The Modified Risk of Paradoxical Embolism Score Is Associated with Patent Foramen Ovale in Patients with Ischemic Stroke: A Nationwide US Analysis.

BACKGROUND: The Risk of Paradoxical Embolism (RoPE) score was developed to identify stroke-related patent foramen ovale (PFO) in patients with cryptogenic stroke. METHODS: We conducted a retrospective analysis of the 2016 to 2020 National Inpatient Sample to determine the performance of the modified RoPE score in identifying the presence of a PFO in patients with acute ischemic stroke (AIS). RESULTS: A total of 3,338,805 hospital admissions for AIS were analysed and 3.0% had PFO. Patients with PFO were younger compared to those without a PFO (median 63 years vs. 71 years, p < 0.001) and fewer were female (46.1% vs. 49.7%, p < 0.001). The patients with PFO had greater mean modified RoPE scores (4.0 vs. 3.3, p < 0.001). The area under the curve for the RoPE score in predicting PFOs was 0.625 (95%CI 0.620-0.629). The best diagnostic power of the RoPE score was achieved with a cut-off point of ≥4 where the sensitivity was 55% and the specificity was 64.2%. A cut-off point of ≥5 increased the specificity (83.1%) at the expense of sensitivity (35.8%). The strongest predictor of PFOs was deep vein thrombosis (OR 3.97, 95%CI 3.76-4.20). CONCLUSIONS: The modified RoPE score had modest predictive value in identifying patients with PFO among patients admitted with AIS.

The Usefulness of Outpatient Cardiac Telemetry in Patients with Cryptogenic Stroke.

Introduction: Atrial fibrillation (AF), apart from non-stenotic supracardiac atherosclerosis and neoplastic disease, is the leading cause of cryptogenic stroke, including embolic stroke of un-determined source (ESUS). The aim of our study was to determine the prevalence of AF in ESUS patients based on 30-day telemetric heart rate monitoring initiated within three months after stroke onset. Another aim was to identify factors that increase the likelihood of detecting subsequent AF among ESUS patients. Material and Methods: patients with first-ever stroke classified as per the ESUS definition were eligible for this study. All patients underwent outpatient 30-day telemetric heart rate monitoring. Results: In the period between 2020 and 2022, 145 patients were included. The mean age of all qualified patients was 54; 40% of eligible patients were female. Six patients (4.14%), mostly male patients (4 vs. 2), were diagnosed with AF within the study period. In each case, the diagnosis related to a patient whose stroke occurred in the course of large vessel occlusion. Episodes of AF were detected between day 1 and 25 after starting ECG monitoring. Out of the analyzed parameters that increase the probability of, A.F.; only supraventricular extrasystoles proved to be an independent factor regarding an increased risk of AF [OR 1.046, CI 95% 1.016-1.071, p-value < 0.01]. Conclusions: The use of telemetry heart rhythm monitoring in an outpatient setting can detect AF in 4% of ESUS patients who have undergone prior diagnostic procedures for cardiogenic embolism. Supraventricular extrasystoles significantly increases the likelihood of AF detection in patients with ESUS within three months following stroke. Comorbid coronary artery disease, diabetes and hypertension, rather than a single-factor clinical burden, increase the likelihood of AF detection in older ESUS patients. ESUS in the course of large vessel occlusion is probably associated with an increased likelihood of cardiogenic embolism.

Predictors of Paroxysmal Atrial Fibrillation in Patients With a Cryptogenic Stroke: Selecting Patients for Long-Term Rhythm Monitoring.

BACKGROUND: After a cryptogenic stroke, patients will often require prolonged cardiac monitoring; however, the subset of patients who would benefit from long-term rhythm monitoring is not clearly defined. OBJECTIVE: Using significant predictors of AF using age, sex, comorbidities, baseline 12-lead electrocardiogram, short term rhythm monitoring and echocardiogram data, we created a risk score and compared it to previously published risk scores. METHODS: Patients admitted to Montefiore Medical Center between May 2017 and June 2022 with a primary diagnosis of cryptogenic stroke or TIA who underwent long-term rhythm monitoring with an implantable cardiac monitor were retrospectively analyzed. RESULTS: Variables positively associated with a diagnosis of clinically significant atrial fibrillation include age (p < 0.001), race (p = 0.022), diabetes status (p = 0.026), and COPD status (p = 0.012), the presence of atrial runs (p = 0.003), the number of atrial runs per 24 hours (p < 0.001), the total number of atrial run beats per 24 hours (p < 0.001) and the number of beats in the longest atrial run (p < 0.001), LA enlargement (p = 0.007) and at least mild mitral regurgitation (p = 0.009). We created a risk stratification score for our population, termed the "ACL score." The ACL score demonstrated superiority to the CHA2DS2-VASc score and comparability to the C2HEST score for predicting device-detected AF. CONCLUSION: The ACL score enables clinicians to better predict which patients are more likely to be diagnosed with device-detected AF after a cryptogenic stroke.

Multikingdom oral microbiome interactions in early-onset cryptogenic ischemic stroke.

Although knowledge of the role of the oral microbiome in ischemic stroke is steadily increasing, little is known about the multikingdom microbiota interactions and their consequences. We enrolled participants from a prospective multicentre case-control study and investigated multikingdom microbiome differences using saliva metagenomic datasets (n = 308) from young patients diagnosed with cryptogenic ischemic stroke (CIS) and age- and sex-matched stroke-free controls. Differentially abundant taxa were identified using Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC2). Functional potential was inferred using HUMANn3. Our findings revealed significant differences in the composition and functional capacity of the oral microbiota associated with CIS. We identified 51 microbial species, including 47 bacterial, 3 viral, and one fungal species associated with CIS in the adjusted model. Co-abundance network analysis highlighted a more intricate microbial network in CIS patients, indicating potential interactions and co-occurrence patterns among microbial species across kingdoms. The results of our metagenomic analysis reflect the complexity of the oral microbiome, with high diversity and multikingdom interactions, which may play a role in health and disease.

Impact of frailty index on cardiovascular outcomes and readmissions of patent foramen ovale closure procedure: a propensity matched national analysis.

BACKGROUND: Transcatheter patent foramen ovale (PFO) occluder device is a procedure mostly performed to prevent secondary stroke as a result of paradoxical emboli traversing an intracardiac defect into the systemic circulation. The complications and outcomes following the procedure remain poorly studied. We aimed to investigate morbidity and mortality associated with occluder device procedures using hospital frailty index score stratification. METHODS: The Nationwide Readmission Database was employed to identify patients admitted for PFO closure from 2016 to 2020. Two groups divided by index frailty score were compared to report adjusted odds ratio (aOR) for primary and secondary cardiovascular outcomes. Outcomes included in-hospital mortality, acute kidney injury, acute ischemic stroke, and post-procedure bleeding. Statistical analysis was performed using STATA v.17. RESULTS: Of the 2,063 total patients who underwent the procedure, 45% possessed intermediate to high frailty scores while the other 55% had low frailty scores. The first cohort had higher odds of in-hospital mortality (aOR 6.3, 95% CI 2.05-19.5), acute kidney injury (aOR 17.6, 95% CI 9.5-32.5), and stroke (aOR 3.05, 95% CI 1.5-5.8) than the second cohort. There was no difference in the incidence of post-procedural bleeding and cardiac tamponade and 30/90/180-day readmission rates between the two cohorts. Hospitalizations in the first cohort were associated with a higher median length of stay and total cost. CONCLUSION: High to intermediate frailty scores may predict an increased risk of in-hospital mortality in patients undergoing PFO occluder device procedures.

Recurrent Small Bowel Obstruction Related to Cryptogenic Multifocal Ulcerating Stenosing Enteropathy.

Cryptogenic multifocal ulcerating stenosing enteropathy is a rare idiopathic small bowel enteropathy characterized by multiple small intestinal strictures and superficial ulcerations, often with clubbing. We present a case of a 25-year-old man who originally initially presented with small bowel obstruction believed to be secondary to suspected Crohn's disease who was ultimately diagnosed with cryptogenic multifocal ulcerating stenosing enteropathy.

Direct oral anticoagulants in embolic stroke of undetermined source: an updated meta-analysis.

The efficacy and safety of direct oral anticoagulants (DOAC) in patients with embolic stroke of undetermined source (ESUS) remains unclear. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCT) comparing DOACs versus aspirin in patients with ESUS. Risk ratios (RR) and 95% confidence intervals (CI) were computed for binary endpoints. Four RCTs comprising 13,970 patients were included. Compared with aspirin, DOACs showed no significant reduction of recurrent stroke (RR 0.95; 95% CI 0.84-1.09; p = 0.50; I2 = 0%), ischemic stroke or systemic embolism (RR 0.97; 95% CI 0.80-1.17; p = 0.72; I2 = 0%), ischemic stroke (RR 0.92; 95% CI 0.79-1.06; p = 0.23; I2 = 0%), and all-cause mortality (RR 1.11; 95% CI 0.87-1.42; p = 0.39; I2 = 0%). DOACs increased the risk of clinically relevant non-major bleeding (CRNB) (RR 1.52; 95% CI 1.20-1.93; p < 0.01; I2 = 7%) compared with aspirin, while no significant difference was observed in major bleeding between groups (RR 1.57; 95% CI 0.87-2.83; p = 0.14; I2 = 63%). In a subanalysis of patients with non-major risk factors for cardioembolism, there is no difference in recurrent stroke (RR 0.98; 95% CI 0.67-1.42; p = 0.90; I2 = 0%), all-cause mortality (RR 1.24; 95% CI 0.58-2.66; p = 0.57; I2 = 0%), and major bleeding (RR 1.00, 95% CI 0.32-3.08; p = 1.00; I2 = 0%) between groups. In patients with ESUS, DOACs did not reduce the risk of recurrent stroke, ischemic stroke or systemic embolism, or all-cause mortality. Although there was a significant increase in clinically relevant non-major bleeding, major bleeding was similar between DOACs and aspirin.

Diagnostic Utility of N-Terminal Pro-B-Type Natriuretic Peptide in Identifying Atrial Fibrillation Post-Cryptogenic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) significantly contributes to acute ischemic stroke, with undetected AF being a common culprit in cryptogenic strokes. N-terminal pro-B-type natriuretic peptide (NT-proBNP), indicative of myocardial stress, has been proposed as a biomarker for AF detection, aiding in the selection of patients for extended cardiac monitoring. However, the diagnostic accuracy of NT-proBNP remains uncertain. METHODS: We conducted a meta-analysis to evaluate the diagnostic accuracy of NT-proBNP in detecting AF among cryptogenic stroke patients. A comprehensive literature search was conducted across PubMed, Embase, and Cochrane databases to identify relevant studies. Studies reporting NT-proBNP levels in stroke patients and data on the proportion of patients with AF above a specified cut-off were included. Meta-analyses were performed using the midas command in STATA. RESULTS: Seven studies encompassing 2171 patients were included in the analysis, of which five studies contained cohorts with cryptogenic strokes. Among patients with cryptogenic stroke, NT-proBNP demonstrated a diagnostic accuracy of 80% (Area Under the Receiver Operating Curve 0.80 [95% CI 0.76-0.83]), with a sensitivity of 81% (95% CI 0.68-0.89) and a specificity of 68% (95% CI 0.60-0.75). CONCLUSION: Our meta-analysis indicates that NT-proBNP exhibits a good-to-very-good diagnostic accuracy for detecting AF in patients with cryptogenic stroke. These findings suggest potential implications for utilizing NT-proBNP in guiding the selection of patients for prolonged cardiac monitoring, thereby aiding in the management of cryptogenic stroke cases.

Morphological Features of Patent Foramen Ovale Compared Between Older and Young Patients With Cryptogenic Ischemic Stroke.

BACKGROUND: The morphology of a patent foramen ovale (PFO) with a high-risk for cryptogenic ischemic stroke (CS) is an important factor in the selection of patients for transcatheter closure, but the morphological features of PFO in older patients with a history of CS are less known because the most data are obtained from younger patients.Methods and Results: The study included 169 patients who had a history of CS and PFO. The prevalence of high-risk morphologies of PFO assessed by transesophageal echocardiography was compared between patients aged ≥60 years and patients aged <60 years. We also assessed the presence of septal malalignment of PFO on the aortic wall. The probability of CS due to PFO was evaluated using the PFO-Associated Stroke Causal Likelihood classification system. Patients aged ≥60 years had a significantly higher prevalence of atrial septal aneurysm than patients aged <60 years. The prevalence of large right-to-left shunt, long-tunnel of PFO, or Eustachian valve or Chiari's network was similar between patients aged ≥60 years and <60 years. Septal malalignment was observed more frequently in patients aged ≥60 years than in those <60 years old. Nearly 90% of patients aged ≥60 years were classified as 'possible' in the PFO-Associated Stroke Causal Likelihood classification system. CONCLUSIONS: High-risk morphologies of PFO are common in older patients with a history of CS, as well as in younger patients.

Device Closure or Antithrombotic Therapy After Cryptogenic Stroke in Elderly Patients With a High-Risk Patent Foramen Ovale.

BACKGROUND AND PURPOSE: In young patients (aged 18-60 years) with patent foramen ovale (PFO)-associated stroke, percutaneous closure has been found to be useful for preventing recurrent ischemic stroke or transient ischemic attack (TIA). However, it remains unknown whether PFO closure is also beneficial in older patients. METHODS: Patients aged ≥60 years who had a cryptogenic stroke and PFO from ten hospitals in South Korea were included. The effect of PFO closure plus medical therapy over medical therapy alone was assessed by a propensity-score matching method in the overall cohort and in those with a high-risk PFO, characterized by the presence of an atrial septal aneurysm or a large shunt. RESULTS: Out of the 437 patients (mean age, 68.1), 303 (69%) had a high-risk PFO and 161 (37%) patients underwent PFO closure. Over a median follow-up of 3.9 years, recurrent ischemic stroke or TIA developed in 64 (14.6%) patients. In the propensity score-matched cohort of the overall patients (130 pairs), PFO closure was associated with a significantly lower risk of a composite of ischemic stroke or TIA (hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.24-0.84; P=0.012), but not for ischemic stroke. In a subgroup analysis of confined to the high-risk PFO patients (116 pairs), PFO closure was associated with significantly lower risks of both the composite of ischemic stroke or TIA (HR: 0.40; 95% CI: 0.21-0.77; P=0.006) and ischemic stroke (HR: 0.47; 95% CI: 0.23-0.95; P=0.035). CONCLUSION: Elderly patients with cryptogenic stroke and PFO have a high recurrence rate of ischemic stroke or TIA, which may be significantly reduced by device closure.

Microcephaly type 22 and autism spectrum disorder: A case report and review of literature.

INTRODUCTION: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a multifaceted etiology. This case report explores the ischemic cryptogenic vascular dissection as a potential underlying cause of ASD. METHODS: A 9-year-old child presented with symptoms of ASD, including social interaction difficulties, repetitive behaviors, and cognitive challenges. Despite conventional ASD treatments, significant improvement was only observed after addressing an underlying ischemic cryptogenic vascular dissection identified through DCE-CT. RESULTS: Following a reconstructive treatment approach to the vascular dissection, the patient showed marked improvement in cognitive functions, social abilities, and a reduction in ASD-related symptoms whether during the perioperative period or during approximately 5-month follow-up. CONCLUSION: This case suggests that ischemic cryptogenic vascular dissection may contribute to the symptoms of ASD. Identifying and treating underlying vascular anomalies may offer a new avenue for mitigating ASD symptoms, emphasizing the need for comprehensive diagnostic estimations in ASD management.

Transcatheter PFO closure for cryptogenic stroke: current approaches and future considerations.

Patent Foramen Ovale (PFO) is a common congenital atrial septal defect present in 20%-35% of the general population. Although generally considered a benign anatomic variant, a PFO may facilitate passage of a thrombus from the venous to arterial circulation, thereby resulting in cryptogenic stroke or systemic embolization. A PFO is detected in nearly one half of patients presenting with cryptogenic stroke and often considered the most likely etiology when other causes have been excluded. In this review, we discuss the contemporary role of transcatheter closure of PFO in the treatment of cryptogenic stroke, including devices currently available for commercial use in the United States (Amplatzer PFOTM Occluder and GoreTM Cardioform Septal Occluder) and a novel suture-mediated device (NobleStitchTM EL) under clinical investigation. To provide the best care for cryptogenic stroke patients, practitioners should be familiar with the indications for PFO closure and corresponding treatment options.

Discrimination of pediatric cryptogenic multifocal ulcerous stenosing enteritis from small bowel Crohn's disease and gastrointestinal tuberculosis: A retrospective study (with videos).

INTRODUCTION: Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is a rare entity that mimics various inflammatory strictures of the small intestine. Pediatric literature is scarce. We analyzed the clinical, radiological, endoscopic and histopathological features of children with CMUSE that differentiate it from small bowel Crohn's disease (SBCD) and gastrointestinal tuberculosis (GITB). METHODS: CMUSE was diagnosed by the following criteria: (1) unexplained small bowel strictures with superficial ulcers, (2) chronic/relapsing ulcers of small bowel after resection, (3) no signs of systemic inflammation, (4) absence of other known etiologies of small bowel ulcers. SBCD and GITB were diagnosed based on standard criteria. The clinical features, laboratory parameters, radioimaging, endoscopy (including video capsule endoscopy [VCE], intra-operative endoscopy), histopathological features and treatment outcome were noted. RESULTS: Out of 48, CMUSE was diagnosed in 13 (27%) isolated small bowel and ileocecal strictures, while GITB and SBCD accounted for 41% and 21% cases, respectively. Common presentations were sub-acute obstruction (46%), obscure gastrointestinal bleeding (38%) and protein-losing enteropathy (38%). CMUSE patients had significantly longer disease duration compared to SBCD and GITB (p < 0.001). SBCD (90.0%) and GITB (85%) cases had elevated C-reactive protein (CRP), none with CMUSE had elevated CRP (p < 0.001). The disease was localized in jejunum (100%) and proximal ileum (56%) in CMUSE, ileocecal region (85%) in GITB, but evenly distributed in small intestine in SBCD. Endoscopy showed evenly placed, superficial, circumferential ulcers with strictures in CMUSE, deep linear ulcers in SBCD and circumferential ulcers in GITB. Upfront immunosuppression was given in four; three (75%) of them relapsed. Only surgery was done in three with one (25%) having relapse. Upfront surgery followed by immunosuppression was used in six, but all relapsed and two required repeat surgery. CONCLUSION: CMUSE is important but underdiagnosed in children. Lack of constitutional symptoms, normal inflammatory parameters and characteristic ulcers with strictures helped in differentiating CMUSE from GITB and SBCD.

Imaging features for the identification of atrial fibrillation in cryptogenic stroke patients.

BACKGROUND: Whether specific imaging aspects can be used to identify cryptogenic stroke (CS) patients with high risk of underlying atrial fibrillation (AF) remains unclear. The purpose of this study was to evaluate brain-imaging features in CS patients and their utility as AF predictors. METHODS: The Nordic Atrial Fibrillation and Stroke study was a prospective observational study of CS and transient ischemic attack patients undergoing 12-month cardiac-rhythm monitoring, biomarker and clinical assessments. In this imaging sub-study, brain magnetic resonance imaging and computed tomography scans from 106 patients were assessed for acute and chronic ischemic lesions in relation to AF occurrence and included in a score to predict AF. Receiver operating characteristics (ROC) curve was used to evaluate the discriminative ability of the score and for its dichotomization for predictive model. RESULTS: Age, periventricular white-matter hyperintensities (PVWMH), acute lesion size, and vessel occlusion were significantly associated with AF. Acute and chronic cortical infarcts as well as chronic cerebellar infarcts were numerically more frequent in the AF group than the non-AF group. A score consisting of six features (0-6 points) was proposed (age ≥ 65 years, chronic cortical or cerebellar lesions, acute cortical lesions, PVWMH ≥ 2 in Fazekas scale, vessel occlusion, and acute lesion size ≥ 10 mm). Area under ROC curve was 0.735 and a score of ≥ 3 points was a predictor of AF. CONCLUSIONS: The suggested score was shown to identify CS patients with an increased risk of underlying AF.

Cryptogenic organizing pneumonia: clinical outcomes of 60 consecutive cases.

Background: Cryptogenic organizing pneumonia (COP) improves rapidly following corticosteroid treatment; however, relapse is common. Therefore, this retrospective observational study aimed to clarify the clinical outcomes of COP and identify the predictive factors for relapse. Methods: The laboratory findings, pulmonary function test results, computed tomography (CT) findings, and clinical outcomes of 60 consecutive COP patients treated at our institution between 2007 and 2013 were retrospectively reviewed. The clinical characteristics of COP patients who did and did not show improvement were compared to identify the predictive factors for relapse in patients showing improvement. Results: Forty-one patients showed improvement without relapsing (Group 1), whereas thirteen relapsed after showing improvement (Group 2). Six patients did not show any improvement (Group 3). The serum Krebs von den Lungen-6 (KL-6) levels in Group 3 were greater than those in Groups 1 and 2 (P=0.004). The incidence of traction bronchiectasis and reticular opacities in Group 3 was higher than that in Groups 1 and 2 (P=0.048 and P=0.006, respectively). The cut-off levels of C-reactive protein (CRP), blood neutrophil fraction (%neutrophils) and lymphocyte fraction (%lymphocytes) for predicting relapse were 6.84 mg/dL, 68.7% and 14.1% in Groups 1 and 2, respectively. The log-rank test revealed that high serum CRP levels (P<0.001), high %neutrophils (P=0.003) and low %lymphocytes (P=0.006) showed significant correlations with a shorter time to the first relapse episode. Conclusions: Chest CT findings depicting pulmonary fibrosis and high serum KL-6 levels were correlated with the non-improvement of COP. Blood test results indicating inflammatory reactions were correlated with relapse in patients with COP showing improvement.

Unusual Cause of Acute Stroke in a Young Woman with Patent Foramen Ovale - Duplicated Inferior Vena Cava and May-Thurner Syndrome.

The etiology of acute ischemic stroke (AIS) may often remain uncertain despite diligent work-up, especially in young people. Although patent foramen ovale (PFO) is a frequent association during such work-up, the actual source of thromboembolism, like deep vein thrombosis (DVT), may not be found. Such associative pathology makes it challenging to prescribe anticoagulation for secondary stroke prevention. We describe a young woman with a known history of PFO who presented with AIS and underwent endovascular reperfusion therapy. Post-thrombectomy, she developed hypoxic respiratory failure due to pulmonary embolism. Initiation of therapeutic anticoagulation was complicated by a retroperitoneal bleed necessitating imaging studies for etiological work-up. Computed tomographic angiography and venogram showed no active contrast extravasation but demonstrated duplication of the inferior vena cava with DVT in the right iliofemoral vein (RIFV). The proximity of the right common iliac artery compressing RIFV against the pelvic inlet is described as May-Thurner syndrome (MTS). Afterward, the patient was successfully treated with anticoagulation and PFO closure. MTS is a rare and underdiagnosed cause of iliofemoral DVT. In patients with known PFO, MTS is a possible cause that needs consideration. Hence, appropriate diagnostic tests are necessary to initiate appropriate management and to prevent AIS recurrence.

Ischemic stroke and the emerging role of left atrial function.

INTRODUCTION: Ischemic stroke is a leading cause of morbidity and mortality worldwide. Emerging evidence suggests that left atrial (LA) dysfunction could play a role in the pathophysiology of ischemic stroke, as a possible contributor and as a predictive biomarker. AREAS COVERED: This narrative review details the intricate relationship between LA function, atrial fibrillation (AF), and ischemic stroke. We discuss imaging techniques used to assess LA function, the mechanisms by which impaired LA function may contribute to stroke, and its potential as a prognostic marker of stroke. EXPERT OPINION: There is a lack of evidence-based treatments of LA dysfunction in both primary and secondary stroke prevention. This is partly due to the lack of a practical clinical definition and unanswered questions concerning the clinical implications of LA dysfunction in patients without AF. Until such questions are resolved, addressing well-known cardiovascular risk factors, like hypertension and obesity, should be prioritized for preventing AF and ischemic stroke. These risk factors are closely tied to atrial remodeling, emphasizing the importance of targeting primary modifiable factors for preventing future morbidity and mortality.

Association of Left Atrial Stiffness With Risk of Cryptogenic Ischemic Stroke in Young Adults.

Background: Incidence of cryptogenic ischemic stroke (CIS) in young adults is increasing. Early left atrial (LA) myopathy might be 1 of the underlying mechanisms, but this has only been scarcely explored. Objectives: The purpose of this study was to assess the association between increased LA stiffness and CIS in young adults. Methods: In the multicenter SECRETO (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome) study, LA function was analyzed by speckle tracking echocardiography in 150 CIS patients (aged 18-49 years) and 150 age- and sex-matched controls. Minimum and maximum LA volumes, LA reservoir and contractile strain were measured. LA stiffness was calculated by the ratio: mitral peak E-wave velocity divided by mitral annular e' velocity (E/e')/LA reservoir strain and considered increased if ≥0.22. Increased LA volumes, LA stiffness, and/or reduced LA strain indicated LA myopathy. Logistic regression was used to determine the relation between LA stiffness and CIS and the clinical variables associated with LA stiffness. Results: Increased LA stiffness was found in 36% of patients and in 18% of controls (P < 0.001). Increased LA stiffness was associated with a 2.4-fold (95% CI: 1.1-5.3) higher risk of CIS after adjustment for age, sex, comorbidities, and echocardiographic confounders (P = 0.03). In patients, obesity, pre-CIS antihypertensive treatment, older age, and lower LA contractile strain were all related to increased LA stiffness (all P < 0.05). Conclusions: LA myopathy with increased LA stiffness and impaired LA mechanics more than doubles the risk of CIS in patients under the age of 50 years. This provides new insights into the link between LA dysfunction and CIS at young ages. (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome [SECRETO]; NCT01934725).