Renke Maas

Plasma Asymmetric Dimethylarginine and Incidence of Cardiovascular Disease and Death in the Community

Background— Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction. Although elevated ADMA has been associated with an increased risk of cardiovascular disease events and death in referral samples, the prognostic significance of ADMA in the community has not been adequately evaluated. Methods and Results— We related plasma ADMA, l-arginine (Arg), and the ratio of Arg to ADMA to the incidence of cardiovascular disease (fatal or nonfatal myocardial infarction, coronary insufficiency, angina pectoris, stroke or transient ischemic attack, intermittent claudication, or heart failure) and death in 3320 Framingham Offspring Study participants (1769 women; mean age, 59 years). Over a follow-up period of 10.9 years, 281 individuals of 2956 free of cardiovascular disease at baseline developed incident cardiovascular disease, and 285 participants died. In multivariable models adjusting for established risk factors and other biomarkers (B-type natriuretic peptide, renin, homocysteine, urine albumin excretion, and C-reactive protein), ADMA and the ratio of Arg to ADMA were significantly associated with all-cause mortality (adjusted-hazard ratio [HR] per 1-SD increment, 1.21; 95% CI, 1.07 to 1.37; and HR per 1-SD increment, 0.80; 95% CI, 0.69 to 0.93, respectively), whereas Arg was not (HR per 1-SD increment, 0.89; 95% CI, 0.77 to 1.02). We noted effect modification by diabetes status; ADMA was associated with death in individuals without diabetes (adjusted HR per 1-SD increment, 1.30; 95% CI, 1.13 to 1.50) but not in individuals with diabetes (adjusted HR per 1-SD increment, 0.85; 95% CI, 0.62 to 1.16). ADMA, Arg, and the ratio of Arg to ADMA were not associated with cardiovascular disease incidence (P>0.10). Conclusions— In our large community-based sample, ADMA was significantly associated with all-cause mortality, particularly in nondiabetic individuals.

The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function

The incidence of erectile dysfunction increases with diabetes, hypertension, hypercholesterolaemia, cardiovascular disease and renal failure. All these conditions are associated with endothelial dysfunction. This review addresses the pathophysiology of erectile dysfunction with a special focus on new insights into nitric oxide (NO)-mediated pathways, oxidative stress and parallels to endothelial dysfunction. NO appears to be the key mediator promoting endothelium-derived vasodilation and penile erection. The possibility is discussed that elevated plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthase inhibitor, may provide an additional pathomechanism for various forms of erectile dysfunction associated with cardiovascular risk factors and disease. Likewise, the role of endothelium-derived factors mediating NO-independent pathways is evaluated.

Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality—An update on patient populations with a wide range of cardiovascular risk

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthases. By inhibiting NO formation, ADMA causes endothelial dysfunction, vasoconstriction, elevation of blood pressure, and aggravation of experimental atherosclerosis. Cross-sectional studies in humans have revealed that ADMA plasma concentration is elevated in numerous populations with vascular diseases or at high cardiovascular risk. However, the potential causal relationship between elevated ADMA and cardiovascular events and mortality in humans can only be revealed in prospective clinical studies. This review gives an overview of currently available data from prospective clinical studies in which ADMA has been measured in populations at high, intermediate, or low global vascular risk. Although the analytical methods used to quantify ADMA varied and statistical approaches to assess the association of ADMA with risk differed, these data reveal that ADMA is significantly associated with an increased risk of incident cardiovascular events and total mortality in subjects at a broad range of global risk. Hazard ratios were mostly in a range comparable to that of traditional cardiovascular risk markers even after multivariable adjustments, suggesting that ADMA may be suitable as a diagnostic marker for risk assessment, and that the biochemical pathways that regulate ADMA may be promising therapeutic approaches to treat cardiovascular disease in the future.

Clinical Pharmacokinetics of Antioxidants and Their Impact on Systemic Oxidative Stress

Dietary antioxidants play a major role in maintaining the homeostasis of the oxidative balance. They are believed to protect humans from disease and aging. Vitamin C (ascorbic acid), vitamin E (tocopherol), β-carotene and other micronutrients such as carotenoids, polyphenols and selenium have been evaluated as antioxidant constituents in the human diet. This article addresses data provided from clinical trials, highlighting the clinical pharmacokinetics of vitamin C, vitamin E, β-carotene, lycopene, lutein, quercetin, rutin, catechins and selenium.The bioavailability of vitamin C is dose-dependent. Saturation of transport occurs with dosages of 200–400) mg/day. Vitamin C is not protein-bound and is eliminated with an elimination half-life (t½) of 10 hours. In Western populations plasma vitamin C concentrations range from 54–91 µmol/L. Serum α- and γ-tocopherol range from 21 µmol/L (North America) to 27 µmol/L (Europe) and from 3.1 µmol/L to 1.5 µmol/L, respectively. α-Tocopherol is the most abundant tocopherol in human tissue. The bioavailability of all-rac-α-tocopherol is estimated to be 50% of R,R,R-α-tocopherol. The hepatic α-tocopherol transfer protein (α-TTP) together with the tocopherol-associated proteins (TAP) are responsbile for the endogenous accumulation of natural α-tocopherol. Elimination of α-tocopherol takes several days with a t½ of 81 and 73 hours for R,R,R-α-tocopherol and all-rac-α-tocopherol, respectively. The t½ of tocotrienols is short, ranging from 3.8–4.4 hours for γ- and α-tocotrienol, respectively. γ-Tocopherol is degraded to 2, 7, 8-trimethyl-2-(β-carboxyl)-6-hyrdoxychroman by the liver prior to renal elimination. Blood serum carotenoids in Western populations range from 0.28–0.52 p,mol/L for β-carotene, from 0.2–0.28 for lutein, and from 0.29–0.60 for lycopene. All-trans-carotenoids have a better bioavailability than the 9-cis-forms. Elimination of carotenoids takes several days with a t½ of 5-7 and 2–3 days for β-carotene and lycopene, respectively. The bioconversion of β-carotene to retinal is dose-dependent, and ranges between 27% and 2% for a 6 and 126mg dose, respectively. Several oxidised metabolites of carotenoids are known. Flavonols such as quercetin glycosides and rutin are predominantly absorbed as aglycones, bound to plasma proteins and subsequently conjugated to glucuronide, sulfate, and methyl moieties. The t½ ranges from 12–19 hours. The bioavailabillity of catechins is low and they are eliminated with a t½ of 2–4 hours. Catechins are degraded to several γ-valerolactone derivatives and phase II conjugates have also been identified. Only limited clinical pharmacokinetic data for other polyphenols such as resveratrol have been reported to date.

Analysis of the Relationship between Norepinephrine and Asymmetric Dimethyl Arginine Levels among Patients with End-Stage Renal Disease

High sympathetic activity and alterations in nitric oxide synthesis attributable to accumulation of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have recently been identified as potential causal mechanisms for the high cardiovascular mortality rates among patients with ESRD. The link between these risk factors has not been studied. Therefore, the relationship between plasma norepinephrine (NE) and ADMA levels was examined in a large cohort of hemodialysis patients (n = 224), and whether these factors interacted in predicting all-cause mortality and new cardiovascular event rates among those patients was investigated. Plasma ADMA levels were strongly associated with plasma NE levels (P < 0.001) and to a lesser extent with heart rate (P < 0.01). In multivariate analyses, the ADMA-NE correlation was observed to be independent of age, gender, serum albumin levels, arterial pressure and antihypertensive treatment, duration of dialysis treatment, diabetes mellitus, and other risk factors. NE was an independent significant predictor of both death and cardiovascular events in Cox models not including ADMA. However, when ADMA was introduced into those models, NE became a largely nonsignificant predictor of those outcomes, whereas plasma ADMA levels emerged as a highly significant predictor of both death (P < 0.001) and cardiovascular events (P < 0.001). These findings suggest that ADMA is an intervening factor in the causal pathway leading to those outcomes. Plasma NE and ADMA concentrations are strongly related among patients with ESRD. These two factors are likely to be involved in the same causal pathway leading to death and cardiovascular events among those patients.

Symmetric dimethylarginine predicts all-cause mortality following ischemic stroke

OBJECTIVE Methylarginines have been shown to interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA, and monomethylarginine, NMMA) and the cellular l-arginine uptake system (ADMA, NMMA and symmetric dimethylarginine, SDMA), thereby causing endothelial dysfunction. ADMA is a predictor of cardiovascular events and mortality in diverse populations. METHODS We investigated whether methylarginines are predictors of mortality in 394 patients after acute ischemic stroke during 7.4 years of follow-up. RESULTS Patients who died (N=231) were older and more frequently had one of the traditional risk factors for stroke (previous stroke/TIA, atrial fibrillation, prevalent ischemic heart disease, peripheral vascular disease, each p<0.05). ADMA (0.52 micromol/l vs. 0.50 micromol/l, p=0.015) and SDMA (0.56 micromol/l vs. 0.43 micromol/l, p<0.001) were higher in patients who died. In multivariable-adjusted hazard models, SDMA but not ADMA or NMMA was an independent predictor of all-cause mortality after stroke (SDMA, hazard ratio 2.41 (1.55-3.72), p<0.001; ADMA, hazard ratio 1.43 (0.99-2.07), p=0.06). SDMA was significantly associated with atrial fibrillation (0.55 micromol/l vs. 0.50 micromol/l, p=0.03) but there was no significant interaction between SDMA and AF in relation to mortality (p=0.81). SDMA remained significantly associated with mortality after adjusting for eGFR and also additionally adjusting for C-reactive protein, albumin, beta-thromboglobulin, and von Willebrand factor. CONCLUSION Our study demonstrates that SDMA is an independent predictor of total mortality after acute stroke irrespective of renal function. SDMA is associated with atrial fibrillation, endothelial and platelet activation, and may therefore play a previously unknown role in the pathophysiology of stroke.

Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA)

Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are found in various clinical settings, including renal failure, coronary heart disease, hypertension, diabetes and preeclampsia. In healthy people acute infusion of ADMA promotes vascular dysfunction, and in mice chronic infusion of ADMA promotes progression of atherosclerosis. Thus, ADMA may not only be a marker but also an active player in cardiovascular disease, which makes it a potential target for therapeutic interventions. This review provides a summary and critical discussion of the presently available data concerning the effects on plasma ADMA levels of cardiovascular drugs, hypoglycemic agents, hormone replacement therapy, antioxidants, and vitamin supplementation. We assess the evidence that the beneficial effects of drug therapies on vascular function can be attributed to modification of ADMA levels. To develop more specific ADMA-lowering therapies, mechanisms leading to elevation of plasma ADMA concentrations in cardiovascular disease need to be better understood. ADMA is formed endogenously by degradation of proteins containing arginine residues that have been methylated by S-adenosylmethionine-dependent methyltransferases (PRMTs). There are two major routes of elimination: renal excretion and enzymatic degradation by the dimethylarginine dimethylaminohydrolases (DDAH-1 and -2). Oxidative stress causing upregulation of PRMT expression and/or attenuation of DDAH activity has been suggested as a mechanism and possible drug target in clinical conditions associated with elevation of ADMA. As impairment of DDAH activity or capacity is associated with substantial increases in plasma ADMA concentrations, DDAH is likely to emerge as a prime target for specific therapeutic interventions.

Suppression of paroxysmal atrial tachyarrhythmias - results of the SOPAT trial

AIM The indication to treat paroxysmal atrial fibrillation (PAF) is controversial. The Suppression of Paroxysmal Atrial Tachyarrhythmias (SOPAT) trial was designed to answer the following questions: (1) What is the average rate of spontaneous events of symptomatic PAF with and without anti-arrhythmic medication? (2) what is the prevalence of severe side-effects? and (3) is the fixed combination of Quinidine + Verapamil inferior to the efficacy of sotalol or not? METHODS AND RESULTS Within 60 months 172 centres in Germany, Poland, and The Slovak Republic prospectively enrolled 1033 patients (mean age 60 years, 62% male) with documented frequent episodes of symptomatic PAF. Patients were randomised to either Quinidine + Verapamil 480/240 mg/d (high dose; 263 patients), Quinidine + Verapamil 320/160 mg/d (low dose; 255 patients), Sotalol 320 mg/d (264 patients) or placebo (251 patients), of which 1012 patients entered the intention-to-treat analysis. The primary endpoint was the time to first recurrence of symptomatic PAF or premature discontinuation. Secondary outcome parameters were the total number of symptomatic episodes and tolerability of the tested drugs. Patients were followed for a period of up to 12 months by daily and symptom-triggered trans-telephonic ECG-monitoring (Tele-ECG). The mean time under treatment was 233 +/- 152 days. Regarding the primary endpoint, all active treatments were superior to placebo and not different from each other. A total of 756 patients reached the primary endpoint within 105.7 +/- 8.7 d (mean +/- SEM) in the placebo group, vs. Quinidine + Verapamil (high dose) (150.4 +/- 10 d, p = 0.0061), vs. Quinidine + Verapamil (low dose) (148.9 +/- 10.6 d, p = 0.0006), vs. Sotalol (145.6 +/- 93 d, p = 0.0007). All three treatments were also effective in the reduction of AF burden (days with symptomatic AF [%] mean +/- SD, p vs. placebo): Quinidine + Verapamil (high dose) (3.4 +/- 12, p = 0.0001), Quinidine + Verapamil (low dose) (4.5 +/- 12.3, p = 0.008) and Sotalol (2.9 +/- 6.5, p = 0.026) compared to placebo (6.1 +/- 13.5). A total of four deaths, 13 syncopes, and one ventricular tachycardia (VT) occurred during the active study period, of which one death and one VT were related to Quinidine/Verapamil. CONCLUSION Taken together, anti-arrhythmic therapy with the fixed combination of Quinidine + Verapamil is as effective as Sotalol in the reduction of the recurrence rate of symptomatic PAF with a low but definite risk of severe side-effects.

Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients

BACKGROUND Endothelial dysfunction as assessed by asymmetric dimethylarginine (ADMA) and inflammation has been consistently linked to atherosclerosis, death, and cardiovascular (CV) events in ESRD patients. Inflammation amplifies the effect of ADMA on the severity of atherosclerosis in ESRD patients, but it is still unknown whether inflammation and ADMA interact in the high risk of death and CV events in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a cohort of 225 hemodialysis patients, we investigated the interaction between inflammatory biomarkers (C-reactive protein and IL-6) and ADMA as predictors of death and CV events over an extended follow-up (13 years). RESULTS During follow-up, 160 patients died, and 123 had CV events. With crude and multiple Cox regression analyses, an interaction was found between inflammation biomarkers and ADMA for explaining death and CV events in ESRD patients. The adjusted hazard ratios (HRs) for death (HR, 2.18; 95% confidence interval [CI], 1.34 to 3.54) and CV outcomes (HR, 2.59; 95% CI, 1.47 to 4.55) of patients with C-reactive protein and ADMA above the median were higher than expected in the absence of interaction under the additive model (1.15 and 1.97, respectively) and significantly higher than in patients with only one biomarker above the median. Data analyses carried out by stratifying patients according to IL-6 provided similar results. CONCLUSIONS These data support the hypothesis that inflammation amplifies the risk of death and CV events associated with high ADMA levels in ESRD. These analyses further emphasize the need for intervention studies to attenuate inflammation and high ADMA levels in this population.

A randomized and controlled pilot trial of beta-blockers for the treatment of recurrent syncope in patients with a positive or negative response to head-up tilt test.

VENTURA, R., et al.: A Randomized and Controlled Pilot Trial of b‐Blockers for the Treatment of Recurrent Syncope in Patients with a Positive or Negative Response to Head‐Up Tilt Test. The aim of this study was to assess the efficacy of lipophilic β‐blockers in preventing recurrent neurocardiogenic syncope and the value of head‐up tilt test (HUT) in predicting response to therapy. The efficacy of β‐blockers in recurrent syncope is controversial. The value of HUT in predicting efficacy of therapy has not been investigated. Fifty‐six patients (44 ± 18 years, 36 women) with recurrent syncope (> 1 event in the last 6 months) of suspected neurocardiogenic origin were included in the study. Independent of the response to HUT, patients were randomized to receive metoprolol or propanolol at the maximal tolerated dose (28 patients, group A, 86 ± 23 vs 98 ± 29 mg/d) or no pharmacological therapy (28 patients, group B). The primary endpoint was the first recurrence of syncope. During the 1‐year of follow‐up, 20 patients of group A and 8 of group B had no recurrence. In group A, of 20 patients without recurrences 12 had a positive and 8 a negative HUT result while of 8 patients with recurrences 5 had a positive and 3 a negative response to HUT. In the group B, of 20 patients with recurrences 10 had a positive and 10 a negative HUT result while of 8 patients without recurrences 4 had a positive and 4 a negative response to HUT. In a multivariate Cox‐regression analysis, medical therapy was the only independent factor for predicting recurrence of syncope (P = 0.004); HUT had no influence in this regard (P = 0.773). In conclusion, lipophilic β‐blockers appear efficacious in preventing recurrent syncope of suspected neurocardiogenic origin. The efficacy of therapy seems to be not predicted by HUT.