Asymmetric Dimethylarginine as a Vascular Risk Factor in Antiepileptic Drug Treated Individuals

We have read the recent article by El-Farahaty et al with great interest. They studied metabolic and atherogenic effects of longterm antiepileptic drugs in a group of 69 Egyptian epileptic patients on antiepileptic drug monotherapy for at least 2 years. Patients were divided into 5 subgroups according to antiepileptic drugs used (valproate, carbamazepine, lamotrigine, topiramate, and levetiracetam). They recruited 34 controls for their study. The authors have measured fasting lipid profile (total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), lipoprotein(a), homocysteine, free thyroxine, thyroid-stimulating hormone, and common carotid artery intima-media thickness in patient and control groups. They demonstrated significantly higher mean values of low-density lipoprotein cholesterol, low-density lipoprotein/high-density lipoprotein ratio, lipoprotein(a), homocysteine, significantly lower mean value of high-density lipoprotein cholesterol, and also significantly larger diameter of common carotid artery intima-media thickness in each drug treated group versus control group. The authors concluded that their study supported that long-term monotherapy treatment with valproate, carbamazepine, lamotrigine, and topiramate had altered markers of vascular risk that might enhance atherosclerosis, whereas levetiracetam exerted minimal effect. They have discussed atherosclerotic markers together with lipid profile, subclinical hypothyroidism, and carotid artery intima-media thickness and assessed their individual longterm metabolic and vascular effects. However, the authors failed to note the role of asymmetric dimethylarginine on the vascular system. It is an endogenous inhibitor of nitric oxide synthase and may cause endothelial dysfunction. A high level of asymmetric dimethylarginine is associated with many of cardiovascular risk factors. Available prospective studies suggest associations between circulating asymmetric dimethylarginine concentration and cardiovascular disease outcomes. Oz et al first demonstrated elevated asymmetric dimethylarginine levels in epileptic patients treated with antiepileptic drugs. They studied asymmetric dimethylarginine levels in 35 newly diagnosed epilepsy patients before and after valproic acid (n 1⁄4 17) and carbamazepine (n1⁄4 18) monotherapies. They found that asymmetric dimethylarginine levels significantly increased after (3rd month) valproic acid (P 1⁄4 .002) and carbamazepine (P 1⁄4 .024) groups. They concluded that elevated asymmetric dimethylarginine levels may be responsible for the increased cardiovascular risk in patients with epilepsy who are receiving antiepileptic drug therapy. This issue has been discussed previously. Ozdemir et al investigated serum asymmetric dimethylarginine, homocysteine, lipid, folate, and vitamin B12 levels in 44 epileptic children under valproic acid monotherapy and 28 healthy children aged between 4 and 16 years. Serum Hcy, asymmetric dimethylarginine, and vitamin B12 levels were higher in patients than in controls (P < .001 for tHcy and asymmetric dimethylarginine levels; P < .05 for vitamin B12 levels). On the other hand Emeksiz et al found no significant differences in homocysteine, asymmetric dimethylarginine, nitric oxide, vitamin B12 and folate levels between children treated with valproic acid, oxcarbazepine, and control groups. We think that the role of asymmetric dimethylarginine should be considered in children treated with antiepileptic drugs. It appears to be another important factor that may increase the long-term risk of atherosclerotic disease in children with epilepsy.