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Cystatin C (CysC) is associated with cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined the clinical correlates and heritability of CysC and determined if associations between CVD risk factors and CysC differed by CKD status. Among Framingham Heart Study offspring (examined from 1998-2001, n = 3,241, mean age 61 years, 54% women), the 95(th) percentile cut-point was developed for CysC in a healthy subset (n = 779) after excluding participants with diabetes, hypertension, low high-density lipoproteins, obesity, smoking, high triglycerides, prevalent CVD, and CKD (as defined by glomerular filtration rate60 mL/min per 1.73 m(2)). Multivariable logistic regression was used to evaluate the association between CVD risk factors and high CysC (CysCor =95(th) percentile cut-point). In a family-based subset (n = 1,188), we estimated CysC heritability using the variance-components method. The cut-point for high CysC was 1.07 mg/L. Age, hypertension treatment, low diastolic blood pressure, body mass index, low high-density lipoprotein cholesterol, and smoking were associated with high CysC in multivariable models. These factors and estimated glomerular filtration rate (egFR) explained 39.2% of CysC variability (R(2)). Excluding CKD did not materially change associations. Multivariable-adjusted heritability for CysC was 0.35 (p0.001). In conclusion, high CysC is associated with CVD risk factors even in the absence of CKD. The strong associations between CysC and CVD risk factors may partially explain why CysC is a strong predictor of incident CVD.

Assays for natriuretic peptides have received considerable attention as potential screening tests for congestive heart failure and left ventricular dysfunction. However, information regarding the impact of age, sex, and other physiologic characteristics on natriuretic peptide levels is limited. We examined a healthy reference sample of 911 subjects (mean age 55 years, 62% women) from the Framingham Heart Study who were free of hypertension, valvular disease, diabetes, atrial fibrillation, obesity, coronary heart disease, congestive heart failure, and renal failure, and who had normal left ventricular systolic function. Plasma brain natriuretic peptide and N-terminal atrial natriuretic peptide levels were measured, and multivariable regression used to assess correlates of natriuretic peptide levels. The strongest predictors of higher natriuretic peptide levels were older age and female sex. Other multivariable predictors included lower diastolic blood pressure (higher pulse pressure), lower body mass index, and higher left atrial size. Reference limits were then formulated based on the empirical distribution of natriuretic peptide levels by gender both across all ages and partitioned by age. Age-pooled reference limits compared with age-specific limits classified a higher proportion of healthy elderly subjects (17% vs 2.5%), but a lower proportion of healthy young subjects (1% vs 2.5%) as "abnormal." We conclude that interpretation of natriuretic peptide levels should take into consideration gender and possibly age. The reference limits derived from this large, healthy community-based sample will aid in the identification of elevated natriuretic peptide levels in clinical practice.

A greater life expectancy has led to an increasing proportion of elderly patients. Increasing age is an important risk factor for cardiovascular disease, but the mechanism of risk is not well understood. Because thrombosis plays a key role in plaque development and the onset of acute coronary syndromes, the age-related increase in cardiovascular risk may be a result of a prothrombotic imbalance. The study aim was to examine the relation between age and thrombotic potential in the Framingham Offspring Cohort. Hemostatic factors previously associated with cardiovascular risk were measured in 3,230 patients (55% women) without evidence of cardiovascular disease who were participating in cycle 5 of the Framingham Offspring Study. The subjects were divided by age into decades. Advancing age was associated with a significant increase in fibrinogen and von Willebrand factor levels and measures of impaired fibrinolytic potential (plasminogen activator inhibitor and tissue plasminogen activator antigens). For men, the mean fibrinogen levels were 21% higher in thoseor =70 years versus those aged40 years (326 vs 268 mg/dl, p0.001 for linear trend). The mean fibrinogen levels were 15% higher in older than in younger women (330 vs 286 mg/dl, p0.001). The significant relations persisted after multivariate adjustment. In conclusion, advancing age is associated with elevated levels of hemostatic factors indicative of a prothrombotic state. Because these factors are also associated with endothelial dysfunction, these findings are consistent with an injurious effect of age on the endothelium. Measures to reduce thrombotic potential may be of particular value in the elderly, because they counter the prothrombotic state that develops with aging.