The Role of Asymmetric Dimethylarginine and Arginine in the Failing Heart and its Vasculature

Marlieke Visser; Walter J. Paulus; Mechteld A.R. Vermeulen; Milan C. Richir; Mariska Davids; Willem Wisselink; Bas A.J.M. de Mol; Paul A.M. van Leeuwen


Eur J Heart Fail. 2010;12(12):1274-1281. 

In This Article

Arginine in the Failing Heart and its Vasculature

Arginine and Arginase

As stated previously, plasma arginine levels can be low under conditions of stress, for example following surgery, when this amino acid is excessively catabolized by arginase. Here, the catabolized arginine is no longer available to NOS, hence subsequent NO synthesis by NOS is diminished. As a result, the actions of NO on the heart and its vasculature are disturbed, and superoxide might be produced, which can be harmful for cardiac functioning.[12] Moreover, the polyamines and proline formed after arginase catabolism might be implicated in the development of coronary vascular lesions and subsequent cardiac dysfunctioning.[26] However, the effect of low plasma arginine levels on heart function and blood flow remains unclear when considering the conflicting results of studies performed by our group.[6,27,28] Prins et al.[27] found paradoxical changes after arginase infusion in rats: blood flow to the heart increased while vascular resistance in the heart decreased. In a second rat study, Prins et al.[28] found both unchanged heart rate and stroke volume after arginase infusion. Only after lipopolysaccharide infusion, low arginine levels resulted in higher heart rates and lower stroke volumes, which together maintained cardiac output. Richir et al.[6] infused both arginase and ADMA in rats, which decreased cardiac output and stroke volume. The ratio between the levels of arginine and ADMA probably plays a role in these contradictory results, as this ratio might be a better indicator of NO availability and concomitant haemodynamic and cardiac function than arginine or ADMA concentration alone. For example, when ADMA levels are high, NO synthesis might still be possible when arginine levels are sufficiently high to dislocate ADMA and serve as a substrate for NOS. This hypothesis is supported by the recently reported positive correlation between the arginine/ADMA ratio and cardiac output in critically ill patients.

Arginine Therapy

Studies investigating the impact of arginine on cardiomyocytes are scarce. One in vitro study simulated ischaemia followed by reoxygenation with arginine in myocardial biopsies of patients undergoing CABG surgery.[29] In this study, arginine significantly decreased lactate dehydrogenase leakage but had no effect on viability or oxygen consumption. In another study, pre-anoxic treatment with arginine in a human ventricular heart cell model protected against cellular injury in a dose–dependent way.[30] Additionally, arginine treatment during reoxygenation protected heart cells from low-volume anoxia injury and increased NO production.

In contrast, many clinical trials have been performed in which the effect of arginine administration, either given by infusion or orally, on cardiac and especially vascular function, has been investigated (extended discussion[31]). In healthy volunteers, intravenous arginine infusion significantly reduced systolic and diastolic blood pressure, and increased heart rate, and plasma catecholamine levels.[32] In endotoxin-treated rat hearts, arginine infusion increased coronary blood flow and restored perfusion in ischaemic areas.[10] Furthermore, arginine infusion potentiated the paracrine myocardial contractile effects of receptor-mediated coronary endothelium stimulation in transplant recipients.[33] In summary, the results from other cardiovascular studies using arginine infusion are generally consistent with respect to the beneficial effects of this amino acid on cardiovascular function.

However, the results from cardiovascular studies where oral arginine supplementation was used are not fully consistent. Most of these studies have shown positive or no effects. A possible explanation might be that arginine plasma concentrations have to be elevated above the physiological concentration range in order to induce acute vasodilator effects. Furthermore, it has been proposed that acute arginine supplementation has more effect on NO bioavailability than long-term arginine administration.[31] This might explain, for example, the lack of effect of long-term arginine treatment on ventricular remodelling and heart failure[34] and quality of life[35] in hypertensive rats and in patients with chronic systolic heart failure, respectively. Conversely, in one study increased mortality rates were found in the patient group that received oral arginine after acute myocardial infarction.[36] However, this effect was most probably not an effect of arginine supplementation as plasma arginine levels were not raised in patients that died, and four of the six deaths in the arginine group were almost certainly not related to the amino acid.

In inflammatory states arginine supplementation is more complicated, as more than one study has demonstrated increased mortality rates while administering arginine in critically ill patients.[37] The negative results might be explained by both the involved NOS isoform and the arginine/ADMA ratio. For instance in shock, an arginine-induced excess in NO production by iNOS might be deleterious, as it might lead to detrimental vasodilation and to increased formation of peroxynitrite leading to cellular damage. On the other hand, an increase in NO facilitated by eNOS is of vital importance as it can mediate microvascular vasodilatation. Hence, NO availability needs to be perfectly balanced. Therefore, the effect of arginine supplementation might be influenced by the presence of ADMA. Furthermore, as the arginine/ADMA ratio is in part dependent on the activities of its degrading enzymes arginase and DDAH, the activities of these enzymes might also influence the effect of arginine supplementation.

Therefore, besides the arginine/ADMA ratio, future studies should explore the profile of arginase and DDAH in both blood plasma and cardiac tissue of patients with cardiac dysfunction. The results of these studies could then be used to find out which patient profiles might benefit from arginine supplementation. Given the potential risks of arginine supplementation in inflammatory states, this intervention should first be performed in an experimental setting with and without concomitant iNOS inhibition. Second, the effect of normal nutrition, which itself contains small amounts of arginine, on arginine and ADMA metabolism in the heart, should be investigated. Subsequently, studies can investigate the effect of arginine supplementation or ADMA removal directly or indirectly by influencing arginase and DDAH in cardiac diseases.


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