Jan T. Kielstein

ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans

Background and Purpose— Preclinical studies have revealed that the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), increases vascular tone in cerebral blood vessels. Marked elevations of ADMA blood levels were found in patients with diseases characterized by decreased cerebral perfusion, such as ischemic stroke. Arterial stiffness is an independent predictor of stroke and other adverse cardiovascular events. The aim of this study was to investigate the influence of a systemic subpressor dose of ADMA on arterial stiffness and cerebral perfusion in humans. Methods— Using a double-blind, vehicle-controlled study design, we allocated 20 healthy men in random order to infusion of either ADMA (0.10 mg ADMA/kg per min) or vehicle over a period of 40 minutes. Arterial stiffness was assessed noninvasively by pulse wave analysis. All volunteers underwent measurement of cerebral perfusion by dynamic contrast-enhanced perfusion magnetic resonance imaging of the brain. Results— Infusion of ADMA significantly decreased total cerebral perfusion by 15.1±4.5% (P=0.007), whereas blood flow in the vehicle group increased by 7.7±2.8% (P=0.02). ADMA also increased arterial stiffness as assessed by measurement of the augmentation index (−12.6±1.9 to −9.6±1.5, P=0.007). Conclusions— Our results document for the first time that subpressor doses of ADMA increase vascular stiffness and decrease cerebral perfusion in healthy subjects. Thus, ADMA is an important endogenous modulator of cerebral vascular tone and may be involved in the pathogenesis of cerebrovascular disease.

Asymmetric dimethylarginine Correlates with Measures of Disease Severity, Major Adverse Cardiovascular Events and All-Cause Mortality in Patients with Peripheral Arterial Disease

Peripheral arterial disease (PAD) is associated with major cardiovascular morbidity and mortality. Abnormalities in nitric oxide metabolism due to excess of the NO synthase inhibitor asymmetric dimethylarginine (ADMA) may be pathogenic in PAD. We explored the association between ADMA levels and markers of atherosclerosis, function, and prognosis. A total of 133 patients with symptomatic PAD were enrolled. Ankle—brachial index (ABI), walking time, vascular function measures (arterial compliance and flow-mediated vasodilatation) and plasma ADMA level were assessed for each patient at baseline. ADMA correlated inversely with ABI (r = —0.238, p = 0.003) and walking time (r = —0.255, p = 0.001), independent of other vascular risk factors. We followed up 125 (94%) of our 133 initial subjects with baseline measurements (mean 35 months). Subjects with ADMA levels in the highest quartile (> 0.84 μmol/l) showed a significantly greater occurrence of a major adverse cardiovascular event (MACE) compared to those with ADMA levels in the lower three quartiles (p = 0.001). Cox proportional-hazards regression analysis revealed that ADMA was a significant predictor of MACE, independent of other risk factors including age, sex, blood pressure, smoking history, diabetes and ABI (hazard ratio = 5.1, p < 0.001). Measures of vascular function, such as compliance, flow-mediated vasodilatation (FMVD) and blood pressure, as well as markers of PAD severity, including ABI and walking time, were not predictive. In conclusion, circulating levels of ADMA correlate independently with measures of disease severity and major adverse cardiovascular events. Agents that target this pathway may be useful for this patient population. Clinical Trial Registration — URL: http:// www.clinicaltrials.gov. Unique identifier: NCT00284076

Effects of asymmetric dimethylarginine (ADMA) infusion in humans

Increased blood concentrations of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) can be found in patients with cardiovascular risk factors such as age, hypertension, diabetes, insulin resistance, hypercholesterolemia, hypertriglyceridemia, chronic kidney disease, and hyperhomocystinemia. ADMA has been shown to be a strong and independent predictor of cardiovascular and overall mortality in selected patient populations. Furthermore, in patients with chronic kidney disease, it is a strong and independent risk marker for decrease of renal function, progression to end-stage renal disease, and mortality. Infusion of exogenous ADMA in humans helped to elucidate its role in the pathogenesis of endothelial dysfunction. Pathophysiologically relevant concentrations of ADMA have been shown to decrease heart rate and cardiac output and to increase systemic vascular resistance and pulmonary vascular resistance. ADMA decreases effective renal plasma flow and increases renovascular resistance in a dose-related manner. Moreover, administration of ADMA causes significant sodium retention and blood pressure increase. These studies also revealed that ADMA is less potent than the synthetic NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and behaves differently in respect to onset of action, which can be explained by the different routes of elimination as well as different cellular transport mechanisms. Collectively these results document that ADMA has well-defined effects on cardiovascular and renal function in healthy subjects. It is therefore conceivable that ADMA causes sustained changes in vascular function through an intracellular action in endothelial cells at blood concentrations found in patients with cardiovascular pathology.

Asymmetric dimethylarginine : a new player in the pathogenesis of renal disease?

Purpose of reviewThis review summarizes current knowledge on asymmetric dimethylarginine, renal function in health and disease, and renal disease progression and examines interventions that may modify the plasma concentration of this methylarginine. Recent findingsNitric oxide deficiency may occur in patients with chronic kidney disease and may contribute to accelerate progression of chronic kidney disease, hypertension and cardiovascular complications. An increase of endogenous nitric oxide inhibitors like asymmetric dimethylarginine seems to play a major role in this process. The kidneys are crucial in both, in reabsorbing and generating L-arginine as well as in eliminating asymmetric dimethylarginine primarily by the enzyme dimethylarginine dimethylaminohydrolase and to a minor degree by urinary excretion. Asymmetric dimethylarginine accumulation predicts both accelerated renal function loss and death in patients with chronic kidney disease and incident cardiovascular complications in patients with end stage renal disease. SummaryAsymmetric dimethylarginine is a new risk factor potentially implicated in the progression of renal insufficiency and in the high rate of cardiovascular complications of patients with chronic kidney disease.

Two Cardiovascular Risk Factors in One? Homocysteine and Its Relation to Glomerular Filtration Rate

Background: Hyperhomocysteinemia is thought to be an independent risk factor for cardiovascular disease, but the association between renal dysfunction and homocysteine may not have been fully taken into account. We performed a meta-analysis of studies that report correlations between glomerular filtration rate (GFR) and homocysteine plasma levels. Methods: Using a prespecified research strategy, we identified 41 studies involving 26,617 participants that reported Pearson or Spearman correlation coefficients for the association between 1/GFR and homocysteine. The summary correlation coefficients with 95% CI were obtained by pooling the logarithmic Z values derived from the individual trial correlation coefficients. Subgroup analysis was performed to compare results for measured GFR using clearance methods and various estimates of GFR. Results: The pooled correlation coefficient between homocysteine and 1/GFR was 0.37 (CI 0.32–0.40, p < 0.0001). The correlation coefficient based on various estimates of GFR was 0.33 (CI 0.29–0.38, p < 0.0001), and for measured GFR it was 0.45 (CI 0.39–0.51, p < 0.0001). The correlation coefficient was higher when GFR was measured using clearance methods compared with various estimates GFR (1.36 [CI 1.13–1.65], p = 0.0014). Conclusions: Homocysteine plasma levels significantly depend on renal function. This correlation is even more robust when GFR is measured using clearance methods. Therefore, in order to assess whether homocysteine is an independent cardiovascular risk factor, accurate adjustments for renal dysfunction are essential.

Letter by Kielstein et al Regarding Article, “High-Dose Allopurinol Improves Endothelial Function by Profoundly Reducing Vascular Oxidative Stress and Not by Lowering Uric Acid”

To the Editor: We read with interest the paper by George and colleagues1 about the benefit of high-dose allopurinol on endothelial dysfunction in patients with class II or III heart failure. The authors suggest that on the basis of the steep dose–response relationship between allopurinol and endothelial function, a dose of 600 mg/d yields the most improvement in endothelial function. We are concerned about the implications of …

Extended Daily Dialysis

Key elements defining a renal replacement therapy as extended daily dialysis (EDD) are extended dialysis time (usually 8–18 h) and slow dialysate and blood flow rates. Prospective controlled studies in critically ill patients have documented that small solute clearance with EDD is comparable with that of intermittent hemodialysis (IHD) and continuous venovenous hemofiltration (CVVH). Patient’s cardiovascular stability during EDD is similar to continuous renal replacement therapy (CRRT). Nightly EDD treatments have the added benefit of unrestricted access of intensive care unit (ICU) staff to the patient during the day, minimizing interference of renal replacement therapy with other ICU activities. EDD combines several advantages of both intermittent and continuous techniques

Letter by Kielstein et al Regarding Article, “Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure”

To the Editor: Chronic renal disease, even with minor impairment of renal function, has only recently been recognized as a cardiovascular risk factor. Hillege et al1 confirmed and extended this knowledge substantially in their article. In their study, renal impairment was predictive of adverse outcome in patients with a broad spectrum of heart failure. Although the epidemiological relationship seems to be …