Plasma concentrations of arginine and asymmetric dimethylarginine do not reflect their intracellular concentrations in peripheral blood mononuclear cells

Objective

Production of nitric oxide (NO) from arginine is inhibited by endogenously produced monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA). Elevated levels of ADMA, by limiting NO production, may lead to endothelial dysfunction and cardiovascular disease. Symmetric dimethylarginine (SDMA) and the arginine homolog homoarginine have also been associated with cardiovascular disease. Although NO synthesis, as well as generation of MMA, ADMA, SDMA and homoarginine, occurs intracellularly, these biomarkers are usually measured in plasma. Despite extensive transmembrane transport, it is not clear whether plasma levels of these biomarkers are a valid proxy for their intracellular levels in the cardiovascular system. Since it is difficult to obtain vascular tissue from healthy humans, we explored the relations between concentrations of these biomarkers in plasma and intracellular concentrations in peripheral blood mononuclear cells (PBMC).

Methods

In PBMC and plasma of 27 healthy subjects, concentrations of arginine, MMA, ADMA, SDMA, and homoarginine were determined using stable isotope dilution liquid chromatography tandem mass spectrometry.

Results

In PBMC, significant positive correlations were observed among arginine and its methylated forms (ρ = 0.43 to 0.81) and these correlations were slightly less pronounced in plasma. Homoarginine was not significantly correlated with (methylated) arginine in either PBMC or plasma. Plasma concentrations of arginine and its methylated forms showed non-significant inverse associations with their respective intracellular concentrations in PBMC and only for homoarginine was a weak positive association observed (ρ = 0.37).

Conclusion

In healthy individuals, plasma levels of arginine, MMA, ADMA, and SDMA poorly reflect their intracellular levels in PBMC.     

Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. A systematic review

Background

The development of pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) is multifactorial with a number of biomarkers serving as mediators of neurohormonal activation [B-type natriuretic peptide (BNP) and its N-terminal-pro-fragment (NT-proBNP)], endothelial dysfunction [asymmetric dimethylarginine (ADMA)] and cellular proliferation [vascular endothelial growth factor (VEGF)].

Methods

We systematically reviewed the literature for trials studying the role of these biomarkers in the clinical evaluation, prognosis and management of patients with PAH related to CHD (CHD–PAH).

Results

Twenty-six studies were included in the systematic review, involving a total of 1113 patients with CHD–PAH. These patients had higher BNP, NT-proBNP and ADMA levels and higher VEGF expression when compared with healthy controls. Baseline and serial values of plasma levels of natriuretic peptides were shown to be significant predictors of survival. ADMA concentration was elevated in patients with CHD–PAH when compared with patients with simple CHD without PAH, whereas VEGF expression was particularly high in patients with CHD and persistent PAH after corrective surgery of the underlying heart disease.

Conclusion

Right heart dysfunction, endothelial inflammation and proliferation are mirrored by plasma levels of the corresponding biomarkers among patients with CHD–PAH. There is early evidence to suggest that natriuretic peptides, in particular, may be a simple and effective tool for determining prognosis and timing for therapeutic interventions in patients with CHD–PAH.     

Therapeutic Role of Bosentan in Hypertension: Lessons from the Model of Perinephritic Hypertension

Since its discovery in 1988, there has been increasing evidence that endothelin-1 (ET-1) plays an important role in the pathophysiology of hypertension and its related end-organ damages. First studies, using ET-1 administration in animals or in humans suspected this role by demonstrating the hypertensive properties of ET-1. The latter, due to stimulation of ET_A receptors inducing sustained vasoconstriction have been reported to follow transient vasodilation linked with activation of an endothelial ET_B receptor releasing nitric oxide (NO). In certain instances, ET_B smooth-muscle receptors might also induce contraction. Cloning of these receptors helped to develop ET-1 receptor antagonists. As soon as one of them became available, bosentan, a dual (ET_A and ET_B) ET-1 receptor antagonist, we tested its effects in the canine model of perinephritic hypertension. Bosentan was found to exert striking hypotensive effects, due to peripheral vasodilation but without affecting cardiac function. In further experiments, we observed that effects of bosentan were additional to those of ACE inhibitors or angiotensin II antagonists. This opened new therapeutic perspectives and also suggested a proper role of ET-1 in hypertension, independent of the renin-angiotensin system. To explain this role, we demonstrated a real imbalance characterized by an impairment of the NO system in favor of the ET-1 pathway. Recent studies suggest that such an imbalance may also occur in human hypertension. Furthermore, the contribution of ET-1 to human hypertension appears more convincing since bosentan was shown to decrease blood pressure in hypertensive subjects. Finally, ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damages. Whether or not these compounds are able to prevent or to reverse target organ injuries in man remains to be investigated.     

Changes in the arginine methylation of organ proteins during the development of diabetes mellitus

Aim

In this study, we examined changes in asymmetric dimethylarginine (ADMA), dimethylarginine dimethylaminohydrolase (DDAH), nitric oxide synthesis (NOS), and the arginine methylation of organ proteins during the development of diabetes in mice.

Methods

Db/db mice developed significant obesity and fasting hyperglycemia during diabetogenesis. During diabetogenesis, the expression of ADMA and nNOS was increased, while that of DDAH1 and protein-arginine methyltransferase 1 (PRMT1) was decreased. Additionally, arginine methylation in the liver and adipose tissue was altered during diabetogenesis.

Results

Changes were evident at 75, 60, and 52 kDa in liver tissue and at 38 and 25 kDa in adipose tissue. Collectively, DDAH and ADMA are closely associated with the development of obesity and diabetes, and the arginine methylation levels of certain proteins were changed during diabetes development.

Conclusion

Protein arginine methylation plays a role in the pathogenesis of diabetes.     

Relation of asymmetrical dimethylarginine levels with renal outcomes in hypertensive patients with and without type 2 diabetes mellitus

Aim

The aim of the study was to evaluate the association between high plasma ADMA levels, a biomarker of endothelial dysfunction, with the progression of albuminuria and chronic kidney disease (CKD) in hypertensive patients, with and without type 2 diabetes mellitus.

Inverse relations of serum phosphatidylcholines and lysophosphatidylcholines with vascular damage and heart rate in patients with atherosclerosis

Background and aims

The rapidly growing discipline of lipidomics allows the study of a wide spectrum of lipid species in body fluids and provides new insights into the pathogenesis of cardiovascular disease. We investigated serum phosphatidylcholine (PC) and lysophosphatidylcholine (lysoPC) species in relation to arterial stiffness, hemodynamics, and endothelial dysfunction in symptomatic patients with atherosclerosis and in healthy controls.

Angiotensin receptor blocker vs ACE inhibitor effects on HDL functionality in patients on maintenance hemodialysis

Background and Aims

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) reduce cardiovascular events in the general population. Maintenance hemodialysis (MHD) patients are at high cardiovascular risk but few studies have directly addressed the comparative efficacy of these drugs. MHD disrupts the normally atheroprotective actions of high density lipoprotein (HDL), therefore, we compared ACEI or ARB treatment on HDL functions in MHD.

A novel metabolic balance model for describing the metabolic disruption of and interactions between cardiovascular-related markers during acute myocardial infarction

Objective

After acute myocardial infarction (AMI), an integral evaluation of risk using multimarker approach and the understanding of the pathophysiological processes involved have recently received much attention. This study aimed to develop a model to integrally evaluate the metabolic disruption of cardiovascular-related markers and unveil their interactions after AMI.

Methods

AMI was induced in rats by coronary artery ligation. Several cardiovascular-related markers in plasma and the heart were determined during AMI. A metabolic balance model was developed using matrix equations to assess the metabolic disturbance of, and interactions between, these markers.

Results

Metabolic balance maps intuitively depicted the metabolic disruption of cardiovascular-related markers after AMI. The deviation and magnitude of the disruption were quantitatively and integrally described by φ and k (the dynamic parameter of metabolic balance disruption), respectively. The metabolic balance was disturbed in both the circulatory system and the heart post-AMI. All of the measured markers appeared to be interactional. Among these markers, kidney function and dimethylarginine dimethylaminohydrolase (DDAH) activity in the heart showed a potent effect on the other markers, whereas asymmetric dimethylarginine (ADMA) levels in plasma and adenosine triphosphate (ATP) contents in the heart were susceptible to the effects of the other markers.

Conclusion

A metabolic balance model was developed to integrally evaluate the disruption of cardiovascular-related markers after AMI, which proposes a new method for evaluating the disease state post-AMI using a multimarker approach. The unveiled interactions between these cardiovascular-related markers are helpful in understanding the pathophysiological processes.     

Does Vitamin D Modulate Asymmetric Dimethylarginine and C-Reactive Protein Concentrations?

Background

Vitamin D deficiency is associated with significant increases in the incidence of cardiovascular risk factors and mortality. However, the mechanisms underlying this association remain unclear. The current study evaluated the possible relationships among vitamin D status, endothelial dysfunction, and inflammation.

Methods

Plasma concentrations of 25-hydroxyvitamin D₃ were determined by radioimmunoassay in a normal population cohort (n = 253) aged 51 to 77 years (mean 63.4 ± 6 years). Asymmetric dimethylarginine, a marker/mediator of endothelial dysfunction, was assayed by high-performance liquid chromatography. High-sensitivity C-reactive protein levels were used as a marker of inflammatory activation.

Results

On univariate analyses, low 25-hydroxyvitamin D₃ levels were inversely correlated with asymmetric dimethylarginine concentrations, high-sensitivity C-reactive protein levels, and body mass index. Seasonal fluctuations in 25-hydroxyvitamin D₃ levels were associated with reciprocal asymmetric dimethylarginine concentration fluctuations. Hypertension and treatment with an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker also were associated with low 25-hydroxyvitamin D₃ levels. On multiple linear analysis, both asymmetric dimethylarginine (β = −0.19, P = .003) and high-sensitivity C-reactive protein (β = −0.14, P = .03) concentrations were inversely correlated with plasma 25-hydroxyvitamin D₃ concentrations; other significant correlates were male gender (β = 0.19, P = .003), calcium levels (β = 0.14, P = .03), and use of angiotensin-converting enzyme inhibitor (β = −0.17, P = .007).

Conclusion

Low 25-hydroxyvitamin D₃ levels are associated with markers of endothelial dysfunction and inflammatory activation, representing potential mechanisms for incremental coronary risk.     

Serum asymmetric dimethylarginine levels in diabetic patients with neuropathy

Objective

The goal of our study was to evaluate the role of asymmetric dimethylarginine (ADMA) in patients with diabetic neuropathy.

Materials and methods

In this study, 58 diabetic patients and 26 healthy volunteers were included. In both groups ADMA measurements were performed together with other biochemical examinations. Nerve conduction studies and Neuropathy Symptom Score (NSS) were administered to the diabetic patients.

Results

ADMA levels were found significantly higher in diabetic patients compared to the control group (p = 0.0001). However, ADMA levels were not statistically significant between diabetic patients with neuropathy and without neuropathy (p = 0.86 and p = 0.47).

Conclusion

These results demonstrate that there is not any significant relationship between ADMA and diabetic neuropathy.     

Plasma asymmetric dimethylarginine predicts death and major adverse cardiovascular events in individuals referred for coronary angiography

Background

Elevated plasma level of asymmetric dimethylarginine (ADMA) was reported to be associated with endothelial dysfunction and atherosclerotic risk factors. We assessed the prognostic value of plasma ADMA levels in 997 consecutive individuals referred for coronary angiography from July 2006 to June 2009.

Methods

ADMA was measured by high performance liquid chromatography. All subjects were followed for a median period of 2.4 years for the occurrence of all-cause mortality, major adverse cardiovascular events (MACE, defined as cardiovascular death, non-fatal myocardial infarction and stroke), and MACE plus clinically-driven target vessel revascularization (TVR).

Results

Plasma ADMA levels were significantly higher in patients with significant coronary artery disease (CAD) (≥ 50% stenosis, n = 655) than those with insignificant CAD (20-50% stenosis, n = 272) and normal coronary artery (< 20% stenosis, n = 70) (0.47 ± 0.10 μmol/l vs 0.44 ± 0.10 μmol/l vs 0.42 ± 0.08 μmol/l, p < 0.001). By multivariate analysis, plasma ADMA level was identified as a significant independent risk factor of significant CAD (OR: 1.29, 95% CI: 1.10−1.50; p = 0.002). Moreover, multivariate Cox regression analysis showed that, comparing with the ADMA tertile I, the highest ADMA tertile was a significant independent predictor for all adverse long-term clinical outcomes. Notably, plasma ADMA level remained associated with the long-term outcomes in non-diabetic individuals, but not in those with diabetes (interaction p = 0.04 for MACE plus TVR).

Conclusions

Our findings suggest that elevated plasma ADMA level might be a risk factor of significant CAD, and might predict worse long-term clinical outcomes in subjects referred for cardiac catheterization, especially in non-diabetic individuals.     

Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease

Background

Sudden cardiovascular death is increased in chronic kidney disease (CKD). Experimental CKD models suggest that angiogenesis and nitric oxide (NO) inhibitors induce myocardial fibrosis and microvascular dropout thereby facilitating arrhythmogenesis. We undertook this study to characterize associations of CKD with human myocardial pathology, NO-related circulating angiogenesis inhibitors, and endothelial cell behavior.

Methods

We compared heart (n = 54) and serum (n = 162) samples from individuals with and without CKD, and assessed effects of serum on human coronary artery endothelial cells (HCAECs) in vitro. Left ventricular fibrosis and capillary density were quantified in post-mortem samples. Endothelial to mesenchymal transition (EndMT) was assessed by immunostaining of post-mortem samples and RNA expression in heart tissue obtained during cardiac surgery. Circulating asymmetric dimethylarginine (ADMA), endostatin (END), angiopoietin-2 (ANG), and thrombospondin-2 (TSP) were measured, and the effect of these factors and of subject serum on proliferation, apoptosis, and EndMT of HCAEC was analyzed.

Results

Cardiac fibrosis increased 12% and 77% in stage 3–4 CKD and ESRD and microvascular density decreased 12% and 16% vs. preserved renal function. EndMT-derived fibroblast proportion was 17% higher in stage 3–4 CKD and ESRD (P_trend = 0.02). ADMA, ANG, TSP, and END concentrations increased in CKD. Both individual factors and CKD serum increased HCAEC apoptosis (P = 0.02), decreased proliferation (P = 0.03), and induced EndMT.

Conclusions

CKD is associated with an increase in circulating angiogenesis and NO inhibitors, which impact proliferation and apoptosis of cardiac endothelial cells and promote EndMT, leading to cardiac fibrosis and capillary rarefaction. These processes may play key roles in CKD-associated CV disease.     

Depletion of NADP(H) due to CD38 activation triggers endothelial dysfunction in the postischemic heart

In the postischemic heart, coronary vasodilation is impaired due to loss of endothelial nitric oxide synthase (eNOS) function. Although the eNOS cofactor tetrahydrobiopterin (BH₄) is depleted, its repletion only partially restores eNOS-mediated coronary vasodilation, indicating that other critical factors trigger endothelial dysfunction. Therefore, studies were performed to characterize the unidentified factor(s) that trigger endothelial dysfunction in the postischemic heart. We observed that depletion of the eNOS substrate NADPH occurs in the postischemic heart with near total depletion from the endothelium, triggering impaired eNOS function and limiting BH₄ rescue through NADPH-dependent salvage pathways. In isolated rat hearts subjected to 30 min of ischemia and reperfusion (I/R), depletion of the NADP(H) pool occurred and was most marked in the endothelium, with >85% depletion. Repletion of NADPH after I/R increased NOS-dependent coronary flow well above that with BH₄ alone. With combined NADPH and BH₄ repletion, full restoration of NOS-dependent coronary flow occurred. Profound endothelial NADPH depletion was identified to be due to marked activation of the NAD(P)ase-activity of CD38 and could be prevented by inhibition or specific knockdown of this protein. Depletion of the NADPH precursor, NADP⁺, coincided with formation of 2’-phospho-ADP ribose, a CD38-derived signaling molecule. Inhibition of CD38 prevented NADP(H) depletion and preserved endothelium-dependent relaxation and NO generation with increased recovery of contractile function and decreased infarction in the postischemic heart. Thus, CD38 activation is an important cause of postischemic endothelial dysfunction and presents a novel therapeutic target for prevention of this dysfunction in unstable coronary syndromes.Endothelial dysfunction is associated with a wide range of cardiovascular diseases including hypercholesterolemia, diabetes, atherosclerosis, hypertension, heart failure, and ischemic heart disease (1). In vivo coronary occlusion induces endothelial dysfunction with decreased endothelial nitric oxide synthase (eNOS)-dependent vasoreactivity, which persists upon reperfusion (2, 3). Persistent diminished flow through the coronary arteries upon reperfusion can lead to cardiac myocyte injury and heart failure (4). Endothelial dysfunction is induced by the marked oxidant stress that occurs following the onset of ischemia and reperfusion (I/R) (5).Normally, vascular tone and coronary vasodilation are modulated by nitric oxide (NO). Synthesis of NO occurs within the endothelium via eNOS, which uses l-arginine and O₂ to form NO and l-citrulline. This enzymatic process uses NADPH as the source of reducing equivalents and requires Ca²⁺/calmodulin, flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, and tetrahydrobiopterin (BH₄) as cofactors. eNOS regulates vasomotor tone and blood pressure by producing NO, which activates soluble guanylate cyclase in vascular smooth muscle, resulting in vasorelaxation (6, 7).In postischemic myocardium, the critical redox-sensitive eNOS cofactor, BH₄, is depleted, leading to eNOS uncoupling with production of superoxide (O₂^•–) instead of NO (8, 9). The essential role of BH₄ in NO production has made it a primary target of therapeutic studies aimed at restoring endothelial function following I/R (10). Preventing loss of and/or replenishing BH₄ has proven beneficial, although recovery of eNOS function post-BH₄ replacement therapy remains incomplete (10, 11). Furthermore, it remains unclear why BH₄ salvage pathways fail to adequately regenerate this critical cofactor. Thus, there is a great need to identify other factor(s) that lead to eNOS dysfunction in the postischemic heart and develop new therapeutic approaches to restore endothelium-dependent vasodilatory function.Studies were performed to characterize the previously unidentified factors that trigger and contribute to postischemic endothelial dysfunction. We observed that marked NADP(H) depletion occurs, resulting in impaired eNOS function and limited BH₄ recycling through NADPH-dependent salvage pathways. Tandem NADPH and BH₄ supplementation resulted in complete restoration of NOS-dependent coronary flow (CF). The profound endothelial NADP(H) depletion was shown to be due to activation of CD38. siRNA-mediated CD38 knockdown in endothelial cells prevented NADP(H) depletion. CD38 inhibition preserved endothelium-dependent CF, eNOS coupling, and NO generation, with enhanced recovery of cardiac contractile function and decreased infarction in the postischemic heart.     

Metabolic syndrome and endothelin-1 mediated vasoconstrictor tone in overweight/obese adults

Objective

To determine whether endothelin (ET)-1 vasoconstrictor tone is greater in overweight and obese adults with the metabolic syndrome (MetS).

Materials/Methods

Forty overweight/obese middle-aged and older adults (age: 43–71 years; BMI: 25.1–36.9 kg/m²) were studied: 20 without MetS (13 M/7 F) and 20 with MetS (13 M/7 F). MetS was established according to NCEP ATP III guidelines. Forearm blood flow (FBF; plethysmography) responses to intra-arterial infusion of selective ET_A receptor blockade (BQ-123; 100 nmol/min; for 60 min) and non-selective ET_A/B receptor blockade (BQ-123 + BQ-788 [50 nmol/min for 60 min]) were determined.

Results

In response to the selective ET_A antagonism, there was a significant increase in forearm blood flow from baseline in both groups. However, the increase in forearm blood flow was significantly higher (P = 0.03; ~ 45%) in the overweight/obese group with MetS than the group without MetS. In contrast, there were no significant group differences in FBF responses to non-selective ET_A/B receptor blockade. Peak vasodilator responses to nonselective ET_A/B blockade were ~ 50% higher than baseline blood flow in the overweight/obese groups without and with MetS.

Conclusion

MetS is associated with higher ET-1 vasoconstrictor tone in overweight/obese adults. The enhanced ET-1 vasoconstrictor activity with MetS is mediated by the ET_A receptor subtype.     

The impact of rapid atrial pacing on ADMA and endothelial NOS

Background

The endothelial nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a well-established risk factor for oxidative stress, vascular dysfunction, and congestive heart failure. The aim of the present study was to determine the impact of rapid atrial pacing (RAP) on ADMA levels and eNOS expression.

Methods and results

ADMA levels were studied in 60 age- and gender-matched patients. Thirty five patients had persistent atrial fibrillation (AF) ≥ 4 months. In AF-patients, parameters were studied before and 24 h after electrical cardioversion. Moreover, ADMA, eNOS expression, and calcium-handling proteins were studied in pigs subjected to RAP as well as in endothelial cell (EC) cultures. ADMA level was significantly higher in AF compared to sinus rhythm patients (p = 0.024). ADMA was highest in AF-patients, who also showed elevated troponin T (TnT) levels. Moreover, ADMA showed a significant linear correlation to TnT (r = 0.47; p < 0.01). After electrical cardioversion ADMA returned to normal within 24 h. In pigs, RAP for 7 h increased ADMA levels (p = 0.018) and TnI (p < 0.05), and reduced mRNA expression of ventricular and aortic eNOS (− 80%; p < 0.05) compared to sham-control. However, ADMA per se did not affect eNOS mRNA level in EC cultures.

Conclusion

The current study shows that acute and persistent episodes of atrial tachyarrhythmia are associated with elevated ADMA levels accompanied by increased ischemic myocardial markers. Moreover, RAP increases ADMA and down-regulates eNOS expression in an ADMA-independent manner. We conclude that the combination of these two separate and potentially synergistic mechanisms may contribute to long-term vascular injury during atrial tachyarrhythmia.     

Relationship of asymmetric dimethylarginine and homocysteine to vascular aging in systemic lupus erythematosus patients

Objective

Systemic lupus erythematosus (SLE) is independently associated with accelerated atherosclerosis and premature arterial stiffening. Asymmetric dimethylarginine (ADMA) and homocysteine are mechanistically interrelated mediators of endothelial dysfunction and correlates of atherosclerosis in the general population. The aim of this study was to assess the relationship of ADMA and homocysteine to subclinical vascular disease in patients with SLE.

Methods

One hundred twenty‐five patients with SLE who were participating in a study of cardiovascular disease underwent clinical and laboratory assessment, carotid artery ultrasonography to detect atherosclerosis, and radial artery applanation tonometry to measure arterial stiffness.

Results

Neither ADMA nor homocysteine correlated with the presence or extent of carotid atherosclerosis. In contrast, ADMA was significantly related to the arterial stiffness index. Independent correlates of arterial stiffening included the ADMA concentration, the presence of diabetes mellitus, older age at the time of diagnosis, longer disease duration, and the absence of anti‐Sm or anti‐RNP antibodies. A secondary multivariable analysis substituting homocysteine for ADMA demonstrated comparable relationships with arterial stiffness (r² = 0.616 for homocysteine and r² = 0.595 for ADMA).

Conclusion

ADMA and homocysteine are biomarkers for and may be mediators of premature arterial stiffening in patients with SLE. Because arterial stiffness has independent prognostic value for cardiovascular morbidity and mortality, its predictors may identify patients who are at increased risk of cardiovascular disease.

     

Asymmetric Dimethylarginine,Race, and Mortality in Hemodialysis Patients

Background and objectives

Levels of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase, are elevated in kidney disease and associated with mortality in white European hemodialysis populations. Nitric oxide production and degradation are partially genetically determined and differ by racial background. No studies have measured asymmetric dimethylarginine in African Americans on dialysis and assessed whether differences exist in its association with mortality by race.

Design, setting, participants, & measurements

Asymmetric dimethylarginine was measured in 259 patients on maintenance hemodialysis assembled from 2004 to 2012 in Boston area outpatient centers. Cox proportional hazards models were used to determine the association between asymmetric dimethylarginine and all-cause mortality, and an interaction with race was tested.

Results

Mean (SD) age was 63 (17) years, 46% were women, and 22% were African American. Mean asymmetric dimethylarginine in non–African Americans was 0.79 µmol/L (0.16) versus 0.70 µmol/L (0.11) in African Americans (P<0.001); 130 patients died over a median follow-up of 2.3 years. African Americans had lower mortality risk than non–African Americans (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.50) that was robust to adjustment for age, comorbidity, and asymmetric dimethylarginine (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.69). An interaction was noted between race and asymmetric dimethylarginine (P=0.03), such that asymmetric dimethylarginine was associated with higher mortality in non–African Americans (adjusted hazard ratio, 1.29; 95% confidence interval, 1.06 to 1.57 per 1 SD higher asymmetric dimethylarginine) but not in African Americans (adjusted hazard ratio, 0.57; 95% confidence interval, 0.28 to 1.18). Additional adjustment for fibroblast growth factor 23 partially attenuated the association for non–African Americans (adjusted hazard ratio, 1.22; 95% confidence interval, 0.98 to 1.50).

Conclusions

African Americans have lower asymmetric dimethylarginine levels and lower hazard for mortality compared with non–African Americans. Levels of asymmetric dimethylarginine did not explain lower hazard for mortality in non–African American patients. High asymmetric dimethylarginine was a risk factor for mortality exclusively in non–African Americans. Mechanisms explaining these relationships need to be evaluated.     

Feasibility Evaluation of Myocardial Cannabinoid Type 1 Receptor Imaging in Obesity: A Translational Approach

Objectives

The aim of this study was to evaluate the feasibility of targeted imaging of myocardial cannabinoid type 1 receptor (CB1-R) and its potential up-regulation in obese mice with translation to humans using [¹¹C]-OMAR and positron emission tomography (PET)/computed tomography (CT).

Increased asymmetric dimethylarginine and enhanced inflammation are associated with impaired vascular reactivity in women with endometriosis

Objective

Enhanced inflammatory responses which may inhibit vascular reactivity, are associated with endometriosis development. Asymmetric dimethylarginine (ADMA), an inhibitor of endogenous nitric oxide synthase, is also implicated in endothelial dysfunction. We aimed to determine whether plasma ADMA and systemic inflammation are associated with endothelial function in women with endometriosis.

Methods

We evaluated 41 women with and 28 women without endometriosis. Plasma levels of lipids and inflammatory markers such as high sensitive-C reactive protein (hs-CRP), serum amyloid protein A (SAA), and interleukin-6 (IL-6) were measured in the two groups. We also measured levels of ADMA and symmetric dimethylarginine (SDMA). High-resolution ultrasonography measured flow-mediated vasodilation (FMD) to assess vasodilatory responses.

Results

FMD was significantly lower in women with endometriosis compared to those without endometriosis (8.39 ± 0.43% vs 10.79 ± 0.54%, P = 0.001). While plasma lipid levels did not differ significantly between groups, levels of AMDA, but not SDMA, were significantly higher in women with endometriosis (409.7 ± 10.1 pmol/L vs 383.0 ± 48.3 pmol/L, P = 0.04). Inflammatory markers were also significantly higher in these women (hs-CRP: 1053.3 ± 252.0 ng/mL vs 272.0 ± 83.3 ng/mL, P = 0.02; SAA: 8.00 ± 1.53 μg/mL vs 3.82 ± 0.42 μg/mL, P = 0.04; IL-6: 2.73 ± 0.75 pg/mL vs 1.05 ± 0.60 pg/mL, P = 0.04). FMD was negatively correlated with plasma levels of ADMA (r = −0.37, P = 0.01) and log hs-CRP (r = −0.34, P = 0.01).

Conclusion

Increased plasma ADMA levels and enhanced inflammation are associated with inhibited endothelial function in women with endometriosis.