American Heart Association

epidemiology and genetics

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.

Red Meat and Processed Meat Consumption Associated with Increased Risk of Stroke

Alexander E. Merkler, MD

Haring B, Misialek JR, Rebholz CM, Petruski-Ivleva N, Gottesman RF, Mosley TH, and Alonso A. Association of Dietary Protein Consumption With Incident Silent Cerebral Infarcts and Stroke: The Atherosclerosis Risk in Communities (ARIC) Stud
y. Stroke. 2015

Diet is an increasingly important topic in the field of cerebrovascular disease. The current study adds to the growing body of evidence that red and processed meat consumption increases the risk of stroke.

Dr. Haring et al evaluated the relationship between dietary protein consumption and stroke using the Atherosclerosis Risk in Communities Study (ARIC). More than 11,000 patients were enrolled in ARIC, a prospective study of middle aged adults, performed at four socioeconomically diverse locations in the United States. Patients included had no history of prior stroke and had no history of diabetes or cardiovascular disease so as to exclude patients that may lead to changes in diet. Dietary protein consumption use was assessed using questionnaires at the initial enrollment visit and then again six to eight years later.

Patients were followed for a median of 22 years. Overall, neither total protein intake nor animal protein consumption was associated with total, ischemic, or hemorrhagic stroke. On the other hand, higher intake of processed meat or red meat was significantly associated with an increased risk of stroke. Furthermore, only red meat consumption was associated with the development of ischemic stroke. No association was found between fish, nut, or low-fat dairy consumption and overall stroke risk.

Limitations include 1) Dietary protein was assessed at only one or two visits early on in the study and dietary habits may have changed over the ensuing years; 2) lack of adjustment for typical vascular risk factors; 3) lack of information regarding the etiology of stroke.

Overall, diet is an extremely important and modifiable stroke risk factor. Further research is warranted to help guide dietary modifications for both primary and secondary stroke counseling.

Atrial fibrillation – related strokes are associated with substantial long-term morbidity and mortality

Neal S. Parikh, MD

Hayden DT, Hannon N, Callaly E, Chroíiniín DN, Horgan G, Kyne L, et al. Rates and Determinants of 5-Year Outcomes After Atrial Fibrillation–Related Stroke: A Population Study. Stroke. 2015

In this issue of Stroke, Dr. Hayden and colleagues report on 5-year outcomes and secondary prevention utilization rates after atrial fibrillation – related strokes (AF-strokes) from North Dublin city.

AF-strokes are associated with greater severity and poor outcomes; however, the authors, in light of the increasing prevalence of atrial fibrillation (AF), seek to report population-level long-term outcomes of AF-strokes.

The data are derived from the Northern Dublin Population Stroke study, a prospective cohort of TIA and stroke patients established in 2006. Only stroke patients with a diagnosis of AF prior to the index stroke or an AF diagnosis within 3 months of the stroke were included in this study. Their outcomes were: 5-year survival, stroke recurrence, disability (by mRS), and nursing home residence in addition to prescription rates for secondary prevention anti-thrombotic medications.

They identified 177 patients with AF-stroke with a mean age of 76.5 and median CHA2DS2-VASc score of 6. Survival data was complete for nearly all patients. For survivors, outcome data was available for at least 90% for each outcome.

Key findings at 5 years:
· Only 39.2% of ischemic AF-stroke survivors were alive. Statin and warfarin prescription were protective.
· Only 14% were alive and independent.
· 21.5% had recurrent stroke.
· 25.9% had required nursing home residence at some time.
· In those surviving at least 28 days, 54.5% were prescribed an anti-platelet alone and 36% received an oral anticoagulant medication.
· Statins were prescribed in 74.1% of patients.

The findings of this study vitally underscore the morbidity and mortality associated with AF and AF-stroke. Additionally, this study confirms the widespread under-utilization of effective secondary prevention measures in this high risk population. The data are increasingly compelling; AF-related stroke prevention is crucial. The time is right to begin uniformly and systematically applying existing therapies.

Can the air we breathe be a risk factor for stroke?

Jay Shah, MD

Scheers H, Jacobs L, Casas L, Nemery B, and Nawrot TS. Long-Term Exposure to Particulate Matter Air Pollution Is a Risk Factor for Stroke: Meta-Analytical Evidence. Stroke. 2015 

Particle pollution, also known as particulate matter (PM), is a mixture of solid particles and liquid droplets found in the air. Inhalable coarse particles (diameter between 2.5-10 micrometers) and fine particles (diameter less than 2.5 micrometers) pose the greatest threat to human health. Potential mechanism includes inducing chronic systemic oxidative stress and inflammation which in-turn may promote atherosclerosis at the vasculature level. Thus, it has been postulated that PM exposure is an under recognized stroke risk factor. Recent meta-analyses characterized the short-term effects of PM on stroke hospitalization and mortality. However, the long-term effects of PM are relatively less known. Therefore, the authors conducted a meta-analysis to quantify the association between stroke risk and long-term PM exposure. The authors reviewed the literature for original studies assessing the association of long-term exposure of PM10 and PM2.5 to stroke events or stroke mortality. 

In total, 20 publications were included with combined >10 million persons and >200,000 stroke events. The studies were fairly evenly balanced between North America, Europe, and Eastern Asia. Hazard ratio with 95% CI was 1.061 for stroke event secondary long-term PM10 exposure and concluded that there exists a positive association between risk of stroke and PM exposure with 2-21% excess risk. Expectedly, there was significant geographical variation.

There are several limitations to this study. Three Chinese and two Japanese studies were excluded from sensitivity analysis due to dissimilarity. This certainly can be confounding as the Chinese studies had demonstrated significantly high PM levels. Another potential confounding variable, as pointed out by the authors, is the possible inaccuracy in determining exposure levels. Authors of the individual trials used data from central monitor stations and made efforts to obtain data from stations in closest proximity to the individual. However, this strategy can be problematic and does not account for important variables such as occupation, location of employment, and time spent outdoors. Several studies also did not capture smoking status and socioeconomic status within their data.

Therefore, data from this meta-analysis should be interpreted with caution. However, this is not to suggest that PM concentrations are not a public health concern. Clearly, there are enough reasons to reduce air pollution ranging from practical purposes (i.e. to improve visibility) to ecological reasons (i.e. to hasten the process of global warming). Furthermore, there is more robust evidence of harmful effects of particle pollution to pulmonary disease. Therefore, policy to decrease particle pollution will clearly be beneficial and may also decrease cardiovascular disease as this meta-analysis suggest.