Vascular risk factors and stroke risk across the life span: A population-representative study of half a million people

Background: The incidence of stroke in developed countries is increasing selectively in young individuals, but whether this is secondary to traditional vascular risk factors is unknown. Methods: We used the Canadian Community Health Survey from 2000 to 2016 to create a large population-representative cohort of individuals over the age of 30 and free from prior stroke. All analyses were stratified by age decile. We linked with administrative databases to determine emergency department visits or hospitalizations for acute stroke until December 2017. We calculated time trends in risk factor prevalence (hypertension, diabetes, obesity, and smoking) using meta-regression. We used Cox proportional hazard models to evaluate the association between vascular risk factors and stroke risk, adjusted for demographic, co-morbid, and social variables. We used competing risk regression to account for deaths and calculated population-attributable fractions. In a sensitivity analysis, we excluded those with prior heart disease or cancer. Results: We included 492,400 people in the analysis with 8865 stroke events over a median follow-up time of 8.3 years. Prevalence of hypertension, diabetes, and obesity increased over time while smoking decreased. Associations of diabetes, hypertension, and obesity with stroke risk were progressively stronger at younger age (adjusted hazard ratio for diabetes was 4.47, 95% confidence interval (CI) = 1.95–10.28 at age 30–39, vs 1.21, 95% CI = 0.93–1.57 at age 80+), although the obesity association was attenuated with adjustment. Smoking was associated with higher risk of stroke without a gradient across age deciles, although had the greatest population-attributable fraction at younger age. The hazard ratio for stroke with multiple concurrent risk factors was much higher at younger age (adjusted hazard ratio for 3–4 risk factors was 8.60, 95% CI = 2.97–24.9 at age 30–39 vs 1.61, 95% CI = 0.88–2.97 at age 80+) and results were consistent when accounting for the competing risk of death and excluding those with prior heart disease or cancer. Conclusions: Diabetes and hypertension were associated with progressively elevated relative risk of stroke in younger individuals and prevalence was increasing over time. The association of obesity with stroke was not significant after adjustment for other factors. Smoking had the greatest prevalence and population-attributable fraction for stroke at younger age. Our findings assist in understanding the relationship between vascular risk factors and stroke across the life span and planning public health measures to lower stroke incidence in the young.

Trials and Treatments for Vascular Brain Health: Risk Factor Modification and Cognitive Outcomes

There is robust evidence linking vascular health to brain health, cognition, and dementia. In this article, we present evidence from trials of vascular risk factor treatment on cognitive outcomes. We summarize findings from randomized controlled trials of antihypertensives, lipid-lowering medications, diabetes treatments (including antidiabetic drugs versus placebo, and intensive versus standard glycemic control), and multidomain interventions (that target several domains simultaneously such as control of vascular and metabolic factors, nutrition, physical activity, and cognitive stimulation etc). We report that evidence on the efficacy of vascular risk reduction interventions is promising, but not yet conclusive, and several methodological limitations hamper interpretation. Evidence mainly comes from high-income countries and, as cognition and dementia have not been the primary outcomes of many trials, evaluation of cognitive changes have often been limited. As the cognitive aging process occurs over decades, it is unclear whether treatment during the late-life window is optimal for dementia prevention, yet older individuals have been the target of most trials thus far. Further, many trials have not been powered to explore interactions with modifiers such as age, race, and apolipoprotein E, even though sub-analyses from some trials indicate that the success of interventions differs depending on patient characteristics. Due to the complex multifactorial etiology of dementia, and variations in risk factors between individuals, multidomain interventions targeting several risk factors and mechanisms are likely to be needed and the long-term sustainability of preventive interventions will require personalized approaches that could be facilitated by digital health tools. This is especially relevant during the coronavirus disease 2019 (COVID-19) pandemic, where intervention strategies will need to be adapted to the new normal, when face-to-face engagement with participants is limited and public health measures may create changes in lifestyle that affect individuals’ vascular risk profiles and subsequent risk of cognitive decline.

Risk Factors, Lifestyle Behaviors, and Vascular Brain Health

Although a relationship between traditional cardiovascular risk factors and stroke has long been recognized, these risk factors likely play a role in other aspects of brain health. Clinical stroke is only the tip of the iceberg of vascular brain injury that includes covert infarcts, white matter hyperintensities, and microbleeds. Furthermore, an individual’s risk for not only stroke but poor brain health includes not only these traditional vascular risk factors but also lifestyle and genetic factors. The purpose of this narrative review is to summarize the state of the evidence on traditional and nontraditional vascular risk factors and their contributions to brain health. Additionally, we will review important modifiers that interact with these risk factors to increase, or, in some cases, reduce risk of adverse brain health outcomes, with an emphasis on genes and biomarkers associated with Alzheimer disease. Finally, we will consider the importance of social determinants of health in brain health outcomes.

Prevalence and Risk Factors Comparison of Anterior and Posterior Intracranial Arterial Stenosis

The prevalence and risk factors of intracranial atherosclerotic stenosis (ICAS) located in the anterior circulation (AC) and posterior circulation (PC) has been scarcely noted in the general population. We aimed to determine ICAS prevalence and risk factor profile of AC and PC in a representative population. Data were from the China Hypertension Survey of Beijing. In total, 4800 people aged 35 years or older were enrolled in this subsurvey for ICAS, and 3954 participants were eligible for analysis. ICAS was assessed by transcranial Doppler. The prevalence of ICAS in AC was much greater than that in PC (11.9% vs. 4.2%), and subjects with ICAS in PC were 3.9 years older than those with ICAS in AC. Multivariable logistics regression showed that the odds of hypertension and diabetes increased by 79% (OR: 1.79, 95% CI: 1.40–2.27) and 35% (OR: 1.35, 95% CI: 1.04–1.75) in those with AC vascular lesions and by 3.35 times (OR: 3.35, 95% CI: 2.49–4.50) and 71% (OR: 1.71, 95% CI: 1.19–2.46) in those with PC vascular lesions compared with those without vascular lesions. Most modifiable vascular risk factors for ICAS appeared to exert similar magnitudes of risk for PC to AC lesions.

Diabetes and other vascular risk factors in association with the risk of lower extremity amputation in chronic limb-threatening ischemia: a prospective cohort study

Background Patients with diabetes are at increased risk of developing chronic limb-threatening ischemia (CLTI) due to peripheral arterial disease, and this often results in lower extremity amputation (LEA). Little is known of the interaction between diabetes and other vascular risk factors in affecting the risk of CLTI. Methods We investigated the association of diabetes, and its interaction with hypertension, body mass index (BMI) and smoking, with the risk of LEA due to CLTI in the population-based Singapore Chinese Health Study. Participants were interviewed at recruitment (1993–1998) and 656 incident LEA cases were identified via linkage with nationwide hospital database through 2017. Multivariate-adjusted Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% CIs for the associations. Results The HR (95% CI) for LEA risk was 13.41 (11.38–15.79) in participants with diabetes compared to their counterparts without diabetes, and the risk increased in a stepwise manner with duration of diabetes (P for trend < 0.0001). Hypertension and increased BMI independently increased LEA risk in those without diabetes but did not increase the risk in those with diabetes (P for interaction with diabetes ≤ 0.0006). Conversely, current smoking conferred a risk increment of about 40% regardless of diabetes status. Conclusions Although diabetes conferred more than tenfold increase in risk of LEA, hypertension and increased BMI did not further increase LEA risk among those with diabetes, suggesting a common mechanistic pathway for these risk factors. In contrast, smoking may act via an alternative pathway and thus confer additional risk regardless of diabetes status.

White Matter Hyperintensity Burden in Cerebral Small Vessel Disease Patients Is Associated with Nocturnal Heart Rate

Background: Age and hypertension are widely considered to be the main risk factors for white matter hyperintensity (WMH), but they do not account for all the pathophysiological mechanisms of WMH.Therefore, identifying novel risk factors is significant to improve our understanding of the etiology and consequences of WMH. Objective: To examine the association of heart rate(HR) and common vascular risk factors with WMH burden in patients hospitalized for Cerebral Small Vessel Disease(CSVD) Method: The study consisted of 778 patients who underwent 24-hour ambulatory blood pressure and HR monitoring and brain magnetic resonance imaging(MRI). The relationship of HR measures and vascular risk factors with the presence of log WMHV4 was analyzed.Univariable and multivariable analysis was carried out to investigate the relationship of incidence of severe WMH (4th quartile, ≥19.64 ml) and HR measures and common vascular risk factors. Results: Multivariate analysis showed that WMHV was independently predicted by nighttime HR ( OR (95% CI): 1.041（1.02~1.062）, P<0.001),Homocysteine ( OR (95% CI): 1.019（1.005~1.033）, P=0.009), and cerebral infarction ( OR (95% CI): 0.463（0.31~0.691）, P<0.001), No similar association was observed for daytime HR、HR variability and other vascular risk factors . Conclusion: As nighttime HR、Hcy increased, log WMHV increased accordingly; furthermore, patients with cerebral infarction were more likely to have higher levels of WMHV. nighttime HR 、Hcy、cerebral infarction was associated with WMHV, suggesting independent roles of their in WMHV. The influence of HRV on WMHV needs to be addressed by further studies.

Circulating Interleukin-6 Levels and Incident Ischemic Stroke: A Systematic Review and Meta-analysis of Prospective Studies

Background and Objectives:Human genetic studies support a key role of interleukin-6 (IL-6) in the pathogenesis of ischemic stroke. Still, there are only limited data from observational studies exploring circulating IL-6 levels as a risk factor for ischemic stroke. Here, we set out to perform a systematic review and meta-analysis of aggregate data on cohort studies to determine the magnitude and shape of the association between circulating IL-6 levels and risk of incident ischemic stroke in the general population.Methods:Following the PRISMA guidelines, we systematically screened the PubMed search engine from inception to March 2021 for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effects models and explored non-linear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS). We used funnel plots and trim-to-fill analyses to assess publication bias.Results:We identified 11 studies (n=27,411 individuals; 2,669 stroke events) meeting our eligibility criteria. Mean age of all included participants was 60.5 years and 54.8% were females. Overall, quality of the included studies was high (median 8 out of 9 NOS points, interquartile range 7 to 9). In meta-analyses, 1-standard deviation increment in circulating log-transformed IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (RR 1.19; 95% CI 1.10 to 1.28). A dose-response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias.Discussion:Higher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.

Stroke Literacy Video for Patients and Families: Symptoms, Risk Factors, and Prevention (Preprint)

BACKGROUND Most vascular events after stroke may be prevented by modifying vascular risk factors through medical and behavioral interventions. Stroke literacy, an understanding of stroke symptoms, risk factors, and treatment, likely contributes to vascular risk factor control and in turn stroke recurrence risk. Video-based interventions targeting stroke literacy may help acute stroke survivors understand stroke and subsequently reduce stroke recurrence. However, failure of prior stroke literacy interventions may be due in part to the fact that the interventions were not theory-driven. OBJECTIVE To develop a video-based educational intervention to improve stroke literacy in hospitalized acute stroke patients. METHODS The 6-step iterative process of Intervention Mapping (IM) was used to develop a video-based educational intervention and related implementation and evaluation plans. RESULTS A 5-minute video-based educational intervention was developed. The IM approach led to successful intervention development by emphasizing stakeholder involvement, generation and adoption, and information retainment in the planning phase of the intervention. CONCLUSIONS An IM approach guided the development of a video-based educational intervention to promote stroke literacy among acute stroke survivors. Future studies are needed to assess the use of technology and digital media to support wide-spread access and participation in video-based health literacy interventions for the stroke population. Studies are needed to assess the impact of video-based educational interventions paired with stroke systems of care optimization to promote stroke recurrence risk reduction. INTERNATIONAL REGISTERED REPORT RR2-https://doi.org/10.1371/journal.pone.0171952

Pathomechanisms of Vascular Depression in Older Adults

Depression in older individuals is a common complex mood disorder with high comorbidity of both psychiatric and physical diseases, associated with high disability, cognitive decline, and increased mortality The factors predicting the risk of late-life depression (LLD) are incompletely understood. The reciprocal relationship of depressive disorder and age- and disease-related processes has generated pathogenic hypotheses and provided various treatment options. The heterogeneity of depression complicates research into the underlying pathogenic cascade, and factors involved in LLD considerably differ from those involved in early life depression. Evidence suggests that a variety of vascular mechanisms, in particular cerebral small vessel disease, generalized microvascular, and endothelial dysfunction, as well as metabolic risk factors, including diabetes, and inflammation that may induce subcortical white and gray matter lesions by compromising fronto–limbic and other important neuronal networks, may contribute to the development of LLD. The “vascular depression” hypothesis postulates that cerebrovascular disease or vascular risk factors can predispose, precipitate, and perpetuate geriatric depression syndromes, based on their comorbidity with cerebrovascular lesions and the frequent development of depression after stroke. Vascular burden is associated with cognitive deficits and a specific form of LLD, vascular depression, which is marked by decreased white matter integrity, executive dysfunction, functional disability, and poorer response to antidepressive therapy than major depressive disorder without vascular risk factors. Other pathogenic factors of LLD, such as neurodegeneration or neuroimmune regulatory dysmechanisms, are briefly discussed. Treatment planning should consider a modest response of LLD to antidepressants, while vascular and metabolic factors may provide promising targets for its successful prevention and treatment. However, their effectiveness needs further investigation, and intervention studies are needed to assess which interventions are appropriate and effective in clinical practice.

Cardiac Magnetic Resonance Radiomics Reveal Differential Impact of Sex, Age, and Vascular Risk Factors on Cardiac Structure and Myocardial Tissue

Background: Cardiovascular magnetic resonance (CMR) radiomics analysis provides multiple quantifiers of ventricular shape and myocardial texture, which may be used for detailed cardiovascular phenotyping.Objectives: We studied variation in CMR radiomics phenotypes by age and sex in healthy UK Biobank participants. Then, we examined independent associations of classical vascular risk factors (VRFs: smoking, diabetes, hypertension, high cholesterol) with CMR radiomics features, considering potential sex and age differential relationships.Design: Image acquisition was with 1.5 Tesla scanners (MAGNETOM Aera, Siemens). Three regions of interest were segmented from short axis stack images using an automated pipeline: right ventricle, left ventricle, myocardium. We extracted 237 radiomics features from each study using Pyradiomics. In a healthy subset of participants (n = 14,902) without cardiovascular disease or VRFs, we estimated independent associations of age and sex with each radiomics feature using linear regression models adjusted for body size. We then created a sample comprising individuals with at least one VRF matched to an equal number of healthy participants (n = 27,400). We linearly modelled each radiomics feature against age, sex, body size, and all the VRFs. Bonferroni adjustment for multiple testing was applied to all p-values. To aid interpretation, we organised the results into six feature clusters.Results: Amongst the healthy subset, men had larger ventricles with dimmer and less texturally complex myocardium than women. Increasing age was associated with smaller ventricles and greater variation in myocardial intensities. Broadly, all the VRFs were associated with dimmer, less varied signal intensities, greater uniformity of local intensity levels, and greater relative presence of low signal intensity areas within the myocardium. Diabetes and high cholesterol were also associated with smaller ventricular size, this association was of greater magnitude in men than women. The pattern of alteration of radiomics features with the VRFs was broadly consistent in men and women. However, the associations between intensity based radiomics features with both diabetes and hypertension were more prominent in women than men.Conclusions: We demonstrate novel independent associations of sex, age, and major VRFs with CMR radiomics phenotypes. Further studies into the nature and clinical significance of these phenotypes are needed.