Left and right ventricular function by echocardiography, tissue doppler imaging, carotid intima media thickness, and asymmetric dimethylarginine levels in female adolescents with vitamin D deficiency.

BACKGROUND: The aim of our study was to assess left and right ventricle systolic and diastolic functions in female adolescents with vitamin D deficiency using conventional echocardiography and pulsed-wave tissue Doppler imaging and to investigate carotid intima media thickness and asymmetric dimethylarginine levels. METHODS: Sixty-six female adolescents were enrolled in this study. The female adolescents were divided into a vitamin D deficiency group (n: 34) and a control group (n: 32). All subjects underwent laboratory blood tests, including asymmetric dimethyl arginine, complete two-dimensional, pulse, and tissue Doppler echocardiography, and measurement of the carotid intima-media thickness. RESULTS: The vitamin D-deficient female adolescent group had normal left and right ventricle systolic and diastolic functions and normal global systolic and diastolic myocardial performance. In the patients with vitamin D deficiency, the carotid intima-media thickness was higher than that in the controls. In the patients within the vitamin D deficiency group, vitamin D was found to be positively correlated with magnesium and negatively correlated with phosphorus and left atrial dimension. CONCLUSIONS: The results of this study demonstrate that vitamin D deficiency in female adolescence is associated with normal myocardial geometry and function. Although it has been associated with normal levels of asymmetric dimethyl arginine concentration, high measured carotid intima-media thickness may reflect endothelial dysfunction.

Association of Umbilical Cord Serum Oxidative Stress Markers, ADMA and Adiponectin with Adverse Fetal Outcomes in Hypertensive Disorders of Pregnancy.

BACKGROUND: Limited studies are available on fetal oxidative stress and endothelial dysfunction and their association with adverse fetal outcomes in hypertensive disorders of pregnancy (HDP). Method: Umbilical cord blood samples were collected at delivery from 134 pregnant women with HDP and 59 controls. Markers of oxidative stress, endothelial dysfunction and inflammation and adipokines were analyzed. Results were correlated with adverse fetal outcomes. Results: Malondialdehyde, total antioxidant status(TAS), ADMA and hsCRP levels were increased in late and early onset preeclampsia. Adiponectin levels were decreased in early onset preeclampsia. High ADMA levels were positively associated with preterm births and fetal mortality and high TAS, protein carbonyl content(PC), ADMA and low adiponectin levels were positively associated with low birth weight babies. Conclusion: Fetal systemic oxidative stress, endothelial dysfunction and inflammation were altered in early and late onset preeclampsia. High TAS, PC and ADMA levels and low adiponectin levels were positively associated with adverse fetal outcomes in HDP.

[Curcumin improves cardiac fibrosis by inhibiting endothelial-mesenchymal transition through NRF2-DDAH-ADMA-NO pathway].

The present study analyzed the correlations between curcumin(Cur), nuclear factor E2 related factor 2(NRF2)-dimethylarginine dimethylaminohydrolase(DDAH)-asymmetric dimethylarginine(ADMA)-nitric oxide(NO) pathway, and endothelial-mesenchymal transition(EndMT) based on SD rats with cardiac fibrosis, and explored the effect and mechanism of Cur in resisting cardiac fibrosis to provide an in-depth theoretical basis for its clinical application in the treatment of heart failure. The cardiac fibrosis model was induced by subcutaneous injection of isoprenaline(Iso) in rats. Thirty-two rats were randomly divided into a control group, a model group, a low-dose Cur group(100 mg·kg~(-1)·d~(-1)), and a high-dose Cur group(200 mg·kg~(-1)·d~(-1)), with eight in each group. After 21 days of treatment, cardiac function was detected by echocardiography, degree of cardiac fibrosis by Masson staining, expression of CD31 and α-SMA by pathological staining, expression of VE-cadherin, vimentin, NRF2, and DDAH by Western blot, and ADMA level by HPLC. Compared with the model group, the Cur groups showed alleviated cardiac fibrosis, accompanied by increased CD31 and VE-cadherin expression and decreased α-SMA and vimentin expression, indicating relieved EndMT. Additionally, DDAH and NRF2 levels were elevated and ADMA and NO expression declined. Cur improves cardiac fibrosis by inhibiting EndMT presumedly through the NRF2-DDAH-ADMA-NO pathway.

Antepartum and postpartum changes in adipokines, endothelial dysfunction, inflammatory markers and other biochemical parameters in preeclamptic women: A prospective observational cohort study.

This study aimed at evaluating the role played by insulin resistance, lipid metabolism disorder, oxidative stress, resistin, vaspin, Interleukin-18 and asymmetric dimethyl arginine as a marker for endothelial dysfunction in the pathogenesis of preeclampsia. This prospective observational cohort study involved 60 women who were classified into: 20 non-pregnant women (group 1 or control group), 20 normally pregnant women (group 2) and 20 preeclamptic women (group 3) at their third trimester. The pregnant women were assessed at their third trimester and further re-evaluated four weeks after delivery. The assessment included demography, assessment of proteinuria and urinary protein to creatinine ratio, blood pressure measurement and assessment of fasting blood glucose, fasting insulin level, lipid panel and the circulating levels of malondialdehyde, resistin, vaspin, interleukin-18 and asymmetric dimethyl arginine. Preeclamptic women showed more atherogenic lipid profile, significantly higher Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and significantly elevated levels of malondialdehyde, resistin, vaspin and interleukin-18 than the other study groups. Serum asymmetric dimethyl arginine concentration showed non-significant difference among the three study groups. The levels of resistin and vaspin showed significant decrease four weeks postpartum in preeclamptic group. We concluded that, preeclampsia was associated with insulin resistance, dyslipidemia, oxidative stress, inflammation and significant changes in adipokines; resistin and vaspin. Furthermore, the significant increase in the serum levels of resistin and vaspin at the third trimester and their significant decline four weeks postpartum in preeclamptic group focus the attention on the role played by these adipokines in the pathogenesis of preeclampsia.

Reduced endothelial nitric oxide synthase activation contributes to cardiovascular injury during chronic kidney disease progression.

Major cardiovascular events are a common complication in patients with chronic kidney disease (CKD). Endothelial dysfunction can contribute to the cardiovascular injury observed in CKD. Here, we used a rat model of acute kidney injury to CKD transition to investigate heart alterations in the pathway activating endothelial nitric oxide synthase (eNOS) and its impact on the cardiac injury observed during CKD progression. Fifty male Wistar rats were subjected to sham surgery (n = 25) or bilateral renal ischemia-reperfusion (IR-CKD) for 45 min (n = 25). Rats were studied on a monthly basis up to 5 mo (n = 5). In another set of sham and IR-CKD rats, l-arginine was administered starting on the third month after renal ischemia. CKD development and cardiac alterations were monitored in all groups. CKD was characterized by a progressive increase in proteinuria and renal dysfunction that was evident after the fifth month of followup. Heart hypertrophy was observed starting on the fourth month after ischemia-reperfusion. There was a significant increase in brain natriuretic peptide levels. In the heart, IR-CKD rats had increased eNOS phosphorylation at threonine 495 and reduced eNOS-heat shock protein-90α interactions. l-Arginine administration prevented the heart alterations observed during CKD and increased eNOS coupling/dimerization and activation. In summary, CKD progression is accompanied by cardiac hypertrophy, fibrosis, oxidative stress, and increased brain natriuretic peptide levels. These alterations were associated with limited eNOS activation in the heart, which may result in reduced nitric oxide bioavailability and contribute to cardiac injury during CKD.

Left and right ventricular function by echocardiography, tissue Doppler imaging, carotid intima-media thickness, and asymmetric dimethyl arginine levels in obese adolescents with metabolic syndrome.

PurposeThe aim of our study was to assess left ventricle and right ventricle systolic and diastolic functions in obese adolescents with metabolic syndrome using conventional echocardiography and pulsed-wave tissue Doppler imaging and to investigate carotis intima-media thickness, and asymmetric dimethyl arginine levels. METHODS: A total of 198 obese adolescents were enrolled in the study. The obese patients were divided into metabolic syndrome group and non-metabolic syndrome group. All subjects underwent laboratory blood tests, including asymmetric dimethyl arginine, complete two-dimensional, pulsed, and tissue Doppler echocardiography, and measurement of the carotid intima-media thickness. RESULTS: Obese adolescents were characterised by enlarged left end-diastolic, end-systolic and left atrial diameters, thicker left and right ventricular walls compared with non-obese adolescents. The metabolic syndrome group had normal left ventricle systolic function, impaired diastolic function, and altered global systolic and diastolic myocardial performance. In the metabolic syndrome obese group patients, left ventricle mass was found positively correlated with body mass index, waist and hip circumferences, diastolic blood pressure, age, and waist-to-hip circumference ratio. The carotid intima-media thickness was found positively correlated with waist and hip circumferences and total cholesterol levels. Asymmetric dimethyl arginine levels were found positively correlated with systolic blood pressure, waist-to-hip circumference ratio, and diastolic blood pressure. CONCLUSIONS: The results of this study demonstrate that metabolic syndrome in adolescence is associated with significant changes in myocardial geometry and function. In addition, it has been associated with a high level of asymmetric dimethyl arginine concentration and thicker carotid intima-media thickness reflecting endothelial dysfunction.

Utility of time of onset of hypertension, ADMA and TAS in predicting adverse neonatal outcome in hypertensive disorders of pregnancy.

Background: Limited studies have been conducted to evaluate the utility of indices for the prediction of the adverse neonatal outcomes in hypertensive disorders of pregnancy (HDP).Method: A total of 174 pregnant women with HDP (gestational hypertension, late onset preeclampsia, and early onset preeclampsia) and 49 controls were sampled during the third trimester. Preterm birth, low birth weight, fetal, and infant mortality and low Apgar scores were assessed.Results: Multivariate analysis confirmed systolic blood pressure (SBP), time of onset of hypertension (TOH), and total antioxidant status (TAS) as predictors of preterm births; TOH and diastolic blood pressure (DBP) to be predictors of low birth weight babies; TOH and asymmetric dimethyl arginine (ADMA) as predictors of fetal mortality and babies with low Apgar at 5 min. We found TOH as the single best predictor for adverse neonatal outcomes.Conclusion: This study identified TOH as an important predictor of most of the adverse neonatal outcomes.

Serum ADMA, endothelial dysfunction, and atherosclerosis in hypervolemic hemodialysis patients

Background/aim: Asymmetric dimethyl arginine (ADMA) is a strong predictor of cardiovascular disease and mortality in patients under hemodialysis treatment. We aimed to investigate the relationship among volume status, endothelial dysfunction, and ADMA in hemodialysis patients. Materials and methods: A total of 120 patients with a history of hemodialysis treatment were included. ADMA and CRP were measured. Echocardiographic evaluation and carotid artery intima-media thickness (CIMT) measurements were performed. Patients were divided into two groups according to clinical evaluation, ultrafiltration rate, vena cava inferior diameter (VCI), and cardiothoracic index (CTI); the two groups were hypervolemic and normovolemic. Results: The hypervolemic group included 61 patients while the normovolemic group included 59 patients. CIMT was higher in the hypervolemic group, but this result was not statistically significant (0.95 mm versus 0.85 mm, P = 0.232). There was a statistically significant difference between the hypervolemic and normovolemic groups in terms of ADMA (P < 0.001) (0.69 ± 0.57 µmol/L and 0.41 ± 0.04 µmol/L, respectively). Positive correlations were observed between serum ADMA, VCI, CTI, CRP, CIMT, and cardiac mass (P < 0.001, P = 0.016, P < 0.001, P = 0.006, P = 0.022, respectively), and negative correlations were observed between ADMA and ejection fraction and albumin (P = 0.024, P = 0.024, respectively). In multiple linear regression analysis, ADMA was independently associated with age, systolic blood pressure, CTI, and volume status. Conclusion: ADMA may be a potential determinant of hypervolemia as well as atherosclerosis in patients under hemodialysis treatment.

Renin-angiotensin system blockade promotes a cardio-renal protection in albuminuric homozygous sickle cell patients.

The management of sickle cell nephropathy (SCN) at an early stage is an important issue to prevent renal and cardiovascular morbidity and mortality. This study aimed to evaluate in this population, whether angiotensin converting enzyme inhibitors (ACEIs) treatment could exert a cardio-renal protection in a SCN cohort. Forty-two SCN patients (urine albumin:creatinine ratio (ACR) > 10 mg/mmol) were treated with ACEIs for 6 months, then evaluated for ACR, measured glomerular filtration rate (mGFR) together with haematological and cardiovascular parameters. A 1-month washout was also performed in order to differentiate short- and long-term ACEIs effects. A decrease in ACR baseline value (>30%) was detected in 62% of cases (mean ACR: 46·4 ± 7·6 and 26·4 ± 3·9 mg/mmol at baseline and 6 months respectively; P = 0·002), whereas mGFR values were unchanged. ACR decrease was detected at 1 month following ACEI initiation (32·9 ± 6·9, P = 0·02) with a persistent trend after withdrawal (P = 0·08). ACEIs also decreased diastolic blood pressure (P = 0·007), pulse wave velocity (P = 0·01), tricuspid regurgitation velocity (TRV; P = 0·04), asymmetric dimethyl arginine (ADMA: P = 0·001) and haemoglobin (P = 0·01) while conventional haemolytic biomarkers were unchanged. Our data suggest that ACEIs are safe and effective at decreasing albuminuria in sickle cell patients with a beneficial effect on specific mortality risk factors, such as TRV and asymmetric dimethyl arginine.

l-citrulline prevents asymmetric dimethylarginine-mediated reductions in nitric oxide and nitrosative stress in primary human airway epithelial cells.

BACKGROUND: Asthma is associated with reduced systemic levels of l-arginine and increased asymmetric dimethylarginine (ADMA). This imbalance leads to nitric oxide synthase (NOS) uncoupling with reduced nitric oxide (NO) formation and greater oxidative and nitrosative stress. Whether this imbalance also occurs in bronchial epitheliumof asthmatics is unknown. OBJECTIVES: We used primary human bronchial epithelial cells (HBECs) from asthmatics and healthy controls to evaluate: (i) ADMA-mediated NOS uncoupling reduces epithelial production of NO and increases oxygen and nitrogen reactive species, and (ii) l-citrulline can reverse this mechanism by recoupling NOS, restoring NO production and reducing oxidative and nitrosative stress. RESULTS: In HBECsIL-13 and INFγ stimulated NOS2 and increased NOx levels. The addition of ADMA reduced NOx and increased H2 O2 levels (p<0.001). Treatment with l-citrulline (800, 1600 µm) rescued NOx when the l-arginine media concentration was 25 µm but failed to do so with higher concentrations (100 µm). Under reduced l-arginine media conditions, HBECs treated with l-citrulline increased the levels of argininosuccinate, an enzyme that metabolizes l-citrulline to l-arginine. l-citrulline prevented the ADMA-mediated increase in nitrotyrosine in HBECs in cells from asthmatics and controls. CONCLUSIONS AND CLINICAL RELEVANCE: Increasing ADMA reduces NO formation and increases oxidative and nitrosative stress in airway epithelial cells. l-citrulline supplementation restores NO formation, while preventing nitrosative stress. These results, suggest that l-citrulline supplementation may indeed be a powerful approach to restore airway NO production and may have a therapeutic potential in diseases in which there is a defective production of NO.

Redox Signaling and Persistent Pulmonary Hypertension of the Newborn.

Reactive oxygen species (ROS) are redox-signaling molecules that are critically involved in regulating endothelial cell functions, host defense, aging, and cellular adaptation. Mitochondria are the major sources of ROS and important sources of redox signaling in pulmonary circulation. It is becoming increasingly evident that increased mitochondrial oxidative stress and aberrant signaling through redox-sensitive pathways play a direct causative role in the pathogenesis of many cardiopulmonary disorders including persistent pulmonary hypertension of the newborn (PPHN). This chapter highlights redox signaling in endothelial cells, antioxidant defense mechanism, cell responses to oxidative stress, and their contributions to disease pathogenesis.

Paraoxonase-1 and myeloperoxidase correlate with vascular biomarkers in overweight patients with newly diagnosed untreated hyperlipidaemia.

BACKGROUND: In hyperlipidaemic state, increased levels of myeloperoxidase (MPO) and decreased paraoxonase-1 (PON1) activity have been reported; however, their relationships with other atherosclerotic biomarkers have not been completely clarified. PATIENTS AND METHODS: Serum concentrations of lipid and inflammatory parameters, MPO levels, and PON1 activities were investigated in 167 untreated hyperlipidaemic patients with and without vascular complications and in 32 healthy controls. Additionally, levels of CD40 ligand (sCD40L) and asymmetric dimethyl arginine (ADMA), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, and oxidized LDL were determined. RESULTS: We found elevated C-reactive protein (CRP), ADMA, sCD40L, sICAM-1 concentrations, and higher MPO levels in patients with vascular complications compared to those without. The PON1 arylesterase activity correlated negatively with sCD40L, ADMA, and sICAM-1 levels, respectively. In contrast, MPO concentrations showed positive correlations with sCD40L, ADMA, and sICAM-1 levels, respectively. CONCLUSIONS: It can therefore be stated that PON1 activity and MPO level correlate strongly with the vascular biomarkers, highlighting the importance of the HDL-associated pro- and antioxidant enzymes in the development of endothelial dysfunction and atherogenesis.

Association between endothelial and platelet function markers and adiponectin in renal transplanted recipients on cyclosporine and tacrolimus immunosuppression based therapy.

AIM: Coagulation abnormalities, endothelial dysfunction and arteriosclerosis play a key role in cardiovascular disease state observed in transplanted patients. Plasma adiponectin levels are lower following kidney transplantation. However, there is still a debate about this topic in the literature. This study evaluated, adiponectin levels associated with markers of endothelial dysfunction and platelet function in renal transplant patients. METHODS: Sixty-six renal transplant patients were studied. Patients were grouped according to immunosuppression regimen. Group 1 (n = 36) were treated with cyclosporine A based regimes and group 2 (n = 30) were treated with tacrolimus based regimes. Plasma adiponectin, asymmetric dimethyl arginine (ADMA), sP-selectin levels and platelet aggregation tests were studied and were compared with those in control group (n = 15, group 3). RESULTS: Adiponectin, sP-selectin and ADMA levels were higher in group 1 and statistically significant differences were observed compared with those of group 2 and group 3, respectively (P < 0.001, P < 0.05, P < 0.05). Platelet aggregation values induced by agonists were lower in group 1 than group 2 and group 3, but the difference did not reach statistical significance (P > 0.05). CONCLUSION: Adiponectin levels are elevated in line with ADMA and sP-selectin levels. Since CsA induces higher adiponectin levels, platelet activation and endothelial dysfunction. These changes may be responsible for the increased risk of post-transplant cardiovascular events in renal transplant patients.

Relationship between Dietary Approaches to Stop Hypertension score and Alternative Healthy Eating Index score with plasma asymmetrical dimethylarginine levels in patients referring for coronary angiography.

BACKGROUND: Asymmetrical dimethyl arginine (ADMA) is a competitive inhibitor in the production of nitric oxide (NO) from arginine and NO plays an important role in the preservation of vascular dilation. Elevated ADMA is a strong predictive factor for coronary artery disease (CAD). Dietary Approaches to Stop Hypertension (DASH) and Alternative Healthy Eating Index (AHEI) patterns contain factors that may influence plasma ADMA levels. The present study examined the association between the DASH score and AHEI score with plasma ADMA concentration in people with suspected heart disease selected for coronary angiography. METHODS: This cross-sectional study was conducted in 148 people aged 40-80 years who were referred for coronary angiography. The DASH diet score and AHEI score were calculated for each individual based on food groups. Plasma ADMA levels were measured by high-performance liquid chromatography. RESULTS: ADMA concentrations were higher in the CAD group compared to the non-CAD group [0.98 (0.37) µmol L(-1) compared to 0.84 (0.42) µmol L(-1) ; P = 0.02]. There was a significant negative association between the quartile DASH score and ADMA concentration (standardised ß = -0.172, P = 0.038). The ADMA concentration was lower in patients who were at the highest quartile of DASH score compared to patients with the lowest quintile score. The ADMA concentration and quartiles of AHEI score were not significantly associated. CONCLUSIONS: Higher scores of the DASH diet are associated with lower plasma ADMA levels and with reduced coronary artery stenosis.

Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis.

Chronic inflammatory diseases such as rheumatoid arthritis (RA) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Since tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti-TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA. Our results suggest a possible effect of anti-TNF drugs on ADMA serum levels; longer studies would be necessary to confirm the role ADMA in assessing cardiovascular risk in RA.

Stimulated nitric oxide production and arginine deficiency in children with cystic fibrosis with nutritional failure.

OBJECTIVE: To determine whether upregulated whole body de novo arginine synthesis and protein breakdown are present as a compensatory mechanism to meet the increased demand for arginine and nitric oxide (NO) production in pediatric patients with cystic fibrosis (CF) and nutritional failure. STUDY DESIGN: In 16 children with CF, studied at the end of antibiotic treatment for a pulmonary exacerbation, and 17 healthy controls, whole body arginine, citrulline (Cit), and protein turnover were assessed by stable isotope methodology and de novo arginine synthesis, arginine clearance, NO synthesis, protein synthesis and breakdown, and net protein balance were calculated. The plasma isotopic enrichments and amino acid concentrations were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Increased arginine clearance was found in patients with CF (P < .001), whereas whole body NO production rate and plasma arginine levels were not different. Whole body arginine production (P < .001), de novo arginine synthesis, and protein breakdown and synthesis (P < .05) were increased in patients with CF, but net protein balance was comparable. Patients with CF with nutritional failure (n = 7) had significantly higher NO production (P < .05), de novo arginine synthesis, Cit production (P < .001), and plasma Cit concentration (P < .05) and lower plasma arginine concentration (P < .05) than those without nutritional failure (n = 9). CONCLUSIONS: Nutritional failure in CF is associated with increased NO production. However, up-regulation of de novo arginine synthesis and Cit production was not sufficient to meet the increased arginine needs leading to arginine deficiency.

Asymmetric and symmetric dimethylarginine in high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE).

Introduction: High altitude exposure may lead to high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE). The pathophysiologic processes of both entities have been linked to decreased nitric oxide (NO) availability. Methods: We studied the effect of acute high altitude exposure on the plasma concentrations of asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-arginine, L-ornithine, and L-citrulline in two independent studies. We further investigated whether these biomarkers involved in NO metabolism were related to HAPH and HAPE, respectively. Fifty (study A) and thirteen (study B) non-acclimatized lowlanders were exposed to 4,559 m for 44 and 67 h, respectively. In contrast to study A, the participants in study B were characterized by a history of at least one episode of HAPE. Arterial blood gases and biomarker concentrations in venous plasma were assessed at low altitude (baseline) and repeatedly at high altitude. HAPE was diagnosed by chest radiography, and HAPH by measuring right ventricular to atrial pressure gradient (RVPG) with transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and the AMS-C score. Results: In both studies SDMA concentration significantly increased at high altitude. ADMA baseline concentrations were higher in individuals with HAPE susceptibility (study B) compared to those without (study A). However, upon high altitude exposure ADMA only increased in individuals without HAPE susceptibility, while there was no further increase in those with HAPE susceptibility. We observed an acute and transient decrease of L-ornithine and a more delayed but prolonged reduction of L-citrulline during high altitude exposure. In both studies SDMA positively correlated and L-ornithine negatively correlated with RVPG. ADMA was significantly associated with the occurrence of HAPE (study B). ADMA and SDMA were inversely correlated with alveolar PO2, while L-ornithine was inversely correlated with blood oxygenation and haemoglobin levels, respectively. Discussion: In non-acclimatized individuals ADMA and SDMA, two biomarkers decreasing endothelial NO production, increased after acute exposure to 4,559 m. The observed biomarker changes suggest that both NO synthesis and arginase pathways are involved in the pathophysiology of HAPH and HAPE.

Biomarkers of the L-Arginine/Dimethylarginine/Nitric Oxide Pathway in People with Chronic Airflow Obstruction and Obstructive Sleep Apnoea.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea (OSA) are common chronic diseases that are associated with chronic and intermittent hypoxemia, respectively. Patients affected by the overlap of COPD and OSA have a particularly unfavourable prognosis. The L-arginine/nitric oxide (NO) pathway plays an important role in regulating pulmonary vascular function. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) interfere with NO production. METHODS: We analysed the serum concentrations of ADMA, SDMA, L-arginine, L-citrulline, and L-ornithine in a large sample of the Icelandic general population together with chronic airflow obstruction (CAO), a key physiological marker of COPD that was assessed by post-bronchodilator spirometry (FEV1/FVC < LLN). OSA risk was determined by the multivariable apnoea prediction (MAP) index. RESULTS: 713 individuals were analysed, of whom 78 (10.9%) showed CAO and 215 (30%) had MAP > 0.5. SDMA was significantly higher in individuals with CAO (0.518 [0.461-0.616] vs. 0.494 [0.441-0.565] µmol/L; p = 0.005), but ADMA was not. However, ADMA was significantly associated with decreasing FEV1 percent predicted among those with CAO (p = 0.002). ADMA was 0.50 (0.44-0.56) µmol/L in MAP ≤ 0.5 versus 0.52 (0.46-0.58) µmol/L in MAP > 0.5 (p = 0.008). SDMA was 0.49 (0.44-0.56) µmol/L versus 0.51 (0.46-0.60) µmol/L, respectively (p = 0.004). The highest values for ADMA and SDMA were observed in individuals with overlap of CAO and MAP > 0.5, which was accompanied by lower L-citrulline levels. CONCLUSIONS: The plasma concentrations of ADMA and SDMA are elevated in COPD patients with concomitant intermittent hypoxaemia. This may account for impaired pulmonary NO production, enhanced pulmonary vasoconstriction, and disease progression.

Effects of RIPC on the Metabolomical Profile during Lower Limb Digital Subtraction Angiography: A Randomized Controlled Trial.

Remote ischemic preconditioning (RIPC) has demonstrated protective effects in patients with lower extremity arterial disease (LEAD) undergoing digital subtraction angiography (DSA) and/or percutaneous transluminal angioplasty (PTA). This study aimed to investigate the impact of RIPC on the metabolomical profile of LEAD patients undergoing these procedures and to elucidate its potential underlying mechanisms. A total of 100 LEAD patients were enrolled and randomly assigned to either the RIPC group (n = 46) or the sham group (n = 54). Blood samples were drawn before and 24 h after intervention. Targeted metabolomics analysis was performed using the AbsoluteIDQ p180 Kit, and changes in metabolite concentrations were compared between the groups. The RIPC group demonstrated significantly different dynamics in nine metabolites compared to the sham group, which generally showed a decrease in metabolite concentrations. The impacted metabolites included glutamate, taurine, the arginine-dimethyl-amide-to-arginine ratio, lysoPC a C24:0, lysoPC a C28:0, lysoPC a C26:1, PC aa C38:1, PC ae C30:2, and PC ae C44:3. RIPC exhibited a 'stabilization' effect, maintaining metabolite levels amidst ischemia-reperfusion injuries, suggesting its role in enhancing metabolic control. This may improve outcomes for LEAD patients. However, additional studies are needed to definitively establish causal relationships among these metabolic changes.

Arginine Therapy for Lung Diseases.

Nitric oxide (NO) is produced by a family of isoenzymes, nitric oxide synthases (NOSs), which all utilize L-arginine as substrate. The production of NO in the lung and airways can play a number of roles during lung development, regulates airway and vascular smooth muscle tone, and is involved in inflammatory processes and host defense. Altered L-arginine/NO homeostasis, due to the accumulation of endogenous NOS inhibitors and competition for substrate with the arginase enzymes, has been found to play a role in various conditions affecting the lung and in pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, and bronchopulmonary dysplasia. Different therapeutic strategies to increase L-arginine levels or bioavailability are currently being explored in pre-clinical and clinical studies. These include supplementation of L-arginine or L-citrulline and inhibition of arginase.