By Thomas S. May
HELSINKI, FINLAND -- June 11, 2007 -- The failure of statins to improve endothelial function in people with high blood levels of asymmetric dimethylarginine (ADMA) can be counteracted by L-arginine treatment, according to new research presented here at the 76th Congress of the European Atherosclerosis Society (EAS).
Statins tend to improve endothelial function by upregulating endothelial nitric oxide synthase (eNOS). However, they do not do so in all individuals, some studies have found. Now, researchers from Germany have discovered the reason why this is so, and they have also found a way to counteract this apparent "malresponsiveness" to statins.
"Our study shows that a significant subgroup of patients who are treated with statins do not respond adequately to this treatment in terms of improvement of vascular function," said Rainer Boger, MD, professor, Institute of Experimental And Clinical Pharmacology And Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. "We have identified a biomarker, ADMA, that is responsible for this malresponsiveness to statins. ADMA has been found in several prospective clinical trials to be a significant predictor of major cardiovascular events and death in patients with high cardiovascular risk," he added.
To determine the role of ADMA in controlling endothelial response to statins, Boger and colleagues measured plasma ADMA levels in 98 healthy elderly subjects, 15 of whom had elevated ADMA levels (highest quartile) and another 15 had low ADMA levels (lowest quartile).
All subjects were treated with simvastatin (40 mg/day), L-arginine sustained-release (3 g/day), or a combination of both, for 3 consecutive weeks, in a randomised, blinded, three-period crossover study, during which endothelium-dependent dilation (EDD) was repeatedly assessed by brachial artery ultrasound.
The investigators found that simvastatin had no appreciable effect on EDD (6.2±1.2% vs. 6.1±0.9%) in subjects with elevated ADMA. However, the addition of L-arginine to simvastatin significantly improved EDD (9.8±1.5% vs. 5.3±0.8%; P <.01). There were also significant improvements in EDD in response to L-arginine alone (8.7±0.7% vs. 4.9±0.8%; P <.02).
In subjects with low ADMA, simvastatin, L-arginine and their combination led to a similar increase in EDD (simvastatin: 9.47±3.16% vs. 6.08±3.77%, P <.001; L-arginine: 10.16±2.85% vs. 5.69±2.99%, P =.02; simvastatin+L-arginine: 8.99±3.06% vs. 6.34±3.26%; P =.001).
Based on these results, the researchers concluded that ADMA is a useful marker that can help differentiate between patients in whom statin treatment will or will not result in improved endothelium-dependent dilation. They also suggested that plasma ADMA levels should be measured in patients eligible for statin treatment, and the addition of L-arginine should be considered in those with high ADMA levels.
[Presentation title: Asymmetric Dimethylarginine (ADMA) Determines the Responsiveness of Endothelial Function to Simvastatin Treatment - Results of a Randomized, Controlled Study. Abstract P768]
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