Differing peak durations of sporadic atrial fibrillation beyond 30 seconds after acute cardioembolic or non- cardioembolic stroke at aged patients

Differing peak durations of sporadic atrial fibrillation beyond 30 seconds after acute cardioembolic or non- cardioembolic stroke at aged patients | 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 Research Article Differing peak durations of sporadic atrial fibrillation beyond 30 seconds after acute cardioembolic or non- cardioembolic stroke at aged patients Akikazu Nomura, Masami Yoshino, Izumi Koyanagi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6678373/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose We aimed to explore the influence of aging on the duration of acute ischemic stroke (AIS)-related sporadic atrial fibrillation (AF) with a comparison of the cardioembolic stroke (CES) and noncardioembolic stroke (NCES) subsets. Methods Prospective 1062 continuous stroke patients were admitted between July 1, 2013, and December 31, 2020, and 877 were classified as having AIS. Of these, 433 patients (CES, n = 145; NCES, n = 288) met the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria by magnetic resonance imaging and angiography. They underwent 24-h Holter monitoring and were divided according to AF duration (> 30 vs. 2.5–30 s) and stratified as prolonged but briefer AF (0.5–6 min) or prolonged AF (≥ 6 min). Results In the NCES group, patients with AF duration > 30 s were significantly older than those with AF duration of 2.5–30 s ( p 30 s had prolonged AF (≥ 6 min), whereas AF duration of 0.5–6 min was significantly more frequent after NCES (odds ratio, 8.5; 95% confidence interval, 2.4–30.4). In participants ≥ 80 years with AF > 30 s, NCES patients had prolonged but briefer AF (0.5–6 min) significantly more often ( p = 0.0069). Conclusions At AF > 30 s, durations ≥ 6 min were observed in almost all patients with acute CES. Prolonged but briefer AF (0.5–6 min) was observed in half of the NCES group. Patients aged ≥ 80 years with AF 0.5–6 min had NCES more often. Institutional Review Board of the Hokkaido Neurosurgical Memorial Hospital (registration number H25-2, 2013.7.1.) acute ischemic stroke aging sporadic atrial fibrillation cardioembolic stroke noncardioembolic stroke Figures Figure 1 Figure 2 Key summary points Aim: AF episodes lasting >30 s are viewed as causative in cardioembolic strokes (CES) and their relation to noncardioembolic stroke (NCES) is unclear. Findings: Patients having NCES with AF duration >30 s were significantly older compared with CES. Nearly all CES patients with AF >30 s had prolonged AF (≥6 min), whereas AF duration of 0.5–6 min was significantly more frequent after NCES. Message: It is necessary to diagnose the stoke subtype and exact AF duration since NCES patients having AF >0.5 s but <6 min require antithrombotic drugs. Background The proportion of adults with atrial fibrillation (AF) in our aging society is increasing, with a rapid upturn among individuals aged ≥ 80 years [ 1 – 3 ]. Aging is an important known risk factor for AF [ 1 – 4 ]. Episodes of AF often become more frequent and more prolonged with advancing age. Additionally, AF often accompanies acute ischemic stroke (AIS); therefore, AF is a major contributing factor to present-day fatalities [ 5 ]. Ischemic stroke can be classified as cardioembolic stroke (CES) or noncardioembolic stroke (NCES) using magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) [ 2 , 3 , 6 ]. CES is a direct result of cardiac thrombus formation, with AF being innate or secondary to an atrial myopathy event as well as a presumptive cause [ 5 – 7 ]. Although NCES is largely attributable to extracardiac thrombi unrelated to AF, prolonged AF is often detected under such circumstances, creating an additional potential for thrombus formation at the heart level. AF is currently implicated in 20–30% of all strokes [ 2 ]; however, its differing implications for stroke subsets have not been addressed in elderly populations. Arrhythmia-induced circulatory stasis is one of three factors critical for thrombus formation. AF lasting > 30 s has been previously cited as a strong risk factor for stroke [ 2 , 3 ]; however, some sources argue that an interval ≥ 6 min is required for a thrombus to form [ 8 – 10 ]. In terms of stroke subsets, the consequences of aging and prolonged AF remain unclear. Therefore, this study aimed to explore the influence of aging on the duration of AIS-related AF with a comparison of CES and NCES subsets. Methods This prospective analysis adhered to the standard reporting guidelines of the STROBE statement and included 1067 eligible study subjects consecutively admitted to our hospital with ischemic stroke between July 1, 2013, and December 31, 2020. Our center is an accredited neurosurgical emergency facility. All patients arriving in 2020 between April 1 and December 31 tested negative for coronavirus disease 2019 upon admission, as assessed with polymerase chain reaction [ 11 ]. Within our territory, neurosurgeons routinely assume care for cases of stroke. Each subject underwent MRI, MRA, transthoracic cardiac ultrasound (TCU), 24-h Holter electrocardiogram (ECG) monitoring, and biomarker testing within the stroke care unit. Patients were stratified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria [ 12 ]. We immediately excluded 97 patients who either died within 7 days after the development of symptoms or were not promptly admitted within 7 days after stroke onset. Another 93 patients failed to qualify for the study because 24-h Holter ECGs were not recorded within 7 days after stroke onset (missing data). We also excluded 305 and 94 patients with sinus rhythm (sporadic supraventricular beats < 2.5 s) and persistent AF for ≥ 24-h periods, respectively, leaving a total of 478 patients (Fig. 1). Regarding stroke etiology, the remaining candidates were further excluded if they classified as TOAST 4 (other determined, n = 17) or TOAST 5 (undetermined, n = 22). Ultimately, there were 438 subjects deemed acceptable for inclusion in the study (CES, n = 145 [TOAST 2]; NCES, n = 293 [TOAST 1, 3]) (Figure 1). All brain imaging studies were evaluated by more than two neurosurgeons. The peak AF durations in the 24-h Holter ECG recordings were initially read by an automated ECG analyzer (SCM-510J revised; Fukuda Denshi, Tokyo, Japan) and then individually interpreted via a technician. A cardiologist eventually reviewed the tracings to confirm the AF duration (Fig. 2 ). The reported sensitivity for the automated ECG analysis was lower than that achieved manually [ 13 ]. Moreover, QRS-complex representations of aberrant conduction are invariably open to debate; therefore, nonsustained AF should be confirmed by a cardiologist [ 10 ]. We subsequently formulated a three-part guideline defining AF as follows: (1) R–R interval variability; (2) absence of P-waves; (3) QRS-complex morphology adhering to the diagnostic criteria [ 14 ]. The TCU results were also interpreted by a cardiologist, and observers were blinded when examining brain imaging studies or 24-h Holter ECG recordings. In total, 438 participants qualified for inclusion in the study, with each displaying episodic supraventricular beats (2.5 s to 30 s) and nature of stroke (CES vs. NCES), and odds ratios (ORs) were generated to reflect the frequency of peak AF duration > 30 s (Table 1 ). We also compared age across these four groups, invoking one-way analysis of variance (ANOVA) with Bonferroni correction (Table 1 ), and further delineated AF episodes > 30 s as > 0.5 but < 6 min (prolonged but briefer AF) or ≥ 6 min (prolonged AF) to gauge frequencies within stroke subsets (Table 1 ). Lastly, Fisher’s exact test served to compare instances of prolonged but briefer (0.5–6 min) AF by stroke subset (CES vs. NCES) for patients ≥ 80 years with AF > 30 s (Table 1 ). Table 1 AF durations in patients with CES and NCES CES NCES AF 2.5–30 s Total patients 107 265 Mean age (years) 76.4 ± 11.5 ** 75.7 ± 10.0 * Age range (years) 39–97 43–100 AF > 30 s Total patients 38 28 Mean age (years) 78.6 ± 9.6 83.6 ± 8.5 *,** Age range (years) 62–94 60–94 AF > 30 s AF 0.5–6 min 4 14 AF ≥ 6 min 34 14 AF > 0.5 min and ≥ 80 years old AF 0.5–6 min 2 11 AF ≥ 6 min 17 10 Data are presented as n, mean ± standard deviation, or range. * p = 0.0008 ** p = 0.0065 CES, cardioembolic stroke; NCES, non-cardioembolic stroke; AF, atrial fibrillation. Of note, the ORs of patients with CES to NCES were similar (OR, 0.89; 95% confidence interval [CI], 0.54–1.48) (Table 2 ) for patients with or without missing data. This study focused on the difference in AF between CES and NCES. Given the presumptive randomness in approximately 10% of the candidates in question, we did not analyze those with missing data. Table 2 Number of patients with CES, NCES, and TOAST 4–5 according to the TOAST criteria CES NCES TOAST 4–5 Missing data 23 55 15 No missing data 257 547 73 CES, cardioembolic stroke; NCES, non-cardioembolic stroke; TOAST, Trial of Org 10172 in Acute Stroke Treatment. All data are expressed as means ± standard deviations, using commercially available software (Ekuseru-Toukei 2012; Social Survey Research Information Co., Tokyo, Japan). Significance was set at p < 0.05 (two-sided), providing established 95% CIs. Our study protocol was developed with input from senior individuals, and our ethical committee, which includes two laypersons among its six members, was instrumental in shaping it. The protocol takes into account the experiences of older patients during hospital admission, considering both their mental and physical condition. We recognize that lifestyle changes vary with patients and aim to understand how physicians can support patients in maintaining their preadmission lifestyle to the greatest extent possible. For example, some patients could not communicate well with the medical staff, and some experienced anxiety, expressed by removing the ECG cords. Some have chronic disease with elevated heart rate. Furthermore, some patients showed signs of senile dementia due to internal factors and/or delirium due to external factors, which sometimes changed day by day in the same patient. A Holter ECG had to be taken within 7 days after symptoms onset. It was difficult for them in an aggravated state to undergo a 24-h Holter ECG. In such cases, the physician in charge decided if it was possible to take readable ECG for a continuous 24-h duration, as they were in the best position to evaluate and care for the patient. This study protocol was reviewed and approved by the Institutional Review Board of the Hokkaido Neurosurgical Memorial Hospital (approval number H25-2). The Ethics Committee of the Hospital waived the need for patient/caregiver consent because of the prospective observational study design. Results Age and sex were similarly distributed among patients with CES (145/438; mean age, 77.0 ± 11.0 years; men, 49.7%) and NCES (293/438; mean age, 76.5 ± 10.1 years; men, 50.5%); the respective ages of the CES and NCES groups did not differ (difference [D], 0.5; 95% CI, − 1.6 to 2.6). A four-way age comparison ANOVA indicated no differences among groups, except within the NCES subset (AF > 30 s vs. AF 2.5–30 s) and for specific stroke groupings (CES at AF 2.5–30 s vs. NCES at AF > 30 s). In the NCES group, patients with AF > 30 s (vs. AF 2.5–30 s) were significantly older (83.6 ± 8.5 vs. 75.7 ± 10.0 years) by comparison (D, 7.9; standard error of mean [SEM], 2.0; p = 0.0008) and similarly surpassed patients with CES in age (76.4 ± 11.5 years) at AF 2.5–30 s (D, 7.2; SEM, 2.2; p = 0.0065). However, the CES group showed a higher occurrence of AF > 30 s than AF 2.5–30 s (OR, 3.4; 95% CI, 2.0–5.8) compared with the NCES group. At AF > 30 s, a greater proportion of patients with CES (vs. NCES) experienced prolonged AF (≥ 6 min), with prolonged but briefer AF (0.5–6 min) occurring significantly more often in the NCES (vs. CES) group (OR, 8.5; 95% CI, 2.4–30.4). Among the oldest patients (age ≥ 80 years) with AF > 30 s, prolonged but briefer AF (0.5–6 min) was significantly more frequent in the NCES group than in the CES group ( p = 0.0069, Fisher’s exact test). Disccusion High rates of detectable AF have been documented in the initial weeks following a stroke [ 15 ]. Such occurrences may offer insights into the mechanisms of index strokes through various means [ 16 ]. During these periods, therapeutic interventions, even those with a tentative benefit, are highly encouraged to prevent subsequent insults [ 2 , 3 ]. Bouts of AF appear to decline by day 8 poststroke [ 15 ] and ensue erratically but in clusters. The present study population was selected accordingly, limited to those examined within 7 days after stroke onset. Our data indicate that nearly all patients with AF > 30 s after CES experienced AF durations ≥ 6 min, whereas only half of those with NCES and AF > 30 s reached the 6-min threshold. The remainder of the NCES group displayed prolonged but briefer periods of AF (> 0.5 but 30 s or ≥ 6 min) reported for the risk of stroke. Although the former limit has prevailed in most studies and is cited in expert guidelines, it is unclear whether AF durations > 30 s are truly predictive of impending stroke [ 8 – 10 ]. The point where blood coagulates in test tubes (whole-blood clotting time), which is at least 6 min [ 17 ], seems a more reasonable estimate of the minimal requirement for thrombus formation [ 8 ]. In most of our patients with acute CES, AF actually exceeded the 6-min mark. Ectopic firing (as a trigger) and a reentrant circus (to maintain the arrhythmia) are the requisites for AF occurrence, whereas the degree of maturity in an abnormal electrical pathway determines the duration of AF. A sufficient AF interval is needed for blood flow to stagnate, prompting intracardiac thrombus formation. AF in the context of CES is believed to involve unknown triggers and mature AF substrates, prolonging it well beyond 6 min to incite intracardiac thrombus formation. In contrast, thrombus formation in NCES has cerebrovascular origins. The ongoing events are unrelated to AF and are otherwise expected consequences of aging; subsequently, AF is a result or incidental feature of NCES, likely instigated through stroke-related triggers. If so stimulated, it is possible to elicit prolonged but briefer AF in a less mature AF substrate. A known link exists between aging and greater AF frequency and longer AF duration [ 2 , 3 ]. The mean age of the NCES group at AF > 30 s was in the 80s, differing prominently from the other three groups, where the mean age was in the 70s. There was no significant age difference when comparing AF > 30 s with AF 2.5–30 s in the CES group; however, patients with AF > 30 s were significantly older than those with AF 2.5–30 s in the NCES group. This implies that a longer time period is needed to develop AF > 30 s in patients with NCES; thus, the risk entailed is largely a feature of advanced age. There are many risk factors for AF [ 4 ]. Advanced age has a non-modifiable and incremental risk for AF. Modifiable risk factors that tax the heart directly are smoking, obesity, hypertension, diabetes mellitus and so on. AF in conjunction with CES has unknown triggers and encourages intracardiac thrombus formation, lasting well beyond 6 min. However, AF is a result or incidental aspect of NCES, likely instigated by stroke-related triggers. There is no direct relation between AF and stroke via thrombus formation. Hence, it is possible to elicit prolonged but briefer AF (> 30sec but 20% of patients with prolonged AF who receive oral anticoagulants as stroke prophylaxis. [ 18 ]. Such refractoriness may reflect those patients with prolonged but briefer AF. The oldest inhabitants (aged ≥ 80 years) of Sapporo, accounting for 2.7% of 1.8 million people as of April 1, 2000, comprised 8.4% of 2.0 million people by January 1, 2021 (D, 5.64; 95% CI, 5.44–5.84) [ 19 ]. Hence, our societal demographics are rapidly changing. However, half of the NCES subset was marked by prolonged but briefer AF. Such patients should be administered antithrombotic drugs for secondary stroke prevention, which acknowledges the threat of eventual thrombus formation as substrates transform over time. Further study of the evolving AF substrate is essential to clarify its relation to NCES and examine potential thrombotic ramifications within the heart. At the onset of societal aging (~ 30 years ago), important issues for such patients are how to live with reduced organ function. [ 20 ]. Now, adults of advanced age (≥ 80 years) abound in our society, and short durations of AF may not necessarily carry adverse clinical implications. Still, the AF substrate will gradually mature over decades, one day reaching the threshold for thrombus formation in patients with NCES. At beginning, modifiable and non-modifiable risk factors work to mature AF substrates. Finally non-modifiable risk factors might be key player to mature AF substrate for NCES. We should pay attention to thrombus formation at brain vessel as well as at heart for aged patients with NCES. We have to cope with modifiable as well as non-modifiable risk factors at advanced aged society. Limitation The present study had some distinct limitations. Our sampling of patients with AF > 30 s and ≥ 80 years old was relatively small though it is hard to obtain such patients, with an occasional inability to specify the stroke subtype. Furthermore, AF may well be absent in some patients with CES, perhaps implicating atrial myopathy. The latter scenario transcends the scope of this study and must be investigated independently. Conclusion Most patients with CES and AF > 30 s in this study registered durations of AF ≥ 6 min at times of AIS, which is sufficient for developing intracardiac thrombus. However, half of those with NCES showed AF durations > 0.5 min but < 6 min, refuting the prospect of intracardiac thrombus. These patients require antithrombotic agents for the prevention of stroke. Therefore, the utility of established benchmarks may differ according to stroke subtype because of the increase in the aged population. We are clearly facing demographic shifts, which are skewed to the oldest of inhabitants. Study has to be urgently performed for advanced old patients. Declarations Competing interests: The authors declare that they have no conflict of interest. Data statement We used all collected data supporting the findings of this study. However, data are available from the corresponding author upon reasonable request. Informed Consent: The need for patient/caregiver consent was waived because of the prospective observational study design. Funding: The authors did not receive support from any organization for the submitted work. 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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-6678373","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":462470867,"identity":"68e3e1db-43a3-444f-99de-a74a310c5ec4","order_by":0,"name":"Akikazu Nomura","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYPACmwQgwQblHCBKSxrpWg4jayEAzNm706Qras7nmfOfTntcwGCTz8B4Fr81lj1nt0meOXa72HJG7nbjGQxplg0M5xLwajG4kbtNsoHtduKGG7zbpHkYDhswMJwxIELLv3OJG86fJUVLY9uBxA0HconVcubsZsvGvmSgw4BaZhikGbAR9Mvx3o03G77ZQRxWUGFjwC9BIMRQADMD0ElsEmeI1wHUAgL8PSRoGQWjYBSMgpEAAF6uSUxr6wg7AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-9883-4251","institution":"Hokkaido Neurosurgical Memorial Hospital","correspondingAuthor":true,"prefix":"","firstName":"Akikazu","middleName":"","lastName":"Nomura","suffix":""},{"id":462470868,"identity":"924bc3c4-99ea-4664-8c07-2c85cd312dd7","order_by":1,"name":"Masami Yoshino","email":"","orcid":"","institution":"Hokkaido Neurosurgical Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masami","middleName":"","lastName":"Yoshino","suffix":""},{"id":462470869,"identity":"160fd9fe-bd42-48b8-b518-05737bac19ca","order_by":2,"name":"Izumi Koyanagi","email":"","orcid":"","institution":"Hokkaido Neurosurgical Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Izumi","middleName":"","lastName":"Koyanagi","suffix":""}],"badges":[],"createdAt":"2025-05-16 07:45:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6678373/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6678373/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83752010,"identity":"f26a0872-4f3b-483a-acdf-bac56113c5c5","added_by":"auto","created_at":"2025-06-02 07:10:00","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56701,"visible":true,"origin":"","legend":"\u003cp\u003ePatient selection flow chart\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6678373/v1/f1d00f25a0d90aa04f3099a6.jpg"},{"id":83752302,"identity":"77817991-222e-46e6-9589-d382ee8aa4ed","added_by":"auto","created_at":"2025-06-02 07:18:00","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":113525,"visible":true,"origin":"","legend":"\u003cp\u003eHolter ECG tracing of 88-year-old patient with NCES (each row=1 min): Each heartbeat plotted by R-R interval creates a line (on left) as triangleindicates, straight line implying uniformity (regular rhythm) and interrupted line suggesting non-uniformity (arrhythmia). At signs of interruption, ECG (on right) can be magnified to distinguish type and duration of arrhythmia.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6678373/v1/60926fae9aa1f275dd7d1e73.jpg"},{"id":85752865,"identity":"4111ed91-7148-4afb-9fdf-db7996f03e84","added_by":"auto","created_at":"2025-07-01 10:25:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":611660,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6678373/v1/1e641317-108e-40f8-9081-f1d276be1be9.pdf"},{"id":83752025,"identity":"63385851-19ff-4a03-a477-746861bbb0bb","added_by":"auto","created_at":"2025-06-02 07:10:01","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":45715,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicalabstract.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6678373/v1/398caf107f7a4148742f6c53.jpg"}],"financialInterests":"","formattedTitle":"Differing peak durations of sporadic atrial fibrillation beyond 30 seconds after acute cardioembolic or non- cardioembolic stroke at aged patients","fulltext":[{"header":"Key summary points","content":"\u003cp\u003e\u003cstrong\u003eAim:\u0026nbsp;\u003c/strong\u003eAF episodes lasting \u0026gt;30 s are viewed as causative in cardioembolic strokes (CES) and their relation to noncardioembolic stroke (NCES) is unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFindings:\u003c/strong\u003e Patients having NCES with AF duration \u0026gt;30 s were significantly older compared with CES.\u0026nbsp;Nearly all CES patients with AF \u0026gt;30 s had prolonged AF (\u0026ge;6 min), whereas AF duration of 0.5\u0026ndash;6 min was significantly more frequent after NCES.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMessage:\u0026nbsp;\u003c/strong\u003eIt is necessary to diagnose the stoke subtype and exact AF duration since NCES patients having AF \u0026gt;0.5 s but \u0026lt;6 min require antithrombotic drugs.\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eThe proportion of adults with atrial fibrillation (AF) in our aging society is increasing, with a rapid upturn among individuals aged ≥ 80 years [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Aging is an important known risk factor for AF [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Episodes of AF often become more frequent and more prolonged with advancing age. Additionally, AF often accompanies acute ischemic stroke (AIS); therefore, AF is a major contributing factor to present-day fatalities [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIschemic stroke can be classified as cardioembolic stroke (CES) or noncardioembolic stroke (NCES) using magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. CES is a direct result of cardiac thrombus formation, with AF being innate or secondary to an atrial myopathy event as well as a presumptive cause [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Although NCES is largely attributable to extracardiac thrombi unrelated to AF, prolonged AF is often detected under such circumstances, creating an additional potential for thrombus formation at the heart level. AF is currently implicated in 20–30% of all strokes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]; however, its differing implications for stroke subsets have not been addressed in elderly populations.\u003c/p\u003e \u003cp\u003eArrhythmia-induced circulatory stasis is one of three factors critical for thrombus formation. AF lasting \u0026gt; 30 s has been previously cited as a strong risk factor for stroke [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]; however, some sources argue that an interval ≥ 6 min is required for a thrombus to form [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In terms of stroke subsets, the consequences of aging and prolonged AF remain unclear. Therefore, this study aimed to explore the influence of aging on the duration of AIS-related AF with a comparison of CES and NCES subsets.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e This prospective analysis adhered to the standard reporting guidelines of the STROBE statement and included 1067 eligible study subjects consecutively admitted to our hospital with ischemic stroke between July 1, 2013, and December 31, 2020. Our center is an accredited neurosurgical emergency facility. All patients arriving in 2020 between April 1 and December 31 tested negative for coronavirus disease 2019 upon admission, as assessed with polymerase chain reaction [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Within our territory, neurosurgeons routinely assume care for cases of stroke. Each subject underwent MRI, MRA, transthoracic cardiac ultrasound (TCU), 24-h Holter electrocardiogram (ECG) monitoring, and biomarker testing within the stroke care unit. Patients were stratified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe immediately excluded 97 patients who either died within 7 days after the development of symptoms or were not promptly admitted within 7 days after stroke onset. Another 93 patients failed to qualify for the study because 24-h Holter ECGs were not recorded within 7 days after stroke onset (missing data). We also excluded 305 and 94 patients with sinus rhythm (sporadic supraventricular beats \u0026lt; 2.5 s) and persistent AF for ≥ 24-h periods, respectively, leaving a total of 478 patients (Fig.\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eRegarding stroke etiology, the remaining candidates were further excluded if they classified as TOAST 4 (other determined, n = 17) or TOAST 5 (undetermined, n = 22). Ultimately, there were 438 subjects deemed acceptable for inclusion in the study (CES, n = 145 [TOAST 2]; NCES, n = 293 [TOAST 1, 3]) (Figure 1).\u003c/p\u003e\u003cp\u003eAll brain imaging studies were evaluated by more than two neurosurgeons. The peak AF durations in the 24-h Holter ECG recordings were initially read by an automated ECG analyzer (SCM-510J revised; Fukuda Denshi, Tokyo, Japan) and then individually interpreted via a technician. A cardiologist eventually reviewed the tracings to confirm the AF duration (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The reported sensitivity for the automated ECG analysis was lower than that achieved manually [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Moreover, QRS-complex representations of aberrant conduction are invariably open to debate; therefore, nonsustained AF should be confirmed by a cardiologist [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. We subsequently formulated a three-part guideline defining AF as follows: (1) R–R interval variability; (2) absence of P-waves; (3) QRS-complex morphology adhering to the diagnostic criteria [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The TCU results were also interpreted by a cardiologist, and observers were blinded when examining brain imaging studies or 24-h Holter ECG recordings.\u003c/p\u003e\u003cp\u003eIn total, 438 participants qualified for inclusion in the study, with each displaying episodic supraventricular beats (2.5 s to \u0026lt; 24 h). We used the \u003cem\u003et\u003c/em\u003e-test to evaluate stroke subsets by age. Subjects were grouped according to AF duration (2.5–30 vs. \u0026gt;30 s) and nature of stroke (CES vs. NCES), and odds ratios (ORs) were generated to reflect the frequency of peak AF duration \u0026gt; 30 s (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). We also compared age across these four groups, invoking one-way analysis of variance (ANOVA) with Bonferroni correction (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), and further delineated AF episodes \u0026gt; 30 s as \u0026gt; 0.5 but \u0026lt; 6 min (prolonged but briefer AF) or ≥ 6 min (prolonged AF) to gauge frequencies within stroke subsets (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Lastly, Fisher’s exact test served to compare instances of prolonged but briefer (0.5–6 min) AF by stroke subset (CES vs. NCES) for patients ≥ 80 years with AF \u0026gt; 30 s (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAF durations in patients with CES and NCES\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCES\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNCES\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAF 2.5–30 s\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal patients\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e265\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean age (years)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.4 ± 11.5\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.7 ± 10.0\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge range (years)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39–97\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43–100\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAF \u0026gt; 30 s\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal patients\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean age (years)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78.6 ± 9.6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83.6 ± 8.5\u003csup\u003e*,**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge range (years)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62–94\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60–94\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAF \u0026gt; 30 s\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAF 0.5–6 min\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAF ≥ 6 min\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAF \u0026gt; 0.5 min and ≥ 80 years old\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAF 0.5–6 min\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAF ≥ 6 min\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eData are presented as n, mean ± standard deviation, or range.\u003c/p\u003e\u003cp\u003e \u003csup\u003e*\u003c/sup\u003e \u003cem\u003ep\u003c/em\u003e = 0.0008 \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e = 0.0065\u003c/p\u003e\u003cp\u003eCES, cardioembolic stroke; NCES, non-cardioembolic stroke; AF, atrial fibrillation.\u003c/p\u003e\u003cp\u003eOf note, the ORs of patients with CES to NCES were similar (OR, 0.89; 95% confidence interval [CI], 0.54–1.48) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) for patients with or without missing data. This study focused on the difference in AF between CES and NCES. Given the presumptive randomness in approximately 10% of the candidates in question, we did not analyze those with missing data.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eNumber of patients with CES, NCES, and TOAST 4–5 according to the TOAST criteria\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCES\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNCES\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTOAST 4–5\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing data\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo missing data\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e257\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e547\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eCES, cardioembolic stroke; NCES, non-cardioembolic stroke; TOAST, Trial of Org 10172 in Acute Stroke Treatment.\u003c/p\u003e\u003cp\u003eAll data are expressed as means ± standard deviations, using commercially available software (Ekuseru-Toukei 2012; Social Survey Research Information Co., Tokyo, Japan). Significance was set at \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05 (two-sided), providing established 95% CIs.\u003c/p\u003e\u003cp\u003e Our study protocol was developed with input from senior individuals, and our ethical committee, which includes two laypersons among its six members, was instrumental in shaping it. The protocol takes into account the experiences of older patients during hospital admission, considering both their mental and physical condition. We recognize that lifestyle changes vary with patients and aim to understand how physicians can support patients in maintaining their preadmission lifestyle to the greatest extent possible. For example, some patients could not communicate well with the medical staff, and some experienced anxiety, expressed by removing the ECG cords. Some have chronic disease with elevated heart rate. Furthermore, some patients showed signs of senile dementia due to internal factors and/or delirium due to external factors, which sometimes changed day by day in the same patient. A Holter ECG had to be taken within 7 days after symptoms onset. It was difficult for them in an aggravated state to undergo a 24-h Holter ECG. In such cases, the physician in charge decided if it was possible to take readable ECG for a continuous 24-h duration, as they were in the best position to evaluate and care for the patient.\u003c/p\u003e\u003cp\u003e This study protocol was reviewed and approved by the Institutional Review Board of the Hokkaido Neurosurgical Memorial Hospital (approval number H25-2). The Ethics Committee of the Hospital waived the need for patient/caregiver consent because of the prospective observational study design.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAge and sex were similarly distributed among patients with CES (145/438; mean age, 77.0\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0 years; men, 49.7%) and NCES (293/438; mean age, 76.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1 years; men, 50.5%); the respective ages of the CES and NCES groups did not differ (difference [D], 0.5; 95% CI, \u0026minus;\u0026thinsp;1.6 to 2.6). A four-way age comparison ANOVA indicated no differences among groups, except within the NCES subset (AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s vs. AF 2.5\u0026ndash;30 s) and for specific stroke groupings (CES at AF 2.5\u0026ndash;30 s vs. NCES at AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s). In the NCES group, patients with AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s (vs. AF 2.5\u0026ndash;30 s) were significantly older (83.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5 vs. 75.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0 years) by comparison (D, 7.9; standard error of mean [SEM], 2.0; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0008) and similarly surpassed patients with CES in age (76.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.5 years) at AF 2.5\u0026ndash;30 s (D, 7.2; SEM, 2.2; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0065). However, the CES group showed a higher occurrence of AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s than AF 2.5\u0026ndash;30 s (OR, 3.4; 95% CI, 2.0\u0026ndash;5.8) compared with the NCES group.\u003c/p\u003e \u003cp\u003eAt AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s, a greater proportion of patients with CES (vs. NCES) experienced prolonged AF (\u0026ge;\u0026thinsp;6 min), with prolonged but briefer AF (0.5\u0026ndash;6 min) occurring significantly more often in the NCES (vs. CES) group (OR, 8.5; 95% CI, 2.4\u0026ndash;30.4). Among the oldest patients (age\u0026thinsp;\u0026ge;\u0026thinsp;80 years) with AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s, prolonged but briefer AF (0.5\u0026ndash;6 min) was significantly more frequent in the NCES group than in the CES group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0069, Fisher\u0026rsquo;s exact test).\u003c/p\u003e"},{"header":"Disccusion","content":"\u003cp\u003eHigh rates of detectable AF have been documented in the initial weeks following a stroke [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Such occurrences may offer insights into the mechanisms of index strokes through various means [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. During these periods, therapeutic interventions, even those with a tentative benefit, are highly encouraged to prevent subsequent insults [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Bouts of AF appear to decline by day 8 poststroke [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and ensue erratically but in clusters.\u003c/p\u003e \u003cp\u003eThe present study population was selected accordingly, limited to those examined within 7 days after stroke onset. Our data indicate that nearly all patients with AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s after CES experienced AF durations\u0026thinsp;\u0026ge;\u0026thinsp;6 min, whereas only half of those with NCES and AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s reached the 6-min threshold. The remainder of the NCES group displayed prolonged but briefer periods of AF (\u0026gt;\u0026thinsp;0.5 but \u0026lt;\u0026thinsp;6 min). Therefore, there were distinct differences between the two benchmark AF durations (\u0026gt;\u0026thinsp;30 s or \u0026ge;\u0026thinsp;6 min) reported for the risk of stroke. Although the former limit has prevailed in most studies and is cited in expert guidelines, it is unclear whether AF durations\u0026thinsp;\u0026gt;\u0026thinsp;30 s are truly predictive of impending stroke [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The point where blood coagulates in test tubes (whole-blood clotting time), which is at least 6 min [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], seems a more reasonable estimate of the minimal requirement for thrombus formation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In most of our patients with acute CES, AF actually exceeded the 6-min mark.\u003c/p\u003e \u003cp\u003eEctopic firing (as a trigger) and a reentrant circus (to maintain the arrhythmia) are the requisites for AF occurrence, whereas the degree of maturity in an abnormal electrical pathway determines the duration of AF. A sufficient AF interval is needed for blood flow to stagnate, prompting intracardiac thrombus formation. AF in the context of CES is believed to involve unknown triggers and mature AF substrates, prolonging it well beyond 6 min to incite intracardiac thrombus formation. In contrast, thrombus formation in NCES has cerebrovascular origins. The ongoing events are unrelated to AF and are otherwise expected consequences of aging; subsequently, AF is a result or incidental feature of NCES, likely instigated through stroke-related triggers. If so stimulated, it is possible to elicit prolonged but briefer AF in a less mature AF substrate.\u003c/p\u003e \u003cp\u003eA known link exists between aging and greater AF frequency and longer AF duration [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The mean age of the NCES group at AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s was in the 80s, differing prominently from the other three groups, where the mean age was in the 70s. There was no significant age difference when comparing AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s with AF 2.5\u0026ndash;30 s in the CES group; however, patients with AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s were significantly older than those with AF 2.5\u0026ndash;30 s in the NCES group. This implies that a longer time period is needed to develop AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s in patients with NCES; thus, the risk entailed is largely a feature of advanced age.\u003c/p\u003e \u003cp\u003eThere are many risk factors for AF [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Advanced age has a non-modifiable and incremental risk for AF. Modifiable risk factors that tax the heart directly are smoking, obesity, hypertension, diabetes mellitus and so on. AF in conjunction with CES has unknown triggers and encourages intracardiac thrombus formation, lasting well beyond 6 min. However, AF is a result or incidental aspect of NCES, likely instigated by stroke-related triggers. There is no direct relation between AF and stroke via thrombus formation. Hence, it is possible to elicit prolonged but briefer AF (\u0026gt;\u0026thinsp;30sec but \u0026lt;\u0026thinsp;6 min) in a less mature AF substrate if so stimulated. Maturity of the substrate may be critical in instances of NCES, taking so long to ripen. Recurrences of stroke are reported in \u0026gt;\u0026thinsp;20% of patients with prolonged AF who receive oral anticoagulants as stroke prophylaxis. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Such refractoriness may reflect those patients with prolonged but briefer AF.\u003c/p\u003e \u003cp\u003eThe oldest inhabitants (aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years) of Sapporo, accounting for 2.7% of 1.8\u0026nbsp;million people as of April 1, 2000, comprised 8.4% of 2.0\u0026nbsp;million people by January 1, 2021 (D, 5.64; 95% CI, 5.44\u0026ndash;5.84) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Hence, our societal demographics are rapidly changing. However, half of the NCES subset was marked by prolonged but briefer AF. Such patients should be administered antithrombotic drugs for secondary stroke prevention, which acknowledges the threat of eventual thrombus formation as substrates transform over time. Further study of the evolving AF substrate is essential to clarify its relation to NCES and examine potential thrombotic ramifications within the heart.\u003c/p\u003e \u003cp\u003eAt the onset of societal aging (~\u0026thinsp;30 years ago), important issues for such patients are how to live with reduced organ function. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Now, adults of advanced age (\u0026ge;\u0026thinsp;80 years) abound in our society, and short durations of AF may not necessarily carry adverse clinical implications. Still, the AF substrate will gradually mature over decades, one day reaching the threshold for thrombus formation in patients with NCES. At beginning, modifiable and non-modifiable risk factors work to mature AF substrates. Finally non-modifiable risk factors might be key player to mature AF substrate for NCES. We should pay attention to thrombus formation at brain vessel as well as at heart for aged patients with NCES. We have to cope with modifiable as well as non-modifiable risk factors at advanced aged society.\u003c/p\u003e \u003cp\u003eLimitation\u003c/p\u003e \u003cp\u003eThe present study had some distinct limitations. Our sampling of patients with AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s and \u0026ge;\u0026thinsp;80 years old was relatively small though it is hard to obtain such patients, with an occasional inability to specify the stroke subtype. Furthermore, AF may well be absent in some patients with CES, perhaps implicating atrial myopathy. The latter scenario transcends the scope of this study and must be investigated independently.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMost patients with CES and AF\u0026thinsp;\u0026gt;\u0026thinsp;30 s in this study registered durations of AF\u0026thinsp;\u0026ge;\u0026thinsp;6 min at times of AIS, which is sufficient for developing intracardiac thrombus. However, half of those with NCES showed AF durations\u0026thinsp;\u0026gt;\u0026thinsp;0.5 min but \u0026lt;\u0026thinsp;6 min, refuting the prospect of intracardiac thrombus. These patients require antithrombotic agents for the prevention of stroke. Therefore, the utility of established benchmarks may differ according to stroke subtype because of the increase in the aged population. We are clearly facing demographic shifts, which are skewed to the oldest of inhabitants. Study has to be urgently performed for advanced old patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eCompeting interests:\u003c/strong\u003e \u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eData statement\u003c/h2\u003e \u003cp\u003eWe used all collected data supporting the findings of this study. However, data are available from the corresponding author upon reasonable request.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eInformed Consent:\u003c/strong\u003e \u003cp\u003e The need for patient/caregiver consent was waived because of the prospective observational study design.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillum RF, Kim YH, McAnulty JH Jr, Zheng ZJ, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJ. Worldwide epidemiology of atrial fibrillation. Circulation. 2014;129:837\u0026ndash;47. doi: 10.1161/CIRCULATIONAHA.113.005119\u003c/li\u003e\n\u003cli\u003eHindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstr\u0026ouml;m-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL; ESC Scientific Document Group. 2020 ESC guideline for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic surgery (EACTS): the Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. 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Cardioembolic stroke. Circ Res. 2017;120:514\u0026ndash;26. doi: 10.1161/CIRCRESAHA.116.308407\u003c/li\u003e\n\u003cli\u003eSchnabel RB, Haeusler KG, Healey JSｍ, Ben F. Searching for atrial fibrillation poststroke: a white paper of the AF-SCREEN international collaboration. Circulation. 2019;140:1834\u0026ndash;50. doi: 10.1161/CIRCULATIONAHA.119.040267\u003c/li\u003e\n\u003cli\u003eDiener HC. To monitor or to not monitor for paroxysmal atrial fibrillation after transient ischemic attack or stroke. Stroke. 2019;45:355\u0026ndash;6. doi: 10.1161/STROKEAHA.113.004036\u003c/li\u003e\n\u003cli\u003eSilver B, Windecker S. Prognostication of fibrillations. Stroke. 2015;46:1155\u0026ndash;7. doi: 10.1161/STROKEAHA.115.008873\u003c/li\u003e\n\u003cli\u003eExtramiana F, Mason-Blanche P. Stroke and atrial fibrillation: where to go from here? Stroke. 2015 46:605\u0026ndash;7. doi: 10.1161/STROKEAHA.114.007809\u003c/li\u003e\n\u003cli\u003ePillai P, Joseph JP, Fadzillah NHM, Mahmod M. COVID-19 and major organ thromboembolism: manifestations in neurovascular and cardiovascular systems. J Stroke Cerebrovasc Dis. 2021;30:105427. doi: 10.1016/j.jstrokecerebrovasdis.2020.105427 \u003c/li\u003e\n\u003cli\u003eAdams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3\u003csup\u003erd\u003c/sup\u003e. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35\u0026ndash;41. doi: 10.1161/01.str.24.1.35\u003c/li\u003e\n\u003cli\u003eRogalewski A, Plumer J, Feldmann T, Oelschl\u0026auml;ger C, Greeve I, Kitsiou A, Schellinger PD, Israel CW, Sch\u0026auml;bitz WR. Detection of atrial fibrillation on stroke units: comparison of manual versus automatic analysis of continuous telemetry. Cerebrovasc Dis 2020;49:647\u0026ndash;55. doi: 10.1159/000511563\u003c/li\u003e\n\u003cli\u003eFuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 Guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257\u0026ndash;e354. doi: 10.1161/CIRCULATIONAHA.106.177292\u003c/li\u003e\n\u003cli\u003eSposato LA, Riccio PM, Hachinski V. Poststroke atrial fibrillation: cause or consequence? Critical review of current views. Neurology. 2014;82:1180\u0026ndash;1186. doi: 10.1212/WNL.0000000000000265\u003c/li\u003e\n\u003cli\u003eThijs V. Atrial fibrillation detection: fishing for an irregular heartbeat before and after stroke. Stroke. 2017;48;2671\u0026ndash;7. doi: 10.1161/STROKEAHA.117.017083\u003c/li\u003e\n\u003cli\u003eMaji D, De La Fuente M, Kucukal E, Sekhon UDS, Schmaier AH, Sen Gupta A, Gurkan UA, Nieman MT, Stavrou EX, Mohseni P, Suster MA. Assessment of whole blood coagulation with Microfluidic dielectric sensor. J Thromb Haemost. 2018;16:2050\u0026ndash;2056. doi: 10.1111/jth.14244\u003c/li\u003e\n\u003cli\u003eSeiffge DJ, Marchis GMD, Koga M et al. David JS, Gian M, Masatoshi K, Maurizio P, Duncan W, Manuel C, Kosmas M, Georgios T, Gareth A, Shoji A, Leo HB, Bruno B, Bernd K, Keith WM, Paolo B, Henrik G, Manabu I, Stefan S, Shadi Y, Martin MB, Philippe L, Masahito T, Monica A, Hans RJ, Alexandros AP, Kazunori T, Michele V, Christopher T, Hiroshi Y, Andrea A, Sohei Y, Valeria C, Stefan TE and David JW. Ischemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation. Ann Neurol 2020;87: 677-87.\u003c/li\u003e\n\u003cli\u003eSapporo City. Basic Resident Register in Sapporo [online]. Available from: https://www.city.sapporo.jp/toukei/jinko/juuki/juuki.html. Accessed 24 May 2024.\u003c/li\u003e\n\u003cli\u003eAkikazu N, Akira K, Satoshi K, Ken I, Kastumi M. Digoxin dose adjusted according to estimated creatinine clearance in elderly patients with cardiac disease. Cardiol Elderly. 1994;2:139-43.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acute ischemic stroke, aging, sporadic atrial fibrillation, cardioembolic stroke, noncardioembolic stroke","lastPublishedDoi":"10.21203/rs.3.rs-6678373/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6678373/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe aimed to explore the influence of aging on the duration of acute ischemic stroke (AIS)-related sporadic atrial fibrillation (AF) with a comparison of the cardioembolic stroke (CES) and noncardioembolic stroke (NCES) subsets.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProspective 1062 continuous stroke patients were admitted between July 1, 2013, and December 31, 2020, and 877 were classified as having AIS. Of these, 433 patients (CES, n = 145; NCES, n = 288) met the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria by magnetic resonance imaging and angiography. They underwent 24-h Holter monitoring and were divided according to AF duration (\u0026gt; 30 vs. 2.5–30 s) and stratified as prolonged but briefer AF (0.5–6 min) or prolonged AF (≥ 6 min).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the NCES group, patients with AF duration \u0026gt; 30 s were significantly older than those with AF duration of 2.5–30 s (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0008). Nearly all CES patients with AF \u0026gt; 30 s had prolonged AF (≥ 6 min), whereas AF duration of 0.5–6 min was significantly more frequent after NCES (odds ratio, 8.5; 95% confidence interval, 2.4–30.4). In participants ≥ 80 years with AF \u0026gt; 30 s, NCES patients had prolonged but briefer AF (0.5–6 min) significantly more often (\u003cem\u003ep\u003c/em\u003e = 0.0069).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt AF \u0026gt; 30 s, durations ≥ 6 min were observed in almost all patients with acute CES. Prolonged but briefer AF (0.5–6 min) was observed in half of the NCES group. Patients aged ≥ 80 years with AF 0.5–6 min had NCES more often.\u003c/p\u003e\n\u003cp\u003eInstitutional Review Board of the Hokkaido Neurosurgical Memorial Hospital (registration number H25-2, 2013.7.1.)\u003c/p\u003e","manuscriptTitle":"Differing peak durations of sporadic atrial fibrillation beyond 30 seconds after acute cardioembolic or non- cardioembolic stroke at aged patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-02 07:09:55","doi":"10.21203/rs.3.rs-6678373/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4cfdfc1b-17b9-4225-95f8-d7004cb9a464","owner":[],"postedDate":"June 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-01T10:17:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-02 07:09:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6678373","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6678373","identity":"rs-6678373","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}