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Relevance of Carotid Plaque Characteristics for Ischemic Stroke and Coronary Heart Disease

Citing the systemic nature of atherosclerosis, the authors of this paper studied the association between extracranial carotid atherosclerosis features and prior ischemic stroke (IS) and coronary heart disease (CHD). 

Patients were selected from the Rotterdam Study. Participants with at least 2.5mm of carotid intima media thickness (IMT) were eligible for this study. Of 3,795 eligible participants, 1,982 underwent MRI of bilateral carotid arteries. MRI was performed on 1.5-Tesla scanners with a carotid artery protocol. All plaques of at least 2mm of thickness were assessed for intraplaque hemorrhage (IPH), lipid core, and calcification. Additionally, wall thickness and degree of stenosis were determined. Participants’ history was queried for prior IS and CHD (non-fatal MI or myocardial revascularization). Covariates were age, sex, smoking status, lipid measurements, BMI, diabetes, and hypertension.

Binomial logistic regression was used to determine the association between individual plaque characteristics and history of IS and CHD. Men and women were examined separately.

One thousand seven hundred thirty-one participants were ultimately included. The mean age was 73 years, and 55% were male. A majority of patients had a history of smoking. IS and CHD were much more common in men, as were vascular risk factors. The mean carotid wall thickness was 3.6mm, and the mean degree of stenosis was 13%. IPH was present in 35%, lipid core in 41%, and calcification in 82%. In terms of outcomes, 105 had a history of IS, and 199 had a history of CHD.

In the overall population, in multivariate analysis, only degree of stenosis was associated with IS. For men, stenosis and IPH were associated with IS. In both the overall population and when stratified by sex, only carotid stenosis was associated with CHD. 

The key finding is that whereas plaque thickness or stenosis were associated with both IS and CHD, IPH was only associated with IS (in men). The dependence on prevalence data and the lack of clinical data (e.g. stroke laterality or mechanism) limit the conclusions that can be drawn from this study. However, this work may foreshadow and stimulate prospective, mechanistically enlightening studies that capitalize on the granularity of MRI data.

Intracranial Atherosclerosis and Coronary Atherosclerosis: Two Twigs from the Same Vascular Branch

Peggy Nguyen, MD

Chung J-W, Bang OY, Lee MJ, Hwang J, Cha J, Choi J-H, et al. Echoing Plaque Activity of the Coronary and Intracranial Arteries in Patients With Stroke. Stroke. 2016

Atherosclerosis is a diffuse process that can affect both the coronary and carotid arteries, but while previous studies have suggested a strong correlation between coronary atherosclerosis and extracranial carotid atherosclerosis, the correlation with intracranial atherosclerosis is less clear. Whereas the mechanism of myocardial infarction from coronary atherosclerosis is likely more similar to ischemic stroke caused by extracranial atherosclerosis, ischemic stroke caused by intracranial atherosclerosis typically falls into two etiologies: branch occlusive disease-type (B-type), where atherosclerosis occludes a perforating artery, versus coronary-type plaque rupture of plaque (C-type), where the atherosclerotic plaque ruptures, causing a shower of multiple embolic infarcts distally. This study attempts to characterize intracranial plaque phenotypes and correlate asymptomatic coronary artery disease (CAD) with intracranial atherosclerotic disease (ICAD) burden.

A total of 81 patients were included the final analysis, drawn from a population of patients admitted within 7 days of symptom onset for treatment of acute ischemic stroke with intracranial atherosclerosis. Patients who had known histories of coronary artery disease were excluded. B-type ICAS was differentiated from C-type ICAS in both anterior and posterior territory strokes. An ICAD score was calculated on the basis of intracranial atherosclerotic burden, with 0 points given for stenosis less than 50%, 1 point for stenosis of 50-99% and 2 points for an occlusion, with all involved intracranial vessels summed for a total score

Asymptomatic CAD was quite common, with a prevalence of just over 80% in the study population. The prevalence of asymptomatic CAD was relatively similar in both B-type and C-type ICAS groups (48% vs 52%) and, as might be expected, the burden of ICAD was positively correlated with the burden of CAD, although non-calcified coronary artery plaque morphology was independently associated with C-type ICAS. As non-calcified coronary plaque increased, remodeling also increased in the symptomatic arteries of patients with ICAS.

This study provides evidence of a positive relationship between coronary and intracranial atherosclerotic burden, and that coronary artery plaque composition (calcified vs non-calcified) might predict intracranial atherosclerosis morphology. The investigators suggest that this should prompt us as clinician to take a more holistic approach to the entire vascular system, rather than solely focus on, for example, the cerebral vasculature, or the coronary arteries. Certainly this might prompt the clinician to, when faced with a stroke patient with C-type ICAS, be more cognizant of the type of likely associated CAD burden, but a study evaluating whether this might also be predictive of acute coronary syndrome, would be of additional benefit.

Clinical Implications and Determinants of Left Atrial Mechanical Dysfunction in Patients with Stroke

Peggy Nguyen, MD

Kim D, Shim CY, Hong G-R, Kim M-H, Seo J, Cho IJ, et al. Clinical Implications and Determinants of Left Atrial Mechanical Dysfunction in Patients With Stroke. Stroke. 2016

Cardiovascular evaluation is an important part of the evaluation of the stroke patient, in part due to its use to diagnose cardioembolic etiologies of stroke, but also to assess for risk of future events. Left atrial enlargement has been associated with recurrent and first episodes of stroke, even in cases where dysrhythmias are not present; however, the mechanism by which this occurs is not well understood. Here, the authors use TTE with speckle tracking imaging to (1) assess enlargement and impaired mechanical function of the left atrium to define the risk of cardioembolism in stroke patients and (2) define the major determinants of left atrial mechanical dysfunction in these patients.

Two hundred forty-eight patients, derived from a larger study population of 316 acute ischemic stroke patients, who were referred for TTE and TEE, were analyzed. All patients underwent routine TTE, a TEE, as well as 2D speckle tracking echocardiography of the left atrium. Left atrial function was defined by the global left atrial longitudinal strain (LALS) and patients were divided into four groups for analyses: Group 1 – small LA with preserved LALS, Group 2 – large LA with preserved LALS, Group 3 – small LA with impaired LALS, and Group 4 – large LA with impaired LALS. Patients with large LA but impaired function (LALS) were significantly older than the other groups and experienced higher frequency of embolic strokes. 

The authors delve deep into the relationship between echo parameters of LA size and function. A global LALS less than 11.5% was found to be more predictive of a LA or LA appendage thrombus than LA volume index. Both global LALS and LA volume index were predictive of parameters which are suggestive of thrombus formation (and therefore, cardioembolic stroke risk), such as decreased LAA emptying velocity < 20 cm/s and complex aortic plaque. Left atrial function is independently correlated with age, LV function, LA volume index, and aortic stiffness.

The global LALS assessed using 2D speckle tracking imaging on TTE, being predictive of parameters suggestive of thrombus formation and being predictive of thrombus itself, provides an additional measurement which we can use to stratify patients, which can be of particular utility for patients who cannot tolerate a TEE. The presence of impaired global LALS may not be sufficient in of itself to warrant anticoagulation without further investigation, but it should prompt further studies, either the more invasive TEE or cardiac CT or MRI, which is not as widely available. 

Validating Functional Outcome Prediction Models in Acute Ischemic Stroke: Testing the ASTRAL and DRAGON Scores

Danny R. Rose, Jr., MD

Cooray C, Mazya M, Bottai M, Dorado L, Skoda O, Toni D, et al. External Validation of the ASTRAL and DRAGON Scores for Prediction of Functional Outcome in Stroke. Stroke. 2016

Given that functional outcome is one of the most commonly used parameters in studying acute stroke treatment, developing accurate prognostication scores would greatly facilitate treatment decisions and improve communicating expectations to patients and families. Cooray et al. sought to validate the two most recently developed scores designed to predict functional outcome at three months, one studied in unselected acute stroke patients (ASTRAL) and the other in acute stroke patients treated with iv-tPA (DRAGON) using the SITS-International Stroke Thrombolysis Register (ISTR), a  global stroke thrombolysis database. Outcomes were dichotomized into modified Rankin Scale (mRS) 0-2 and 3-6 as were done in both of the initial studies, and the area under the curve (AUC) of the receiver operating characteristic (ROC) was used in both scores to assess the overall predictive and discriminative performance.

The ASTRAL score was developed in a single center stroke cohort using multivariate logistic regression analysis. It consists of 6 clinical parameters: age at stroke onset (1 point per 5 years), baseline National Institutes of Health Stroke Scale (NIHSS) score (1 point per NIHSS point), time from symptom onset to admission > 3 hours (2 points), any stroke-related visual field defect (2 points), acute blood glucose >7.3 or <3.7 mmol/L (1 point) and decreased level of consciousness based on item 1a on the NIHSS (3 points). A total of 36,131 iv-tPA treated patients with complete data for the ASTRAL score were registered in the SITS-ISTR database. The main differences between the SITS-ISTR and ASTRAL cohorts were higher mean baseline stroke severity (NIHSS 12 vs 9) and a lower proportion of functional independence at 3 months in SITS, which is likely explained by the higher severity. The AUC-RPC value for functionally dependent outcome (mRS 3-6) of the ASTRAL score using this cohort was 0.790 (95% CI 0.786-0.795). Over the rante of scores, the largest discrepancy between the observed and predicted outcome was found to be 11%.

The DRAGON score was developed in a single center cohort of acute ischemic stroke patients treated with iv-tPA using similar statistical design to the ASTRAL score. It is a 10 point scale and the included parameters are hyperdense cerebral artery sign (1 point) and early infarct signs (1 point) on baseline CT, pre-stroke mRS score >1 (1 point), age (<65 years = 0 points, 65-79 years = 1 point, >80 years ≥ 2 points), acute blood glucose >8 mmol/L (1 point), time from symptom onset to treatment >90 min (1 point) and NIHSS score (0-4 = 0 points, 5-9 = 1 point, 10-15 = 2 points and >15 = 3 points). A total of 33,716 iv-tPA treated patients with complete data for the DRAGON score were registered in the SITS-ISTR database. The main differences between the SITS and DRAGON cohorts were higher median baseline stroke severity (NIHSS 12 vs 9), lower proportion of early infarct signs (16.5% vs 30.6%) and higher onset-to-treatment time in the SITS cohort. The AUC-ROC value for functionally dependent outcome on the DRAGON score using the SITS-ISTR cohort was 0.77 (95% CI 0.769-0.779). The largest discrepancy between observed and predicted outcome was close to 17%.

Despite the limitations of using a retrospective analysis, the authors’ validation of the ASTRAL and DRAGON scores suggest an acceptable prognostic value for both. Despite being designed and validated using an unselected cohort that included thrombolysed and non-thrombolysed patients, the ASTRAL score showed a similar discriminative performance to the DRAGON score in this study. Future studies involving these scores would benefit from collecting data prospectively and including patients receiving endovascular therapy.
By |May 23rd, 2016|clinical|1 Comment

Limited Meta-analysis Suggests Patients with Asymptomatic Carotid Occlusion are at Low Risk of Ipsilateral Stroke, High Risk of Non-stroke Mortality

Danny R. Rose, Jr., MD

Hackam DG. Prognosis of Asymptomatic Carotid Artery Occlusion: Systematic Review and Meta-Analysis. Stroke. 2016

Although carotid artery occlusion is estimated to account for 10-15% of all ischemic strokes and transient ischemic attacks, there is little consensus regarding the long-term prognosis of asymptomatic carotid artery occlusion (ACAO), which is most often found incidentally during workup for cerebrovascular disease. Hackam sought to shed light on this issue by conducting a systematic review of studies that enrolled patients with ACAO that collected follow-up information on the occurrence of ipsilateral ischemic stroke as an outcome measure. 

A total of 13 studies were included in the meta-analysis. The studies enrolled 4406 patients, 718 of whom had ACAO (16%). The median age of patients with ACAO was 67 and 23% were female.  All but two studies used ultrasound to define ACAO diagnostically; however the use of angiography was high overall (66% of subjects). Median follow-up was 2.80 years, with an annual ipsilateral stroke rate of 1.3% (95% CI 0.4-2.1%). Two-year and 5-year rates of stroke were 2.5% and 6.3%, respectively. There was substantial heterogeneity in the base estimate (I2=53%). Annual total stroke was 2.0% (95% CI 0.9-3%; I2=40%). 

Eleven studies reported on ipsilateral TIA, with an annual rate of 1% (95% CI 0.3-1.8% I2=40%) and an annual total TIA rate of 3.0% (95% CI 1.9-4.1% I2=0).  Seven studies reported mortality, with an annual rate of death of 7.7% with marked heterogeneity (95% CI 4.3-11.2% I2=83%). Six studies reported stroke-related death, with an annual rate of 1.1% (95% CI 0.07-2.1% I2=63%). Cardiac death was more frequent at 3.3% per year (95% CI 1.2-5.4% I2=83%). In the prescribed subgroup analysis, studies published on or after the year 2000 had a statistically significantly lower aggregate ipsilateral stroke rate than studies published before 2000 (0.9% to 1.5%, p=0.003). Adjusting for publication bias suggested a revised ipsilateral stroke rate of 0.3% per year (95% CI -0.4 to 1.1%).

Although the study was limited by significant heterogeneity, it suggests that the risk from ACAO is low. With subgroup analysis of studies published after the advent of contemporary medical management of vascular disease and trim-and-fill analysis suggesting a lack of studies published to the left of the mean, the rate is likely lower than the 1.3% per year grand mean that was reported. However, the annual risk of death was quite high (7.7%), likely attributable to ACAO being a surrogate marker of systemic atherosclerosis, possibly carrying a higher risk of cardiac death. 

Further study of this population is warranted. Potential avenues for future study would include a prospective cohort of patients with medically managed carotid stenosis and occlusion with matched controls, following a variety of vascular outcomes. Perfusion or more in-depth angiographic imaging to identify a potential subset of patients at higher risk of stroke could also be of use.  

Heart Rate Variability and Incident Stroke Risk in the Atherosclerosis Risk in Communities Study

Neal S. Parikh, MD
In this issue of Stroke, Amber Fyfe-Johnson and colleagues describe their investigation of the association between heart rate variability (HRV) and incident stroke risk in the Atherosclerosis Risk in Communities (ARIC) Study cohort.

They argue that autonomic nervous system (ANS) dysfunction, as reflected by HRV, may be associated with cardiovascular mortality, coronary heart disease, and mortality in stroke survivors. ANS dysfunction may be associated with dysregulated cerebrovascular autoregulation and blood pressure.

ARIC participants were assessed by EKG for HRV by four measures at visit 1 (1987-1989) and followed through December 31, 2011 for incident stroke by telephone ascertainment, hospital discharge diagnosis review, and state death registry review. Covariates, collected at the index visit and again at visit 4 (1996-1998), included: age, sex, race, smoking/alcohol use, physical activity, body mass index, blood pressure, blood lipids, and diabetes. Patients taking medications that modify HRV (beta-blockers, anti-arrythmics, calcium channel blockers, digoxin) and those with prevalent stroke, coronary disease, or heart failure were excluded.  

Cox proportional hazards models were used to calculate hazard ratios for the relationship between each quintile of HRV measures and stroke.

Of 12,550 ARIC participants, 816 (6.5%) had stroke. Crude cumulative stroke incidence was higher in patients with the lowest HRV quintile (compared to the highest quintile). However, after adjustment for covariates, associations between HRV and stroke risk were attenuated and did not meet statistical significance. In analyses restricted to participants with diabetes, stroke risk was higher in the lowest HRV quintile, but this association was only statistically significant when testing one of four HRV measures (HR 2.0, 95% confidence interval, 1.1-4.0).

The authors conclude that there may be an association between low HRV and incident stroke in populations already at risk – patients with diabetes. Whether this association would withstand adjustment for an expanded list of cardiovascular risk factors in a modern cohort is unclear. However, the importance of identifying simple indicators of stroke risk such as HRV cannot be overstated. 

Hematoma Shape, but not Density, is Predictive of Clinical Outcomes in ICH from the INTERACT2 Study

Peggy Nguyen, MD

Delcourt C, Zhang S, Arima H, Sato S, Al-Shahi Salman R, Wang X, et al. Significance of Hematoma Shape and Density in Intracerebral Hemorrhage: The Intensive Blood Pressure Reduction in Acute Intracerebral Hemorrhage Trial Study. Stroke. 2016

In patients with intracerebral hemorrhage (ICH), parameters such as hematoma volume has been shown to be predictive of hematoma growth and poor clinical outcomes; other characteristics, such as shape and density have been shown to be associated with growth, but evidence demonstrating its predictive value for clinical outcomes has been limited. Here, the authors used data from the INTERACT2 study and evaluated the association of hematoma shape (irregularity) and density (heterogeneity) on 90-day death or disability.

2066 subjects were included for analysis, with 946 subjects having irregular hematomas and 781 subjects having heterogenous hematomas. Of note, there were significant differences between patients with irregular versus regular hematomas, including older age, more severe neurological status, and lobar hemorrhages in the former group, among others. Similarly, patients with heterogenous hematomas, compared to those with homogenous hematomas, were more likely to have lobar hematomas and less likely to have intraventricular extension. Larger hematomas were more likely to be irregular and heterogenous, and this is likely reflected in the differences between each group and their comparators. In addition, the decision to withdraw treatment was more likely to be made among patients with irregular hematomas and among patients with heterogenous hematomas, when compared to their counterparts.

Nevertheless, when controlled for factors such as age, systolic blood pressure, NIHSS, prior use of antithrombotics, location and volume of baseline hematoma, IVH, and decision to withdraw active treatment, irregular hematomas were found to be independently associated with the primary outcome of risk of death or major disability at 90-days (OR 1.60) and major disability at 90 days (OR 1.60) although not with death alone. Heterogenous density did not predict the primary outcome, nor individually, the outcome of death nor disability.

This study is significant in providing some evidence for imaging markers which may be predictive of clinical outcomes in the emergent period, allowing clinicians to adjust decision making and provide better informed counseling to patients and their families.   

What Makes a Lacune?

Peggy Nguyen, MD

The lacune, often used interchangeably with the definition of a stroke of small vessel atherosclerotic etiology, is traditionally based on a size definition of no greater than 15 mm. It is a classic feature of cerebral small vessel disease. However, despite its prolific use in the stroke literature, the exact characteristics and morphological features of a lacune are not well defined. Here, the authors analyzed the shape of incident lacunes in CADASIL, a genetically inherited small vessel arteriopathy, to better define the lacune’s morphological features.

Fifty-seven CADASIL patients with incident lacunes were included in the study, encompassing 88 incident lacunes, only 18 of which were associated with symptoms. The most common locations for lacunes were in the centrum semiovale (n=30) and the basal ganglia (n=27). In spectral shape analysis, elongation and planarity were found to be the primary determinants of lacune shape and tended to align along perforating arteries. Although 15 mm is traditionally used as the upper size limit of a lacune, about 10% of lacunes, particularly when evaluated in planes other than axial, exceeded this size, whereas only 1 lacune was larger than 15 mm in the axial plane.

Not all lacunes are created the same, but there are certainly similarities, and this may have to do with the mechanisms by which they develop. The findings in this study confirm some generalizations of lacunes, such as the common locations, but also refutes some others, for instance, the size of lacunes, particularly when viewed in non-axial planes. These findings are also suggestive of a mechanism in which lacunes of chronic small vessel diseases develop secondary to factors related to vascular anatomy, rather than tract degeneration.

Early Appearance of Spot Sign on CT Perfusion Associated with Hematoma Expansion and Poor Outcome in Small Retrospective Study

Intracerebral hemorrhage (ICH) causes a significant amount of stroke-related morbidity and mortality. Of the various prognostic factors in ICH, hematoma expansion (HE) is one of the few potentially modifiable ones and as such has been a topic of increasing research.
Unfortunately, large-scale randomized controlled trials aimed at preventing hematoma expansion have not shown robust results, possibly owing to the limited ability of clinicians to predict which patients are at greatest risk. The “spot sign,” a radiographic sign representing the leakage of contrast with a hematoma on CT scan has recently become a topic of extensive study with respect to its ability to predict hematoma expansion. As described previously, a recently published meta-analysis suggested that the sensitivity and positive predictive value of the spot sign was related to the time from ictus to scan acquisition and may not adequately predict HE when it is detected. Additionally, other studies have shown that using CT perfusion (CTP) improves the detection rate of the spot sign. Wang et al. sought to explore the relationship between spot sign characteristics on CTP (including number, timing, and maximum density) to evaluate the relationship between these characteristics and the risk of HE as well as clinical outcome.
The authors’ retrospectively reviewed a total of 83 patients from a prospectively collected database of consecutive patients with supratentorial SICH. Patients receiving surgical evacuation of their hematoma were excluded from the outcome analysis, and additionally were excluded from HE analysis if the intervention took place prior to the 24 h follow-up CT scan. Patients who died prior to the 24 h follow-up CT scan were excluded from the HE analysis.  Patients with secondary causes of ICH were also excluded. A total of eleven patients (6 with positive spot sign) were excluded from the HE analysis, and twelve patients (7 with positive spot sign) were excluded from outcome analysis due to receiving surgical evaluation. Excluded patients had higher SBP and DBP, over a three-fold greater median hematoma volume (52.30 mL vs 15.80 mL, P=0.029) and a nearly two-fold higher median NIHSS (21 vs 11, P=0.004). 

Baseline clinical variables included patient demographics, medical history, medications, onset to imaging time (OIT), baseline National Institute of Health Stroke Scale (NIHSS), and laboratory results. The clinical outcomes assessed were NIHSS at 24 h, in-hospital mortality, and modified Rankin Scale (mRS) including death at 3 months follow-up. Spot sign was assessed with CTP and the timing of occurrence (time from the start of scan to first detection of spot sign), total number of spots, maximum spot attenuation, and axial dimensions were recorded. The median time of onset to CP was 180 (120 to 240) minutes. Hematoma expansion was defined as an absolute ICH growth ≥ 6 mL or relative growth ≥ 33% as recorded on 24 h follow-up CT scan. 

The rate of spot sign was higher in patients with HE than those without (62.5% vs 12.5%, P<0.001). The presence of spot sign was independently associated with HE after correcting for APTT, glucose, NIHSS, baseline hematoma volume, and antiplatelet use. There was a trend for an association between the presence of spot sign and 3-month mortality (32% vs 8%, OR=5.649; 95% CI 0.913-34.954; P=0.063) after multivariate analysis. Spot sign was detected much earlier in patients with HE than those without (18.75 s vs 26.87 s, P=0.007). The timing of spot sign was significantly correlated with both absolute and relative ICH volume growth, and there was no association between the other spot sign characteristics and HE. The authors defined a subset of spot sign patients as having an “early occurring spot sign (EOSS),” defined as detection of the spot sign before 23.13 seconds. EOSS was found to have 0.67 sensitivity and 0.90 specificity for HE. On multivariate analysis, EOSS was an independent predictor of HE (OR=28.835; 95% CI, 6.960-119.458; P<0.001) and 3-month mortality (OR=22.377, 95% CI, 1.773-282.334; P=0.016). EOSS maintained a higher specificity for HE compared to spot sign (91% vs 74%).

In this single-center cohort of SICH patients, spot sign as assessed by CTP was associated with HE. The authors also found that early detection of the spot sign was the most important characteristic with respect to predicting HE and significantly correlated with ICH growth. The primary limitations of the study were related to the retrospective nature of the study, the relatively small sample size, and the use of a single center for recruitment and determining imaging parameters. External validation with a larger sample size and standardized imaging parameters will be necessary. In addition, the high rate of excluded surgical evacuation patients with positive spot sign may have led to an underestimation of the spot sign’s PPV with respect to mortality. It is also important to note that the predictive value and associations with spot sign on CTP in this study should not be applied patients evaluated with single-phase CT angiography. However, replicating this study with multi-phase CTA could be feasible and represents a potential future avenue of research.

Sumoylation of NCX3 a Possible Mechanism of Neuroprotection in Ischemic Preconditioning

Peggy Nguyen, MD

Cuomo O, Pignataro G, Sirabella R, Molinaro P, Anzilotti S, Scorziello A, et al. Sumoylation of LYS590 of NCX3 f-Loop by SUMO1Participates in Brain Neuroprotection Induced byIschemic Preconditioning. Stroke. 2016

Small ubiquitin-like modifier (SUMO) conjugation, or sumoylation, is a post-translational modification of various proteins similar to ubiquination, and has been noted in stress conditions including anoxia, hypothermia, and hypoxia. Changes in sumolyation patterns have been reported after brain ischemia, where it is thought to be possibly protective. To this end, the authors here attempt to further elucidate a possible mechanism underlying the role of sumoylation of the transmembrane protein NCX3, which is thought to be an effector of neuroprotection in ischemic mouse models.

Using mouse models, the authors identified 3 significant findings:
  • First, that SUMO1 conjugation does increase at various times points following induced ischemia via transient middle cerebral artery occlusion (tMCAO) (at 5 and 24 hours), after preconditioning (at 3, 5, 24, and 72 hours) and when preconditioning was combined with tMCAO (at 5 hours).
  • Second, using immunohistochemical stains, the authors identified NCX and SUMO1 colocalization to the neuronal cell bodies in the primary cortical neurons, with a probable sumoylation site in the NCX f-loop of the antiporter. 
  • Third, in SUMO1 knockdown mouse models, NCX3 expression decreased 72 hours after tMCAO  and after preconditioning + tMCAO and displayed a significant increase in ischemic volume after tMCAO at 24 and 72 hours after tMCAO induction.

Identifying targets for neuroprotection seems to be the next frontier in the world of stroke research. This takes us one step closer to characterizing the mechanisms underlying the possible neuroprotectant effect of ischemic preconditioning, whereby targeting either sumoylation of NCX, or regulation of NCX itself, may lead to the development of better neuroprotectants.