New tools to predict and new therapeutic targets to treat life-threatening ventricular arrhythmias

With thanks to Amelia Meier-Batschelet, Johanna Huggler, 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 ‘2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: developed by the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC), endorsed by the Association for European Paediatric and Congenital Cardiology (AEPC)’.1 The first general part has new sections on diagnostic evaluation, including pharmacological provocative tests, genetic testing, and a systematic work-up of probands and relatives with primary electrical diseases. Comprehensive flowcharts and recommendations for the diagnostic evaluation at first presentation with a ventricular arrythmia (VA) of patients without a previously known cardiac disease are provided for five frequently encountered clinical scenarios. Practical recommendations for optimization of implantable cardioverter defibrillator programming and algorithms for management of patients experiencing regular wide complex tachycardia and electrical storm are presented. The second part of the guidelines is structured according to disease-specific management, providing a link to the updated ESC CardioMed chapter for additional content. Risk stratification, sudden cardiac death prevention, treatment of VA, and management of family members are addressed in a systematic fashion. Indications for cardiac magnetic resonance imaging, genetic testing, and updated indications for catheter ablation of ventricular arrhythmias are presented. Flowcharts summarizing the workflow for diagnostis and treatment are provided for the disease entities. A novel concept of this document is the table of evidence. The trials and studies that have been selected to support a recommendation are systematically described in the table of evidence after careful review of the available data and the applied methodology, prioritizing papers published after 2015. Strong mediating and moderating effect of sinus rhythm at 12 months on the first primary outcome of the EAST-AFNET 4 trial. The presence of sinus rhythm at 12 months explains about 81% of the effect of early rhythm control on the first primary outcome, a composite of cardiovascular death, stroke, or hospitalization for heart failure, or acute coronary syndrome. This can be appreciated in the first horizontal line in the graph (natural effect). There is hardly any effect of early rhythm control in patients who are not in sinus rhythm at the 12-month visit, visible in lack of a controlled direct effect in patients not in sinus rhythm at 12 months. Atrial fibrillation recurrence at any time up to the 12-month visit, in contrast, only explains 31% of the effect of early rhythm control, due to the small differences between the effects of the two subgroups (controlled effect in patients without AF recurrence and patients with AF recurrence). The analysis is adjusted for baseline characteristics that may confound the treatment effects on the mediator or the mediator effect on the outcome. Total effect indicates the adjusted treatment effect on the outcome; natural direct effect indicates the adjusted treatment effect due to the observed distribution of the mediator; controlled direct effect indicates the adjusted treatment effect for subgroups of patients with and without sinus rhythm or with and without atrial fibrillation recurrence at 12 months.5 Several factors can affect sinus rhythm, and recent studies have suggested that its preservation may have a beneficial effect on prognosis.2–4 In a Fast Track Clinical Research article entitled ‘Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: the EAST-AFNET 4 trial’, Lars Eckardt, from the University Hospital Münster in Germany, and colleagues point out that a strategy of systematic, early rhythm control (ERC) improves cardiovascular outcomes in patients with atrial fibrillation (AF). It is not known how this outcome-reducing effect is mediated.5 Using the Early treatment of Atrial fibrillation for Stroke prevention Trial (EAST—AFNET 4) dataset, potential mediators of the effect of ERC were identified in the total study population at 12-month follow-up and were further interrogated by use of a four-way decomposition of the treatment effect in an exponential model predicting future primary outcome events. Fourteen potential mediators of ERC were identified at the 12-month visit. Of these, sinus rhythm at 12 months explained 81% of the treatment effect of ERC compared with usual care during the remainder of follow-up (4.1 years). In patients not in sinus rhythm at 12 months, ERC did not reduce future cardiovascular outcomes. Inclusion of AF recurrence in the model only explained 31% of the treatment effect, and inclusion of systolic blood pressure at 12 months only 10%. There was no difference in outcomes in patients who underwent AF ablation compared with those who did not undergo AF ablation (Figure 1). The authors conclude that in the EAST-AFNET 4 trial, the effectiveness of early rhythm control is mediated by the presence of sinus rhythm at 12 months. Clinicians implementing ERC should aim for rapid and sustained restoration of sinus rhythm in patients with recently diagnosed AF and cardiovascular comorbidities. The contribution is accompanied by an Editorial by Dominik Linz, from the Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht in The Netherlands, and William McIntyre from McMaster University in Hamilton, Canada.6 The authors point out that in general, the implementation of ERC will require a multidisciplinary approach with a shared decision-making process to discuss the benefits of rhythm control therapy. To give all patients with recently diagnosed AF and concomitant cardiovascular conditions access to an ERC approach, remote digital care pathways may be required to allow immediate initiation of ERC strategies and ensure continuous patient education, risk factor and lifestyle modification, and monitoring of the success of ERC, focusing on a reduction in AF burden and improvement of AF-related symptoms and quality of life. It follows naturally that with such an approach, achieving and maintaining sinus rhythm is a marker of success. However, when, and how to measure remain open questions. A more pressing question, though, is what to do for the patient who remains in AF despite our best efforts. Cumulative event rates of study outcomes associated with age at menopause (all log-rank P-values <.001).7 Premature menopause is a potential risk factor for several diseases. In a Clinical Research article entitled ‘Age at menopause and risk of heart failure and atrial fibrillation: a nationwide cohort study’, Jean Shin, from the Korea University College of Medicine in South Korea, and colleagues aimed to examine the association of premature menopause and age at menopause with the risk of heart failure (HF) and AF.7 A total of 1 401 175 postmenopausal women, who had undergone health examination provided by the Korean National Health Insurance Service, were included, and their reproductive histories were collected. Multivariable Cox proportional hazard models were performed to determine the hazard ratios (HRs) of incident HF and AF, according to the history of premature menopause and age at menopause. At a mean follow-up of 9.1 years, the prevalence of new cases of HF and of AF was 3% and 3.2%, respectively. Women with history of premature menopause had a significantly higher risk of HF (HR: 1.33) and AF (HR: 1.09), compared with women without the history. Compared with women aged ≥50 years at menopause, those aged 45−49, 40−44, and <40 years at menopause showed a significantly increased trend in HRs for the incident risk of both HF and AF (P for trend <.001) (Figure 2). The authors conclude that their findings suggest that postmenopausal women with a history of premature menopause or early menopausal age may have an increased risk of HF and AF. These reproductive factors should be considered for preventing the future risk of HF and AF. The contribution is accompanied by an Editorial by Tina Torbati, from the Cedars-Sinai Smidt Heart Institute in Los Angeles, CA (USA), and colleagues.8 The authors highlight that as Shin et al. conclude, female-specific risk factors such as reproductive history should be considered for HF and AF risk prediction and preventive strategies. Women who experience premature or early menopause are at increased risk for adverse cardiovascular outcomes—it does not appear that oestrogen alone can be blamed. The editorialists commend the authors for adding to the existing and growing body of literature regarding this topic. Further work investigating reproductive history, including the menopause transition, for cardiovascular disease prediction and prevention in women is needed. Cardiac pacing plays a key role in several diseases.9–12 Permanent trans-septal left bundle branch area pacing (LBBAP) is a promising new pacing method for both brady-arrhythmia and HF indications. However, data regarding safety, feasibility, and capture type are limited to relatively small, usually single-centre studies. In a Clinical Research article entitled ‘Left bundle branch area pacing outcomes: the multicentre European MELOS study’, Marek Jastrzębski, from Jagiellonian University in Krakow, Poland, and colleagues indicate that in this large multicentre international collaboration, outcomes of LBBAP were evaluated.13 This is a registry-based observational study that included patients in whom LBBAP device implantation was attempted at 14 European centres and for any indication. The study comprised 2533 patients (mean age 73.9 years, female 57.6%, HF 27.5%). LBBAP lead implantation success rate for brady-arrhythmia and for HF indications was 92.4% and 82.2%, respectively. The learning curve was steepest for the initial 110 cases and plateaued after 250 cases. Independent predictors of LBBAP lead implantation failure were HF, broad baseline QRS, and left ventricular end-diastolic diameter. The predominant LBBAP capture type was left bundle fascicular capture (70%), followed by left ventricular septal capture (21%), and proximal left bundle branch capture (9%). Capture threshold (0.77 V) and sensing (10.6 mV) were stable during a mean follow-up of 6.4 months. The complication rate was 11.7%. Complications specific to the ventricular transseptal route of the pacing lead occurred in 209 patients (8.3%). The authors conclude that LBBAP is feasible as a primary pacing technique for both brady-arrhythmia and HF indications. Success rate in HF patients and safety need to be improved. For wider use of LBBAP, randomized trials are necessary to assess clinical outcomes. This manuscript is accompanied by an Editorial by Michele Brignole, from the IRCCS Istituto Auxologico Italiano in Milan, Italy, and Richard Sutton from Imperial College in London, UK.14 They note that what we know thanks to the MELOS registry results is that LBBAP, and more generally conduction system pacing (CSP), is feasible and relatively easy to perform in most, but not in all, patients, by experienced physicians after a sufficient learning curve. The price to be paid is excess periprocedural complications 2–3-fold higher than conventional pacing modalities. The 60-year history of cardiac pacing shows that in the future, technical improvements (insertion tools and dedicated leads) will greatly decrease complications towards more acceptable values. What remains unknown is the magnitude of added clinical benefit of this ‘para-physiological pacing’ in terms of HF, arrhythmias, and mortality reduction. There is an urgent need for large randomized controlled clinical trials. Until those trials are reported, inferiority of conventional pacing modes cannot be assumed in clinical practice because greater clinical benefit of CSP must supersede its greater complication rate. The clinical benefit will probably vary from case to case. Fragmented QRS complex with visible notching on standard 12-lead electrocardiogram (ECG) is understood to represent depolarization abnormalities and to signify risk of cardiac events. Depolarization abnormalities with similar prognostic implications likely exist beyond visual recognition, but no technology is presently suitable for quantification of such invisible ECG abnormalities. In a Clinical Research article entitled ‘QRS micro-fragmentation as a mortality predictor’, Katerina Hnatkova from Imperial College in London, UK, and colleagues present such a technology.15 A signal processing method projects all ECG leads of the QRS complex into optimized three perpendicular dimensions, reconstructed the ECG back from this three-dimensional projection, and quantified the difference (QRS ‘micro’-fragmentation, QRS-μf) between the original and reconstructed signals. QRS-μf was assessed in three different populations: cardiac patients with implantable cardioverter defibrillator, cardiac patients with severe abnormalities, and the general population. The predictive value of QRS-μf for mortality was investigated both univariably and in multivariable comparisons with other risk factors including visible QRS ‘macro’-fragmentation (QRS-Mf). The analysis was made in a total of 7779 subjects of whom 504 died during the first 5 years of follow-up. In all three populations, QRS-μf was strongly predictive of survival (P < .001 univariably, and P < .001 to P = .024 in multivariable regression analyses). When QRS-μf was used in multivariable analyses, QRS-Mf and QRS duration lost their predictive value. The authors conclude that QRS-μf is a powerful mortality risk factor independent of several previously established risk indices. Electrophysiological abnormalities that contribute to increased QRS-μf values are likely responsible for the predictive power of visible QRS-Mf. The contribution is accompanied by an Editorial by Richard Hauer from the University Medical Center Utrecht in The Netherlands.16 Hauer concludes that compared with previous fractionation methodology, the presented micro-fractionation analysis is quantitative and not subjective. The method offers prediction of mortality in patients with cardiac disease as well as in the general population. Future studies should focus on applicability in different clinical settings, its role combined with other risk predictors, and its diagnostic value in early disease stages. Finally, as indicated by the authors, micro-fractionation analysis may not be limited to the QRS complex but might also be applicable to the T wave and the P wave. They conclude that the authors must be congratulated for this highly clinically relevant contribution to mortality prediction with a promising new tool. Ventricular arrhythmias are a major factor in the occurrence of morbidity and sudden death in patients with cardiovascular disease, and an important therapeutic target.17–21 Disturbances of Ca2+ homeostasis in the heart contribute to the initiation and maintenance of cardiac arrhythmias. Extrasystolic increases in intracellular Ca2+ lead to delayed after-depolarizations and triggered activity, which can result in heart rhythm abnormalities. In a Translational Research article entitled ‘TRPM4 inhibition by meclofenamate suppresses Ca2+-dependent triggered arrhythmias’, Frone Vandewiele, from KU Leuven in Belgium, and colleagues indicate that it is being suggested that the Ca2+-activated non-selective cation channel TRPM4 is involved in the aetiology of triggered activity, but the exact contribution and in vivo significance are still unclear.22In vitro electrophysiological and calcium imaging techniques, as well as in vivo intracardiac and telemetric electrocardiogram measurements in physiological and pathophysiological conditions, were performed. In two distinct Ca2+-dependent pro-arrhythmic models, freely moving Trpm4−/− mice displayed a reduced burden of cardiac arrhythmias. Looking further into the specific contribution of TRPM4 to the cellular mechanism of arrhythmias, TRPM4 was found to contribute to a long-lasting Ca2+ overload-induced background current, thereby regulating cell excitability in Ca2+ overload conditions. To expand these results, a compound screening revealed meclofenamate as a potent antagonist of TRPM4. In line with the findings from Trpm4−/− mice, 10 µM meclofenamate inhibited the Ca2+ overload-induced background current in ventricular cardiomyocytes, and 15 mg/kg meclofenamate suppressed catecholaminergic, polymorphic, ventricular tachycardia (CPVT)-associated arrhythmias in a TRPM4-dependent manner. The authors conclude that the presented data establish that TRPM4 represents a novel target in the prevention and treatment of Ca2+-dependent triggered arrhythmias. The manuscript is accompanied by an Editorial by Jordi Heijman, from the Maastricht University in The Netherlands, and Dobromir Dobrev from the University of Duisburg-Essen in Germany.23 The authors note that the identification of novel molecular mechanisms create opportunities for new therapeutic strategies, including repurposing of approved drugs and combination therapy. Indeed, low-dose meclofenamate or flecainide alone did not significantly suppress arrhythmias in CPVT mice, whereas their combination had a pronounced anti-arrhythmic effect. Whereas much remains to be done, such approaches may help to overcome the gap to clinical approval and application of novel anti-arrhythmic drugs that are desperately needed. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Refitting the predictor variables included in a model in a new cohort usually exaggerates its calibration performance’, Yong-Ming He from the The First Affiliated Hospital of Soochow University in Suzhou City, P.R. China, comments on the recent publication ‘Ethnicity-dependent performance of the Global Registry of Acute Coronary Events risk score for prediction of non-ST-segment elevation myocardial infarction in-hospital mortality: nationwide cohort study’ by Saadiq M Moledina from Keele University, Stoke-on-Trent, UK.24,25 Moledina et al. respond in a separate comment.26 The editors hope that this issue of the European Heart Journal will find the interest of its readers. Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work.