Methodological Limitations in the Assessment of Intermittent Ventricular Pre-Excitation in WPW Syndrome

Methodological Limitations in the Assessment of Intermittent Ventricular Pre-Excitation in WPW Syndrome | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Journal of Cardiovascular Electrophysiology This is a preprint and has not been peer reviewed. Data may be preliminary. 12 August 2025 V1 Latest version Share on Methodological Limitations in the Assessment of Intermittent Ventricular Pre-Excitation in WPW Syndrome Authors : Ayesha Abbas , Muhammad Riyyan , Sawaira Sajid , Muhammad Saeed Qazi 0009-0002-8509-3738 [email protected] , and Mohammad Mujtaba Khokhar Authors Info & Affiliations https://doi.org/10.22541/au.175497123.36759490/v1 Published Journal of Cardiovascular Electrophysiology Version of record Peer review timeline 247 views 161 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Dear Editor, We read with interest the study by Robles et al. examining intermittent ventricular pre-excitation in patients with Wolff-Parkinson-White syndrome (1). This registry contributes valuable data to an underexplored area, however, we have observed methodological concerns that constrain the clinical applicability of their findings. First, the study’s most significant limitation lies in the imbalance between symptomatic and asymptomatic patients within the intermittent pre-excitation group. With only 9 asymptomatic patients among 79 with intermittent pre-excitation, the statistical power to detect meaningful differences is compromised (1). This sample size cannot reliably exclude clinically important differences in electrophysiological parameters between symptomatic and asymptomatic intermittent patients, rendering the study’s conclusions about risk equivalence statistically unsupported. Power calculations would likely require 50-100 asymptomatic patients per group to detect moderate effect sizes in accessory pathway properties (2). Second, the heterogeneous use of isoproterenol across centers, along with varying sedation practices and equipment preferences creates systematic variability that could obscure the true differences between groups (1). Isoproterenol is a powerful heart stimulant that can make accessory pathways conduct electricity faster and trigger arrhythmias more easily than would occur naturally in patients’ daily lives (3). Studies comparing provoked versus baseline electrophysiological parameters show that catecholamine stimulation can dramatically alter pathway characteristics, potentially masking important differences between intermittent and persistent pre-excitation groups (4). Third, the definition used for symptomatic patients in this study as those reporting palpitations regardless of documented arrhythmias, accounts for another methodological weakness. This broad categorization does not distinguish between patients with confirmed tachyarrhythmias and those with non-specific symptoms, potentially misclassifying patients and obscuring true risk differences (1). Considering that symptom perception can be influenced by awareness of the cardiac condition, this classification bias could systematically inflate the apparent similarity between groups. Finally, the study’s international, retrospective, multicenter design introduces selection bias and heterogeneity in patient populations, referral practices and electrophysiological techniques. The unmeasured confounders could account for the observed similarities between groups given the relatively small effect sizes being studied. The 20-year data collection period spans through evolutions in clinical practice, diagnostic criteria and risk assessment approaches and this introduces temporal bias which could confound contemporary relevance. Exclusion of patients with central sleep apnea or inadequate monitoring may also have systematically excluded important subgroups. Future studies should prioritize standardized protocols, adequate sample sizes and prospective data collection to address these limitations. In conclusion, the study’s deduction that intermittent pre-excitation requires invasive assessment does align with evolving clinical evidence which suggests that non-invasive risk stratification has limited negative predictive value in excluding high-risk pathways. However, we believe this recommendation should be based on the established limitations of non-invasive testing rather than the equivalence of risk parameters demonstrated in this study. Title : Methodological Limitations in the Assessment of Intermittent Ventricular Pre-Excitation in WPW Syndrome Authors: Ayesha Abbas 1 ; [email protected] Muhammad Riyyan 2 ; [email protected] Sawaira Sajid 2 ; [email protected] Muhammad Saeed Qazi 3 ; [email protected] Mohammad Mujtaba Khokhar 1 ; [email protected] Affiliations: 1 Shalamar Medical and Dental College, Lahore, Pakistan 2 Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan 3 Bilawal Medical College, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan Corresponding Author Muhammad Saeed Qazi Bilawal Medical College, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan Email: [email protected] Acknowledgments: None Statement and Declaration: Funding : None Conflict of Interest: None Ethical Approval: Ethical Approval was not required for the conduct of this study Declaration of AI : AI was not used during the preparation of this manuscript Authors Contribution: All authors contributed to the conception, drafting, and critical revision of the manuscript. All authors approved the final version for submission and agreed to be accountable for all aspects of the work. Dear Editor, We read with interest the study by Robles et al. examining intermittent ventricular pre-excitation in patients with Wolff-Parkinson-White syndrome (1). This registry contributes valuable data to an underexplored area, however, we have observed methodological concerns that constrain the clinical applicability of their findings. First, the study’s most significant limitation lies in the imbalance between symptomatic and asymptomatic patients within the intermittent pre-excitation group. With only 9 asymptomatic patients among 79 with intermittent pre-excitation, the statistical power to detect meaningful differences is compromised (1). This sample size cannot reliably exclude clinically important differences in electrophysiological parameters between symptomatic and asymptomatic intermittent patients, rendering the study’s conclusions about risk equivalence statistically unsupported. Power calculations would likely require 50-100 asymptomatic patients per group to detect moderate effect sizes in accessory pathway properties (2). Second, the heterogeneous use of isoproterenol across centers, along with varying sedation practices and equipment preferences creates systematic variability that could obscure the true differences between groups (1). Isoproterenol is a powerful heart stimulant that can make accessory pathways conduct electricity faster and trigger arrhythmias more easily than would occur naturally in patients’ daily lives (3). Studies comparing provoked versus baseline electrophysiological parameters show that catecholamine stimulation can dramatically alter pathway characteristics, potentially masking important differences between intermittent and persistent pre-excitation groups (4). Third, the definition used for symptomatic patients in this study as those reporting palpitations regardless of documented arrhythmias, accounts for another methodological weakness. This broad categorization does not distinguish between patients with confirmed tachyarrhythmias and those with non-specific symptoms, potentially misclassifying patients and obscuring true risk differences (1). Considering that symptom perception can be influenced by awareness of the cardiac condition, this classification bias could systematically inflate the apparent similarity between groups. Finally, the study’s international, retrospective, multicenter design introduces selection bias and heterogeneity in patient populations, referral practices and electrophysiological techniques. The unmeasured confounders could account for the observed similarities between groups given the relatively small effect sizes being studied. The 20-year data collection period spans through evolutions in clinical practice, diagnostic criteria and risk assessment approaches and this introduces temporal bias which could confound contemporary relevance. Exclusion of patients with central sleep apnea or inadequate monitoring may also have systematically excluded important subgroups. Future studies should prioritize standardized protocols, adequate sample sizes and prospective data collection to address these limitations. In conclusion, the study’s deduction that intermittent pre-excitation requires invasive assessment does align with evolving clinical evidence which suggests that non-invasive risk stratification has limited negative predictive value in excluding high-risk pathways. However, we believe this recommendation should be based on the established limitations of non-invasive testing rather than the equivalence of risk parameters demonstrated in this study. References : 1. Robles, A.G., Palamà, Z., Santoro, F., Rauber, M., Antolič, B., Gianfrancesco, D., Bartolomucci, F., Pellegrino, P., Alfieri, S., Borelli, A., Scarà, A., Luca, G.D.M.D., de Ruvo, E., Calò, L., Jan, M., Pernat, A., Romano, S. and Sciarra, L. (2025), Intermittent Ventricular Pre-Excitation: Clinical Features and Electrophysiological Properties. Journal of Cardiovascular Electrophysiology. https://doi.org/10.1111/jce.70035 2. Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, Munafò MR. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013 May;14(5):365-76. doi: 10.1038/nrn3475. Epub 2013 Apr 10. Erratum in: Nat Rev Neurosci. 2013 Jun;14(6):451. PMID: 23571845. 3. Jemtrén A, Saygi S, Åkerström F, Asaad F, Bourke T, Braunschweig F, Carnlöf C, Drca N, Insulander P, Kennebäck G, Nordin AP, Sadigh B, Rickenlund A, Saluveer O, Schwieler J, Svennberg E, Tapanainen J, Turkmen Y, Bastani H, Jensen-Urstad M. Risk assessment in patients with symptomatic and asymptomatic pre-excitation. Europace. 2024 Feb 1;26(2):euae036. doi: 10.1093/europace/euae036. PMID: 38363996; PMCID: PMC10873488. 4. Escudero CA, Ceresnak SR, Collins KK, Pass RH, Aziz PF, Blaufox AD, Ortega MC, Cannon BC, Cohen MI, Dechert BE, Dubin AM, Motonaga KS, Epstein MR, Erickson CC, Fishberger SB, Gates GJ, Capone CA, Nappo L, Kertesz NJ, Kim JJ, Valdes SO, Kubuš P, Law IH, Maldonado J, Moore JP, Perry JC, Sanatani S, Seslar SP, Shetty I, Zimmerman FJ, Skinner JR, Marcondes L, Stephenson EA, Asakai H, Tanel RE, Uzun O, Etheridge SP, Janson CM. Loss of ventricular preexcitation during noninvasive testing does not exclude high-risk accessory pathways: A multicenter study of WPW in children. Heart Rhythm. 2020 Oct;17(10):1729-1737. doi: 10.1016/j.hrthm.2020.05.035. Epub 2020 Jun 1. PMID: 32497761. Information & Authors Information Version history V1 Version 1 12 August 2025 Peer review timeline Published Journal of Cardiovascular Electrophysiology Version of Record 18 Aug 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Journal of Cardiovascular Electrophysiology Keyword basic: cardiac fibrillation/defibrillation Authors Affiliations Ayesha Abbas Shalimar Medical and Dental College View all articles by this author Muhammad Riyyan Liaquat University of Medical & Health Sciences View all articles by this author Sawaira Sajid Liaquat University of Medical & Health Sciences View all articles by this author Muhammad Saeed Qazi 0009-0002-8509-3738 [email protected] Liaquat University of Medical & Health Sciences View all articles by this author Mohammad Mujtaba Khokhar Shalimar Medical and Dental College View all articles by this author Metrics & Citations Metrics Article Usage 247 views 161 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ayesha Abbas, Muhammad Riyyan, Sawaira Sajid, et al. Methodological Limitations in the Assessment of Intermittent Ventricular Pre-Excitation in WPW Syndrome. Authorea . 12 August 2025. 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