Philip Choi

Enhanced Store Overload-Induced Ca2+ Release and Channel Sensitivity to Luminal Ca2+ Activation are Common Defects of RyR2 Mutations Linked to Ventricular Tachycardia and Sudden Death

Ventricular tachycardia (VT) is the leading cause of sudden death, and the cardiac ryanodine receptor (RyR2) is emerging as an important focus in its pathogenesis. RyR2 mutations have been linked to VT and sudden death, but their precise impacts on channel function remain largely undefined and controversial. We have previously shown that several disease-linked RyR2 mutations in the C-terminal region enhance the sensitivity of the channel to activation by luminal Ca2+. Cells expressing these RyR2 mutants display an increased propensity for spontaneous Ca2+ release under conditions of store Ca2+ overload, a process we referred to as store overload–induced Ca2+ release (SOICR). To determine whether common defects exist in disease-linked RyR2 mutations, we characterized 6 more RyR2 mutations from different regions of the channel. Stable inducible HEK293 cell lines expressing Q4201R and I4867M from the C-terminal region, S2246L and R2474S from the central region, and R176Q(T2504M) and L433P from the N-terminal region were generated. All of these cell lines display an enhanced propensity for SOICR. HL-1 cardiac cells transfected with disease-linked RyR2 mutations also exhibit increased SOICR activity. Single channel analyses reveal that disease-linked RyR2 mutations primarily increase the channel sensitivity to luminal, but not to cytosolic, Ca2+ activation. Moreover, the Ca2+ dependence of [3H]ryanodine binding to RyR2 wild type and mutants is similar. In contrast to previous reports, we found no evidence that disease-linked RyR2 mutations alter the FKBP12.6–RyR2 interaction. Our data indicate that enhanced SOICR activity and luminal Ca2+ activation represent common defects of RyR2 mutations associated with VT and sudden death. A mechanistic model for CPVT/ARVD2 is proposed.

Silent Infarcts and Cerebral Microbleeds Modify the Associations of White Matter Lesions With Gait and Postural Stability Population-Based Study

Background and Purpose— Although cerebral white matter lesions (WMLs), silent infarcts (SIs), and microbleeds (MBs) are individually associated with poorer gait and balance, it is unknown if they interact. We studied the interactions of WML volume with SI and MB on gait and postural stability. Methods— Participants in a population-based study aged 60 to 86 years underwent brain MRI, computerized gait measurement, and a physiological profile assessment of postural stability. Segmentation procedures and standard rating methods were used to measure WML, SI, and MB. Linear regression was used to test interactions between lesions on gait and postural stability, adjusting for age, sex, and total intracranial volume. Results— There were 395 participants (mean age, 72 years; SD, 7.0). SIs were predominantly located in subcortical frontal white matter and in deep gray structures, and MBs were largely lobar. Participants with SI or MB had higher WML volumes than those without (P<0.001 and P=0.05, respectively). The presence of SI (P for interaction=0.01) or MB (P for interaction <0.01) magnified the adverse association of WML volume with gait. SI (P for interaction=0.02), but not MB, magnified the adverse association of WML volume with postural stability. Conclusions— Subclinical cerebrovascular lesions are adversely associated with gait and postural stability in older people in a cumulative fashion.

Trends Over Time in the Risk of Stroke After an Incident Transient Ischemic Attack

Background and Purpose— Long-term population trends in the early risk of stroke after transient ischemic attack (TIA) are unknown. We hypothesized that there has been an appreciable decline in the risk of stroke after TIA for the last decade. Methods— Population-level cohort study from Victoria, Australia (population 5.6 million), using linked data from hospitals, emergency departments, and death records (2001–2011), with a 2-year clearance period to define incident TIAs. Age-specific rates/1000, yearly incident rate ratios, and age–sex-adjusted risk of stroke after TIA were computed. Results— The mean age of 46 971 patients with TIA was 71 (SD=15), 52% women. In patients ≥65 years, annual TIA rates declined between 2001 and 2011 from 5.8 to 4.8/1000 (men) and from 5.3 to 4.2/1000 (women). Yearly incident rate ratios were 0.97 (95% confidence interval, 0.96–0.98) in men and 0.97 (95% confidence interval, 0.97–0.98) in women. Overall, the 90-day stroke risk was 3.1%. Age–sex-adjusted risk of stroke at 90 days after a TIA decreased by 3% per year (odds ratio for the effect of year, 0.97; 95% confidence interval, 0.95–0.99). Male sex, direct discharge from emergency departments, public hospital care, stroke unit care, and absence of vascular risk factors were associated with a downward yearly trend of stroke within 90 days of TIA. Conclusions— Over the last 10 years, there has been a measurable decline in the 90-day risk of stroke after an incident TIA and overall decline in rates of TIA in Victoria, Australia. These trends may reflect improved primary and secondary prevention efforts for the last decade.

Endovascular Therapy for Ischemic Stroke

The utility of intravenous tissue plasminogen activator (IV t-PA) in improving the clinical outcomes after acute ischemic stroke has been well demonstrated in past clinical trials. Though multiple initial small series of endovascular stroke therapy had shown good outcomes as compared to IV t-PA, a similar beneficial effect had not been translated in multiple randomized clinical trials of endovascular stroke therapy. Over the same time, there have been parallel advances in imaging technology and better understanding and utility of the imaging in therapy of acute stroke. In this review, we will discuss the evolution of endovascular stroke therapy followed by a discussion of the key factors that have to be considered during endovascular stroke therapy and directions for future endovascular stroke trials.

Deconstruction of Interhospital Transfer Workflow in Large Vessel Occlusion: Real-World Data in the Thrombectomy Era

Background and Purpose— Interhospital transfer is a critical component in the treatment of acute anterior circulation large vessel occlusive stroke transferred for mechanical thrombectomy. Real-world data for benchmarking and theoretical modeling are limited. We sought to characterize transfer workflow from primary stroke center (PSC) to comprehensive stroke center after the publication of positive thrombectomy trials. Methods— Consecutive patients transferred from 3 high-volume PSCs to a single comprehensive stroke center between January 2015 and August 2016 were included in a retrospective study. Factors associated with key time metrics were analyzed with emphasis on PSC intrahospital workflow. Results— Sixty-seven patients were identified. Median age was 74 years (interquartile range [IQR], 63.5–78) and National Institutes of Health Stroke Scale 17 (IQR, 12–21). Median transfer time measured by PSC-door-to-comprehensive stroke center-door was 128 minutes (IQR, 107–164), of which 82.8% was spent at PSCs (door-in-door-out [DIDO]; 106 minutes; IQR, 86–143). The lengthiest component of DIDO was computed-tomography-to-retrieval-request (median 59.5 minutes; IQR, 44–83). The 37.3% had DIDO exceeding 120 minutes. DIDO times differed significantly between PSCs (P=0.01). In multivariate analyses, rerecruiting the initial ambulance crew for transfer (P<0.01) and presentation during working hours (P=0.04) were associated with shorter DIDO times. Conclusions— In a metropolitan hub-and-spoke network, PSC-door-to-comprehensive stroke center-door and DIDO times are long even in high-volume PSCs. Improving PSC workflow represents a major opportunity to expedite mechanical thrombectomy and improve patient outcomes.

Visualizing Acute Stroke Data to Improve Clinical Outcomes

Acute stroke care has highly time-dependent treatments that require teams of personnel to achieve good outcomes. It is estimated that for every minute the middle cerebral artery remains blocked in an ischemic stroke, 1.9 million neurons are lost.1 Reducing the variance and improving door-to-needle (DTN) time for thrombolysis and time from computed tomography (CT)-to-groin puncture for endovascular therapy will improve outcomes for patients with stroke.1–5 Therefore, reducing variance and improving treatment times are critical components for quality assurance efforts in stroke care. Feedback of DTN performance data has been used in quality improvement initiatives for acute stroke treatment.6,7 In a similar manner, we have observed that the first step of simply providing healthcare personnel with their measured metrics is an inducement to improve and work faster. However, the acute stroke performance data need to be presented in manner that is easy to understand, and it should be available through commonly used modalities to facilitate widespread use. ### Background on Information Visualization Information visualization is a discipline in its own right that combines graphical display in static or dynamic form to reveal a new understanding of data. In clinical medicine, novel methods of information visualization can lead to improved clinical outcomes at both the population and individual levels.8 Famously, in the mid-1800s, John Snow was able to isolate a contaminated water-well and show that cholera was water born by mapping the location and frequency of cholera infections in London’s Soho district.9 Florence Nightingale used her rose petal graphic to show the rise in mortality because of hospital-acquired infections during the Crimean war.10 Simplifying clinical concepts into graphics that are easy to understand can provide insight into the causes of poor health outcomes and lead to positive changes. ### Visualizations in Health Care There has been a rise in the use of …

Utility of Computed Tomographic Perfusion in Thrombolysis for Minor Stroke

Background and Purpose— The use of thrombolysis in acute minor ischemic stroke (MIS) remains controversial. We sought to determine the safety and efficacy of intravenous tissue-type plasminogen activator (IV-tPA) in acute MIS patients with demonstrable penumbra on computed tomographic perfusion study. Methods— Consecutive MIS patients with National Institutes of Health Stroke Scale ⩽3 were identified from a prospective single tertiary-center database over a 4.5-year period (2011–2015). Cases with demonstrable penumbra were analyzed according to treatment received: IV-tPA versus standard stroke-unit care without thrombolysis. Results— Seventy-three patients of 195 acute MIS admissions had a demonstrable penumbra (34 IV-tPA versus 39 standard stroke-unit care). Overall median National Institutes of Health Stroke Scale and premorbid modified Rankin Scale were 2 and 0, respectively. Median age was 73.2 (interquartile range, 67.3–82.8) years. There were no differences in baseline demographics, risk factors, stroke localization and cause, rates of vascular occlusion (38.2% versus 38.5%; P=1.000), or mean penumbral volume (41.3 versus 25.1 mL; P=0.150; IV-tPA versus standard stroke-unit care) between groups. There were no symptomatic intracerebral hemorrhages in either group. Patients treated with IV-tPA were more likely to have an excellent functional outcome at discharge (88.2% versus 53.9%; P=0.002) and 90 days (91.2% versus 71.8%; P=0.042). Ordinal analysis demonstrated a favorable shift in modified Rankin Scale with IV-tPA both at discharge (odds ratio, 5.23; 95% confidence interval, 1.83–12.20) and 90 days (odds ratio, 4.35; 95% confidence interval, 1.77–11.36). Conclusions— In selected MIS patients with demonstrable penumbra on computed tomographic perfusion, IV-tPA is safe and associated with significant improvement in functional outcome at discharge and 90 days.

‘Fogging’ resulting in normal MRI 3 weeks after ischaemic stroke

CT of the brain is often negative in acute stroke. The absence of changes suggestive of infarction on MRI of the brain in the setting of a recent stroke is unusual. An otherwise fit and well 69-year-old Caucasian man presented to the hospital with a 26-h history of acute mild right hemiparesis. CT brain on arrival showed no abnormality. MRI brain was also normal 3 weeks post stroke with abnormality seen only at 11 weeks. Stroke remains a clinical diagnosis. The time of the stroke must be taken into consideration when interpreting MRI brain images. Infarct may be ‘invisible’ on MRI in the subacute phase of ischaemic stroke.

CT perfusion predicts tissue injury in TIA and minor stroke

Diffusion-weighted imaging (DWI) changes in transient ischaemic attack and minor ischaemic stroke (TIA/MIS) patients predict a poorer prognosis with increased risk of recurrent strokes and persistent disability [1, 2]. Identifying these patients in the hyperacute setting may allow early risk stratification to aid clinical decision making. Recent reports evaluating the prognostic value of CT perfusion studies (CTP) have predominantly focused on moderate to severe stroke patients [3, 4]. In this study, we sought to determine the utility of CTP as a prognostic modality in TIA/MIS patients by investigating the association between acute ischaemic changes on CTP and the presence of abnormal restricted diffusion on follow-up DWI magnetic resonance imaging (DWI-positive). We compared the prevalence of a DWI-positive result between patients with and without a CTP ischaemic lesion among 138 consecutive TIA/MIS patients identified from a prospective tertiary stroke centre database over 4.5 years (2011–2015). The main inclusion criteria were (1) presentation within 4.5 h of symptoms onset, (2) NIH Stroke Scale B3, (3) underwent CTP while symptomatic and (4) had follow-up DWI. CTP ischaemic lesion was defined as an area of prolonged time-to-peak corresponding to the presenting symptoms as assessed by two experienced raters blinded to all other clinical information. TIA was defined using time-based criteria as a focal cerebral ischaemic event with symptoms lasting less than 24 h. T test, Fisher exact test and logistic regression were used for statistical analysis. Overall, the mean age was 71.8 years (standard deviation 13.3), and the median presenting NIH Stroke Scale was 2 [interquartile range (IQR) 1–3] (Table 1). Median symptoms duration was 110 min (IQR 78–145) among twenty-nine TIA patients (21.0%). Sixty-two patients had a CTP ischaemic lesion in the study cohort. Twenty-eight patients (20.3%) received intravenous alteplase thrombolysis at the discretion of the treating neurologist. Among non-thrombolysed patients (n = 110), those with CTP ischaemic lesions were significantly more likely to have a DWI-positive result (100% vs, 49.3%, p\ 0.01), have atrial fibrillation (AF) (34.3% vs. 16.0%, p = 0.046) and be disabled on discharge (modified Rankin Scale C2) (40.6% vs. 25.6%, p = 0.04) compared to patients with a normal CTP. In addition, CTP ischaemic lesion was associated with a significant shift in the distribution of modified Rankin Scale towards higher disability at discharge (odds ratio 3.33; 95% confidence interval, 1.56–7.09). There were no differences between groups among baseline demographics, presenting NIH Stroke Scale domains involved, stroke location, cardiovascular risk factors and CTP ischaemic lesion volume. CTP had high specificity (100%, 95% confidence interval 89.3–100%), high positive predictive value (100%, 95% confidence interval 87.7–100%) but moderate sensitivity (48.6%, 95% confidence interval 36.7–60.7%) in detecting a DWI-positive result in non-thrombolysed patients. All patients with CTP ischaemic lesions developed abnormal restricted diffusion unless alteplase thrombolysis was administered (100 vs. 77.8%; p\ 0.01). & Felix C. Ng ng.fcffelix@gmail.com

Seven days of non-invasive cardiac monitoring early postischaemic stroke or TIA increases atrial fibrillation detection rate compared with current guideline-based practice.

Commentary on: Higgins P, Macfarlane PW, Dawson J, et al. Non-invasive cardiac event monitoring to detect atrial fibrillation after ischemic stroke: a randomized, controlled trial. Stroke 2013;44:2525–31.[OpenUrl][1][Abstract/FREE Full Text][2] Atrial fibrillation (AF) is an established risk factor for stroke, and anticoagulation treatment is effective in reducing recurrent stroke risk. Guidelines recommend the use of clinical prediction tools to select patients with AF for anticoagulation therapy. It has long been recognised that paroxysmal AF (PAF) may pose a similar stroke risk to persistent AF, but the association between the duration of PAF and stroke risk remains uncertain. The best method to detect PAF has yet to be conclusively determined.1 ,2 This randomised controlled trial examines whether prolonged, non-invasive cardiac monitoring poststroke is superior to guideline-based standard treatment in PAF detection. The trial assessed the detection of AF in … [1]: {openurl}?query=rft.jtitle%253DStroke%26rft_id%253Dinfo%253Adoi%252F10.1161%252FSTROKEAHA.113.001927%26rft_id%253Dinfo%253Apmid%252F23899913%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=strokeaha&resid=44/9/2525&atom=%2Febmed%2F19%2F4%2F152.atom