American Heart Association

epidemiology and genetics

MHTFR C677T Mutation Is Associated With an Increased Risk of Lacunar Stroke

Alexander E. Merkler, MD

Rutten-Jacobs LCA, Traylor M, Adib-Samii P, Thijs V, Sudlow C, Rothwell PM, et al. Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype. Stroke. 2016

Discovering modifiable risk factors of ischemic stroke is the future of stroke prevention. Hyperhomocysteinemia is associated with an increased risk of stroke and the most common MHTFR mutation, the MHTFR C677T mutation, leads to increased levels of homocysteine. However, previous studies evaluating the effect of lowering homocysteine levels with B vitamins have been negative in terms of reducing overall stroke risk. 

In the current manuscript, Dr. Rutten-Jacobs et al evaluate the association between the MHTFR C677T variant and small vessel disease. The authors evaluated the association between the MHTFR C677T mutation and both stroke subtype and white matter hyperintensity volume under the hypothesis that hyperhomocysteinemia only increases the risk of small vessel disease. In addition, as previous literature has shown an association between hypertension and homocysteine, the authors stratified patients by the presence of hypertension.

The authors identified 1359 cases of lacunar strokes, almost 4000 cases of large vessel and cardioembolic strokes and over 14 000 controls. The MHTFR C677T mutation was significantly associated with lacunar stroke and white matter hyperintensity volume, but not with other stroke subtypes. Furthermore, stratifying the lacunar strokes by hypertension status, confirmed the association the MHTFR C677T mutation with lacunar strokes in hypertensive, but not in normotensive patients.

The MHTFR C677T variant is associated with an elevated risk of specifically lacunar stroke and in patients who are hypertensive. The study adds further support that hyperhomocysteinemia is a risk factor for small vessel disease but not other subtypes of ischemic stroke. The manuscript should serve as a prime example of the importance of correctly choosing an outcome – perhaps B vitamins may successfully reduce stroke in patients with hyperhomocysteinemia when specifically lacunar stroke is chosen as the outcome of interest.

Validating the Montreal Cognitive Assessment for Stroke and TIA Patients

Neal S. Parikh, MD

Citing the high prevalence of cognitive impairment in patients with stroke, the authors call for better methods to easily detect cognitive impairment in this population. The authors aim to validate the Montreal Cognitive Assessment (MoCA) for classifying patients into three groups: low-, intermediate- and high-likelihood of moderate-severe cognitive impairment.


Three hundred and ninety patients referred to a stroke prevention clinic after stroke or TIA or other potentially cerebrovascular disease completed the MoCA. The mean age was 62 (range 17-94), and 53% were female. Patients were non-aphasic and English-speaking. Of the 390 patients, 34% had ischemic or hemorrhagic stroke, 34% had possible or probable TIA, and 32% had other vascular or non-vascular diagnoses (e.g. migraine). The gold standard for receiver operator characteristic/area under the curve analyses was an extensive neuropsychological battery.

The median MoCA score was 25 and did not differ significantly between diagnosis groups. By neuropsychological testing, 13% had moderate-severe cognitive impairment, and 30% had mild impairment.

Using a single cut-point for classification as moderate-severe impairment, test characteristics were optimal for MoCA <23 (sensitivity 60%, specificity 90%).


When two cut-points were assessed, the intermediate likelihood range was 23-27. In other words, a score of >27 reliably excluded patients with moderate-severe impairment (sensitivity 96%, negative predictive value 98%). A score of <23 reliably identified patients with moderate-severe impairment (specificity 90%, positive predictive value 49%). Of patients scoring in the intermediate likelihood range (23-27), 8% had moderate-severe impairment. The authors do not report the breakdown of the remaining 92% in terms of mild versus no cognitive impairment.


The MoCA may therefore help for identify patients unlikely to have cognitive impairment (e.g. “rule out”), but, as expected for a screening test, is not specific (e.g. not diagnostic). In their sample, 62% of patients fell into the intermediate group, and only 8% of these patients had moderate-severe cognitive impairment; this suggests that the intermediate range may not be a helpful category. However, for targeting assessments and interventions in clinical practice and research, the high specificity cut-point (MoCA<23) will certainly be of use.






Preexisting Heart Disease Underlies Newly Diagnosed Atrial Fibrillation After Acute Ischemic Stroke

Allison E. Arch, MD

Rizos T, Horstmann S, Dittgen F, Täger T, Jenetzky E, Heuschmann P, et al. Preexisting Heart Disease Underlies Newly Diagnosed Atrial Fibrillation After Acute Ischemic Stroke. Stroke. 2016

Atrial fibrillation (afib) is a risk factor for ischemic stroke. In patients who just had a stroke, a proportion of them will be diagnosed with afib in the post-stroke period. Does afib diagnosed immediately after a stroke carry the same risk for future stroke as afib that was already a known diagnosis? Is it associated with cardiovascular disease, or does the stroke itself cause a neurogenic arrhythmia that may not portend the same future stroke risk? These are the questions that Rizos and colleagues addressed in their single center observational study.

The authors included 1,397 stroke patients who were entered into a prospective database. In the 320 patients who had afib recorded in the hospital, 64% had a known diagnosis of afib. The remaining 36% had a new diagnosis of afib. Comparing those with known afib to those newly diagnosed, both groups had the same amounts of coronary artery disease, left atrial dilation, and low ejection fractions on echocardiogram. In other words, the newly diagnosed afib group had the same cardiovascular profile as the known afib group. Therefore, patients with new afib and stroke may just have afib due to underlying cardiovascular disease, and not from neurogenic strain on the heart.

This has implications for secondary stroke prevention. Whether or not atrial fibrillation was a known or a new diagnosis at the time of ischemic stroke, Rizos and colleagues show that both groups have the same underlying cardiovascular risk profile. Therefore, one may conclude that both groups should undergo the same stroke secondary prevention strategies.  

Impaired Higher-Level Functional Capacity Predicts Stroke Occurrence

Ilana Spokoyny, MD

Murakami K, Tsubota-Utsugi M, Satoh M, Asayama K, Inoue R, Ishiguro A, et al. Impaired Higher-Level Functional Capacity as a Predictor of Stroke in Community-Dwelling Older Adults: The Ohasama Study. Stroke. 2016

Does impairment of higher level functional capacity (intellectual, social, and instrumental activities of daily living such as cooking, cleaning, shopping) predict stroke in patients who are independent in basic ADLs? Should we probe as deeply into our patients’ higher level functional capacity as we do into their past medical history? The authors of this study address these important questions in a study of 1500 Japanese patients over age 60. These patients were independent for basic ADLs, and had not had a prior stroke.

After following the patients for about 10 years, the authors found that 191 of 1493 developed a first-time stroke. As expected, age played a role: those with impaired higher level functional capacity were older than those with normal capacity, and those who had strokes were older than those who did not. Overall TMIG-IC score (measurement of higher level functional capacity) was associated with significantly higher probability of developing stroke overall in multivariate analysis. The intellectual activity subscore was the only subscore which remained significant for the overall group. When the group was stratified by age, sex, and hypertension, the intellectual activity subscore was significantly associated with stroke in women only. Social role was significantly associated with stroke in those patients 75 years or older.



It is important to ask if the association is causative – or whether there are common risk factors for stroke as well as impairment in higher level functional capacity. In this study, the association persisted after adjusting for age and risk factors. The authors suggest that higher level functional impairment may represent early cerebrovascular disease, such as silent strokes. Determining the degree of white matter disease and correlating with higher level functional status would be the logical next step to follow this study. Determining baseline function, including higher level functional capacity, is useful and may help predict stroke. It would be interesting to compare the post-stroke level of independence of stroke patients with and without baseline higher level functional impairment. I suspect that those with higher level functional impairment, even if they were independent for basic ADLs, would have more significant post-stroke disability after adjusting for location and size of stroke. Lower cognitive reserve may portend a more protracted course and more difficulty rehabilitating from a stroke. Having data on a patient’s baseline status would be helpful in predicting stroke occurrence (shown in this study) and possibly predicting outcomes post-stroke.

Breakfast Intake Inversely Associated With Incident Stroke

Neal S. Parikh, MD

Kubota Y, Iso H, Sawada N, Tsugane S, The JPHC Study Group. Association of Breakfast Intake With Incident Stroke and Coronary Heart Disease: The Japan Public Health Center–Based Study. Stroke. 2016

The association between breakfast intake and good health is often touted in popular culture.

The authors cite studies demonstrating associations between skipping breakfast and multiple metabolic derangements and vascular risk factors including obesity, hypertension, dyslipidemia and glucose intolerance. Given these findings and the findings of a study of male US health professionals suggesting an inverse relationship between breakfast intake and coronary heart disease, the authors studied the association between breakfast intake and incident stroke and coronary heart disease.

The study was a population-based, prospective study using the Japan Public Health Center-Based (JPHC) study. Of 140,420 Japanese adults who were eligible, the study included 82,772 participants who had answered a breakfast intake questionnaire in the late 1990s and were free of prevalent stroke or coronary heart disease. Breakfast intake was defined as frequency of breakfast intake per week with daily breakfast as the reference. Covariates included age, sex, BMI, hypertension, hyperlipidemia, diabetes, blood pressure and cholesterol medications, smoking, exercise, sleep, stress, cohabitation, nature of employment, alcohol intake, caloric intake, and intake of vegetables, fruit, fish, soy, dairy, nuts, fat, fiber, and sodium. The outcomes were incident stroke (ischemic, subarachnoid hemorrhage, cerebral hemorrhage), MI, and sudden cardiac death.

The 82,772 participants provided 1,050,030 patient-years of follow-up. Participants who ate breakfast less frequently were less healthy and less likely to be on appropriate medication (e.g. for hypertension and hyperlipidemia). There were 4,642 cases of coronary heart disease and 3,772 strokes (including 1050 cerebral hemorrhages, 417 subarachnoid hemorrhages, 2,286 ischemic strokes).

After adjusting for potential confounders including dietary and lifestyle factors, total cardiovascular disease was associated with complete breakfast omission (HR, 1.14; CI 1.01-1.27) as was total stroke (HR 1.18, CI 1.04-1.34). An association was seen between breakfast omission and cerebral hemorrhage (HR, 1.36, CI 1.10-1.70) but not with coronary heart disease, subarachnoid hemorrhage, or cerebral infarction. The association between breakfast omission and stroke was only seen in non-users of anti-hypertensive medications.

The main limitation is that breakfast intake frequency was a time-fixed variable, which means that the methods did not account for the possibility of breakfast habits changing over time. Second, those omitting breakfast were less healthy, which raises the real possibility of residual confounding, especially as the confidence interval nearly crossed 1.0 for total cardiovascular disease.

Nonetheless, as the authors explain, there is a plausible causal pathway from breakfast omission to morning hypertension and cerebral hemorrhage. Additionally, to its merit, the study exhaustively controlled for vascular risk factors and dietary and lifestyle factors. This study suggests that failure to regularly eat breakfast is associated with cardiovascular disease, particularly hemorrhagic stroke. It may therefore indeed be healthful to eat breakfast daily.

Hemorrhagic stroke risk increased with certain NSAIDs: A meta-analysis of the data

Peggy Nguyen, MD

Ungprasert P, Matteson EL, and Thongprayoon C. Nonaspirin Nonsteroidal Anti-Inflammatory Drugs and Risk of Hemorrhagic Stroke: A Systematic Review and Meta-Analysis of Observational Studies. Stroke. 2016

The risk of cardiovascular events with NSAIDs has recently been publicized in the general media, with the FDA strengthening its warning on the association of NSAIDs with myocardial infarction and strokes in the past year. The relationship between NSAIDs and stroke risk, however, particularly hemorrhagic stroke, is ill-defined. The authors here performed a comprehensive meta-analysis reviewing the risk of hemorrhagic stroke in patients taking NSAIDs.

This meta-analysis identified 10 studies (7 case-control, 3 cohort studies) encompassing 1,489,120 patients. There was some heterogeneity across the studies, but most studies identified NSAID exposure as use of any NSAIDs until the index date or within 30 days prior to index date. Pertinently, there was a small, but not statistically significant, increased risk of hemorrhagic stroke (RR 1.09, 95% CI 0.98 – 1.22). Statistical analysis was also done for individual NSAIDs when data was available from a minimum of 3 studies, with a statistically significant increase for hemorrhagic stroke with diclofenac (RR 1.27, 95% CI 1.02 – 1.59) and meloxicam (RR 1.27, 95% CI 1.08 – 1.50). The highest risk estimate was seen in rofecoxib users, although it was not statistically significant (RR 1.35, 95% CI 0.88 – 2.06). The statistical significance was not significantly changed with sensitivity analyses, although the relative risk was increased for diclofenac and meloxicam in one analysis to 1.46 and 1.48, respectively.


As the authors point out, the results of the meta-analysis should be interpreted with caution. The lack of a significant association with NSAIDs as a whole may be a function of the reversibility of NSAID inhibition on COX-1. Selection bias may exist; due to the cardiovascular warning associated with NSAIDs, the exposed group may in fact be healthier than the non-exposed group, in which case, the risk of hemorrhagic stroke may actually be underestimated. Nevertheless, the results are at least suggestive that in patients who are at increased risk for hemorrhagic stroke, for example, a patient with amyloid angiopathy, it is not unreasonable that these medications be avoided.

Neurofibromatosis type 1 and its relationship with stroke

Allison E. Arch, MD

Terry AR, Jordan JT, Schwamm L, and Plotkin SR. Increased Risk of Cerebrovascular Disease Among Patients With Neurofibromatosis Type 1: Population-Based Approach. Stroke. 2016

Neurofibromatosis type I (NF1) is associated with multiple different tumor types. As it turns out, it may also be associated with vasculopathy and stroke. The link between NF1 and vascular events has been previously addressed in the literature, but it remains poorly understood. In this article, Terry and colleagues explored the relationship between NF1 and stroke in a case-control study. The authors used the population in the US Nationwide Inpatient Sample to screen for NF1 admissions between 1998 – 2009. Then they matched controls to cases in a 5:1 ratio, using the variables age, gender, geographic region, hospital size, and hospital type (rural, urban non-teaching, or urban teaching).

The results showed that NF1 was associated with an increased odds of stroke in hospitalized patients, most notably hemorrhagic strokes. The odds of any stroke was 1.2 (p<0.0001), and the odds of intracerebral hemorrhage was 1.9 (p<0.0001). Patients with NF1 had strokes at a younger age, and the adult patients with NF1 and stroke had a lower prevalence of stroke risk factors, including a lower prevalence of diabetes, atherosclerosis, and atrial fibrillation.

This is a significant finding. Currently, if a patient with NF1 presents with acute neurologic findings, tumor and tumor-associated morbidities are highest on the differential diagnosis. However, if NF1 is also associated with stroke, then vascular events should now also be considered.

Peri-menopausal vasomotor symptom trajectories and carotid intima media thickness

Neal S. Parikh, MD
 

Thurston RC, El Khoudary SR, Tepper PG, Jackson EA, Joffe H, Chen HY, and Matthews KA. Trajectories of Vasomotor Symptoms and Carotid Intima Media Thickness in the Study of Women’s Health Across the Nation. Stroke. 2016

Thurston and colleagues sought to assess the relationship between trajectories of menopause-related vasomotor symptoms (VMS) (such as hot flashes and night sweats) and carotid intima media thickness (IMT).
The authors note that the patterns of VMS vary substantially among women; symptoms can occur prior to menopause, during or for long periods after. Temporal variations and differences in patterns are hypothesized to have different physiologic underpinnings and sequela, including for cardiovascular disease. 

The Study of Women’s Health Across the Nation (SWAN) – a multiethnic, longitudinal cohort of peri-menopausal women between the ages of 42-52 not using oral contraceptive or hormone therapy, served as the study cohort. The cohort enrollment assessments occurred in 1996-1997. After up to 13 annual visits, women underwent carotid ultrasound imaging.

811 of 1512 women with IMT data were ultimately included. They were required to have had at least 3 visits during which they completed questionnaires regarding VMS and to be notably free of a history of stroke or myocardial infarction. IMT was measured at the common carotid artery. The mean and maximal IMT were used for analyses. Covariates were site, age, ethnicity, education, BMI, blood pressure, lipid profile, diabetes, smoking status, use of cardiovascular medications and anxiety.

A statistical approach termed “group based growth trajectory modeling” was used to identify four distinct trends: consistently low VMS burden, consistently high VMS burden, early-onset (self-limited) VMS and late-onset VMS. At baseline, high VMS burden and early onset VMS were associated with cardiovascular disease risk factors.

Unadjusted, consistently high VMS burden was associated with increased IMT. Of the four trajectories, early onset VMS (onset up to 10 years prior to final menstrual period and subsiding over several years) was associated with increased mean and maximal IMT in linear regression adjusted for demographics and cardiovascular disease risk factors.

It seems, then, that early-onset VMS is independently associated with carotid IMT, a marker of cardiovascular disease. These findings may help future studies target women with early-onset VMS, in whom these symptoms may be most relevant to the pathophysiology of cardiovascular disease.

Recurrent ischemic stroke risk in children

Neal S. Parikh, MD

Fullerton HJ, Wintermark M, Hills NK, Dowling MM, Tan M, Rafay MF, et al. Risk of Recurrent Arterial Ischemic Stroke in Childhood: A Prospective International Study. Stroke. 2015

Citing a paucity of contemporary pediatric stroke recurrence risk data, Fullerton and colleagues conducted a prospective study to measure recurrent stroke rates and risk factors for recurrent strokes in children.

Patients were enrolled from 2010 to 2014 from 37 centers across 9 countries for the Vascular effects of Infection in Pediatrics (VIPS) protocol. Strokes were classified as having definite, possible or no arteriopathy and then further subdivided into transient cerebral arteriopathy, arterial dissection, moyamoya, vasculitis, or other. Strokes without arteriopathy were classified as idiopathic, cardioembolic or other. The researchers also collected data regarding infections in the 3 weeks prior to the index stroke and patients’ vaccination statuses.

355 children were enrolled and followed over a median of 2 years. 87% were treated with antithrombotic medications. There were 42 recurrent strokes, all ischemic, at a median of 23 days from index stroke. 6.8% had 1-month recurrence; 12% had 1-year recurrence.

The only predictor of recurrent stroke was definite arteriopathy, which increased the hazard of recurrence by five-fold compared to idiopathic index stroke. 21% of children with index stroke due to definite arteriopathy experienced a recurrent stroke. The highest recurrence rate was for children with moyoamoya disease. 75% of recurrent strokes occurred within 12 weeks of index stroke. Of note, though these authors previously showed recent infection and unvaccinated status to be associated with incident stroke, these variables were not associated with recurrent stroke risk.

The high stroke recurrence rate in children with arteriopathy is remarkable. As the authors conclude, arteriopathy – particularly forms in children such as transient cerebral arteriopathy and moyamoya disease – may have unique pathophysiologic underpinnings and therefore treatments.

Something in the Air…Causing Stroke?

Ilana Spokoyny, MD

Sade MY, Novack V, Ifergane G, Horev A, and Kloog I. Air Pollution and Ischemic Stroke Among Young Adults. Stroke. 2015 

Air pollution is known to cause inflammation, and small particulate matter has been linked to cardiovascular disease. The proposed mechanisms of stroke caused by particulate matter is direct entry into the CNS via olfactory tract, and oxidative stress caused by inhalation of the particulate matter. The authors of this Israeli study hypothesized that exposure to small particulates is associated with increased stroke incidence in young adults. Young adults in particular have lower cardiovascular risk factors, and are more likely to have stroke due to metabolic or toxic causes. Previous studies connecting air pollution to stroke had mixed results, but as the authors point out, a major flaw was the method used to measure particulate matter. The typical manner of measuring the pollution level was based on centrally located monitoring stations, which were either inaccurate in representing rural populations not living near a monitoring station or did not represent them at all. The authors used an innovative method of estimating the concentration of particulate matter, using daily satellite remote sensing data with a 1km spatial resolution.

The study was done using data from the largest HMO in Southern Israel, and included patients admitted to the only acute neurological care center in the area. The average amount of pollution at a patient’s home address on the day of their stroke was calculated and adjusted for daily average temperature and humidity. The pollution data was used in a case-crossover design, such that a patient’s exposure on the day of his/her stroke was compared to the exposure in other time periods of that same patient, so each subject served as his/her own control.

Approximately 4800 patients were included, 90% of whom had ischemic stroke. An association was seen between ischemic stroke and both PM-10 (particulate matter smaller than 10μm, OR 1.11) and PM-2.5 (particulate matter smaller than 2.5μm, OR 1.10) calculated on day of stroke, but this association was only seen in patients under 55 years old and did not persist in the overall population or for hemorrhagic stroke. No association was found with the particulate matter concentration 1-4 days prior to the stroke. One hypothesis for this association only being seen in young adults is that atherosclerosis (seen more in older patients) makes the vessels less reactive, and thereby less susceptible to the vascular effects of air pollution.

Interestingly, there was a higher stroke risk associated with increases in the particulate matter at lower ranges of overall pollution (i.e an increase in PM-10 from 30 to 48 μm/m3 was associated with a higher odds ratio than an increase in PM-10 from 160 to 178 μm/m3. The lower range of particulate matter is more likely to be associated with traffic (compared to higher levels which are typically due to natural pollutants such as dust). Additionally, a stronger association between pollution and stroke was seen in patients whose homes were within 75 meters of a main road, again implicating traffic pollution.

Several limitations of the study are noted by the authors, include incomplete data on smoking as well as traffic noise and gaseous air pollution. We should also consider that the patients may not have been home on the day of their stroke, so the pollution measure at their house, however accurate, may be irrelevant. If workplace location were known, and traffic pollution is implicated, it would be interesting to estimate the exposure by combining data on the patient’s commute as well as home and workplace particulate matter measurements. Additionally, it is likely that chronic exposure to particulate matter increases the cardiovascular and stroke risk, and we see some evidence of this in the current paper (increased risk of stroke in patients living in proximity to a major road). While the pollution measure in the 1-4 days preceding the day of stroke presentation did not correlate with stroke risk, obtaining a longer-term estimate of the cumulative exposure may be useful to study in the future. Overall, the increased risk of stroke associated with increased particulate matter (likely traffic related) is critical information which may help influence policy surrounding air pollution standards.