Learning from epidemiology: atrial fibrillation, peripheral artery disease, and twin pregnancy

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on arrhythmias, epidemiology, and prevention contains the Viewpoint article ‘The year in cardiovascular medicine 2024: the top 10 papers in cardio-oncology’ by EHJ Editors Alexander R. Lyon, Teresa López-Fernández, and Joerg Herrmann: the second contribution to this successful series of articles for year 2024.1 The Issue continues with a focus on arrhythmia, epidemiology, prevention, and public health policies. The management of atrial fibrillation (AF) is complex.2–9 In a Meta-Analysis article entitled ‘Major clinical outcomes in symptomatic vs asymptomatic atrial fibrillation: a meta-analysis’, Paschalis Karakasis from the Aristotle University of Thessaloniki in Greece, and colleagues note that because recent investigations have provided conflicting results, the present study aimed to evaluate the association between symptom status and clinical outcomes in patients with AF.10 Medline, Cochrane Library, and Scopus were searched up to 25 March 2024. Triple-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled using random-effects meta-analyses. Thirty-six studies (∼218 000 participants) were included. Based on the frequentist analysis, symptomatic individuals had no significant difference in the risk of all-cause mortality (hazard ratio [HR] 0.97), cardiovascular mortality (HR 1.04), thromboembolism (HR 1.06), stroke (HR 1.06), hospitalization (HR 1.34), and myocardial infarction (HR 0.98) compared with the asymptomatic group. Symptomatic patients had a 33% significantly higher risk of new-onset heart failure (HR 1.33) and a 30% significantly lower risk of progression to permanent AF (HR 0.70). The Bayesian analysis yielded comparable results, yet the association between symptom status and new-onset heart failure was not significant (HR 1.27). Symptomatic patients had significantly higher odds of receiving antiarrhythmic drugs (odds ratio [OR] 1.64) and ablation therapy (OR 1.47) compared with asymptomatic cases (Figure 1). Major clinical outcomes in patients with symptomatic vs asymptomatic atrial fibrillation. AF, atrial fibrillation; CI, confidence interval; CrI, credible interval; HR, hazard ratio; OR, odds ratio. *A two-tailed P-value < .05 was considered statistically significant10 The authors conclude that the risk of major clinical outcomes does not differ between individuals with and without AF-related symptoms. Asymptomatic patients have a greater hazard of progression to permanent AF. The contribution is accompanied by an Editorial by Paulus Kirchhof, Marc Lemoine, and Laura Rottner from the University Hospital Hamburg-Eppendorf in Germany.11 The authors note that this comprehensive meta-analysis clearly demonstrates that asymptomatic AF causes a large burden of disease. The data identify ways to improve the lives of patients with asymptomatic AF and highlight unmet medical needs in this large population. The results of this meta-analysis illustrate five main tasks ahead: (i) early identification of asymptomatic patients with a high AF burden and a high risk of AF-related complications; (ii) timely initiation of therapy in patients with asymptomatic AF (anticoagulation, early rhythm control, rate control, and therapy of concomitant cardiovascular conditions) to reduce outcomes, to prevent AF progression, and to reduce AF burden; (iii) better identification of patients with AF at high risk of stroke, heart failure, myocardial infarction, and cardiovascular death, and targeted screening methods that include risk markers and AF burden; (iv) development of simple, effective, safe, and scalable rhythm control therapy concepts; and (v) continuation of symptom-improving therapy in patients with symptomatic AF. Lower extremity peripheral arterial disease (PAD) presents a substantial disease burden, yet lifetime estimates remain scant.12–15 In a Clinical Research article entitled ‘Lifetime risk of lower extremity peripheral arterial disease: a Danish nationwide longitudinal study’, Mette Søgaard from the Aalborg University, in Denmark, and colleagues indicate that this nationwide study quantified the lifetime risk of PAD and its clinical outcomes in Denmark.16 This cohort study included ∼4 300 000 individuals in Denmark aged 40–99 years between 1998 and 2018. The authors estimated the lifetime risk using a modified survival analysis method, considering death as a competing risk event. Over a median 15 year follow-up, ∼152 000 individuals were diagnosed with PAD (median age at diagnosis 71 years). The overall lifetime risk of PAD from age 40 was 11.6%, decreasing from 12.9% in 1998–2002 to 11% in 2013–18. Males had a higher lifetime risk than females (13% vs 10%). Socioeconomic disparities were evident, with higher risks for those with lower educational levels (risk difference 3.4%) and lower income (risk difference 0.4%). One year after PAD diagnosis, 21% had undergone lower limb revascularization, 8% had experienced a major amputation, and 16% had died. At 5 years, the corresponding proportions were 26, 11, and 40.8%, respectively. The risk of lower limb revascularization showed little variation by sex and socioeconomic status, whereas there was a strong socioeconomic gradient for major amputation and all-cause death. The authors conclude that >1 in 10 Danish individuals are diagnosed with symptomatic PAD during their lifetime. The diagnosis of PAD is associated with high morbidity and mortality at 1 and 5 years of follow-up after the diagnosis. The contribution is accompanied by an Editorial by Christine Espinola-Klein from the University Medical Centre of the Johannes Gutenberg-University Mainz in Germany.17 Espinola-Klein notes that this important study highlights the urgent need for action. Atherosclerosis is a worldwide epidemic, and PAD can be regarded as a marker of advanced atherosclerosis. The best way would be to prevent or at least delay the development of PAD. Modifiable risk factors are responsible for ∼70% of the PAD risk. A healthy lifestyle including healthy diet, regular exercise training, and avoiding smoking is crucial to reach this goal. Another important point is the early management of treatable risk factors such as elevated blood pressure, LDL cholesterol, diabetes, and obesity. Last, but not least, we urgently need health campaigns to improve awareness of PAD and thus save lives and legs. Sex-specific risk factors are generating increasing interest.18–20 Increased cardiovascular demand in twin pregnancies, even those without hypertensive disease of pregnancy (HDP), may pose a greater risk for cardiovascular complications compared with singletons. In a Clinical Research article entitled ‘Hospitalization for cardiovascular disease in the year after delivery of twin pregnancies’, Ruby Lin from the Rutgers Robert Wood Johnson Medical School in New Brunswick, NJ, USA, and colleagues compared the risk of cardiovascular disease (CVD)-related hospitalizations and mortality within the year following delivery in relation to HDP between twin and singleton pregnancies.21 Using the Nationwide Readmissions Database of US hospitals from 2010 to 2020, the rates of CVD readmission in four exposure groups (twin deliveries with and without HDP and singleton deliveries with and without HDP) were estimated. Cox proportional hazard regression models were used to determine associations with singletons without HDP as the reference. Of 36 million delivery hospitalizations, the rates of CVD readmission in twin and singleton pregnancies were 1105 and 734 per 100 000 delivery admissions, respectively. Compared with singletons without HDP, the adjusted HR of CVD readmission was highest for twins with HDP (HR 8.219), followed by singletons with HDP (HR 5.89) and then twins without HDP (HR 1.95) (Figure 2). The authors conclude that compared with singletons without HDP, twin pregnancies, even in the absence of HDP, are associated with increased risks for CVD complications in the first year post-partum. These findings highlight the increased strain twin pregnancies place on the maternal cardiovascular system. They also advocate the need for appropriate pre-conception counselling for those with cardiovascular risk factors undergoing infertility treatment, which increase the risks of multi-foetal gestation, and increased post-partum surveillance in twin pregnancies. This manuscript is accompanied by an Editorial by Katherine E. Economy, Alexandria F. Williams, and Anne Marie Valente from Harvard Medical School in Boston, MA, USA.22 The authors highlight that research is needed to investigate how technology and post-partum remote monitoring programmes can be leveraged to engage post-partum patients in preventative care to optimize cardiometabolic risk profiles, such as diabetes screening, referrals to exercise and nutrition programmes, lactation support, and mental health resources. As Lin et al. emphasize, expansion of insurance coverage is vital to supporting the transition of care from the immediate post-partum period to throughout the life span. In addition to focusing on single embryo transfers to reduce incidence of multiples, access to contraceptive care, abortion care, and multi-foetal reduction are equally important to reduce the burden of multiple gestations, HDP, and long-term CVD in women. Looking forward, this work highlights several important opportunities that exist for us to join as cardiologists and obstetricians to collaborate on improving the quality and duration of post-partum care, particularly for those who had twin pregnancies, as well as to address racial and socioeconomic disparities in long-term CVD risk for women. The cholinergic system is distributed in the nervous system, mediating electrical conduction through acetylcholine (ACh). In a Translational Science article entitled ‘An endogenous cholinergic system controls electrical conduction in the heart’, Duanyang Xie from the Tongji University in Shanghai, China, and colleagues aim to identify whether the heart possesses an intact endogenous cholinergic system and to explore its electrophysiological functions and relationship with arrhythmias in both humans and animals.23 The components of the heart’s endogenous cholinergic system were identified by a combination of multiple molecular cell biology techniques. The relationship of this system with cardiac electrical conduction and arrhythmias was analysed through electrophysiological techniques. An intact cholinergic system including ACh, ACh transmitter vesicles, ACh transporters, ACh metabolic enzymes, and ACh receptors was identified in both human and mouse ventricular cardiomyocytes (VCs). The key components of the system significantly regulated the conductivity of electrical excitation among VCs. The influence of this system on electrical excitation conduction was further confirmed both in the mice with α4 or α7 nicotinic ACh receptor (nAChR) knockouts and in the monolayers of human induced pluripotent stem cell-derived cardiomyocytes. Mechanistically, ACh induced an inward current through nAChRs to reduce the minimum threshold current required to generate an action potential in VCs, thereby enhancing the excitability that acts as a prerequisite for electrical conduction. Importantly, defects in this system were associated with fatal ventricular arrhythmias in both patients and mice. Xie et al. conclude that this study identifies an integrated cholinergic system inherent to the heart, rather than external nerves, that can effectively control cardiac electrical conduction. The discovery reveals arrhythmia mechanisms beyond classical theories and opens up new directions for arrhythmia research. The contribution is accompanied by an Editorial by Dobromir Dobrev from the University Duisburg-Essen in Germany and Sami Noujaim from the University of South Florida, USA.24 The authors note that the study by Xie et al. demonstrated that an nAChR-driven cholinergic system exists in ventricular cardiomyocytes and is involved in normal cardiac conduction and arrhythmogenesis. A better understanding of how this system contributes to cardiac excitability and electrical propagation in disease might inform the development of new antiarrhythmic strategies. It is possible that both stimulation (inhalation exposure to nicotine) and inhibition (down-regulation of nAChRs in disease) of the ventricular cholinergic system are proarrhythmic. Clearly, we are just beginning to understand the details of the cardiomyocyte cholinergic system, and further extensive research is needed to better define and therapeutically exploit the cardiomyocyte cholinergic system. Enhanced inflammatory signalling causally contributes to development of AF. Gasdermin D (GSDMD) is an important downstream effector of several inflammasome pathways. However, the role of GSDMD, particularly the cleaved N-terminal (NT)-GSDMD, in non-immune cells remains elusive. In a Translational Research article entitled ‘Atrial cardiomyocyte-restricted cleavage of gasdermin D promotes atrial arrhythmogenesis’, Na Li from the Baylor College of Medicine in Houston, USA and colleagues aimed to elucidate the function of NT-GSDMD in atrial cardiomyocytes (ACMs) and determine its contribution to atrial arrhythmogenesis.25 Human atrial appendages were used to assess the protein levels and localization. A modified adeno-associated virus 9 was employed to establish ACM-restricted overexpression of NT-GSDMD in mice. The cleavage of GSDMD was enhanced in ACMs of AF patients. ACM-restricted overexpression of NT-GSDMD in mice increased susceptibility to pacing-induced AF. The NT-GSDMD pore formation facilitated interleukin-1β (IL-1β) secretion from ACMs, promoting macrophage infiltration, while up-regulating ‘endosomal sorting complexes required for transport’-mediated membrane repair mechanisms, prevented inflammatory cell death (pyroptosis) in ACMs. Up-regulated NT-GSDMD directly targeted mitochondria, increasing mitochondrial reactive oxygen species (ROS) generation, which triggered proarrhythmic calcium release events. The NT-GSDMD-induced arrhythmogenesis was mitigated by the mitochondrial-specific antioxidant mitoTEMPO. A mutant NT-GSDMD lacking pore formation capability failed to cause mitochondrial dysfunction or induce atrial arrhythmia. Genetic ablation of Gsdmd prevented spontaneous AF development in a mouse model. The authors conclude that the findings establish a unique pyroptosis-independent role of NT-GSDMD in ACMs and arrhythmogenesis, which involves ROS-driven mitochondrial dysfunction. Mitochondrial-targeted therapy, either by reducing ROS production or by inhibition of GSDMD, prevents AF inducibility, positioning GSDMD as a novel therapeutic target for AF prevention. In a Rapid Communications contribution entitled ‘Sex-specific clinical course of young patients with Brugada syndrome’, Tomohiko Imamura and colleagues from the Kyoto University Graduate School of Medicine in Japan indicate that Brugada syndrome (BrS) is an inherited arrhythmia that causes sudden death due to ventricular arrhythmias.26 Despite its autosomal-dominant inheritance, the prevalence of Brugada-type ST elevation is male dominant in adults, suggesting that specific modifiers may promote the BrS phenotype in men or protect from BrS in women. Paediatric BrS shows no significant sex differences and a higher risk of lethal arrhythmic events (LAEs); however, age-dependent changes in clinical findings around puberty remain unclear. Therefore, the authors aimed to clarify the sex differences in the number of diagnoses and LAEs by age and in electrocardiogram (ECG) findings before and after puberty, and identify risk factors for LAEs in young patients with BrS. This cohort study included patients with inherited arrhythmias referred, for genetic testing, to Kyoto University and Shiga University of Medical Science from hospitals across Japan between 1996 and 2020. Among patients with clinically suspected BrS, the authors analysed probands aged ≤20 years identified as having probable or definite BrS, using a Shanghai scoring system score of ≥3.5 to minimize false positives. Of the 68 young patients with BrS, this study analysed 57 probands: 42 male and 15 female patients. The proportion of female patients among newly diagnosed patients decreased from 42% in pre-puberty to 0% in post-puberty. Notably, no female patient experienced LAEs after puberty, and there was no significant difference in clinical characteristics between pre- and post-puberty diagnosed age groups, apart from the sex proportion. The authors conclude that the number of new diagnoses and the incidence of LAEs decreases in female patients with BrS after puberty; approximately half of the female patients show attenuation of Brugada-type ST elevations. Testosterone has been considered to contribute to the male predominance in BrS. However, these results suggest that increased oestradiol may have a protective effect against BrS, consistently with previous findings. This study provides critical insights into developing risk stratification specific to young patients with BrS. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Coronary revascularization in randomized clinical trials comparing transcatheter and surgical aortic valve replacement: is it time to bridge the gap?’, Hugo M. Aarts from the University Medical Center Utrecht in the Netherlands and colleagues comment on the recent publication ‘Transcatheter aortic valve implantation in low-risk tricuspid or bicuspid aortic stenosis: the NOTION-2 trial’ by Troels Højsgaard Jørgensen from the Copenhagen University Hospital in Denmark.27,28 Jørgensen et al. respond in a separate comment.29 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.