Low-Circulating Homoarginine is Associated with Dilatation and Decreased Function of the Left Ventricle in the General Population

Low homoarginine is an independent marker of mortality in heart failure patients and incident cardiovascular events. Whether homoarginine is related with healthier cardiac structure and function is currently unclear. We used data of the population-based Study of Health in Pomerania (SHIP-Trend) to assess this relation. Homoarginine was measured in serum using liquid chromatography-tandem mass spectrometry. Linear regression models assessed the relation between homoarginine and several structural as well as functional parameters and N-terminal pro B-type natriuretic peptide (NTproBNP). All models were adjusted for age, sex, body mass index, and renal function. A total of 3113 subjects (median age 48 (25th percentile 37 to 75th percentile 60) years, 46% male) were included. A standard deviation decrease in homoarginine was associated with a larger left ventricular diastolic diameter (0.3;95%-confidence interval (CI): 0.2 to 0.5 mm;p < 0.001), left ventricular systolic diameter (0.38;95%-CI: -0.22 to 0.54 mm;p < 0.001) as well as a less relative wall thickness (-0.003 95%-CI: -0.006 to -0.0008;p = 0.01), left ventricular ejection fraction (-0.47;95%-CI: -0.79 to -0.15%;p < 0.01) and fractional shortening (-0.35;95%-CI: -0.62 to 0.07%;p = 0.01). Low homoarginine was also related to higher NTproBNP (-0.02 95%-CI: -0.034 to -0.009 log pg/mL;p < 0.01). Lower serum homoarginine is associated with dilatation of the heart and decreased function. Prospective clinical studies should assess if homoarginine supplementation improves cardiac health in subjects with low serum concentrations

Spacelike Singularities and Hidden Symmetries of Gravity

We review the intimate connection between (super-)gravity close to a spacelike singularity (the "BKL-limit") and the theory of Lorentzian Kac-Moody algebras. We show that in this limit the gravitational theory can be reformulated in terms of billiard motion in a region of hyperbolic space, revealing that the dynamics is completely determined by a (possibly infinite) sequence of reflections, which are elements of a Lorentzian Coxeter group. Such Coxeter groups are the Weyl groups of infinite-dimensional Kac-Moody algebras, suggesting that these algebras yield symmetries of gravitational theories. Our presentation is aimed to be a self-contained and comprehensive treatment of the subject, with all the relevant mathematical background material introduced and explained in detail. We also review attempts at making the infinite-dimensional symmetries manifest, through the construction of a geodesic sigma model based on a Lorentzian Kac-Moody algebra. An explicit example is provided for the case of the hyperbolic algebra E10, which is conjectured to be an underlying symmetry of M-theory. Illustrations of this conjecture are also discussed in the context of cosmological solutions to eleven-dimensional supergravity.Comment: 228 pages. Typos corrected. References added. Subject index added. Published versio

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium

Aims Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. Methods and results An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. Conclusion Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints

Admission levels of asymmetric and symmetric dimethylarginine predict long-term outcome in patients with community-acquired pneumonia

During infection, there is an activation of the L-arginine-nitric-oxide pathway, with a shift from nitric oxide synthesis to a degradation of L-arginine to its metabolites, asymmetric and symmetric dimethylarginine (ADMA and SDMA). However, the prognostic implications for short-term or long-term survival remains unclear. We investigated the association of L-arginine, ADMA, and SDMA with adverse clinical outcomes in a well-defined cohort of patients with community-acquired pneumonia (CAP).; We measured L-arginine, ADMA, and SDMA in 268 CAP patients from a Swiss multicenter trial by mass spectrometry and used Cox regression models to investigate associations between blood marker levels and disease severity as well as mortality over a period of 6 years.; Six-year mortality was 44.8%. Admission levels of ADMA and SDMA (μmol/L) were correlated with CAP severity as assessed by the pneumonia severity index (r = 0.32, p &lt; 0.001 and r = 0.56, p &lt; 0.001 for ADMA and SDMA, respectively) and higher in 6-year non-survivors versus survivors (median 0.62 vs. 0.48; p &lt; 0.001 and 1.01 vs. 0.85; p &lt; 0.001 for ADMA and SDMA, respectively). Both ADMA and SDMA were significantly associated with long-term mortality (hazard ratios [HR] 4.44 [95% confidence intervals (CI) 1.84 to 10.74] and 2.81 [95% CI 1.45 to 5.48], respectively). The effects were no longer significant after multivariate adjustment for age and comorbidities. No association of L-arginine with severity and outcome was found.; Both ADMA and SDMA show a severity-dependent increase in patients with CAP and are strongly associated with mortality. This association is mainly explained by age and comorbidities.; ISRCTN95122877 . Registered 31 July 2006

Associations of occupational and leisure-time physical activity with all-cause mortality: an individual participant data meta-analysis

This is the final version. Available from BMJ Publishing Group via the DOI in this record. Data availability statement. Data may be obtained from a third party and are not publicly available. All aggregated data are provided in this manuscript, including the supplementary files. Part of the individual participant are available on request, while other parts may be obtained from a third party and are not publicly available.Objective - Health effects of different physical activity domains (ie, during leisure time, work and transport) are generally considered positive. Using Active Worker consortium data, we assessed independent associations of occupational and leisure-time physical activity (OPA and LTPA) with all-cause mortality. Design - Two-stage individual participant data meta-analysis. Data source - Published and unpublished cohort study data. Eligibility criteria - Working participants aged 18–65 years. Methods - After data harmonisation, we assessed associations of OPA and LTPA with all-cause mortality. In stage 1, we analysed data from each study separately using Cox survival regression, and in stage 2, we pooled individual study findings with random-effects modelling. Results - In 22 studies with up to 590 497 participants from 11 countries, during a mean follow-up of 23.1 (SD: 6.8) years, 99 743 (16%) participants died. Adjusted for LTPA, body mass index, age, smoking and education level, summary (ie, stage 2) hazard ration (HRs) and 95% confidence interval (95% CI) for low, moderate and high OPA among men (n=2 96 134) were 1.01 (0.99 to 1.03), 1.05 (1.01 to 1.10) and 1.12 (1.03 to 1.23), respectively. For women (n=2 94 364), HRs (95% CI) were 0.98 (0.92 to 1.04), 0.96 (0.92 to 1.00) and 0.97 (0.86 to 1.10), respectively. In contrast, higher levels of LTPA were inversely associated with mortality for both genders. For example, for women HR for low, moderate and high compared with sedentary LTPA were 0.85 (0.81 to 0.89), 0.78 (0.74 to 0.81) and 0.75 (0.65 to 0.88), respectively. Effects were attenuated when adjusting for income (although data on income were available from only 9 and 6 studies, for men and women, respectively). Conclusion - Our findings indicate that OPA may not result in the same beneficial health effects as LTPA.The Netherlands Organisation for Health Research and DevelopmentFederal Ministry for Education and ResearchDeutsche Forschungsgemeinschaft (DFG)Martin-Luther-University of Halle-WittenbergFederal Employment OfficeMinistry of Education and Cultural Affairs of Saxony-AnhaltMinistry of Economics, Science and Digitization of Saxony-AnhaltEU European Regional Development Fund (ERDF)Swedish Research CouncilHelmholtz Zentrum MünchenGerman Research Center for Environmental HealthGerman Federal Ministry of Education and Research (BMBF)State of Bavari