Frits R. Rosendaal

The relative contribution of mechanical stress and systemic processes in different types of osteoarthritis: the NEO study

Objective To study the relative contribution of surrogates for mechanical stress and systemic processes with osteoarthritis (OA) in weight-bearing and non-weight-bearing joints. Methods The Netherlands Epidemiology of Obesity study is a population-based cohort including 6673 participants (range 45–65 years, 56% women, median body mass index 26 kg/m2). Weight (kg) and fat mass (kg) were measured, fat-free mass (kg) was calculated. The metabolic syndrome was defined following the Adult Treatment Panel III criteria. Knee and hand OA were defined according to the American College of Rheumatology clinical criteria. Logistic regression analyses were performed to associate surrogates for mechanical stress (such as weight, fat-free mass) and systemic processes (such as metabolic syndrome) with OA in knees alone, knees and hands or hands alone, adjusted for age, sex, height, smoking, education and ethnicity, and when appropriate for metabolic factors and weight. Results Knee, knee and hand, and hand OA were present in 10%, 4% and 8% of the participants, respectively. Knee OA was associated with weight and fat-free mass, adjusted for metabolic factors (OR 1.49 (95% CI 1.32 to 1.68) and 2.05 (1.60 to 2.62), respectively). Similar results were found for OA in knees and hands (OR 1.51 (95% CI 1.29 to 1.78) and 2.17 (95% CI 1.52 to 3.10) respectively). Hand OA was associated with the metabolic syndrome, adjusted for weight (OR 1.46 (95% CI 1.06 to 2.02)). Conclusions In knee OA, whether or not in co-occurrence with hand OA, surrogates for mechanical stress are suggested to be the most important risk factors, whereas in hand OA alone, surrogates for systemic processes are the most important risk factors.

Increased end-stage diabetic nephropathy in Indo-Asian immigrants living in the Netherlands

Abstract.Aims/hypothesis: We aimed to investigate the risk of end-stage diabetic nephropathy due to Type II (non-insulin-dependent) diabetes mellitus in Indo-Asian immigrants from Surinam. Methods: A demographically based case-control study was carried out in Surinamese Indo-Asian immigrants and Dutch Caucasian subjects. All patients with end-stage diabetic nephropathy who had started dialysis between 1990 and 1998 were identified through a national registry of all patients entering a renal replacement program in the Netherlands. The general population of native Dutch and Surinamese Indo-Asians were considered the control subjects. Results: Among Indo-Asian immigrants, the age adjusted relative risk of end-stage diabetic nephropathy was 38 (95 % CI 16 to 91) compared with the native Dutch population. The duration of diabetes until the start of dialysis treatment was similar in both ethnic groups, about 17 years. Conclusion/interpretation: The Indo-Asian subjects had a nearly 40-fold increase in the risk for end-stage diabetic nephropathy due to Type II diabetes, compared with the native Dutch population. This was higher than expected on the basis of the eightfold higher prevalence of diabetes in the Indo-Asian population. The similar duration of diabetes until the start of dialysis treatment in both ethnic groups supports the hypothesis of a higher incidence of diabetic nephropathy in the Indo-Asian diabetic population. Early and frequent screening for diabetes and microalbuminuria is recommended in Indo-Asian subjects. [Diabetologia (2002) 45: 337–341]

Adiposity and hand osteoarthritis: the Netherlands Epidemiology of Obesity study

IntroductionObesity, usually characterized by the body mass index (BMI), is a risk factor for hand osteoarthritis (OA). We investigated whether adipose tissue and abdominal fat distribution are associated with hand OA.MethodsThe Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45 to 65 years, including 5315 participants (53% women, median BMI 29.9 kg/m2). Fat percentage and fat mass (FM) (kg) were estimated using bioelectrical impedance analysis. The waist-to-hip ratio (WHR) was calculated. In 1721 participants, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) (cm2) were assessed using abdominal MR imaging. Hand OA was defined according to the ACR criteria.Odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of fat percentage, FM, WHR, VAT and SAT with hand OA using logistic regression analyses per standard deviation, stratified by sex and adjusted for age.ResultsHand OA was present in 8% of men and 20% of women. Fat percentage was associated with hand OA in men (OR 1.34 (95% CI 1.11 to 1.61)) and women (OR 1.26 (1.05 to 1.51)), as was FM. WHR was associated with hand OA in men (OR 1.45 (1.13 to 1.85)), and to a lesser extent in women (OR 1.17 (1.00 to 1.36)). Subgroup analysis revealed that VAT was associated with hand OA in men (OR1.33 (1.01 to 1.75)). This association increased after additional adjustment for FM (OR 1.51 (1.13 to 2.03)).ConclusionsFat percentage, FM and WHR were associated with hand OA. VAT was associated with hand OA in men, suggesting involvement of visceral fat in hand OA.

Deeper Penetration of Erythrocytes into the Endothelial Glycocalyx Is Associated with Impaired Microvascular Perfusion

Changes in endothelial glycocalyx are one of the earliest changes in development of cardiovascular disease. The endothelial glycocalyx is both an important biological modifier of interactions between flowing blood and the vessel wall, and a determinant of organ perfusion. We hypothesize that deeper penetration of erythrocytes into the glycocalyx is associated with reduced microvascular perfusion. The population-based prospective cohort study (the Netherlands Epidemiology of Obesity [NEO] study) includes 6,673 middle-aged individuals (oversampling of overweight and obese individuals). Within this cohort, we have imaged the sublingual microvasculature of 915 participants using sidestream darkfield (SDF) imaging together with a recently developed automated acquisition and analysis approach. Presence of RBC (as a marker of microvascular perfusion) and perfused boundary region (PBR), a marker for endothelial glycocalyx barrier properties for RBC accessibility, were assessed in vessels between 5 and 25 µm RBC column width. A wide range of variability in PBR measurements, with a mean PBR of 2.14 µm (range: 1.43–2.86 µm), was observed. Linear regression analysis showed a marked association between PBR and microvascular perfusion, reflected by RBC filling percentage (regression coefficient β: −0.034; 95% confidence interval: −0.037 to −0.031). We conclude that microvascular beds with a thick (“healthy”) glycocalyx (low PBR), reflects efficient perfusion of the microvascular bed. In contrast, a thin (“risk”) glycocalyx (high PBR) is associated with a less efficient and defective microvascular perfusion.

The role of fat mass and skeletal muscle mass in knee osteoarthritis is different for men and women: the NEO study

OBJECTIVE To investigate if the amount of fat mass (FM) or skeletal muscle mass (SMM) is more strongly associated with knee osteoarthritis (OA), in both men and women. METHODS The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45-65 years, including 5313 participants (53% female, median body mass index (BMI) 29.9 kg/m(2)). FM (kg), fat percentage, SMM (kg) and skeletal muscle (SM) percentage were estimated using bioelectrical impedance analysis (BIA). Clinical OA was defined following the ACR criteria. Structural OA was defined based on magnetic resonance imaging (MRI) in 1142 participants. Logistic regression analyses were used to examine the associations of all body composition measures with clinical and structural knee OA per standard deviation (SD), stratified by sex and adjusted for age and height. RESULTS Clinical or structural OA was present in 25% and 14% of women and 12% and 13% of men, respectively. FM and fat percentage were positively associated with clinical knee OA in men and women. SMM was positively associated, while the SM percentage was negatively associated with clinical OA in both men and women. The FM/SMM ratio was positively associated with clinical OA. All determinants showed even stronger ORs for structural knee OA. In men, SMM was more strongly associated with knee OA as compared to FM whereas in women, FM was most strongly associated. CONCLUSION Especially a high FM/SMM ratio seems to be unfavorable in knee OA. In men, SMM is most strongly associated with knee OA whereas in women FM seems to be of most importance.

Individual contributions of visceral fat and total body fat to subclinical atherosclerosis: The NEO study

BACKGROUND Both overall and abdominal adiposity are established risk factors for cardiovascular disease. Visceral adipose tissue (VAT) and total body fat (TBF) are strongly correlated and previous studies did not make this distinction. OBJECTIVE We aimed to distinguish individual contributions of TBF, VAT, and the ratio of VAT to abdominal subcutaneous adipose tissue (VAT/SAT) to subclinical atherosclerosis in men and women. METHODS In this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, we assessed VAT and SAT with magnetic resonance imaging, TBF with bio-electrical impendence analysis, and carotid Intima-Media Thickness (cIMT) with ultrasound. We performed linear regression analyses of standardized values of TBF, VAT, VAT/SAT with cIMT. We adjusted the models for confounding factors (age, sex, ethnicity, education, smoking, alcohol, physical activity), and either for VAT or TBF. RESULTS This analysis included 2451 participants, 53% men with mean (SD) cIMT of 615 (91)μm. After adjustment for confounding factors, the difference in cIMT (95% CI) per SD in VAT was 14 (8,21)μm in men and 18 (13,24)μm in women. After adjustment for TBF, this attenuated to 5 (-3,13)μm in men and 13 (5,20)μm in women. In the full model, differences in cIMT (95% CI) per SD of TBF were 14 (6,22)μm in men and 8 (0,16)μm in women, and per SD of VAT/SAT were 7 (-1,15)μm and 9 (3,16)μm respectively. CONCLUSIONS In this population-based study, VAT contributed beyond overall adiposity to subclinical atherosclerosis, particularly in women. This implies a specific role of VAT in the early development of atherosclerosis.

Renal disease in relatives of Indo-Asian Type 2 diabetic patients with end-stage diabetic nephropathy

Aims/HypothesisIndo-Asian immigrants in The Hague, The Netherlands, have a nearly 40-fold higher risk of end-stage diabetic nephropathy compared to the Caucasian population. To detect a genetic susceptibility for nephropathy within the Indo-Asian population, we assessed whether familial clustering of nephropathy occurs in families of Indo-Asian Type 2 diabetic patients.MethodsWe compared nephropathy prevalence between two groups of first-degree relatives of Indo-Asian patients with Type 2 diabetes; the first group (case relatives) consisted of 169 relatives of patients with end-stage diabetic nephropathy; the second group (control relatives) consisted of 161 relatives of diabetic patients who had no nephropathy. The case and control relatives were examined for diabetes, blood pressure, renal function, microalbuminuria and urine dipstick measurements.ResultsThe mean age was 41 years and similar in the case and control relatives. Diabetes was distributed equally in both family groups. We did not find more nephropathy in first-degree relatives of Indo-Asian Type 2 diabetic patients with end-stage diabetic nephropathy in comparison with the control-relatives.Conclusion/interpretationWe could not detect a genetic susceptibility for diabetic nephropathy within the Indo-Asian population. The lack of familial clustering of renal disease in Indo-Asian diabetic patients points to a general genetic or environmental susceptibility for diabetic nephropathy in this population.

Body Fat, Especially Visceral Fat, Is Associated with Electrocardiographic Measures of Sympathetic Activation

Obesity is associated with sympathetic activation, but the role of different fat depots is unclear. The association between body fat, specifically visceral fat, and electrocardiographic measures of sympathetic activation in a population with structurally normal hearts was investigated.

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Background—The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results—We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10−10). The APOE &egr;2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10−12) and 1.4% reduced carotid intima–media thickness (P=4×10−14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the &egr;2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of &egr;2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10−11). Conclusions—Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE &egr;2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

Smoking is associated with increased resting energy expenditure in the general population: The NEO study

OBJECTIVE Animal studies and human studies in small selected populations have shown a positive association between nicotine smoking and resting energy expenditure (REE), but data in large cohorts are lacking. We aimed to investigate the association between smoking behavior and REE in a large, population-based study. DESIGN Population-based cross-sectional study. METHODS In this cross-sectional analysis of baseline measurements from the Netherlands Epidemiology of Obesity (NEO) study (n=6673), we included participants with REE measurement by indirect calorimetry who were not using lipid or glucose lowering drugs (n=1189). We used linear regression analysis to examine the association of smoking status (never, former, occasional, current smoker) and smoking quantity (pack years) with REE per kilogram (kg) fat free mass (FFM) and with REE adjusted for FFM. Models were adjusted for age, sex, ethnicity, educational level, physical activity, energy intake and body mass index (BMI). RESULTS Mean (standard deviation, SD) age was 55.2 (5.9) years and BMI was 26.3 (4.4) kg/m(2). 60% of the participants were women. Mean (SD) REE/FFM (kcal/day/kg FFM) was for male never smokers 25.1 (2.0), male current smokers 26.4 (2.8), female never smokers 28.9 (2.5) and female current smokers 30.1 (3.7). After adjustment, only current smokers had a higher REE/FFM (mean difference 1.28, 95% CI 0.64, 1.92), and a higher REE adjusted for FFM (mean difference 60.3 kcal/day, 95% CI 29.1, 91.5), compared with never smokers. There was no association between pack years and REE/FFM (mean difference -0.01, 95% CI -0.06, 0.04) or REE adjusted for FFM (mean difference 0.2, 95% CI -2.4, 2.8) in current smokers. CONCLUSION Current smoking is associated with a higher resting energy expenditure compared with never smoking in a large population-based cohort.