Mary J. MacLeod

Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke.

Recent studies have identified a major locus for risk for coronary artery disease and myocardial infarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk.

Statin Treatment and Stroke Outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

Background and Purpose— Laboratory experiments suggest statins reduce stroke severity and improve outcomes. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial was a placebo-controlled, randomized trial designed to determine whether treatment with atorvastatin reduces strokes in subjects with recent stroke or transient ischemic attack (n=4731). We analyzed SPARCL trial data to determine whether treatment favorably shifts the distribution of severities of ischemic cerebrovascular outcomes. Methods— Severity was assessed with the National Institutes of Health Stroke Scale, Barthel Index, and modified Rankin Scale score at enrollment (1 to 6 months after the index event) and 90 days poststroke in subjects having a stroke during the trial. Results— Over 4.9 years, strokes occurred in 576 subjects. There were reductions in fatal, severe (modified Rankin Scale score 5 or 4), moderate (modified Rankin Scale score 3 or 2), and mild (modified Rankin Scale score 1 or 0) outcome ischemic strokes and transient ischemic attacks and an increase in the proportion of event-free subjects randomized to atorvastatin (P<0.001 unadjusted and adjusted). Results were similar for all outcome events (ischemic and hemorrhagic, P<0.001 unadjusted and adjusted) with no effect on outcome hemorrhagic stroke severity (P=0.174 unadjusted, P=0.218 adjusted). If the analysis is restricted to those having an outcome ischemic stroke (ie, excluding those having a transient ischemic attack or no event), there was only a trend toward lesser severity with treatment based on the modified Rankin Scale score (P=0.0647) with no difference based on the National Institutes of Health Stroke Scale or Barthel Index. Conclusion— The present exploratory analysis suggests that the outcome of recurrent ischemic cerebrovascular events might be improved among statin users as compared with nonusers.

Risk of Stroke and Cardiovascular Events After Ischemic Stroke or Transient Ischemic Attack in Patients With Type 2 Diabetes or Metabolic Syndrome: Secondary Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

OBJECTIVEnTo perform a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which tested the effect of treatment with atorvastatin in reducing stroke in subjects with a recent stroke or transient ischemic attack, to explore the effects of treatment in subjects with type 2 diabetes mellitus or metabolic syndrome (MetS).nnnMETHODSnThe 4731 subjects enrolled in the SPARCL trial were classified as having type 2 diabetes mellitus at enrollment (n = 794), MetS retrospectively (n = 642), or neither diabetes nor MetS (n = 3295, the reference group) based on data collected at baseline. Cox regression models were used to determine whether the effect of treatment on the primary end point (combined risk of nonfatal and fatal stroke) and secondary end points (major coronary events, major cardiovascular events, any coronary heart disease event, and any revascularization procedure) varied based on the presence of type 2 diabetes mellitus or MetS.nnnRESULTSnSubjects with type 2 diabetes mellitus had increased risks of stroke (hazard ratio [HR] = 1.62; 95% confidence interval [CI], 1.33-1.98; P < .001), major cardiovascular events (HR = 1.66; 95% CI, 1.39-1.97; P < .001), and revascularization procedures (HR = 2.39; 95% CI, 1.78-3.19; P < .001) compared with the reference group. Subjects with MetS were not at increased risk for stroke (P = .78) or major cardiovascular events (P = .38) but more frequently had revascularization procedures (HR = 1.78; 95% CI, 1.26-2.5; P = .001). There were no treatment × subgroup interactions for the SPARCL primary end point (P = .47).nnnCONCLUSIONSnThe SPARCL subjects with type 2 diabetes were at higher risk for recurrent stroke and cardiovascular events. This exploratory analysis found no difference in the effect of statin treatment in reducing these events in subjects with or without type 2 diabetes or MetS. Trial Registration clinicaltrials.gov Identifier: NCT00147602.

The Causative Classification of Stroke system: an international reliability and optimization study.

Background: Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence-based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. Methods: Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. Results: The κ value for causative classification was 0.80 (95% confidence interval [CI] 0.78–0.81) for the 5-subtype, 0.79 (95% CI 0.77–0.80) for the 8-subtype, and 0.70 (95% CI 0.69–0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: κ = 0.81 (95% CI 0.79–0.82) for the 5-subtype, 0.79 (95% CI 0.77–0.80) for the 8-subtype, and 0.79 (95% CI 0.78–0.80) for the 16-subtype CCS. The κ value for phenotypic classification was 0.79 (95% CI 0.77–0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93–0.98) for cardioembolism, 0.88 (95% CI 0.85–0.91) for small artery occlusion, and 0.79 (0.76–0.82) for other uncommon causes. Conclusions: CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras.

Lack of association between apolipoprotein E genoype and ischaemic stroke in a Scottish population

Background Apolipoprotein E ε4 allele has been associated with increased risk of coronary heart disease, and is also a major genetic susceptibility locus for Alzheimers disease. Some studies have shown an association between apoE genotype and ischaemic stroke or outcome following stroke, while other studies have failed to do so.

Drug Treatment of Hypertension Complicating Diabetes Mellitus

Hypertension and diabetes mellitus are both common conditions associated with a high morbidity and mortality. When the two conditions occur together, as they do in 50% of diabetic individuals, the result is a 7.2-fold increase in mortality. If hypertension occurs in association with diabetes mellitus and diabetic nephropathy, mortality rises to 37-fold above that of a healthy population.Despite the increase in incidence of nephropathy, cardiovascular disease remains the major cause of death in diabetic individuals. Therapy should therefore take into consideration the results of large, placebo-controlled trials which have shown reduction in cardiovascular morbidity and mortality as a result of active treatment. Although studies with the newer antihypertensive agents such as calcium antagonists and angiotensin converting enzyme (ACE) inhibitors are ongoing, only diuretics and β-adrenoceptor antagonists have been clearly shown to reduce cardiovascular risk.Despite concerns regarding adverse metabolic effects and loss of hypoglycaemic awareness, β-blockers and diuretics do have a role in the management of diabetic patients. While it is clear that ACE inhibitors reduce the progression of diabetic nephropathy, evidence suggests that diuretics may be just as effective. However, unlike diuretics or β-blockers, ACE inhibitors have no proven benefit in the prevention of stroke or myocardial infarction. Despite the claims of metabolic neutrality made for many antihypertensive agents there appears to be no advantage in their use in the majority of hypertensive diabetic patients, except where there exist specific contraindications to established therapies.

Genome-Wide Analysis of Blood Pressure Variability and Ischemic Stroke

Background and Purpose— Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke. Methods— A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings. Results— The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (P=1.4×10−8). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97–1.07; P=0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97–1.16; P=0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89–1.07; P=0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97–1.17; P=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (P=0.18). Conclusions— We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.

Emotion processing and social participation following stroke: study protocol

BackgroundThe International Classification of Functioning, Disability and Health (ICF) defines participation as a person’s performance in life situations, including the size of social networks, and satisfaction with social contacts. Stroke survivors are known to experience a reduction in the number of their social networks and contacts, which cannot be explained solely in terms of activity limitations caused by physical impairment. Problems of emotional processing, including impaired mood, emotion regulation and emotion perception, are known to occur following stroke and can detrimentally influence many aspects of social interaction and participation. The aim of this study is to investigate whether emotion processing impairments predict stroke survivors’ restricted social participation, independent of problems with activity limitation.Methods/designWe aim to recruit 125 patients admitted to NHS Grampian with a confirmed diagnosis of stroke. All participants will be assessed on measures of emotion processing, social participation and activity limitation at approximately one month post stroke and again at approximately one year post stroke in order to assess change over time.DiscussionIt is important to develop a greater understanding of the emotional factors which may underlie key social deficits in stroke recovery in an ageing population where stroke is one of the leading causes of severe, complex disability. This research may enable us to identify those who are risk of participation restriction and target them in the acute stroke phase of stroke so that adverse outcome is avoided and rehabilitation potential is fulfilled.

The role of emotion regulation on social participation following stroke

UNLABELLEDnFollowing stroke, individuals often experience reduced social participation, regardless of physical limitations. Impairments may also occur in a range of cognitive and emotional functions. Successful emotion regulation, which has been identified as important in psychological adaptation to chronic illness, is associated with better perceived psychological well-being and social functioning. However, there is little evidence about the effect of stroke on emotion regulation difficulties, and associated impact on important outcomes in recovery from stroke.nnnOBJECTIVESnThe objectives were (1) to determine whether people who have had a stroke reported greater difficulties in emotion regulation than controls and (2) to establish whether emotion regulation difficulties relate to social participation.nnnMETHODSn75 stroke and 40 healthy participants completed measures of emotion regulation (DERS), social participation (Modified Functional Limitation Profile [mFLP], WHOQoL-Bref) and activity limitations (mFLP). Stroke participants were seen at the acute stage (63 days post-stroke) for Study 1 and 18 months post-stroke for Study 2.nnnRESULTSnIn Study 1, acute-stage stroke patients had significant impairments on impulse control, awareness of emotions, and strategies for emotion regulation. There was also evidence that emotion regulation difficulties (impulse control, awareness and clarity about emotions) were associated with social participation in the stroke sample, even after controlling for potential confounders. In Study 2, there was evidence that, in the chronic-stage post-stroke, difficulties with strategy and acceptance of emotions were associated with social participation restrictions. Whilst emotion regulation as a whole in the acute phase predicted social participation in the chronic phase of stroke, no one domain of emotion regulation was a significant predictor of social participation >1 year later.nnnDISCUSSIONnThese results indicate that multiple aspects of emotion regulation are impaired following stroke, with implications for social participation and recovery.nnnPRACTITIONER POINTSnThis research highlights the following important clinical implications: Following a stroke, emotion regulation can be immediately and persistently affected, with post-stroke individuals experiencing greater difficulties with their emotion regulation than control participants. Emotion regulation can significantly predict important stroke outcomes including social participation and quality of life, over and above physical limitations and other post-stroke confounders. This study highlights the potential for developing a behaviour change intervention to address emotion regulation difficulties and thus ensuring individuals maximize their potential rehabilitation outcome. Cautions of the study for consideration: Emotion regulation was a self-report measure, and proxy measures would have been desirable. We are unable to establish if the post-stroke individuals differed from the controls on their emotion regulation prior to stroke.

Reciprocal Interaction of 24-Hour Blood Pressure Variability and Systolic Blood Pressure on Outcome in Stroke Thrombolysis

Background and Purpose— Significance and management of blood pressure (BP) changes in acute stroke care are unclear. Here, we aimed to investigate the impact of 24-hour BP variability (BPV) on outcome in patients with acute ischemic stroke treated with intravenous thrombolysis. Methods— From the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis registry, 28u2009976 patients with documented pre-treatment systolic BP at 2 and 24 hours were analyzed. The primary measure of BP variability was successive variability. Data were preprocessed using coarsened exact matching. We assessed early neurological improvement, symptomatic intracerebral hemorrhage (SICH), and long-term functional outcome (modified Rankin Scale [mRS] at 90 days) by binary and ordinal regression analyses. Results— Attempts to explain successive variation for analysis of BPV with patients characteristics at admission found systolic BP (5.5% variance) to be most influential, yet 92% of BPV variance remained unexplained. Independently from systolic BP, successive variation for analysis of BPV was associated with poor functional outcome mRS score of 0 to 2 (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.90–0.98), disadvantage across the shift of mRS (OR, 1.04; 95% CI, 1.01–1.08), mortality (OR, 1.10; 95% CI, 1.01–1.08), SICHSITS (OR, 1.14; 95% CI, 1.06–1.23), and SICHECASS (OR, 1.24; 95% CI, 1.10–1.40; ECASS [European Cooperative Acute Stroke Study 2]). Analyzing successive variation for analysis of BPV as a function of pre-treatment, systolic BP significantly improved the prediction of functional outcome (mRS score of 0–1, mRS score of 0–2, neurological improvement, mRS-shift: all Pinteraction<0.01). Excluding patients with atrial fibrillation in a sensitivity analysis gave consistent results overall. Conclusions— This study suggests the need for a more individual BP management accounting for pre-treatment BP and the acute BP course (ie, BPV) to achieve best possible outcome for the patient.