The most significant finding of the present study is that plasma levels of SDMA, measured at hospital presentation, are elevated in NSTEMI patients with CKD, and are independent early predictors of the composite outcome of cardiac death and myocardial infarction.
Chronic kidney disease is present in a substantial proportion of patients with ACS and represents a potent and independent risk factor for short- and long-term adverse outcome 
. The reasons for this close association, however, are not completely clear and cannot be entirely explained by the clustering of the traditional cardiovascular risk factors. Besides clinical and therapeutic differences, it is likely that peculiar characteristics of renal insufficiency may play a considerable role 
. It has been hypothesized that the excessive risk associated with CKD can be attributed, at least in part, to endothelial dysfunction and reduced bioavailability of NO, a potential link between CKD and cardiovascular disease.
Elevated plasma concentrations of ADMA have been found in various clinical settings, ranging from critically ill patients admitted to the Intensive Care Unit 
to patients with CKD 
and end-stage renal disease 
, with stable coronary artery disease 
, and to those undergoing coronary angiography 
and non-cardiac surgery 
. In all these conditions, elevation of ADMA has been identified as an independent risk factor for future adverse cardiovascular events and death. It has been proposed that, by inhibiting NO synthesis, ADMA may contribute directly to endothelial dysfunction, depression of cardiac function, progression of chronic renal disease, and organ failure 
. Recently, ADMA has also been measured in patients with ACS 
. In a study by Cavusoglu et al. 
, plasma levels of ADMA were measured in a cohort of 182 men with ACS. The authors found that elevated plasma levels of ADMA were powerful and independent predictors of adverse cardiovascular outcomes. In particular, ACS patients who had the upper tertile of baseline ADMA had a significantly higher two-year mortality than those in the lower two tertiles combined (23.8% vs. 8.6%; P
In most previous studies, investigators focused mainly on ADMA and, until recently, little attention has been paid to the role of its structural isomer SDMA. To our knowledge, this is the first study evaluating the association between plasma levels of both dimethylarginines and long-term outcome in ACS. In our study, no increase in ADMA levels in plasma were found in comparison with healthy subjects, not even when the whole study group, as well as the two subsets of patients stratified according to the presence or absence of CKD, were considered. Moreover, no significant association between ADMA levels and clinical outcome was observed. Some important clinical (patients characteristics, type [STEMI vs. NSTEMI] and severity of ACS), methodological and analytical (ELISA vs. HPLC) differences among studies may explain the apparent inconsistency between our data and those previously published, regarding the capacity of ADMA to predict cardiac events in ACS 
Both dymethylarginines are physiologically present in plasma as a product of normal protein turnover. However, as SDMA is mainly eliminated by renal excretion, whereas ADMA is largely metabolized, it is not surprising to find a closer relationship between renal impairment and SDMA than with ADMA. The increase in SDMA observed in our study in CKD patients, as well as the good correlation found between SDMA and eGFR, are in agreement with a previous meta-analysis showing a strong correlation between SDMA and renal function 
. As there is a high concentration of the ADMA degrading enzyme (DDAH) in the kidney, it is also conceivable that the decline in renal excretory function is paralleled by a reduction of DDAH activity (in the kidney). This, and the fact that about 10% of ADMA formed is also excreted by the kidneys, might explain why also ADMA is weakly related to parameters of renal function in some of the studies, including the present one.
When patients were stratified by median SDMA plasma concentration, a significant difference in long-term clinical outcome was found. Notably, SDMA was a stronger predictor of cardiac events, in particular re-infarction, than CKD, as defined according to GFR estimated by serum creatinine. The mechanism(s) linking SDMA and outcome, however, remains uncertain. Several mechanisms may potentially explain this association. First, SDMA might directly influence the outcome of ACS patients by participating to cause reduction in NO production and induction of endothelial dysfunction. Although SDMA has not been shown to directly affect NO synthase activity in vitro
, we cannot exclude its influence on the production of NO in some clinical conditions characterized by its increase in plasma. Indeed, SDMA may have an indirect effect on NO synthesis, by inhibiting the y+ transporter that mediates the intracellular uptake of L-arginine and renal tubular arginine absorption 
. These two mechanisms might indirectly inhibit NO synthesis by interfering with L-arginine uptake. Second, SDMA accumulation in the plasma due to reduced renal clearance might only reflect kidney dysfunction. Many studies have shown a good correlation between SDMA and established estimates of GFR in humans, as well as in animal models 
. Based on these premises, SDMA fulfills all criteria for an ideal GFR marker, i.e. stable production rate, free glomerular filtration, and lack of tubular reabsorption 
. On the other hand, estimates of GFR from serum creatinine may lack in necessary sensitivity due to considerable inter-individual variability in muscle mass, protein intake, age, and sex 
. This limitation is even more critical in ACS, a clinical setting in which no renal baseline conditions are available and serum creatinine levels at hospital admission cannot be considered a true stable value because the occurrence of a transient hemodynamic impairment, which in turn results in the increase of serum creatinine in the plasma. Moreover, creatinine increase may lag far behind glomerular filtration changes, because of its delayed rise after renal injury, due to the slow variations in its metabolism and the exponential relationship existing between these two variables. Thus, it is likely that SDMA is able to more accurately reflect glomerular filtration than creatinine and its levels in plasma may better identify the “true” CKD patients with a worse prognosis. According to this hypothesis, the lower SDMA values in CKD controls than in NSTEMI patients with CKD, might be explained by the higher eGFR in the former than in the latter group (51±7 and 48±9 ml/min per 1.73 m2
, respectively). The list of mechanisms through which SDMA might directly contribute to unfavorable outcomes in ACS patients, however, is most likely not yet complete. In our study, SDMA levels in plasma were correlated with hs-CRP levels at hospital presentation, suggesting a possible role in promoting inflammatory response. A recent study has shown that SDMA is involved in the inflammatory process of CKD, by activating intracellular monocytic expression of interleukin 6 and tumor necrosis factor-alpha in vitro
, whereas ADMA does not. This pro-inflammatory profile has been confirmed in a clinical study in which SDMA was associated with inflammatory markers 
. Finally, a possible procoagulant state due to induction of tissue factor expression by peripheral monocytes, like that demonstrated for ADMA in ACS patients, cannot be excluded for SDMA 
Our data provide a basis for future studies which will investigate whether determination of SDMA, as well as its pharmacologic modulation, may help to guide care and improve outcomes of ACS patients. Irrespectively of its potential role in the pathophysiology of long-term adverse cardiac events, SDMA determination may have a considerable clinical usefulness in risk stratification of ACS patients. In particular, measurement of SDMA might allow for a more accurate and early recognition of CKD patients, who may require drug dose adjustments, renal prophylactic strategies, and targeted therapeutic interventions. Moreover, in these patients, long-term prognostic stratification may be more precise. Notably, in our study, we identified a potential cutoff value of SDMA of 0.46 µmol/L (median value) for risk classification.
Our study has some limitations. First, the size of the population is small and the findings need to be confirmed in larger studies. Similarly, the number of cardiac events is small, possibly due to the exclusion of high-risk patients from the study. Although this may represent an important limitation, the impossibility to differentiate between CKD and acute kidney injury on the bases of a single creatinine value measured at hospital admission, could have almost certainly lead to overestimate the number of patients with CKD. Nonetheless, the ADMA and SDMA levels in ACS patients developing acute kidney injury, as well as their possible association with short- and long-term outcomes, are not known and should be matter of future investigation. Second, being an observational study, our data do not unequivocally demonstrate that SDMA increase in plasma levels contributes to mortality and re-infarction. Further studies should investigate the relationship between SDMA increase and endothelial dysfunction, possibly evaluating endothelial-dependent vasodilatory response. Finally, we cannot exclude the possibility that some medications, taken by patients before hospital admission, may have influenced our results. Indeed, ADMA concentration has been shown to significantly decrease in ACS patients after a short-term medical therapy