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This Focus Issue on genetics and arrhythmias contains the State of the Art Review article ‘Diet and risk of atrial fibrillation: a systematic review’ by Monika Gawałko from the University of Warsaw in Poland, and colleagues 1 An optimal diet plays a key role in prevention of cardiovascular diseases.2–4 Comprehensive modification of established atrial fibrillation (AF) risk factors combined with dietary interventions and breaking deleterious habits has been shown to reduce AF burden and recurrence. Numerous AF risk factors, such as diabetes, obesity, or hypertension, can be partially related to dietary and lifestyle choices. Therefore, dietary interventions may have potential as a therapeutic approach in AF. Based on available data, current guidelines recommend alcohol abstinence or reduction to decrease AF symptoms, burden, and progression, and do not indicate the need for caffeine abstention to prevent AF episodes (unless it is a trigger for AF symptoms). Uncertainty persists regarding harms or benefits of other dietary factors including chocolate, fish, salt, polyunsaturated and monounsaturated fatty acids, vitamins, and micronutrients. This article provides a systematic review of the association between AF and both dietary patterns and components. Additionally, it discusses potentially related mechanisms and introduces different strategies to assess patients’ nutrition patterns, including mobile health solutions and diet indices. Finally, it highlights the gaps in knowledge requiring future investigation.
In a State of the Art Review article entitled ‘Clinical trials in-a-dish for cardiovascular medicine’, Xuekun Wu from the Stanford University School of Medicine in Stanford, CA, USA, and colleagues note that cardiovascular diseases persist as a global health challenge that requires methodological innovation for effective drug development.5 Conventional pipelines relying on animal models suffer from high failure rates due to significant interspecies variation between humans and animal models. In response, the recently enacted Food and Drug Administration Modernization Act 2.0 encourages alternative approaches including induced pluripotent stem cells (iPSCs). Human iPSCs provide a patient-specific, precise, and screenable platform for drug testing, paving the way for cardiovascular precision medicine. This review discusses milestones in iPSC differentiation and their applications from disease modelling to drug discovery in cardiovascular medicine. It then explores challenges and emerging opportunities for the implementation of ‘clinical trials in-a-dish’. Concluding, this review proposes a framework for future clinical trial design with strategic incorporations of iPSC technology, microphysiological systems, clinical pan-omics, and artificial intelligence to improve success rates and advance cardiovascular healthcare.
Clinical medicine requires the integration of various forms of patient data including demographics, symptom characteristics, electrocardiogram (ECG) findings, laboratory values, biomarker levels, and imaging studies. In another State of the Review article entitled ‘Artificial intelligence in cardiovascular medicine: clinical applications’, Thomas Lüscher from the University of Zurich in Switzerland, and colleagues indicate that decision-making on optimal management should be based on a high probability that the envisaged treatment is appropriate, provides benefit, and bears no or little potential harm.6 To that end, personalized risk–benefit considerations should guide the management of individual patients to achieve optimal results. These basic clinical tasks have become more and more challenging with the massively growing data now available; artificial intelligence and machine learning (AI/ML) can provide assistance to clinicians by obtaining and comprehensively preparing the history of patients, analysing face and voice and other clinical features, by integrating laboratory results, biomarkers, and imaging. Furthermore, AI/ML can provide a comprehensive risk assessment as a basis of optimal acute and chronic care.7–14 The clinical usefulness of AI/ML algorithms should be carefully assessed, validated with confirmation datasets before clinical use, and repeatedly re-evaluated as patient phenotypes change. This review provides an overview of the current data revolution that has changed and will continue to change the face of clinical medicine radically, if properly used, to the benefit of physicians and patients alike.
A total of 920 Chinese patients with persistent AF undergoing first ablation were randomized to oral SSYX or matched placebo for 12 months. The recurrence of atrial arrhythmia (left), Kaplan–Meier curves depicting the time to the first recurrence of atrial arrhythmia after the 3-month blanking period (middle), and quality of life at 12-month follow-up (right) were evaluated. SSYX, Shensong Yangxin; CI, confidence interval; AF, atrial fibrillation; RD, rate difference; HR, hazard ratio.15
Despite advances in technology and techniques, the recurrence rate of persistent AF following catheter ablation remains high. The Shensong Yangxin (SSYX) capsule, a renowned traditional Chinese medicine formula, is used in the treatment of cardiac arrhythmias. In a Clinical Research article entitled ‘Atrial tachyarrhythmia prevention by Shensong Yangxin after catheter ablation for persistent atrial fibrillation: the SS-AFRF trial’, He Huang from the Cardiovascular Research Institute of Wuhan University in China, and colleagues aimed to investigate whether SSYX can improve clinical outcomes in patients who have undergone catheter ablation for persistent AF.15 A multicentre, randomized, double-blind, placebo-controlled clinical trial was conducted at 66 centres in China among 920 patients with persistent AF undergoing first ablation. Participants were randomized to oral SSYX, 1.6 g thrice daily (n = 460), or matched placebo (n = 460) for 12 months. The primary endpoint was recurrent atrial tachyarrhythmias lasting for ≥30 s following a blanking period of 3 months. A key secondary endpoint was quality of life (QoL). Analyses were performed according to the intention-to-treat principle.16–18 A total of 920 patients underwent randomization (460 assigned to the SSYX group and 460 assigned to the placebo group). During the follow-up of 12 months, patients assigned to SSYX had a higher event-free rate from recurrent atrial tachyarrhythmias when compared with the placebo group (12-month Kaplan–Meier event-free rate estimates, 85.5% and 77.7%, respectively, P = .001). Patients assigned to receive SSYX had a better QoL score at 12 months compared with those randomized to placebo. There was no significant difference in the incidence of serious adverse events between the two groups (Figure 1).
The authors conclude that treatment with SSYX following radiofrequency catheter ablation for persistent AF reduces the incidence of recurrent atrial tachyarrhythmias and leads to clinically significant improvements in QoL during a 12-month follow-up in a Chinese population. This manuscript is accompanied by an Editorial by Milton Packer from the Baylor University Medical Center in Dallas, TX, USA.19 Packer notes that traditional Chinese medicines are being standardized and commercialized, and are undergoing formal evaluation in large-scale double-blind placebo-controlled trials. Most of these medicines are derived from diterpenoids and triterpenoids, which are synthesized by plants for their cytoprotective effects, and they minimize imbalances in cardiomyocyte cellular signalling, which lead to plaque rupture, cardiomyocyte loss and myocardial fibrosis, and the generation of cardiac rhythm abnormalities. Sceptics should remember that Western medicine was born in botany, and most of our established treatments are derived from plant and animal sources. Although physicians in the West might be perturbed by the holistic administration of dozens of nature-sourced medicinals that simultaneously deliver hundreds of molecules with potential cardiovascular structural and functional effects, in the final analysis, the results of rigorous randomized placebo-controlled trials will speak for themselves.
In a Clinical Research article entitled ‘The AORTA Gene score for detection and risk stratification of ascending aortic dilation’ James Pirruccello from the University of California San Francisco in CA, USA, and colleagues assessed whether a model incorporating clinical features and a polygenic score would improve diameter estimation and prediction of adverse thoracic aortic events over clinical features alone.20 Aortic diameter estimation models were built with a 1.1 million-variant polygenic score (AORTA Gene) and without it. Models were validated internally in 4394 UK Biobank participants and externally in 5469 individuals from Mass General Brigham Biobank (MGB), 1298 from the Framingham Heart Study (FHS), and 610 from All of Us. Model fit for adverse thoracic aortic events was compared in the UK Biobank and All of Us participants. AORTA Gene explained more of the variance in thoracic aortic diameter compared with clinical factors alone: 39% vs. 29% in UK Biobank, 36% vs. 32% in MGB, 42% vs. 33% in FHS, and 35% vs. 29% in All of Us. AORTA Gene had a greater area under the receiver operating characteristic curve for identifying a diameter ≥4 cm: 0.84 vs. 0.78 (P < .0001) in UK Biobank, 0.81 vs. 0.77 in MGB (P < .0001), 0.86 vs. 0.81 in FHS (P < .0001), and 0.83 vs. 0.79 (P = .0078) in All of Us. AORTA Gene was more informative for adverse thoracic aortic events in UK Biobank (P = .0042) and All of Us (P = .049).
The authors conclude that a comprehensive model incorporating polygenic information and clinical risk factors explains 35%–42% of the variation in ascending aortic diameter, improving the identification of ascending aortic dilation and adverse thoracic aortic events compared with clinical risk factors. The contribution is accompanied by an Editorial by John DePaolo, David Zhang, and Scott Damrauer from the University of Pennsylvania, PA, USA.21 The authors highlight that Pirruccello et al. have produced an additional and important step towards true precision medicine to inform individual-level risk of thoracic aortic disease. They have shown that the addition of genetic information in the AORTA Gene model performs better in predicting ascending thoracic aortic dilation across multiple cohorts. They provide new evidence that AORTA Gene associates with incident adverse thoracic aortic events. While additional studies will be required to prospectively study AORTA Gene implementation and its potential to improve the care of patients with thoracic aortic dilation and disease, this work substantially moves the field towards the reality of precision medicine for diagnosing and treating thoracic aortic disease.
Role of anti-NaV1.5 autoantibodies in Brugada syndrome. The figure demonstrates how these autoantibodies, when present in patient plasma, can elicit the coved-type ST-segment elevation resembling the human type 1 Brugada syndrome electrocardiographic pattern in wild-type mice and significantly reduce sodium current density, supporting their diagnostic and pathogenic significance in the disease. BrS, Brugada syndrome; ECG, electrocardiographic; IgG, immunoglobulin G.22
Patients suffering from Brugada syndrome (BrS) are predisposed to life-threatening cardiac arrhythmias. Diagnosis is challenging due to the elusive ECG signature that often requires unconventional ECG lead placement and drug challenges to be detected. In a Translational Research article entitled ‘NaV1.5 autoantibodies in Brugada syndrome: pathogenetic implications’, Adriana Tarantino from IRCCS Policlinico San Donato in Milan, Italy, and colleagues indicate that although NaV1.5 sodium channel dysfunction is a recognized pathophysiological mechanism in BrS, only 25% of patients have detectable SCN5A variants.22 Given the emerging role of autoimmunity in cardiac ion channel function, this study explores the presence and potential impact of anti-NaV1.5 autoantibodies in BrS patients. Using engineered HEK293A cells expressing recombinant NaV1.5 protein, plasma from 50 BrS patients and 50 controls was screened for anti-NaV1.5 autoantibodies via western blot, with specificity confirmed by immunoprecipitation and immunofluorescence. The impact of these autoantibodies on sodium current density and their pathophysiological effects were assessed in cellular models and through plasma injection in wild-type mice. Anti-NaV1.5 autoantibodies were detected in 90% of BrS patients vs. 6% of controls, yielding a diagnostic area under the curve of 0.92, with 94% specificity and 90% sensitivity. These findings were consistent across varying patient demographics and independent of SCN5A mutation status. Electrophysiological studies demonstrated a significant reduction specifically in sodium current density. Notably, mice injected with BrS plasma showed Brugada-like ECG abnormalities, supporting the pathogenic role of these autoantibodies (Figure 2).
The authors conclude that the study demonstrates the presence of anti-NaV1.5 autoantibodies in the majority of BrS patients, suggesting an immunopathogenic component of the syndrome beyond genetic predisposition. These autoantibodies, which could serve as additional diagnostic markers, also prompt reconsideration of the underlying mechanisms of BrS, as evidenced by their role in inducing the ECG signature of the syndrome in wild-type mice. These findings encourage a more comprehensive diagnostic approach and point to new avenues for therapeutic research. The manuscript is accompanied by an Editorial by Niels Voigt and Funsho Fakuade from the University Medical Center Göttingen in Germany and Jana Grune from the Deutsches Herzzentrum der Charité (DHZC) in Berlin, Germany.23 The authors conclude that taking a cue from the success of the vaccines deployed in the prevention and management of coronavirus disease 2019 (COVID-19), which relies on the production of antibodies in response to viral spike proteins, the peptide–autoantibody strategy may proffer a novel approach for managing cardiac arrhythmias. Along these lines, patients with genetic or idiopathic channelopathies could be immunized with synthesized peptides of parts of specific ion channels to induce autoantibody production that will rectify dysfunctional ion channels in these patients and prevent untoward effects such as life-threatening cardiac arrhythmia. Although this is still an idea for the future, it is beyond question that antibody-mediated modulation of ion channels presents a new route for the prevention and management of cardiac channelopathies and other cardiac arrhythmias.
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, enarini outside the submitted work.
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.
