Twenty year predictors of peripheral arterial disease (PAD) compared with coronary heart disease (CHD) in the Scottish Heart Health Extended Cohort (SHHEC)

Background Coronary heart disease (CHD) and peripheral arterial disease (PAD) affect different vascular territories. Supplementing baseline findings with assays from stored serum, we compared their twenty-year predictors. Methods and Results Recruited randomly across Scotland 1984-1995 and followed through 2009 for death and hospital diagnoses, of 15 737 disease-free men and women aged 30-75y, 3098 developed CHD (19.7%), and 499 PAD (3.2%). Hazard ratios (HRs) for 45 variables in the Cox model were adjusted for age and sex, and for factors in the 2007 ASSIGN cardiovascular risk score. Forty four were entered into parsimonious predictive models, tested by c-statistics and NRIs (Net Reclassification Improvements). Many HRs diminished with adjustment and parsimonious modeling, leaving significant survivors. HRs were mostly higher in PAD. New parsimonious models increased the c-statistic and NRI over ASSIGN variables alone, but varied in their components and ranking. CHD and PAD shared seven of the nine factors from ASSIGN: age, sex, family history, socioeconomic status, diabetes mellitus, tobacco smoking, and systolic blood pressure (SBP), (but not total, nor HDL-cholesterol), plus four new ones: NT-pro BNP, cotinine, hsC-Reactive Protein, and cystatin-C. Highest ranked HRs for continuous factors in CHD were: age, total cholesterol, hsTroponin, NT-pro-BNP, cotinine, apolipoprotein A, waist circumference, (…plus ten more); in PAD: age, hsCRP, SBP, expired carbon monoxide, cotinine, socioeconomic status, lipoprotein (a), (…plus five more). Conclusion The mixture of shared with disparate determinants for arterial disease in the heart and the legs implies non-identical pathogenesis–cholesterol dominant in the former–inflammation (hsCRP, diabetes, smoking) in the latter

Associations of Hemostatic Variables with Cardiovascular Disease and Total Mortality: The Glasgow MONICA Study

The associations of plasma levels of hemostatic factors, other than fibrinogen, with risks of cardiovascular disease (CVD) and all-cause mortality are not well defined. In two phases of the Glasgow MONICA study, we assayed coagulation factors (VII, VIII, IX, and von Willebrand factor), coagulation inhibitors (antithrombin, protein C, protein S), coagulation activation markers (prothrombin fragment 1þ2, thrombin–antithrombin complexes, D-dimer), and the fibrinolytic factors, tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor type 1. Over 15 to 20 years, we followed up between 382 and 1,123 men and women aged 30 to 74 years, without baseline CVD, for risks of CVD and mortality. Age- and sex-adjusted hazard ratios (HRs) for CVD (top third vs bottom third) were significant only for factor VIII (1.30; 95% confidence interval [CI], 1.06–1.58) and factor IX (1.18; 95% CI, 1.01–1.39); these HRs were attenuated by further adjustment for CVD risk factors: 1.17 (95% CI, 0.94–1.46) and 1.07 (95% CI, 0.92–1.25), respectively. In contrast, factor VIII (HR, 1.63; 95% CI, 1.35–1.96), D-dimer (HR, 2.34; 95% CI, 1.26–4.35), and t-PA (HR, 2.81; 95% CI, 1.43–5.54) were strongly associated with mortality after full risk factor adjustment. Further studies, including meta-analyses, are required to assess the associations of these hemostatic factors with the risks of stroke and heart disease and causes of mortality

Prime mover or fellow traveller:25-hydroxy vitamin D’s seasonal variation, cardiovascular disease and death in the Scottish Heart Health Extended Cohort (SHHEC)

BACKGROUND: Theoretical links between seasonal lack of sunlight, hypovitaminosis D and excess cardiovascular disease and death prompted our adding novel to conventional cohort analyses. METHODS: We tested three postulates on 13 224 Scottish Heart Health Extended Cohort participants, assayed for 25-hydroxyvitamin D (25OHD) and followed for 22 years. (i) Endpoints enumerated by month of occurrence mirror annual seasonal oscillation in 25OHD. (ii) Endpoint seasonality is increased in people with below median 25OHD. (iii) Low 25OHD predicts endpoints independently of major risk factors. RESULTS: Baseline median 25OHD level was 36.4 (other quartiles 26.7, 51.7) nmol/l. The March trough was half the August peak, both well after seasonal solstices. (i) There was no demonstrable monthly variation in First Cardiovascular Event (n = 3307). Peaks and troughs for All Death and Cardiovascular Death (n = 2987, 1350) were near the solstices, earlier than extremes of 25OHD. (ii) Endpoint variability showed no difference between those above and below median 25OHD. (iii) Cox model hazard ratios (HR), by decreasing 25OHD, increased modestly and nonspecifically for all endpoints examined, with no threshold, the gradients diminishing by  ∼ : 60% following multiple adjustment. For Cardiovascular Disease, HR, by 20 (∼SD) nmol/l decrease, = 1.224 (1.175, 1.275) adjusted for age and sex; additionally adjusted for family history, deprivation index, smoking, systolic blood pressure, total and HDL cholesterol, = 1.093 (1.048, 1.139); All Deaths = 1.238 (1.048, 1.139) and 1.098 (1.050, 1.149). 25OHD made no independent contribution to cardiovascular discrimination and reclassification. CONCLUSIONS: Our analyses challenge vitamin D's alleged role as major prime mover in cardiovascular disease and mortality.</p

Does sticky blood predict a sticky end? Associations of blood viscosity, haematocrit and fibrinogen with mortality in the West of Scotland

There is increasing evidence that blood viscosity and its major determinants (haematocrit, plasma viscosity and fibrinogen) are associated with an increased risk of incident cardiovascular events; however, their associations with mortality are not established. We therefore studied the associations of these variables with cardiovascular events and total mortality in 1238 men and women aged 25-64 years, followed for 13 years in the first North Glasgow MONICA (MONItoring CArdiovascular disease) survey and West of Scotland centres in the Scottish Heart Health Study. After adjustment for age and sex, increasing whole blood viscosity, plasma viscosity, haematocrit and fibrinogen (analysed by both von Clauss and heat precipitation assays) were significantly associated with mortality. Only the association for fibrinogen (von Clauss assay) remained significant after adjustment for major cardiovascular risk factors. We conclude that clottable fibrinogen may be independently associated with mortality. However, the significance of this association, and the extent to which viscosity is associated with mortality, remain to be established in larger studies and meta-analyses

CHOLESTEROL LOWERING AND THE RISK OF CORONARY HEART DISEASE

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24843/1/0000269.pd

C-reactive protein: associations with haematological variables, cardiovascular risk factors and prevalent cardiovascular disease

C-reactive protein (CRP) has been proposed as a risk factor for cardiovascular disease; however, this association is confounded by mutual relationships with both classical and haematological cardiovascular risk factors. We, therefore, measured CRP with a high-sensitivity assay in stored plasma samples from 414 men and 515 women in the north Glasgow MONICA (MONItoring trends in CArdiovascular diseases) survey, to study its correlation with haematological variables, classical risk factors and prevalent cardiovascular disease. CRP correlated with age, oral contraceptive use, menopause and most classical cardiovascular risk factors (except blood pressure). CRP also correlated with plasma levels of the pro-inflammatory cytokine interleukin 6, and haematocrit, viscosity, red cell aggregation, white cell count, and coagulation factors [fibrinogen, factor (F) VII in women, FVIII, FIX] and inhibitors (antithrombin and protein C in women; protein S) but not coagulation activation markers. CRP was significantly associated with prevalent cardiovascular disease in both men (P = 0.03) and women (P = 0.009), however, the association became non-significant after adjustment for firstly classical risk factors, then fibrinogen. We conclude that correlations with classical and haematological risk factors account for a substantial component of the association of CRP with prevalent cardiovascular disease, but there is evidence of a residual, independent effect among women

Diabetes status-related differences in risk factors and mediators of heart failure in the general population:results from the MORGAM/BiomarCaRE consortium

Background: The risk of heart failure among diabetic individuals is high, even under tight glycemic control. The correlates and mediators of heart failure risk in individuals with diabetes need more elucidation in large population-based cohorts with long follow-up times and a wide panel of biologically relevant biomarkers. Methods: In a population-based sample of 3834 diabetic and 90,177 non-diabetic individuals, proportional hazards models and mediation analysis were used to assess the relation of conventional heart failure risk factors and biomarkers with incident heart failure. Results: Over a median follow-up of 13.8 years, a total of 652 (17.0%) and 5524 (6.1%) cases of incident heart failure were observed in participants with and without diabetes, respectively. 51.4% were women and the mean age at baseline was 48.7 (standard deviation [SD] 12.5) years. The multivariable-adjusted hazard ratio (HR) for heart failure among diabetic individuals was 2.70 (95% confidence interval, 2.49–2.93) compared to non-diabetic participants. In the multivariable-adjusted Cox models, conventional cardiovascular disease risk factors, such as smoking (diabetes: HR 2.07 [1.59–2.69]; non-diabetes: HR 1.85 [1.68–2.02]), BMI (diabetes: HR 1.30 [1.18–1.42]; non-diabetes: HR 1.40 [1.35–1.47]), baseline myocardial infarction (diabetes: HR 2.06 [1.55–2.75]; non-diabetes: HR 2.86 [2.50–3.28]), and baseline atrial fibrillation (diabetes: HR 1.51 [0.82–2.80]; non-diabetes: HR 2.97 [2.21–4.00]) had the strongest associations with incident heart failure. In addition, biomarkers for cardiac strain (represented by nT-proBNP, diabetes: HR 1.26 [1.19–1.34]; non-diabetes: HR 1.43 [1.39–1.47]), myocardial injury (hs-TnI, diabetes: HR 1.10 [1.04–1.16]; non-diabetes: HR 1.13 [1.10–1.16]), and inflammation (hs-CRP, diabetes: HR 1.13 [1.03–1.24]; non-diabetes: HR 1.29 [1.25–1.34]) were also associated with incident heart failure. In general, all these associations were equally strong in non-diabetic and diabetic individuals. However, the strongest mediators of heart failure in diabetes were the direct effect of diabetes status itself (relative effect share 43.1% [33.9–52.3] and indirect effects (effect share 56.9% [47.7-66.1]) mediated by obesity (BMI, 13.2% [10.3–16.2]), cardiac strain/volume overload (nT-proBNP, 8.4% [-0.7–17.4]), and hyperglycemia (glucose, 12.0% [4.2–19.9]). Conclusions: The findings suggest that the main mediators of heart failure in diabetes are obesity, hyperglycemia, and cardiac strain/volume overload. Conventional cardiovascular risk factors are strongly related to incident heart failure, but these associations are not stronger in diabetic than in non-diabetic individuals. Active measurement of relevant biomarkers could potentially be used to improve prevention and prediction of heart failure in high-risk diabetic patients

Diabetes and heart failure associations in women and men:Results from the MORGAM consortium

Background: Diabetes and its cardiovascular complications are a growing concern worldwide. Recently, some studies have demonstrated that relative risk of heart failure (HF) is higher in women with type 1 diabetes (T1DM) than in men. This study aims to validate these findings in cohorts representing five countries across Europe. Methods: This study includes 88,559 (51.8% women) participants, 3,281 (46.3% women) of whom had diabetes at baseline. Survival analysis was performed with the outcomes of interest being death and HF with a follow-up time of 12 years. Sub-group analysis according to sex and type of diabetes was also performed for the HF outcome. Results: 6,460 deaths were recorded, of which 567 were amongst those with diabetes. Additionally, HF was diagnosed in 2,772 individuals (446 with diabetes). A multivariable Cox proportional hazard analysis showed that there was an increased risk of death and HF (hazard ratio (HR) of 1.73 [1.58–1.89] and 2.12 [1.91–2.36], respectively) when comparing those with diabetes and those without. The HR for HF was 6.72 [2.75–16.41] for women with T1DM vs. 5.80 [2.72–12.37] for men with T1DM, but the interaction term for sex differences was insignificant (p for interaction 0.45). There was no significant difference in the relative risk of HF between men and women when both types of diabetes were combined (HR 2.22 [1.93–2.54] vs. 1.99 [1.67–2.38] respectively, p for interaction 0.80). Conclusion: Diabetes is associated with increased risks of death and heart failure, and there was no difference in relative risk according to sex