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.

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.

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.

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.

Vascular risk burden is a key player in the early progression of Alzheimer's disease

Understanding whether vascular risk factors synergistically potentiate Alzheimer's disease progression is important in the context of emerging treatments for preclinical Alzheimer's disease. The existence of a synergistic relationship could suggest that the combination of therapies targeting Alzheimer's disease pathophysiology and vascular risk factors might potentiate treatment outcomes. In the present retrospective cohort study, we tested whether vascular risk factor burden interacts with Alzheimer's disease pathophysiology to accelerate neurodegeneration and cognitive decline in cognitively unimpaired subjects. We evaluated 503 cognitively unimpaired participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Baseline vascular risk factor burden was calculated considering the history of cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, stroke or transient ischemic attack, smoking, atrial fibrillation, and left ventricular hypertrophy. Alzheimer's disease pathophysiology was evaluated using cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ1-42) reflecting brain amyloidosis (A) and tau phosphorylated at threonine 181 (p-tau181) reflecting brain tau pathology (T). Individuals were dichotomized as having an elevated vascular risk factor burden (V+ if having two or more vascular risk factors) and as presenting preclinical Alzheimer's disease [(AT)+ if having abnormal CSF p-tau181 and Aβ1-42 levels]. Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer's Cognitive Composite. Linear mixed-effects models revealed that an elevated vascular risk factor burden synergistically interacted with Alzheimer's disease pathophysiology to drive longitudinal increases in plasma NfL levels (β = 5.08, P = 0.016) and cognitive decline (β = -0.43, P = 0.020). Additionally, we observed that vascular risk factor burden was not associated with CSF Aβ1-42 or p-tau181 changes over time. Survival analysis demonstrated that individuals with preclinical Alzheimer's disease and elevated vascular risk factor burden [(AT)+V+] had a significantly greater risk of clinical progression to cognitive impairment (adjusted Hazard Ratio = 3.5, P < 0.001). Our results support the notion that vascular risk factor burden and Alzheimer's disease pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive decline. These findings can help in providing the blueprints for the combination of vascular risk factor management and Alzheimer's disease pathophysiology treatment in preclinical stages. Moreover, we observed plasma NfL as a robust marker of disease progression that may be used to track therapeutic response in future trials.

Prevalence of the Frank’s sign by aetiopathogenic stroke subtype: A prospective analysis

Background and purpose The Frank’s sign is a diagonal earlobe crease running from the tragus to the edge of the auricle at an angle of 45°. Many studies have associated this sign with coronary artery disease and some with cerebrovascular disease. The objective of this study was to analyse the prevalence of the Frank’s sign in patients suffering from acute stroke with a particular focus on its prevalence in each of the five aetiopathogenic stroke subtypes. Special interest is given to embolic stroke of undetermined source (ESUS), correlating the sign with clinical and radiological markers that support an underlying causal profile in this subgroup. Methods Cross-sectional descriptive study including 124 patients admitted consecutively to a stroke unit after suffering an acute stroke. The Frank’s sign was evaluated by the same blinded member of the research team from photographs taken of the patients. The stroke subtype was classified following SSS-TOAST criteria and the aetiological study was performed following the ESO guidelines. Results The Frank’s sign was present in 75 patients and was more prevalent in patients with an ischaemic stroke in comparison with haemorrhagic stroke (63.9 vs. 37.5, p<0.05). A similar prevalence was found in the different ischaemic stroke subtypes. The Frank’s sign was significantly associated with age, particularly in patients older than 70 who had vascular risk factors. Atherosclerotic plaques found in carotid ultrasonography were significantly more frequent in patients with the Frank’s sign (63.6%, p<0.05). Analysing the ESUS, we also found an association with age and a higher prevalence of the Frank’s sign in patients with vascular risk factors and a tendency to a high prevalence of atherosclerosis markers. Conclusion The Frank’s sign is prevalent in all aetiopathogenic ischaemic stroke subtypes, including ESUS, where it could be helpful in suspecting the underlying cardioembolic or atherothrombotic origin and guiding the investigation of atherosclerosis in patients with ESUS and the Frank’s sign.