The relationship between haemoglobin concentrations and obstructive sleep apnea syndrome: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis investigates the relationship between haemoglobin (Hb) concentrations and obstructive sleep apnea syndrome (OSAS). METHODS: Following PRISMA guidelines, we searched PubMed, EMBASE, and Cochrane Library from inception to March 8, 2024. Eligible studies included cross-sectional, cohort, and case-control designs comparing Hb concentrations in OSAS patients and healthy controls. Two reviewers independently screened records and extracted data. The risk of bias was assessed using the Joanna Briggs Institute checklist. RESULTS: A total of 27 studies involving 6499 OSAS subjects and 5199 controls were included. Hb concentrations were significantly higher in OSAS patients compared to controls (SMD: 0.28; 95 % CI: 0.18 to 0.39; I2 = 84.4 %). Subgroup analysis by OSAS severity showed that severe OSAS patients had higher Hb concentrations than those with mild/moderate OSAS. Sensitivity analyses confirmed the robustness of the findings. However, 7 studies reported opposite results, indicating possible regional or methodological differences. CONCLUSION: Hb concentrations are elevated in OSAS patients, with higher levels observed in severe cases. The significant heterogeneity and the predominance of studies from Turkey highlight the need for further research in diverse populations. Limitations include potential publication bias and variability in study designs.

Association between blood Pentraxin-3 concentrations and rheumatic diseases: A systematic review and meta-analysis.

BACKGROUND: Among the Pentraxins, the long Pentraxin-3 (PTX-3) is associated with several processes, particularly in the earliest phases of the innate humoral response. Increased blood PTX-3 concentrations have been observed in a wide range of conditions, from infectious to cardiovascular disorders. Since its increase is more rapid than C-reactive protein (CRP), PTX-3 can be useful to detect and monitor early inflammation. To dissect its pathophysiological role in rheumatic diseases (RD), we conducted a systematic review and meta-analysis comparing blood PTX-3 concentrations in RD patients and healthy individuals and investigating possible associations with clinical, demographic, and study characteristics. METHODS: We performed a search of published evidence until April 2024 in PubMed, Web of Science and Scopus, which led to the selection of 60 relevant manuscripts from a total of 1072 records. RESULTS: Our synthesis revealed a statistically significant difference in PTX-3 concentrations between RD patients and controls (standard mean difference, SMD = 1.02, 95% CI 0.77-1.26, p < .001), that correlated with CRP concentrations. The effect size was associated with geographical region of study conduction, RD type, with a reduction of the observed heterogeneity in patients with low LDL-cholesterol and triglycerides concentrations. CONCLUSIONS: Our study has shown a significant increase in blood PTX-3 concentrations in RD patients, which was associated with specific patient characteristics. Nevertheless, additional studies are needed to better define the utility of measuring PTX-3 in the early phase of RD. Our study was conducted in compliance with the PRISMA 2020 statement (study protocol available at PROSPERO CRD42024516600).

Ischemia-Modified Albumin (IMA) Is Associated with Poor Survival in Patients with Newly Diagnosed Idiopathic Pulmonary Fibrosis (IPF): A Pilot Study.

There are increasing efforts to better predict adverse outcomes for idiopathic pulmonary fibrosis (IPF). Our aim was to assess the prognostic potential of ischemia-modified albumin (IMA), an established circulating marker of ischemia and, more recently, oxidative stress, in a cohort of 56 IPF patients recruited between 2015 and 2023 at the University of Sassari, Italy. Demographic and functional parameters and serum IMA concentrations were measured at baseline. Non-survivors had significantly higher IMA concentrations vs. survivors (508 ± 64 vs. 474 ± 42 mABSU, respectively; p = 0.035). The Kaplan-Meier analysis showed a significant association between higher IMA values and poor survival (HR: 3.32, 95% CI from 1.06 to 10.4, p = 0.039). In the Cox regression analysis, this association remained significant after adjusting for the force expiratory volume at 1 s, the total lung capacity, lymphocyte count, and pharmacological treatment (HR: 1.0154, 95% CI from 1.0035 to 1.0275, p = 0.01). IMA, an oxidative stress biomarker measurable using relatively simple and available methods, is independently associated with mortality in IPF. Therefore, its determination may enhance risk stratification and treatment decisions. Prospective studies involving larger cohorts are needed to confirm this association and to endorse the use of IMA in routine practice.

Methotrexate and cardiovascular prevention: an appraisal of the current evidence.

New evidence continues to accumulate regarding a significant association between excessive inflammation and dysregulated immunity (local and systemic) and the risk of cardiovascular events in different patient cohorts. Whilst research has sought to identify novel atheroprotective therapies targeting inflammation and immunity, several marketed drugs for rheumatological conditions may serve a similar purpose. One such drug, methotrexate, has been used since 1948 for treating cancer and, more recently, for a wide range of dysimmune conditions. Over the last 30 years, epidemiological and experimental studies have shown that methotrexate is independently associated with a reduced risk of cardiovascular disease, particularly in rheumatological patients, and exerts several beneficial effects on vascular homeostasis and blood pressure control. This review article discusses the current challenges with managing cardiovascular risk and the new frontiers offered by drug discovery and drug repurposing targeting inflammation and immunity with a focus on methotrexate. Specifically, the article critically appraises the results of observational, cross-sectional and intervention studies investigating the effects of methotrexate on overall cardiovascular risk and individual risk factors. It also discusses the putative molecular mechanisms underpinning the atheroprotective effects of methotrexate and the practical advantages of using methotrexate in cardiovascular prevention, and highlights future research directions in this area.

Does hyperglycemia affect arginine metabolites in critically ill patients? A prospective cohort and in vitro study.

BACKGROUND: Changes in the arginine metabolites asymmetric dimethyl-L-arginine (ADMA) and L-homoarginine and acute blood glucose concentrations have been shown to cause endothelial dysfunction and be independently associated with mortality in Intensive Care Unit (ICU) patients. The aim of this study was to investigate whether hyperglycemia potentially modulates these arginine metabolite concentrations to provide a mechanism that may link hyperglycemia and mortality in this patient group. METHODS: A clinical and in vitro study were undertaken. Glucose, glycosylated hemoglobin-A1c (HbA1c) and the stress hyperglycemia ratio (SHR) (to quantify absolute, chronic and relative hyperglycemia respectively) were measured in 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU. SHR was calculated by dividing the admission glucose by the estimated average glucose over the last 3 months, which was derived from HbA1c. ADMA and L-homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. The activity of dimethylarginine-dimethylaminohydrolase 1 (DDAH1), the main enzyme regulating ADMA concentrations, was assessed at varying glucose concentrations in vitro by quantifying the conversion of ADMA to citrulline in HEK293 cells that overexpress DDAH1. RESULTS: In the clinical study, plasma ADMA was not significantly associated with any measure of hyperglycemia. L-homoarginine was positively associated with glucose (ß = 0.067, p = 0.018) and SHR (ß = 0.107, p < 0.001) after correction for glomerular filtration rate. However, as L-homoarginine is a negative predictor of mortality, the direction of these associations are the opposite of those expected if hyperglycemia was affecting mortality via changes in L-homoarginine. In vitro DDAH1 activity was not significantly influenced by glucose concentrations (p = 0.506). CONCLUSION: In critically ill patients the association between relative hyperglycemia and mortality is not mediated by changes in ADMA or L-homoarginine. Trial registration ANZCTR Trial ID ACTRN12615001164583.

A Capillary Electrophoresis-Based Method for the Measurement of Hydroxychloroquine and Its Active Metabolite Desethyl Hydroxychloroquine in Whole Blood in Patients with Rheumatoid Arthritis.

A capillary electrophoresis method was developed to detect and measure hydroxychloroquine (HCQ) and its active metabolite desethyl hydroxychloroquine (DHCQ) in whole blood in patients with rheumatoid arthritis. The best separation in terms of peak area reproducibility, migration time, peak shape, and resolution of adjacent peaks was obtained in a 60 cm, 75 µm i.d. uncoated fused-silica capillary using a background electrolyte mixture of an aqueous 55 mmol/L TRIS solution brought to pH 2.6 with phosphoric acid and methanol (85:15) and a voltage and a temperature of separation of 20 kV and 30 °C, respectively. Analytes were separated in less than 12 min, with excellent linearity (R2 ≥ 0.999) in the concentration range of 0.5-8 µmol/L. The recovery of analytes spiked in whole blood was 99-101% for HCQ and 98-99% for DHCQ. Analysis of five samples from patients with rheumatoid arthritis receiving HCQ 400 mg daily yielded mean steady-state concentrations of 2.27 ± 1.61 and 1.54 ± 0.55 µmol/L for HCQ and DHCQ, respectively, with a HCQ to DHCQ ratio of 1.40 ± 0.77.

ADMA and homoarginine independently predict mortality in critically ill patients.

BACKGROUND: Arginine metabolites are associated with cardiovascular and all-cause mortality in several patient groups. We investigated whether arginine metabolites are associated with mortality in patients with critical illness and whether associations are independent of other factors affecting prognosis in an Intensive Care Unit (ICU). METHODS: 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU were studied. Arginine, asymmetric dimethyl-l-arginine (ADMA), monomethyl-l-arginine (MMA), symmetric dimethyl-l-arginine (SDMA) and l-homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society. RESULTS: In this cohort, 163 patients (14.1%) died. ADMA (odds ratio = 1.159 (1.033-1.300) per 0.1 µmol/L increment, p = 0.012), homoarginine (odds ratio = 0.963 (0.934-0.992), p = 0.013) and risk of death score (odds ratio = 1.045 (1.037-1.053) per 1% increment, p < 0.001) were independently associated with mortality in ICU patients. The area under the receiver operator characteristic curve for risk of death score, ADMA and homoarginine combined for mortality was greater than for risk of death score alone (0.815 (95% CI 0.790-0.837) vs 0.796 (95% CI 0.781-0.820), p = 0.019). Other arginine metabolites were not independently associated with mortality. CONCLUSIONS: ADMA is positively and homoarginine negatively associated with mortality in ICU patients, independent of other clinical factors. Measuring ADMA and homoarginine may refine models to predict ICU mortality. Reducing ADMA and increasing homoarginine are potential therapeutic targets to reduce mortality in critically ill patients.

Plasma homoarginine concentrations in ewe's pregnancy and association with the number of fetuses.

A striking increase in homoarginine concentrations, about more than 100-fold that observed in humans, was recently reported during pregnancy in a nutritionally induced model of intra-uterine growth restriction in ewes. To determine whether this phenomenon is at least partially related to the nutritional regimen, estrus synchronization, or analytical method, thirty-four one-year-old primiparous, non-synchronized, and well-fed Sarda breed ewes were exposed to fertile rams allowing those who came into estrus to naturally mate. Plasma arginine, homoarginine, asymmetric dimethylarginine, symmetric dimethylarginine, mono methylarginine, and citrulline concentrations were measured in each sample using LC-MS/MS. Homoarginine concentrations showed a 44-fold variation between the highest and the lowest values while the fluctuations of arginine and its analogues and metabolites were much smaller, between 1.1 and 1.6-fold. Repeated-measures correlation analysis showed a significant negative correlation between homoarginine/arginine and arginine/asymmetric dimethylarginine ratios (Rm = -0.40; P < 0.000001). Furthermore, median homoarginine concentrations significantly increased with the number of fetuses. The marked increase in homoarginine concentrations with advancing gestational age is genuine and independent of mating, feeding, diet, and hormone treatment. The higher homoarginine concentrations found in ewes bearing multiple fetuses suggest the presence of a physiological link between this arginine analog and energy metabolism in pregnancy that warrants further investigation.

S-Methyl-L-Ergothioneine to L-Ergothioneine Ratio in Urine Is a Marker of Cystine Lithiasis in a Cystinuria Mouse Model.

Cystinuria, a rare inherited aminoaciduria condition, is characterized by the hyperexcretion of cystine, ornithine, lysine, and arginine. Its main clinical manifestation is cystine stone formation in the urinary tract, being responsible for 1-2% total and 6-8% pediatric lithiasis. Cystinuria patients suffer from recurrent lithiasic episodes that might end in surgical interventions, progressive renal functional deterioration, and kidney loss. Cystinuria is monitored for the presence of urinary cystine stones by crystalluria, imaging techniques or urinary cystine capacity; all with limited predicting capabilities. We analyzed blood and urine levels of the natural antioxidant L-ergothioneine in a Type B cystinuria mouse model, and urine levels of its metabolic product S-methyl-L-ergothioneine, in both male and female mice at two different ages and with different lithiasic phenotype. Urinary levels of S-methyl-L-ergothioneine showed differences related to age, gender and lithiasic phenotype. Once normalized by L-ergothioneine to account for interindividual differences, the S-methyl-L-ergothioneine to L-ergothioneine urinary ratio discriminated between cystine lithiasic phenotypes. Urine S-methyl-L-ergothioneine to L-ergothioneine ratio could be easily determined in urine and, as being capable of discriminating between cystine lithiasis phenotypes, it could be used as a lithiasis biomarker in cystinuria patient management.

B-Type Natriuretic Peptide Concentrations, COVID-19 Severity, and Mortality: A Systematic Review and Meta-Analysis With Meta-Regression.

Alterations in cardiac biomarkers have been reported in patients with coronavirus disease 2019 (COVID-19) in relation to disease severity and mortality. We conducted a systematic review and meta-analysis with meta-regression of studies reporting B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) plasma concentrations in COVID-19. We searched PubMed, Web of Science, and Scopus, between January 2020 and 2021, for studies reporting BNP/NT-proBNP concentrations, measures of COVID-19 severity, and survival status (PROSPERO registration number: CRD42021239190). Forty-four studies in 18,856 COVID-19 patients were included in the meta-analysis and meta-regression. In pooled results, BNP/NT-proBNP concentrations were significantly higher in patients with high severity or non-survivor status when compared to patients with low severity or survivor status during follow up (SMD = 1.07, 95% CI: 0.89-1.24, and p < 0.001). We observed extreme between-study heterogeneity (I 2 = 93.9%, p < 0.001). In sensitivity analysis, the magnitude and the direction of the effect size were not substantially modified after sequentially removing individual studies and re-assessing the pooled estimates, (effect size range, 0.99 - 1.10). No publication bias was observed with the Begg's (p = 0.26) and Egger's (p = 0.40) t-tests. In meta-regression analysis, the SMD was significantly and positively associated with D-dimer (t = 2.22, p = 0.03), myoglobin (t = 2.40, p = 0.04), LDH (t = 2.38, p = 0.02), and procalcitonin (t = 2.56, p = 0.01) concentrations. Therefore, higher BNP/NT-proBNP plasma concentrations were significantly associated with severe disease and mortality in COVID-19 patients.

Serum CK-MB, COVID-19 severity and mortality: An updated systematic review and meta-analysis with meta-regression.

OBJECTIVES: We conducted a systematic review and meta-analysis with meta-regression of creatine kinase-MB (CK-MB), a biomarker of myocardial injury, in COVID-19 patients. METHODS: We searched PubMed, Web of Science and Scopus, for studies published between January 2020 and January 2021 that reported CK-MB, COVID-19 severity and mortality (PROSPERO registration number: CRD42021239657). RESULTS: Fifty-five studies in 11,791 COVID-19 patients were included in the meta-analysis. The pooled results showed that CK-MB concentrations were significantly higher in patients with high disease severity or non-survivor status than patients with low severity or survivor status (standardized mean difference, SMD, 0.81, 95% CI 0.61 to 1.01, p<0.001). The rate of patients with CK-MB values above the normal range was also significantly higher in the former than the latter (60/350 vs 98/1,780; RR â€‹= â€‹2.84, 95%CI 1.89 to 4.27, p<0.001; I2 â€‹= â€‹19.9, p â€‹= â€‹0.254). Extreme between-study heterogeneity was observed (I2 â€‹= â€‹93.4%, p<0.001). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified (effect size range, 0.77 to 0.84). Begg's (p â€‹= â€‹0.50) and Egger's (p â€‹= â€‹0.86) t-tests did not show publication bias. In meta-regression analysis, the SMD was significantly and positively associated with the white blood count, aspartate aminotransferase, myoglobin, troponin, brain natriuretic peptide, lactate dehydrogenase, and D-dimer. CONCLUSIONS: Higher CK-MB concentrations were significantly associated with severe disease and mortality in COVID-19 patients. This biomarker of myocardial injury might be useful for risk stratification in this group.

Methodological Fallacies in the Determination of Serum/Plasma Glutathione Limit Its Translational Potential in Chronic Obstructive Pulmonary Disease.

This study aimed to review and critically appraise the current methodological issues undermining the suitability of the measurement of serum/plasma glutathione, both in the total and reduced form, as a measure of systemic oxidative stress in chronic obstructive pulmonary disease (COPD). Fourteen relevant articles published between 2001 and 2020, in 2003 subjects, 1111 COPD patients, and 892 controls, were reviewed. Nine studies, in 902 COPD patients and 660 controls, measured glutathione (GSH) in the reduced form (rGSH), while the remaining five, in 209 COPD patients and 232 controls, measured total GSH (tGSH). In the control group, tGSH ranged between 5.7 and 7.5 µmol/L, whilst in COPD patients, it ranged between 4.5 and 7.4 µmol/L. The mean tGSH was 6.6 ± 0.9 µmol/L in controls and 5.9 ± 1.4 µmol/L in patients. The concentrations of rGSH in the control group showed a wide range, between 0.47 and 415 µmol/L, and a mean value of 71.9 ± 143.1 µmol/L. Similarly, the concentrations of rGSH in COPD patients ranged between 0.49 and 279 µmol/L, with a mean value of 49.9 ± 95.9 µmol/L. Pooled tGSH concentrations were not significantly different between patients and controls (standard mean difference (SMD) = -1.92, 95% CI -1582 to 0.0219; p = 0.057). Depending on whether the mean concentrations of rGSH in controls were within the accepted normal range of 0.5-5.0 µmol/L, pooled rGSH concentrations showed either a significant (SMD = -3.8, 95% CI -2.266 to -0.709; p < 0.0001) or nonsignificant (SMD = -0.712, 95% CI -0.627 to 0.293; p = 0.48) difference. These results illustrate the existing and largely unaddressed methodological issues in the interpretation of the serum/plasma concentrations of tGSH and rGSH in COPD.

Asymmetric Dimethylarginine: a Key Player in the Pathophysiology of Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis in Rheumatoid Arthritis?

Patients with rheumatoid arthritis (RA), a chronic and disabling autoimmune condition that is characterized by articular and extra-articular manifestations and a pro-inflammatory and pro-oxidant state, suffer from premature atherosclerosis and excessive cardiovascular disease burden. A key step in the pathogenesis of atherosclerosis is impaired synthesis of the endogenous messenger nitric oxide (NO) by endothelial cells which, in turn, alters local homeostatic mechanisms and favors vascular damage and plaque deposition. While the exact mechanisms of endothelial dysfunction in RA remain to be established, there is good evidence that RA patients have relatively high circulating concentrations of the methylated arginine asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of endothelial NO synthase (eNOS). This review discusses the biological and pathophysiological role of ADMA, the interplay between ADMA, inflammation and oxidative stress, and the available evidence on the adverse impact of ADMA on endothelial function and atherosclerosis and potential ADMA-lowering therapies in RA patients.

Systematic Review and Meta-Analysis of the Blood Glutathione Redox State in Chronic Obstructive Pulmonary Disease.

The aim of this systematic review and meta-analysis was to assess the blood concentrations of the total and reduced forms of the low-molecular-weight antioxidant thiol glutathione (GSH) in chronic obstructive pulmonary disease (COPD) patients in comparison to healthy individuals. A literature search was conducted in the PubMed and Web of Science databases from inception until June 2020. In the 18 studies identified (involving a total of 974 COPD patients and 631 healthy controls), the pooled reduced GSH concentrations were significantly lower in patients with COPD than controls (SMD = -3.04, 95% CI = -4.42 to -1.67; p < 0.001). By contrast, the pooled total GSH concentrations were significantly higher in patients with COPD than controls (SMD = 0.42, 95% CI = 0.11 to 0.73; p = 0.009). Our meta-analysis showed that the blood concentrations of reduced GSH, even in the presence of higher total GSH concentrations, were significantly lower in patients with COPD when compared to healthy controls. This suggests that an impaired antioxidant defense system plays an important role in the pathogenesis of COPD.

Hercynine, Ergothioneine and Redox State in Stallion's Seminal Plasma.

The dependence of a stallion's spermatozoa on oxidative phosphorylation for energy requirements results in an unconventional relationship between reactive oxygen species (ROS) production and fertility. In such a scenario, antioxidant activity must be finely controlled and not affect the essential functions of ROS. Some in vivo evidence suggests that the naturally occurring antioxidant ergothioneine (ERT) interferes with the critical roles of ROS/reactive nitrogen species (RNS) in pro-oxidant states but not in healthy tissues. The measurement of ERT in seminal plasma collected from 14 stallions (five Anglo-Arab, five Sella Italiano and four Thoroughbreds of which three are Arabian and one English) aged 16 ± 6 years (range 6-25 years) confirms that ERT is present at high concentrations in this biological fluid, between 16.80 and 971.48 µmol/L. Although the presence of high ERT concentrations in the seminal plasma of a stallion has long been known, its exact biological role is uncertain. This might be due to the peculiar antioxidant cycle of ERT, specifically its rapid recovery, which potentially masks concentration fluctuations and, therefore, the extent of its physiological effects. The measurement of the ERT precursor and redox metabolite hercynine (ERY) may overcome such issues, as ERY does not undergo regeneration processes. ERY was detectable and measurable in the seminal plasma of all stallions at a median concentration of 7.50 (IQR 15.26) nmol/L. The analysis of the association between the ERT and ERY, as well as with other established antioxidants such as glutathione and cysteine, suggests that ERT may play a major role in the antioxidant machinery of seminal plasma, and that ERY might serve as a new combined marker of oxidative stress and semen quality.

Oxidative Stress Biomarkers and Peripheral Endothelial Dysfunction in Rheumatoid Arthritis: A Monocentric Cross-Sectional Case-Control Study.

Previous studies have suggested that oxidative stress may heighten atherosclerotic burden in rheumatoid arthritis (RA), but direct evidence is lacking. OBJECTIVE: To evaluate the relationship between established plasma oxidative stress biomarkers and peripheral endothelial dysfunction (ED), a marker of early atherosclerosis, in RA. METHODS: Paroxonase-1 (PON-1), protein-SH (PSH), and malondialdehyde (MDA) were measured in 164 RA patient s and 100 age- and sex-matched healthy controls without previous cardiovascular events. Peripheral ED, evaluated by flow-mediated pulse amplitude tonometry, was defined by log-transformed reactive hyperemia index (Ln-RHI) values < 0.51. RESULTS: PON-1 activity and PSH concentrations were significantly reduced in RA patients compared to controls. In regression analysis, increased plasma MDA levels were significantly associated with reduced Ln-RHI [B coefficient (95% CI) = -0.003 (-0.005 to -0.0008), p = 0.008] and the presence of peripheral ED (OR (95% CI) = 1.75 (1.06-2.88), p = 0.028). Contrary to our expectations, increased PON-1 activity was significantly associated, albeit weakly, with the presence of ED (OR (95% CI) = 1.00 (1.00-1.01), p = 0.017). CONCLUSIONS: In this first evidence of a link between oxidative stress and markers of atherosclerosis, MDA and PON-1 showed opposite associations with peripheral vasodilatory capacity and the presence of ED in RA. Further studies are needed to determine whether this association predicts atherosclerotic events in the RA population.

Comprehensive arginine metabolomics and peripheral vasodilatory capacity in rheumatoid arthritis: A monocentric cross-sectional study.

BACKGROUND: The relationship between plasma arginine metabolites influencing vascular homeostasis and peripheral vasodilatory capacity in rheumatoid arthritis (RA) patients is not known. METHODS: l-arginine (Arg), monomethyl-l-arginine (MMA), l-homoarginine (hArg), asymmetric dimethyl-l-arginine (ADMA), symmetric dimethyl-l-arginine, and l-citrulline (Cit) were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 164 RA patients and 100 age- and sex-matched healthy controls without previous cardiovascular events. Log-transformed reactive hyperemia index (Ln-RHI) evaluated by flow-mediated pulse amplitude tonometry (PAT, EndoPAT2000 device) was assessed as surrogate measure of peripheral vasodilatory capacity in RA patients. Ln-RHI values <0.51 indicated peripheral endothelial dysfunction (ED). The relationship between plasma arginine metabolite concentrations, RA descriptors and peripheral vasodilatory capacity was evaluated by bivariate correlation and regression analyses. RESULTS: Plasma ADMA concentrations were significantly higher, and plasma hArg concentrations significantly lower, in RA patients than in controls (0.53 ± 0.09 vs 0.465 ± 0.07 µmol/L and 1.50 ± 0.60 vs 1.924 ± 0.78 µmol/L, respectively; p < 0.001 for both comparisons). Bivariate correlation analysis demonstrated no significant correlation between arginine metabolites and disease descriptors. In regression analysis in RA patients, higher plasma ADMA concentrations were independently associated with presence of ED [OR(95% CI) = 77.3(1.478-4050.005), p = 0.031] and lower Ln-RHI [B coefficient(95% CI) = -0.57(-1.09 to -0.05), p = 0.032]. CONCLUSIONS: ADMA was significantly, albeit weakly, associated with impaired microcirculatory vasodilatory capacity and peripheral endothelial dysfunction in RA. This suggests an important pathophysiological role of this metabolite in the vascular alterations observed in this patient group.

Systemic transsulfuration pathway thiol concentrations in chronic obstructive pulmonary disease patients.

BACKGROUND: It is amply reported that patients with chronic obstructive pulmonary disease (COPD) have increased risk of cardiovascular disease (CVD). Recent evidence suggests that COPD patients have elevated concentrations of plasma homocysteine (Hcy), a transsulfuration pathway analyte that is commonly regarded as a CVD risk factor. DESIGN: We comprehensively investigated the plasma concentrations of transsulfuration pathway analytes, and their relationship with markers of oxidative stress and inflammation, to identify which low molecular thiols might play a pathophysiological role both in CVD and in COPD. Hcy, cysteine (Cys), glutathione (GSH), cysteinylglycine (CysGly), glutamylcysteine (GluCys), taurine (Tau), oxidative stress markers (TBARS and protein-SH, PSH) and the inflammation marker kynurenine/tryptophan (Kyn/Trp) ratio were measured in 54 COPD patients and 54 control subjects. RESULTS: We found increased concentrations of total Hcy (P < .01) and total CysGly (P < .05) in COPD patients when compared to controls. Total Hcy and CysGly were also significantly associated with abnormal lung function parameters and COPD severity. In COPD patients, total Hcy was significantly associated with the Kyn/Trp ratio (P = .0017) whereas total CysGly was significantly associated with both PSH (P = .0298) and the Kyn/Trp ratio (P = <.0001). CONCLUSION: Both total Hcy and CysGly concentrations were significantly associated with the presence and severity of COPD and with markers of oxidative stress (total CysGly) and inflammation (total Hcy and CysGly). This suggests that specific low molecular mass thiols might play a role in the inflammatory and oxidative stress pathways involved in both CVD and COPD.

Methotrexate and Vasculoprotection: Mechanistic Insights and Potential Therapeutic Applications in Old Age.

Increasing age is a strong, independent risk factor for atherosclerosis and cardiovascular disease. Key abnormalities driving cardiovascular risk in old age include endothelial dysfunction, increased arterial stiffness, blood pressure, and the pro-atherosclerotic effects of chronic, low-grade, inflammation. The identification of novel therapies that comprehensively target these alterations might lead to a major breakthrough in cardiovascular risk management in the older population. Systematic reviews and meta-analyses of observational studies have shown that methotrexate, a first-line synthetic disease-modifying anti-rheumatic drug, significantly reduces cardiovascular morbidity and mortality in patients with rheumatoid arthritis, a human model of systemic inflammation, premature atherosclerosis, and vascular aging. We reviewed in vitro and in vivo studies investigating the effects of methotrexate on endothelial function, arterial stiffness, and blood pressure, and the potential mechanisms of action involved. The available evidence suggests that methotrexate might have beneficial effects on vascular homeostasis and blood pressure control by targeting specific inflammatory pathways, adenosine metabolism, and 5' adenosine monophosphate-activated protein kinase. Such effects might be biologically and clinically relevant not only in patients with rheumatoid arthritis but also in older adults with high cardiovascular risk. Therefore, methotrexate has the potential to be repurposed for cardiovascular risk management in old age because of its putative pharmacological effects on inflammation, vascular homeostasis, and blood pressure. However, further study and confirmation of these effects are essential in order to adequately design intervention studies of methotrexate in the older population.

New horizons in arginine metabolism, ageing and chronic disease states.

The elucidation of the metabolic pathways of the amino acid arginine and their role in health and disease have been an intensive focus of basic and clinical research for over a century. The recent advent of robust analytical techniques for biomarker assessment in large population cohorts has allowed the investigation of the pathophysiological role of specific arginine metabolites in key chronic disease states in old age, particularly those characterised by a reduced synthesis of endothelial nitric oxide, with consequent vascular disease and atherosclerosis. Two arginine metabolites have been increasingly studied in regard to their potential role in risk stratification and in the identification of novel therapeutic targets: the methylated arginine asymmetric dimethylarginine (ADMA) and the arginine analogue homoarginine. Higher circulating concentrations of ADMA, a potent inhibitor of nitric oxide synthesis, have been shown to predict adverse cardiovascular outcomes. By contrast, there is emerging evidence that homoarginine might exert cardioprotective effects. This review highlights recent advances in the biological and clinical role of ADMA and homoarginine in cardiovascular disease and other emerging fields, particularly chronic obstructive pulmonary disease, dementia, and depression. It also discusses opportunities for future research directions with the ultimate goal of translating knowledge of arginine metabolism, and its role in health and disease, into the clinical care of older adults.