Aims Studies with implantable cardiac monitors (ICMs) show that one-third of patients with cryptogenic stroke/transient ischaemic attack (TIA) have episodes of subclinical atrial fibrillation (SCAF) and benefit switching from antiplatelet- to anticoagulant therapy. However, ICMs are costly and resource demanding. We aimed to build a score based on participant’s baseline characteristics that could assess individual risk of SCAF. Methods and results In a prospective study, 236 eligible patients with a final diagnosis of cryptogenic stroke/TIA had an ICM implantated during the index hospitalization. Pre-specified evaluated variables were: CHA2DS2-VASc, P-wave duration, P-wave morphology, premature atrial beats (PAC)/24 h, supraventricular tachycardia/24 h, left atrial end-systolic volume index (LAVI), Troponin-T, NT-proBNP, and D-dimer. SCAF was detected in 84 patients (36%). All pre-specified variables were significantly associated with SCAF detection in univariate analysis. P-wave duration, followed by PAC/24 h, NT-proBNP, and LAVI, had the largest ratio of SCAF prevalence between its upper and lower quartiles (3.3, vs. 3.2, vs. 3.1 vs. 2.8, respectively). However, in a multivariate analysis, only PAC/24t, P-wave duration, P-wave morphology, and LAVIs remained significant predictors and were included in the PROACTIA score. Subclinical atrial fibrillation prevalence was 75% in the highest vs. 10% in the lowest quartile of the PROACTIA score with a 10-fold higher number of patients with an atrial fibrillation burden >6 h in the highest vs. the lowest quartile. Conclusion The PROACTIA score can identify patients with cryptogenic stroke/TIA at risk of subsequent SCAF detection. The large difference in SCAF prevalence between groups may provide a basis for future tailored therapy. Clinical trial registration Clinical Trial Registration: ClinicalTrials.gov; NCT02725944.

Aims Left atrial (LA) strain is promising in prediction of clinical atrial fibrillation (AF) in stroke patients. However, prediction of subclinical AF is critical in patients with embolic strokes of undetermined source (ESUS). The aim of this prospective study was to investigate novel LA and left atrial appendage (LAA) strain markers in prediction of subclinical AF in ESUS patients. Methods and results A total of 185 patients with ESUS, mean age 68 ± 13years, 33% female, without diagnosed AF, were included. LAA and LA function by conventional echocardiographic parameters and reservoir strain (Sr), conduit strain (Scd), contraction strain (Sct), and mechanical dispersion (MD) of Sr were assessed with transoesophageal and transthoracic echocardiography. Subclinical AF was detected by insertable cardiac monitors during follow-up. LAA strain was impaired in 60 (32%) patients with subclinical AF compared to those with sinus rhythm: LAA-Sr, 19.2 ± 4.5% vs. 25.6 ± 6.5% (P < 0.001); LAA-Scd, −11.0 ± 3.1% vs. −14.4 ± 4.5% (P < 0.001); and LAA-Sct, −7.9 ± 4.0% vs. −11.2 ± 4% (P < 0.001), respectively, while LAA-MD was increased, 34 ± 24 ms vs. 26 ± 20 ms (P = 0.02). However, there was no significant difference in phasic LA strain or LA-MD. By ROC analyses, LAA-Sr was highly significant in prediction of subclinical AF and showed the best AUC of 0.80 (95% CI 0.73–0.87) with a sensitivity of 80% and a specificity of 73% (P < 0.001). LAA-Sr and LAA-MD were both independent and incremental markers of subclinical AF in ESUS patients. Conclusion LAA function by strain and mechanical dispersion predicted subclinical AF in ESUS patients. These novel echocardiographic markers may improve risk stratification in ESUS patients.

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Akerhus University Hospital Dept. of Cardiology Background Cryptogenic stroke/TIA (CS) is supposed to be associated with intracardiac thrombus formation and left atrial (LA) structure, in particular thrombus formation in left atrial appendage (LAA). However, there is little evidence if thromboembolic risk is associated with LAA morphology in patients with CS. Purpose We aimed to investigate, if different LAA morphology types may predict thromboembolic risk in patients with CS. Methods In this prospective study (mean follow-up 859 ± 226 days), 185 patients with CS (mean age 68 ±13 years, 33% female) without history of AF were included. All patients underwent complete transesophageal echocardiography in sinus rhythm after index CS (mean 5 ± 3days). Occurrence of LAA thrombus, sludge or spontaneous echo contrast (SEC) were defined as thromboembolic risk and LAA structure was evaluated by 2D and 3D transesophageal echocardiography. Multilobate LAA was defined as LAA with  > 1 lobes. Results Of the 185 included patients, LAA type chicken wing was found in 79 (43%), type windsock in 64 (35%), type cactus in 35 (19%) and type cauliflower in 7 (4%). Thrombus formation occurred in 29/185 (16%), LAA sludge in 112/185 (61%), and LAA SEC in 74/185 (40%), which is increased compared to data in the general population. We found SEC in sludge in 65/112 (58%), SEC in thrombus in 18/29 (62%) and sludge in thrombus in 27/29 (93%). SEC and sludge were significantly associated with thrombus formation, (p < 0.001 and p < 0.01, respectively). Finally, thromboembolic risk occurred in 123 (67%) of all patients with CS. Moreover, LAA type chicken wing was significantly associated with thromboembolic risk (p < 0.01), while all other LAA types were not. Multilobate LAA occurred in 115 (62%) of all patients and predicted thromboembolic risk vs. non-lobated LAA (p= 0.04). In a multivariate analysis LAA type chicken wing and multilobate LAA were independently predictors of thromboembolic risk, figure 1. Conclusions Patients with cryptogenic stroke/TIA without history of AF showed increased thromboembolic risk, and SEC and sludge were significantly associated with LAA thrombus formation. Only LAA type chicken wing and multilobate LAA predicted independently thromboembolic risk in this study. Abstract Figure.

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Background Left atrial (LA) function by strain has shown to be promising to predict clinical atrial fibrillation (AF) in patients with cryptogenic stroke/TIA. However, there is little knowledge, if this novel method may prospectively predict subclinical AF (SCAF) and moreover, if left atrial appendage (LAA) function by strain and mechanical dispersion may be more sensitive to improve prediction of SCAF. Purpose The aim of the present study was to investigate if LA and LAA function by strain could improve the prediction of SCAF in patients at risk. Methods In this prospective study (mean follow-up 859±226 days), 185 patients with cryptogenic stroke/TIA, mean age 68±13 years, 33% female and no history of clinical AF or SCAF, were included. All participants underwent 2D and 3D transesophageal and transthoracic echocardiography in sinus rhythm after index cryptogenic stroke/TIA (mean 5±3days). LAA and LA functions by phasic strain, including reservoir strain (Sr), conduit strain (Scd) and contraction strain (Sct) and mechanical dispersion of Sr were assessed. SCAF episodes were detected by cardiac monitoring during follow up (mean 257±273 days). Results LAA function by strain was decreased in those with SCAF (60/32% of all patients) compared to those without: Sr: 19.2±4.5% vs. 25.6±6.5% (p<0.001), Scd: −11.0±3.1% vs. −14.4±4.5% (p<0.001), Sct: −7.9±4.0% vs. −11.2±4% (p<0.001), respectively, while mechanical dispersion by Sr strain was increased, 34±24ms vs. 26±20ms (p=0.02). However, LA function by strain and mechanical dispersion did not differ in patients with SCAF compared to patients without. By ROC analyses, LAA strain and mechanical dispersion were highly significant in prediction of SCAF. LAA reservoir strain showed the best AUC of 0.80 (95% CI 0.73–0.87) with a cut-off value of 22.2%, sensitivity of 80%, and specificity of 73%, p<0.001. (Figure) Conclusions For the first time, we showed, that left atrial appendage function by strain and mechanical dispersion predicts SCAF, as opposed to left atrial function. Left atrial appendage function by strain may be useful in risk prediction in patients at considerable AF risk. FUNDunding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Department of Cardiology, Akershus University Hospital, Oslo/Lørenskog, Norway

Background Studies with implantable cardiac rhythm monitors (ICRM) have shown that a 1/3 of patients with cryptogenic stroke/transitory ischemic attack (TIA) have episodes of subclinical atrial fibrillation (SCAF) as one of the potential risk factor for cerebral embolism. However, ICRM are costly and resource demanding. Purpose The PROACTIA study seeks to test a pre-specified scoring system to assess individual risk of SCAF in order to offer tailored therapy to patients after cryptogenic stroke/TIA. Methods Patients admitted with first time cryptogenic stroke or TIA were eligible for the study and underwent blood sampling, cerebral CT/MRI, carotid Doppler ultrasound, ECG, 24h-HolterECG, transthoracic transesophageal echocardiography, registration of medical history and implantation of ICRM during the index hospitalization The scoring system was composed of variables that have previously been found associated with AF occurrence: CHA2DS2-VASc, P-wave duration (P-dur), premature atrial contractions (PAC)/24h, supraventricular runs (SVR)/24h, left atrial end-systolic volume index (LAVI), and the biomarkers TnT, NT-proBNP and D-dimer. Data are presented as median (inter quartile range). Results Within 25 months, 434 patients screened and 251 patients were included in the present study and had an ICRM implanted. Eleven patients were later excluded yielding a study cohort of 176 patients with cerebral infarction and 61 with TIA that were followed for 833 (633–1028) days. AF was detected in 36%. It took 113 (25–336) days to detect AF, and 5 (2–14) days from AF-detection to initiation of NOAC. All variables were significantly increased in AF patients: no-AF vs AF: CHADS-VASC: 4 (3–5) vs 5 (4–6)*, LAVI mL/m2: 35 (28–40) vs 40 (35–50)**, PAC/24h: 69 (29–211) vs 347 (59–1917)**, SVR / 24-h: 1 (0–3) vs 3 (1–17)**, P-dur ms: 100 (100–120) vs 120 (100–120)**, D-dimer mg/L: 0,3 (0,2–0,6) vs 0,5 (0,3–0,9)**, TnT ng/L: 10 (7–16) vs 15 (9–27)**, NT-proBNP ng/L: 103 (49–283) vs 245 (102–774)**. *p<0.01, **p<0.001. Multivariate analysis yielded the following model: −8.524 + 0.057*LAVI (p<0.001) + 0.035*P-dur (p<0.001) + 0.873*LogPAC/24h (p<0.001). ROC analysis using leave-one-out cross validation: AUC=0.77. Applying the model to our population, it would identify a high-risk group (>80% true positive) consisting of 17 true positive and 4 false positive, and a low-risk group (<5% false negative) consisting of 17 true negative and 1 false negative. Conclusions ICRM detected SCAF in 36% of cryptogenic stroke/TIA patients within 27 months. LAVI, PAC/24h and P-duration were strong independent predictors of SCAF enabling a meaningful risk stratification that can be used for tailoring therapy in cryptogenic stroke/TIA patients. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Stiftelsen Dam

Background A large proportion of patients with cryptogenic stroke or transitory ischemic attack (TIA) have underlying subclinical atrial fibrillation (SCAF) detected on follow up. It is not clear whether SCAF is the underlying primary entity in the pathogenesis of stroke in these patients, or merely a marker of atrial myopathy associated with left atrial remodeling, fibrosis and inflammation. Purpose As a hypothesis generating study, we investigated a panel of selected biomarkers involved in fibrosis, inflammation, and thrombosis: growth differentiation factor 15 (GDF-15), transforming growth factor b (TGFb), galectin-3, soluble suppressor of tumorgenicity2 (sST2), von Willebrand factor (vWF), Tissue metalloprotease1 (TIMP1), Matrix metalloprotease9 (MMP9), Emmprin, Interleukin6 (IL6), C-reactive protein (CRP), Tissue factor (TF), Plasminogen activator inhibitor (PAI1), and their relation to the occurrence of SCAF during follow-up in patients after cryptogenic stroke or TIA. We hypothized that biomarker levels were increased in patients with subclinical AF. Methods 236 patients, median age 71 years (range 21–94) of which 38% were women, with their first cryptogenic stroke or TIA were included 2–4 days after the index event and followed with an Implantable Cardiac Rhythm Monitor for >1 year. Echocardiography and blood sampling were performed at inclusion. ELISA methods were used. Results SCAF occurred in 84 patients (36%). Only GDF-15 was significantly increased in AF- vs no-AF patients: 1010 pg/mL (inter quartile range: 814–1416) vs 860 pg/mL (inter quartile range: 622–1197) (p=0.018), and correlated with the number of premature atrial contractions (PAC)/24h (by Holter ECG during index hospitalization) (rs=0.314, p<0.001) and AF-burden during follow-up (rs=0.149, p=0.022). Furthermore, there was a significant trend across quartiles of GDF-15 for having AF, and patients in the three highest quartiles (Q2–4) compared with Q1 had an odd ratio of having AF of 2.16 (95% CI 1.10–4.25), adjusted for sex and body mass index. The significance, however, was lost when adjusting for age, which correlated significantly to GDF-15 (rs=0.283; p<0.001). ROC curve analyses showed an AUC of 0.593 (0.52–0.68) for GDF-15 compared to 0.617 (0.54–0.69) for age. GDF-15 was also associated with co-morbidities such as hypertension (p<0.001), diabetes (p<0.001), and vascular disease (p<0.001). Conclusion In patients with a cryptogenic stroke or TIA experiencing SCAF during follow up, only levels of GDF-15 were elevated and correlated with PAC/24h and AF-burden. However, GDF-15 was highly related to age and co-morbidities and did not add significantly to the prediction of AF in a multivariate analysis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Stiftelsen Dam, Norwegian Atrial Fibrillation Research Network