American Heart Association

Monthly Archives: June 2015

CAAn superficial siderosis in CAA be a sign of worse outcome?

Vikas Pandey, MD

Beitzke M, Enzinger C, Wünsch G, Asslaber M, Gattringer T, and Fazekas F, et al. Contribution of Convexal Subarachnoid Hemorrhage to Disease Progression in Cerebral Amyloid Angiopathy. Stroke. 2015

Cerebral amyloid angiopathy (CAA) is an entity that previously was very inconsistently described and diagnosis. This is inherent in any diagnostic criteria (in this case, Boston) that contains terms such as possibly and probably in the different grading levels. With the advent of improved magnetic resonance sequences such as gradient echo and susceptibility weighted imaging, the diagnosis of amyloid has been more prevalent and can be made with more certainty. The usual next step after diagnosis is to look for indicators of prognosis and the group cited out of Austria looked to identify mechanisms for why those patients with superficial siderosis present on the cortex had poorer outcome. 

The authors performed a longitudinal analysis of clinical and neuroimaging data over a 9 year period and collected data for 38 patients found to have convexal subarachnoid hemorrhage. Out of these, they found that 29 or 76% where found to have imaging features consistent with CAA and 26 or 68% had imaging findings consistent with superficial siderosis. After a mean follow up time of approximately 24 months it was found that 15 of the patients (39%) suffered recurrent of their convexal subarachnoid hemorrhages and additionally 14 patients (37%) had suffered lobar intracranial hemorrhages. Interestingly, the group was able to obtain pathology for one of the patients in their cohort which showed leakage of meningeal vessels affected by CAA. They found that there may be some connection with convexity subarachnoid hemorrhages expanding into the brain parenchyma causing lobar intracerebral hemorrhages.

The data points toward recurrent subarachnoid hemorrhages being a poor predictive factor of outcome in patients with CAA as previously unrelated links of lobar ICH in patients with previous subarachnoid hemorrhages are now being connected given the improved knowledge of CAA, however the authors have provided further evidence that this link exists. The future of the area of research will likely be developing strict preventative measures in those with convexity subarachnoid hemorrhages to prevent ICH, especially if they meet criteria for CAA.

Systolic Blood Pressure Control: Increased mortality in patients if too low?

Michelle Christina Johansen, MD

Okin PM, Kjeldsen SE, and Devereux RB. Systolic Blood Pressure Control and Mortality After Stroke in Hypertensive Patients. Stroke. 2015

What is the ideal blood pressure range for our patients? Even now in the age of modern medicine there remains debate regarding optimal blood pressure control. The familiar target that is taught in medical school is <140/90 but clearly this must be dependent on the patient population as well as the evaluated outcome. The American Heart Association (AHA) issued a new guideline this year regarding treatment of hypertension in patients with coronary artery disease (CAD) and there was much discussion at the International Stroke Conference regarding blood pressure control for intracerebral hemorrhage. The AHA statement “A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (carotid artery disease, PAD, abdominal aortic aneurysm)” is supported by level IIb evidence and would suggest more aggressive control.

What about when lower blood pressures are maintained over a long period of time? What is the impact of this upon mortality? Okin et. al seek to address this question through their post-hoc analysis of data from the LIFE study. The LIFE study enrolled 9,193 patients with hypertension and ECG left ventricular hypertrophy (LVH) in a prospective, double blind study that aimed to establish whether selective blocking of angiotensin II improves LVH and reduced cardiovascular (CV) morbidity and death. They demonstrated that losartan compared to atenolol resulted in significant reduction in the primary endpoint of cardiovascular morbidity and mortality as well as LVH. There was discussion after completion of the study regarding possible conflict of interest with Merck that was not declared by the author after a letter was circulated in Scandinavia regarding the results of the study.

Okin et. al found 541 patients who had an incident stroke during routine LIFE study follow-up with 403 being atherothrombotic, 84 embolic and 54 hemorrhagic. Patients were classified into three groups according to average on-treatment systolic blood pressure (SBP) after stroke: <144 (lowest), 144-157 and >157 (highest). Baseline BP measurements were those at time of LIFE enrollment. The risk of all cause and cardiovascular mortality in patients in the lowest and highest tertile were compared to those in the middle (144-157). During a mean follow up of about 2 years, 170 patients died and 135 from CV causes.

The authors found that SBP<144 was associated with significantly higher all-cause mortality and SBP>157 with significantly higher CV and all-cause mortality. Multivariate analysis only showed SBP<144 as a significant predictor of CV and all-cause mortality. The authors re performed the analysis restricting the outcome to death occurring >90 days after initial stroke and the outcome was the same.

How is this study to be interpreted? Is SBP <144mm Hg associated with a significantly increased risk of CV and all cause mortality? The study population was hypertensives on treatment with LVH thereby limiting generalizability. Are we therefore to steer our HTN patients with LVH away from aggressive control for fear of increased risk of death? The authors are to be commended for their attempt to answer this important question but there are many limitations to the study. The study design is post hoc with some critics referring to this as “data drudging” implying that the more you dig, the more dirt you bring up. The investigators acknowledge that it cannot be determined whether low SBP is causative of mortality or simply a marker of existing disease. Perhaps if the data had been divided further separating out those with BP <130 which is suggested by the guideline, there might be more light shed on the issue. There is a randomized, controlled trial (SHOT) which will examine lower SBP during long-term follow-up post stroke and perhaps help address the many remaining questions.

How Important is it to Take a Family History?

Ali Saad, MD

Thijs V, Grittner U, Dichgans M, Enzinger C, Fazekas F, Giese AK, et al. Family History in Young Patients With Stroke. Stroke. 2015

This group asked the question of whether family history mattered depending on your stroke type and sex. they used the database from a prospective Fabry disease study. the participants were aged 18-55.

Work up for everyone entailed:
– bloods: routine bloods, crp, ana, anc, RF, Factor V, prothrombin, antiphospholipid, fabry work up with alpha galactosidase screening
– cardiac ultrasound
– ekg

They found that 37.3% of about 4000 TIA/stroke pts had a positive family history of some kind of stroke (including bleeds and vasculitis). The split between whether the stroke history came from the mother or father’s side was 50-50. however females tended to have more maternal than paternal lineage history (54.6% vs 45.4%, p=0.027). Patients with a parental history of stroke also more commonly had siblings with stroke, although the absolute difference wasn’t that great (3.6% vs 2.6%, p=0.047). Patients with a family history of strokes in the parents were not more likely to have children with strokes (0.3% vs 0.2%, p=0.75).

They found no association for stroke subtype by TOAST criteria. cervical artery dissection actually had a lower frequency of family history of stroke.

One of the strengths of this study is that they used MRI-confirmed strokes 82% of the time and didn’t just rely on clinical assessment.

These findings are line with coronary heart disease having family history as an established risk factor.

Limitations of this study include:
– limited to a European population
– no control group
– pediatric population was not included
– carotid imaging was not mentioned as one of the diagnostics they did in the work up
– genetics aside, similar environments and lifestyles among family members could be potential confounders
– given the patient population is relatively young, TOAST criteria may not be the best modality for classifying stroke subtype as the patients are less likely to have large vessel athero or cardioembolic strokes so this method is likely underpowered
– the effect on women may be underestimated as the parents of this patient population are relatively young compared to other cohorts and women are more likely to have their strokes at an older age
– the study relies on self reported family history of stroke, the criteria for which were not clearly defined. in my experience, patients often confuse MI and other diagnoses with what they believe to be a stroke.

How does this study change my practice?
I’ll continue to take a focused family history as I think it’s just part of being a good doctor, but in the absence of a clear genetic hypercoagulable state and I can say that there is a study showing that a family history may put you at risk but stronger evidence is needed. I don’t think this information currently has any practical implications for direct patient care.

Migraine and small vessel disease: cause or effect?

Chirantan Banerjee, MD
Arkink EB, Terwindt GM, de Craen AJM, Konishi J, van der Grond J, van Buchem MA, et al. Infratentorial Microbleeds: Another Sign of Microangiopathy in Migraine. Stroke. 2015 
Migraine with aura is a proven risk factor for ischemic stroke. Migraine is also a phenotypic manifestation of several genetic vasculopathies like CADASIL which primarily affect small intracranial vasculature. The temporal cause-effect relationship between migraine and small vessel disease however is difficult to clearly elucidate. Migraine has been associated with small vessel endothelial damage and hypercoagulability which may lead to small vessel disease. On the other hand, microcirculatory vasoconstriction during cortical spreading depression leads to migraine headaches. Regardless of which came first, their is no denying their coexistence. 

Migraine has been associated with white matter hyperintensities on MRI in several studies. Cerebral microbleeds(CMBs), especially in subcortical structures is also thought to be associated with small vessel disease leading to Charcot-Bouchard aneurysms and subsequent rupture.

In the current study by Arkink et al, the authors looked at data from the PROSPER MRI database and used a validated headache questionnaire to identify 63 migraineurs out of 506 patients. A couple of authors scored CMBs and classified them into lobar, basal ganglia and infratentorial.

They found no difference in the overall prevalence of CMBs between migraineurs and controls, but there was a borderline statistically significant difference in infratentorial CMBs in patients with migraine without aura vs controls (14% vs 4%, p 0.048). Also, migraineurs with CMBs were more likely to have infarcts and vice versa. Apart from the small sample size of migraineurs, the main drawback of the study is that hypertension was more common among migraineurs as compared to controls, which may have driven the findings as a confounder. One also has to remember that this cohort includes patient aged 73-85 years, and so any effect of migraine on CMBs may be lost in the noise generated from underlying high prevalence of cerebrovascular risk factors. Regardless, this study proves again that there seems to be an association between migraine and infratentorial microcirculation. Problem is, we still don’t know which came first.

Same, But Different – Genome-Wide Association of Studies of Stroke in African Americans

Mark N. Rubin, MD

Carty CL, Keene KL, Cheng YC, Meschia JF, Chen WM, Nalls M, et al. Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. Stroke. 2015

So, it turns out mom and Depeche Mode are both right: we are unique and special, but “People are People” and we have a fair amount in common with one another.

A large group of stroke genetics investigators have leveraged their cohort and case-control studies to provide us with the first published snapshot of genome-wide association studies (GWAS) in a large African-American cohort. Acknowledging that most GWAS work in stroke published so far has been in patients of European descent, the authors formed this research alliance with an eye toward understanding if and how GWAS studies are different in patients of differing ethnicity. To study this in the African-American population is of special importance as they tend to experience strokes at an earlier age and of higher severity than White Americans.

In a combined cohort of 14,746 African-American patients, they studied 1,365 ischemic strokes (1,592 total strokes) and validated their findings against a previously published GWAS study in a cohort of European descent. They sought both novel single nucleotide polymorphisms (SNP) and similarity to those associated with stroke in the patients of European descent. In brief, they found some of both: there were unique loci as well as “suggestive evidence of replication for…loci previously associated with stroke in European-Ancestry populations, pointing to potential shared mechanisms for stroke susceptibility.”

This study represents the first large-scale GWAS meta-analysis of stroke in African Americans, which is important, but it also achieves that very satisfying humanistic balance that we all like to think we are all the same, but different.

Tweet: Same, But Different – Genome-Wide Association Studies of Stroke in African Americans @StrokeAHA_ASA @MarkNRubinMD

Targeting WNK3 in experimental stroke

Michelle Christina Johansen, MD

Begum G, Yuan H, Kahle KT, Li L, Wang S, Shi Y, et al. Inhibition of WNK3 Kinase Signaling Reduces Brain Damage and Accelerates Neurological Recovery After Stroke. Stroke. 2015 

Research targeting experimental stroke provides the foundation for future initiatives that lead to clinical implementation. Begum et al in their study investigate the WNK3-SPAK/OSR1 pathway in order to determine the role it plays in regulation of the bumetanide-sensitive Na-K-Cl cotransporter (NKCC1). This cotransporter has been shown to play an important role in the pathophysiology of experimental stroke but its exact mechanism has remained yet unexplained. By way of brief review, WNK3 (with no lysine) is a kinase that activates SPAK/OSR1 which in turn stimulates NKCC1. A similar pathway has been well researched in renal epithelial homeostasis but not in the brain. In vitro, inactivated WNK3 is a potent inhibitor of NKCC1 thus making it an attractive target for research. 

In their experiment, WNK3 wild-type (WT) and knockout (KO) mice were subjected to ischemic stroke via MCA occlusion for 60 minutes. Sensorimotor neurological deficit in the mice were evaluated post stroke. Infarct volume and hemispheric swelling was calculated postmortem and wet weight of the tissue was measured. A total of 61 mice were used in the study. All measurements were performed by investigators who were blinded to the study.

The researchers found that there was no difference in regional cerebral blood flow in the WNK3 KO and WNK3 WT littermates after MCA occlusion but after 24h of reperfusion, KO brains exhibited a marked reduction in cortical infarct volume relative to the wild type. Smaller infarcts were also noted in KO at 3 days post MCA occlusion by MRI and exhibited significantly less demyelination of the external capsule white matter tracks. This was shows to have ramifications functionally as KO mice exhibited accelerated recovery. There was decreased hemispheric swelling and albumin infiltration in KO mice. The investigators founds that focal cerebral ischemia activates NKCC1 by the WNK and SPAK/OSRI kinases and that this signaling pathway was regulated differently depending on brain region and cell type. No ischemic cell death was evident in untreated WNK3 KO neurons or in those treated with SPAK/OSR1 siRNAs (silencing RNAs).

The authors conclude that genetic inactivation of WNK3 or siRNA-mediated knockdown of SPAK/OSRI prevents demyelination and reduces primary oligodendrocyte death highlighting that this signaling complex serves as a potential target for neuroprotection and preservation of myelination following stroke. The team should be commended for working to elucidate the WNK3 pathway in the cerebrum. While this work is in its infantile state, one can only hope that WNK3 inhibition in the clinical setting would yield similar results.

MRI-Based Assessment of Carotid Plaque Morphology

Rizwan Kalani, MD

Gijsen FJH, Nieuwstadt HA, Wentzel JJ, Verhagen HJM, van der Lugt A, and van der Steen AFW.
Carotid Plaque Morphological Classification Compared With Biomechanical Cap Stress: Implications for a Magnetic Resonance Imaging–Based Assessment. Stroke. 2015 

A large number of surgeries are conducted for carotid stenosis, which is typically based on degree of luminal stenosis. This approach has many limitations – two-thirds of carotid plaque thromboembolism is thought to result from non-significant stenosis and the a large number of surgeries need to be performed to prevent a single stroke in the setting of high-grade carotid stenosis. Understanding plaque pathology may assist in risk stratification. A previously described histopathological scheme classified carotid plaques as thin fibrous cap atheroma (with lipid-rich necrotic core and presumed to be at increased risk of rupture), pathological intimal thickening and fibrous cap atheroma (both of which are more fibrous and more stable). A biomechanical stress analysis to distinguish vulnerable plaques from stable ones (based on plaque morphology, tissue properties, and hemodynamics) can be performed with carotid MRI, but its efficacy has not been established. In this manuscript, Gijsen et al performed both histological classification and peak cap stress computation of carotid plaque sections from patients who underwent endarterectomy for >70% stenosis.

Carotid plaque sections from 34 patients were obtained for histopathological analysis and numerical MRI simulation. Fibrous cap thickness was measured and peak cap stress (in kilopascals) was computed. The authors found that that sections classified as pathological intimal thickening had the lowest stress and that those with thin fibrous cap atheroma had the highest peak cap stress. However, there was significant discordance between classifications – 64% of the thin fibrous cap atheromas had high peak cap stress (high-risk) and 56% of the cross sections not classified as a thin fibrous cap atheromas had low peak cap stress (low-risk). MRI-based stress computation was imprecise and underestimated peak cap stress. Within the low-stress group, however, there actually was consistent agreement between histological classification and peak cap stress measurement by MRI.

This study suggests that MRI-based identification of low-risk carotid plaques may be possible. Evaluation of additional features – such as intraplaque hemorrhage, inflammation, and calcification – may further improve identification of stable carotid plaques. The practical utility of this would be to identify individuals who may not benefit from surgical intervention. However, this concept would need to be tested in a clinical trial to evaluate its efficacy and value.

Is Warfarin Prejudice International?

Ali Saad, MD

Sjölander M, Eriksson M, Asplund K, Norrving B, and Glader EL. Socioeconomic Inequalities in the Prescription of Oral Anticoagulants in Stroke Patients With Atrial Fibrillation. Stroke. 2015

This study looked at differences in prescribing patterns for oral anticoagulants (OAC) in 12,088 patients with Afib from the Swedish stroke registry. They found that 36.3% of patients were prescribed these drugs and several factors influenced prescribing pattern. Here are the odds ratios with 95% CIs:

Patients born in other Nordic countries vs those born in Sweden
OR 0.82, 0.68-0.98

Patients born in non-European countries vs those born in Sweden
OR 0.65, 0.42-0.99

University education vs primary school
OR 1.2, 1.05-1.36

Highest income vs lowest income level
OR 1.19, 1.06-1.33

Older vs age 18-69
Age 70-79
OR 0.84 (0.73–0.96)

Aged 80-89
OR 0.39 (0.34–0.44)

Aged 90
OR 0.13 (0.10–0.15) 

It seems that Swedish practitioners are most likely to prescribe anticoagulation to younger, Swedish-born people who make a lot of money and have a college degree. This is consistent with studies in other countries which show that OACs are being under-prescribed and that there are socio-economic disparities. age appears to play the biggest role.

Interestingly, patients with vascular risk factors (30.4%) were less likely to be prescribed OACs compared to those without them (39.6%). Although not surprisingly, people who were older, living alone, had dependant ADLs, or were not discharged home were less likely to be prescribed them.

Limitations of this study include:
– swedish-only population
– the OACs in question would have included the DAOCs (xarelto, dabigatran, or apixaban) which may have different prescribing patterns from warfarin and the study did not distinguish between which agent or drug class the patients were prescribed
– the data only looked at prescription for secondary prevention after first stroke, not primary prevention or after repeated strokes
– patients in the study were not controlled for possible risk factors for hemorrhage, patients’ mRS, or other relative contraindications for OACs
– determining whether a patient was not prescribed an anticoagulant is based on hospital discharge data, but these patients may have gotten their prescriptions during follow up in clinic, especially if they were not seen by a stroke specialist. This may also be relevant in non-Swedes who followed up with their doctors in their countries of origin after discharge.

How does this study change my practice?
Personally, I’m aggressive with prescribing OACs so I don’t think it’ll have much effect. the message that I get out of this study is quite the opposite; prescribing practices are changing significantly. Looking at the trends, 30.9% of patients left the hospital with OACs in 2009 and this increased to 43.3% in 2012. There was a steady increase throughout the years as well as a 10% jump from 2010 to 2011 when the first DAOCs were introduced. The introduction of DAOCs as well as Joint Commission’s guidelines for stroke center certification are making it making more likely that patients will leave on OAC when warranted. There will always be disparities and the reasons for not prescribing OACs to someone can be variegated and nuanced, making it challenging to study through national registers alone.

Size doesn’t matter, if the patient has a stroke in one of these two locations

Daniel Korya, MD

Rangaraju S, Streib C, Aghaebrahim A, Jadhav A, Frankel M, and Jovin TG. Relationship Between Lesion Topology and Clinical Outcome in Anterior Circulation Large Vessel Occlusions. Stroke. 2015 
We use the ASPECT score in my hospital prior to deciding on whether or not a patient is likely to have a good outcome from endovascular thrombectomy. It is used because it is simple. We look at the imaging, and count areas of involvement. The cortical areas are broken up into 7 parts with a point each, and the sub-cortex is broken up into 3 parts, each one of those gets a point:

If the ASPECT score is less than 7, we tend to get a little hesitant about taking the added risk of endovascular therapy. But, that is because we assume that every point on the ASPECT score is created equal. But, are they? That is essentially the question that Dr. Rangaraju and his colleagues aimed to answer in this recently published study.

They used the DWI ASPECTS, which is the MRI cousin of the original ASPECT. The locations are the same. All the patients in this study had either, ICA, M2 or M2 MCA occlusions and were treated with endovascular therapy. There were 213 patients in the study. Their DWI ASPECTS were evaluated within 12-72 hours after thrombectomy, and multivariable logistic regression was used to determine the correlation between the 10 DWI ASPECTS locations and outcome based on the 90-day mRS. The reason they used post-treatment imaging, they argued, was because the pre-treatment ASPECTS may be misleading since the eventual infarct may be significantly different than the first impression on a CT scan due to variation in time to recanalization of the occluded vessel.

The study was well designed, and although the patients were extracted from a prospective endovascular registry, the DWI ASPECTS was calculated retrospectively. There were a few other limitations of the study, but the findings are interesting and probably representative of “real-life” scenarios.

The conclusion of this study suggested that if the left M4 region (superior frontal) or the right M6 region (superior parietal) were involved on the DWI ASPECTS, then the patient was significantly more likely to have a poor outcome after endovascular treatment. Destruction of the left M4 and right M6 territories correspond to aphasia and hemineglect, respectively. It made sense that these two areas should carry more weight with regard to outcome since their effects on independence and function are potentially profound.

Blood pressure after after acute ischemic stroke: treat it or leave it

Chirantan Banerjee, MD

Lee M, Ovbiagele B, Hong KS, Wu YL, Lee JE, Rao NM, et al. Effect of Blood Pressure Lowering in Early Ischemic Stroke: Meta-Analysis. Stroke. 2015 

Blood Pressure (BP) control acutely after an ischemic stroke has been a matter of debate for decades. High blood pressure is common after an acute ischemic stroke, especially in patients with premorbid hypertension. Although a number of studies, both retrospective and prospective have examined the relationship between blood pressure lowering acutely after stroke and outcome, there is no clear consensus, as the results have been inconsistent. This may be secondary to the fact that every patient’s optimal blood pressure acutely after a stroke is likely different, contingent on vessel status, stroke etiology and severity. Data from IST-3 showed a U-shaped curve between admission BP and functional outcome. Based on results of the COSSACS study, the 2013 AHA guidelines posited that initiation of antihypertensive therapy within 24 hours of stroke is relatively safe in patients who have hypertension and are neurologically stable unless a specific contraindication to restarting treatment is known. But we lack Class I evidence to answer if blood pressure lowering is beneficial or harmful acutely after a stroke. 

In the current study, Lee et al performed a meta-analysis of 12 randomized clinical trials using random effects modeling, comparing active lowering of blood pressure beyond 3 days versus control, which included discontinuation or continuation of home blood pressure medications without addition of a new agent. For the primary outcome of death or dependency (mRS 3-6) at 3 months or at trial end point, there was no difference between the two groups (RR 1.04, 0.96-1.13). The main limitation of the study is that there was no stroke subtyping possible, which may be very important, as large vessel, lacunar, and embolic strokes likely respond differently to blood pressure lowering.

While we wait for future trials like ENCHANTED, this meta-analysis echoes that active blood pressure reduction starting ~3 days after acute ischemic stroke is safe and reasonable.