| COMMENTARIES |
Asymmetric Dimethylarginine and Coronary Artery Disease
Asife Sahinarslan and Atiye Cengel,
Gazi University, School of Medicine, Cardiology
Department, Besevler,
Ankara, Turkey
Endothelium, the inner surface of the vasculature, is responsible for maintenance of the normal vascular functions, like control of vascular tonus, homeostasis, and inflammation, through secretion of vasoactive molecules. The most important molecule which regulates the functions of endothelium is nitric oxide (NO). NO is synthesized from L-arginine by the help of nitric oxide synthase (NOS).
Endothelial dysfunction which is accepted as the first clinical step in the process of atherosclerosis is characterized mainly by the insufficiency of NO. This causes problems in vasoactive, anticoagulant, and anti-inflammatory effects of healthy endothelium which starts the atherosclerotic process in the body. Atherosclerosis is the most important mechanism in the occurrence of coronary artery disease. Since it has a progressive nature, the management of atherosclerosis and, as a consequence of it, coronary artery disease is very difficult. Anything that decreases NO can start the atherosclerotic process in the body. For many years, investigators searched for the events causing NO insufficiency.
Asymmetric dimethylarginine (ADMA) which is an end product in protein catabolism decreases nitric oxide bioavailability by interfering with its synthesis. It competes with L-arginine for the active site of endothelial nitric oxide synthase which is the main enzyme in synthesis of NO.
ADMA has been found to be associated with classical risk factors for coronary artery disease like hypertension, diabetes mellitus, and hyperlipidemia. Miyazaki et al. showed a strong correlation between ADMA and carotid intima media thickness in healthy persons [1]. This was important evidence for the relation between ADMA and atherosclerosis. Then, Zoccali and coworkers showed that ADMA was one of the most important predictors of cardiovascular events in hemodialysis patients [2]. In another study, Valkonen et al. showed that this was true also for the patients with normal renal function [3]. They found that the risk of acute coronary syndrome was 3.9 times more in the patients with highest plasma ADMA quartile. Other studies have also showed the relationship between the plasma ADMA level and extent of coronary artery disease measured angiographically [4,5]. In CARDIAC study investigators found that plasma ADMA concentration was 20% higher in patients with coronary artery disease in comparison to control group, and the risk of coronary artery disease was increasing 2.35 times with 1μmol/L increase in plasma ADMA concentration [6]. In the AtheroGene study ADMA was found as one of the most powerful markers of cardiovascular events among 1,874 patients with stable coronary artery disease. The cardiovascular event risk was 2.48 times greater in the group with the highest levels of ADMA in comparison to the group with the lowest level of ADMA [7]. These studies show that ADMA is an important factor in the pathophysiology of coronary artery disease and can be used as a marker in risk stratification.
There are two different mechanisms for elimination of ADMA: 1) Renal excretion and 2) inactivation by dimethylarginine dimethylaminohydrolase (DDAH). Abnormalities in renal function can cause an increase in plasma ADMA level and this may contribute to the increased risk for cardiovascular events in these patients. On the other side, DDAH is also very important for the regulation of plasma ADMA level. Probably the problems related with the activity of this enzyme are responsible for the elevation of plasma ADMA level in patients with normal renal function. The activity of DDAH can be suppressed by increased oxidative stress. The conditions like hypertension, diabetes mellitus, and hyperlipidemia which are accepted as risk factors for coronary artery disease are all characterized by an increased oxidative stress in the environment. Inhibition of DDAH due to oxidative stress causes an increase in plasma ADMA level. Increased plasma ADMA level leads to exaggeration of NO insufficiency and a further increase in oxidative stress because of NOS uncoupling resulting in progression of atherosclerosis. Any attempt to decrease oxidative stress or inhibit ADMA may provide the break of this cycle. Treatment of factors leading to increased oxidative stress conditions or L-arginine supplementation to decrease ADMA activity may help solve this problem. Drugs like statins can modify NOS gene expression and lead to increased synthesis of NO. But in some studies statin treatment could not improve endothelial dysfunction. In a recent study, pravastatin was found to increase myocardial blood flow in patients with low ADMA levels [8]. This finding is thought to be related with low ADMA levels. Authors think that the ADMA concentration was not sufficient to block NOS. Since ADMA is the competitive inhibitor of NOS, L-arginine/ADMA ratio is accepted as a more accurate measure of NOS substrate availability than the L-arginine level. L-arginine supplementation increases this ratio independent of the ADMA levels. This may lead to an increase in NO production and may prevent endothelial dysfunction and accumulation of ADMA due to inhibition of DDAH resulting from increased oxidative stress. Although this worked in experimental models, we still do not know the exact results of this strategy.
In the highlights of current evidence we can only say that ADMA is one of the keystones in pathophysiology of coronary artery disease and can be used in risk stratification but further studies are needed to understand the benefit of therapies directed to decrease plasma ADMA levels.References