Genetic testing reveals PRKAG2 syndrome mimicking sarcomeric hypertrophic cardiomyopathy in an adolescent: a case report

Genetic testing reveals PRKAG2 syndrome mimicking sarcomeric hypertrophic cardiomyopathy in an adolescent: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Genetic testing reveals PRKAG2 syndrome mimicking sarcomeric hypertrophic cardiomyopathy in an adolescent: a case report Zonghui Hou, Xuechen Liu, Mengqi Zhao, Junxiang Pan, Feiyang Wang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9151431/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 12 You are reading this latest preprint version Abstract Background: PRKAG2 syndrome is a rare autosomal dominant glycogen storage cardiomyopathy caused by pathogenic variants in the PRKAG2 gene. It typically presents with left ventricular hypertrophy, ventricular pre-excitation, and conduction system disease, which can closely mimic sarcomeric hypertrophic cardiomyopathy (HCM) on routine imaging. Early recognition is crucial because its natural history, arrhythmic risk, and management differ substantially from those of classic hypertrophic cardiomyopathy. Case presentation: A 12-year-old boy presented with exertional chest tightness. Physical examination revealed a grade 2/6 systolic murmur at the left sternal border, while serial electrocardiograms demonstrated intermittent ventricular pre-excitation. Twenty-four-hour Holter monitoring recorded sinus bradycardia with intermittent pre-excitation, rare supraventricular ectopy, and multiple sinus pauses longer than 2 seconds (maximum RR interval of 2.28 seconds), occurring predominantly during sleep. Transthoracic echocardiography revealed asymmetric left ventricular hypertrophy with preserved systolic function and no evidence of left ventricular outflow tract obstruction. He was initially diagnosed with non-obstructive hypertrophic cardiomyopathy, intermittent ventricular pre-excitation, sick sinus syndrome, sinus bradycardia, and sinus arrest. However, the coexistence of myocardial hypertrophy, ventricular pre-excitation, and conduction abnormalities raised strong clinical suspicion for PRKAG2 syndrome. Subsequent genetic testing identified a heterozygous pathogenic missense variant in PRKAG2 , confirming the diagnosis. An electrophysiological study localized a fasciculoventricular pathway adjacent to the His bundle. Radiofrequency catheter ablation was deferred due to the high risk of complete atrioventricular block and the absence of documented tachyarrhythmia. During 1 year of follow-up, the patient remained clinically stable without high-risk arrhythmic events. Conclusions: This case highlights the importance of considering PRKAG2 syndrome in young patients presenting with left ventricular hypertrophy accompanied by ventricular pre-excitation and conduction abnormalities. Genetic testing is essential for distinguishing PRKAG2 syndrome from sarcomeric hypertrophic cardiomyopathy and for guiding accurate risk stratification and individualized management. PRKAG2 syndrome hypertrophic cardiomyopathy ventricular pre-excitation cardiac conduction disease gene mutation Figures Figure 1 Figure 2 Figure 3 Introduction PRKAG2 cardiac syndrome is an autosomal-dominant disorder caused by mutations in PRKAG2 , which encodes the γ2 regulatory subunit of AMP-activated protein kinase (AMPK) [ 1 , 2 ]. These mutations result in abnormal glycogen accumulation within cardiomyocytes and the cardiac conduction system, producing a characteristic phenotype of myocardial hypertrophy, ventricular pre-excitation, and conduction disturbances [ 3 ]; although its precise prevalence remains uncertain, PRKAG2 syndrome is estimated to account for approximately 1–2% of patients clinically diagnosed with hypertrophic cardiomyopathy (HCM) [ 1 ]. Clinically and morphologically, PRKAG2 syndrome often overlaps with sarcomeric HCM and may be indistinguishable on conventional imaging modalities such as echocardiography [ 4 ]. Despite these phenotypic similarities, PRKAG2 syndrome has a distinct pathophysiological mechanism driven by glycogen storage rather than sarcomeric protein abnormalities [ 5 , 6 ]. This difference contributes to a higher prevalence of conduction system involvement, including sinus node dysfunction, atrioventricular (AV) block, and ventricular arrhythmias, ultimately leading to an increased risk of sudden cardiac death [ 1 ]. Failure to distinguish these entities early may delay appropriate management decisions, particularly regarding electrophysiological monitoring, ablation strategies, and the consideration of pacemaker or implantable cardioverter-defibrillator (ICD) implantation [ 7 , 8 ]. This report describes an adolescent boy with myocardial hypertrophy, intermittent ventricular pre-excitation, and significant sinus node dysfunction, in whom genetic testing identified a pathogenic PRKAG2 mutation, thereby establishing the definitive diagnosis. Case presentation A 12-year-old boy was admitted with recurrent chest tightness triggered by vigorous exercise. The episodes were accompanied by shortness of breath, lasted approximately 10 minutes, and resolved spontaneously with rest. He denied syncope, presyncope, palpitations, chest pain, headache, dizziness, or visual disturbances. There was no known history of cardiac disease, and the family history was negative for cardiomyopathy, conduction disorders, or sudden cardiac death. On admission, blood pressure and oxygen saturation were within normal limits for his age, and cardiac enzyme levels were also normal. Cardiac auscultation revealed a grade 2/6 systolic murmur at the left sternal border. There were no clinical signs of heart failure or peripheral edema. Repeated 12-lead electrocardiograms demonstrated sinus rhythm with intermittent ventricular pre-excitation, evidenced by delta waves and a short PR interval during pre-excited beats. Twenty-four-hour Holter monitoring recorded 85,372 beats, with a minimum heart rate of 34 beats/min, a maximum of 109 beats/min, and an average of 63 beats/min. Sinus bradycardia with intermittent ventricular pre-excitation was observed, along with only two isolated premature atrial contractions. Multiple sinus pauses exceeding 2 seconds were documented, predominantly during sleep, with the longest RR interval measuring 2.28 seconds. Transthoracic echocardiography demonstrated asymmetric left ventricular hypertrophy; specifically, the interventricular septum and mid-to-inferior segments were markedly thickened, with maximal wall thicknesses of 25 mm (septal), 26 mm (mid-lateral), and 27 mm (apical)(Figure 1).. The left atrium was enlarged, and both mild mitral regurgitation and impaired left ventricular diastolic function were observed. No systolic anterior motion of the mitral valve was present. The mean and peak pressure gradients across the left ventricular outflow tract were 5.65 mmHg and 16 mmHg, respectively, consistent with non-obstructive HCM. Prior to admission to our hospital, cardiac magnetic resonance imaging (CMR) had been performed at another institution. CMR demonstrated diffuse hypertrophy of the left ventricular myocardium, with a maximal interventricular septal thickness of approximately 16.4 mm at the mid-septal level. Mild right ventricular myocardial thickening was also observed, with a maximal thickness of approximately 9 mm. These findings were initially considered consistent with hypertrophic cardiomyopathy. Based on the clinical presentation and investigations, the patient was initially diagnosed with non-obstructive hypertrophic cardiomyopathy, intermittent ventricular pre-excitation, sick sinus syndrome, sinus bradycardia, and sinus arrest. However, the combination of marked myocardial hypertrophy, ventricular pre-excitation, and conduction abnormalities in such a young patient raised strong suspicion for PRKAG2 syndrome. Targeted next-generation sequencing of cardiomyopathy- and conduction-related genes was subsequently performed. Genetic analysis identified a heterozygous missense variant in PRKAG2 (c.1423A>G, p.K475E) located in exon 13 (NM_016203). This variant was absent from population databases (gnomAD, ExAC, and 1000 Genomes) and was predicted to be deleterious by multiple in silico algorithms (REVEL 0.898; SIFT, PolyPhen-2, MutationTaster). Because parental genetic testing was not performed due to financial constraints, the possibility of inheritance cannot be definitively excluded. Based on available evidence, the variant was classified as pathogenic. The identification of the PRKAG2 (p.K475E) mutation established the definitive diagnosis of PRKAG2 cardiac syndrome. (FIGURE 2) Discussion PRKAG2 syndrome is an important phenocopy of hypertrophic cardiomyopathy, characterized by the coexistence of myocardial hypertrophy, ventricular pre-excitation, and conduction system abnormalities [ 3 , 5 ]. In the present case, the patient initially presented with asymmetric left ventricular hypertrophy and was suspected to have non-obstructive hypertrophic cardiomyopathy based on imaging findings. However, the presence of intermittent ventricular pre-excitation and significant sinus node dysfunction in a young patient raised immediate suspicion for PRKAG2 syndrome. Subsequent genetic testing confirmed a pathogenic PRKAG2 mutation, establishing the definitive diagnosis. Previous studies have demonstrated that PRKAG2 syndrome often mimics sarcomeric hypertrophic cardiomyopathy both clinically and morphologically, which can lead to misdiagnosis when genetic testing is not performed [ 4 ]. Porto et al. reported that patients with PRKAG2 mutations frequently present with ventricular pre-excitation and progressive conduction system disease in addition to left ventricular hypertrophy [ 3 ]. Similarly, Thevenon and colleagues observed a high prevalence of arrhythmic complications, including atrial arrhythmias, atrioventricular block, and ventricular arrhythmias in patients with PRKAG2 syndrome [ 5 ]. Compared with classic sarcomeric hypertrophic cardiomyopathy, PRKAG2 syndrome tends to present at a younger age and is more commonly associated with conduction abnormalities and accessory pathways [ 7 ]. In the present case, an electrophysiological study identified a fasciculoventricular pathway adjacent to the His bundle, a feature that has previously been described in association with PRKAG2 syndrome [ 10 ]. Accessory pathways located near the His bundle pose a substantial procedural risk, as catheter ablation may result in complete atrioventricular block. Therefore, catheter ablation was deferred in this patient due to the absence of tachyarrhythmia and the high procedural risk. The pathophysiological mechanism underlying PRKAG2 syndrome differs fundamentally from that of sarcomeric hypertrophic cardiomyopathy. PRKAG2 encodes the γ2 regulatory subunit of AMPK, a key regulator of cellular energy metabolism [ 1 , 6 ]. Gain-of-function mutations in PRKAG2 lead to constitutive AMPK activation, resulting in increased glucose uptake and intracellular glycogen accumulation within cardiomyocytes [ 11 ]. This metabolic disturbance contributes to myocardial hypertrophy and produces a phenotype resembling hypertrophic cardiomyopathy. In addition to glycogen storage, AMPK-mediated electrical remodeling of the cardiac conduction system may contribute to the sinus node dysfunction and conduction abnormalities observed in PRKAG2 syndrome [ 12 , 13 ] (FIGURE 3). Experimental studies have demonstrated that activation of γ2-AMPK can directly regulate the intrinsic heart rate by altering pacemaker channel expression and sinoatrial node automaticity [ 12 ]. Early recognition of PRKAG2 syndrome has important clinical implications; because the clinical presentation may mimic sarcomeric hypertrophic cardiomyopathy, genetic testing plays a crucial role in establishing the correct diagnosis. Identifying PRKAG2 syndrome is clinically imperative because disease progression, arrhythmic risk, and management strategies differ from those of classic hypertrophic cardiomyopathy [ 7 , 14 ]. Patients may require long-term rhythm surveillance and, in some cases, pacemaker or implantable cardioverter-defibrillator implantation due to progressive conduction disease. Several limitations should be acknowledged. First, this report describes a single case, which limits the generalizability of the findings. Second, parental genetic testing was not performed; therefore, it remains unclear whether the PRKAG2 variant identified in this patient was inherited or occurred de novo. Finally, the follow-up duration was relatively short and does not allow for the assessment of long-term arrhythmic risk. In summary, this case highlights the importance of considering PRKAG2 syndrome in young patients presenting with myocardial hypertrophy accompanied by ventricular pre-excitation and conduction abnormalities. Early genetic testing is essential for accurate diagnosis and individualized management. Conclusions This case illustrates that PRKAG2 syndrome should be strongly suspected in young patients presenting with the combination of LV hypertrophy, pre-excitation, and conduction disease, making genetic testing essential for accurate diagnosis and risk stratification. Its distinct arrhythmic profile requires individualized decisions regarding ablation and device therapy, underscoring the importance of early recognition for appropriate surveillance and timely intervention. Declarations Ethics approval and consent to participate This study does not violate any ethical principles. Necessary clearances have been obtained from Institutional review committee. Informed consent has been obtained from the patient for the purpose of publication. Competing interests The authors declare no competing interests. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modifed the licensed material.You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativeco mmons.org/licenses/by-nc-nd/4.0/. Author Contributions (I)Writing the manuscript:Z Hou ;(II)Writing the figures and tables:J.Pan and M.Zhao ;The format of organizing an article:X Liu and F.Wang;(III) Revise the manuscript and finalized the final version: L Wang. (IV)All authors read and approved the final manuscript. Funding No funding or sponsorship was received for this article. Data Availability Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. References Hu D, Hu D, Liu L, et al. Identification, clinical manifestation and structural mechanisms of mutations in AMPK-associated cardiac glycogen-storage disease. EBioMedicine. 2020;54:102723. Monophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: natural history. J Am Coll Cardiol, 2005, 45(6): 922-930. Porto AG, Brun F, Severini GM, et al. Clinical spectrum of PRKAG2 syndrome. Circ Arrhythm Electrophysiol. 2016;9(1):e003121. Sara Hoss S, Harry R. Differential of hypertrophic cardiomyopathy versus secondary conditions that mimic hypertrophic cardiomyopathy. 3rd ed. Elsevier; 2022. Thevenon J, Laurent G, Ader F, et al. High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations. Europace, 2017, 19(4): 651-659. Gollob MH． Glycogen storage disease as a unifying mechanism of disease in the PRKAG2 cardiac syndrome［J］． Biochem Soc Trans，2003，31 ( Pt 1) : 228- 231． Lopez‑Sainz A, Dominguez F, Lopes LR, et al. Clinical features and natural history of PRKAG2 variant cardiac glycogenosis[J]. J Am Coll Cardiol, 2020, 76(2): 186‑197. DOI: 10.1016/j.jacc.2020.05.029. Nicholls M. The 2014 ESC Guidelines on the diagnosis and management of hypertrophic cardiomyopathy have been published. Eur Heart J. 2014;35(41):2849-2850. PENA J L B, SANTOS W C, SIQUEIRA M H A, et al. Glycogen storage cardiomyopathy ( PRKAG2 ): diagnostic findings of standard and advanced echocardiography techniques [J]. European Heart Journal - Cardiovascular Imaging, 2021, 22(7): 800–7. STERNICK E B, OLIVA A, GERKEN L M, et al. Clinical, electrocardiographic, and electrophysiologic characteristics of patients with a fasciculoventricular pathway: The role of PRKAG2 mutation [J]. Heart Rhythm, 2011, 8(1): 58–64. Xu Y, Gray A, Hardie DG, et al. A novel, de novo mutation in the PRKAG2 gene: infantile‑onset phenotype and the signaling pathway involved[J]. Am J Physiol Heart Circ Physiol, 2017, 313(2): H283‑H292. DOI: 10.1152/ ajpheart.00813.2016. Albernaz SM，Honorato⁃Sampaio K，Monteiro D G，et al. Sud⁃ den death associated with a novel H401Q PRKAG2 mutation［J］. Europace，2020，22（8）：1278. YAVARI A, BELLAHCENE M, BUCCHI A, et al. Mammalian γ2 AMPK regulates intrinsic heart rate [J]. Nature Communications, 2017, 8(1). Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines[J]. Circulation, 2020, 142(25):e533‑e557. DOI: 10.1161/CIR.0000000000000938. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 06 May, 2026 Reviews received at journal 05 May, 2026 Reviews received at journal 03 May, 2026 Reviews received at journal 03 May, 2026 Reviewers agreed at journal 26 Apr, 2026 Reviewers agreed at journal 25 Apr, 2026 Reviewers agreed at journal 25 Apr, 2026 Reviewers invited by journal 23 Apr, 2026 Editor invited by journal 14 Apr, 2026 Editor assigned by journal 22 Mar, 2026 Submission checks completed at journal 22 Mar, 2026 First submitted to journal 17 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9151431","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":633802187,"identity":"248ac1cf-1143-4ee9-869a-46a57965c050","order_by":0,"name":"Zonghui Hou","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Zonghui","middleName":"","lastName":"Hou","suffix":""},{"id":633802189,"identity":"0af30d28-2893-416b-a233-751b9b8b98c9","order_by":1,"name":"Xuechen Liu","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Xuechen","middleName":"","lastName":"Liu","suffix":""},{"id":633802190,"identity":"a123fb3d-e455-4b83-bb68-5dec8c27ec0f","order_by":2,"name":"Mengqi Zhao","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Mengqi","middleName":"","lastName":"Zhao","suffix":""},{"id":633802191,"identity":"5290fe5b-173b-4ccd-a1a7-883f5b21975d","order_by":3,"name":"Junxiang Pan","email":"","orcid":"","institution":"The First Affiliated Hospital of Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Junxiang","middleName":"","lastName":"Pan","suffix":""},{"id":633802192,"identity":"eca1188b-e214-436d-bcf8-7052a64ee364","order_by":4,"name":"Feiyang Wang","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Feiyang","middleName":"","lastName":"Wang","suffix":""},{"id":633802193,"identity":"afc8ca39-b529-4e54-9a3e-40b3c8f64521","order_by":5,"name":"Chunbo Wang","email":"","orcid":"","institution":"The First Affiliated Hospital of Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Chunbo","middleName":"","lastName":"Wang","suffix":""},{"id":633802195,"identity":"0d276d18-c1eb-4629-b3c9-8fb43bba5eb3","order_by":6,"name":"Lianyi Wang","email":"data:image/png;base64,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","orcid":"","institution":"The First Affiliated Hospital of Tsinghua University","correspondingAuthor":true,"prefix":"","firstName":"Lianyi","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-03-17 17:23:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9151431/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9151431/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108821976,"identity":"81ed9ac5-c50a-430c-8e9b-c2de1ec78cac","added_by":"auto","created_at":"2026-05-08 16:47:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":343857,"visible":true,"origin":"","legend":"\u003cp\u003eTransthoracic echocardiography findings. (A) Parasternal long-axis view . (B) Apical four-chamber view . Figures 1A and 1B collectively demonstrate asymmetric left ventricular hypertrophy, with marked thickening of the interventricular septum and mid-to-inferior wall segments.No segmental wall motion abnormalities were observed.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9151431/v1/5c6bb1b31967d502052873e4.png"},{"id":108822018,"identity":"127b004f-4d96-4734-b3fe-c48f97cfbc50","added_by":"auto","created_at":"2026-05-08 16:47:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1029155,"visible":true,"origin":"","legend":"\u003cp\u003eDiagnostic workflow for the patient.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9151431/v1/e9b687116335d340351941c1.png"},{"id":108822037,"identity":"c8de9ab4-eb60-4f02-a054-e705c6dba920","added_by":"auto","created_at":"2026-05-08 16:47:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":898206,"visible":true,"origin":"","legend":"\u003cp\u003ePathophysiological mechanism of PRKAG2 syndrome.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9151431/v1/65cdaf13a684ba3b6de38273.png"},{"id":108823113,"identity":"536ba313-8b38-40e9-bbd4-8cf761c2e387","added_by":"auto","created_at":"2026-05-08 16:52:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2427305,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9151431/v1/b9185287-74f8-4983-aba5-10ae29cf3f65.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Genetic testing reveals PRKAG2 syndrome mimicking sarcomeric hypertrophic cardiomyopathy in an adolescent: a case report","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cem\u003ePRKAG2\u003c/em\u003e cardiac syndrome is an autosomal-dominant disorder caused by mutations in \u003cem\u003ePRKAG2\u003c/em\u003e, which encodes the γ2 regulatory subunit of AMP-activated protein kinase (AMPK) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. These mutations result in abnormal glycogen accumulation within cardiomyocytes and the cardiac conduction system, producing a characteristic phenotype of myocardial hypertrophy, ventricular pre-excitation, and conduction disturbances [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]; although its precise prevalence remains uncertain, \u003cem\u003ePRKAG2\u003c/em\u003e syndrome is estimated to account for approximately 1\u0026ndash;2% of patients clinically diagnosed with hypertrophic cardiomyopathy (HCM) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinically and morphologically, \u003cem\u003ePRKAG2\u003c/em\u003e syndrome often overlaps with sarcomeric HCM and may be indistinguishable on conventional imaging modalities such as echocardiography [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Despite these phenotypic similarities, \u003cem\u003ePRKAG2\u003c/em\u003e syndrome has a distinct pathophysiological mechanism driven by glycogen storage rather than sarcomeric protein abnormalities [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This difference contributes to a higher prevalence of conduction system involvement, including sinus node dysfunction, atrioventricular (AV) block, and ventricular arrhythmias, ultimately leading to an increased risk of sudden cardiac death [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Failure to distinguish these entities early may delay appropriate management decisions, particularly regarding electrophysiological monitoring, ablation strategies, and the consideration of pacemaker or implantable cardioverter-defibrillator (ICD) implantation [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This report describes an adolescent boy with myocardial hypertrophy, intermittent ventricular pre-excitation, and significant sinus node dysfunction, in whom genetic testing identified a pathogenic \u003cem\u003ePRKAG2\u003c/em\u003e mutation, thereby establishing the definitive diagnosis.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 12-year-old boy was admitted with recurrent chest tightness triggered by vigorous exercise. The episodes were accompanied by shortness of breath, lasted approximately 10 minutes, and resolved spontaneously with rest. He denied syncope, presyncope, palpitations, chest pain, headache, dizziness, or visual disturbances. There was no known history of cardiac disease, and the family history was negative for cardiomyopathy, conduction disorders, or sudden cardiac death.\u003c/p\u003e\n\u003cp\u003eOn admission, blood pressure and oxygen saturation were within normal limits for his age, and cardiac enzyme levels were also normal. Cardiac auscultation revealed a grade 2/6 systolic murmur at the left sternal border. There were no clinical signs of heart failure or peripheral edema. Repeated 12-lead electrocardiograms demonstrated sinus rhythm with intermittent ventricular pre-excitation, evidenced by delta waves and a short PR interval during pre-excited beats. Twenty-four-hour Holter monitoring recorded 85,372 beats, with a minimum heart rate of 34 beats/min, a maximum of 109 beats/min, and an average of 63 beats/min. Sinus bradycardia with intermittent ventricular pre-excitation was observed, along with only two isolated premature atrial contractions. Multiple sinus pauses exceeding 2 seconds were documented, predominantly during sleep, with the longest RR interval measuring 2.28 seconds.\u003c/p\u003e\n\u003cp\u003eTransthoracic echocardiography demonstrated asymmetric left ventricular hypertrophy; specifically, the interventricular septum and mid-to-inferior segments were markedly thickened, with maximal wall thicknesses of 25 mm (septal), 26 mm (mid-lateral), and 27 mm (apical)(Figure 1).. The left atrium was enlarged, and both mild mitral regurgitation and impaired left ventricular diastolic function were observed. No systolic anterior motion of the mitral valve was present. The mean and peak pressure gradients across the left ventricular outflow tract were 5.65 mmHg and 16 mmHg, respectively, consistent with non-obstructive HCM.\u003c/p\u003e\n\u003cp\u003ePrior to admission to our hospital, cardiac magnetic resonance imaging (CMR) had been performed at another institution. CMR demonstrated diffuse hypertrophy of the left ventricular myocardium, with a maximal interventricular septal thickness of approximately 16.4 mm at the mid-septal level. Mild right ventricular myocardial thickening was also observed, with a maximal thickness of approximately 9 mm. These findings were initially considered consistent with hypertrophic cardiomyopathy. Based on the clinical presentation and investigations, the patient was initially diagnosed with non-obstructive hypertrophic cardiomyopathy, intermittent ventricular pre-excitation, sick sinus syndrome, sinus bradycardia, and sinus arrest.\u003c/p\u003e\n\u003cp\u003eHowever, the combination of marked myocardial hypertrophy, ventricular pre-excitation, and conduction abnormalities in such a young patient raised strong suspicion for \u003cem\u003ePRKAG2\u003c/em\u003e syndrome. Targeted next-generation sequencing of cardiomyopathy- and conduction-related genes was subsequently performed. Genetic analysis identified a heterozygous missense variant in \u003cem\u003ePRKAG2\u003c/em\u003e (c.1423A\u0026gt;G, p.K475E) located in exon 13 (NM_016203). This variant was absent from population databases (gnomAD, ExAC, and 1000 Genomes) and was predicted to be deleterious by multiple in silico algorithms (REVEL 0.898; SIFT, PolyPhen-2, MutationTaster). Because parental genetic testing was not performed due to financial constraints, the possibility of inheritance cannot be definitively excluded. Based on available evidence, the variant was classified as pathogenic. The identification of the \u003cem\u003ePRKAG2\u003c/em\u003e (p.K475E) mutation established the definitive diagnosis of \u003cem\u003ePRKAG2\u003c/em\u003e cardiac syndrome. (FIGURE 2)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cem\u003ePRKAG2\u003c/em\u003e syndrome is an important phenocopy of hypertrophic cardiomyopathy, characterized by the coexistence of myocardial hypertrophy, ventricular pre-excitation, and conduction system abnormalities [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In the present case, the patient initially presented with asymmetric left ventricular hypertrophy and was suspected to have non-obstructive hypertrophic cardiomyopathy based on imaging findings. However, the presence of intermittent ventricular pre-excitation and significant sinus node dysfunction in a young patient raised immediate suspicion for \u003cem\u003ePRKAG2\u003c/em\u003e syndrome. Subsequent genetic testing confirmed a pathogenic \u003cem\u003ePRKAG2\u003c/em\u003e mutation, establishing the definitive diagnosis.\u003c/p\u003e\n\u003cp\u003ePrevious studies have demonstrated that \u003cem\u003ePRKAG2\u003c/em\u003e syndrome often mimics sarcomeric hypertrophic cardiomyopathy both clinically and morphologically, which can lead to misdiagnosis when genetic testing is not performed [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Porto et al. reported that patients with \u003cem\u003ePRKAG2\u003c/em\u003e mutations frequently present with ventricular pre-excitation and progressive conduction system disease in addition to left ventricular hypertrophy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Similarly, Thevenon and colleagues observed a high prevalence of arrhythmic complications, including atrial arrhythmias, atrioventricular block, and ventricular arrhythmias in patients with \u003cem\u003ePRKAG2\u003c/em\u003e syndrome [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Compared with classic sarcomeric hypertrophic cardiomyopathy, \u003cem\u003ePRKAG2\u003c/em\u003e syndrome tends to present at a younger age and is more commonly associated with conduction abnormalities and accessory pathways [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eIn the present case, an electrophysiological study identified a fasciculoventricular pathway adjacent to the His bundle, a feature that has previously been described in association with \u003cem\u003ePRKAG2\u003c/em\u003e syndrome [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Accessory pathways located near the His bundle pose a substantial procedural risk, as catheter ablation may result in complete atrioventricular block. Therefore, catheter ablation was deferred in this patient due to the absence of tachyarrhythmia and the high procedural risk.\u003c/p\u003e\n\u003cp\u003eThe pathophysiological mechanism underlying \u003cem\u003ePRKAG2\u003c/em\u003e syndrome differs fundamentally from that of sarcomeric hypertrophic cardiomyopathy. \u003cem\u003ePRKAG2\u003c/em\u003e encodes the \u0026gamma;2 regulatory subunit of AMPK, a key regulator of cellular energy metabolism [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Gain-of-function mutations in \u003cem\u003ePRKAG2\u003c/em\u003e lead to constitutive AMPK activation, resulting in increased glucose uptake and intracellular glycogen accumulation within cardiomyocytes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This metabolic disturbance contributes to myocardial hypertrophy and produces a phenotype resembling hypertrophic cardiomyopathy. In addition to glycogen storage, AMPK-mediated electrical remodeling of the cardiac conduction system may contribute to the sinus node dysfunction and conduction abnormalities observed in \u003cem\u003ePRKAG2\u003c/em\u003e syndrome [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] (FIGURE 3). Experimental studies have demonstrated that activation of \u0026gamma;2-AMPK can directly regulate the intrinsic heart rate by altering pacemaker channel expression and sinoatrial node automaticity [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eEarly recognition of \u003cem\u003ePRKAG2\u003c/em\u003e syndrome has important clinical implications; because the clinical presentation may mimic sarcomeric hypertrophic cardiomyopathy, genetic testing plays a crucial role in establishing the correct diagnosis. Identifying \u003cem\u003ePRKAG2\u003c/em\u003e syndrome is clinically imperative because disease progression, arrhythmic risk, and management strategies differ from those of classic hypertrophic cardiomyopathy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Patients may require long-term rhythm surveillance and, in some cases, pacemaker or implantable cardioverter-defibrillator implantation due to progressive conduction disease.\u003c/p\u003e\n\u003cp\u003eSeveral limitations should be acknowledged. First, this report describes a single case, which limits the generalizability of the findings. Second, parental genetic testing was not performed; therefore, it remains unclear whether the \u003cem\u003ePRKAG2\u003c/em\u003e variant identified in this patient was inherited or occurred de novo. Finally, the follow-up duration was relatively short and does not allow for the assessment of long-term arrhythmic risk.\u003c/p\u003e\n\u003cp\u003eIn summary, this case highlights the importance of considering \u003cem\u003ePRKAG2\u003c/em\u003e syndrome in young patients presenting with myocardial hypertrophy accompanied by ventricular pre-excitation and conduction abnormalities. Early genetic testing is essential for accurate diagnosis and individualized management.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis case illustrates that \u003cem\u003ePRKAG2\u003c/em\u003e syndrome should be strongly suspected in young patients presenting with the combination of LV hypertrophy, pre-excitation, and conduction disease, making genetic testing essential for accurate diagnosis and risk stratification. Its distinct arrhythmic profile requires individualized decisions regarding ablation and device therapy, underscoring the importance of early recognition for appropriate surveillance and timely intervention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate This study does not violate any ethical principles. Necessary clearances have been obtained from Institutional review committee. Informed consent has been obtained from the patient for the purpose of publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eOpen Access This article is licensed under a Creative Commons\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAttribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modifed the licensed material.You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article\u0026rsquo;s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article\u0026rsquo;s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativeco mmons.org/licenses/by-nc-nd/4.0/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(I)Writing the manuscript:Z Hou ;(II)Writing the figures and tables:J.Pan and M.Zhao ;The format of organizing an article:X Liu and F.Wang;(III) Revise the manuscript and finalized the final version:\u0026nbsp;L Wang. (IV)All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding or sponsorship was received for this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHu D, Hu D, Liu L, et al. Identification, clinical manifestation and structural mechanisms of mutations in AMPK-associated cardiac glycogen-storage disease. EBioMedicine. 2020;54:102723.\u003c/li\u003e\n\u003cli\u003eMonophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: natural history. J Am Coll Cardiol, 2005, 45(6): 922-930.\u003c/li\u003e\n\u003cli\u003ePorto AG, Brun F, Severini GM, et al. Clinical spectrum of \u003cem\u003ePRKAG2 \u003c/em\u003esyndrome. Circ Arrhythm Electrophysiol. 2016;9(1):e003121. \u003c/li\u003e\n\u003cli\u003eSara Hoss S, Harry R. Differential of hypertrophic cardiomyopathy versus secondary conditions that mimic hypertrophic cardiomyopathy. 3rd ed. Elsevier; 2022. \u003c/li\u003e\n\u003cli\u003eThevenon J, Laurent G, Ader F, et al. High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to \u003cem\u003ePRKAG2\u003c/em\u003e mutations. Europace, 2017, 19(4): 651-659. \u003c/li\u003e\n\u003cli\u003eGollob MH． Glycogen storage disease as a unifying mechanism of disease in the \u003cem\u003ePRKAG2 \u003c/em\u003ecardiac syndrome［J］． Biochem Soc Trans，2003，31 ( Pt 1) : 228- 231．\u003c/li\u003e\n\u003cli\u003eLopez‑Sainz A, Dominguez F, Lopes LR, et al. Clinical features and natural history of \u003cem\u003ePRKAG2 \u003c/em\u003evariant cardiac glycogenosis[J]. J Am Coll Cardiol, 2020, 76(2): 186‑197. DOI: 10.1016/j.jacc.2020.05.029.\u003c/li\u003e\n\u003cli\u003eNicholls M. The 2014 ESC Guidelines on the diagnosis and management of hypertrophic cardiomyopathy have been published. Eur Heart J. 2014;35(41):2849-2850. \u003c/li\u003e\n\u003cli\u003ePENA J L B, SANTOS W C, SIQUEIRA M H A, et al. Glycogen storage cardiomyopathy (\u003cem\u003ePRKAG2\u003c/em\u003e): diagnostic findings of standard and advanced echocardiography techniques [J]. European Heart Journal - Cardiovascular Imaging, 2021, 22(7): 800\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eSTERNICK E B, OLIVA A, GERKEN L M, et al. Clinical, electrocardiographic, and electrophysiologic characteristics of patients with a fasciculoventricular pathway: The role of \u003cem\u003ePRKAG2\u003c/em\u003e mutation [J]. Heart Rhythm, 2011, 8(1): 58\u0026ndash;64.\u003c/li\u003e\n\u003cli\u003eXu Y, Gray A, Hardie DG, et al. A novel, de novo mutation in the \u003cem\u003ePRKAG2 \u003c/em\u003egene: infantile‑onset phenotype and the signaling pathway involved[J]. Am J Physiol Heart Circ Physiol, 2017, 313(2): H283‑H292. DOI: 10.1152/ ajpheart.00813.2016.\u003c/li\u003e\n\u003cli\u003eAlbernaz SM，Honorato⁃Sampaio K，Monteiro D G，et al. Sud⁃ den death associated with a novel H401Q \u003cem\u003ePRKAG2 \u003c/em\u003emutation［J］. Europace，2020，22（8）：1278. \u003c/li\u003e\n\u003cli\u003eYAVARI A, BELLAHCENE M, BUCCHI A, et al. Mammalian \u0026gamma;2 AMPK regulates intrinsic heart rate [J]. Nature Communications, 2017, 8(1).\u003c/li\u003e\n\u003cli\u003eOmmen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines[J]. Circulation, 2020, 142(25):e533‑e557. DOI: 10.1161/CIR.0000000000000938. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"PRKAG2 syndrome, hypertrophic cardiomyopathy, ventricular pre-excitation, cardiac conduction disease, gene mutation","lastPublishedDoi":"10.21203/rs.3.rs-9151431/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9151431/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003e\u003cem\u003ePRKAG2\u003c/em\u003esyndrome is a rare autosomal dominant glycogen storage cardiomyopathy caused by pathogenic variants in the \u003cem\u003ePRKAG2\u003c/em\u003e gene. It typically presents with left ventricular hypertrophy, ventricular pre-excitation, and conduction system disease, which can closely mimic sarcomeric hypertrophic cardiomyopathy (HCM) on routine imaging. Early recognition is crucial because its natural history, arrhythmic risk, and management differ substantially from those of classic hypertrophic cardiomyopathy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003eA 12-year-old boy presented with exertional chest tightness. Physical examination revealed a grade 2/6 systolic murmur at the left sternal border, while serial electrocardiograms demonstrated intermittent ventricular pre-excitation. Twenty-four-hour Holter monitoring recorded sinus bradycardia with intermittent pre-excitation, rare supraventricular ectopy, and multiple sinus pauses longer than 2 seconds (maximum RR interval of 2.28 seconds), occurring predominantly during sleep. Transthoracic echocardiography revealed asymmetric left ventricular hypertrophy with preserved systolic function and no evidence of left ventricular outflow tract obstruction. He was initially diagnosed with non-obstructive hypertrophic cardiomyopathy, intermittent ventricular pre-excitation, sick sinus syndrome, sinus bradycardia, and sinus arrest. However, the coexistence of myocardial hypertrophy, ventricular pre-excitation, and conduction abnormalities raised strong clinical suspicion for \u003cem\u003ePRKAG2\u003c/em\u003e syndrome. Subsequent genetic testing identified a heterozygous pathogenic missense variant in \u003cem\u003ePRKAG2\u003c/em\u003e, confirming the diagnosis. An electrophysiological study localized a fasciculoventricular pathway adjacent to the His bundle. Radiofrequency catheter ablation was deferred due to the high risk of complete atrioventricular block and the absence of documented tachyarrhythmia. During 1 year of follow-up, the patient remained clinically stable without high-risk arrhythmic events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThis case highlights the importance of considering \u003cem\u003ePRKAG2\u003c/em\u003e syndrome in young patients presenting with left ventricular hypertrophy accompanied by ventricular pre-excitation and conduction abnormalities. Genetic testing is essential for distinguishing \u003cem\u003ePRKAG2\u003c/em\u003e syndrome from sarcomeric hypertrophic cardiomyopathy and for guiding accurate risk stratification and individualized management.\u003c/p\u003e","manuscriptTitle":"Genetic testing reveals PRKAG2 syndrome mimicking sarcomeric hypertrophic cardiomyopathy in an adolescent: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-08 16:25:05","doi":"10.21203/rs.3.rs-9151431/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-06T07:50:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T11:01:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-03T16:31:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-03T09:55:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"149093595503685353501193664767086489494","date":"2026-04-26T05:42:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284346128684121442049515717024433903380","date":"2026-04-25T12:31:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"330971379165155005422120061640499553737","date":"2026-04-25T05:54:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-24T03:05:52+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-14T17:46:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-23T02:56:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-23T02:55:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2026-03-17T17:19:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f00a50b2-f4ef-428c-9ea4-d61d9d0e4c27","owner":[],"postedDate":"May 8th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-06T07:50:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T11:01:54+00:00","index":77,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-03T16:31:52+00:00","index":76,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-03T09:55:42+00:00","index":75,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-08T16:25:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-08 16:25:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9151431","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9151431","identity":"rs-9151431","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}