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Spermidine, a naturally occurring polyamine, extends the lifespan of mice and is cardioprotective in both aged mice and hypertensive rats. In humans, high dietary spermidine intake is associated with reduced blood pressure and a lower incidence of cardiovascular disease. Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo , coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.

The proteinogenic branched-chain amino acids (BCAAs) valine, leucine and isoleucine might play an unrecognised crucial role in the development of depression through their activation of the mammalian target of rapamycin (mTor) pathway. The aim of this research project is to evaluate whether BCAAs are altered in patients with major depression and might thus be appropriate biomarkers for major depression. The concentrations of valine, leucine and isoleucine were determined in 71 in-patients with major depression and 48 healthy controls by high-pressure liquid chromatography. Psychiatric and laboratory assessments were obtained at the time of in-patient admittance. The BCAAs are significantly decreased in patients with major depression in comparison with healthy subjects (valine: Mann-Whitney-U: 968.0; p <0.0001, leucine: Mann-Whitney-U: 1246.5; p = 0.013, isoleucine: Mann-Whitney-U: 1252.5; p = 0.014). Furthermore, as shown by Spearman's rank correlation coefficients, there is a significant negative correlation between valine, leucine and isoleucine concentrations and the Hamilton Depression Rating Scale (HAMD-17) as well as Beck Depression Inventory (BDI-II) scores. Our study results are strong evidence that in patients with major depression, BCAAs might be appropriate biomarkers for depression. Reduced activation of the mammalian target of rapamycin (mTor) due to a reduction of BCAAs might play a crucial unrecognised factor in the etiology of depression and may evoke depressive symptomatology and lower energy metabolism in patients with major depression. In the future, mTor and its up- and downstream signalling partners might be important targets for the development of novel antidepressants.

This study investigated associations of inflammation-based biomarkers with endothelial dysfunction and lipids and their predictive value for clinical outcome parameters in patients with giant cell arteritis (GCA). A total of 138 patients with inactive GCA were retrospectively analyzed to investigate potential differences in inflammatory biomarkers regarding clinical GCA subtypes and potential correlations between inflammatory parameters with markers of endothelial dysfunction and lipid parameters. Additionally, the predictive role of inflammatory biomarkers for clinical outcomes, including disease relapse, all-cause mortality, cardiovascular events, and glucocorticoid adverse effects, was analyzed. GCA individuals without concomitant symptoms of polymyalgia rheumatica and those who received initial glucocorticoid pulse therapy exhibited significantly higher levels of white blood cells and neutrophils (all with p < 0.05). No other significant differences were observed between inflammatory biomarkers and clinical GCA subtypes. Additionally, significant correlations were identified between selected inflammation-based ratios and specific markers of endothelial dysfunction and lipid parameters (all with p < 0.05). Elevated white blood cells and neutrophils were significant and independent predictors of disease relapse in GCA (all with p < 0.05) in multiple logistic regression analysis. No significant associations were found between any other inflammatory biomarker and the occurrence of cardiovascular events, mortality, or glucocorticoid-related adverse effects. In patients with inactive GCA, selected inflammatory parameters correlated with endothelial dysfunction and dyslipidemia and may be predictive of disease relapse.

ContextObesity is associated with hypoadiponectemia, dyslipidemia, and increased risk of cardiovascular disease (CVD). Mechanisms linking these conditions remain to be fully understood. Cholesterol efflux capacity (CEC) is a crucial functional property of high-density lipoprotein (HDL) that strongly predicts CVD incidence.ObjectiveWe investigated whether age, fat distribution, and other obesity-related factors affect CEC in juvenile and adult overweight/obese participants of the STYJOBS/EDECTA cohort (NCT00482924).DesignWe performed an observational study.Main Outcome MeasuresCEC and its association with body measures and related metabolic parameters was assessed in 683 participants (281 juveniles, of whom 227 were overweight/obese; 402 adults, of whom 197 were overweight/obese).ResultsPearson correlation analysis showed that, after Bonferroni correction, CEC was significantly inversely correlated with body mass index (BMI), carotid diameter, waist circumference, waist-to-hip, waist-to-height ratio, oxidized low-density lipoprotein, and uric acid and with the liver markers alanine-aminotransferase and choline esterase. CEC was positively correlated with HDL cholesterol, total cholesterol, apolipoprotein A1, and adiponectin in adults, whereas in juveniles only apolipoprotein A1 showed a significant positive correlation with CEC. Age-stratified linear regression analyses with CEC as the outcome variable identified adiponectin as the most significant predictor of CEC in adults. The results did not change when either BMI or waist-to-hip ratio as a factor of fat distribution was included in the models.ConclusionsHypoadiponectemia is a robust predictor of reduced cholesterol efflux capacity in adults irrespective of BMI and fat distribution. Further investigations are needed to assess whether adiponectin is a causal determinant of CEC.Hypoadiponectemia is a predictor of reduced HDL CEC in adults. Adiponectin production may be a crucial modulator of HDL function with implications for cardiovascular risk.

Early depressive symptoms within the first days after acute myocardial infarction (AMI) are mainly manifested with performance parameters (lack of energy, concentration difficulties, reduction in physical functioning). Homoarginine (hArg), a non-proteinogenic amino acid, might increase the availability of nitric oxide (NO). NO controls vasodilatation, blood flow, mitochondrial respiration and improves performance. Therefore, low plasma hArg levels after an AMI might impact performance-related early depressive symptoms. This longitudinal study aims to determine the course of plasma hArg concentrations immediately, on the fourth day and 6 months after AMI and investigates the associations between hArg and early depressive symptoms. A decrease in hArg levels, as observed in AMI patients on the fourth day after AMI, was independent of gender, age, body-mass-index and AMI type. After six months, hArg concentrations no longer differed significantly from baseline values. Females had lower hArg concentrations shortly after and also four days after the AMI compared to males. Within the first days after AMI HAMD-17 and BDI-II total depression scores and performance-related early depressive symptoms such as lack of energy, concentration difficulties and reduction in physical functioning correlated with low hArg concentrations.

Background So far, studies on possible association of plasma lipid levels and depressive disorder are contradictory. This prospective work aimed at assessing a plasma lipid profile in individuals with major depression and healthy controls. Methods In total, 94 patients with major depression and 152 healthy controls were included in this prospective study. After an overnight fasting state of 12 h they underwent blood drawing for triglyzerides (TG), total cholesterol, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol measurements. All participants were evaluated in a clinical interview and filled out the self-rating Beck Depression Inventory (BDI-II) scale to identify depressive symptomatology. Results Ninety-four patients with major depression showed significantly higher median (interquartile range) plasma TG levels (108.0 [75.8–154.1] vs. 84.0 [63.0–132.2] mg/dL, P  = 0.014) and significantly lower HDL-cholesterol levels (55.0 [46.9–123.0] vs. 61.5 [47.4–72.6] mg/dL, P  = 0.049) compared to 152 individuals without depression, respectively. Total and LDL-cholesterol concentrations were observed slightly higher in patients with major depression. Significant positive correlation was found between TG, total cholesterol and LDL-cholesterol concentrations and the BDI-II score ( p  = 0.027, 0.048 and 0.018), and in tendency negative correlation between HDL-cholesterol levels and the BDI-II score ( P  = 0.091), respectively. Conclusions Depressive individuals were found with adverse plasma lipid patterns of higher TG and lower HDL-cholesterol levels compared to healthy controls. On this basis, the authors would suggest the implementation of routine lipid measurements in order to stratify these patients by their cardiovascular risk.

PurposeRegular exercise reduces obesity and the risk of cardiovascular disease. However, health-promoting benefits of physical activity are commonly associated with increased inflammation and oxidative stress. Here, we tested whether constant moderate exercise is able to prevent or attenuate the oxidative/nitrosative stress, inflammation, and serum lipids in lean and obese rats.MethodsFour-month-old female Sprague Dawley rats received standard or a high-fat diet. Animals were subjected to a physical activity protocol, consisting of 30 min forced treadmill exercise for 5 consecutive days per week during 10 months. Baseline and sedentary (non-exercised) rats were used as controls. Lipids, oxidized low-density lipoprotein cholesterol, nitric oxide metabolites, and pro- and anti-inflammatory markers were measured in blood collected upon euthanasia.ResultsAt variance to young baseline control rats, 14-month-old animals fed normal diet had increased plasma lipid levels, including total cholesterol and triglycerides, which were further elevated in rats that consumed a high-fat diet. While treadmill exercise did not lower the amount of serum lipids in standard diet group, forced physical activity reduced non-high-density lipoprotein cholesterol in response to high-fat diet feeding. Exercised rats fed standard diet or high-fat diet had lower abundancy of nitric oxide metabolites, which coincided with increased levels of oxidized low-density lipoprotein cholesterol. Accordingly, the amount of nitric oxide metabolites correlated inversely with oxidized low-density lipoprotein cholesterol and homo-arginine. Exercise significantly reduced inflammatory cytokines in high-fat diet fed rats only.ConclusionOur study suggests that regular exercise alters the equilibrium between oxidative and anti-oxidative compounds and reduces pro-inflammatory cytokines.

Background: Rising data suggest that COVID-19 affects vascular endothelium while the underlying mechanisms promoting COVID-19-associated endothelial dysfunction and inflammatory vasculopathy are largely unknown. The aim was to evaluate the contribution of COVID-19 to persisting vascular injury and to identify parameters linked to COVID-19-associated endothelial dysfunction and inflammatory vasculopathy. Methods: In a cross-sectional design, flow-mediated dilation (FMD), nitroglycerine-related dilation (NMD), pulse-wave velocity (PWV), augmentation index, intima-media thickness (IMT), compounds of the arginine and kynurenine metabolism, homocysteine, von Willebrand factor (vWF), endothelial microparticles (EMP), antiendothelial cell antibodies, inflammatory, and immunological parameters, as well as nailfold capillary morphology were measured in post-COVID-19 patients, patients with atherosclerotic cardiovascular diseases (ASCVD) and healthy controls without prior or recent SARS-CoV-2 infection. Results: Post-COVID-19 patients had higher values of PWV, augmentation index, IMT, asymmetric and symmetric dimethylarginine, vWF, homocysteine, CD31+/CD42b– EMP, C-reactive protein, erythrocyte sedimentation rate, interleukin-6, and β-2-glycoprotein antibodies as well as lower levels of homoarginine and tryptophan compared to healthy controls (all with p < 0.05). A higher total number of pathologically altered inflammatory conditions and higher rates of capillary ramifications, loss, caliber variability, elongations and bushy capillaries with an overall higher microangiopathy evolution score were also observed in post-COVID-19 patients (all with p < 0.05). Most parameters of endothelial dysfunction and inflammation were comparably altered in post-COVID-19 patients and patients with ASCVD, including FMD and NMD. Conclusion: COVID-19 may affect arterial stiffness, capillary morphology, EMP and selected parameters of arginine, kynurenine and homocysteine metabolism as well as of inflammation contributing to COVID-19-associated endothelial dysfunction and inflammatory vasculopathy.

Pathogenic mucormycetes induce diseases with considerable morbidity and mortality in immunocompromised patients. Virulence data comparing different Mucorales species and various underlying risk factors are limited. We therefore compared the pathogenesis of inhalative infection by Rhizopus (R.) arrhizus and Lichtheimia (L.) corymbifera in murine models for predominant risk factors for onset of infection. Mice with diabetes or treated with cyclophosphamide or cortisone acetate were challenged via the intranasal route with an isolate of R. arrhizus or L. corymbifera, respectively. Clinical, immunological and inflammation parameters as well as efficacy of posaconazole prophylaxis were monitored over 14 days. Whereas immunocompetent mice showed no clinical symptoms after mucormycete infection, mice treated with either cyclophosphamide (CP) or cortisone acetate (CA) were highly susceptible. Animals infected with the isolate of R. arrhizus showed prolonged survival and lower mortality, compared to those exposed to the L. corymbifera isolate. This lower virulence of R. arrhizus was risk factor-dependent, since diabetic mice died only after infection with Rhizopus, whereas all Lichtheimia-infected diabetic animals survived. Under posaconazole prophylaxis, both mucormycetes were able to establish breakthrough infections in CA- and CP-treated mice, but the course of infection was significantly delayed. Detailed analysis revealed that susceptibility of CA- and CP-treated mice could not be mimicked by exclusive lack or downmodulation of neutrophils, platelets or complement, but can be supposed to be the consequence of a broad immunosuppressive effect induced by the drugs. Both Lichtheimia corymbifera and Rhizopus arrhizus induce invasive mycoses in immunocompromised hosts after inhalative infection. Key parameters such as virulence and immunopathogenesis vary strongly according to fungal species and underlying risk group. Selected neutropenia is no sufficient risk factor for onset of inhalative mucormycosis.

Major depression is a well-known risk factor for cardiovascular diseases and increased mortality following myocardial infarction. However, biomarkers of depression and increased cardiovascular risk are still missing. The aim of this prospective study was to evaluate, whether nitric-oxide (NO) related factors for endothelial dysfunction, such as global arginine bioavailability, arginase activity, L-arginine/ADMA ratio and the arginine metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) might be biomarkers for depression-induced cardiovascular risk. In 71 in-patients with major depression and 48 healthy controls the Global Arginine Bioavailability Ratio (GABR), arginase activity (arginine/ornithine ratio), the L-arginine/ADMA ratio, ADMA, and SDMA were determined by high-pressure liquid chromatography. Psychiatric and laboratory assessments were obtained at baseline at the time of in-patient admittance and at the time of hospital discharge. The ADMA concentrations in patients with major depression were significantly elevated and the SDMA concentrations were significantly decreased in comparison with the healthy controls. Even after a first improvement of depression, ADMA and SDMA levels remained nearly unchanged. In addition, after a first improvement of depression at the time of hospital discharge, a significant decrease in arginase activity, an increased L-arginine/ADMA ratio and a trend for increased global arginine bioavailability were observed. Our study results are evidence that in patients with major depression ADMA and SDMA might be biomarkers to indicate an increased cardiovascular threat due to depression-triggered NO reduction. GABR, the L-arginine/ADMA ratio and arginase activity might be indicators of therapy success and increased NO production after remission.