Endothelial Function Assessed by Digital Volume Plethysmography Predicts the Development and Progression of Type 2 Diabetes Mellitus

Background Endothelial dysfunction is a consequence of type 2 diabetes mellitus, but it is unclear whether endothelial dysfunction of conductance versus resistance vessels may also precede type 2 diabetes mellitus development. Methods and Results In a population‐based cohort of 15 010 individuals from the GHS (Gutenberg Health Study) (aged 35–74 years at enrollment in 2007–2012), we identified 1610 cases of incident pre–diabetes mellitus and 386 cases of incident type 2 diabetes mellitus by hemoglobin A1c (HbA1c) and/or medical history between 2012 and 2017. Endothelial function of conductance and resistance vessels was measured by flow‐mediated dilation and digital volume plethysmography–derived reactive hyperemia index, respectively. Multivariable regression modeling was used to estimate β coefficients of HbA1c levels at follow‐up and relative risks of incident (pre–)diabetes mellitus. Reactive hyperemia index was independently associated with HbA1c after multivariable adjustment for baseline HbA1c, sex, age, socioeconomic status, arterial hypertension, waist/height ratio, pack‐years of smoking, non–high‐density lipoprotein/high‐density lipoprotein ratio, physical activity, family history of myocardial infarction/stroke, prevalent cardiovascular disease, medication use, and C‐reactive protein (β=−0.020; P=0.0029). The adjusted relative risk per SD decline in reactive hyperemia index was 1.08 (95% CI, 1.02–1.15; P=0.012) for incident pre–diabetes mellitus and 1.16 (95% CI, 1.01–1.34; P=0.041) for incident type 2 diabetes mellitus. Flow‐mediated dilation independently increased the relative risk for developing pre–diabetes mellitus by 8% (95% CI, 1.02–1.14; P=0.012), but it was not independently associated with incident type 2 diabetes mellitus (relative risk, 1.01; 95% CI, 0.86–1.19; P=0.92) and with HbA1c (β=−0.003; P=0.59). Conclusions Endothelial dysfunction of resistance rather than conductance vessels may precede the development of (pre–)diabetes mellitus. Assessment of endothelial function by digital volume plethysmography may help to identify subjects at risk for development of type 2 diabetes mellitus

Hypertensive Retinopathy is Not Associated with Low or High Birth Weight – Results from the Population-Based German Gutenberg Health Study

Achim Fieß,1,* Sandra Gißler,1,* Philipp S Wild,2– 4 Karl J Lackner,5 Thomas Münzel,6 Matthias Michal,7 Michael S Urschitz,8 Norbert Pfeiffer,1 Alexander K Schuster1 1Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 2Preventive Cardiology and Preventive Medicine - Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 3Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 4German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany; 5Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 6Center for Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 7Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 8Division of Pediatric Epidemiology, Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany*These authors contributed equally to this workCorrespondence: Achim Fieß, Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany, Tel +49-6131-17-5150, Fax +49-6131-17-8495, Email [email protected]: This study investigates the association between self-reported birth weight (BW) and the prevalence of hypertensive retinopathy (HR) in a large population-based cohort in Germany, as part of the Gutenberg Health Study (GHS). The study involved analyzing fundus photographs of 6855 participants, aged 35 to 74, to assess signs of HR, classified according to the Mitchell-Wong Classification. The research aimed to explore the correlation between fetal growth restriction indicated by BW and the frequency of HR. The results showed that the frequency of HR did not significantly differ among groups with different BW ranges. In the univariable analysis, HR was initially associated with high BW, but this association disappeared after adjusting for age, sex, and cardiovascular risk factors. No association was found between low BW and HR. The study reveals novel insights as there are no prior population-based studies specifically exploring this association.Keywords: birth weight, hypertensive retinopathy, epidemiology, population-based stud

Depressive symptoms predict the incidence of common chronic diseases in women and men in a representative community sample

Background: Depression, the most frequent and harmful mental disorder, has been associated with specific somatic diseases as the leading cause of death. The purposes of this prospective study were to predict incident chronic diseases based on baseline depressive symptoms and to test sex-dependent effects. Methods: In a representative German community sample of over 12 000 participants, baseline depressive symptoms (assessed using the Patient Health Questionnaire-9) were tested as a predictor of new onset of cardiovascular disease (CVD), chronic obstructive lung disease, diabetes, cancer, and migraine at 5-year follow-up. To study disease incidence, we created subsamples for each chronic disease by excluding participants who already had the respective disease at baseline. Potential confounders were included in logistic regression models and sex-specific analyses were performed. Results: Controlling for demographic characteristics and loneliness, in men and women, baseline depressive symptoms were predictive of CVD, chronic obstructive lung disease, diabetes, and migraine, but not of cancer. When we additionally adjusted for metabolic and lifestyle risk factors, there was an 8% increase of chronic obstructive lung disease and migraine per point of depressive symptoms. There was a trend for CVD (4%; p = 0.053). Sex-sensitive analyses revealed trends for the relevance of depressive symptoms for CVD in men (p = 0.065), and for diabetes in women (p = 0.077). Conclusions: These findings underscore the need to implement screening for depression in the treatment of major somatic illnesses. At the same time, depressed patients should be screened for metabolic and lifestyle risk factors and for somatic diseases and offered lifestyle interventions

The association of chronic anxiousness with cardiovascular disease and mortality in the community : results from the Gutenberg Health Study

In a large German community sample of adults, we investigated the association of chronic anxiousness with cardiovascular disease and mortality. Self-reported anxiousness from 11,643 German adults between 40 and 80 years of age from the Gutenberg Health Study (GHS) was analyzed over 5 years. Multivariable regression modeling assessed the relation between the variables, cardiovascular disease and mortality. Twelve percent of the participants reported consistently raised (chronic) anxiousness over at least 2.5 years. Anxiousness was more often reported by female, younger participants with a lower socioeconomic status, smokers and those with a family history of stroke and myocardial infarction. New onset of cardiovascular disease was linked to chronic anxiousness in men and new onset of anxiousness in women. However, chronic anxiousness did not predict all-cause mortality. Our results revealed that anxiousness is highly prevalent in German adults from middle to old age, affecting women in particular. In our study, we found sex-specific associations between new onset of cardiovascular disease and different forms of anxiousness in men and women. We suggest that even subclinical levels of anxiety need to be considered as cardiovascular risk factors. To elucidate potential harm of anxiousness for mental and physical health, we propose sex-specific analyses in further research studies, taking age and the course of anxiousness into account

Infrared Conductivity in Layered dd-wave Superconductors

We calculate the infrared conductivity of a stack of coupled, two-dimensional superconducting planes within the Fermi liquid theory of superconductivity. We include the effects of random scattering processes and show that the presence of even a small concentration of resonant impurities, in a $d$-wave superconductor, has an important effect on both the in-plane and $c$-axis transport properties, which could serve as signatures for $d$-wave pairing.Comment: 18 pages in a RevTex (3.0) file plus 5 postscript figures (uuencoded). Replaced with minor changes as it will appear in the Physical Review B {\bf 52} issue 1 Oct. 199

Endothelial overexpression of TGF-β-induced protein impairs venous thrombus resolution

Endothelial cells play a critical role during venous thrombus remodeling, and unresolved, fibrotic thrombi with irregular vessels obstruct the pulmonary artery in patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study sought to identify endothelial mediators of impaired venous thrombus resolution and to determine their role in the pathogenesis of the vascular obstructions in patients with CTEPH. Endothelial cells outgrown from pulmonary endarterectomy specimens (PEA) were processed for mRNA profiling, and nCounter gene expression and immunohistochemistry analysis of PEA tissue microarrays and immunoassays of plasma were used to validate the expression in CTEPH. Lentiviral overexpression in human pulmonary artery endothelial cells (HPAECs) and exogenous administration of the recombinant protein into C57BL/6J mice after inferior Vena cava ligation were employed to assess their role for venous thrombus resolution. RT2 PCR profiler analysis demonstrated the significant overexpression of factors downstream of transforming growth factor beta (TGFβ), that is TGFβ-Induced Protein (TGFBI or BIGH3) and transgelin (TAGLN), or involved in TGFβ signaling, that is follistatin-like 3 (FSTL3) and stanniocalcin-2 (STC2). Gene expression and immunohistochemistry analysis of tissue microarrays localized potential disease candidates to vessel-rich regions. Lentiviral overexpression of TGFBI in HPAECs increased fibrotic remodeling of human blood clots in vitro, and exogenous administration of recombinant TGFBI in mice delayed venous thrombus resolution. Significantly elevated plasma TGFBI levels were observed in patients with CTEPH and decreased after PEA. Our findings suggest that overexpression of TGFBI in endothelial promotes venous thrombus non-resolution and fibrosis and is causally involved in the pathophysiology of CTEPH

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Heavy reliance on plants for Romanian cave bears evidenced by amino acid nitrogen isotope analysis

Heavy reliance on plants is rare in Carnivora and mostly limited to relatively small species in subtropical settings. The feeding behaviors of extinct cave bears living during Pleistocene cold periods at middle latitudes have been intensely studied using various approaches including isotopic analyses of fossil collagen. In contrast to cave bears from all other regions in Europe, some individuals from Romania show exceptionally high δ15N values that might be indicative of meat consumption. Herbivory on plants with high δ15N values cannot be ruled out based on this method, however. Here we apply an approach using the δ15N values of individual amino acids from collagen that offsets the baseline δ15N variation among environments. The analysis yielded strong signals of reliance on plants for Romanian cave bears based on the δ15N values of glutamate and phenylalanine. These results could suggest that the high variability in bulk collagen δ15N values observed among cave bears in Romania reflects niche partitioning but in a general trophic context of herbivory

One session of remote ischemic preconditioning does not improve vascular function in acute normobaric and chronic hypobaric hypoxia

Application of repeated short duration bouts of ischemia to the limbs, termed remote ischemic preconditioning (RIPC), is a novel technique that may have protective effects on vascular function during hypoxic exposures. In separate parallel-design studies, at sea-level (SL; n=16), and after 8-12 days at high-altitude (HA; n=12; White Mountain, 3800m), participants underwent either a sham protocol or one session of 4x5 minutes of dual-thigh cuff occlusion with 5-minutes recovery. Brachial artery flow-mediated dilation (FMD; ultrasound), pulmonary artery systolic pressure (PASP; echocardiography), and internal carotid artery flow (ICA; ultrasound) were measured at SL in normoxia and isocapnic hypoxia [end-tidal PO (PETO ) maintained to 50mmHg], and during normal breathing at HA. The hypoxic ventilatory response (HVR) was measured at each location. All measures at SL and HA were obtained at baseline (BL), 1 hour, 24 hours, and 48 hours post-RIPC or sham. At SL, RIPC produced no changes in FMD, PASP, ICA flow, end-tidal gases or HVR in normoxia or hypoxia. At HA, although HVR increased 24 hours post RIPC compared to BL (2.05{plus minus}1.4 vs. 3.21{plus minus}1.2 L•min-1•%SaO2-1, p<0.01), there were no significant differences in FMD, PASP, ICA flow, resting end-tidal gases. Accordingly, a single session of RIPC is insufficient to evoke changes in peripheral, pulmonary, and cerebral vascular function in healthy adults. Although chemosensitivity may increase following RIPC at HA, this did not confer any vascular changes. The utility of a single RIPC session seems unremarkable during acute and chronic hypoxia