Brugada syndrome.25,26 Risk stratification in Brugada syndrome remains particularly challenging as arrhythmic events can occur throughout life, and studies with long follow-ups are sparse. In a third research article ‘A score model to predict risk of events in patients with Brugadasyndrome’, Juan Sieira and colleagues from the Uuniversity of Brussels in Belgium investigated the long-term outcome and risk stratification of 400 Brugada syndrome patients with a mean age of 41 years.27 Clinical presentation was aborted sudden cardiac death in 5.0%, syncope in 28%, and asymptomatic in 67%. Familial antecedents of sudden cardiac death were found in 46%, of which 7.8% occurred in first-degree relatives younger than 35 years. An implantable cardioverter defibrillator was placed in 44%. During a mean follow-up of 81 months, 34 arrhythmic events occurred, accounting for an event rate of 1.4% per year. Variables associated with events were: (i) aborted sudden cardiac death with a hazard ratio of 20; (ii) syncope with a hazard ratio of 3.7; (iii) spontaneous type I Brugada syndrome with a hazard ratio of 2.7; (iv) male gender with a hazard ratio of 2.7; (v) early sudden cardiac death in first-degree relatives with a hazard ratio of 2.9; (vi) sinus node dysfunction with a hazard ratio of 5.0; (vii) inducible ventricular arrhythmias with a hazard ratio of 4.7; and (viii) proband status with a hazard ratio of 2.1 (Figure 1). A model including ECG pattern, early familial sudden cardiac death antecedents, inducible arrhythmias, presentation as syncope or as aborted sudden cardiac death, and sinus node dysfunction had a predictive performance of 0.82. A score >2 conferred a 5-year event probability of 9.2%. Thus, Brugada syndrome patients remain at risk many years after diagnosis. Early sudden cardiac death in first-degree relatives and sinus node dysfunction are risk factors for arrhythmic events which might help in the stratification and management of such patients. Selected risk model to predict events. (A) Score corresponding to each item. Sudden cardiac death refers to presentation as aborted sudden cardiac death. (B) Event probability according to the Kaplan–Meier method in each score category (from Sieira J, Conte G, Ciconte G, Chierchia G-B, Casado-Arroyo R, Baltogiannis G, Di Giovanni G, Saitoh Y, Juliá J, Mugnai G, La Meir M, Wellens F, Czapla J, Pappaert G, de Asmundis C, Brugada P. A score model to predict risk of events in patients with Brugada Syndrome. See pages 1756–1763). Atrial fibrillation occurs increasingly more often as left ventricular function worsens,28 but the molecular mechanisms of this phenomenon remain elusive. Dierk Thomas and colleagues from the University of Heidelberg in Germany address this issue in their article ‘Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy’.29 The authors hypothesized that repolarizing K2P3.1 K+ channels, previously implicated in atrial fibrillation, may contribute to shaping the atrial action potential, forming a specific electrical substrate with left ventricular dysfunction that might represent a target for a future personalized therapy. Ion channel expression was quantified by real-time PCR and western blot in 175 patients with different stages of left ventricular dysfunction. Membrane currents and action potentials were recorded from atrial cardiomyocytes using the patch-clamp technique. In patients in sinus rhythm, severely reduced left ventricular function was associated with decreased atrial K2P3.1 expression. In contrast, chronic atrial fibrillation resulted in increased K2P3.1 levels, while paroxysmal atrial fibrillation was not linked to K2P3.1 remodelling (Figure 2). Left ventricular dysfunction-related suppression of K2P3.1 currents prolonged atrial action potential duration compared with patients with preserved left ventricular function. In individuals with concomitant left ventricular dysfunction and chronic atrial fibrillation, atrial action potential duration was determined by left ventricular dysfunction-associated prolongation and shortening, respectively, consistent with changes in K2P3.1 abundance. In patients with chronic atrial fibrillation, K2P3.1 inhibition attenuated atrial action potential duration shortening irrespective of left ventricular function, whereas in individuals with paroxysmal atrial fibrillation and severely reduced left ventricular function K2P3.1 blockade resulted in disproportionately marked prolongation of atrial action potential duration. The authors conclude that left ventricular dysfunction is associated with a reduction of atrial K2P3.1 channel expression, while chronic atrial fibrillation leads to increased K2P3.1 abundance. Differential remodelling of K2P3.1 and atrial action potential duration may provide a basis for patient-tailored antiarrhythmic strategies in the future. The role of K2P3.1 K+ channels in atrial arrhythmogenesis and antiarrhythmic therapy. Chronic atrial fibrillation (cAF) and left ventricular dysfunction antagonistically determine atrial action potential duration (APD) via changes in K2P3.1 subunit abundance and current density. In cAF patients, increased K2P3.1 levels accelerate AP repolarization and shorten APD. By contrast, left ventricular dysfunction is associated with reduced atrial K2P3.1 expression and function, resulting in prolongation of repolarization and APD. Patient-specific remodelling of K2P3.1 and APD affects anti-arrhythmic therapy: AP prolongation in patients with reduced left ventricular function reduces effectiveness of K2P3.1 blockade, whereas K2P3.1 K+ current inhibition is expected to be particularly effective in patients with cAF and shortened AP (from Schmidt C, Wiedmann F, Zhou X-B, Heijman J, Voigt N, Ratte A, Lang S, Kallenberger SM, Campana C, Weymann A, De Simone R, Szabo G, Ruhparwar A, Kallenbach K, Karck M, Ehrlich JR, Baczko I, Borggrefe M, Ravens U, Dobrev D, Katus HA, Thomas D. Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy. See pages 1764–1774). The editors hope that this issue of the European Heart Journal will be of interest to its readers.

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