Serum IGFBP-1 Concentration as a Predictor of Outcome after Ischemic Stroke—A Prospective Observational Study

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates insulin-like growth factor-I (IGF-I) bioactivity, and is a central player in normal growth, metabolism, and stroke recovery. However, the role of serum IGFBP-1 (s-IGFBP-1) after ischemic stroke is unclear. We determined whether s-IGFBP-1 is predictive of poststroke outcome. The study population comprised patients (n = 470) and controls (n = 471) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Functional outcome was evaluated after 3 months, 2, and 7 years using the modified Rankin Scale (mRS). Survival was followed for a minimum of 7 years or until death. S-IGFBP-1 was increased after 3 months (p 2) after 7 years [fully adjusted odds ratio (OR) per log increase 2.9, 95% confidence interval (CI): 1.4-5.9]. Moreover, higher s-IGFBP-1 after 3 months was associated with a risk of poor functional outcome after 2 and 7 years (fully adjusted: OR 3.4, 95% CI: 1.4-8.5 and OR 5.7, 95% CI: 2.5-12.8, respectively) and with increased mortality risk (fully adjusted: HR 2.0, 95% CI: 1.1-3.7). Thus, high acute s-IGFBP-1 was only associated with poor functional outcome after 7 years, whereas s-IGFBP-1 after 3 months was an independent predictor of poor long-term functional outcome and poststroke mortality

Cancer and stroke : commonly encountered by clinicians, but little evidence to guide clinical approach

The association between stroke and cancer is well-established. Because of an aging population and longer survival rates, the frequency of synchronous stroke and cancer will become even more common. Different pathophysiologic mechanisms have been proposed how cancer or cancer treatment directly or via coagulation disturbances can mediate stroke. Increased serum levels of D-dimer, fibrin degradation products, and CRP are more often seen in stroke with concomitant cancer, and the clot retrieved during thrombectomy has a more fibrin- and platelet-rich constitution compared with that of atherosclerotic etiology. Multiple infarctions are more common in patients with active cancer compared with those without a cancer diagnosis. New MRI techniques may help in detecting typical patterns seen in the presence of a concomitant cancer. In ischemic stroke patients, a newly published cancer probability score can help clinicians in their decision-making when to suspect an underlying malignancy in a stroke patient and to start cancer-screening studies. Treating stroke patients with synchronous cancer can be a delicate matter. Limited evidence suggests that administration of intravenous thrombolysis appears safe in non-axial intracranial and non-metastatic cancer patients. Endovascular thrombectomy is probably rather safe in these patients, but probably futile in most patients placed on palliative care due to their advanced disease. In this topical review, we discuss the epidemiology, pathophysiology, and prognosis of ischemic and hemorrhagic strokes as well as cerebral venous thrombosis and concomitant cancer. We further summarize the current evidence on acute management and secondary preventive therapy.Peer reviewe

S100b in acute ischemic stroke clots is a biomarker for post-thrombectomy intracranial hemorrhages

Background and purposePost-thrombectomy intracranial hemorrhages (PTIH) are dangerous complications of acute ischemic stroke (AIS) following mechanical thrombectomy. We aimed to investigate if S100b levels in AIS clots removed by mechanical thrombectomy correlated to increased risk of PTIH.MethodsWe analyzed 122 thrombi from 80 AIS patients in the RESTORE Registry of AIS clots, selecting an equal number of patients having been pre-treated or not with rtPA (40 each group). Within each subgroup, 20 patients had developed PTIH and 20 patients showed no signs of hemorrhage. Gross photos of each clot were taken and extracted clot area (ECA) was measured using ImageJ. Immunohistochemistry for S100b was performed and Orbit Image Analysis was used for quantification. Immunofluorescence was performed to investigate co-localization between S100b and T-lymphocytes, neutrophils and macrophages. Chi-square or Kruskal-Wallis test were used for statistical analysis.ResultsPTIH was associated with higher S100b levels in clots (0.33 [0.08–0.85] vs. 0.07 [0.02–0.27] mm2, H1 = 6.021, P = 0.014*), but S100b levels were not significantly affected by acute thrombolytic treatment (P = 0.386). PTIH was also associated with patients having higher NIHSS at admission (20.0 [17.0–23.0] vs. 14.0 [10.5–19.0], H1 = 8.006, P = 0.005) and higher number of passes during thrombectomy (2 [1–4] vs. 1 [1–2.5], H1 = 5.995, P = 0.014*). S100b co-localized with neutrophils, macrophages and with T-lymphocytes in the clots.ConclusionsHigher S100b expression in AIS clots, higher NIHSS at admission and higher number of passes during thrombectomy are all associated with PTIH. Further investigation of S100b expression in AIS clots by neutrophils, macrophages and T-lymphocytes could provide insight into the role of S100b in thromboinflammation

Self-perceived psychological stress and ischemic stroke: a case-control study

<p>Abstract</p> <p>Background</p> <p>A growing body of evidence suggests that psychological stress contributes to coronary artery disease. However, associations between stress and stroke are less clear. In this study, we investigated the possible association between ischemic stroke and self-perceived psychological stress, as measured by a single-item questionnaire, previously reported to be associated with myocardial infarction.</p> <p>Methods</p> <p>In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 consecutive patients with acute ischemic stroke (aged 18 to 69 years) and 600 age-matched and sex-matched population controls were recruited. Ischemic stroke subtype was determined according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Self-perceived psychological stress preceding stroke was assessed retrospectively using a single-item questionnaire.</p> <p>Results</p> <p>Permanent self-perceived psychological stress during the last year or longer was independently associated with overall ischemic stroke (multivariate adjusted odds ratio (OR) 3.49, 95% confidence interval (CI) 2.06 to 5.93). Analyses by stroke subtype showed that this association was present for large vessel disease (OR 3.91, 95% CI 1.58 to 9.67), small vessel disease (OR 3.20, 95% CI 1.64 to 6.24), and cryptogenic stroke (OR 4.03, 95% CI 2.34 to 6.95), but not for cardioembolic stroke (OR 1.48, 95% CI 0.64 to 3.39).</p> <p>Conclusion</p> <p>In this case-control study, we found an independent association between self-perceived psychological stress and ischemic stroke. A novel finding was that this association differed by ischemic stroke subtype. Our results emphasize the need for further prospective studies addressing the potential role for psychological stress as a risk factor for ischemic stroke. In such studies ischemic stroke subtypes should be taken into consideration.</p

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design

Background: Worldwide, about 1.3 million annual ischaemic strokes (IS) occur in adults aged <50 years. Of these early-onset strokes, up to 50% can be regarded as cryptogenic or associated with conditions with poorly documented causality like patent foramen ovale and coagulopathies. Key hypotheses/aims: (1) Investigate transient triggers and clinical/sub-clinical chronic risk factors associated with cryptogenic IS in the young; (2) use cardiac imaging methods exceeding state-of-the-art to reveal novel sources for embolism; (3) search for covert thrombosis and haemostasis abnormalities; (4) discover new disease pathways using next-generation sequencing and RNA gene expression studies; (5) determine patient prognosis by use of phenotypic and genetic data; and (6) adapt systems medicine approach to investigate complex risk-factor interactions. Design: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is a prospective multi-centre case–control study enrolling patients aged 18–49 years hospitalised due to first-ever imaging-proven IS of undetermined etiology. Patients are examined according to a standardised protocol and followed up for 10 years. Patients are 1:1 age- and sex-matched to stroke-free controls. Key study elements include centralised reading of echocardiography, electrocardiography, and neurovascular imaging, as well as blood samples for genetic, gene-expression, thrombosis and haemostasis and biomarker analysis. We aim to have 600 patient– control pairs enrolled by the end of 2018. Summary: SECRETO is aiming to establish novel mechanisms and prognosis of cryptogenic IS in the young and will provide new directions for therapy development for these patients. First results are anticipated in 2019

Obesity and the Risk of Cryptogenic Ischemic Stroke in Young Adults

Objectives: We examined the association between obesity and early-onset cryptogenic ischemic stroke (CIS) and whether fat distribution or sex altered this association. Materials and Methods: This prospective, multi-center, case-control study included 345 patients, aged 18-49 years, with first-ever, acute CIS. The control group included 345 age-and sex-matched stroke-free individuals. We measured height, weight, waist circumference, and hip circumference. Obesity metrics analyzed included body mass index (BMI), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), and a body shape index (ABSI). Models were adjusted for age, level of education, vascular risk factors, and migraine with aura. Results: After adjusting for demographics, vascular risk factors, and migraine with aura, the highest tertile of WHR was associated with CIS (OR for highest versus lowest WHR tertile 2.81, 95%CI 1.43-5.51; P=0.003). In sex-specific analyses, WHR tertiles were not associated with CIS. However, using WHO WHR cutoff values (>0.85 for women, >0.90 for men), abdominally obese women were at increased risk of CIS (OR 2.09, 95%CI 1.02-4.27; P=0.045). After adjusting for confounders, WC, BMI, WSR, or ABSI were not associated with CIS. Conclusions: Abdominal obesity measured with WHR was an independent risk factor for CIS in young adults after rigorous adjustment for concomitant risk factors.Peer reviewe

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 one 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.Peer reviewe

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Reduced long-term mortality after successful resective epilepsy surgery : a population-based study

Background We investigated all-cause and epilepsy-related mortality in patients operated with resective epilepsy surgery and in non-operated patients with drug-resistant epilepsy. Our hypothesis was that patients who proceed to surgery have lower mortality over time compared with non-operated patients. Method Data from 1329 adults and children from the Swedish National Epilepsy Surgery Register and 666 patients with drug-resistant epilepsy who had undergone presurgical work-up but not been operated were analysed. The operated patients had follow-ups between 2 and 20 years. We used the Swedish Cause of Death Register to identify deaths. Autopsy reports were collected for patients with suspected sudden unexpected death in epilepsy (SUDEP). Kaplan-Meier and Cox regression analyses were performed to identify predictors for mortality and SUDEP. Results SUDEP accounted for 30% of all deaths. Surgery was associated with lower all-cause mortality (HR 0.7, 95% CI 0.5 to 0.9), also when adjusted for age, sex and tonic-clonic seizures at inclusion. The benefit of surgery seemed to persist and possibly even increase after 15 years of follow-up. Risk factors of mortality for operated patients were persisting seizures and living alone. Of the operated patients, 37% had seizures, and these had a higher risk of mortality (HR 2.1, 95% CI 1.4 to 3.0) and SUDEP (HR 3.5, 95% CI 1.7 to 7.3) compared with patients with seizure freedom at last follow-up. Conclusions In this large population-based epilepsy surgery cohort, operated patients had a lower all-cause mortality compared with non-operated patients with drug-resistant epilepsy. Seizure freedom was the most important beneficial factor for both all-cause mortality and SUDEP among operated patients