Urinary asymmetric dimethylarginine (ADMA) is a predictor of mortality risk in patients with coronary artery disease.

BACKGROUND: Asymmetric dimethylarginine (ADMA) causes endothelial dysfunction by inhibiting endothelial nitric oxide synthase. Elevated ADMA plasma levels comprise a major risk factor for coronary artery disease (CAD) and predict coronary events. ADMA is metabolised by dimethylarginine dimethylaminohydrolases (DDAHs) to citrulline and dimethylamine (DMA) and is partly excreted unchanged via the kidney. Unlike circulating ADMA, very little is known about urinary ADMA and DMA concentrations and a predictive value in CAD patients. METHODS AND RESULTS: Seventy-seven consecutive patients admitted to hospital because of stable angina (mean age 65.9 ± 1.1 years) were enrolled and followed-up for 28 [1-28] months. All patients underwent cardiac catheterization and were divided into patients with no CAD or 1-3-vessel disease (CAD 1-3). Urinary ADMA levels (corrected for creatinine excretion) were lower in severely diseased patients (CAD 3, p<0.05) whereas the DMA/ADMA ratio was significantly increased (p<0.05 CAD 3 vs. CAD 0). In a stepwise multivariate regression analysis the ADMA/creatinine ratio correlated with cardiac function (r=0.5, p<0.0001) and LDL concentrations (r=0.27, p=0.01). A total of 12 patients died during follow-up, 9 due to cardiovascular causes. Importantly, low urinary ADMA concentrations predicted future cardiovascular death (p<0.01) and overall death (p<0.05). CONCLUSION: In CAD patients low urinary ADMA concentrations are associated with impaired cardiac function and predict cardiovascular as well as all-cause mortality. The potential clinical value of urinary ADMA as a new biomarker for the diagnosis of CAD or cardiac dysfunction is intriguing, but warrants further studies.

Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine.

OBJECTIVES: We tested the hypothesis that asymmetric dimethylarginine (ADMA) may be an endogenous inhibitor of endothelial progenitor cells (EPCs). BACKGROUND: Endothelial progenitor cells play a pivotal role in regeneration of injured endothelium, thereby limiting the formation of atherosclerotic lesions. Reduced numbers of EPCs may affect progression of coronary artery disease. Regulation of EPC mobilization and function is mediated in part by nitric oxide (NO). Endogenous inhibitors of NO synthases, such as ADMA, contribute to endothelial dysfunction and injury. METHODS: We used flow cytometry and in vitro assays to investigate the relationship between EPC number and function with ADMA plasma levels in patients with stable angina. RESULTS: The plasma concentration of ADMA was related to the severity of coronary artery disease and correlated inversely with the number of circulating CD34+/CD133+ progenitor cells (r = -0.69; p < 0.0001) and endothelial colony forming units (CFUs) (r = -0.75; p < 0.0001). Adjusting for all patient characteristics, we confirmed these findings in multivariate regression analyses. In vitro differentiation of EPCs was repressed by ADMA in a concentration-dependent manner. Compared with untreated cells, ADMA reduced EPC incorporation into endothelial tube-like structures to 27 +/- 11% (p < 0.001). Asymmetric dimethylarginine repressed the formation of CFUs from cultured peripheral blood mononuclear cells to 35 +/- 7% (p < 0.001). Asymmetric dimethylarginine decreased endothelial nitric oxide synthase activity in EPCs to 64 +/- 6% (p < 0.05) when compared with controls. Co-incubation with the hydroxymethyl glutaryl coenzyme A reductase inhibitor rosuvastatin abolished the detrimental effects of ADMA. CONCLUSIONS: Asymmetric dimethylarginine is an endogenous inhibitor of mobilization, differentiation, and function of EPCs. This contributes to the cardiovascular risk in patients with high ADMA levels and may explain low numbers and function of EPCs in patients with coronary artery disease.

[Suspicious circumstances on discovery of the cadaver]. / Suspekte Leichenauffindesituationen.

The authors report on three autopsy cases in which the findings at the death scene gave rise to the suspect of non-natural, in two cases even violent causes of death. The medico-legal and criminalistic investigations led to surprising results: Death was due to acute intoxication with narcotics, supposed delirium tremens and a suicide attempt in the presence of bronchopneumonia. External force was ruled out in all three fatalities by cooperative work of police investigators and forensic medicine.