28Aging is associated with an increased risk of cardiovascular disease and death. Here we 29show that oral supplementation of the natural polyamine spermidine extends the lifespan of 30 mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving 31 diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy 32 and mitochondrial respiration, and it also improved the mechano-elastical properties of 33 cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed 34 subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that 35 lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that 36 were fed a high-salt diet, a model for hypertension-induced congestive heart failure, 37 spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and 38 prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the 39 progression to heart failure. In humans, high levels of dietary spermidine, as assessed from 40 food questionnaires, correlated with reduced blood pressure and a lower incidence of 41 cardiovascular disease. Our results suggest a new and feasible strategy for the protection 42 from cardiovascular disease. 43Author's manuscript to Eisenberg et al.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

A part from skeletal diseases, vitamin D deficiency is considered a risk factor for cardiovascular events and mortality. [1][2][3][4][5][6] Nevertheless, it remains unclear whether low 25-hydroxyvitamin D (25[OH]D) concentrations are a significant causal risk factor or are simply related to adverse outcomes because of reverse causation and confounding factors, such as obesity, reduced mobility with low sunlight exposure, poor nutrition, or inflammation. [1][2][3][4][5][6] Because high blood pressure (BP) has emerged as the leading risk factor for the global disease burden, it is important to evaluate whether vitamin D has a beneficial effect on lowering BP to clarify the potential role of vitamin D for public health. 7 Large observational studies and meta-analyses have shown that low 25(OH)D concentrations are a significant risk marker for arterial hypertension. 8,9 Molecular effects of vitamin D receptor activation, such as suppression of the renin-angiotensin-aldosterone system (RAAS), nephroprotective actions, or improvements in endothelial/vascular function, suggest Abstract-Vitamin D deficiency is a risk factor for arterial hypertension, but randomized controlled trials showed mixed effects of vitamin D supplementation on blood pressure (BP). We aimed to evaluate whether vitamin D supplementation affects 24-hour systolic ambulatory BP monitoring values and cardiovascular risk factors. The Styrian Vitamin D Hypertension Trial is a single-center, double-blind, placebo-controlled study conducted from June 2011 to August 2014 at the endocrine outpatient clinic of the Medical University of Graz, Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxyvitamin D levels below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day as oily drops (n=100) or placebo (n=100) for 8 weeks. Primary outcome measure was 24-hour systolic BP. Secondary outcome measures were 24-hour diastolic BP, N-terminal-pro-B-type natriuretic peptide, QTc interval, renin, aldosterone, 24-hour urinary albumin excretion, homeostasis model assessment-insulin resistance, triglycerides, highdensity lipoprotein cholesterol, and pulse wave velocity. Methods Study DesignThe Styrian Vitamin D Hypertension Trial was sponsored by the Medical University of Graz, Austria, and is a single-center, double-blind, placebo-controlled, parallel-group study conducted at the Medical University of Graz, Austria. The publication of this trial adheres to the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement. 29 The trial was initially registered at http://www.clinicaltrialsregister.eu (EudraCT number, 2009-018125-70) and was additionally registered at clinicaltrials.gov (ClinicalTrials.gov Identifier NCT02136771). ParticipantsEligible study participants were adults aged ≥18 years with arterial hypertension and a 25(OH)D serum concentration below 30 ng/mL (multiply by 2.496 to convert ng/mL to nmol/L). Arterial hypertension was classified in patients with an office BP of systol...

Background-Homoarginine is an amino acid derivative that may increase nitric oxide availability and enhance endothelial function. The effect of the level of homoarginine on cardiovascular outcome and mortality is unknown. Methods and Results-We assessed cardiovascular and all-cause mortality according to homoarginine levels in a cohort of 3305 subjects referred for coronary angiography from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study. After investigating the relation of homoarginine with kidney function and markers of endothelial dysfunction, we explored its effects on adverse outcomes in a second high-risk cohort of 1244 patients with type 2 diabetes mellitus receiving maintenance hemodialysis (4D study [Die Deutsche Diabetes Dialyse Studie]). In the LURIC study, mean serum homoarginine levels were 2.6Ϯ1.1 mol/L. During a median follow-up of 7.7 years, 766 patients died. After adjustments for age and sex, patients in the lowest quartile (Ͻ1.85 mol/L) had a Ͼ4-fold higher rate of dying of cardiovascular disease (hazard ratio 4.1, 95% confidence interval 3.0 to 5.7) than patients in the highest quartile (Ͼ3.1 mol/L). Lower homoarginine levels were associated with lower estimated glomerular filtration rate and higher levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Hemodialysed patients had lower mean homoarginine levels of 1.2Ϯ0.5 mol/L and experienced a 5-fold increased mortality rate compared with LURIC patients (608 deaths during a median follow-up of 4 years). Homoarginine consistently affected mortality, which was 2-fold higher in 4D study patients in the lowest quartile (Ͻ0.87 mol/L) than in patients in the highest quartile (Ͼ1.4 mol/L). Conclusions-Homoarginine levels are independently associated with cardiovascular and all-cause mortality in patients referred for coronary angiography and in patients undergoing hemodialysis. Future studies are needed to elucidate the underlying pathomechanisms. (Circulation. 2010;122:967-975.)