ADMA Levels Research Articles

SGLT2 inhibition improves coronary flow velocity reserve and contractility: role of glucagon signaling.

SGLT2 inhibitors, a T2DM medication to lower blood glucose, markedly improve cardiovascular outcomes but the underlying mechanism(s) are not fully understood. SGLT2i's produce a unique metabolic pattern by lowering blood glucose without increasing insulin while increasing ketone body and glucagon levels and reducing body weight. We tested if glucagon signaling contributes to SGLT2i induced improvement in CV function. Cardiac contractility and coronary flow velocity reserve (CFVR) were monitored in ob/ob mice and rhesus monkeys with metabolic syndrome using echocardiography. Metabolic status was characterized by measuring blood ketone levels, glucose tolerance during glucose challenge and Arg and ADMA levels were measured. Baysian models were developed to analyse the data. Dapagliflozin improved CFVR and contractility, co-application of a glucagon receptor inhibitor (GcgRi) blunted the effect on CFVR but not contractility. Dapagliflozin increased the Arg/ADMA ratio and ketone levels and co-treatment with GcgRi blunted only the Dapagliflozin induced increase in Arg/ADMA ratio but not ketone levels. Since GcgRi co-treatment only reduced the Arg/ADMA increase we hypothesize that dapagliflozin via a glucagon-signaling dependent pathway improves vascular function through the NO-signaling pathway leading to improved vascular function. Increase in ketone levels might be a contributing factor in SGLT2i induced contractility increase and does not require glucagon signaling.

Elevated plasma level of arginine and its metabolites at labor among women with preeclampsia: A prospective cohort study.

Preeclampsia complicates 3-5% of all pregnancies and is associated with higher levels of asymmetric (ADMA) and symmetric (SDMA) dimethylarginines. Dimethylarginines are inhibitors of nitric oxide, which is a uterine smooth muscles relaxant. Women with hypertensive disorders experience a shorter labor duration compared to normotensive women. However, very little is known about the possible biochemical mechanisms behind differences in labor duration. In this study we aimed to investigate if women with preeclampsia had higher levels of arginines (ADMA, SDMA and L-arginine) at labor than controls, and also investigate the association between arginines and labor duration. The study was based on data from the Swedish, Uppsala County population-based, prospective cohort BASIC, between 2009 and 2018. Arginines were analyzed by Ultra-High Performance Liquid Chromatography using plasma samples taken at labor from women with preeclampsia (n=47) and normotensive pregnancy (n=90). We also analyzed inflammation markers CRP, TNF-R1, TNF-R2 and GDF-15. Women with preeclampsia had higher levels of ADMA (p<0.001), SDMA (p<0.001), L-arginine (p<0.001), TNF-R1 (p<0.001), TNF-R2 (p=0.03) and GDF-15 (p<0.01) compared to controls. Further, ADMA and SDMA, not inflammation markers, were negatively correlated to labor duration in preeclampsia. No correlations were observed when comparing arginines and inflammation markers. Among women with preeclampsia, our novel findings of higher level of arigines, negative correlation of arginines to duration of labor and absence of correlation of arginines to inflammation markers might support the theory that it is not inflammation but arginines which could be associated with shorter duration of labor in preeclampsia.

Asymmetric dimethylarginine serum concentration in normal weight and obese CKD patients treated with hemodialysis

IntroductionAsymmetric dimethylarginine (ADMA), a cardiovascular risk factor, increases in renal failure. The aim of this study was to investigate ADMA levels in normal weight and obese patients on hemodialysis.MethodsIn this cross-sectional study, 43 normal weight and 43 obese patients on regular hemodialysis were examined. Malnutrition-inflammation score (MIS), anthropometry, circulating ADMA, lipid profiles including triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipid ratios, glucose homeostasis parameters, blood pressure, and high-sensitivity C-reactive protein (hs-CRP) were assessed.ResultsSerum levels of ADMA were significantly lower in the obese compared to the normal weight patients (10268.2 ± 10092.4 vs. 13765.2 ± 9951.3 ng/l, P = 0.03). At the same time MIS score (6.1 ± 2.4 vs. 10.7 ± 3.2, P < 0.001), systolic blood pressure (119 ± 26.8 vs. 134.2 ± 24.7 mmHg, P = 0.018) and mean arterial pressure (91.3 ± 18.6 vs. 100.9 ± 15.9 mmHg, P = 0.028) were significantly lower in the obese than the normal weight group. Fasting blood glucose (P = 0.045), TG/HDL (P = 0.03), TC/HDL (P = 0.019), and LDL/HDL (P = 0.005) ratios, and hs-CRP (P = 0.015) levels were significantly higher in the obese than in the normal weight group.ConclusionCirculating ADMA was significantly lower in obese than in normal weight patients on hemodialysis, which was concomitant with lower MIS, indicating a better nutritional inflammatory status, and lower blood pressure.

Symmetric Dimethylarginine Predicts Previously Undetected Atrial Fibrillation in Patients With Ischemic Stroke.

Atrial fibrillation (AF) is a stroke risk factor that often remains undetected at hospital admission. Long-term Holter monitoring helps to identify patients with previously unrecognized AF. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are elevated in AF in cross-sectional studies. We analyzed ADMA, SDMA, and other L-arginine metabolites to assess their association with AF in the Find-AF trial. We included 280 patients presenting with acute cerebral ischemia. Patients presenting in sinus rhythm received 7-day Holter-ECG. Biomarkers were quantified by ultra-performance liquid chromatography-tandem mass spectrometry. We also analyzed protein methylation and L-arginine-related metabolites in human induced pluripotent stem cell-derived cardiomyocytes invitro. ADMA and SDMA were elevated in 44 patients who presented with AF. SDMA, but not ADMA, was significantly elevated in patients newly diagnosed with AF in Holter-ECG as compared with those in sinus rhythm. SDMA plasma concentration >0.571 μmol/L significantly predicted presence of AF in Holter-ECG (area under the curve=0.676 [0.530-0.822]; P=0.029; sensitivity 0.786, specificity 0.572). SDMA levels further increased in patients with AF during the first 24 hours in hospital, and ADMA levels remained stable. Invitro, induced pluripotent stem cell-derived cardiomyocytes showed increased symmetric protein methylation and elevated SDMA during rapid pacing (2.0 Hz versus 0.5 Hz), whereas asymmetric protein methylation and ADMA were unchanged. SDMA at admission was significantly elevated in stroke patients presenting with AF and showed a moderate but significant prospective association with previously unrecognized AF. Thus, stroke patients with elevated SDMA concentration at admission may specifically benefit from extended Holter-ECG monitoring.

Levels of asymmetric dimethylarginine in plasma and aqueous humor: a key risk factor for the severity of fibrovascular proliferation in proliferative diabetic retinopathy.

Proliferative diabetic retinopathy (PDR) is a common diabetes complication, significantly impacting vision and quality of life. Previous studies have suggested a potential link between arginine pathway metabolites and diabetic retinopathy (DR). Connective tissue growth factor (CTGF) plays a role in the occurrence and development of fibrovascular proliferation (FVP) in PDR patients. However, the relationship between arginine pathway metabolites and FVP in PDR remains undefined. This study aimed to explore the correlation between four arginine pathway metabolites (arginine, asymmetric dimethylarginine[ADMA], ornithine, and citrulline) and the severity of FVP in PDR patients. In this study, plasma and aqueous humor samples were respectively collected from 30 patients with age-related cataracts without diabetes mellitus (DM) and from 85 PDR patients. The PDR patients were categorized as mild-to-moderate or severe based on the severity of fundal FVP. The study used Kruskal-Wallis test to compare arginine, ADMA, ornithine, and citrulline levels across three groups. Binary logistic regression identified risk factors for severe PDR. Spearman correlation analysis assessed associations between plasma and aqueous humor metabolite levels, and between ADMA and CTGF levels in aqueous humor among PDR patients. ADMA levels in the aqueous humor were significantly greater in patients with severe PDR than in those with mild-to-moderate PDR(P=0.0004). However, the plasma and aqueous humor levels of arginine, ornithine, and citrulline did not significantly differ between mild-to-moderate PDR patients and severe PDR patients (P>0.05). Binary logistic regression analysis indicated that the plasma (P=0.01) and aqueous humor (P=0.006) ADMA levels in PDR patients were risk factors for severe PDR. Furthermore, significant correlations were found between plasma and aqueous humor ADMA levels (r=0.263, P=0.015) and between aqueous humor ADMA and CTGF levels (r=0.837, P<0.001). Elevated ADMA levels in plasma and aqueous humor positively correlate with the severity of FVP in PDR, indicating ADMA as a risk factor for severe PDR.

Elevated Plasma Levels of Arginines During Labor Among Women with Spontaneous Preterm Birth: A Prospective Cohort Study.

Preterm birth (PTB) is a leading cause of infant mortality and morbidity. The pathogenesis of PTB is complex and involves many factors, including socioeconomy, inflammation and infection. Asymmetric dimethylarginine, ADMA and symmetric dimethylarginine, SDMA are involved in labor as inhibitors of nitric oxide, a known relaxant of the uterine smooth muscles. Arginines are scarcely studied in relation to PTB and we aimed to investigate arginines (ADMA, SDMA and L-arginine) in women with spontaneous PTB and term birth. The study was based on data from the population-based, prospective cohort BASIC study conducted in Uppsala County, Sweden, between September 2009 and November 2018. Arginines were analyzed by Ultra-High Performance Liquid Chromatography using plasma samples taken at the onset of labor from women with spontaneous PTB (n = 34) and term birth (n = 45). We also analyzed the inflammation markers CRP, TNF-R1 and TNF-R2 and GDF-15. Women with spontaneous PTB had higher plasma levels of ADMA (p<0.001), and L-Arginine (p = 0.03). In addition, inflammation marker, TNF-R1 (p = 0.01) was higher in spontaneous PTB compared to term birth. Further, in spontaneous PTB, no significant correlations could be observed when comparing levels of arginines with inflammation markers, except ADMA versus CRP. These findings provide novel evidence for the potential involvement of arginines in the pathogenesis of spontaneous PTB and it seems that arginine levels at labor vary independently of several inflammatory markers. Further research is warranted to investigate the potential of arginines as therapeutic targets in the prevention and management of spontaneous PTB.

Association between protein arginine N-methyltransferase 1 polymorphism and overt diabetic nephropathy: Role of asymmetric dimethylarginine in vascular tone

Backgroundω-NG,NG-asymmetric dimethylarginine (ADMA) regulates vascular tone and may participate in the pathogenesis of diabetic nephropathy (DN). ObjectiveTo investigate whether single-nucleotide polymorphisms (SNPs) around the protein arginine N-methyltransferase 1 gene (PRMT1) influence ADMA dynamics and DN incidence and severity. MethodsThis study utilized a hospital-based database containing 310 Japanese patients with type 2 diabetes mellitus (T2DM). The association of PRMT1-related tagged SNPs with DN stage distribution was examined using a dominant model of minor alleles. PRMT1 mRNA, serum ADMA, reactive hyperemia-peripheral arterial tonometry index (RHI), and brachial-ankle pulse wave velocity (baPWV) were compared between the genotype-based subgroups of causal SNP, and correlations between these variables were evaluated. ResultsThe composition of DN stages significantly differed between the GG and GA + AA subgroups of rs892151 (p = 0.026). In a propensity-matching cohort of rs892151, the GA + AA subgroup had an increased incidence of overt DN (odds ratio 2.92, 95 % confidence interval 1.12–7.62, p = 0.028), along with higher PRMT1 mRNA, serum ADMA levels, and baPWV than the GG subgroup (p < 0.001, p = 0.023 and 0.047, respectively). There were correlations between PRMT1 mRNA and serum ADMA levels, between serum ADMA levels and RHI, and between baPWV and urinary albumin excretion (r = 0.335, p < 0.001, r = -0.221, p = 0.029, and r = 0.254, p = 0.004, respectively). ConclusionsT2DM patients carrying the PRMT1-related variant rs892151 were susceptible to overt DN. ADMA-mediated endothelial dysfunction and arterial stiffness may be involved in the variant-related pathogenesis of overt DN.

Early and late-onset preeclampsia: effects of DDAH2 polymorphisms on ADMA levels and association with DDAH2 haplotypes.

To examine whether the DDAH2 promoter polymorphisms -1415G/A (rs2272592), -1151A/C (rs805304) and -449G/C (rs805305), and their haplotypes, are associated with PE compared with normotensive pregnant women, and whether they affect ADMA levels in these groups. A total of 208 pregnant women were included in the study and classified as early-onset (N=57) or late-onset PE (N =49), and as normotensive pregnant women (N = 102). Pregnant with early-onset PE carrying the GC and GG genotypes for the DDAH2 -449G/C polymorphism had increased ADMA levels (P=0.01). No association of DDAH2 polymorphisms with PE in single-locus analysis was found. However, the G-C-G haplotype was associated with the risk for late-onset PE. It is suggested that DDAH2 polymorphisms could affect ADMA levels in PE, and that DDAH2 haplotypes may affect the risk for PE.

Clinical efficacy and safety of Picamilon in patients with progressive chronic cerebral ischemia

To study the efficacy and safety of the drug Picamilon with various therapy regimens in patients with stage II chronic cerebral ischemia (CCI). An open cohort clinical study involved 50 patients diagnosed with stage II CCI aged 51 to 69 years (average age 62.2±8.98 years). Patients received Picamilon first parenterally 200 mg (100 mg/ml, 2 ml) intravenously for 10 days, then orally in 50 mg tablets 3 times a day for 60 days. The total duration of therapy in the group was 70 days. The study included 3 visits (before treatment, after completion of the course, 1.5 months after completion of treatment). The dynamics of cognitive status according to the Montreal Cognitive Assessment Scale, vegetative disorders according to the A.M. Vane scale, neurological disorders according to the A.I. Fedin scale, and sleep quality according to the Ya. I. Levin scale were compared. The state of cerebral blood flow and endothelium was studied before and after treatment: dopplerography of cranial vessels, assessment of the level of methylated forms of arginine (ADMA, MMA, SDMA) and their ratios. The registration of adverse events against the background of therapy and the tolerability of treatment by patients was also carried out. Against the background of Picamilon treatment, a significant positive dynamics of the MoCA scale results was observed in the general sample of patients, increasing in the delayed period (20.9, 24.6 and 25.9, p<0.0001 and p=0.0006); sleep normalization was observed in 55% of patients by Visit 2 and in 81% of patients by Visit 3 (p<0.0001 and p=0.0025). Improvement of neurological functions is noted in 84% of patients, the score on the Fedin A.I. scale significantly decreases after treatment from 17.4±9.34 to 8.06±6.84 (p<0.0001) and to 5.31±5.71 in the delayed period (p=0.0002). Normalization of vegetative status was observed in 38% of patients with stage II CCI, and in 60% of cases there was a decrease in the severity of vegetative dystonia syndrome (p=0.0001). Picamilon therapy has high efficacy in assessing clinical outcomes (100%), good tolerability in 98% of patients and is characterized by a favorable safety profile (in 92% of patients). Picamilon significantly affects the parameters of cerebral hemodynamics: increases the linear velocity of blood flow, reduces the thickness of the intima-media complex and the resistance index. It affects markers of NO metabolism and endothelial function: significantly reduces elevated levels of ADMA and ADMA/MMA and (ADMA+SDMA)/MMA ratios. The use of Picamilon is effective in patients with stage II CCI in the form of step therapy contributes to a significant regression of neurological deficit, cognitive impairment, improvement of sleep quality and autonomic function; improves vascular endothelial function, reduces the risk of cardiovascular complications. Picamilon is a pathogenetic therapy agent that prevents the progression of CCI.

Schisantherin A protects hepatocyte via upregulating DDAH1 to ameliorate liver fibrosis in mice

BackgroundHepatic fibrosis is the pivotal determinant in the progression of chronic liver diseases towards cirrhosis or advanced stages. Studies have shown that Schisantherin A (Sin A), the primary active compound from Schizandra chinensis (Turcz.) Baill., exhibits anti-hepatic fibrosis effects. However, the mechanism of Sin A in liver fibrosis remain unclear. PurposeTo examine the effects and underlying mechanism of Sin A on hepatic fibrosis. Study design and methodsThe effects and mechanism of Sin A were investigated using liver fibrosis mouse models induced by carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN), as well as H2O2-induced hepatocyte injury in vitro. ResultsSin A treatment ameliorated hepatocyte injury, inflammation, hepatic sinusoidal capillarization, and hepatic fibrosis in both CCl4-induced and DMN-induced mice. Sin A effectively reversed the reduction of DDAH1 expression, the p-eNOS/eNOS ratio and NO generation and attenuated the elevation of hepatic ADMA level induced by CCl4 and DMN. Knockdown of DDAH1 in hepatocytes not only triggered hepatocyte damage, but it also counteracted the effect of Sin A on protecting hepatocytes in vitro. ConclusionOur findings indicate that Sin A ameliorates liver fibrosis by upregulating DDAH1 to protect against hepatocyte injury. These results provide compelling evidence for Sin A treatment in liver fibrosis.

Developmental dynamics of homoarginine, ADMA and SDMA plasma levels from birth to adolescence

Guanidino compounds such as dimethylarginines (SDMA, ADMA) and L-homoarginine ((L-)hArg) can interfere with bioavailability and function of the main NO-donor L-arginine (L-Arg). High ADMA and SDMA but low L-hArg concentrations have been associated with cardio- and cerebrovascular events and mortality in adults. The role of guanidino compounds in paediatric patients remains less clear. We, therefore, compared guanidino compound levels in plasma samples of 57 individuals with chronic kidney disease (CKD) and 141 individuals without CKD from the age of 0 to 17 years, including patients with different comorbidities by correlation and regression analyses. We found highest hArg, SDMA and ADMA concentrations in neonates (Kruskal–Wallis, p < 0.001 for all). From the age of 1 year on, hArg levels increased, whereas SDMA und ADMA levels further decreased in children. SDMA and ADMA are higher in children with CKD independent of GFR (mean factor 1.92 and 1.38, respectively, p < 0.001 for both), and SDMA is strongly correlated with creatinine concentration in children with CKD (Spearman’s rho 0.74, p < 0.001). We provide guanidino compound levels in a large sample covering all paediatric age groups for the first time. Our data can be used to assess the role of guanidino compounds such as hArg in disease states, i.e. cerebro- and cardiovascular disorders in childhood and adolescence.

Plasma levels of arginines at term pregnancy in relation to mode of onset of labor and mode of childbirth.

The exact biochemical mechanisms that initiate labor are not yet fully understood. Nitric oxide is a potent relaxant of uterine smooth muscles until labor starts, and its precursor is L-arginine. Asymmetric (ADMA) and symmetric (SDMA) dimethylarginines, are potent NO-inhibitors. However, arginines (dimethylarginines and L-arginine) are scarcely studied in relation to labor and childbirth. We aimed to investigate arginines in women with spontaneous (SLVB) and induced (ILVB) term labor with vaginal birth and in women undergoing elective caesarean section (ECS). Women at gestational week 16-18 were recruited to the population-based prospective cohort study BASIC at the Uppsala University Hospital, Sweden. Plasma samples taken at start of labor were analyzed for arginines, from SLVB (n=45), ILVB (n=45), and ECS (n=45), using Ultra-High Performance Liquid Chromatography. Between-group differences were assessed using Kruskal-Wallis and Mann-Whitney U-test. Women with SLVB and ILVB had higher levels of ADMA (p<.0001), SDMA (p<.05) and lower L-arginines (p<.01), L-arginine/ADMA (p<.0001), and L-arginine/SDMA (p<.01, respectively <.001) compared to ECS. However, ILVB had higher ADMA (p<.0001) and lower L-arginine (p<.01), L-arginine/ADMA (p<.0001), and L-arginine/SDMA (p<.01) compared to SLVB. Results are adjusted for gestational length at birth and cervical dilatation at sampling. Our novel findings of higher levels of dimethylarginines in term vaginal births compared to ECS give insights into the biochemical mechanisms of labor. These findings might also serve as a basis for further studies of arginines in complicated pregnancies and labor.

Role of Angiopoietic Coronary Endothelial Dysfunction in the Pathogenesis of Ischemic Cardiomyopathy.

The angiopoietic endothelial dysfunction in ischemic cardiomyopathy (ICMP) remains unexplored. The identification of the imbalance of endothelial dysfunction mediators and the number of endothelial progenitor (EPC) and desquamated (EDC) cells in patients with coronary heart disease (CHD) with and without ICMP. A total of 87 patients (47 with ICMP and 40 without ICMP) were observed. The content of EPCs (CD14+CD34+VEGFR2+) in vein blood and EDCs (CD45-CD146+) in the blood from the coronary sinus and cubital vein was determined by flow cytometry. The contents of HIF-1α and HIF-2α in vein blood as well as that of ADMA and endothelin-1 in sinus plasma and angiopoietin-2, MMP-9 and galectin-3 in both samples were assessed using ELISA, and VEGF, PDGF, SDF-1 and MCP-1 contents using immunofluorescence. ADMA and endothelin-1 levels in the sinus blood were comparable between the patient groups; a deficiency of HIF-1α and excess of HIF-2α were detected in the vein blood of ICMP patients. The EDC content in the vein blood increased in CHD patients regardless of ICMP, and the concentrations of VEGF-A, VEGF-B, PDGF, MCP-1, angiopoietin-2, and MMP-9 were normal. In ICMP patients, vein blood was characterized by an excess of galectin-3 and sinus blood by an excess of EDCs, angiopoietin-2, MMP-9 and galectin-3. ICMP is accompanied by angiopoietic endothelial dysfunction.

Study of Homocysteine, SDMA, ADMA, UMOD, AVP, and KIM-1 in serum of chronic renal disease patients suffering from Type-2 diabetes in Basra Province

Chronic kidney disease (CKD) is a reduction in renal function manifested by a GFR of less than 60 mL/min per 1.73 m2 or kidney damage marker, or maybe both, last about 3 months, regardless of actual cause. Diabetes mellitus (DM) seem to be the causative factors of CKD in all high- middle-income regions, as well as in numerous low country income. Mellitus accounts for 30–50% of all CKD and affects 285 million (6.4%) individuals globally. A case-control study included 30 CKD patients with T2DM and 30 healthy subjects as a control group who visited Al-Basrah Teaching Hospital in Al-Basrah province between October 2021 and February 2022. The Age average for study population was (25-60) years. Serum levels of human AVP, ADMA, KIM-1, HCY, UMOD, and SDMA were measured by a sandwich-ELISA technique. The results revealed a highly significant increase in the levels of homocysteine, SDMA, ADMA, AVP, and KIM-1 in CKD-diabetic patients (P &lt; 0.05) and a highly significant decrease in the level of UMOD (P&lt;0.05) compared to control. According to the results, we conclude: Hyperhomocysteinemia occurs in chronic and end-stage kidney diseases. A potential indicator of renal health, uromodulin allows for the early identification of CKD. This tubular secretion marker may possibly represent intrinsic "kidney function" and residual nephron mass in addition to glomerular filtration. The oxidative stress markers ADMA and SDMA are both known to contribute significantly to the emergence of endothelial dysfunction. Increased kidney damage molecule-1 and arginein vasopressin levels suggest that these molecules may be involved in the etiology of declining renal function.

“Study of association of serum lipid profile, IL-6, &amp; ADMA levels with subclinical hypothyroidism”

Background &amp; Objectives: Subclinical hypothyroidism (SCH) represents the mildest form of thyroid hormone deficiency and may be associated with adverse consequences. SCH is defined as an elevated serum thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) level with normal levels of free thyroxine (FT4) that affects up to 10% of the adult population. The identification of patients with subclinical hypothyroidism having an increased cardiovascular risk is of great importance in the present era. The aim of the study was to evaluate cardiovascular risk factors in patients with subclinical hypothyroidism.&#x0D; Methods: 120 patients with subclinical hypothyroidism and 120 age and gender matched healthy euthyroid controls in the age group of 18-70 years were included in the study. Body mass index (BMI), lipid profile, and levels of serum biomarkers were estimated in both the groups and further compared using student t-test. Lipid profile was also correlated with the serum ADMA &amp; IL-6 and the results were analyzed using Pearson’s correlation coefficient.&#x0D; Results: Patients with subclinical hypothyroidism had significantly higher levels of serum TSH, IL-6 and ADMA. Similarly, serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly increased and HDL-C was significantly decreased in SCH patients when compared to the same parameters of controls (p&lt;0.001). Significant positive correlations were found among lipid profile and serum IL-6 &amp; ADMA.&#x0D; Conclusions: The present study concluded that the SCH patients presented increased concentrations of cardiovascular disease (CVD) risk factors viz. IL-6, ADMA &amp; lipid profile. The potential benefits of diagnosis and treatment of subclinical hypothyroidism may have possible advantages firstly by preventing the progression to overt hypothyroidism and secondly decrease the risk of death from cardiovascular disease by starting appropriate therapy to improve lipid parameters.&#x0D;

“Study of association of serum lipid profile, IL-6, &amp; ADMA levels with subclinical hypothyroidism”

Background &amp; Objectives: Subclinical hypothyroidism (SCH) represents the mildest form of thyroid hormone deficiency and may be associated with adverse consequences. SCH is defined as an elevated serum thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) level with normal levels of free thyroxine (FT4) that affects up to 10% of the adult population. The identification of patients with subclinical hypothyroidism having an increased cardiovascular risk is of great importance in the present era. The aim of the study was to evaluate cardiovascular risk factors in patients with subclinical hypothyroidism. Methods: 120 patients with subclinical hypothyroidism and 120 age and gender matched healthy euthyroid controls in the age group of 18-70 years were included in the study. Body mass index (BMI), lipid profile, and levels of serum biomarkers were estimated in both the groups and further compared using student t-test. Lipid profile was also correlated with the serum ADMA &amp; IL-6 and the results were analyzed using Pearson’s correlation coefficient. Results: Patients with subclinical hypothyroidism had significantly higher levels of serum TSH, IL-6 and ADMA. Similarly, serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly increased and HDL-C was significantly decreased in SCH patients when compared to the same parameters of controls (p&lt;0.001). Significant positive correlations were found among lipid profile and serum IL-6 &amp; ADMA. Conclusions: The present study concluded that the SCH patients presented increased concentrations of cardiovascular disease (CVD) risk factors viz. IL-6, ADMA &amp; lipid profile. The potential benefits of diagnosis and treatment of subclinical hypothyroidism may have possible advantages firstly by preventing the progression to overt hypothyroidism and secondly decrease the risk of death from cardiovascular disease by starting appropriate therapy to improve lipid parameters.

Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach.

Rheumatoid arthritis (RA) has been associated with changes in lipid, arginine and NO metabolism with increased cardiovascular (CV) risk. The aim of this study is to evaluate the effect of tofacitinib, a Janus kinase (JAK) inhibitor, on arginine and methionine metabolism in correlation with inflammation, functional and pathological vascular changes during one-year treatment of patients with RA. Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound at baseline and after 6 and 12 months. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels at these time points. Twenty-six patients (13 on each arm) completed the study. CRP, ESR and DAS28 decreased significantly during one-year treatment with tofacitinib. Arginine and ADMA showed a negative univariate correlation with CRP but not with FMD, PWV or IMT. Tofacitinib at 10 mg bid significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. ADMA and SDMA levels did not change in our study. Methionine showed negative correlation with FMD at baseline and positive correlation with PWV after 12 months. No change was observed in FMD and PWV but a significant increase was measured in IMT at 6 and 12 months. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with anti-CCP after one-year treatment. With respect to vascular pathophysiology, only PWV and methionine correlated with each other. One-year tofacitinib treatment suppressed systemic inflammation and improved functional status in RA. FMD, PWV have not been affected by one-year tofacitinib treatment., while IMT increased further despite treatment. Increased arginine and methionine might contribute to the anti-inflammatory effects of tofacitinib. Increased arginine availability with no changing ADMA may protect FMD and PWV from deterioration. The increase of IMT in the anti-inflammatory environment cannot be explained by arginine or methionine metabolism in this study.

Abstract 14718: Using Renal-Specific Cyclo-Oxygenase-2-Deficient Mice to Understand the Pro-Thrombotic Effects of Non-Steroidal Anti-Inflammatory Drugs

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) work by inhibiting the enzyme cyclooxygenase (COX)2 but their use increases thrombotic risk. We have shown that COX2 inhibition increases plasma methylarginines ADMA and LNMMA in mice and man. Methylarginines are controlled in the kidney but circulate causing inhibition of anti-thrombotic vascular NO by competing with L-arginine for the active site of eNOS. However, the causative links between renal COX2 (which is expressed predominately in fibroblasts), methylarginines and thrombosis remain unproven. Hypothesis: Here we hypothesised that deletion of COX2 from fibroblasts would result in a renal-specific COX2-deficiency and be sufficient to increase methylarginine levels and drive vascular NO dysfunction and a pro-thrombotic phenotype. Methods: Fibroblast COX2-deficient mice were generated from Fsp1-Cre and Ptgs2 flox strains. COX2 levels were measured by RT-qPCR, methylarginines by LC/MS/MS, vascular NO function as acetylcholine-induced dilation by myography and thrombosis in vivo after FeCl 3 -carotid injury. Results: Fibroblast COX2-deficient mice showed reduced COX2 expression in the renal medulla (Fig A) but not renal cortex, aorta, lung, colon, thymus or brain. This was associated with increased plasma ADMA and LNMMA levels (Fig B) and reduced NO-dependent dilatation of carotid arteries (Fig C). Fibroblast COX2-deficiency accelerated thrombosis after carotid artery injury which could be reversed by pre-treating animals with L-arginine (50mg/kg; 5 days) which displaces methylarginines from eNOS (Fig D). Conclusions: These data provide the first direct demonstration that renal COX2 regulates methylarginine levels to control systemic endothelial and thrombotic function. As such, they indicate that inhibition of renal COX2 contributes to the thrombotic risk seen in patients taking NSAIDs and suggest L-arginine supplementation as a potential rescue therapy to mitigate this.

Abstract 14913: Renal Function Underpins Cox-2: Methylarginine Axis in Mouse and Man

Introduction and Hypothesis: Through the production of prostacyclin (PGI2), cyclooxygenase (COX)-2 protects the cardio-renal system. Restraining methylarginines (ADMA, SDMA), which are biomarkers of renal and cardiovascular disease and inhibitors (ADMA) of cardioprotective endothelial nitric oxide synthase (eNOS), has been suggested as a contributory pathway. However, the relationship between renal function, COX-2 and methylarginines remains unclear. Methods: Using plasma from genetically modified mice with germline global deletion of COX-2 or PGI 2 synthase (PGIS) and human plasma from a unique individual lacking COX-derived prostaglandins due to a loss of cPLA 2 , before and after receiving a cPLA 2 -replete transplanted donor kidney, we measured methylarginines, arginine and citrulline using UHPLC-MS/MS. Renal function was assessed by measuring cystatin C by ELISA. To eliminate the impact of renal function in vivo , methylarginine and PGI 2 release from organotypic kidney slices in culture were quantified by ELISA. Results: Plasma ADMA, SDMA, citrulline and cystatin C, were similarly elevated in samples from the patient lacking COX/PGI 2 capacity compared to levels in healthy volunteers. Renal function, ADMA, SDMA and citrulline returned towards normal range when the patient received a genetically normal kidney, capable of COX/PGI 2 activity. Cystatin C correlated with ADMA, SDMA and citrulline. Loss of COX-2 or PGIS in mice increased plasma levels of ADMA, SDMA and cystatin C. As in human, SDMA, ADMA and citrulline but not arginine positively correlated with cystatin C. Levels of analytes in conditioned media of kidney slices (24h) were not altered in tissue from COX-2 KO (6-keto=14.0±1.8, ADMA=1.0±0.06, SDMA=0.30±0.05; n=8) compared to wildtype mice (66-keto=15.0±1.7, ADMA=0.98±0.06, SDMA=0.24±0.01; n=12). Conclusions: COX-2 and PGI2 are critical regulators of renal function. Plasma methylarginines are integrally linked to renal homeostasis.

Interaction of asymmetric dimethylarginine, troponin I level, and diabetes mellitus 2 type severity in patients with acute myocardial infarction

Introduction: The most important cause of mortality in the world is cardiovascular disease (CVD). Dysfunction of the endothelium is the initiating and exacerbating cause of atherosclerosis. Acute myocardial infarction (AMI) in patients with a history of diabetes mellitus (DM) leads to a higher mortality and severe disease course. Methods: The research design included 120 patients: Group 1 – AMI patients and concomitant DM type (n = 70) and Group 2 – AMI patients (n = 50) without concomitant DM type 2. 20 practically healthy persons were part of the reference groups. All patients were treated using instrumental and laboratory examinations in compliance with the current orders of the Ministry of Health of Ukraine. Results: The average level of ADMA on the first day of the AMI in patients of Group 1 was 1.57 ± 0.11 mmol/l; Group 2 – 0.61 ± 0.06 mmol/l; reference group – 0.17 ± 0.023 mmol/l (p1;2 &lt; 0.00001, p1;3 &lt; 0.001, p2;3 &lt; 0.01). The average level of troponin I on the first day of the AMI in Group 1 was 4.89 ± 2.46 ng/ml; Group 2 – 2.67 ± 2.06 ng/ml; reference group – 0.06 ± 0.04 ng/ml (p1-2 &lt; 0.00001, p1-3 &lt; 0.00001, p2-3 &lt; 0.00001). The direct marked correlation between ADMA and troponin I levels was revealed in the course of the correlation analysis (r = 0.687; p &lt; 0.05). Conclusion: Asymmetric dimethylarginine is concluded to act as a marker of endothelial dysfunction. This has a high diagnostic value in cases of the acute myocardial infarction, especially where the patients have diabetes mellitus type 2. The research revealed the hyperactivity of troponin I in patients with the examined comorbid pathology. In the course of the correlation analysis, a direct marked correlation was revealed between the levels of asymmetric dimethylarginine and troponin I (p &lt; 0.05). Correlation analysis between the marker of endothelial dysfunction and the marker of myocardial damage in the patients in Group 1 as per the form of diabetes mellitus type 2 demonstrated a direct marked correlation in the case of a mild form of carbohydrate metabolism disorder and a strong correlation in the case of moderate and severe forms of carbohydrate metabolism disorder.