Journal of Clinical Medicine Article Left Atrium Assessment by Speckle Tracking Echocardiography in Cryptogenic Stroke: Seeking Silent Atrial Fibrillation Mireia Ble 1,2, *, Begoña Benito 3,4 , Elisa Cuadrado-Godia 3,5 , Sílvia Pérez-Fernández 3,6 , Miquel Gómez 7 , Aleksandra Mas-Stachurska 2,3 , Helena Tizón-Marcos 2,3 , Lluis Molina 2,3,7 , Julio Martí-Almor 2,3 and Mercè Cladellas 1,2,3 1 Medicine Department, Universidad Autónoma de Barcelona, 08035 Barcelona, Spain; mcladellas@psmar.cat 2 Cardiology Department, Hospital del Mar, Parc de Salut Mar, 08003 Barcelona, Spain; amasstachurska@psmar.cat (A.M.-S.); HTizon@parcdesalutmar.cat (H.T.-M.); lmolina@psmar.cat (L.M.); JMarti@parcdesalutmar.cat (J.M.-A.) 3 Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain; b.benito.v@gmail.com (B.B.); ECuadrado@parcdesalutmar.cat (E.C.-G.); silvia_medina2712@hotmail.com (S.P.-F.) 4 Cardiology Department, Hospital Vall d’Hebron, 08035 Barcelona, Spain 5 Neurology Department, Hospital del Mar, Parc de Salut Mar, 08003 Barcelona, Spain 6 CIBER of Cardiovascular Diseases (CIBERCV), 08003 Barcelona, Spain 7 Cardiology Department, Hospital de Barcelona, 08034 Barcelona, Spain; miquelgomez@scias.com * Correspondence: mble@parcdesalutmar.cat; Tel.: +34-932-483-018   Abstract: Silent atrial fibrillation (AF) may be the cause of some cryptogenic strokes (CrS). The aim of the study was to analyse atrial size and function by speckle tracking echocardiography in Citation: Ble, M.; Benito, B.; CrS patients to detect atrial disease. Patients admitted to the hospital due to CrS were included Cuadrado-Godia, E.; Pérez- Fernández, S.; Gómez, M.; Mas- prospectively. Echocardiogram analysis included left atrial ejection fraction (LAEF) and atrial strain. Stachurska, A.; Tizón-Marcos, H.; Insertable cardiac monitor was implanted, and AF was defined as an episode of ≥1 min in the first Molina, L.; Martí-Almor, J.; Cladellas, year after stroke. Left atrial enlargement was defined as indexed volume > 34 mL/m2 . Seventy- M. Left Atrium Assessment by five consecutive patients were included, aged 76 ± 9 years (arterial hypertension 75%). AF was Speckle Tracking Echocardiography diagnosed in 49% of cases. The AF group had higher atrial volume and worse atrial function: peak in Cryptogenic Stroke: Seeking Silent atrial longitudinal strain (PALs) 19.6 ± 5.7% vs. 29.5 ± 7.2%, peak atrial contraction strain (PACs) Atrial Fibrillation. J. Clin. Med. 2021, 8.9 ± 3.9% vs. 16.5 ± 6%, LAEF 46.8 ± 11.5% vs. 60.6 ± 5.2%; p < 0.001. AF was diagnosed in 20 10, 3501. https://doi.org/10.3390/ of 53 patients with non-enlarged atrium, and in 18 of them, atrial dysfunction was present. The jcm10163501 multivariate logistic regression analysis demonstrated an independent association between detection of AF and atrial volume, LAEF, and strain. Cut-off values were obtained: LAEF < 55%, PALs < 21.4%, Academic Editor: Amir Jadidi and PACs < 12.9%. In conclusion, speckle tracking echocardiography in CrS patients improves silent Received: 8 July 2021 atrial disease diagnosis, with or without atrial enlargement. Accepted: 4 August 2021 Published: 9 August 2021 Keywords: atrial fibrillation; echocardiography; atrial strain; atrial disease; cryptogenic stroke Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Nowadays, stroke is one of the main causes of morbidity and mortality, leading to it being the second cause of death worldwide (World Health Organisation http://who.int/ home-page/index.es.shtml (accessed on 8 July 2021)). Despite new technologies and the carrying out of accurate diagnostic procedures, between 20 and 30% of ischemic strokes Copyright: © 2021 by the authors. are of unknown cause and currently are classified as being cryptogenic stroke (CrS) [1,2]. Licensee MDPI, Basel, Switzerland. Several mechanisms can lead to CrS and, among these, cardioembolic stroke due to silent This article is an open access article atrial fibrillation (AF) could be detected in up to 30% of cases [1,2]. distributed under the terms and Left atrium (LA) size is a strong predictor of cardioembolic stroke and AF [3,4]. conditions of the Creative Commons However, the presence of atrial enlargement in other diseases such as diastolic dysfunction Attribution (CC BY) license (https:// and arterial hypertension limits its interpretation to assess thromboembolic risk. Moreover, creativecommons.org/licenses/by/ it has been described that the paroxysmal AF can also be present with normal LA size [5]. 4.0/). J. Clin. Med. 2021, 10, 3501. https://doi.org/10.3390/jcm10163501 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 3501 2 of 10 Recently, speckle tracking echocardiography has been widely accepted as a novel technology for evaluating mechanics, function, and LA remodelling useful in the prediction of AF [6,7]. Previous studies have shown a significant association between decreased LA strain and stroke [8,9], even in patients with low-risk CHADS2 score ≤ 1 [10]. AF in CrS can appear as a paroxysmal and asymptomatic form, which leads to un- derdiagnosed cases [11,12]. This has important implications due to the lack of appropriate secondary stroke prevention with anticoagulation. In this regard, continuous electrocardio- graphic monitoring has been shown to be superior to the intermittent or short recordings for detecting AF [13,14]. In spite of the proven usefulness of all these echocardiographic parameters and prolonged monitoring to detect AF, there are no studies that have evaluated both techniques together in patients with CrS. For this reason, the main objective of the study was to evaluate prospectively atrial anatomy and function using speckle tracking echocardiography in patients with CrS and detection of silent AF by an insertable cardiac monitor. 2. Materials and Methods From October 2013 to September 2016, patients between 50 and 89 years old who were admitted to the Stroke Unit with CrS according to the SSS-TOAST criteria were prospectively included. Patients with permanent contraindication for oral anticoagulant treatment or indication for anticoagulation for other reasons, those whose life expectancy was lower than 1 year, and those with severe comorbidity or disabling stroke (modified Rankin scale > 4) were ruled out. CrS diagnosis was in accordance with clinical practice guidelines [15] when magnetic resonance angiography or angioCT displayed a non-lacunar brain infarct that excluded extracranial and intracranial arterial stenosis or occlusion due to atherosclerosis, vas- culitis, or dissection and ruling out a cardioembolic source. All patients underwent a comprehensive work-up during admission, including 12-lead ECG, transthoracic echocar- diography, brain computed tomography, blood test, and neurovascular imaging (mag- netic resonance angiography, angioCT, and/or 2D ultrasound of supra-aortic trunks and intracranial territory). 2.1. Patient Monitoring All patients were continuously ECG-monitored for at least 48 h and underwent implant of an insertable cardiac monitor before hospital discharge. AF was defined as an episode ≥ 1 min in the first year after the stroke. The device used was the Biomonitor-2 (Biotronik® ) that has specific algorithms for the detection of AF, defined by a variability of RR > 12.5%; bradycardia (<30 bpm), asystole (>3 s), and tachycardia events (>160 bpm) were also recorded, as well as episodes manually activated by the user in case of symptoms. The insertable cardiac monitor allows for reading and obtaining data daily by telematic message to the treating team (Biotronik Home Monitoring, HM). The insertable loop recorder was read and interpreted by cardiologists specialised in arrhythmias, without knowledge of echocardiographic results. 2.2. Echocardiographic Analysis of Atrial Anatomy and Function Standard 2D transthoracic echocardiogram was performed with General Electric Vivid E9 equipment (GE Healthcare Vingmed, Trodheim, Norway) that included anatomical and functional assessment of the left atrium. All patients were in sinus rhythm. Atrial size was assessed according to the recommendations for quantification of chambers [16] by different methods: anteroposterior diameter, biplanar area, and 2D biplanar volume. LA enlargement was considered when indexed volume was greater than 34 mL/m2 . The atrial function study included left atrial ejection fraction (LAEF) and speckle tracking. For the analysis of biplanar LAEF, we used the following formula: maximum vol- ume − minimum volume/maximum volume × 100. GE Q-analysis application was used J. Clin. Med. 2021, 10, x FOR PEER REVIEW 3 of 10 The atrial function study included left atrial ejection fraction (LAEF) and speckle J. Clin. Med. 2021, 10, 3501 3 of 10 tracking. For the analysis of biplanar LAEF, we used the following formula: maximum volume − minimum volume/maximum volume × 100. GE Q-analysis application was used to analyse the strain. Speckle tracking echocardiography is a technique that uses acoustic to analyse the back-scatter strain. Speckle (speckles) tracking generated echocardiography by the is a technique reflected ultrasound beam. The thatdisplacement uses acoustic of back-scatter (speckles) generated by the reflected ultrasound beam. this speckles is considered to follow myocardial movement and represents myocardialThe displacement of this speckles is considered to follow myocardial movement and represents deformation. LA endocardial surface is manually traced by a point-and-click approach in myocardial deformation. LA endocardial surface is manually traced by a point-and-click approach four-chamber view, between the mitral annulus to the opposite mitral annulus side and in four-chamber view, between the mitral annulus to the opposite mitral annulus side excluding pulmonary veins and LA appendage. An epicardial surface tracing is then au- and excluding pulmonary veins and LA appendage. An epicardial surface tracing is then tomatically generated by the system, thus creating a region of interest (ROI), and after automatically generated by the system, thus creating a region of interest (ROI), and after manual manualadjustment adjustmentof ofROI, ROI, width width the softwaredivides the software dividesinto intosix sixsegments. segments.Lastly, Lastly, thethe soft- soft- ware analyses and generates longitudinal strain curves for each segment ware analyses and generates longitudinal strain curves for each segment and a mean curve and a mean curve of allof all segments. segments. The speckle The speckle analysis analysis reflects reflects the pathophysiology the pathophysiology of the of the left left atrium: atrium: the the maximum maximum systolic systolic global global longitudinal longitudinal strain strain (PALs), (PALs), corresponding corresponding to theto the atrial atrial reser- reservoir voir phase, phase, andand thethe atrial atrial contraction contraction strain strain (PACs), (PACs), corresponding corresponding to the to the contractile contractile pumppump phase phase[17] [17](Figure (Figure 1). 1). The The frame ratewas frame rate wasmaintained maintainedatat a level a level > 50 > 50 frames/s, frames/s, andand onset onset of of theQRS the QRScomplex complexwaswas used used as a reference referencepoint point(R-R (R-Rgating). gating). Figure 1. Analysis Figure ofof 1. Analysis left leftatrial atrialmyocardial myocardial deformation by2D deformation by 2Dspeckle speckle tracking. tracking. (A)(A) Four-chamber Four-chamber (4CH) (4CH) apical apical longitudi- longitudinal nalstrain strainofof a patient without AF with normal strain and (B) a patient with AF and reduced strain. PALs: peak atrial a patient without AF with normal strain and (B) a patient with AF and reduced strain. PALs: peak atrial longitudinal longitudinal strain. PACs: peak atrial contraction strain. PACs: peak atrial contraction strain. strain. 2.3. 2.3.Clinical ClinicalFollow-Up Follow-Up AAclinical clinicalcontrol controlwas wascarried carriedoutoutininneurology neurologyand andcardiology cardiologyoutpatients outpatientsatat3,3,6,6, and 12and 12 months, months, together together with awith a daily daily telematic telematic follow-up. follow-up. In of In case case of detection detection of AF of by AFthe by thethe device, device, the was registry registry was checked, checked, and onceand the once the presence presence of AF was of confirmed, AF was confirmed, anticoagu- anticoagulation treatment lation treatment was started. was started. Afterthis After thisperiod, period, the the patients patients continued continuedwith withtheir theirtelematic telematicand standard and standardclinical clinical control in order to evaluate the recurrence of a new stroke and control in order to evaluate the recurrence of a new stroke and AF burden. AF burden. The study followed national and international guidelines (Declaration of Helsinki) and The study followed national and international guidelines (Declaration of Helsinki) was approved by the local ethical committee CEIC-Parc de Salut Mar (code 2013/5055/I). and was approved by the local ethical committee CEIC-Parc de Salut Mar (code All patients signed the informed consent form. 2013/5055/I). All patients signed the informed consent form. 2.4. Statistical Analysis 2.4. Statistical Analysisvariables were checked to follow a normal distribution using the The numerical The numerical Shapiro–Wilk variablestests, and QQ-Plots wereandchecked to follow their values a normal as are presented distribution using the mean ± standard Shapiro–Wilk and QQ-Plots deviation. Categorical tests, variables areand their values expressed are presented by frequency as mean ±Differences and percentages. standard de- between viation. the two groups, Categorical withare variables or without AF, by expressed were evaluatedand frequency using the chi-squared percentages. test Differences or Fisher’s test for categorical variables and Student’s t-test for independent between the two groups, with or without AF, were evaluated using the chi-squared samples fortest continuous variables. J. Clin. Med. 2021, 10, 3501 4 of 10 Multivariate logistic regression analysis adjusted for age and sex was performed in several models. It included the variables indexed 2D volume, LAEF, PALs, and PACs in order to detect the association between them and the presence of AF in all patients. The area under the curve (AUC) of the receiver operating characteristic (ROC) analysis is presented for each model. To obtain the best cut-off points that discriminate the patients with the highest probability of presenting AF, we used bootstrapping analysis (with 1000 repetitions) for each of the following variables: indexed 2D volume, LAEF, PALs, and PACs, defined as the median of all points and the 2.5 and 97.5 percentiles as the confidence interval. A value of p < 0.05 was considered statistically significant. Statistical software R version 3.4.2 (R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria) was used. 3. Results 3.1. Demographic Characteristics and Atrial Fibrillation During the study period, a total of 530 ischemic stroke patients between 50 and 89 years of age were seen at our hospital. After complete work-up during hospital stay, 80 patients were diagnosed with a cryptogenic stroke and met the eligibility criteria to participate in the study. During follow-up, five patients were ruled out for several reasons: complex aortic atherosclerotic plaques (n = 1), structural heart disease in echocardiogram (n = 2), or refusing insertable cardiac monitor (n = 2). Finally, the study group consisted of 75 patients with a mean age of 76 ± 9 years (56% male). AF was detected in 37 (49%) patients during follow-up. The rate of AF detection after the stroke was 16 (21%) from implantation to 3 months, 11 (15%) at 6 months, and 10 (13%) at 12 months. Initially, the AF was paroxysmal, but during the study follow up, AF recurrence was detected in 20 cases (temporal range from 2 min to 3 h), and AF became permanent in 11 cases. No significant differences in demographic characteristics or risk factors were observed between patients with or without AF, with the exception of more advanced age in the group with AF (78 vs. 73 years, p = 0.047) (Table 1). Table 1. Clinical characteristics and echocardiographic parameters of patients with or without atrial fibrillation. Non AF (n = 38) AF (n = 37) p Age 73.4 ± 9.7 77.6 ± 8.3 0.047 Gender (male) 23 (60.5%) 19 (51.4%) 0.570 Arterial hypertension 29 (76.3%) 28 (75.7%) 1.000 Diabetes 8 (21.1%) 9 (24.3%) 0.950 Dyslipidemia 21 (55.3%) 19 (51.4%) 0.914 Body mass index (kg/m2 ) 27 ± 4.14 28.1 ± 5.08 0.310 Glomerular filtration rate (mL/min) 76.4 ± 22.2 70.3 ± 26.2 0.286 Coronary artery disease 1 (2.63%) 3 (8.11%) 0.358 Lung disease 5 (13.2%) 4 (10.8%) 1.000 Previous stroke 6 (15.8%) 7 (18.9%) 0.958 CHA2 DS2 -VASc score 4.79 ± 1.43 5.22 ± 1.20 0.167 Echocardiogram LVEF (%) 63.2 ± 3.85 63.2 ± 2.83 0.996 LV mass (g) 172 ± 39.5 173 ± 56.3 0.924 Indexed LV mass (g/m2 ) 96.9 ± 19.6 98.1 ± 29.1 0.827 LA diameter (mm) 35 ± 4.03 38.5 ± 4.82 <0.001 LA area (cm2 ) 16.8 ± 2.55 19.8 ± 3.58 <0.001 2D LA volume (mL) 47.9 ± 12.5 60.8 ± 16.2 <0.001 Indexed 2D LA volume (mL/m2 ) 27 ± 6.49 34.7 ± 9.77 <0.001 J. Clin. Med. 2021, 10, 3501 5 of 10 Table 1. Cont. Non AF (n = 38) AF (n = 37) p Enlarged LA (>34 mL/m2 ) 5 (13%) 17 (46%) Normal LA volume 33 (87%) 20 (54%) 0.002 2D LAEF (%) 60.6 ± 5.2 46.8 ± 11.5 <0.001 PALs (%) 29.5 ± 7.24 19.6 ± 5.73 <0.001 PACs (%) 16.5 ± 6 8.99 ± 3.92 <0.001 LV: left ventricular; EF: ejection fraction; LA: left atrial. The mean follow-up was carried out for 58.5 months (interquartile range: 50.1–65.2). Patients diagnosed with AF and under anticoagulation treatment did not have any neuro- logical ischemic event. On the other hand, of the group of patients who remained in sinus rhythm during the initial 12 months, only one patient was admitted for stroke together with the onset of AF at 13 months. 3.2. Atrial Characteristics and AF Detection On univariate analysis, the biplanar area, the anteroposterior diameter, and the 2D atrial volume were higher in the group of patients with AF compared to the group without AF (p < 0.001). Likewise, the group of patients with AF showed impairment of LA contrac- tile function with worse LAEF (46.8 ± 11.5% vs. 60.6 ± 5.2%, p < 0.001), reduced reservoir function (PALs: 19.6 ± 5.7% vs. 29.5 ± 7.2%, p < 0.001), and lower LA contraction (PACs: 8.9 ± 3.9% vs. 16.5 ± 6%, p < 0.001) (Table 1). Multivariate logistic regression analysis adjusted for age and sex (Table 2) showed that LA volume or LAEF, as well as reservoir function (PALs) or atrial contraction (PACs), were associated with the detection of AF in patients with CrS. ROC curves analyses of these echocardiographic parameters showed a good sensitivity and specificity for detection of AF (Figure 2). After these results, bootstrapping analysis was performed to determine the optimal cut-off value of LA function parameters associated with AF (see Figure S1 in Supplementary Materials). These optimal thresholds related to AF were LAEF < 55%, PALs < 21.4%, and PACs < 12.9%. Table 2. Multivariate logistic regression analysis models to detect atrial fibrillation after a cryptogenic stroke. OR IC 95% p Model 1 Age 1.04 0.98–1.11 0.216 Men 1.40 0.47–4.15 0.546 Left atrial volume 1.13 1.05–1.21 0.001 Model 2 Age 1.04 0.96–1.12 0.342 Men 0.63 0.16–2.41 0.627 LAEF 0.80 0.72–0.89 <0.001 Model 3 Age 1.01 0.94–1.09 0.783 Men 1.90 0.47–7.71 0.370 PALs 0.80 0.71–0.84 <0.001 Left atrial volume 1.12 1.02–1.23 0.013 Model 4 Age 1.05 0.97–1.13 0.223 Men 1.69 0.44–6.48 0.446 PACs 0.72 0.59–0.87 0.001 Left atrial volume 1.10 1.00–1.20 0.057 LAEF: left atrial ejection fraction; PALs: peak atrial longitudinal strain; PACs: peak atrial contraction strain. J. Clin. Med. 2021, 10, x FOR PEER REVIEW 6 of 10 J. Clin. Med. 2021, 10, 3501 6 of 10 LAEF: left atrial ejection fraction; PALs: peak atrial longitudinal strain; PACs: peak atrial contrac- tion strain. 2. Results FigureFigure of receiver-operating 2. Results characteristic of receiver-operating characteristic curve analysisfor curve analysis forpredicting predicting silent silent AFallinpatients AF in all patients afterAUC: after CrS. CrS. AUC: area under area under the curve. the curve. 3.3.3.3. AtrialFibrillation Atrial Fibrillation Burden Burden and andNormal Normaloror Enlarged LeftLeft Enlarged Atrium Atrium AsAs shown in Figure 3, 22 of the 75 (29%) patients had enlarged LA, and in 17 (77%) shown in Figure 3, 22 of the 75 (29%) patients had enlarged LA, and in 17 (77%) of of them, AF was detected: paroxysmal AF in 10 and permanent in 7 cases. Furthermore, them, AF was detected: paroxysmal AF in 10 and permanent in 7 cases. Furthermore, in in 53 patients with normal LA volume, AF also presented in 20 (38%). Despite normal 53 atrial patients with normal LA volume, AF also presented in 20 (38%). Despite normal atrial size, myocardial LA strain analysis or LAEF detected the presence of atrial dysfunc- size, myocardial LA strain tion in 29 patients, and inanalysis 18 (62%)orofLAEF them,detected the presence AF was diagnosed: of atrial dysfunction paroxysmal—14 and in 29 patients, and in 18 (62%) of them, AF was diagnosed: paroxysmal—14 and permanent— 4. In contrast, in 24 patients with normal atrial size and function, AF was only diagnosed in two (8%, p < 0.001) cases, both paroxysmal. J. Clin. Med. 2021, 10, x FOR PEER REVIEW 7 of 10 J. Clin. Med. 2021, 10, 3501 7 of 10 permanent—4. In contrast, in 24 patients with normal atrial size and function, AF was only diagnosed in two (8%, p < 0.001) cases, both paroxysmal. Figure3.3.Tree Figure Treediagram diagramshowing showingresults resultsofofechocardiographic echocardiographicparameters parametersaccording accordingtotowhether whetherleft left atrium was or was not enlarged. atrium was or was not enlarged. 4.4.Discussion Discussion The Theresults resultsfrom fromour ourstudy studydemonstrate demonstratethe thevalue valueofofechocardiogram echocardiogramfor fordetection detectionofof atrial atrialdisease diseaseinin the thesetting setting of of CrSCrSusing usingcombined combined analysis of size analysis and and of size atrialatrial function by 2D function by speckle tracking. 2D speckle Moreover, tracking. echocardiographic Moreover, echocardiographic cut-off pointspoints cut-off were were obtained in association obtained in associ- with ationAF after with AF CrS, with after CrS,orwith without LA enlargement. or without LA enlargement. Atrial Atrial remodelling represents an alterationininatrial remodelling represents an alteration atrialsize sizeand andfunction functionsecondary secondarytoto cellular cellular changes in the atrial tissue. Clinical observations suggest that severalrisk changes in the atrial tissue. Clinical observations suggest that several riskfactors factors such suchas asadvanced advanced age, age, arterial hypertension, and arterial hypertension, and diabetes diabetesmellitus mellitusmay maylead leadtoto atrial atrial re- remodelling modelling with withthe thedevelopment development of of interstitial interstitial fibrosis fibrosis and andincreased increasedatrial atrialvolume volume[18,19]. [18,19]. InInclinical clinicalpractice, practice,these theseparameters parameterscan canbe beassessed assessedby byusing usingimaging imagingtechniques techniques[20,21]. [20,21]. InInparticular, particular, the degree of atrial fibrosis is inversely correlated with the valueofofthe the degree of atrial fibrosis is inversely correlated with the value thestrain strain bybyechocardiography, echocardiography,a afact factconfirmed confirmedininhistological histologicalstudies studies[22]. [22]. Previous Previousstudies studieshavehavedemonstrated demonstratedthat thatLALAenlargement enlargementby byechocardiography echocardiographyisisa a strong strong predictor of AF [23]. However, the functional remodelling evaluatedby predictor of AF [23]. However, the functional remodelling evaluated byreducing reducing myocardial deformation has been shown to be more sensitive myocardial deformation has been shown to be more sensitive in detecting subclinical in detecting subclinical atrial atrialdysfunction dysfunctionthan thanatrial atrialenlargement enlargement[24–26]. [24–26].InInthis thisregard, regard,retrospective retrospectivestudiesstudies performed in CrS have shown that speckle tracking echocardiography performed in CrS have shown that speckle tracking echocardiography improved improved thethe di- diagnostic accuracy of AF in slightly enlarged atria [27,28]. These agnostic accuracy of AF in slightly enlarged atria [27,28]. These findings have been findings have been con- confirmed in the present study by multivariable regression: LA strain and LAEF showed firmed in the present study by multivariable regression: LA strain and LAEF showed an an independent association with AF (Table 2). The area under the ROC curve (AUC) of LA independent association with AF (Table 2). The area under the ROC curve (AUC) of LA volume taken alone was weaker at predicting AF than volume and atrial strain together, volume taken alone was weaker at predicting AF than volume and atrial strain together, as shown in Figure 2. Kusunose et al demonstrated LA strain prediction value of AF in as shown in Figure 2. Kusunose et al demonstrated LA strain prediction value of AF in embolic stroke of undetermined source but without insertable loop recorder [29]. embolic stroke of undetermined source but without insertable loop recorder [29]. Furthermore, the optimal cut-off points obtained to predict AF were determined by bootstrapping analysis: LAEF < 55%, PALs < 21.4%, and PACs < 12.9%. Similar results have been reported in other contexts, such as predicting recurrence of AF after catheter ablation [30]. Silent AF was diagnosed in 38% (20 of 53) of patients with normal LA size, J. Clin. Med. 2021, 10, 3501 8 of 10 and myocardial analysis detected the presence of LA dysfunction in 29 patients; of them, in 18 (62%), AF was detected, 14—paroxysmal, and 4—permanent (Figure 3). In contrast, in 24 patients with normal atrial size and function, AF was only diagnosed in two (18%) patients. These results confirm previous findings described by Pagola et al. [5], who found AF in 86% of CrS patients with normal LA size and decreased LA strain in 33%. These outcomes show the importance of routine atrial function assessment in clinical practice to better understand mechanisms of thrombogenesis after CrS due to the prognostic implications that it entails. Atrial hypocontractility results in abnormal stasis of blood within the atrium, supporting the emerging concept of atrial cardiomyopathy as a cause of stroke [31]. In the present study, patients who presented AF and were treated with oral anticoagulants, despite the recurrence of the arrhythmia, did not have another stroke. Our results highlight a higher incidence of AF (49%) than that published in the literature [32]. This disagreement with previous reports may be due to different facts. Risk of AF increases exponentially with age, because AF is a disease of older adults and is usually associated with multiple comorbidities [33]. In our study, the mean age group was 76 years old, and 75% had arterial hypertension. In addition, the patients who presented AF were older than those without arrhythmia (78 vs. 73 years, p = 0.047). In most of the studies with CrS, the age of population included was usually under 70 years. On the other hand, continuous monitoring with an insertable cardiac monitor prior to hospital discharge allowed the diagnosis of 21% of AF during the first 3 months. In the CRYSTAL AF study [34], the inclusion of patients was carried out up to 90 days post-stroke, and the mean age of the patients was 61 years. In the SURPRISE study [35], the implantation of the insertable cardiac monitor was also long after the CrS (median of 69 days) and the study population was younger than ours. Moreover, a recent study has shown that the diagnosis of AF by using an insertable cardiac monitor compared to conventional strategy increased AF detection after CrS [36]. The limitations of our study require mention. Our study was carried out in a single centre with a small number of patients, although similar to that of previously published reports in the literature [37]. Future studies in a greater population should confirm our findings; in particular, the values of myocardial deformation, as a consequence of their variability. AF guidelines [38] define clinical AF as lasting at least 30 s; although the AF burden related outcomes are not clear, we consider the definition of ≥1 min’s duration, given that this cut-off value showed prognostic implications in a previous study after CrS [36]. 5. Conclusions Speckle tracking echocardiography is an extremely useful technique to improve the diagnosis of atrial disease in cryptogenic stroke. It could be of great assistance in stratifying the thromboembolic risk, especially in elderly patients with or without atrial enlargement. Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/jcm10163501/s1. Figure S1: Bootstrapping analysis graphs for the echocardiographic parame- ters analysed: left atrial ejection fraction (LAEF), peak atrial longitudinal strain (PALs), and peak atrial contraction strain (PACs). Author Contributions: Methodology, B.B., E.C.-G., M.C., M.B.; formal analysis, S.P.-F., M.C., M.B.; investigation, M.C., M.B.; image acquisition, M.C., M.B., M.G., A.M.-S., L.M.; writing—original draft preparation, M.C., M.B.; writing—review and editing, M.C., M.B.; resources H.T.-M., L.M., J.M.-A., B.B. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Instituto de Salud Carlos III-FIS (Fondo de Investigación Sanitaria, PI13/01830). Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of CEIC-Parc de Salut Mar. J. Clin. Med. 2021, 10, 3501 9 of 10 Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. References 1. Saver, J.L. Cryptogenic Stroke. N. Engl. J. Med. 2016, 374, 2065–2074. [CrossRef] 2. Hart, R.G.; Diener, H.-C.; Coutts, S.B.; Easton, J.D.; Granger, C.B.; O’Donnell, M.; Sacco, R.L.; Connolly, S.J. Embolic strokes of undetermined source: The case for a new clinical construct. Lancet Neurol. 2014, 13, 429–438. [CrossRef] 3. 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