American Heart Association

Monthly Archives: May 2014

The Age of Collagen in Intracranial Saccular Aneurysms

Sebina Bulic, MD


Nima Etminan, Rita Dreier, Bruce A. Buchholz, Kerim Beseoglu, Peter Bruckner, Christian Matzenauer, et al. A
ge of Collagen in Intracranial Saccular Aneurysms. Stroke. 2014


Some suggest that cerebral aneurysms form and then grow at a constant rate, others that growth alternates stochastically between periods of stability and instability or growth, during which they are prone to rupture. This would, in part help to understand discrepancy between the low risk of rupture of small, incidentally detected aneurysms and the high proportion of small aneurysms in patients with SAH. Obtaining more understanding about formation and natural history of cerebral aneurysms is of great significance given fatality rate of ruptured aneurysm of 35%.



In this very elegantly designed study, the authors used radiocarbon birth dating of collagen type I to estimate its chronological development and turnover to investigate chronological development of cerebral aneurysms. Collagen type I is the most common collagen type in cerebral aneurysms. Between 1955 and 1963 after above ground nuclear bomb tests, sharp increase and subsequent slow attenuation of atmospheric 14CO2 concentrations occurred. This allows measurement precision in radiocarbon birth dating with temporal resolution of 1 to 3 years.

36 ruptured and 10 unruptured aneurysms harvested during surgical clipping had sufficient amounts of collagen for further analysis. This collagen was compared with extracts from ten samples from human cerebral as well as two samples from extra-cerebral arteries from five cadavers and five collagen samples of known age from newborn mouse tendons, however cerebral aneurysms and controls did not share a dominant structural protein which could be used for comparison of collagen dynamics.

Except in 3 samples, all collagen samples were 5 years or less old. The age of collagen was independent of aneurysm clinical and morphological presentation such as: ruptured and unruptured, largest aneurysmal diameter and irregularity. It was also independent of patients age. Mean collagen age was 1.6 ± 1.2 years for patients with risk factors such as hypertension, cigarette smoking or cocaine use, comparing with 3.9 ± 3.3 years for patients without risk factors.  
Inability to compare collagen turnover in control sites with harvested aneurysms, limited authors of reaching the conclusion that the age of collagen in the cerebral aneurysms is different than control. Their findings, however indicate that there is ongoing collagen type I biosynthesis in cerebral aneurysms due to dynamic remodeling, and that this remodeling seems to be significantly accelerated in patients with listed risk factors. By tightly controlling hypertension, cigarette smoking and cocaine use in patients with incidentally diagnosed cerebral aneurysms, not fulfilling criteria for surgical clipping or endovascular coiling, perhaps we can halt their progression.



An apple a day keeps stroke away


There is emerging evidence that behavioral modification can modify your risk of stroke. Although it seems intuitive that a healthy lifestyle, with a balanced diet and exercise, would reduce stroke risk, the effects of these interventions are difficult to quantify. However, recently the evidence has begun to mount about the success of healthy diets reduces risk of stroke. Hu et al. explore this important question with a meta-analysis about fruit and vegetable consumption and the risk of stroke. In this paper, twenty prospective cohort studies were included which used fruit and vegetable consumption as the exposure, and risk of stroke as the outcome.



The authors found that the highest versus the lowest level of fruit and vegetable consumption was associated with more than a 20% reduction in the risk of stroke. To account for publication bias, they excluded 3 studies that reported a small effect size, with no difference in the result. They suggest that increase fruit and vegetable consumption may reduce blood pressure and have a favorable effect on cardiovascular risk factors. They also point out that while cohort studies are associational, several of Hill’s criteria for causation are met. They implicate that the one criteria not met is the evidence for “experiment”, or randomizing participants to giving fruits and vegetables t vs. placebo to see if stroke is truly reduced.  This last “experiment” is the challenge in diet research, as these studies are often difficult to conduct and measure adherence to dietary patterns. Often, the outcome, such as stroke, is not immediate, and these studies can be long a costly. The success of the recent PREDIMED trial, however, suggests that these dietary intervention trials can be done, and do provide helpful evidence for dietary interventions to reduce stroke risk.

Live Blogging from the ESC 2014: Results of the TIAregistry.org Study Presented

There was a revolution in Transient Ischemic Attack (TIA) care in 2000 with the publication of the seminal report by SC Johnson and colleagues (JAMA 2000;284:2901­2906) of the high risks of stroke and vascular events following an index event. In the following years TIA risk scores such as the ABCD2 (Lancet 2007;369:283-292 ) were developed and promulgated throughout routine neurological care. At the European Stroke Conference in Nice Professor Pierre Amarenco presented the results of a modern TIA cohort collected through the use of the TIAregistry.org web-site, and the results were very interesting and likely to inform clinical practice.

The TIAregistry.org project evaluated short and long-term outcomes and refine risk assessment paradigms. Subjects had to be free of disability at baseline and have been evaluated for thei TIA in <7 days from onset, ideally <24 hours. A total of 4798 were recruited over 2.5 years: 4581 had complete data. The mean age was 66, 60% were men, 60% hypertensive and over half presented with a motor weakness syndrome. The ABCD2 scores were on the higher end with >70% scoring 4 or more. Imaging-demonstrated acute infarction was seen in 33% of cases, 16% had extracranial stenosis. Treatment was excellent with >90% on antithrombolic and >70% on antihypertensive and dyslipidemic agents. During follow-up <6% had a major vascular event, 4.7% had a stroke.
This study further validated the ABCD2 score in a real-world cohort obtained from a registry. Of note when the ABCD<4, 40% had a major finding (vessel stenosis, atrial fibrillation, infarct on imaging), when ABCD>=4, 75% had a major finding.  Even in the low-risk group the hazard ratio for stroke was 3.5 when any major finding was revealed.

Although modern prevention therapy has cut the number or recurrent events by half, this important work demonstrates that TIA is a neurological emergency requiring immediate evaluation. The current paradigm is using the ABCD2 score to risk stratify, followed by screening of the brain with MRI, the cervical arteries, fasting lipids and heart rhythm monitoring. The timing and location of the evaluation may vary based on the risk score. TIAregistry.org has shown us that we have come a long way in preventing stroke after TIA, but it remains a dangerous and important disease process.

Declining risk of recurrent stroke: credit to secondary prevention measures

Vivek Rai, MD

Pennlert J, Eriksson M, Carlberg B and Wiklund PG. Long-Term Risk and Predictors of Recurrent Stroke Beyond the AcutePhase. Stroke 2014.


Several studies have reported varied risk of recurrent stroke after an index event. Traditional risk factors such as advanced age, diabetes, previous myocardial infarction, smoking, atrial fibrillation etc have been reported to predict stroke recurrence. Pennlert et al investigated long-term risk and predictors of recurrent stroke in Northern Sweden between 1995-2008 utilizing population based MONICA stroke incidence registry. 



The authors identified 6700 patients of ischemic stroke (IS) or intracerebral hemorrhage (ICH) who survived for more than 28 days and were followed for a mean of 4 years (26,597 person-years). Authors report that overall cumulative stroke recurrence risk was 6%, 16% and 25% at 1, 5 and 10 years respectively. Interestingly, patients in the most recent cohort (2004-2008) had a 36% lower risk of recurrent stroke than patients in the first cohort (1995-1998) although among traditional risk factors only MI was less prevalent in the most recent cohort.

The study might underestimate the risk of recurrent stroke because recurrence during early phase (28 days) after qualifying event is not accounted for in this registry. Nevertheless, the results show declining risk of recurrent stroke over the last 2 decades which, in my opinion authors rightly point out, is representative of improved secondary prevention measures such as reduced smoking, aggressive lipid lowering measures and lifestyle modifications. Despite the declining rates, stroke recurrence remain an important clinical problem contributing significantly to morbidity and mortality.

Blogging Live from the ESC 2014 Clinical Trials Session

European Stroke Conference (ESC)
May 6-9, 2014 

May 8, 2014

There was a revolution in Transient Ischemic Attack (TIA) care in 2000 with the publication of the seminal report by SC Johnson and colleagues (JAMA 2000;284:2901­2906) of the high risks of stroke and vascular events following an index event. In the following years TIA risk scores such as the ABCD2 (Lancet 2007;369:283-292 ) were developed and promulgated throughout routine neurological care. At the European Stroke Conference in Nice Professor Pierre Amarenco presented the results of a modern TIA cohort collected through the use of the TIAregistry.org web-site, and the results were very interesting and likely to inform clinical practice.



The TIAregistry.org project evaluated short and long-term outcomes and refine risk assessment paradigms. Subjects had to be free of disability at baseline and have been evaluated for thei TIA in <7 days from onset, ideally <24 hours. A total of 4798 were recruited over 2.5 years: 4581 had complete data. The mean age was 66, 60% were men, 60% hypertensive and over half presented with a motor weakness syndrome. The ABCD2 scores were on the higher end with >70% scoring 4 or more. Imaging-demonstrated acute infarction was seen in 33% of cases, 16% had extracranial stenosis. Treatment was excellent with >90% on antithrombolic and >70% on antihypertensive and dyslipidemic agents. During follow-up <6% had a major vascular event, 4.7% had a stroke.

This study further validated the ABCD2 score in a real-world cohort obtained from a registry. Of note when the ABCD<4, 40% had a major finding (vessel stenosis, atrial fibrillation, infarct on imaging), when ABCD>=4, 75% had a major finding.  Even in the low-risk group the hazard ratio for stroke was 3.5 when any major finding was revealed.

Although modern prevention therapy has cut the number or recurrent events by half, this important work demonstrates that TIA is a neurological emergency requiring immediate evaluation. The current paradigm is using the ABCD2 score to risk stratify, followed by screening of the brain with MRI, the cervical arteries, fasting lipids and heart rhythm monitoring. The timing and location of the evaluation may vary based on the risk score. TIAregistry.org has shown us that we have come a long way in preventing stroke after TIA, but it remains a dangerous and important disease process.

May 7, 2014
There were many interesting presentations at clinical trials session of the 23rd European Stroke Conference on May 6, 2014. One of the most interesting and important for clinical practice was the Efficacy of Nitric Oxide in Stroke (ENOS) study presented by Phillip Bath on behalf of the ENOS study group. This randomized study of over 4000 subjects had two main arms; the first was treatment with transdermal glyceryl trinitrate (GTN, nitroglycerine) vs. control and the second was continuation or discontinuation of home antihypertensive therapy in the acute stroke week. Each arm yielded findings relevant to clinical practice.


The GTN arm looked at the effect of BP lowering by transdermal nitroglycerine on death and dependency at three months and was neutral. GTN was safe and lowered BP by about 7mmHg systolic/4mmHg diastolic compared with control. The median time to enrolment was 26 hours. In subgroup analysis, the group treated <6 hours from onset seemed to show a benefit in outcome, whereas later time periods did not. This comes at the heels of the recently published The Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT, Stroke. 2013 (11) 3120-8) which demonstrated clinical benefits of BP lowering with transdermal GTN for stroke patients enrolled in the field in a time period < 4 hours. Does this mean that hyper-acute BP lowering is feasible and exciting to study in the future? Is there something about GTN which is particularly neuroprotective or beneficial in stroke? Does the combination of an early subgroup analysis of a large trial combined (ENOS) with an independent small pilot study (RIGHT) make the idea of acute BP lowering with GTN interesting for future study?

The second arm of premorbid antihypertensive stop or continue in acute stroke is very important question that we all deal with as clinicians. I tend to hold antihypertensive for a few days in the acute phase whereas my colleagues often continue the agents. In ENOS, the largest study to address this question, there was no difference in outcomes and the study was neutral for discontinuation vs. continuation. There were significant differences in BP in the two arms throughout the study, which indicates that the two groups were being treated differently. Of the adverse events, it appeared that those randomized to continuing antihypertensive pills in the presence of dysphasia had higher rates of pneumonia. This is probably the last study to answer this question and along with the earlier COSSACS indicate that continuing or stopping antihypertensive not affect outcome in acute stroke. Will this change your practice? I feel more confident in routinely withholding antihypertensive pills for a few days, but would never withhold statin. Stopping statin in the acute phase is bad, stopping antihypertensive pills, not so bad.

Disparate Results? Diet and Carotid Disease

Jennifer Dearborn, MD

Allison MA, Aragaki A, Eaton C, Li W, Van Horn L, Daviglus ML, and Berger JS. Effect of Dietary Modification on Incident Carotid Artery Disease in Postmenopausal Women: Results From the Women’s Health InitiativeDietary Modification Trial. Stroke. 2014

In this study, a low-fat diet was not linked to a lower incidence of carotid artery disease, associated with stroke. The Women’s Health Initiative Diet Modification Trial randomized 48,835 women to a diet intervention or control based on decreasing fat intake to less than 20% of total calories and increasing intake of fruits, vegetables and whole grains. This same cohort previously examined outcomes of this intervention on incident stroke, and found no difference in rates of ischemic or hemorrhagic stroke in the intervention arm. This study looked at incident carotid disease (of which there were only 277 in the total population), as defined by an overnight hospitalization with coding for symptomatic carotid disease. 



This study may be taken as further evidence that “low fat” may not be better for vascular disease of the brain. Its strength is in its size and scope in a large cohort with rigorously measured confounders. A limitation of the study is that it used hospital based coding to look at symptomatic disease, rather using an imaging marker of plaque progression, such as intima media thickness as an intermediary. Recently, the PREDIMED study showed that a Mediterranean Diet supplemented with nuts was associated with delayed progression of carotid artery intima media thickness and plaque height, as measured by ultrasound. The Mediterranean Diet is not low fat; instead it is replete with olive oil, nuts and “good fats” along with moderate alcohol. These different conclusions may stem from the difference in the dietary intervention studied. This study should encourage us to examine the concept of the “healthy diet” and to better define what this means for vascular disease of the brain. A healthy lifestyle and diet should decrease stroke, right?

Improving Stroke Prediction with N-terminal pro-B-type natriuretic peptide (NT-proBNP)

Hassanain Toma, MD

Cushman M, Judd SE, Howard VJ, Kissela B, Gutiérrez OM, Jenny NS, et al. N-Terminal Pro–B-type Natriuretic Peptide and Stroke Risk: The Reasons for Geographic and Racial Differences in Stroke Cohort. Stroke. 2014


The REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort is a national population-based cohort study evaluating racial and geographic disparities in stroke incidence and mortality. Using this cohort, Cushman et al. evaluated the association of the cardiac function biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) with first time strokes in whites and blacks over 5.4 years. They showed that NT-proBNP levels were similar in whites and blacks, and did not differ by region. In addition, participants in the top quartile had 2.9 times the risk of stroke and 9.1 times the risk of cardioembolic stroke, when compared to the bottom quartile. Finally in 27% of participants, NT-proBNP levels accurately predicted stroke risk.




Although NT-proBNP failed to shed light on the racial and geographic disparities in stroke incidence and mortality, its utility in predicting stroke risk appears to be promising. The diagnostic utility for NT-proBNP is probably too early for primetime, but I can see its utility in cryptogenic strokes. Imagine an elderly stroke patient whose NT-proBNP falls within the top quartile of this study, and whose ASCOD phenotyping grade is A3,S0,C3,O0,D0, and is pending a prolonged 30-day loop monitoring. Would you anticoagulate?