Patent foramen ovale (PFO) is frequently identified in young patients with ischemic stroke. Randomized controlled trials provide robust evidence supporting PFO closure in selected patients with ...cryptogenic ischemic stroke; however, several questions remain unanswered. This report summarizes current knowledge on the epidemiology of PFO-associated stroke, the role of PFO as a cause of stroke, and anatomic high-risk features. We also comment on breakthrough developments in patient selection algorithms for PFO closure in relation to the PFO-associated stroke causal likelihood risk stratification system. We further highlight areas for future research in PFO-associated stroke including the efficacy and safety of PFO closure in the elderly population, incidence, and long-term consequences of atrial fibrillation post-PFO closure, generalizability of the results of clinical trials in the real world, and the need for assessing the effect of neurocardiology teams on adherence to international recommendations. Other important knowledge gaps such as sex, race/ethnicity, and regional disparities in access to diagnostic technologies, PFO closure devices, and clinical outcomes in the real world are also discussed as priority research topics.
BACKGROUND AND PURPOSE—Cirrhosis—clinically overt, advanced liver disease—is associated with an increased risk of hemorrhagic stroke and poor stroke outcomes. We sought to investigate whether ...subclinical liver disease, specifically liver fibrosis, is associated with clinical and radiological outcomes in patients with primary intracerebral hemorrhage.
METHODS—We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive–Intracerebral Hemorrhage. We included adult patients with primary intracerebral hemorrhage presenting within 6 hours of symptom onset. We calculated 3 validated fibrosis indices—Aspartate Aminotransferase–Platelet Ratio Index, Fibrosis-4 score, and Nonalcoholic Fatty Liver Disease Fibrosis Score—and modeled them as continuous exposure variables. Primary outcomes were admission hematoma volume and hematoma expansion. Secondary outcomes were mortality, and the composite of major disability or death, at 90 days. We used linear and logistic regression models adjusted for previously established risk factors.
RESULTS—Among 432 patients with intracerebral hemorrhage, the mean Aspartate Aminotransferase–Platelet Ratio Index, Fibrosis-4, and Nonalcoholic Fatty Liver Disease Fibrosis Score values on admission reflected intermediate probabilities of fibrosis, whereas standard hepatic assays and coagulation parameters were largely normal. After adjusting for potential confounders, Aspartate Aminotransferase–Platelet Ratio Index was associated with hematoma volume (β, 0.20 95% CI, 0.04–0.36), hematoma expansion (odds ratio, 1.6 95% CI, 1.1–2.3), and mortality (odds ratio, 1.8 95% CI, 1.1–2.7). Fibrosis-4 was also associated with hematoma volume (β, 0.27 95% CI, 0.07–0.47), hematoma expansion (odds ratio, 1.9 95% CI, 1.2–3.0), and mortality (odds ratio, 2.0 95% CI, 1.1–3.6). Nonalcoholic Fatty Liver Disease Fibrosis Score was not associated with any outcome. Indices were not associated with the composite of major disability or death.
CONCLUSIONS—In patients with largely normal liver chemistries, 2 liver fibrosis indices were associated with admission hematoma volume, hematoma expansion, and mortality after intracerebral hemorrhage.
BACKGROUND AND PURPOSE:One-fifth of ischemic strokes are embolic strokes of undetermined source (ESUS). Their theoretical causes can be classified as cardioembolic versus noncardioembolic. This ...distinction has important implications, but the categories’ proportions are unknown.
METHODS:Using data from the Cornell Acute Stroke Academic Registry, we trained a machine-learning algorithm to distinguish cardioembolic versus non-cardioembolic strokes, then applied the algorithm to ESUS cases to determine the predicted proportion with an occult cardioembolic source. A panel of neurologists adjudicated stroke etiologies using standard criteria. We trained a machine learning classifier using data on demographics, comorbidities, vitals, laboratory results, and echocardiograms. An ensemble predictive method including L1 regularization, gradient-boosted decision tree ensemble (XGBoost), random forests, and multivariate adaptive splines was used. Random search and cross-validation were used to tune hyperparameters. Model performance was assessed using cross-validation among cases of known etiology. We applied the final algorithm to an independent set of ESUS cases to determine the predicted mechanism (cardioembolic or not). To assess our classifier’s validity, we correlated the predicted probability of a cardioembolic source with the eventual post-ESUS diagnosis of atrial fibrillation.
RESULTS:Among 1083 strokes with known etiologies, our classifier distinguished cardioembolic versus noncardioembolic cases with excellent accuracy (area under the curve, 0.85). Applied to 580 ESUS cases, the classifier predicted that 44% (95% credibility interval, 39%–49%) resulted from cardiac embolism. Individual ESUS patients’ predicted likelihood of cardiac embolism was associated with eventual atrial fibrillation detection (OR per 10% increase, 1.27 95% CI, 1.03–1.57; c-statistic, 0.68 95% CI, 0.58–0.78). ESUS patients with high predicted probability of cardiac embolism were older and had more coronary and peripheral vascular disease, lower ejection fractions, larger left atria, lower blood pressures, and higher creatinine levels.
CONCLUSIONS:A machine learning estimator that distinguished known cardioembolic versus noncardioembolic strokes indirectly estimated that 44% of ESUS cases were cardioembolic.
Nontraumatic intracerebral hemorrhage (ICH) is independently associated with a long-term increased risk of major arterial ischemic events. While the relationship between ICH location and ischemic ...risk has been studied, whether hematoma volume influences this risk is poorly understood.
We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) trials. The exposure was hematoma volume, treated as a continuous measure in the primary analysis, and dichotomized by the median in the secondary analyses. The outcome was a symptomatic, clinically overt ischemic stroke, adjudicated centrally within each trial. We evaluated the association between hematoma volume and the risk of an ischemic stroke using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics.
Of 1470 patients with ICH, the mean age was 61.7 (SD, 12.8) years, and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (interquartile range, 7.2-35.7). During a median follow-up of 107 days (interquartile range, 91-140), a total of 30 ischemic strokes occurred, of which 22 were in patients with a median ICH volume of ≥17.3 mL and a cumulative incidence of 4.6% (95% CI, 3.1-7.1). Among patients with a median ICH volume <17.3 mL, there were 8 ischemic strokes with a cumulative incidence of 3.1% (95% CI, 1.7-6.0). In primary analyses using adjusted Cox regression models, ICH volume was associated with an increased risk of ischemic stroke (hazard ratio, 1.02 per mL increase 95% CI, 1.01-1.04). In secondary analyses, ICH volume of ≥17.3 mL was associated with an increased risk of ischemic stroke (hazard ratio, 2.5 95% CI, 1.1-7.2), compared with those with an ICH volume <17.3 mL.
In a heterogeneous cohort of patients with ICH, initial hematoma volume was associated with a heightened short-term risk of ischemic stroke.
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Background:
Whether silent myocardial infarction (MI) is a risk factor for ischemic stroke remains uncertain.
Hypothesis:
Silent MI is associated with incident ischemic stroke.
Methods:
...The Cardiovascular Health Study prospectively enrolled community-dwelling individuals ≥65 years of age with follow-up through June 30, 2015. For this study, we included participants from the first study cohort (enrolled in 1989-1990) without prevalent stroke or baseline electrocardiographic (ECG) evidence of MI. Our exposures were silent and clinically apparent MI. Silent MI was defined as new evidence of Q-wave MI, without clinical symptoms of MI, on ECGs performed during annual study visits from 1989-1999. Clinically apparent (overt) MI was adjudicated on the basis of information about chest pain, ECG changes, and cardiac enzymes. The primary outcome was incident ischemic stroke. Secondary outcomes were ischemic stroke subtypes: non-lacunar, lacunar, and other/unknown. Cox proportional hazards analysis was used to model the association between time-varying MI status (silent, overt, or no MI) and stroke after adjustment for baseline demographics and vascular risk factors. Due to a violation of the proportional hazards assumption, the association between overt MI and stroke was modeled separately for short-term (within 30 days) and long-term (beyond 30 days) risk.
Results:
Among 4,224 participants included in this analysis, 362 (8.6%) had an incident silent MI, 421 (10.0%) an incident overt MI, and 377 (8.9%) an incident ischemic stroke during a median follow-up of 9.8 years. After adjustment for demographics and comorbidities, silent MI was independently associated with subsequent ischemic stroke (HR, 1.47; 95% CI, 1.01-2.16). Overt MI was associated with ischemic stroke both in the short term (HR, 80; 95% CI, 53-119) and long term (HR, 1.60; 95% CI, 1.04-2.44). In secondary analyses, the association between silent MI and stroke was limited to non-lacunar ischemic stroke (HR 2.18; 95% CI, 1.24-3.83).
Conclusions:
In a community-based sample, we found an association between silent MI and ischemic stroke, specifically non-lacunar stroke. These findings suggest that silent MI may be a novel risk factor for ischemic stroke.
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Background and Purpose:
Emerging data suggest an increased risk of arterial ischemic events after intracerebral hemorrhage (ICH), but their impact on ICH outcomes is unclear. This study ...aimed to evaluate the risk of death among ICH survivors with and without an incident arterial ischemic event.
Methods:
We performed a retrospective cohort study using claims data from Medicare beneficiaries with a non-traumatic ICH from January 2008 to October 2015. Our exposure was an arterial ischemic event, defined as a composite of acute ischemic stroke or myocardial infarction (MI), identified using validated ICD-9-CM diagnosis codes. The outcome was death. After excluding ischemic events and deaths in the first 30 days after ICH discharge to prevent carryover of diagnosis codes from the initial hospitalization, we used marginal structural models to analyze the risk of death among ICH patients with and without an arterial ischemic event, after adjusting for demographics and vascular comorbidities as time-varying covariates. In secondary analyses, we studied the mortality risk separately after an ischemic stroke and MI.
Results:
Among 8,222 Medicare beneficiaries with an ICH, 2,371 (28.8%) had an arterial ischemic event. During a median follow up time of 2.0 years (interquartile range, 0.8-3.8), the cumulative mortality rate was 7.0% (95% confidence interval CI, 6.5-7.5%) in patients with an arterial ischemic event and 4.0% (95% CI, 3.8-4.2%) in patients without an arterial ischemic event. In the marginal structural model, the occurrence of an arterial ischemic event was associated with an increased risk of death (hazard ratio HR, 1.6; 95% confidence interval CI, 1.5- 1.7). In secondary analyses, the mortality risk was elevated after both an ischemic stroke (HR, 1.5; 95% CI, 1.4-1.6), and a MI (HR, 2.6; 95% CI, 2.1-3.2).
Conclusions:
In a large population-based cohort, we found that elderly patients who survived an ICH had an increased risk of death after a subsequent ischemic stroke or MI. Careful exploration of secondary cardiovascular and stroke prevention strategies may be warranted in these patients.
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Introduction:
Arterial dissections often have no known identifiable risk factor. Whether infection/inflammation may play a role in the development of arterial dissection is uncertain.
...Hypothesis:
Influenza-like illness (ILI) is associated with a heightened risk of arterial dissection.
Methods:
We performed a case-crossover analysis using administrative claims data on emergency department visits and acute care hospitalizations from 2006 to 2015 in NY and 2005-2015 in FL. We used previously validated
International Classification of Diseases, Ninth Revision, Clinical Modification
codes to identify patients with ILI and arterial dissection. Arterial dissection included the composite of cervical artery dissection (carotid and vertebral), coronary artery dissection, and aortic dissection. We compared the risk of arterial dissection in successive 30-day periods after ILI versus the corresponding 30-day periods one year earlier. We used McNemar test for matched data to calculate the absolute risk increases.
Results:
We identified 2,838,178 patients with ILI. The absolute increase in arterial dissection was 0.005% (95% CI, 0.004-0.006%) in the thirty days post ILI compared with the same period one year earlier (OR 3.3, 95% CI, 2.5-4.4). The absolute increase in arterial dissection attenuated over successive 30-day periods after ILI and was no longer significant after 120 days post ILI (Figure). Our results were similar in secondary analyses evaluating cervical, coronary, and aortic dissections separately.
Conclusions:
ILI is associated with a heightened short-term risk of arterial dissection. Further studies are warranted to evaluate mechanisms of how ILI and/or related inflammation leads to a heightened risk of systemic and cerebrovascular dissections.
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Introduction:
Acute ischemic stroke (AIS) may be the first sign of occult cancer. We aimed to better define the incidence of cancer in the year after AIS and to identify clinical ...factors associated with new cancer diagnoses.
Methods:
This was a retrospective cohort study using data from the Cornell Acute Stroke Academic Registry (CAESAR) on patients hospitalized at our center with AIS from 2011-2015. Patients with history of cancer were excluded. Through automated electronic data capture and manual abstraction of inpatient and outpatient medical records, we collected data on patients’ demographics, comorbidities, presentation, radiographic characteristics, stroke subtype, and clinical outcomes. Patients were followed for 1 year after the index AIS for a new diagnosis of pathologically-confirmed cancer. Cox hazards regression adjusting for the competing risk of death was used to evaluate associations between clinical factors and incident cancer. Factors significantly associated in multivariable analysis were entered into a risk stratification score, and this score’s discriminatory ability was evaluated by Harrell’s C-statistic.
Results:
After excluding 253 patients with history of cancer, this analysis included 963 patients with AIS. During a mean follow-up of 222 days, 16 patients (1.7%; 95% CI, 1.0-2.7%) were diagnosed with cancer. The most common cancers were lung (n=7) and leukemia (n=4) and the median time to cancer diagnosis was 13 days (IQR, 7-194 days). Among patients with cryptogenic stroke, the 1-year cancer incidence rate was 1.7% (95% CI, 0.6-3.7%). Clinical factors associated with incident cancer in multivariable analysis were venous thromboembolism during the AIS hospitalization (HR, 12.5; 95% CI, 3.3-47.0), unexplained weight loss within 6 months (HR 11.7; 95% CI, 3.3-42.0), and three-territory acute infarcts (HR, 4.1, 95% CI, 1.3-13.4). These factors were used to create a clinical score that had a C-statistic of 0.7 (95% CI, 0.5-0.8).
Conclusions:
In a large urban cohort of AIS, the estimated 1-year incidence of first-ever cancer was 1.7%. Unexplained weight loss, concomitant venous thromboembolism, and three-territory acute infarction pattern may serve as clues to occult cancer with AIS.
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Introduction:
Clinically silent cerebrovascular disease is present in 40% of persons over the age of 60. We hypothesize that polygenic susceptibility to atrial fibrillation is ...associated with the burden of white matter disease in persons without atrial fibrillation or history of ischemic stroke.
Methods:
We conducted a nested genetic and neuroimaging study within the UK Biobank, a large cohort study that enrolled community dwelling Britons aged 40 to 65 at recruitment. We used data on a subcohort of patients evaluated with brain MRIs. The volume of white matter hyperintensities (WMH) was estimated using the BIANCA lesion segmentation tool. Genomic data was ascertained via genotyping with the Affymetrix UK Biobank Axiom array followed by imputation with 1000 Genomes reference panels. To model the polygenic susceptibility to atrial fibrillation (AFIB), we constructed a polygenic risk score (PRS) using 957 independent genetic risk variants known to significantly associate with atrial fibrillation. We used logistic and linear regression to test for association between the PRS and WMH.
Results:
A total of 38,914 study participants underwent brain MRI imaging in the UK Biobank. Of these, we excluded 124 (0.3%) with a history of stroke and 926 (2.4%) with AFIB. 37,864 study participants were included in this study, of which 19,059 (50.3%) had WMH. High genetic risk of AFIB was not associated with no-versus-any WMH (p=0.51). When evaluating persons with WMH lesions, high genetic risk of AFIB was associated with higher WMH volume (per 1 SD increase of the PRS, beta 0.019, SE 0.006; p=0.01). Gender was an important effect modifier of this association (interaction p=0.03): while high genetic risk of AFIB was associated with a significant increase in WMH volume in females (per 1 SD increase of the PRS, beta 0.03, SE 0.008; p<0.001), no association was found for males (p=0.99).
Conclusions:
Polygenic susceptibility to atrial fibrillation is associated with more severe silent cerebrovascular disease in persons without atrial fibrillation. Further research should evaluate whether this genetic information can be used to identify persons for tailored diagnostic or therapeutic interventions.
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Background:
Cervical artery dissection (CAD) often affects young, otherwise healthy people. Few data exist on whether patients with CAD face an increased vulnerability to aortic ...dissection. Herein we tested the hypothesis that CAD is associated with an increased risk of aortic dissection.
Methods:
We performed a retrospective cohort study using statewide administrative claims data from all Emergency Department visits and admissions at nonfederal hospitals in Florida from 2005 to 2015 and New York from 2006 to 2015. We used previously validated International Classification of Disease, Ninth Revision, Clinical Modification codes (ICD-9-CM) to identify patients with CAD and aortic dissection. Patients with prevalent aortic dissection were excluded. Our exposure variable was CAD and the outcome was incident aortic dissection after discharge from CAD hospitalization. Survival statistics were used to calculate incidence rates and Cox proportional hazards analysis was used to determine the association between CAD and aortic dissection while adjusting for demographics and vascular risk factors. In a secondary analysis, we excluded patients who had a traumatic CAD, defined as having concomitant ICD-9-CM codes for head or neck trauma at the time of CAD.
Results:
Among 19,715,114 patients, 4,537 (0.02%) had a CAD. The mean age of patients with CAD was 52.3±16.4 years. During 4.2±3.1 years of follow up, 16,571 patients were diagnosed with an aortic dissection (0.08%). The incidence of aortic dissection was 2.5 (95% CI, 1.7-3.7) per 1,000 patients per year in those with CAD versus 0.2 (95% CI, 0.2-0.2) per 1,000 patients per year in those without CAD. After adjustment for demographics and vascular risk factors, we found that CAD was associated with subsequent aortic dissection (HR 3.0, 95% CI, 2.1-4.5). Our results were similar in a secondary analysis excluding patients with traumatic CAD (HR 3.3, 95% CI, 2.2-4.8).
Conclusions:
In a large population-based cohort, we found that CAD was associated with a 3-fold increased risk of aortic dissection. Future studies should evaluate the utility of performing screening aortic imaging in patients with CAD.
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