American Heart Association

Monthly Archives: April 2014

Rising tide: Gender and stroke rates in rural China

Peter Hannon, MD

Wang J, Ning X, Yang L, Tu J, Gu H, Zhan C, et al. Sex Differences in Trends of Incidence and Mortality of First-Ever Strokein Rural Tianjin, China, From 1992 to 2012. Stroke. 2014

Stroke is quickly rising the ranks around the world as a leading cause of death and disability. Gender differences in stroke incidence and outcomes have been documented for some time, however not in rural China. In this article by Wang et. al., the authors utilized a stroke surveillance program in Tianjin, China to monitor stroke incidence and comorbidities in 14,920 residents in a rural community over 20 years from 1992-2012. Per the authors, over one half of the population in China lives in rural settings, and previous to this study gender difference in stroke incidence and outcome had not been rigorously investigated and published. The population studied were primarily low-income farmers with illiteracy rates ranging 30-40%, and until 2008, very few residents were covered by national medical insurance.

Within this population, 908 patients had diagnosed strokes (TIAs were not included), with 40% being women. The incidence of stroke increased annually for both men and women, but more so for women (8% vs 5.8%). Outcomes were limited to mortality at 30 days, and authors did not find significant differences between the genders. The prevalence of HTN, DM, obesity and alcohol was significantly higher in 2011 than 1991, and the prevalence of obesity and diabetes was higher in women. In one small public health victory, the prevalence of smoking dropped from 43% to 37% among men.

This study highlights the increasing incidence of stroke in rural China, and in particular the burden of stroke on women in this population. As in other countries, the increased prevalence of historically “western” medical diseases such as HTN, DM and obesity seems to be playing a significant role in higher stroke rates. I would have been particularly interested in more detail regarding disability outcomes of the stroke patients in addition to the mortality numbers. While mortality rates were equivalent between the sexes in this study, would women have higher rate of disability as recently shown in other studies? It seems this would have been a nice opportunity to compare disability in this population to those in other studies as well.

Post-Stroke Hyperglycemia: A Blessing or a Curse?

Matthew Edwardson, MD

Robbins NM and Swanson RA. Opposing Effects of Glucose on Stroke and Reperfusion Injury: Acidosis, Oxidative Stress, and Energy Metabolism. Stroke. 2014

Hyperglycemia can contribute to infarct expansion and reperfusion injury post-stroke. Aggressive blood sugar management, however, shows no clear benefit in early human trials. This review by Robbins & Swanson breaks down the biochemical processes associated with brain glucose metabolism in the setting of stroke. The authors bring great clarity to the complex processes involved and provide hope that at least a subset of hyperglycemic stroke patients may benefit from aggressive glycemic control.

Rat models teach us a great deal about the effects of hyperglycemia post-stroke. Most of these experiments suggest that hyperglycemia increases morbidity and mortality. Interestingly, hyperglycemia does not worsen outcome and may actually benefit those animals with a core lesion and no penumbra. Robbins & Swanson suggest this is because cerebral blood flow is so low in the core that tissue is damaged beyond repair regardless of circulating glucose levels. Lacunar infarcts may behave similarly since they reflect areas of no collateral flow. Correction of hyperglycemia in animals with penumbra does seem to be beneficial. A key difference between rat and human hyperglycemia post-stroke is that hyperglycemia in rat models is almost always iatrogenic. In humans, the elevated blood sugar probably reflects more of a stress response. The authors highlight that this may hinder translational efforts.

Despite concerns about translation to human trials, there are reasons to remain optimistic. Clinically, humans react largely the same as rats to post-stroke hyperglycemia. There is strong evidence to suggest that hyperglycemia causes worse outcomes in humans. In addition, humans lacking evidence of ischemic penumbra (i.e. little diffusion/perfusion mismatch) are not affected by circulating blood glucose levels.

Perhaps a study of tight glycemic control in subjects selected for diffusion/perfusion mismatch is called for. The authors conclude with a discussion of the association between hyperglycemia and reperfusion injury, suggesting we may want to exclude more hyperglycemic patients from IV-TPA. To my knowledge the hemorrhage rate increases linearly with blood sugar level, so the presence of hyperglycemia alone, if mild-moderate, is not a good reason to withhold IV-TPA. The ongoing SHINE trial, which compares aggressive glucose control to standard care in hyperglycemic patients stratified by treatment with IV-TPA, should shed some light on this topic.

SWI microbleeds not associated with higher risk of post-tPA hemorrhage

IV tPA (IVT) for ischemic stroke is associated with a 3% to 4% increase in the risk of symptomatic intracranial hemorrhage (sICH), often leading to poor outcomes. Although this represents a considerable hazard, the benefits of tPA are robust and warrant careful consideration of the risk/benefit profile in all patients with possible ischemic stroke. Clinical models to predict which patients will be at higher risk for sICH have had mixed results and researchers have begun to utilize high resolution gradient echo T2* MRI sequences to examine if their increased sensitivity can better predict risk of hemorrhage and prognosis.

Pascal Gratz et al. examined a cohort of 392 ischemic stroke patients treated with with IVT, endovascular therapy (EVT) or IVT followed by EVT, who also had a pre-treatment MRI with susceptibility-weighted imaging (SWI). Several radiologists retrospectively reviewed the MRIs to identify cerebral microbleeds (CMBs), which were characterized as consistent with hypertension if they were deep and as amyloid angiopathy if more superficial in older patients. CMB were detected in 20.2% and sICH was present in 5.4% and asymptomatic in 19.4%. The presence of CMB within the stroke did not increase the risk for ICH or worsen outcome, even if CMB burden, predominant location or presumed etiology were taken into account. There was a small increase in the risk of ICH outside the infarct with increasing CMB burden, but the effect was marginal and barely reached significance.

This data argues against the use of SWI for ICH risk stratification prior to IVT, EVT, or IVT/EVT. We should not delay the administration of IVT, the most effective therapy for acute ischemic stroke, for advanced imaging unless it clearly indicates that the patient will not benefit from tPA. A recent article showed a statistically significant association between the gradient echo T2* “brush sign” in patients with ischemic stroke treated with IVT and subsequent hemorrhagic transformation. While this was a small trial, and not measuring sICH, the results suggest that there may be utility for gradient echo T2* advanced imaging and further study is warranted. The debate surrounding the effectiveness of EVT is ongoing and SWI may be more important in this population, whose morbidity is often related to sICH. These results should again encourage physicians to give tPA when patients meet criteria, and not defer based on concerns about prior CMBs. 

Cerebral microbleeds and thrombolysis for acute stroke: should we be concerned?

Deepa P. Bhupali, MD

Gratz PP, El-Koussy M, Hsieh K, von Arx S, Mono ML, Heldner MR, et al. Preexisting Cerebral Microbleeds on Susceptibility-Weighted Magnetic Resonance Imaging and Post-Thrombolysis Bleeding Risk in 392 Patients. Stroke. 2014

Jung et al. explore the topic of whether cerebral microbleeds (CMB) increase the risk of hemorrhage after receiving IV tPA or endovascular reperfusion therapy.  Specifically, they used pre-treatment susceptibility-weighted MR to identify CMB and then reimaged patients after they had IV thrombolysis, endovascular therapy, or IV thrombolysis followed by endovascular therapy.  They found that CMB detected on pretreatment SWI did not increase the risk for symptomatic or asymptomatic intracerebral hemorrhage.

There have been a few studies that have looked at the relationship between CMB, thrombolysis and the risk of ICH.  The data are not consistent and, at this point, do not affect our decision making process when considering patients for thrombolysis.   The research by Jung’s team is thoughtful but has largely left the issue of CMB and post-thrombolysis ICH unresolved.    As the authors point out, one of the major limiting factors of their work was the fact that it was underpowered which leads to somewhat inconclusive information.  Furthermore, their data suggest that even if there is a risk, whatever that risk may be, it is too small to change our approach to thrombolysis. 

Regarding post-thrombolysis hemorrhage, we know that in addition to the thrombolytic therapy, risk factors for clinically significant hemorrhagic transformation are stroke size, stroke severity and age.  It is difficult to know what to make of CMB; however, for now, it is clear that they should not influence our decisions regarding thrombolytic therapy in the acute stroke setting.

Using the retina as a window into the brain- Retinal nerve fiber layer defects and stroke

Seby John, MD

Reference to the eye being a window into our soul has dated back to the 1st century BC. While this nebulous concept has been difficult to study, we do know that the retina manifests changes in many brain disorders, and as such is a “window into the brain”. This seems logical since the retina is an embryological extension of the CNS and shares anatomical, functional and physiological similarities to the brain itself. With evolving technology, we now have the ability to obtain detailed three-dimensional images from within the retina using optical coherence tomography (OCT). 

Wang and colleagues examined whether strokes are associated with retinal nerve fiber layer defects (RNFLDs) using OCT. They studied 154 patients with acute ischemic stroke, and 2890 subjects from a population-based group (Beijing Eye Study) in whom OCTs were performed and history of previous stroke was available. After adjusting for risk factors, they found that acute stroke and history of previous stroke was significantly associated with RNFLDs. Conversely, presence of RNFLDs was also significantly associated with acute or previous stroke.

The authors suggest that RNFLDs be added to list of ophthalmological findings present in stroke patients. Previously, a number of retinal microvascular abnormalities such as arterio-venous nicking and arteriolar thinning have been shown to be associated with stroke and hypertension. However, these findings have also been found in normal subjects. In contrast, RNFLDs seem to have a higher diagnostic specificity although it is not pathognomonic. In addition, the RNFLDs remain a permanent marker on the retina compared to vascular abnormalities that may reverse.

The RNFLDs seen on OCT allows us to visualize these “retinal microinfarcts” that may be a harbinger of eventual cerebral stroke. The detection of these by ophthalmologists should perhaps prompt assessment and optimization of cardiovascular risk factors to prevent further sequellae. 

Localized Retinal Nerve Fiber Layer Defects and Stroke

Sebina Bulic, MD

Wang D, Li Y, Wang C, Xu L, You QS, Wang YX, et al. Localized Retinal Nerve Fiber Layer Defects and Stroke. Stroke. 2014

Retina is our “window to the brain” and can be assessed by numerous non-invasive techniques. Many cerebral vascular and neurodegenerative experts have studied retinal thickness, geometry, vascular supply and so on seeking for the associations and answers related to their fields.  

In this study, Li at al studied 154 patients with acute ischemic stroke diagnosed based on TOAST classification. All patients underwent spectral-domain optical coherence tomography (OCT) of the retina for the detection of localized retinal nerve fiber layer defects (RNFLDs) within seven days after the onset of stroke. A RNFLD was defined as a sector on the OCT printout in which the RNFL contour line dipped into the red zone for a length of <180°. The study group was compared with a control group, which was formed from the population of the Beijing Eye Study 2011 with 2890 subjects.
In a first step of the analysis, patients with acute stroke were compared to a control population free of stroke. In a second step, the group of participants of the Beijing Eye Study with previous stroke was compared with the group of participants of the Beijing Eye Study without previous stroke. In a third step of the analysis, the hospital-based group and the Beijing Eye Study with previous stroke group were merged.  In a final fourth step of the analysis, the presence of localized RNFLDs was taken as dependent variable. Multiple runs of univariant and multivariant analysis were performed.

This investigation combining a hospital-based study group with a population-based group showed that acute or previous stroke was significantly associated with localized RNFLDs (P<0.001) after adjusting for parameters such as age, gender, arterial hypertension and diabetes mellitus. In a reverse manner, presence of localized RNFL defects was significantly associated with cerebral stroke (P<0.001) in multivariate analysis. Study also established association of localized RNFDLs and arterial hypertension.  

Localized RNFLDs can be assessed by noninvasive OCT imaging may be added to the panel of retinal morphological features of stroke. So, relationship is established, now what to do with it?

Is Framingham Stroke Risk Score overestimating the risk of stroke?

Vivek Rai, MD

McClure LA, Kleindorfer DO, Kissela BM, Cushman M, Soliman EZ, and Howard G. Assessing the Performance of the Framingham Stroke Risk Score in theReasons for Geographic and Racial Differences in Stroke Cohort. Stroke. 2014

The most well-known and therefore widely used stroke risk score is Framingham Stroke Risk Score, which was developed in 1990’s. Other tools have been offered recently for risk stratification, such as ASCVD and CHS risk score, but FSRS remains the standard for predicting stroke risk in general population. FSRS and other risk scores do not account for impact of race because the study population had few black participants. Reasons for Geographic And Racial Differences in Stroke (REGARDS) study assessed the performance of FSRS in both blacks and whites.

The REGARDS study used national population based cohort that recruited 30,239 participants of 45 years of age or older, with 45% male and 55% female; 42% black and 58% white between 2003 and 2007. McClure and colleagues compared the observed stroke rates to that predicted by FSRS in 27,748 stroke-free at baseline participants who were followed for an average of 5.6 years. The authors report that FSRS accurately predicted higher stroke rate in patients deemed to be at higher risk due to presence of traditional risk factors such as age, sex, diabetes, smoking etc. but also that FSRS overestimated the risk by about 2 times in all race-sex strata. The overestimation was consistent in subgroups of FSRS risk factors and was highest among those with highest risk.

This very interesting study reinforces the validity of FSRS in predicting stroke risk but also shows that FSRS may be overestimating risk in today’s population. The reasons for this overestimation may lie in the study itself (such as only 5.6 years of follow up period is used to determine 10-year stroke risk) or may reflect decreasing incidence of stroke due to better (as compared to 1990’s) primary prevention. I think the study points towards a valid concern that the tools developed for risk assessment over 20 years ago may not be entirely accurate today and as such future research should be directed towards estimating the stroke risk more accurately, which is important for research planning and stroke prevention in community.

How good is the the Framingham Stroke Risk Score in a Predominantly Black Population?

Waimei Tai, MD
McClure et al did an interesting study where they took the Framingham Stroke Risk Calculator (FSRC) and calculated the risk scores of their cohort of patients in the REGARDS trial. They then compared the estimated stroke events to the observed stroke events to see if the FSRC was a good predictor of actual stroke events. They learned that the FSRC was good at stratifying who was at higher risk, but tended to overestimate the number of events this group would have. This was consistent across different strata in the REGARDS groups.

They authors do comment on a few reasons why this maybe the case including: overall temporal decline in stroke incidence as the decades have passed and better preventative measures have taken place to control for risk factors; use of adjudicated events versus self-reported events as in the initial validation studies. The authors suggest that the biggest contributors to the FSRC being an overestimator of risk is the overall decline of stroke incidence over the decades.

This means that some of our prevention measures are working, patients and their healthcare providers are working to reduce the incidence of stroke with medication, lifestyle modifications, re-vascularization in some cases. But more work still needs to be done.

I think this study is more relevant as it contributes to the larger conversation about the recent AHA/ACC guidelines on lipid management .  As a believer that an ounce of prevention is worth a pound of cure, I am still a proponent of aggressive lipid management, even if the current epidemiologic studies suggest that stroke incidence is declining. Perhaps it is because of the very preventative work we are actively engaging in.

Sex does matter: Outcomes after acute ischemic stroke in Austria

Peter M. Hannon, MD

Gattringer T, Ferrari J, Knoflach M, Seyfang L, Horner S, Niederkorn K, et al. Sex-Related Differences of Acute Stroke Unit Care: Results From theAustrian Stroke Unit Registry. Stroke. 2014

Over the last decade, a number of studies have investigated gender disparities in stroke etiology, care and outcomes. Authors Gattringer et. al. have utilized a nationwide Stroke Unit registry in Austria to explore some of these potential disparities. From 2005-2012, 47,209 patients (47% women) were identified who were admitted and worked up for acute ischemic stroke (AIS) and TIA at specialized Stroke Unit facilities throughout Austria.   

Authors found that women admitted were significantly older (77.9 vs. 70.3 yrs), had higher preexisting disability and more severe strokes (median NIHSS 4 vs 3) at admission.  Correcting for age, there was no significant sex-related difference in onset-to-door times, times to and rates of neuroimaging, door to needle times and rates of IV tPA administration (14.5% for both sexes). After taking into account multiple potential clinical confounders including age, stroke severity and preexisting disability, authors found that female stroke patients had a higher rate of disability, dependency and need of permanent nursing after 3 months, but lower mortality rate. While acute stroke care seemed equitable among men and women, authors did find that despite a significantly higher of diagnosed atrial fibrillation among female patients, there was no difference in the rates of anticoagulation use at follow-up, suggesting under-treatment at discharge.    

Follow-up rates were relatively low (40%), yet this study reaffirms prior findings of worse disability in female stroke patients after discharge as compared to men, and more importantly, does so in the setting of apparent equitable acute stroke care and comparable rates of neurorehabilitation. Clearly there are forces at work that cause our female stroke patients to have worse functional outcomes after discharge, such as weaker social support and older or deceased spouses. Knowing this, what steps can we take to help improve outcomes in this population?  From this study at least, a good place to start may be taking a hard look at the care, support system and comorbidities of our female stroke patients, especially after discharge.

Meta-analysis shows association between cognitive impairment and future stroke

Adam de Havenon, MD

Rostamian S, Mahinrad S, Stijnen T, Sabayan B, and de Craen AJM. Cognitive Impairment and Risk of Stroke: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. Stroke. 2014

Dementia and cognitive impairment are well associated with prior stroke and white matter lesion burden. Less well established is the future risk of stroke for patients with cognitive impairment, but no vascular history. A guiding principle in the quest to find effective treatment for dementia is to identify patients at risk of developing dementia and treating them preemptively with established therapeutics or enrolling them jn research trials.

Somayeh Rostamian et al.’s meta-analysis looked at 12 studies that tested cognitive function and followed patients to see if they had stroke. The vast majority of the 82,899 patients had no history of stroke and during the 3 to 21 years of follow-up there were 3043 stroke events (3.7%). The meta-analysis controlled for traditional vascular risk factors. The RR for stroke was 1.19 for every downward standard deviation in global cognitive performance, with insignificant differences in RR if the impairment was executive function, attention, memory, or language function.
The studies included in this meta-anlaysis have several limitations, the most vexing being that only one study reported MRI data, which was limited to structural morphology and a white matter hyperintensity score, making it difficult to exclude patients with mild cognitive impairment from subclinical strokes. Only 3 studies did repeat cognitive testing and without longitudinal data, it is difficult to ascertain if the incident strokes were significant from a cognitive perspective. Ultimately, physicians evaluating a patient with new cognitive impairment should always consider nascent vascular dementia and multiple guidelines, including the AAN guidelines, specify just that and call for structural brain imaging at diagnosis. As such, the association reported in this study seems low yield, both for its limited novelty and low RR.