What is the clinical relevance of measuring ADMA levels?

ADMA is a marker of endothelial dysfunction

 In experimental animals ADMA levels start to increase very rapidly after the induction of dietary hypercholesterolemia. At that time, no overt atherosclerotic lesions can be found macroscopically (Figure 21).
Similarly, in clinically healthy human subjects with isolated hypercholesterolemia and other cardiovascular risk factors elevated ADMA plasma levels have been observed (cf. Figure 18) [8, 71].



Figure 21. ADMA concentrations in cholesterol-fed rabbits over time. Immediately after the onset of a high cholesterol diet ADMA levels start to increase, long before overt atherosclerotic plaques are detectable (from [71] with kind permission of the publishers).


These data suggest that ADMA is an early marker of the initial stages of atherogenesis, which may be useful in the setting of primary prevention to assess a patient`s total cardiovascular risk beyond the information generated by traditional risk factors.

In cholesterol-fed rabbits elevated ADMA levels are correlated with the extent of intimal thickening in the carotid artery, which is regarded as a useful surrogate marker for the progression of atherosclerosis in this animal model (Figure 22) [72].
 

Figure 22. Relationship between ADMA levels and intima/media thickness of the carotid artery in cholesterol-fed rabbits. The statistical relationship between both parameters is closer than that between intima/media thickness and serum cholesterol in this animal model (from [72] with kind permission of the publishers).


Intima-media thickness in the carotid artery as measured by ultrasonography has been shown to be related to the progression of atherosclerosis in humans as well. In a clinical study in patients with end-stage renal failure, a statistically significant relationship between ADMA levels and carotid artery intima-media thickness was observed (Figure 23); in that study, ADMA was the prognostic factor that had the highest predictive power for intimal thickening among all factors tested [73].
 

Figure 23. Relationship between ADMA levels and intima/media thickness of the carotid artery in hemodialysis patients. In this study ADMA was the serujm marker which provided the best prognosis for the degree of progression of intimal thickening during 12 months of follow-up (from [73] with kind permission of the publishers).


Elevated ADMA levels are associated with reduced systemic NO production. The latter can be assessed as reduced urinary excretion of the stable NO metabolites, nitrite and nitrate, in urine, and an impaired endothelium-dependent vasodilation [7, 8].
Taken together, these studies strongly suggest that ADMA is a marker for endothelial dysfunction in humans.
The observation of endothelial dysfunction in a given patient is regarded by many cardiologists as an indicator of an elevated cardiovascular risk for major adverse cardiovascular events or death. This conclusion has been drawn from several prospective clinical studies which have reported that patients with endothelial dysfunction (either measured as vasoconstriction in response to intraarterial infusion of acetylcholine or as impaired flow-induced vasodilation in the brachial artery) have a significantly elevated risk of experiencing major adverse cardiovascular events or death as compared to patients with functionally intact endothelium (either determined as vasodilation in reponse to intraarterial acetylcholine or as flow-induced vasodilation within the range of a healthy control group) in the last few years [74, 75].

As ADMA directly impairs the physiological, NO-dependent functions of the endothelial lining - as described in detail above -, its primary pathophysiological mechanism of action is different from all other known risk factors like hypertension (pressure overload of the arterial wall, reduced arterial elasticity), hypercholesterolemia (uptake of (oxidized) LDL into the intimal layer, generation of foam cells and local inflammation), smoking (induction and potentiation of oxidative damage of cellular structures within the arterial wall), etc. Accordingly, it can be expected that the deleterious effects of ADMA are independent of other risk factors and add to their effects.

ADMA is a novel cardiovascular risk facto

 Beyond the established relationship between elevated ADMA concentration and endothelial dysfunction that was described above, several studies have directly addressed the possible relationship between elevated ADMA levels and the incidence of major adverse cardiovascular events - even more, several groups of researchers observed an association between elevated ADMA concentration and death of any cause.
Miyazaki and co-workers [54] measured plasma ADMA levels in 116 clinically healthy humans who had no overt signs of coronary or peripheral arterial disease. They found a significant relationship between ADMA concentration and age, mean arterial blood pressure, and glucose tolerance. In a multivariate regression analysis, a significant relationship between ADMA and intima-media thickness of the carotid artery was found. From this study the authors concluded that ADMA is a marker for cardiovascular disease.
In a prospective clinical study ADMA plasma levels and numerous other traditional and emerging cardiovascular risk markers were determined in 225 patients with end-stage renal failure undergoing regular hemodialysis treatment [29]. After a median follow-up of 33.4 months, during which all major adverse cardiovascular events and fatalities were recorded and evaluated by an independent committee, 120 major cardiovasular events (fatal and non-fatal) and 83 deaths (53 deaths from cardiovascular causes) were detected. In a multivariate Cox regression analysis, only ADMA and age emerged as significant, independent predictors of the incidence of major adverse cardiovascular events and death of any cause. Patients whose initial ADMA plasma concentration had been above the 75th percentile had a 3-fold elevation of the risk of experiencing a major adverse cardiovascular event as compared to patients whose ADMA had initially been below the median (Figure 24).
 

Figure 24. Incidence of major adverse cardiovascular events in hemodialysis patients during three years of follow-up in relationship to their initial ADMA levels. Patients with high ADMA levels have a high probability of experiencing a major adverse cardiovascular event or death (Data from [29]).


Another group of investigators from the Netherlands studied the survival of patients undergoing intensive care unit treatment, and aimed to identify novel risk factors for survival during ICU treatment [68]. Among all biochemical markers of organ function and disease risk that were measured in this study, ADMA was the factor with the highest predictive power. Patients with elevated ADMA levels had a 17-fold increased risk of fatality during ICU treatment.

Currently numerous case-control studies and prospective clinical trials are being undertaken throughout the world including a wide variety of patient populations that will contribute further to our understanding of the role of ADMA as an independent risk factor for cardiovascular disease and mortality. The data generated in these studies will enhance our ability to determine the role of ADMA as a novel risk factor, and to explore its diagnostic role in different diseases.