Recurrent Stroke in Patients With Cryptogenic Stroke and Left Ventricular Injury: The Cardiac Abnormalities in Stroke Prevention and Recurrence (CASPR) Study.

Clinical management of patients with acute stroke and the approach used for secondary prevention depends upon clarification of pathogenesis. Although most strokes are a consequence of cerebrovascular disease, ≈15% to 20% of ischemic (nonhemorrhagic) strokes have been attributed to cardiogenic embolism.1 In practice, determination of the stroke mechanism is fraught with uncertainty, particularly when the possibility of thromboembolism emanating from atherosclerotic lesions in the aorta or cervical arteries is considered. When cardiogenic embolism is suspected, cardiac ultrasound is the principal method used to identify the potential source. The finding of left atrial enlargement has been shown to bear a significant relationship to the risk of stroke in a multivariate analysis of population-based data from the Framingham Heart Study2. The most frequent confounding variable is atrial fibrillation, occurring in >2 million patients in North America and in over half of all patients with cardiogenic embolism. Criteria for selection of patients with acute ischemic stroke for transesophageal echocardiography (TEE) to search for a potential cardiac source of embolism are controversial, particularly because cardiogenic embolism is often an uncertain diagnosis that is inferred merely on the basis of the finding of potential cardiac source. Even after extensive investigation, ≈40% of ischemic stroke patients have no clearly identifiable pathogenesis (cryptogenic stroke).3 In one study, 62% of patients younger than 60 years of age without an obvious source of cerebral infarction and 23% of those with arterial lesions had potential sources of cardiogenic embolism identified by TEE ( P =0.0007 for the difference).4 See p 2625 Among the cardiac anomalies detected by TEE that have been implicated as risk factors for stroke are patent foramen ovale (PFO) and atrial septal aneurysm (ASA).5,6⇓ The foramen ovale, a remnant of the fetal circulation, remains patent through adulthood in ≈1 in 4 …

Severe left ventricular (LV) systolic dysfunction (ejection fraction [EF] < 30%) is a known cardiovascular risk factor and a major cause of cardioembolism. However, less severe forms of LV disease (LVD), such as mild-to-moderate LV dysfunction and LV wall motion abnormalities (LVWMAs), are considered potential minor cardiac sources in Embolic Stroke of Undetermined Source (ESUS), but their role is underexplored. This study aims to evaluate the prevalence of LVD in ESUS and its association with adverse vascular events and mortality. Retrospective, single-center study including consecutive ESUS patients admitted from January 2016 to May 2024. LVD was defined as either global systolic dysfunction (LV ejection fraction 30%-49%) or regional LVWMAs, unrelated to acute or recent (within 4 weeks) myocardial infarction. Univariate and multivariate Cox regression analyses evaluated the association of LVD with a primary composite outcome (including ischemic stroke recurrence, acute coronary events, and all-cause mortality), and its components separately. Among the 556 ESUS patients (median age 71 years [IQR 60-80], 44.6% female), 95 (17.1%) had LVD, including 51 (53.7%) with reduced LVEF (30%-49%), and 81 (85.3%) presenting LVWMAs. During follow-up (median 30 months), LVD(+) patients had significantly higher rates of the composite outcome (41.0% vs 21.3%, p < 0.001), ischemic stroke recurrence (13.7% vs 5.9%, p = 0.007), acute coronary events (7.4% vs 2.4%, p = 0.012), and all-cause mortality (28.4% vs 15.2%, p = 0.002), compared to LVD(-) patients. Multivariate Cox regression analysis showed that LVD independently increased the risk of ischemic stroke recurrence (adjusted HR 2.13, 95%CI 1.08-4.24, p = 0.032) and the composite outcome (aHR 1.92, 95%CI 1.27-2.90, p = 0.002), but not acute coronary events (aHR 1.65; 95%CI 0.54-5.01, p = 0.374), or all-cause mortality (aHR 1.62; 95%CI 0.98-2.70, p = 0.062). LVD is significantly associated with an increased risk of ischemic stroke recurrence and adverse outcomes in ESUS patients. These findings highlight the clinical importance of identifying and optimizing LVD management among ESUS to improve long-term outcomes in this population.

Introduction: Patent foramen ovale (PFO) is a potential source of cardiac embolism in cryptogenic ischemic stroke, but it may also be incidental. Right-to-left shunt (RLS) size may predict PFO-related stroke, but results have been controversial. In this cohort study of medically-managed PFO patients with cryptogenic stroke, we aimed to investigate the association of shunt size with recurrent stroke, mortality, newly detected atrial fibrillation (AF), and to identify predictors of recurrent stroke. Methods: Patients with cryptogenic stroke who screened positive for a RLS using a transcranial Doppler bubble study were included. Patients who underwent PFO closure were excluded. Subjects were divided into two groups: small (Spencer Grade 1, 2, or 3; n = 135) and large (Spencer Grade 4 or 5; n = 99) shunts. The primary outcome was risk of recurrent stroke, and the secondary outcomes were all-cause mortality and newly detected AF. Results: The study cohort included 234 cryptogenic stroke patients with medically-managed PFO. The mean age was 50.5 years, and 31.2% were female. The median period of follow-up was 348 (IQR 147-1096) days. The rate of recurrent ischemic stroke was higher in patients with large shunts than in those with small shunts (8.1% vs. 2.2%, p = 0.036). Multivariate analyses revealed that a large shunt was significantly associated with an increased risk of recurrent ischemic stroke [aOR 4.09 (95% CI 1.04–16.0), p = 0.043]. Conclusions: In our cohort of cryptogenic stroke patients with medically managed PFOs, those with large shunts were at a higher risk of recurrent stroke events, independently of RoPE score and left atrium diameter.

Background Prolonged and intensified rhythm monitoring is recommended to detect atrial fibrillation (AF) in patients with cryptogenic stroke (CS). Continuous monitoring using implantable cardiac monitors (ICM) results in AF detection rates of up to 30%. Although higher age has been identified as an independent risk factor for AF in patients post CS, there are no specific recommendations for the implantation of ICM in younger patients. Furthermore, the temporal relationship between AF and recurrent stroke in patients with continuous monitoring is a relevant issue and scarcely investigated. Objectives (1)To analyze age-related AF rates in patients with CS and continuous rhythm monitoring using ICM. (2)To determine the rates of oral anticoagulation and recurrent strokes in patients with ICM-detected AF after CS. (3)To describe the temporal relationship of AF detection and recurrent stroke in these patients. Methods From 02/2014 to 11/2021, patients with CS provided with ICMs were systematically followed. All patients underwent 72-h ECG monitoring, transcranial doppler ultrasound and transthoracic echocardiography according to current guidelines prior to ICM insertion. Follow-up was performed by means of a regular outpatient presentation every three months and included medical history, physical examination, and interrogation of the ICM. AF was defined as any episode of absolute arrhythmia &amp;gt;30 seconds. Results One hundred and eighty-six patients (mean age 65 ± 12 years) were included in this analysis. AF was detected in 62 patients (33 %) during a mean follow-up of 36 ± 23 months. AF was found in 6 % (3/52), 27 % (17/62), 56 % (31/55) and 65 % (11/17) (p &amp;lt; 0.001) in patients aged &amp;lt; 60 years, 60-69 years, 70-79 years and ≥ 80 years, respectively (see Figure 1). All patients with AF under 60 years had an impaired systolic left ventricular function (left ventricular ejection fraction &amp;lt; 50 %). Oral anticoagulation was initiated in 85% of the patients with AF. Recurrent stroke occurred in 34 patients (18.3%) of whom fifteen had a diagnosis of AF. In nine patients, AF was diagnosed before the occurrence of a recurrent stroke. In four patients, AF was diagnosed after recurrent stroke and in one patient, AF and recurrent stroke occurred simultaneously (see Figure 2). Conclusion AF was absent in cryptogenic stroke patients with preserved ejection fraction and younger than 60 years. AF prevalence increased with age. The temporal relationship of AF and recurrent stroke was weak. Further research is needed to better identify stroke patients at risk of AF and recurrent stroke. Figure 1: Time to first detection of Atrial fibrillation in patients aged &amp;lt; 60 years, 60-69 years, 70-79 years and ≥80 years, respectively. Figure 2: Temporal relationship of first detected atrial fibrillation (AF) and recurrent stroke in patients with cryptogenic stroke.Figure 1Figure 2

Background- Risk factors for stroke recurrence are still not fully defined. Angiopoietin-2 is a very important mediator in the vessel development and repair. We hypothesized that altered expression of angiopoietin-2 will confer risk of stroke recurrence. Methods - The association of plasma angiopoietin-2 (determined by using ELISA) and the variants in angiopoietin-2 promoter with stroke recurrence was tested in 1735 patients with stroke of three subtypes, lacunar infarct (n=475), atherothrombotic (n=794) and hemorrhage (n=466), for a period of following-up 4.5 years (mean), the association was evaluated by using Kaplan-Meier analysis and the Cox regression models. Results -We found that angiopoietin-2 levels were associated with risk of stroke recurrence in lacunar infarct patients. Taking the lowest quartile as reference, the adjusted hazard ratio (HR) and 95% confidence intervals (CI) for stroke recurrence was 1.47 (0.75–2.88) for the second quartile, 2.44 (1.31–4.56) for the third and 2.00 (1.05–3.85) for the fourth. Allele T of rs3739391 in angiopoietin-2 promoter was associated with elevated angiopoietin-2 levels and increased risk of stroke recurrence in patients with lacunar infarct with HR 1.72 (1.09–2.72) relative to the allele C, but neither in those with atherothrombotic nor in those with hemorrhagic stroke. Conclusion- Our results indicate that both angiopoietin-2 and allele T of rs3739391 might be the risk marker for stroke recurrence in the patients with lacunar infarction. These findings may help to improve future prevention or therapy strategies for stroke.

BackgroundAtherosclerotic dyslipidemia (AD) is associated with an increased risk of cardiovascular diseases and stroke events, but the effect of AD among acute ischemic stroke (AIS) patients undergoing intravenous thrombolysis is unclear. This study aimed to investigate the relationship between AD and long-term stroke recurrence in AIS patients undergoing intravenous thrombolysis.MethodsThis prospective cohort study included 499 AIS patients treated with intravenous thrombolysis. Stroke subtype was classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria, patients’ clinical characteristics, and results from multiple diagnostic tests. The primary endpoint event was ischemic stroke recurrence; the time to first AIS recurrence was estimated using Kaplan‒Meier analysis and compared using the two-sided Log rank test. Cox univariate and multivariate regression analyses were used to assess the association between AD and long-term stroke recurrence.ResultsOf the 499 patients with AIS treated with rt-PA intravenous thrombolysis, 80 (16.0%) had AD, and 60 (12.0%) had a stroke recurrence event. Kaplan‒Meier analysis showed that the stroke recurrence rate was significantly higher in patients with AD than in those without AD (p = 0.035, log rank test) and in the large-artery disease (LAD) subtype (p = 0.006, log rank test). Multivariate Cox regression analysis showed that AD (HR = 2.363, 95% CI: 1.294–4.314, P = 0.005) and atrial fibrillation (HR = 2.325, 95% CI: 1.007–5.366, P = 0.048) were associated with an increased risk of long-term stroke recurrence in AIS patients who underwent intravenous thrombolysis. Furthermore, AD was associated with an increased risk of stroke recurrence in patients undergoing intravenous thrombolysis in the LAD subtype (HR = 3.122, 95% CI: 1.304–7.437, P = 0.011).ConclusionWe found that AD increases the risk of long-term stroke recurrence in AIS patients undergoing intravenous thrombolysis. This association may be stronger in the LAD subtype.

Sex differences in stroke outcomes have been noted, but whether this extends to stroke recurrence is unclear. We examined sex differences in recurrent stroke using data from the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial. We assessed the risk of recurrent stroke in women compared to men using data from the POINT trial. Adults >18 years old were randomized within 12 hours of onset of minor ischemic stroke or transient ischemic attack (TIA), and followed for up to 90 days for ischemic stroke, our primary outcome. We used Cox proportional hazards model adjusted for demographics and stroke risk factors to evaluate the association between sex and stroke recurrence. We used interaction term testing and prespecified subgroup analyses to determine if the association between sex and recurrent stroke differed by age (<60 versus >60 years old), locale (US versus non-US), and index event type (stroke versus TIA). Last, we evaluated whether sex modified the effect of common stroke risk factors on stroke recurrence. Of 4,881 POINT trial participants with minor stroke or high-risk TIA, 2,195 (45%) were women. During the 90-day follow-up period, 267 ischemic strokes occurred; 121 were in women and 146 in men. The cumulative risk of recurrent ischemic stroke was not significantly different among women (5.76%; 95% CI, 4.84%-6.85%) compared to men (5.67%; 95% CI, 4.83%-6.63%). Women were not at a different risk of recurrent ischemic stroke compared to men (hazard ratio [HR], 1.02; 95% CI, 0.80-1.30) in unadjusted models or after adjusting for covariates. However, there was a significant interaction of age with sex (P=0.04). Among patients <60 years old, there was a non-significantly lower risk of recurrent stroke in women compared to men (HR 0.66; 95% CI 0.42-1.05). Last, sex did not modify the association between common stroke risk factors and recurrent stroke risk. Among patients with minor stroke or TIA, the risk of recurrent ischemic stroke and the impact of common stroke risk factors did not differ between men and women.

This study aims to analyze the risk factors for stroke recurrence in patients with symptomatic intracranial artery stenosis and explore their long-term prognosis. By retrospectively analyzing the relationship between intracranial artery stenosis and stroke recurrence, this study provides clinical evidence for the prevention of stroke recurrence. This study retrospectively collected data from 181 patients diagnosed with cerebral infarction or transient ischemic attack (TIA) due to symptomatic intracranial artery stenosis between February 2020 and February 2023 at our hospital, with a follow-up period of 2 years. Patients were divided into a recurrence group and a nonrecurrence group based on whether they experienced a stroke recurrence (cerebral infarction or TIA). Baseline characteristics, clinical data, and imaging data were analyzed. Additionally, univariate and multivariate regression analyses were performed to assess the relationship between related risk factors and stroke recurrence. During the follow-up period, 65 patients (35.9%) had a stroke recurrence, including 42 cases of cerebral infarction and 23 cases of TIA. Univariate regression analysis showed that age, hypertension, diabetes, hyperlipidemia, and severe intracranial artery stenosis (≥70%) significantly increased the risk of stroke recurrence. Multivariate regression analysis further confirmed that hyperlipidemia (OR = 3.80, P <.001), diabetes (OR = 2.60, P = .015), and severe stenosis (OR = 4.20, P <.001) were independent risk factors for stroke recurrence. Furthermore, a synergistic pathogenic effect between diabetes and severe stenosis significantly increased the risk of stroke recurrence (interaction effect OR = 3.25, P = .008). This study indicates that hyperlipidemia, diabetes, and severe intracranial artery stenosis are important independent risk factors for stroke recurrence. The interaction between diabetes and severe stenosis may exacerbate the risk of stroke recurrence. Therefore, clinical attention should be given to the management of these high-risk factors to reduce the risk of stroke recurrence.

Introduction: Symptomatic Non-stenotic Carotid (SyNC) disease is an increasingly recognized etiology in ischemic stroke, particularly in the presence of certain high-risk plaque features. The aim of this population level clinical-imaging study was to examine the risk of ipsilateral and recurrent stroke in patients with SyNC with 5-year follow-up. In addition, we aimed to identify plaque features that predict higher risk of ipsilateral and recurrent stroke in this population. Methodology: All patients presenting with stroke or transient ischemic attack (TIA) in fiscal year 2019/20 were identified using administrative data. All baseline and follow up imaging within 5-years of presentation was analyzed. CT Angiograms were assessed for plaque features such as degree of stenosis, plaque thickness, calcification, plaque irregularity, ulceration, positive rim sign, and focal vessel caliber increase. Parenchymal imaging was reviewed for infarct presence on the same side as carotid disease (concordant stroke). Analyses were performed at the patient and carotid level comparing 1-50% stenosis versus no stenosis using unadjusted and adjusted (for age and sex) logistic regression analysis. Patients with carotid stenosis &gt;50% were excluded from the analysis. Results: Among 1249 patients presenting with stroke or TIA, 658 (52.7%) patients had 0-50% stenosis. Of the total 658 patients included, 153 (23.5%) had concordant stroke and 76 (11.6%) had recurrent stroke. Of the 76 patients that developed recurrence, 49 (7.4%) patients had SyNC on the ipsilateral side. In adjusted analyses, there was significantly increased odds of concordant stroke at index presentation with 1-50% stenosis [aOR 3.56, 95% CI 2.99 – 4.25] and increasing plaque thickness (per mm) [aOR 1.19, 95% CI 1.03 – 1.38]. Similarly, adjusted analysis showed significant increase in odds of recurrent concordant stroke with 1-50% stenosis [aOR 2.39, 95% CI 1.94 – 2.95], plaque thickness [aOR 1.32, 95% CI 1.05 – 1.67], and plaque ulceration [aOR 3.86, 95% CI 1.31 – 11.35]. Conclusion: This retrospective population-level study demonstrates that non-stenotic carotid disease carries a significant risk of ipsilateral and recurrent stroke, particularly with degree of stenosis, increasing plaque thickness, and ulceration. These findings suggest that current risk stratification may underemphasize non-stenotic plaques, warranting further prospective validation to guide monitoring and treatment strategies.

Introduction: Prolonged QT interval has been associated with first stroke of any type in the general population. Whether QT prolongation predicts recurrent stroke is unknown. Hypothesis: We hypothesized that QT prolongation would be associated with increased risk of recurrent stroke in individuals who recently suffered a cryptogenic stroke. Methods: The Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial randomized individuals with cryptogenic stroke and atrial cardiopathy to apixaban versus aspirin to assess the prevention of recurrent strokes. We excluded participants with missing QT interval data and those who had ventricular conduction defects or pacemakers. The baseline electrocardiogram (ECG) was the first technically adequate ECG to be done after stroke onset. QT interval was corrected for heart rate (QTc) using a cohort-specific correction formula, as well as the Framingham, Hodges, Bazett, and Fridericia formulae. For each QTc variable, prolonged QTc was defined as &gt;450 ms in men or &gt;460 ms in women. Cox proportional hazards models were used to assess the association between QTc and recurrent stroke. Models were adjusted for randomization arm, age, sex, race, smoking, hypertension, diabetes, prior stroke, and N-terminal pro-B-type natriuretic peptide. Results: Among 881 participants, 139 (15.8%) had a prolonged cohort-specific QTc. Over a mean of 1.8 years, 62 recurrent strokes of any type occurred (crude rate 7.0%, annualized rate 3.9% per year). After multivariable adjustment, prolongation of cohort-specific QTc was associated with decreased risk of stroke (hazard ratio [95% confidence interval] = 0.72 [0.54-0.95] per standard deviation and 0.16 [0.04-0.64] for prolonged vs. normal QTc). These findings were consistent across all methods of QT correction ( Table) . Accounting for QRS duration, incident atrial fibrillation, and the competing risk of death did not change the results. Conclusions: In a population with recent cryptogenic stroke and atrial cardiopathy, QTc prolongation was associated with a lower risk of recurrent stroke. These findings contrast with the association observed between QTc prolongation and stroke in the general population, which may reflect selection bias or bias from ECGs obtained in the acute phase of stroke. If replicated, these findings suggest that repolarization markers like QTc may play different roles in stroke risk stratification for first versus recurrent stroke.

Aspirin and Extended-Release Dipyridamole vs. Clopidogrel for Recurrent Stroke

There are few reports on proinflammatory cytokines and risk of primary or recurrent stroke. We studied the association of interleukin (IL)-6, IL-18, and tumor necrosis factor-alpha (TNF-alpha) with recurrent stroke in a nested case-control study derived from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). We performed a nested case-control study of 591 strokes (472 ischemic, 83 hemorrhagic, 36 unknown subtype) occurring during a randomized, placebo-controlled multicenter trial of perindopril-based therapy in 6105 patients with a history of stroke or transient ischemic attack. Controls were matched for age, treatment group, sex, region, and most recent qualifying event at entry to the parent trial. IL-6 and TNF-alpha, but not IL-18, were associated with risk of recurrent ischemic stroke independently of conventional risk markers. Adjusted odds ratios comparing the highest to lowest third of their distributions were 1.33 (95% CI, 1.00 to 1.78) for IL-6 and 1.46 (1.02 to 2.10) for TNF-alpha. No inflammatory marker was associated with hemorrhagic stroke risk. In multivariable models, IL-6 and TNF-alpha fully explained observed associations of C-reactive protein and fibrinogen with risk of ischemic stroke, but TNF-alpha retained borderline significance after full adjustment. Inflammatory markers associated with the acute-phase response (IL-6, TNF-alpha, C-reactive protein, and fibrinogen, but not IL-18) are associated with risk of recurrent stroke. These markers are dependent on each other in multivariable models, and once all were included, only TNF-alpha retained a borderline association. Markers of generalized inflammation of the acute-phase response are associated with recurrent stroke, rather than IL-6, C-reactive protein, or fibrinogen in particular.

Meta-Analysis of Secondary Prevention of Cryptogenic Stroke

IntroductionIntracranial stenosis (ICS) is believed to convey a high risk of recurrent ischaemic stroke, but the SAMMPRIS trial failed to show superiority of ICS stenting over intensive medical management. However,...

Patent Foramen Ovale Closure for Remote Stroke: Better Late Than Never?