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Introduction Detailed mechanisms in the pathophysiology of diabetes disease are poorly understood, but structural alterations in various organ systems incur an elevated risk for cardiovascular events and adverse outcome. The aim of this study was to compare multiorgan subclinical disease phenotypes by magnetic resonance (MR) imaging to study differences between subjects with prediabetes, diabetes, and normal controls. Materials and Methods Subjects without prior cardiovascular disease were enrolled in a prospective case-control study and underwent multiorgan MR for the assessment of metabolic and arteriosclerotic alterations, including age-related white matter changes, hepatic proton density fat fraction, visceral adipose tissue volume, left ventricular remodeling index, carotid plaque, and late gadolinium enhancement. Magnetic resonance features were summarized in a phenotypic-based score (range, 0-6). Univariate, multivariate correlation, and unsupervised clustering were performed. Results Among 243 subjects with complete multiorgan MR data sets included in the analysis (55.6 ± 8.9 years, 62% males), 48 were classified as subjects with prediabetes and 38 as subjects with diabetes. The MR phenotypic score was significantly higher in subjects with prediabetes and diabetes as compared with controls (mean score, 3.00 ± 1.04 and 2.69 ± 0.98 vs 1.22 ± 0.98, P < 0.001 respectively), also after adjustment for potential confounders. We identified 2 clusters of MR phenotype patterns associated with glycemic status (P < 0.001), independent of the MR score (cluster II-metabolic specific: odds ratio, 2.49; 95% CI, 1.00-6.17; P = 0.049). Discussion Subjects with prediabetes and diabetes have a significantly higher phenotypic-based score with a distinctive multiorgan phenotypic pattern, which may enable improved disease characterization.

OBJECTIVE Cutoff values for increased exercise blood pressure (BP) are not established in hypertension guidelines. The aim of the study was to assess optimal cutoff values for increased exercise BP to predict incident hypertension. METHODS Data of 661 normotensive participants (386 women) aged 25-77 years from the Study of Health in Pomerania (SHIP-1) with a 5-year follow-up were used. Exercise BP was measured at a submaximal level of 100 W and at maximum level of a symptom-limited cycle ergometry test. Cutoff values for increased exercise BP were defined at the maximum sum of sensitivity and specificity for the prediction of incident hypertension. The area under the receiver-operating characteristic curve (AUC) and net reclassification index (NRI) were calculated to investigate whether increased exercise BP adds predictive value for incident hypertension beyond established cardiovascular risk factors. RESULTS In men, values of 160 mmHg (100 W level; AUC = 0.7837; NRI = 0.534, P

Background— Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor play important roles in angiogenesis, vascular remodeling, local tumor growth, and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown. Methods and Results— We performed a genome-wide association study for circulating Ang-2, sTie-2, and hepatocyte growth factor in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. In multivariable-adjusted models, sTie-2 and hepatocyte growth factor concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers (top P =2.40×10 −65 [rs2273720] and 3.64×10 −19 [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels ( P =5.05×10 −8 in Framingham Heart Study and 8.39×10 −5 in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with P =1.84×10 −33 in Framingham Heart Study; P =2.53×10 −30 in Study of Health in Pomerania) and Ang-2 (rs8176746 with P =2.07×10 −8 in Framingham Heart Study; P =0.001 in Study of Health in Pomerania) levels on a genome-wide significant level. The top genetic loci were explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the interindividual variation in biomarker levels. Conclusions— Genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating hepatocyte growth factor, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.

Objective— Because population-based data are lacking, we assessed the cross-sectional association between serum testosterone levels and endothelial function, as measured by flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) of the brachial artery, in men from the population-based Study of Health in Pomerania. Methods and Results— Personal characteristics, including major cardiovascular confounders, were collected in 722 men, aged 25 to 85 years. Serum total testosterone and sexual hormone-binding globulin (SHBG) levels were determined by chemiluminescence immunoassays. Free testosterone levels were calculated according to the law of mass action. FMD and NMD measurements were performed using standardized ultrasound techniques. FMD and NMD values below the 20th percentile were considered decreased. Multivariable logistic regression analyses revealed an association for each decrement of total testosterone standard deviation (6.0 nmol/L) with decreased FMD after adjustment for potential confounders (odds ratio 1.30, 95% confidence interval 1.04–1.63; P =0.023). Multiple adjusted findings for free testosterone were similar (odds ratio 1.37, 95% confidence interval 1.06–1.76; P =0.016). There was no such association of SHBG levels with decreased FMD. Neither testosterone nor SHBG levels were significantly associated with decreased NMD. Conclusion— Lower serum total and free testosterone levels are associated with impaired endothelial function in this population-based sample of men.

Objective The aim of the present study was to investigate the association of fatty liver disease (FLD) with blood pressure (BP) and hypertension in a general population sample with prospective 5-year follow-up examinations. Design and methods We used data from the Study of Health in Pomerania, conducted in the northeastern part of Germany. The study population comprised 3191 individuals aged 20-79 years. FLD was defined as the presence of a hyperechogenic pattern of the liver and increased serum alanine transferase (ALT) levels. Results Multivariable analyses revealed that FLD was associated with increased DBP and hypertension at baseline and with increased SBP and hypertension at follow-up. In individuals with FLD, the chance of hypertension at baseline and follow-up was three-fold higher [odds ratio (OR) 2.8; 95% confidence interval (CI) 1.3-6.2 and OR 3.1; 95% CI 1.7―5.8, respectively] compared to individuals without FLD. In the subgroup of individuals not receiving antihypertensive medication, FLD was associated with all BP-related variables at baseline and follow-up. Analyses further suggest that these associations were independent of alcohol consumption and further confounders. Conclusion FLD defined by liver hyperechogenity and increased ALT levels is associated with progression of BP over time and incident hypertension. In individuals with FLD, BP should be checked regularly and interventions addressing behavioural risk factors for FLD and hypertension should be initiated if necessary. Ultrasound should be implemented as a method to detect FLD in individuals with increased ALT levels in routine medical care.