Body composition as determinant of thrombin generation in plasma: the Hoorn study.

OBJECTIVE: The association between obesity and cardiovascular disease and venous thromboembolism might, at least partially, be explained by a hypercoagulable state. The extent to which body fat mass and its distribution contribute to a hypercoagulable state is unknown. In this study, we investigated the association between body composition and thrombin generation and evaluated the potential mediating role of low-grade inflammation. METHODS AND RESULTS: We studied 586 individuals from the Hoorn Study (mean age, 69.7 ± 6.5 years, 298 women) in whom body composition was assessed by whole body dual-energy absorptiometry. Thrombin generation was measured using the calibrated automated thrombogram. Multiple regression analyses showed a positive association between total body fat and thrombin generation in women but not in men. In addition, detailed analyses of regional body composition showed that central but not peripheral fat mass was associated with greater thrombin generation and that there was a trend toward an inverse association with peripheral lean mass. The reported positive associations were partially attenuated by low-grade inflammation, however. CONCLUSIONS: Body fat mass, in particular a central pattern of fat distribution, is associated with higher levels of thrombin generation in elderly women but not in men. This association may partially be explained by adiposity-related low-grade inflammation, but this hypothesis needs to be further investigated in mechanistic/prospective studies.

Germline and somatic mosaicism in a family with multiple endocrine neoplasia type 1 (MEN1) syndrome.

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1. Family description In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes. The deletion was confirmed in his son by high-resolution array analysis. Based on the array data, we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1. Conclusions To our knowledge, this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism.

Higher central fat mass and lower peripheral lean mass are independent determinants of endothelial dysfunction in the elderly: the Hoorn study.

OBJECTIVE: To investigate whether an adverse body composition is associated with endothelial dysfunction (ED) and the extent to which any such association could be explained by low-grade inflammation (LGI) and/or insulin resistance (HOMA2-IR). METHODS: We studied 475 individuals from the Hoorn Study [mean (range) age, 68.9 (60-87) years, 245 women). Body composition was assessed by whole body dual-energy absorptiometry. Endothelial dysfunction was measured functionally, by flow-mediated dilation (FMD) and by circulating biomarkers. Associations were examined with multiple linear regression models and mediation analyses according to the ab product of coefficients method. RESULTS: After adjustment for age, sex, glucose metabolism status, prior cardiovascular disease and lifestyle factors, total and central fat mass were positively associated with the ED score [ß = 0.16 (95% CI 0.04-0.29) and ß = 0.18 (0.05-0.31), respectively] and inversely, although not statistically significantly, with FMD. Peripheral fat mass was not associated with the ED score or FMD. There was a significant favourable association between peripheral lean mass and FMD [ß = 0.13 (0.00-0.26)], but not with the ED score. The association between total and central fat mass and the ED score was, to a great extent, mediated by LGI and HOMA2-IR. In contrast, LGI or HOMA2-IR did not mediate the association between peripheral lean mass and FMD. CONCLUSION: Higher levels of central, but not peripheral fat mass were adversely associated with ED, which was attributable to body composition-related LGI and insulin resistance. In contrast, peripheral lean mass was beneficially associated with ED, but this seemed to be unrelated to LGI or insulin resistance.

Impaired glucose metabolism and type 2 diabetes are associated with hypercoagulability: potential role of central adiposity and low-grade inflammation--the Hoorn Study.

INTRODUCTION: Type 2 diabetes (DM2) is associated with greater risk for cardiovascular disease (CVD), which may, at least partially, be explained by prothrombotic alterations. We therefore investigated; first, the extent to which individuals with impaired glucose metabolism (IGM) and/or DM2 had greater levels of thrombin generation than those with normal glucose metabolism (NGM); and second, whether any differences were independent of other cardiovascular risk factors, such as smoking, hypertension, dyslipidaemia, (micro)albuminuria, glycemic control and (central) adiposity, and/or were potentially 'mediated' by low-grade inflammation (high-sensitivity C-reactive protein (hsCRP)). MATERIALS AND METHODS: We studied 744 individuals from the Hoorn Study (275 NGM, 176 IGM and 293 DM2, mean age 68.6 ± 7.1 years). Thrombin generation in platelet-poor plasma was measured using the Calibrated Automated Thrombogram and three parameters were derived: lag time, peak height and endogenous thrombin potential (ETP). Data were analyzed with multiple linear regression analyses. RESULTS: After adjustment for age, sex, prior CVD and smoking status, individuals with IGM or DM2 had a longer lag time [ß = 0.14 min (95% CI: 0.02; 0.26)], higher peak height [ß = 7.29 nM (-1.33; 15.91)] and ETP [ß = 35.65 nM*min (0.97; 70.34)] than those with NGM. These differences were attenuated to ß = 0.06 min (-0.07; 0.19), 3.82 nM (-5.46; 13.10) and 16.34 nM*min (-20.92; 53.59), respectively, when further adjusted for waist circumference and hsCRP. CONCLUSION: Individuals with IGM or DM2 had up to 4% higher thrombin generation compared with NGM, which may be explained, to a great extent, by the greater levels of central adiposity and related low-grade inflammation characterizing these individuals.

Metabolic syndrome in nondiabetic individuals associated with maladaptive carotid remodeling: the Hoorn Study.

BACKGROUND: The metabolic syndrome (MetS) is associated with an increased risk of stroke. Arterial remodeling could play an important role herein as maladaptive remodeling is a risk factor for stroke. The purpose of this study was to investigate whether MetS was associated with maladaptive remodeling of the carotid artery and if any such association was independent of hemodynamic variables. METHODS: We studied 385 (n = 195 women) nondiabetic, elderly subjects. A MetS z-score (average of sex-specific z-scores of the five MetS traits) was constructed. Intima-media thickness (IMT) and interadventitial diameter (IAD) were assessed by ultrasonography, and lumen diameter (LD), and circumferential wall stress (CWS) were calculated. Multiple linear regression analysis was used to investigate the association between MetS and carotid remodeling. RESULTS: After adjustment for age, sex, height, prior cardiovascular disease (CVD), dyslipidemia, and smoking, MetS was independently associated with a greater IAD (regression coefficient (ß) per s.d. increase in MetS z-score (95% confidence interval), 0.45 mm (0.28; 0.63)), LD (0.41 mm (0.25; 0.58)) and CWS (5.56 kPa (3.71; 7.42)). These associations were attenuated after additional adjustment for inflammatory, metabolic and particularly hemodynamic variables, but remained statistically significant. No significant association was found between MetS and IMT (0.020 mm (-0.006; 0.046)). CONCLUSIONS: MetS is associated with maladaptive remodeling of the carotid artery, which is the result of changes in LD, IAD, and, to a lesser extent, IMT. This process is independent of hemodynamic variables. Whether this association and process will be observed in a broader population and explains the increased risk of stroke in MetS deserves further study.

Microalbuminuria and cardiovascular autonomic dysfunction are independently associated with cardiovascular mortality: evidence for distinct pathways: the Hoorn Study.

OBJECTIVE: Microalbuminuria is associated with cardiovascular mortality, particularly among individuals with type 2 diabetes, but the mechanisms underlying this association are not completely understood. Microalbuminuria is known to be associated with cardiovascular autonomic dysfunction (C-AD), and C-AD in turn is associated with cardiovascular mortality. The purpose of this study, therefore, was to investigate whether C-AD can explain the relationship between microalbuminuria and cardiovascular mortality. RESEARCH DESIGN AND METHODS: We studied 490 individuals from a population-based cohort of individuals aged 50-75 years who were followed for a median period of 13.6 years. Microalbuminuria was defined as an albumin-to-creatinine ratio > or =2.0 mg/mmol in an early-morning spot-urine sample. Ten parameters reflecting different aspects of cardiovascular autonomic function were measured and compiled into a total score of C-AD (mean of separate z scores). The association between C-AD and microalbuminuria was estimated by multiple linear regression, and relative risks (RRs) for cardiovascular mortality were estimated by Cox proportional hazards analyses. RESULTS: After adjustments for age, sex, glucose tolerance status, and other risk factors, C-AD was associated with microalbuminuria (beta = 0.16 [95% CI 0.01-0.33]), and both microalbuminuria (RR 2.09 [1.07-4.08]) and C-AD (1.74 [1.04-2.89]) were associated with cardiovascular mortality. These associations did not change after further mutual adjustment for C-AD (2.13 [1.09-4.17]) or microalbuminuria (1.76 [1.05-2.94]), respectively. CONCLUSIONS: Both microalbuminuria and C-AD are independently associated with cardiovascular mortality, and the excess mortality attributable to microalbuminuria cannot be explained by C-AD.