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

Disclosures

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

In This Article

Asymmetric Dimethylarginine in the Failing Heart and its Vasculature

Asymmetric Dimethylarginine

Since ADMA has been shown to inhibit NO synthesis its role in cardiac, and especially (coronary) vascular dysfunction has been investigated extensively. Elevated ADMA levels have been found in a variety of cardiac diseases (Table 1). More importantly, ADMA is indicated to have prognostic capacities for disease progression and mortality in heart failure patients (Figure 2), in critically ill patients,[4] and in the community.[5] Furthermore, ADMA infusion has been shown to impair relaxation of coronary arteries, induce myocardial remodelling, deteriorate cardiac function, and cause myocardial ischaemia (Table 2). Together with low arginine levels (as induced by arginase infusion), ADMA infusion further deteriorated stroke volume and cardiac output in rats.[6] The detrimental effects of ADMA on the heart and subsequent outcome might be explained by disturbed NO synthesis.[1] Nevertheless, NOS inhibitors have been proposed as a treatment for the overproduction of NO in sepsis and cardiogenic shock. The underlying hypothesis is that the increased production of NO by iNOS in shock contributes to hypotension and multiple organ dysfunction. However, results of several randomized trials investigating NOS inhibitors are conflicting. In cardiogenic shock patients, NOS inhibition resulted in a modest increase in mean arterial pressure[7] and reduced mortality rate.[8] In contrast, in a large clinical trial, another NOS inhibitor increased the mortality rate of septic shock patients.[9] Mortality and adverse events in the treatment group were associated with cardiovascular death and haemodynamic dysfunction, including heart failure and decreased cardiac output. In addition, administration of NOS inhibitors reduced coronary flow and induced local ischaemia in endotoxin-treated rat hearts.[10] These effects can probably be explained by microvascular pathology due to inhibition of eNOS, which can ultimately result in myocardial dysfunction. Therefore, non-selective inhibition of NOS cannot be recommended in the critically ill patient.

Figure 2.

Asymmetric dimethylarginine as a predictor of prognosis in patients with heart failure (references for Nicholls (2007), Wilson Tang (2008) and Usui (1998) can be found in the online Supplementary material). ADMA, asymmetric dimethylarginine; NOS, nitric oxide synthase; HF, heart failure; ROS, reactive oxygen species.

Overall, many studies have shown that ADMA can induce detrimental effects (Tables 1 and 2). These unfavourable actions are primarily the result of diminished NO availability, resulting in disturbed vasodilatation and anti-thrombotic, anti-inflammatory, and anti-apoptotic actions that overall might induce cardiac dysfunction (Figure 2). Furthermore, ADMA is able to uncouple NOS after which NOS becomes a source of superoxide radicals instead of producing NO (Figure 3). Asymmetric dimethylarginine infusion has been shown to increase superoxide production (Table 2). The increase in production of reactive oxygen species after NOS uncoupling can inhibit DDAH activity[11] and can lead to oxidation of cellular components in cardiomyocytes, such as proteins critical for excitation–contraction coupling.[12] It can also lead to increased susceptibility of cardiomyocytes to cell death, which can finally lead to cardiac dysfunction.

Figure 3.

(A) Arginine-induced NO production; (B) ADMA-provoked NOS uncoupling. ADMA, asymmetric dimethylarginine; CAT, cationic amino acid transporter; NO, nitric oxide; NOS, nitric oxide synthase.

The increased plasma ADMA levels seen in several diseases of the heart and its vasculature might be explained by either increased intracellular production and/or decreased excretion from the plasma. However, PRMT-1 expression was unchanged in the hearts of dogs with congestive heart failure.[13] Altered expression of CAT, which transports ADMA across the cell membrane, is also doubtful since both reductions and increases in CAT expression have been found in heart failure patients.[14,15] Another explanation might be found in high ADMA levels resulting from impaired renal function, which is often seen in heart failure patients. However, in patients with coronary artery disease, ADMA correlated negatively with glomerular filtration rate (eGFR, used as indicator for renal function),[16] whereas in patients with acute myocardial infarction, a relationship between ADMA and eGFR was not present.[17] Finally, increased ADMA levels can be the result of reduced DDAH activity and/or expression. Since ADMA catabolism is mainly regulated by DDAH, it can be hypothesized that a reduction in DDAH induction is the main contributing factor to elevated ADMA levels in cardiac dysfunction.

Dimethylarginine Dimethylaminohydrolase

It has been estimated that DDAH metabolizes >80% of the ~300 µmol of ADMA that is generated daily in humans.[18] Furthermore, complete malfunction of DDAH can lead to a daily increase in plasma ADMA concentrations of ~5 µmol/L. Indeed, DDAH activity and expression were reduced in dogs with congestive heart failure[13] and atrial fibrillation.[19] The results of murine studies suggest that DDAH has healing capacities, as its expression and activity increased after ischaemia[20] and reperfusion,[21] and overexpression of the enzyme reduced reperfusion injury.[21] In the infarcted rat heart, the increased levels and activity of both DDAH-1 and DDAH-2 were associated with a retained arginine/ADMA ratio.[20] Therefore, DDAH may provide local regulation of ADMA and subsequent NO synthesis, specifically in cells that play a role in the healing process after myocardial infarction. This explanation is in line with results from a study in human umbilical vein endothelial cells (HUVECs) in which DDAH-2 upregulation was associated with an increase in vascular endothelial growth factor expression, which stimulated angiogenesis and enhanced vessel tube formation.[22] Overall, these studies imply the ability of DDAH to locally regulate ADMA concentrations and the concomitant NO synthesis in the heart. Studies are now needed to investigate whether this mechanism of DDAH metabolism is also applicable in the human heart.

Therapy

As it is clear that ADMA can induce deleterious effects in the heart and its vasculature, treatments are needed that can reduce ADMA levels or alter its metabolism. Studies that have investigated such treatments used either pharmacological therapies such as cardiovascular drugs, or non-pharmacological therapies such as invasive procedures and nutritional interventions. Pharmacological studies focusing on lowering ADMA levels in cardiac diseases show promising results (Table 3). However, the mechanisms by which these treatments reduce ADMA levels are still not fully understood. The expression and/or activity of DDAH are probably upregulated. Indeed, beta-blockers reduced ADMA levels via an increase in DDAH-2 expression and activity in HUVECs.[23] Furthermore, all-trans-retinoic acid[24] and insulin[25] stimulated DDAH expression[24] and activity[25] which resulted in decreased ADMA levels in murine endothelial cells and HUVECs, respectively. A possible mechanism might be that these treatments lower oxidative stress which preserves DDAH activity and reduces accumulation of ADMA.[11] Unfortunately, to the best of our knowledge, there are no studies investigating DDAH induction or PRMT inhibition in the normal or diseased heart. Interestingly, ADMA levels are reduced in patients after invasive procedures such as percutaneous coronary intervention and coronary artery bypass grafting (CABG) (Table 3). Of the nutritional interventions, the amino acid arginine is the most extensively investigated nutrient, which can lower plasma ADMA levels by reversing its competitive inhibition of NOS.

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