Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study.

Essentials Chronic kidney disease (CKD) is associated with procoagulant and inflammatory biomarkers. We studied the association of CKD and venous thromboembolism (VTE) in a case-cohort study. Factor VIII, D-dimer and C-reactive protein appeared to explain the association of CKD and VTE. Statin use was protective against VTE in those with and without CKD. SUMMARY: Background Chronic kidney disease (CKD) is associated with venous thromboembolism (VTE) risk via unknown mechanisms. Whether factors associated with reduced VTE risk in the general population might also be associated with reduced VTE risk in CKD patients is unknown. Objectives To determine whether thrombosis biomarkers attenuate VTE risk, and whether factors associated with reduced VTE risk are similarly effective in CKD patients. Methods Baseline biomarkers were measured in a cohort (294 VTE cases; 939 non-cases) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationwide prospective cohort study of 30 239 persons aged ≥45 years with 4.3 years of follow-up. The hazard ratio (HR) of VTE per 10 mL min-1 1.73 m-2 decrease in estimated glomerular filtration rate (eGFR), and the percentage attenuation of this HR by each biomarker, were calculated. Associations of protective factors (physical activity, lower body mass index [BMI], and aspirin, warfarin and statin use) with VTE were estimated in those with and without CKD. Results The HR for VTE with lower eGFR was 1.13 (95% confidence interval [CI] 1.02-1.25), and VTE risk was attenuated by 23% (95% CI 5-100) by D-dimer, by 100% (95% CI 50-100) by factor VIII, and by 15% (95% CI 2-84) by C-reactive protein. Normal BMI was associated with lower VTE risk in those without CKD (HR 0.47, 95% CI 0.32-0.70), but not in those with CKD (HR 1.07, 95% CI 0.51-2.22). Statin use, physical activity and warfarin use were associated with lower VTE risk in both groups. Conclusions Procoagulant and inflammatory biomarkers mediated the association of eGFR with VTE. Higher physical activity, statin use and warfarin use mitigated VTE risk in those with CKD and those without CKD, but normal BMI did not mitigate VTE risk in CKD patients.

Galectin-3 and risk of ischaemic stroke: Reasons for Geographic and Racial Differences in Stroke cohort.

BACKGROUND AND PURPOSE: Galectin-3 is a biomarker of atherosclerotic and cardiovascular disease, and may be a useful marker for ischaemic stroke risk. METHODS: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled and examined 30 239 US participants between 2003 and 2007 (41% black, 59% white and 55% in the southeastern stroke belt). Baseline galectin-3 was measured in 526 subjects with incident ischaemic stroke over 5.4 years and in a cohort random sample (CRS) of 947 participants. Cox proportional hazards models were used to calculate hazard ratios (HRs) of ischaemic stroke by quartiles of galectin-3. RESULTS: In the CRS, galectin-3 was significantly higher with older age, black race, female sex, body mass index, hypertension, diabetes mellitus and kidney disease, and also in those who developed incident stroke. Participants with galectin-3 levels in the fourth versus first quartile had a 2.3-fold increased stroke risk [95% confidence interval (CI) 1.6, 3.4] in an unadjusted model. An interaction with age was found (P = 0.06), and therefore age-stratified analyses were performed. Amongst those younger than age 64, baseline galectin-3 in the second-fourth quartiles was associated with increased stroke risk (HR 3.0, 95% CI 1.6, 5.5) compared to the first quartile in an age-, race- and sex-adjusted model. The HR was 2.0 (95% CI 1.0, 4.0) with multivariable adjustment. There was no association amongst older participants. CONCLUSIONS: Galectin-3 was associated with incident ischaemic stroke in younger but not older individuals. Confirmation of this finding, and elucidation of its implications for stroke pathophysiology and prevention, is needed.

Associations of coagulation factors IX and XI levels with incident coronary heart disease and ischemic stroke: the REGARDS study.

Essentials Coagulation factors (F) IX and XI have been implicated in cardiovascular disease (CVD) risk. We studied associations of FIX and FXI with incident coronary heart disease (CHD) and stroke. Higher FIX antigen was associated with incident CHD risk in blacks but not whites. Higher levels of FIX antigen may be a CHD risk factor among blacks. SUMMARY: Background Recent studies have suggested the importance of coagulation factor IX and FXI in cardiovascular disease (CVD) risk. Objectives To determine whether basal levels of FIX or FXI antigen were associated with the risk of incident coronary heart disease (CHD) or ischemic stroke. Patients/Methods The REasons for Geographic And Racial Differences in Stroke (REGARDS) study recruited 30 239 participants across the contiguous USA between 2003 and 2007. In a case-cohort study within REGARDS, FIX and FXI antigen were measured in participants with incident CHD (n = 609), in participants with incident ischemic stroke (n = 538), and in a cohort random sample (n = 1038). Hazard ratios (HRs) for CHD and ischemic stroke risk were estimated with Cox models per standard deviation higher FIX or FXI level, adjusted for CVD risk factors. Results In models adjusting for CHD risk factors, higher FIX levels were associated with incident CHD risk (HR 1.19; 95% confidence interval [CI] 1.01-1.40) and the relationship of higher FXI levels was slightly weaker (HR 1.15; 95% CI 0.97-1.36). When stratified by race, the HR of FIX was higher in blacks (HR 1.39; 95% CI 1.10-1.75) than in whites (HR 1.06; 95% CI 0.86-1.31). After adjustment for stroke risk factors, there was no longer an association of FIX levels with ischemic stroke, whereas the association of FXI levels with ischemic stroke was slightly attenuated. Conclusions Higher FIX antigen levels were associated with incident CHD in blacks but not in whites. FIX levels may increase CHD risk among blacks.

Association of stroke risk biomarkers with stroke symptoms: the Reasons for Geographic and Racial Differences in Stroke cohort.

Essentials Stroke symptom history predicts future stroke and may indicate prior unrecognized stroke. We studied associations of stroke symptoms with stroke risk biomarkers. Several stroke risk biomarkers were independently associated with stroke symptom history. Findings support a hypothesis that stroke symptoms may represent unrecognized stroke. SUMMARY: Background History of stroke symptoms in the absence of prior diagnosed stroke or transient ischemic attack (TIA) is associated with future stroke risk, as are biomarkers of inflammation, cardiac function and hemostasis. Objective To better elucidate the pathobiology of stroke symptoms, we studied associations of these biomarkers with history of stroke symptoms. Methods The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 30 239 black and white Americans age 45 years and older in 2003-7. In cross-sectional analyses in a random sample of 960 participants without prior stroke or TIA, levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), fibrinogen, factor VIII (FVIII), factor XI (FXI), C-reactive protein (CRP) and D-dimer were studied in relation to self-reported history of six sudden onset stroke symptoms. Results There were 190 participants with at least one stroke symptom and 770 without. Adjusting for age, race, sex and stroke risk factors, NT-proBNP, FXI, CRP and D-dimer in the top vs. bottom quartile were associated with prevalent stroke symptoms with odds ratios 2.69 (95% confidence interval [CI], 1.45-4.98), 1.65 (95% CI, 1.00-2.73), 2.21 (95% CI, 1.32-3.71) and 2.14 (95% CI, 1.22-3.75), respectively. Conclusions Strong associations of stroke risk biomarkers with stroke symptoms in persons without a clinical history of cerebrovascular disease support a hypothesis that some of these stroke symptoms represent unrecognized cerebrovascular disease. Future work is needed to determine whether these biomarkers identify persons with stroke symptoms who have a particularly high stroke risk.

Associations between socio-economic status and dietary patterns in US black and white adults.

Socio-economic status (SES) has been associated with measures of diet quality; however, such measures have not directly captured overall eating practices in individuals. Based on the factor analysis of fifty-six food groups from FFQ, associations between patterns of food consumption and SES were examined in a nationwide sample of 17,062 black (34·6%) and white participants (age >45 years) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Logistic regression models adjusted for age, sex, racial group and geographic region were used to examine adherence to five emergent dietary patterns (convenience, plant-based, sweets/fats, southern and alcohol/salads) according to four levels each of individual education, household income and community-level SES. Further models assessed adherence to these dietary patterns by racial group, and an overall model including both racial groups examined whether the relationships between SES and adherence to these dietary patterns differed among black and white participants. For all the three measures of SES, higher SES had been associated with greater adherence to plant-based and alcohol/salads patterns, but lower adherence to sweets/fats and southern patterns. Statistically significant differences between black and white participants were observed in the associations between household income and adherence to alcohol/salads, individual education and adherence to plant-based and sweets/fats, and community SES and adherence to convenience patterns. As adherence to dietary patterns has been shown to be associated with health outcomes in this population (e.g. stroke), the present study offers valuable insight into behavioural and environmental factors that may contribute to health disparities in the diverse US population.

ABO blood type and stroke risk: the REasons for Geographic And Racial Differences in Stroke Study.

BACKGROUND: ABO blood type is an inherited trait associated with coagulation factor levels and vascular outcomes. OBJECTIVES: To assess the association of blood type with stroke and whether blood type contributes to racial disparities in stroke in the United States. PATIENTS AND METHODS: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study recruited 30 239 participants between 2003 and 2007. Using a case-cohort design, blood type was genotyped in 646 participants with stroke and a 1104-participant cohort random sample. Cox models that adjusted for Framingham stroke risk factors were used to assess the association of blood type with stroke. RESULTS: During 5.8 years of follow-up, blood types A or B vs. type O were not associated with stroke. Blood type AB vs. O was associated with an increased risk of stroke (adjusted hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.01-3.30). The association of blood type AB vs. O was greater in those without diabetes (adjusted HR 3.33, 95% CI 1.61-6.88) than those with diabetes (adjusted HR 0.49, 95% CI 0.17-1.44) (P interaction = 0.02). Factor VIII levels accounted for 60% (95% CI 11%-98%) of the association of AB blood type and stroke risk. CONCLUSION: Blood type AB is associated with an increased risk of stroke that is not attenuated by conventional stroke risk factors, and factor VIII levels were associated with 60% of the association. While blood type AB is rare in the US population, it is a significant stroke risk factor and may play an important role in stroke risk in these individuals.