New light shed on syncope and sudden cardiac death

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on arrhythmias contains a State of the Art Review entitled ‘Post-operative atrial fibrillation: from mechanisms to treatment’ by Mario Gaudino from Weill Cornell Medicine in New York City, NY, USA.1 The causes, triggers, and mechanisms of atrial fibrillation (AF) are well known to be multiple.2–6 The authors point out that post-operative AF (POAF) is common and, despite progress in prevention and treatment, remains an important clinical problem for patients undergoing a variety of surgical procedures, and in particular cardiac surgery. POAF significantly increases the duration of post-operative hospital stay, hospital costs, and the risk of recurrent AF in the years after surgery; moreover, POAF has been associated with a variety of adverse cardiovascular events (including stroke, heart failure, and mortality), although it is still unclear if this is due to a causal relationship or simple association. New data have recently emerged on the pathophysiology of POAF, and new preventive and therapeutic strategies have been proposed and tested in randomized trials. This review summarizes the current evidence on the pathogenesis, incidence, prevention, and treatment of POAF and highlights future directions for clinical research. Management of cardiac arrest is a major clinical challenge.7–11 In a Meta-analysis article entitled ‘Coronary angiography after cardiac arrest without ST-elevation myocardial infarction: a network meta-analysis’, Sebastian Heyne from the University of Cologne in Germany, and colleagues assess the effect of early coronary angiography (CAG) compared with selective CAG (late and no CAG) for patients after out-of-hospital cardiac arrest without ST-elevation myocardial infarction (NSTE-OHCA).12 A systematic literature search was performed using the EMBASE, MEDLINE, and Web of Science databases without restrictions on publication date. Randomized controlled trials (RCTs) and non-randomized studies (NRS) comparing the effect of early CAG with selective CAG after NSTE-OHCA on survival and/or neurological outcomes were included. Meta-analyses were performed based on a random effects model. Meta-analyses showed a statistically significant increase in survival after early CAG compared with selective CAG in the overall analysis [odds ratio (OR) 1.40, P < 0.01]. This effect was lost in the subgroup analysis of RCTs (OR 0.89, P = 0.29). Furthermore, random effects model network meta-analysis of NRS based on a Bayesian method showed statistically significant increased survival after late compared with early CAG (OR 4.20). Heyne et al. conclude that previously reported superiority of early CAG after NSTE-OHCA is based on NRS at high risk of selection and survivorship bias. The meta-analysis of RCTs does not support routinely performing early CAG after NSTE-OHCA. The contribution is accompanied by an Editorial by Holger Thiele, Anne Freund, and Steffen Desch from the Heart Center Leipzig at University of Leipzig and Leipzig Heart Institute in Germany.13 Thiele and colleagues conclude that we should also address the question of future distribution of financial resources in OHCA research. The pre-hospital phase in OHCA is frequently decisive for determining outcomes. Scientific and clinical advances in this field might overall exert a much higher impact on outcome compared with in-hospital measures. This discussion might be further reinforced in that we seem to be faced with changing patient characteristics in OHCA, increasingly frequently towards non-coronary causes. Cumulative incidence of conduction disease by baseline regular exercise intensity. Adjusted Kaplan–Meier cumulative incidence curves for conduction disease according to exercise intensity level. The curves were smoothed using randomly imputed failure times between exam visits and adjusted for age, gender, race, education, body mass index, diabetes, hypertension, coronary heart disease, smoking, and alcohol.16 Cardiac conduction disease can lead to syncope, heart failure, and death, while predictors are poorly known.14,15 In a Clinical Research article entitled ‘Lifestyle habits associated with cardiac conduction disease’, Emilie Frimodt-Møller from the University of California San Francisco in California, USA, and colleagues utilized data from the Cardiovascular Health Study, a population-based cohort study of adults ≥65 years with annual 12-lead electrocardiograms (ECGs) obtained over 10 years, to examine relationships between baseline characteristics, including lifestyle habits, and conduction disease.16 Of 5050 participants (mean age 73 years; 52% women), prevalent conduction disease included 257 with first-degree atrioventricular block, 99 with left anterior fascicular block, 9 with left posterior fascicular block, 193 with right bundle branch block (BBB), 76 with left BBB, and 102 with intraventricular block at baseline. After multivariable adjustment, older age, male sex, a larger body mass index (BMI), hypertension, and coronary heart disease were associated with a higher prevalence of conduction disease, whereas White race and more physical activity were associated with a lower prevalence. Over a median follow-up of 7 (interquartile range 1–9) years, 1036 developed incident conduction disease. Older age, male sex, a larger BMI, and diabetes were each associated with incident conduction disease. Of lifestyle habits, more physical activity was associated with a reduced risk, while smoking and alcohol did not exhibit a significant association (Figure 1). The authors conclude that while some difficult to control comorbidities are associated with conduction disease as expected, a readily modifiable lifestyle factor, physical activity, is associated with a lower risk. The contribution is accompanied by an Editorial by Jean Jacques Noubiap and Melissa Middeldorp from the University of Adelaide in Australia.17 Noubiap and Middeldorp highlight that although the prospect of cardiac conduction disease prevention is stirring, there is still a long way to go. First, further studies are needed to better investigate the association between lifestyle behaviours, sociodemographic, environmental, and clinical factors, and incident conduction disease. Such studies should be more representative of the general population and ethnically diverse, and better reflect the dynamic interactions between potential risk factors and the outcome of incident conduction disease. Then, additional studies should explore whether some interventions including lifestyles changes, risk factor control, and medications could prevent the development of conduction disease or indeed reverse it. Syncope is a common and clinically challenging condition.18–20 In a Clinical Research article entitled ‘Genetic variants associated with syncope implicate neural and autonomic processes’, Hildur Aegisdottir from the University of Iceland in Reykjavik, Iceland, and colleagues note that this genome-wide association meta-analysis included ∼56 000 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (UK), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland).21 The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation regarding regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened life span. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk, but did not associate with other disorders. The authors conclude that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health is also present, supporting the importance of a thorough assessment of individuals presenting with syncope. This manuscript is accompanied by an Editorial by Robert Sheldon from the University of Calgary in Canada and Brenda Gerull from the University of Würzburg in Germany.22 The authors conclude that strong features of the study by Hildur Aegisdottir et al. include very large populations and sophisticated analyses. They have detected numerous interesting genomic loci that will raise hypotheses for some time to come, and they may have provided a genetic key to vasovagal syncope. The interpretation of the data is limited by its strongly Northern European population, potential difficulties with phenotypic ascertainment, several population inclusion biases, and multiple aetiologies of syncope swept up in a single diagnostic code. Nonetheless, this is an ambitious and provocative study. The study enrolled a cohort of 22 324 children who underwent a mean of 2.9 annual pre-participation screenings that included history, physical examination, resting ECG, and exercise testing. Cardiovascular diseases at risk of sudden cardiac death were identified in 69 children (0.3%). The diagnostic yield of each screening session was 0.12% at the first evaluation and 0.1% at repeat evaluation. Moreover, it was 0.05% in children 7–11 years old vs. 0.12% in those aged 12–18. During a follow-up of 7.5 ± 3.7 years, one child with normal pre-participation screening findings experienced an episode of resuscitated cardiac arrest during sports activity. HD, heart disease; LV, left ventricular; IQR, interquartile range.23 In another Clinical Research article entitled ‘Value of screening for the risk of sudden cardiac death in young competitive athletes’, Patrizio Sarto from the Sports Medicine Unit regional referral centre in Treviso, Italy, and colleagues aimed to report the long-term findings of the Italian programme of cardiovascular pre-participation screening (PPS) in young, competitive athletes.23 The study assessed the diagnostic yield for diseases at risk of sudden cardiac death (SCD), the costs of serial evaluations, and the long-term outcomes of PPS in a large population of Italian young competitive athletes (age range, 7–18 years). The PPS was repeated annually and included medical history, physical examination, resting electrocardiogram, and stress testing; additional tests were reserved for athletes with abnormal findings. Over an 11-year study period, 22 324 consecutive young competitive athletes (62% males; mean age 12 years at first screening) underwent a total of 65 397 annual evaluations. Cardiovascular diseases at risk of SCD were identified in 69 children (0.3%) and included congenital heart diseases (n = 17), channelopathies (n = 14), cardiomyopathies (n = 15), non-ischaemic left ventricular scar with ventricular arrhythmias (n = 18), and others (n = 5). At-risk cardiovascular diseases were identified over the entire age range and more frequently in children ≥12 years old and on repeat evaluation. The estimated cost per diagnosis was €73 312. During a follow-up of 7.5 years, one child with normal PPS findings experienced an episode of resuscitated cardiac arrest during sports activity (event rate of 0.6/100.000 athletes/year) (Figure 2). The authors conclude that the PPS programme leads to the identification of cardiovascular diseases at risk of SCD over the whole study age range of young competitive athletes and more often on repeat evaluations. Among screened children, the incidence of sport-related cardiac arrest during long-term follow-up is low. The contribution is accompanied by an Editorial by Cheyenne Beach and Rachel Lampert from the Yale University School of Medicine in New Haven, CT, USA.24 The authors conclude that these data support the use of repeated cardiovascular screenings and the availability of automatic external defibrillators. They raise questions regarding the optimal age at first screen and various screening modalities. The tragic nature of sudden cardiac arrest in children and adolescents and our common goal to reduce sudden cardiac arrest risk while encouraging healthy and safe physical activity provide impetus for ongoing optimization for pre-participation screening. The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.