BACKGROUND:Increased body mass index (BMI) leads to blood volume increase and left atrial enlargement (LAE). It is not known whether BMI and BMI change in midlife predispose to LAE later in life in a sex-biased manner. METHODS:Data from 1051 women and 889 men aged 42 years (baseline), followed for 26 years in the Hordaland Health Study, were analysed. LAE was identified from LA volume/height2 using sex-specific thresholds. Associations between baseline BMI and LAE at follow-up were explored in sex-specific Poisson regression analyses and reported as relative risk (RR) with 95% CIs. RESULTS:At baseline, overweight was less common in women than men while obesity prevalence did not differ. At follow-up, the LAE prevalence was similar (48% in women, 46% in men; p=0.47). Overweight was associated with a significantly higher risk of LAE in women than men, RR 1.45 (95% CI 1.27 to 1.65) and RR 1.26 (95% CI 1.09 to 1.46), respectively, risk difference 0.16 (95% CI 0.08 to 0.25). Obesity was associated with a high risk of LAE in both women and men, RR 1.48 (95% CI 1.14 to 1.92) and RR 1.41 (95% CI 1.05 to 1.90), risk difference 0.12 (-0.11 to 0.34). The relative excess risk due to interaction was 0.25 (95% CI 0.02 to 0.49), indicating a positive additive interaction between female sex and overweight. CONCLUSIONS:Increased BMI in early midlife was more strongly associated with LAE later in life in women. These results point to a sex-biased vulnerability to overweight-induced LAE and highlight the importance of weight control in midlife, especially in women.

AIMS:Little is known about sex-specific associations between elevated blood pressure (BP) in early midlife and presence of increased arterial stiffness later in life. METHODS AND RESULTS:BP was measured in 1127 women and 938 men, mean age 42 years (baseline), and categorized as non-elevated BP (<120/70 mmHg), elevated BP (120-139/70-89 mmHg) and hypertension (≥140/90 mmHg). Increased arterial stiffness was identified as carotid-femoral pulse wave velocity (cf-PWV) > 10 m/s. Associations between BP at baseline with increased arterial stiffness 27 years later were assessed in logistic regression analysis adjusted for baseline body mass index, diabetes, smoking, heart rate, lipids, age and education, and reported as odds ratios (OR) and 95% confidence intervals (CI). At baseline, 62% of women and 67% of men had elevated BP and 9% of women vs. 26% of men had hypertension (P < 0.001). At follow-up, 17% of women and 31% of men had increased arterial stiffness (P < 0.001). In adjusted analysis, having elevated BP or hypertension at baseline as compared with non-elevated BP were both associated with increased arterial stiffness 27 years later in women (OR 2.78 [95% CI 1.74-4.42] and OR 4.62 [95% CI 2.48-8.58]), but not in men (OR 1.10 [95% CI 0.58-2.10] and OR 1.33 [95% CI 0.67-2.66]), and P for sex-interaction 0.01. CONCLUSION:In the Hordaland health study, having elevated BP or hypertension in early midlife were associated with increased arterial stiffness 27 years later in women, but not in men. These findings underscore the importance of managing BP in early midlife for optimal CVD prevention in women.

BACKGROUND:In young adults, the risk factors (RFs) for cryptogenic ischemic stroke (CIS) remain unclear. We aimed to investigate the association between recent mechanical venous thrombosis RFs (VTRFs) and young-onset CIS in this multicenter sex- and age-matched case-control study. METHODS:Five hundred forty-six patients aged 18 to 49 years (median age, 41 [34-46] years; 47.3% women) with a recent CIS and 546 stroke-free community-based controls were included in the study across 19 European centers between October 2013 and November 2022. Mechanical VTRFs, including surgical treatment, nonsurgical intervention, injury, and immobilization occurring within 90 days prestroke, were assessed using standardized, structured interviews. Conditional logistic regression was used to assess the association of mechanical VTRFs with CIS. Age, sex, level of education, and traditional and nontraditional stroke RFs were included as confounders. RESULTS:Mechanical VTRFs within 14 days prestroke were more prevalent in cases than controls (15.4% versus 9.6%) and independently associated with CIS after adjustment for demographics and traditional stroke RFs (odds ratio [OR], 1.67 [95% CI, 1.05-2.67]). In age-stratified analysis, this association remained significant after additional adjustment for nontraditional RFs in 18- to 39-year-olds (OR, 2.36 [95% CI, 1.02-5.46]) but was not significant in the 40- to 49-year age group (OR, 1.50 [95% CI, 0.73-3.08]). In addition, mechanical VTRFs were associated with CIS in cases with clinically relevant patent foramen ovale in a fully adjusted model (OR, 2.06 [95% CI, 1.21-3.51]) but not in those without (OR, 1.29 [95% CI, 0.76-2.18]). No significant associations were observed for mechanical VTRFs occurring >14 days before stroke. Baseline blood thrombophilia markers did not differ between cases with and without mechanical VTRFs 0 to 14 or 15 to 90 days before stroke. CONCLUSIONS:Recent mechanical VTRFs occurring within 14 days preceding stroke contribute to the risk of young-onset CIS, particularly in younger individuals and those with a clinically relevant patent foramen ovale. This risk does not appear to be conveyed by thrombophilic factors assessed. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01934725.

Abstract Obesity-associated inflammation predisposes to cardiovascular disease (CVD). We investigated the association of biological sex with the plasma inflammatory protein profile in individuals with obesity. Clinical and proteomic data from 450 women and men with a body mass index (BMI) > 27 kg/m² without known CVD participating in the FAT associated CardiOvasculaR dysfunction study were analysed. The Olink Target 96 inflammation panel was employed in biobank samples. Hypertension was more prevalent among men, while age, BMI, and prevalences of obesity, diabetes and smoking did not differ between the sexes (all p > 0.05). In multivariable analyses, obesity was associated with downregulation of interleukin (IL) 7, IL 12 subunit beta, IL 6, and C-X-C motif chemokine 11, and upregulation of sulfotransferase 1A1 and SIR2-like protein 2 in women (all p < 0.05). In men, obesity was associated with downregulation of monocyte chemotactic protein 3, tumour necrosis factor superfamily member 12, IL 10 and protein S100-A12, and upregulation of neurotrophin-3 (all p < 0.05). In sum, the targeted protein profile in obesity differed by biological sex and there was no overlap in the differentially regulated proteins between women and men with obesity. The results suggest that pathophysiological mechanisms in obesity-associated inflammation and immune dysregulation may be sex-biased.

BACKGROUND: The incidence of cryptogenic ischemic stroke (CIS) in young adults is increasing, particularly among those without traditional vascular risk factors. Thrombophilia may contribute to CIS pathogenesis, yet guidelines differ on the relevance of screening. We investigated the sex-specific prevalence of routinely applied thrombophilia screening in young-onset CIS and its association with clinical characteristics and standard laboratory results. METHODS: We included young patients with CIS aged 18 to 49 years from the SECRETO study (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome). Routinely used thrombophilia panels obtained at admission and repeated testing within 1 year of stroke were analyzed. Ten thrombophilia markers were assessed and categorized according to the grade of deviation into lowest, low, and high thrombosis risks. Factors associated with any deviation in thrombophilia markers were investigated with multivariable logistic regression. RESULTS: Of 598 initially enrolled patients with CIS, 556 undergoing baseline thrombophilia testing were analyzed (median age, 41.0 [interquartile range, 34.1-45.8] years; male:female ratio 1.2:1). Of these, 120 (21.6%) and 36 (6.5%) were retested by 3 and 12 months, respectively. At baseline, any thrombophilia abnormality was observed in 206 patients (37.1%; men, 38.2%; women, 35.7%). High-risk thrombophilia was identified in 29 patients (5.2%) at baseline, in 13 retested patients (11.1%) at 3 months, and in 5 retested patients (13.9%) at 12 months. Overall, 45 patients (8.1%) had persistent thrombophilia abnormalities (men, 7.9%; women, 8.3%). Physical inactivity, a history of venous thromboembolism, low HDL (high-density lipoprotein)-cholesterol, and low hemoglobin were associated with any deviation in the thrombophilia markers. Anticoagulation was initiated in 50.0% of patients with abnormal baseline thrombophilia versus 35.7% without (P=0.042) and in 26.9% versus 6.2% with and without persistent abnormalities (P<0.001). CONCLUSIONS: Over a third of young adults with CIS had thrombophilia deviations at admission although high-risk thrombophilia results remained rare. Screening may be considered in young patients with CIS with a history of venous thromboembolism, physical inactivity, and low hemoglobin or HDL-cholesterol.

BACKGROUND:Data on the association between physical activity (PA) and cryptogenic ischaemic stroke (CIS) in young adults are scarce. We investigated the relationship between PA levels and early-onset CIS, stratified by the presence of a high-risk patent foramen ovale (PFO). METHODS:Patients aged 18-49 years with first-ever CIS and sex- and age-matched stroke-free controls were recruited from 19 European centres. PA was assessed using the short International Physical Activity Questionnaire and expressed as Metabolic Equivalents, categorized into percentiles (bottom 10%, 10%-25%, 25%-75% [reference], 75%-90%, top 10%). Associations between PA and CIS were analyzed using conditional logistic regression adjusted for age, education level, traditional risk factors, and non-traditional risk factors. RESULTS:Altogether, 533 patients (median age 41 [interquartile range 34-46]; 47.3% women) and 533 controls were included. Scoring in the top 10% of PA was independently associated with CIS: adjusted odds ratio 2.07; 95% confidence interval 1.22-3.51. Comparing patients without high-risk PFO to all controls, the top 10% PA category (1.78; 1.07-2.94) and the bottom 10% category (1.76; 1.06-2.92) were associated with CIS. No independent association was observed in patients with high-risk PFO. CONCLUSIONS:PA in the top 10% was associated with an increased risk of early-onset CIS in the overall study population. Among patients without a high-risk PFO, both the bottom 10% and top 10% of PA were consistently associated with elevated CIS risk. These findings highlight the need to better understand the mechanisms through which both low and high activity levels may predispose to stroke.

Heart failure (HF) remains a major cause of morbidity, mortality and costs for the healthcare systems worldwide, despite advances in diagnostic and therapeutic strategies. The enhancement of preventive measures is now a priority, but effective prevention requires a multidisciplinary strategy addressing a broad spectrum of comorbidities and risk factors. It must also consider the changes in the prevailing phenotype of the patients with HF with a lower impact of coronary artery disease and the increasing role of renal and metabolic conditions leading mostly to HF with preserved ejection fraction. Prevention of HF must take into consideration arterial hypertension, chronic kidney disease, diabetes mellitus, sedentary lifestyle, obesity, dyslipidemia, female-specific risk factors, as well as adverse effects of chemotherapy and radiotherapy. Other key factors include infections and the protective role of vaccination, and environmental and socio-economic determinants of health. In 2022, a position paper of the Heart Failure Association and the European Association of Preventive Cardiology of the ESC was published as a complete overview on this topic and as a compendium to the 2021 ESC Guidelines on HF. However, since then, significant evidence has emerged regarding the potential to prevent HF, particularly in the context of metabolic disorders, diabetes and kidney diseases. This scientific statement aims to provide an updated perspective, highlighting the importance of a holistic and tailored approach to managing the multifaceted contributors to this syndrome.

BACKGROUND:Familial aggregation of stroke is well-documented, yet few studies have examined associations between stroke subtypes-particularly early-onset cryptogenic ischaemic stroke (eCIS)-and broader family history (FH) of cardiovascular disease. Such associations may provide insights into underlying etiologic mechanisms. METHODS:In this multicentre case-control study, we included eCIS patients aged 18-49 years and matched stroke-free controls. We analysed the association between FH of stroke, venous thromboembolism (VTE), coronary artery disease (CAD), aneurysms and eCIS using multivariable logistic regression, with a subgroup analysis stratifying patients by high-risk patent foramen ovale (HR-PFO). RESULTS:We enrolled 508 eCIS patients (182 [36%] with HR-PFO) and 520 controls. Compared with controls, patients more frequently reported FH of stroke among first-degree relatives (FDR) (20% vs. 14%, P = .01) and grandparents (47% vs. 39%, P = .01), FH of early-onset stroke among FDR (5% vs. 2%, P = .01) and FH of early-onset VTE among FDR (5% vs. 2%, P = .003). In adjusted analyses, eCIS was associated with FH of stroke among FDR (OR 1.50; 95% CI, 1.04-2.16) and grandparents (1.50; 1.12-1.99), with FH of early-onset stroke among FDR (2.36; 1.11-5.04); and with FH of early-onset VTE among FDR (3.45; 1.47-8.13). eCIS was also associated with FH of VTE among FDR (1.80, 1.09-2.98) in the presence of HR-PFO. FH of CAD or aneurysms was not associated with eCIS. CONCLUSION:FH of stroke and VTE, particularly early-onset events and in the presence of HR-PFO, are associated with eCIS. These findings support familial predisposition and highlight prothrombotic mechanisms in eCIS. CLINICAL TRIAL REGISTRATION:www.clinicaltrials.gov/study/NCT01934725.

Objectives The aim of this study was to translate the Attitudes and Beliefs about Cardiovascular Disease (ABCD) Risk Questionnaire into Norwegian and assess its psychometric properties among individuals with a history of myocardial infarction.Design The study adopted a cross-sectional design. The original questionnaire was translated into Norwegian and adapted for use in the target population. The Norwegian version was pilot tested in a sample of patients and then validated in the target population.Setting Norway, using a web-based solution to collect data.Patients A random sample of Norwegian individuals <85 years old with a history of myocardial infarction and no cardiovascular disease before their first myocardial infarction.Main outcome measures Internal consistency was tested using Cronbach’s α and test–retest reliability using intraclass correlation coefficient (ICC). Difficulty and discrimination indices were determined for the Knowledge scale. Confirmatory factor analysis (CFA) was used to assess structural validity of the Risk scale.Results Data for 746 participants (mean age, SD: 66.4, 10.3 years), of which 26.9% females were analysed. The Norwegian version showed satisfactory internal consistency (Cronbach’s α 0.73–0.79) but modest test–retest reliability (ICC 0.35–0.64). The Knowledge scale showed moderate difficulty (0.39–0.84) and good discrimination power (0.44–0.60). The one-factor model CFA for each scale achieved acceptable fit, and the four-factor model showed moderate fit (root mean square error of approximation=0.05, standardised root mean squared residual=0.07, Comparative Fit Index=0.91, Tucker-Lewis Index=0.88).Conclusions The Norwegian translated ABCD Risk Questionnaire demonstrated satisfactory psychometric properties and can be considered a useful instrument for assessing knowledge and risk perception among individuals with a history of myocardial infarction.

BACKGROUND:Previously undetected antiphospholipid antibodies (aPLs) potentially provide explanations for early-onset cryptogenic ischemic stroke (CIS). Prior association studies conducted over a decade ago were inconclusive and not focused on patients with CIS. METHODS:SECRETO is a multi-center case-control study enrolling patients aged 18-49 years with imaging-positive acute CIS and 1:1 matched stroke-free controls. Lupus anticoagulant (LA), anticardiolipin (aCL), and anti-beta2-glycoprotein I (aβ2GPI) IgG antibodies were assessed from blood samples taken at two time points (baseline and 12-weeks) from patients and at a single time point from controls. Conditional logistic regression models assessed the association of aPLs, adjusted for age, level of education, and vascular risk factors. RESULTS:A total of 503 patient-control pairs were analyzed. At either time-point, compared to healthy controls, patients had more frequently positive aβ2GPI (patients 11.9% vs controls 2.0%, p < 0.001). There was no significant difference in the presence of positive LA between patients and controls. In the logistic regression model, at either time-point positive aB2GI and aCL were associated with CIS (odds ratio [OR] 11.22, 95% confidence interval [CI] 4.35-28.95 and OR 20.85, 95% CI 204-213.16, respectively). The frequency of patients with positive aβ2GPI or aCL increased from baseline to 12 weeks (p < 0.001), whereas frequency of positive LA results decreased (p < 0.001). CONCLUSIONS:Positive aβ2GPI and aCL, but not LA, detected either shortly after stroke or after 12 weeks were associated with early-onset CIS. Notably, after the acute phase, frequencies of positive aβ2GPI and aCL increased, whereas LA showed a reverse trend.

Cardiac organ damage (OD) is associated with increased risk of cardiovascular disease. However, limited knowledge exists on cardiac OD in young patients with cryptogenic ischaemic stroke (CIS). To explore prevalence and covariates of cardiac OD in patients with CIS compared to controls participating in the SECRETO study. We analysed data from 427 patients with CIS aged <50 years and 361 age- and sex-matched controls. OD was defined as presence of abnormal left ventricular (LV) geometry (LV hypertrophy or concentric remodelling) or left atrial enlargement (LAE) assessed by echocardiography, using sex-specific threshold values. Compared to controls, patients had higher prevalences of obesity and tobacco smoking, patent foramen ovale (PFO) (52

Cryptogenic ischemic stroke (CIS) is responsible for the increase in young ischemic strokes. We investigated non-alcoholic caffeinated beverages as a trigger for young CIS, in a large multi-center, case–control study. In Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725), patients 18–49 years old suffering first ever CIS were recruited within 2 weeks of symptom onset. A structured questionnaire obtained information on coffee, tea, and cola consumption in the last 12 months, usual daily consumption, consumption 24 h preceding stroke and timing of the last consumption prior to stroke. Case-crossover analysis was performed using the Mantel–Haenszel method. 598 CIS patients (54.7

AIMS:Susceptibility to hypertension-mediated organ damage (HMOD) is influenced by genetics, age, gender, and additional cardiovascular risk factors and comorbidities in the individual patient. All major hypertension guidelines recommend assessment of HMOD to identify high cardiovascular risk. However, in clinical practice, it may be difficult to choose the optimal strategy and diagnostic tools for the individual patient. METHODS AND RESULTS:We reviewed recommendations on HMOD assessment in the 2024 European Society of Cardiology, the 2023 European Society of Hypertension, the 2025 American Heart Association/American College of Cardiology, and the 2020 International Society of Hypertension guidelines to provide an expert opinion on how to optimize the diagnosis of HMOD in clinical practice. Basic assessment of cardiac and renal HMOD is recommended in all patients using electrocardiography, serum creatinine, and estimated glomerular filtration rate, and albumin-creatinine ratio in a morning spot-urine. Advanced tests for HMOD assessment are indicated depending on findings at the initial clinical assessment, whether results are likely to change management, and local availability and resources. Echocardiography remains the preferred initial test and may add prognostic information in most patients. Identification of premature atherosclerosis by ultrasound or coronary artery calcium score or arterial stiffness by pulse wave velocity may be indicated in young and middle-aged individuals with arterial hypertension or blood pressure close to treatment threshold, if likely to change management. CONCLUSION:HMOD is a marker of high cardiovascular risk. Basic assessment should be performed in all patients with arterial hypertension, and more advanced tests in selected patients. LAY SUMMARY:High blood pressure (hypertension) leads to damage of the heart, arteries, eyes, brain, and kidneys, collectively termed hypertension-mediated organ damage (HMOD). Presence of HMOD is associated with a 2-3-fold increased risk of subsequent cardiovascular disease. The hypertension guidelines, therefore, recommend looking for HMOD in the evaluation of patients with hypertension to identify high-risk individuals. To help clinicians make informed decisions on what type of test to choose for HMOD assessment, we have compared the recommendations of the most important recently issued hypertension guidelines.Key findings are:Basic HMOD screening of heart and kidney function should be performed in all individuals with hypertension, including taking an electrocardiogram and blood and urine tests to evaluate kidney function.Targeted advanced HMOD assessment in specialized health care is recommended in selected individuals based on findings in the initial evaluation. This may include ultrasound examination of the heart, kidneys or arteries, measurement of arterial stiffness or imaging of the heart, brain or arteries by computed tomography or magnetic resonance imaging.

BACKGROUND:Infections might transiently trigger ischemic stroke through thromboinflammatory mechanisms, which may be especially relevant in young patients with cryptogenic ischemic stroke (CIS). This study assessed the association between infections, their characteristics, and coagulation biomarkers in young patients with CIS. METHODS:The SECRETO study is a multicenter case-control study at 19 European centers (2013-2022), enrolling first-ever patients with CIS aged 18 to 49 years and age- and sex-matched controls. Self-reported preceding infections within 3 months were assessed using a standardized questionnaire, and blood samples were collected at baseline and 3-month follow-up. The primary outcome was the association between preceding infections and CIS, analyzed using conditional logistic regression adjusted for demographic and vascular risk factors. Secondary outcomes were coagulation biomarkers (VWF [von Willebrand Factor], FVIII [factor VIII], fibrinogen, antithrombin III, and protein C) in relation to infection characteristics. RESULTS:Among 537 matched pairs, infections in the preceding week were associated with 2.6-fold higher CIS odds (odds ratio, 2.64 [95% CI, 1.34-5.20]) after multivariable adjustment. VWF activity was higher in cases than in controls (122 IU/mL versus 100 IU/mL; P<0.001). Within cases only, VWF activity was higher in cases with recent infections compared to those without infection (157 IU/mL versus 121 IU/mL). In controls, VWF levels did not differ by infection status. In stratified case-control analyses, each SD increase in VWF and factor VIII was linked to higher stroke odds in participants with recent infections or fever. CONCLUSIONS:This multicenter case-control study shows that recent infections are associated with higher odds of early onset CIS. Stratified analyses indicate that VWF and factor VIII are more strongly associated with CIS in the presence of recent infections. Future studies should further elucidate infection-related thromboinflammatory mechanisms underlying CIS, including a potential increased sensitivity to inflammatory triggers, and explore whether preventive measures could reduce risk in this population. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01934725.

OBJECTIVES:Periodontitis may promote chronic systemic inflammation leading to elevation of blood pressure (BP) and arterial stiffening. We explored sex-specific associations of periodontitis severity and inflammation with BP and arterial stiffness. METHODS:BP and arterial stiffness by carotid-femoral pulse wave velocity (cf-PWV) were measured in 673 women and 565 men, mean age 68 years. Periodontitis was staged using the European Federation of Periodontology/American Academy of Periodontology 2018 classification. Periodontal inflammation was assessed by full-mouth registration of bleeding on probing (BoP) and number of sites with combined probing pocket-depth (PPD) ≥ 4 mm and BoP. The associations of periodontitis severity and periodontal inflammation with BP and arterial stiffness were tested in sex-specific linear/logistic regression analyses, adjusted for diabetes, smoking, BMI, education, and antihypertensive treatment. RESULTS:Men had higher BP and cf-PWV than women (both P < 0.01). Stage II (moderate) and III/IV (advanced) periodontitis were found in 24 and 76% of women and 18 and 82% of men (P = 0.03). Mean BoP was 55 in both genders (P = 0.91). In adjusted analysis, stage III/IV (advanced) periodontitis was associated with higher SBP and DBP in women only (β = 0.08 and β = 0.09, both P < 0.05). BoP was associated with higher DBP only in women (β = 0.12) (P for sex interaction < 0.05) and with higher cf-PWV in men (β = 0.09) (both P < 0.05). PPD ≥ 4 mm with BoP was associated with increased arterial stiffness in women (P = 0.03). CONCLUSION:Advanced periodontitis and periodontal inflammation were both associated with higher BP only in women, while periodontal inflammation was associated with increased arterial stiffness in both genders.

BACKGROUND:The incidence of young-onset ischemic stroke is rising, driven by cryptogenic ischemic stroke (CIS) and patients without vascular risk factors. This study examines the burden and associations of modifiable traditional, nontraditional, and female sex-specific risk factors with young-onset CIS, stratified by clinically relevant patent foramen ovale (PFO), defined by high-risk features of atrial septal aneurysm or large right-to-left shunt. METHODS:We enrolled consecutive patients aged 18 to 49 years with recent CIS and frequency-matched stroke-free controls of the same age and sex from 19 European sites. Logistic regression assessed the association of risk factor counts (12 traditional, 10 nontraditional, 5 female sex-specific) and individual risk factors, stratified by PFO. Analyses were stratified by sex and age (18-39 and 40-49 years), with computation of population-attributable risk. RESULTS:We included 523 patients (median age, 41 years; 47.3% women; 196 [37.5%] with PFO) and 523 controls. In patients with CIS without PFO, each additional traditional (odds ratio, 1.417 [95% CI, 1.282-1.568]), nontraditional (odds ratio, 1.702 [95% CI, 1.338-2.164]), and female sex-specific risk factor (odds ratio, 1.700 [95% CI, 1.107.1-2.611]) increased CIS risk. For patients with CIS with PFO, each traditional risk factor increased the risk (odds ratio, 1.185 [1.057-1.328]), but only nontraditional risk factors remained significant when fully adjusted (odds ratio, 2.656 [2.036-3.464]). Population-attributable risks for CIS without PFO were 64.7%, 26.5%, and 18.9% for traditional, nontraditional, and female sex-specific risk factors. For CIS with PFO, population-attributable risks were 33.8%, 49.4%, and 21.8%, respectively. Migraine with aura was the most significant contributor, with population-attributable risks of 45.8% for CIS with PFO and 22.7% for CIS without PFO, showing a stronger impact in women. CONCLUSIONS:Despite the initial cryptogenic label of these strokes, traditional risk factors significantly contribute to CIS without PFO, while nontraditional factors seem more critical for CIS with PFO. Migraine with aura plays a prominent role in young-onset CIS development, particularly in women. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01934725.