American Heart Association

epidemiology and genetics

Understanding Changing Temporal Trends in Dementia — Does Improving Vascular Health Have a Role?

Gurmeen Kaur, MBBS

Pase MP, Satizabal C, Seshadri S. Role of Improved Vascular Health in the Declining Incidence of Dementia. Stroke. 2017

It is projected that 13.8 million Americans will have dementia by the year 2050, making it a major public health epidemic. While the overall prevalence is on a rise, every individual’s chance of developing dementia per year is decreasing. The authors used the Framingham Heart Study (FHS) to demonstrate nearly a 20% decrease in developing dementia by a specific age over the past 30 years and have explored the temporal trends of this change.

Improved cardiovascular health and better management of stroke and vascular risk factors may be the reason for this observed decrease. Vascular risk factors have also been implicated in the pathophysiology of both vascular dementia and Alzheimer’s type dementia. A meta-analysis of 14,730 adults, including 862 with a history of stroke and 13,868 controls, demonstrated that a history of stroke increased the risk of AD dementia by 59%. Leukoariosis or increased burden of small vessel disease suggests silent ischemia. Many large databases show that the incidence of strokes is decreasing, which may be a contributing factor to decreased rates of dementia.

Heart Failure Associated With All Types of Strokes at Long-term Follow Up

Peggy Nguyen, MD

Adelborg K, Szépligeti S, Sundbøll J, Horváth-Puhó E, Henderson VW, Ording A, et al. Risk of Stroke in Patients With Heart Failure: A Population-Based 30-Year Cohort Study. Stroke. 2017

Heart failure has previously been identified in association with ischemic stroke, with previous literature citing thrombus formation, hypercoagulable state, endothelial dysfunction and impaired cerebral autoregulation as possible mechanisms underlying ischemia. Additionally, heart failure and stroke share several common etiological conditions, including hypertension and dyslipidemia (Stroke. 2011;42:2977-2982). However, the association between heart failure and hemorrhagic stroke, and the long-term implications of heart failure on all-stroke risk, remained to be clearly elucidated. Here, patients with heart failure (n = 289,353) were compared to an age and gender matched control group (n = 1,446,765), for the outcomes of ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) evaluated at 30 days, 1 year, and 30 years, providing a far more extensive follow up than previous studies.

Calorie-free, But Perhaps Not Risk-free: Artificial Sweeteners and the Risk of Stroke and Dementia

Neal S. Parikh, MD

Pase MP, Himali JJ, Beiser AS, Aparicio HJ, Satizabal CL, Vasan RS, et al. Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia: A Prospective Cohort Study. Stroke.

In this entry, I discuss a recent publication by Matthew Pase and colleagues regarding the risks of stroke and dementia associated with the consumption of sugar-sweetened and artificially sweetened beverages.

Citing conflicting data, the authors sought to examine the association of sugar- or artificially sweetened soft drink intake with incident stroke and dementia in the Framingham Heart study.

Inverse Relationship between HDL2-C Subfraction and Carotid Intima-Media Thickness

Alexander E. Merkler, MD 

Increased carotid-intima media thickness (cIMT) is associated with future cerebrovascular events. Although previous data has shown an inverse relationship between high density lipoprotein cholesterol (HDL-C) and future cerebrovascular events, this association has been challenged in recent trials; therefore, it is uncertain whether HDL-C subfractions have differential effects on cerebrovascular risk.

Using the Northern Manhattan Study (NOMAS), Dr. Tiozzo et al. evaluate the relationship between HDL-C subfractions and cIMT. NOMAS is a prospective cohort study designed to determine stroke incidence and risk factors in a multiethnic urban population in Manhattan.

Nine hundred eighty-eight stroke-free participants with available data on HDL-C subfractions and cIMT measurements using high-resolution ultrasound were evaluated. HDL-C was assessed as HDL2-C and HDL3-C subfractions, and total HDL. cIMT was calculated as the composite measure of the near and the far wall of IMT in the common, internal, and bifurcation of the carotid artery on both sides of the neck. After controlling for demographics, vascular risk factors, LDL, and triglyceride levels, both HDL2-C and total HDL-C were inversely associated with cIMT; the association was even more robust among patients with diabetes. No association was found between HDL3-C and cIMT.

The main limitation is the lack of temporality between HDL-C subfraction measurement and cIMT assessment.

Overall, the results suggest an inverse relationship between total HDL and HDL2-C and cIMT, but not between HDL3-C and cIMT. If confirmed, these results may lead to HDL subfraction targeted therapies to reduce the risk of cerebrovascular disease.

Heart Rate Variability and Incident Stroke Risk in the Atherosclerosis Risk in Communities Study

Neal S. Parikh, MD
In this issue of Stroke, Amber Fyfe-Johnson and colleagues describe their investigation of the association between heart rate variability (HRV) and incident stroke risk in the Atherosclerosis Risk in Communities (ARIC) Study cohort.

They argue that autonomic nervous system (ANS) dysfunction, as reflected by HRV, may be associated with cardiovascular mortality, coronary heart disease, and mortality in stroke survivors. ANS dysfunction may be associated with dysregulated cerebrovascular autoregulation and blood pressure.

ARIC participants were assessed by EKG for HRV by four measures at visit 1 (1987-1989) and followed through December 31, 2011 for incident stroke by telephone ascertainment, hospital discharge diagnosis review, and state death registry review. Covariates, collected at the index visit and again at visit 4 (1996-1998), included: age, sex, race, smoking/alcohol use, physical activity, body mass index, blood pressure, blood lipids, and diabetes. Patients taking medications that modify HRV (beta-blockers, anti-arrythmics, calcium channel blockers, digoxin) and those with prevalent stroke, coronary disease, or heart failure were excluded.  

Cox proportional hazards models were used to calculate hazard ratios for the relationship between each quintile of HRV measures and stroke.

Of 12,550 ARIC participants, 816 (6.5%) had stroke. Crude cumulative stroke incidence was higher in patients with the lowest HRV quintile (compared to the highest quintile). However, after adjustment for covariates, associations between HRV and stroke risk were attenuated and did not meet statistical significance. In analyses restricted to participants with diabetes, stroke risk was higher in the lowest HRV quintile, but this association was only statistically significant when testing one of four HRV measures (HR 2.0, 95% confidence interval, 1.1-4.0).

The authors conclude that there may be an association between low HRV and incident stroke in populations already at risk – patients with diabetes. Whether this association would withstand adjustment for an expanded list of cardiovascular risk factors in a modern cohort is unclear. However, the importance of identifying simple indicators of stroke risk such as HRV cannot be overstated. 

Early Appearance of Spot Sign on CT Perfusion Associated with Hematoma Expansion and Poor Outcome in Small Retrospective Study

Intracerebral hemorrhage (ICH) causes a significant amount of stroke-related morbidity and mortality. Of the various prognostic factors in ICH, hematoma expansion (HE) is one of the few potentially modifiable ones and as such has been a topic of increasing research.
Unfortunately, large-scale randomized controlled trials aimed at preventing hematoma expansion have not shown robust results, possibly owing to the limited ability of clinicians to predict which patients are at greatest risk. The “spot sign,” a radiographic sign representing the leakage of contrast with a hematoma on CT scan has recently become a topic of extensive study with respect to its ability to predict hematoma expansion. As described previously, a recently published meta-analysis suggested that the sensitivity and positive predictive value of the spot sign was related to the time from ictus to scan acquisition and may not adequately predict HE when it is detected. Additionally, other studies have shown that using CT perfusion (CTP) improves the detection rate of the spot sign. Wang et al. sought to explore the relationship between spot sign characteristics on CTP (including number, timing, and maximum density) to evaluate the relationship between these characteristics and the risk of HE as well as clinical outcome.
The authors’ retrospectively reviewed a total of 83 patients from a prospectively collected database of consecutive patients with supratentorial SICH. Patients receiving surgical evacuation of their hematoma were excluded from the outcome analysis, and additionally were excluded from HE analysis if the intervention took place prior to the 24 h follow-up CT scan. Patients who died prior to the 24 h follow-up CT scan were excluded from the HE analysis.  Patients with secondary causes of ICH were also excluded. A total of eleven patients (6 with positive spot sign) were excluded from the HE analysis, and twelve patients (7 with positive spot sign) were excluded from outcome analysis due to receiving surgical evaluation. Excluded patients had higher SBP and DBP, over a three-fold greater median hematoma volume (52.30 mL vs 15.80 mL, P=0.029) and a nearly two-fold higher median NIHSS (21 vs 11, P=0.004). 

Baseline clinical variables included patient demographics, medical history, medications, onset to imaging time (OIT), baseline National Institute of Health Stroke Scale (NIHSS), and laboratory results. The clinical outcomes assessed were NIHSS at 24 h, in-hospital mortality, and modified Rankin Scale (mRS) including death at 3 months follow-up. Spot sign was assessed with CTP and the timing of occurrence (time from the start of scan to first detection of spot sign), total number of spots, maximum spot attenuation, and axial dimensions were recorded. The median time of onset to CP was 180 (120 to 240) minutes. Hematoma expansion was defined as an absolute ICH growth ≥ 6 mL or relative growth ≥ 33% as recorded on 24 h follow-up CT scan. 

The rate of spot sign was higher in patients with HE than those without (62.5% vs 12.5%, P<0.001). The presence of spot sign was independently associated with HE after correcting for APTT, glucose, NIHSS, baseline hematoma volume, and antiplatelet use. There was a trend for an association between the presence of spot sign and 3-month mortality (32% vs 8%, OR=5.649; 95% CI 0.913-34.954; P=0.063) after multivariate analysis. Spot sign was detected much earlier in patients with HE than those without (18.75 s vs 26.87 s, P=0.007). The timing of spot sign was significantly correlated with both absolute and relative ICH volume growth, and there was no association between the other spot sign characteristics and HE. The authors defined a subset of spot sign patients as having an “early occurring spot sign (EOSS),” defined as detection of the spot sign before 23.13 seconds. EOSS was found to have 0.67 sensitivity and 0.90 specificity for HE. On multivariate analysis, EOSS was an independent predictor of HE (OR=28.835; 95% CI, 6.960-119.458; P<0.001) and 3-month mortality (OR=22.377, 95% CI, 1.773-282.334; P=0.016). EOSS maintained a higher specificity for HE compared to spot sign (91% vs 74%).

In this single-center cohort of SICH patients, spot sign as assessed by CTP was associated with HE. The authors also found that early detection of the spot sign was the most important characteristic with respect to predicting HE and significantly correlated with ICH growth. The primary limitations of the study were related to the retrospective nature of the study, the relatively small sample size, and the use of a single center for recruitment and determining imaging parameters. External validation with a larger sample size and standardized imaging parameters will be necessary. In addition, the high rate of excluded surgical evacuation patients with positive spot sign may have led to an underestimation of the spot sign’s PPV with respect to mortality. It is also important to note that the predictive value and associations with spot sign on CTP in this study should not be applied patients evaluated with single-phase CT angiography. However, replicating this study with multi-phase CTA could be feasible and represents a potential future avenue of research.

Recent and Regular Use of Cocaine Significantly Increases Odds of IS in a Case-Control Study of Young Adults

Benjamin R. Kummer, MD

Cheng Y-C, Ryan KA, Qadwai SA, Shah J, Sparks MJ, Wozniak MA, et al. Cocaine Use and Risk of Ischemic Stroke in Young Adults. Stroke. 2016

Case series have reported biologically plausible associations between cocaine use and stroke in young patients, but few studies have rigorously investigated this relationship or the effects of drug ingestion timing or route of ingestion in large populations. Using a case-control design, Cheng and colleagues attempted to confirm the existence of the link between cocaine use and stroke in young patients, and delineate the relationship between timing and route of cocaine on the risk of ischemic stroke (IS). In this study, the authors drew their population from an existing, prospectively collected, case-control registry of 1,100 cases between the ages of 15 and 49 with first-ever IS, and approximately 1,100 controls. Cocaine use and timing/route were recorded on the basis of individual patient recollections (a small subset of patients had urine drug screening), as was confounding clinical and demographic data.
After adjusting for age, gender, ethnicity, smoking, hypertension, and alcohol use, patients that used cocaine in the 24 hours prior (OR 5.7, 95%CI 1.7-19.7) had significantly increased odds of IS compared to controls. However, the odds ratio for IS lost its statistically significance (OR 3.5, 95%CI 0.9-12.6) after removing higher-odds study periods. Patients that had smoked cocaine in the previous 24 hours had even higher adjusted odds of IS (OR 7.9, 95% 1.8-35.0), although no adjustment was made for smoking, hypertension, or alcohol use. Patients that reported smoking cocaine at any point also had slightly increased but not statistically significant adjusted odds of IS (OR 1.2, 95%CI 0.9-1.6). Patients that reported use of at least once in the past 1-30 days had a slightly increased, non-significant adjusted odds of IS (OR 1.1; 95% CI 0.7-1.9).

Overall, the number of patients exposed to cocaine use was very small relative to the sample size. Aside from the small number of observations, which caused effect estimates to be very wide, cases also had a greater proportion of patients with stroke risk factors (HTN, DM2, smoking, black race) than controls. The determination of drug use history could have been influenced by recall bias, and there may have also been a bias in under-reporting drug use by the study population (although this would have generated a conservative bias for the effect estimates). Also, while the logistic regression model was adjusted for some confounders, it was not adjusted for income level, education, employment, and insurance status, as well as important risk factors in young patients, such as hypercoagulable state, hyperlipidemia, family history of stroke, or obesity.
Despite its small number of observations, this study by Cheng and colleagues argues for a biologically plausible relationship between acute cocaine smoking and IS in young patients. It would have been interesting to see whether the association between acute cocaine smoking and IS disappeared with further adjustment for markers of health care access. These findings support urine toxicology screening for young patients with acute IS, although the implications for acute stroke management in such cases are unclear.

Intracranial Aneurysm Growth and Rupture Have Risk Factors in Common in a Large Meta-Analysis

Benjamin R. Kummer, MD

Backes D, Rinkel GJE,  Laban KG, Algra A, and Vergouwen MDI. Patient- and Aneurysm-Specific Risk Factors for Intracranial Aneurysm Growth: A Systematic Review and Meta-Analysis. Stroke. 2016

Three percent of the general population harbors an unruptured intracranial aneurysm (UIA). Due to their unfavorable interventional risk-benefit profile, small, asymptomatic UIAs are often left untreated and followed with serial imaging for growth—a well-established risk factor for aneurysm rupture. Because many factors associated with aneurysm growth are also associated with rupture, patients needing increased frequency of monitoring or even intervention might be identifiable by characteristics associated with aneurysm growth. Building on their previous work on aneurysm growth published in 2015 in Stroke, Baackes and colleagues further the aim of identifying patients at increased risk for rupture in this systemic review and meta-analysis of the clinical and aneurysm-specific factors associated with the growth of UIAs.

Approximately 4,000 patients and 5,000 unruptured intracranial aneurysms were studied, drawn from 18 separate publications and 15 unique patient cohorts (5 separate studies overlapped on 2 independent cohorts), followed over a mean of 2.8 years. The analysis only pooled studies that had clear definitions and effect estimates of aneurysm growth; however, a significant amount of epidemiologic and methodologic heterogeneity was present. Prospective and retrospective designs, studies with different population sizes, growth definitions, imaging modalities (CTA, DSA, MRA), Newcastle-Ottawa publication bias scores (mean 6, SD 1.9), as well as the numbers of growing UIAs were all analyzed together. Sensitivity analyses were performed to account for some, but not all of this heterogeneity. 

As previously shown, many factors associated with aneurysm rupture, like female sex, smoking, hypertension, larger aneurysm size, posterior circulation location and aneurysm shape, were also associated with aneurysm growth. However, the degree of heterogeneity in the effect estimates was moderate to substantial. The presence of multiple UIAs, which has not been readily identified as a factor associated with aneurysmal rupture, was shown to be significantly associated with aneurysm growth, raising the possibility that patients with multiple aneurysms might have a possibly connective-tissue based predilection towards more rapid growth than patients with single aneurysms, although it is important to note that this signal was also confounded by quite heterogeneous effect estimates. In contrast to their well-established association with aneurysmal rupture, family history of SAH and previous SAH were not significant factors for aneurysmal growth. Interestingly, UIA cohorts from Japan (where rates of aneurysmal rupture are higher than in European and North American cohorts) were had a lower risk of aneurysmal growth than North American cohorts. After stratifying effect estimates by study design and quality, the overall relative risk of aneurysm growth was lower in higher quality and prospective study designs than in lower-quality and retrospective designs, again suggesting that bias may have also contributed to the overall results.  

Despite the degree of heterogeneity, which the authors attempted to incompletely adjust for with sensitivity analyses, this meta-analysis suggests that aneurysmal growth and rupture may share a common pathophysiology, and yields some interesting hypothesis-generating findings on UIA growth and rupture.

Silent Brain Infarctions Are Associated With an Increased Risk of Future Stroke

Neal S. Parikh, MD

Citing the potential utility of silent brain infarcts (SBI) as both a possible stroke risk factor and a surrogate outcome in stroke trials, Dr. Gupta and colleagues performed a systematic review and meta-analysis to evaluate the precise association between SBI and subsequent stroke.

The authors selected studies of adults who had baseline MRI-ascertained SBI and at least 12 months of follow-up for clinical stroke. Studies were vetted and abstracted in a rigorous, pre-specified manner. Meta-analyses were performed with random effects modelling, which controls for occult heterogeneity between individual study samples. The risks of selection bias and publication bias were assessed and found to be low.

Thirteen studies were ultimately included. All studies defined SBI as T2 hyperintense lesions at least three millimeters in size, with various methods employed to distinguish SBI from leukoaraiosis and dilated perivascular spaces. Clinical ischemic stroke was typically defined as a neurological deficit lasting greater than 24 hours in the absence of hemorrhage. Not all studies distinguished between ischemic and hemorrhagic stroke.

A total of 14,764 subjects were included, and the mean follow-up for clinical stroke was 76 months. Most subjects were middle-aged or elderly. 3,007 (20%) had SBI on MRI. The crude relative risk of clinical stroke in patients with SBI was 2.94 (95% confidence interval (CI), 2.24-3.86). Eight of the 13 studies provided covariate-adjusted hazard ratios (HR); the aggregate adjusted HR was 2.08 (95% CI, 1.69-2.56).

Subgroup analyses found that the association between SBI and subsequent stroke was present in both stroke-free community-dwelling patients and in patients with prevalent stroke. In both groups, patients with SBI experienced a two-fold increased risk of subsequent stroke.

The major limitations of their study are: variable definitions of SBI as diagnosed on MRIs of variable magnetic field strength, variable inclusion of relevant covariates, inconsistent reporting of ischemic versus hemorrhagic stroke, non-tissue based definition of ischemic stroke, and outdated cohorts (e.g. not subject to contemporary maximum medical therapy of vascular risk factors). These limitations do not, on the whole, negate the study’s findings.

There appears to be a clear, positive association between SBI and subsequent stroke. In current clinical practice, incidental SBIs do not prompt thorough stroke mechanism evaluation or personalized secondary prevention. Our evolving understanding of this entity will surely impact our practice patterns.

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.