The role of asymmetric dimethylarginine and
arginine in the failing heart and its vasculature
Marlieke Visser1,2, Walter J. Paulus3, Mechteld A.R. Vermeulen1, Milan C. Richir4,
Mariska Davids5, Willem Wisselink1, Bas A.J.M. de Mol2,
and Paul A.M. van Leeuwen1*
1Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands;2Department of Cardio-thoracic Surgery, Academic Medical Center University of
Amsterdam, Amsterdam, The Netherlands;3Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands;4Department of Surgery, Medical Center
Alkmaar, Alkmaar, The Netherlands; and5Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Received 4 February 2010; revised 1 June 2010; accepted 10 June 2010; online publish-ahead-of-print 5 October 2010
Nitric oxide (NO) is formed from arginine by the enzyme nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) can inhibit
NO production by competing with arginine for NOS binding. Therefore, the net amount of NO might be indicated by the arginine/ADMA
ratio. In turn, arginine can be metabolized by the enzyme arginase, and ADMA by the enzyme dimethylarginine dimethylaminohydrolase
(DDAH). While ADMA has been implicated as a cardiovascular risk factor, arginine supplementation has been indicated as a treatment
in cardiac diseases. This review discusses the roles of ADMA and arginine in the failing heart and its vasculature. Furthermore, it proposes
nutritional therapies to improve NO availability.
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Asymmetric dimethylarginine † Arginine † Failing heart † Coronary vasculature † Nutritional therapy
Nitric oxide (NO) is a prominent compound in the heart and its
vasculature and plays an intriguing role in the physiology of this
organ.1In the coronary vasculature, NO is involved in vasodilata-
tion, down regulation of cellular adhesion molecules, inhibition of
platelet aggregation, vascular proliferation, and angiogenesis. In car-
diomyocytes, the actions of NO are more complex as it can induce
different, and sometimes opposing effects on cardiac functioning
such as triggering apoptosis and improving left ventricular function.
Nitric oxide is formed from the amino acid arginine by the
enzyme nitric oxide synthase (NOS), simultaneously with citrulline.
Three different isoforms of NOS are known: neuronal NOS
(nNOS or NOS1), endothelial NOS (eNOS or NOS3), and indu-
cible NOS (iNOS or NOS2). Arginine is a semi-essential amino
acid, meaning that under healthy conditions, endogenous arginine
production is adequate for metabolic needs, but under stress con-
ditions, when arginine is excessively catabolized by the enzyme
arginase, dietary intake of this amino acid is required.
asymmetric dimethylarginine (ADMA).2As a consequence, ADMA
by the enzyme dimethylarginine dimethylaminohydrolase (DDAH).
Since ADMA inhibits NO production by competing with arginine for
NOS binding, the net amount of NO production might be indicated
by the ratio between substrate and inhibitor: the arginine/ADMA
ratio. Therefore, the detrimental effect of ADMA might be inhibited
by increasing the concentration of arginine or the concentration of
ofNOS by ADMA. Inthis review, we focus on therole of ADMA and
arginine in the failing heart and its vasculature. Furthermore, we will
discuss therapies to reduce the deleterious effects of ADMA,
especially that of arginine and its precursor’s citrulline and glutamine.
peting with arginine for NOS binding.2N-monomethy L-arginine
concentrations in plasma, however, are much lower compared with
plasma ADMA concentrations. N-monomethy L-arginine is formed
when protein-incorporated arginine is methylated by the enzymes
protein arginine methyltransferases (PRMT)-1 or PRMT-2 (Figure 1).
Protein arginine methyltransferases-1 can subsequently methylate
NMMA, resulting in the formation of ADMA, whereas PRMT-2 can
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Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: email@example.com.
European Journal of Heart Failure (2010) 12, 1274–1281
methylate NMMA into symmetric dimethylarginine (SDMA). After
proteolysis, the methylated arginines are released as unbound forms
in the cytosol where NMMA and ADMA are able to inhibit NOS. In
contrast to ADMA, SDMA is not able to inhibit NOS. All methylated
carriers of the cationic amino acid transporter (CAT) family, from
whichtheycanbetakenupbyothercellsthat use the same transpor-
ters. Cationic amino acid transporters also facilitate the transport of
arginine across the cell membrane. All methylated arginine meta-
bolites are considered to interfere with NO synthesis indirectly,
because the methylated arginine analogues compete with arginine
activity and only small amounts of NMMA are found in the plasma,
ADMA is considered to be the major inhibitor of NO availability.
Asymmetric dimethylarginine is excreted into the urine for ,20%.
The major part of the NOS inhibitor is cleared by the enzymes
DDAH-1 and DDAH-2 resulting in the formation of citrulline and
dimethylamine. Both the expression and the activity of DDAH seem
to be regulated by NO through feedback mechanisms.2
the circulation by CAT into the liver, kidney, and endothelial cells.
Besides dietary intake, arginine availability depends on endogenous
release through protein degradation, on synthesis from citrulline by
the enzymes argininosuccinate synthase (ASS) and argininosuccinate
be converted into arginine in the kidney (Figure 1).
Arginine can be incorporated into proteins by the enzyme
arginyl-tRNA synthetase (ATS) or can be used as a substrate in
four metabolic pathways (Figure 1). First, arginine can be converted
into agmatine by arginine decarboxylase (ADC). The second meta-
bolic pathway is creatine synthesis by the conversion of arginine by
arginine glycine amidinotransferase (AGAT) to guanidinoacetic
acid, which is converted to creatine. Creatine is converted into
creatine phosphate, which is an important form of stored energy
in (cardiac) muscle tissue. The third pathway is the conversion of
arginine into NO and citrulline facilitated by NOS. Nitric oxide
can subsequently diffuse into the vascular smooth muscle layer
resulting in cGMP-mediated relaxation and vasodilation. Although
the concentration of arginine in endothelial cells is higher than
necessary to saturate NOS, it has been shown that increased
extracellular arginine can be taken up by endothelial cells and
can contribute to NO production, a phenomenon called ‘the argi-
nine paradox’.3The arginine/ADMA ratio might play a role in this
paradox since this ratio reflects the amount of substrate (arginine)
relative to inhibitor of NOS (ADMA), which can be considered as
a better indicator of NO production than ADMA or arginine con-
centration separately. The last metabolic pathway of arginine is its
conversion into urea and ornithine by the enzyme arginase. Two
isoforms of arginase are known: type I metabolizes arginine in
Figure 1 Synthesis and metabolism of asymmetric dimethylarginine and arginine. ADC, arginine decarboxylase; ADMA, asymmetric dimethyl-
arginine; AGAT, arginine glycine amidinotransferase; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; ATS, arginyl-tRNA synthe-
tase; CAT, cationic amino acid transporter; DDAH, dimethylarginine dimethylaminohydrolase; NMMA, N-monomethyl-arginine; NO, nitric
oxide; NOS, nitric oxide synthase; OAT, ornithine aminotransferase; ODC, ornithine decarboxylase; PRMT, protein arginine methyltransferase;
SDMA, symmetric dimethylarginine.
Role of ADMA and arginine in the failing heart
the cytosol, whereas type II is active in the mitochondria. Ornithine
can be converted into polyamines by the enzyme ornithine decar-
boxylase (ODC) and into proline and glutamate by ornithine ami-
Asymmetric dimethylarginine in
the failing heart and its vasculature
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 pro-
gression and mortality in heart failure patients (Figure 2), in critically
ill patients,4and in the community.5Furthermore, 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 deterio-
rated stroke volume and cardiac output in rats.6The detrimental
effects of ADMA on the heart and subsequent outcome might
be explained by disturbed NO synthesis.1Nevertheless, NOS
inhibitors have been proposed as a treatment for the overproduc-
tion 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 inhi-
bition resulted in a modest increase in mean arterial pressure7and
reduced mortality rate.8In contrast, in a large clinical trial, another
NOS inhibitor increased the mortality rate of septic shock
patients.9Mortality and adverse events in the treatment group
were associated with cardiovascular death and haemodynamic dys-
function, including heart failure and decreased cardiac output. In
Antoniades (2009)CAD Patients (201)
Table 1 Observational studies on asymmetric dimethylarginine and cardiac diseases
ReferenceConditionSubjects (n) Results
ADMA correlated with, and independently predicted,
vascular superoxide generation
ADMA associated with eNOS coupling
? ADMA in patients
ADMA and arginine/ADMA not associated with cardiovascular
ADMA associated with all-cause mortality
? ADMA was not associated with occurrence of an endpoint
Reperfusion of cardioplegic heart did not release ADMA
? Arterial ADMA by the first post-operative morning
Arginine/ADMA positively correlated with collateral development
Arginine/ADMA and ADMA independently predicted collateral
Patients (81)and controls (40) ? ADMA in unstable compared with stable angina
? Event rate in patients with persistently ? ADMA
Patients and controls (158)
? ADMA in patients
ADMA independently predicted mortality
Patients (23)and controls (26) ? ADMA in patients
Patients and controls (62)
? ADMA and ? arginine/ADMA in patients
ADMA and arginine/ADMA ratio correlated with, and
independently predicted coronary flow
Mice (100)ADMA accumulated in myocardial tissue
? ADMA associated with ? natriuretic peptide levels and LV
? ADMA associated with advanced RV systolic dysfunction
? ADMA independently predicted adverse clinical events
Hospitalized patients (84)
? ADMA in HF patients
ADMA positively correlated with disease severity
Patients (19)Arginine/ADMA correlated positively with CO
? ADMA in survivors compared with non-survivors
? ADMA in patients with AF recurrence
ADMA independently predicted AF recurrence
Bo ¨ger (2009)
Patients and controls (96)
Du ¨ckelmann (2008)
Kocaman (2008) Epicardial coronary artery
Krempl (2005)Stable and unstable angina
Nicholls (2007) Cardiogenic shock
Slow coronary flow
Myocardial I/R injury
Chronic systolic HF
Visser (2010)Septic shock
Xia (2008)Persistent AF
References can be found in the online Supplementary material. ACS, acute coronary syndromes; ADMA, asymmetric dimethylarginine; AF, atrial fibrillation; CAD, coronary artery
disease; CHF, congestive heart failure; CO, cardiac output; eNOS, endothelial nitric oxide synthase, HF, heart failure; LV, left ventricle; RV, right ventricle.
M. Visser et al.
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 pathol-
ogy due to inhibition of eNOS, which can ultimately result in myo-
cardial dysfunction. Therefore, non-selective inhibition of NOS
cannot be recommended in the critically ill patient.
Overall, many studies have shown that ADMA can induce detri-
mental effects (Tables 1 and 2). These unfavourable actions are pri-
marily the result of diminished NO availability, resulting in
disturbed vasodilatation and anti-thrombotic, anti-inflammatory,
and anti-apoptotic actions that overall might induce cardiac dys-
function (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 activity11and can lead
to oxidation of cellular components in cardiomyocytes, such as
proteins critical for excitation–contraction coupling.12It can also
lead to increased susceptibility of cardiomyocytes to cell death,
which can finally lead to cardiac dysfunction.
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.13Altered
expression of CAT, which transports ADMA across the cell mem-
brane, is also doubtful since both reductions and increases in CAT
expression have been found in heart failure patients.14,15Another
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,
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.
Achan (2003)Healthy Volunteers (12)
Cable (2009) Pre-contracted
Richir (2009) HealthyRats (21)
Suda (2004) eNOS deficient Knock-out (10) and
wild-type (10) mice
Takemoto (1997) HealthyRats (100)
Table 2 Studies on asymmetric dimethylarginine infusion and the heart
ReferenceCondition Subjects (n) Results
? HR and CO
Inhibition of endothelium-dependent relaxationCanine (7)
Perfused heartsRat (20)
? Systolic blood pressure, ? HR, ? ventricular stiffness with worsening
of post-ischaemic ventricular dysfunction
? CO and SV
Coronary microvascular lesions and ? superoxide production
Vascular remodelling and myocardial hypertrophy
References can be found in the online Supplementary material. ADMA, asymmetric dimethylarginine; CO, cardiac output; eNOS, endothelial nitric oxide synthase, HR, heart rate;
SV, stroke volume.
Role of ADMA and arginine in the failing heart
ADMA correlated negatively with glomerular filtration rate (eGFR,
used as indicator for renal function),16whereas in patients with
acute myocardial infarction, a relationship between ADMA and
eGFR was not present.17Finally, 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 con-
tributing factor to elevated ADMA levels in cardiac dysfunction.
It has been estimated that DDAH metabolizes .80% of the
?300 mmol of ADMA that is generated daily in humans.18Further-
more, complete malfunction of DDAH can lead to a daily increase
in plasma ADMA concentrations of ?5 mmol/L. Indeed, DDAH
activity and expression were reduced in dogs with congestive
heart failure13and atrial fibrillation.19The results of murine
studies suggest that DDAH has healing capacities, as its expression
and activity increased after ischaemia20and reperfusion,21and
overexpression of the enzyme reduced reperfusion injury.21In
the infarcted rat heart, the increased levels and activity of both
DDAH-1 and DDAH-2 were associated with a retained arginine/
ADMA ratio.20Therefore, 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.22Overall, these studies imply the ability
of DDAH to locally regulate ADMA concentrations and the con-
comitant NO synthesis in the heart. Studies are now needed to
investigate whether this mechanism of DDAH metabolism is also
applicable in the human heart.
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 cardio-
vascular drugs, or non-pharmacological therapies such as invasive
procedures and nutritional interventions. Pharmacological studies
focusing on lowering ADMA levels in cardiac diseases show pro-
mising results (Table 3). However, the mechanisms by which
these treatments reduce ADMA levels are still not fully under-
stood. The expression and/or activity of DDAH are probably upre-
gulated. Indeed, beta-blockers reduced ADMA levels via an
increase in DDAH-2 expression and activity in HUVECs.23Fur-
thermore, all-trans-retinoic acid24and insulin25stimulated DDAH
expression24and activity25which resulted in decreased ADMA
levels in murine endothelial cells and HUVECs, respectively.
A possible mechanism might be that these treatments lower oxi-
dative stress which preserves DDAH activity and reduces accumu-
lation of ADMA.11Unfortunately, to the best of our knowledge,
there are no studies investigating DDAH induction or PRMT
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.
Ajtay (2008)Coronary heart disease (50)
Bae (2005) and Yada (2007) ACS (48) and healthy controls (48), AMI (9) and healthy
Chen (2002)Syndrome X (20)
Table 3 Studies of asymmetric dimethylarginine reducing therapies in cardiac diseases
ReferenceCondition of patients (n) Therapy Effect on
ACE-inhibitors, angiotensin receptor
Sen (2009) and Alfieri (2008)
Chronic HF (18) and healthy controls (9)
Chronic HF (22) and healthy controls (22)
Heart transplantation (32)
Ischaemic HF (145) and healthy controls (42)
Syndrome X (38), HF (22)
Chronic HF (24)
References can be found in the online Supplementary material. ACE, angiotensin converting enzyme; ACS, acute coronary syndromes; ADMA, asymmetric dimethylarginine; AMI,
acute myocardial infarction; CAD, coronary artery disease; CABG, coronary artery bypass grafting; HF, heart failure; PCI, percutaneous coronary intervention.
M. Visser et al.
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.
Arginine in the failing heart
and its vasculature
Arginine and arginase
As stated previously, plasma arginine levels can be low under con-
ditions 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 syn-
thesis 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.12More-
over, the polyamines and proline formed after arginase catabolism
might be implicated in the development of coronary vascular
lesions and subsequent cardiac dysfunctioning.26However, 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.6,27,28Prins et al.27found paradox-
ical 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.28found both unchanged heart rate
and stroke volume after arginase infusion. Only after lipopolysac-
charide infusion, low arginine levels resulted in higher heart rates
and lower stroke volumes, which together maintained cardiac
output. Richir et al.6infused 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 indi-
cator 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 dislo-
cate 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
Studies investigating the impact of arginine on cardiomyocytes are
scarce. One in vitro study simulated ischaemia followed by reoxy-
genation with arginine in myocardial biopsies of patients under-
going CABG surgery.29
In this study, arginine significantly
decreased lactate dehydrogenase leakage but had no effect on via-
bility or oxygen consumption. In another study, pre-anoxic treat-
ment 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
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 inves-
tigated (extended discussion31). In healthy volunteers, intravenous
arginine infusion significantly reduced systolic and diastolic blood
pressure, and increased heart rate, and plasma catecholamine
levels.32In endotoxin-treated rat hearts, arginine infusion increased
coronary blood flow and restored perfusion in ischaemic areas.10
Furthermore, arginine infusion potentiated the paracrine myocar-
dial contractile effects of receptor-mediated coronary endothelium
stimulation in transplant recipients.33In 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 pro-
posed that acute arginine supplementation has more effect on NO
bioavailability than long-term arginine administration.31This might
explain, for example, the lack of effect of long-term arginine treat-
ment on ventricular remodelling and heart failure34and quality of
life35in 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.36However, 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 compli-
cated, as more than one study has demonstrated increased mor-
tality 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 vaso-
dilatation. Hence, NO availability needs to be perfectly balanced.
Therefore, the effect of arginine supplementation might be influ-
enced 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 supplemen-
tation. 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
Role of ADMA and arginine in the failing heart
contains small amounts of arginine, on arginine and ADMA metab-
olism 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.
Citrulline and glutamine therapy
Another method for upregulating the arginine/ADMA ratio is by
increasing the concentration of the arginine precursors, citrulline
or glutamine. These compounds may influence the competitive
inhibition of NOS.
The maintenance of high plasma arginine concentrations may be
problematic because of its catabolism by arginase. The effective-
ness of arginine therapy might be reduced in several cardiovascular
disorders in which intestinal and cytosolic arginase expression and
activity are enhanced.38In contrast to arginine, citrulline is not
metabolized in the intestine or liver and it does not induce
tissue arginase, it even inhibits its activity. Citrulline is largely
absorbed and metabolized by the kidney, where it can be con-
verted into arginine. For these reasons, administration of citrulline
might be an alternative way to improve cardiac functioning in dis-
eases that are associated with arginine deficiency or increased argi-
Compared with the high number of studies investigating the
effect of arginine, only a few investigators have studied the effect
of citrulline supplementation on heart function. In healthy volun-
teers, administration of oral citrulline augmented NO-dependent
signalling.39Oral citrulline supplementation increased plasma con-
centrations of both citrulline and arginine in children undergoing
cardiopulmonary bypass surgery and reduced post-operative pul-
Although these limited results might suggest citrulline sup-
plementation as a promising method in diseases of the heart,
more studies are needed to support the use of citrulline adminis-
tration. Furthermore, it should be taken into account that arginine
obtained by synthesis of citrulline is calculated to represent 78% of
the whole-body plasma citrulline turnover, whereas only 11% of
the whole-body plasma flux of arginine is obtained by de novo syn-
thesis of arginine from citrulline.41
Glutamine is a precursor of citrulline, which in turn is mainly
metabolized to arginine in the kidney. This might make supplemen-
tation of glutamine a more physiological way to produce arginine.
In a rat model, increased plasma arginine levels obtained from a
glutamine-enriched enteral diet induced an increase in splanchnic
blood flow.42However, the mean daily urinary nitrate excretion
in this study did not differ between groups, suggesting that NO
production did not play a role in the vasodilatory responses of glu-
tamine. Other studies have shown inhibitory effects of glutamine
on endothelial NO synthesis.43In contrast to NO production by
the constitutive NOS isoforms, glutamine seems to be required
for NO production by iNOS. This might explain why optimal
plasma glutamine levels are needed for optimal NO synthesis by
iNOS, particularly in conditions such as sepsis and infection,
which is underlined by several studies that have shown valuable
effects of glutamine as an immunological form of nutrition.44
These studies further suggest that supplementation of glutamine
might be more beneficial in disease states of immunological impair-
ment, whereas glutamine might be less advantageous in the failing
heart and its vasculature.
Summary and conclusion
By inhibiting NOS, ADMA affects the correct functioning of the
heart; studies have shown that ADMA is involved in vasoconstric-
tion, cardiac remodelling, fibrosis, disturbance of angiogenesis and
cardiac performance, myocardial ischaemia, and even mortality.
These results show that ADMA is not only a risk factor for cardi-
ovascular disease, but also an indicator of outcome in patients with
cardiac dysfunction. The elevated ADMA levels shown in cardiac
disorders are thought to be the result of diminished activity and/
or expression of its metabolizing enzyme DDAH. Upregulation
of DDAH has been shown to reduce ADMA with a concomitant
increase in NO production resulting in beneficial effects for the
heart and its vasculature. As ADMA competes with arginine for
NOS binding, the net amount of NO might not only depend on
ADMA levels but also on arginine concentrations, which can be
reflected by the arginine/ADMA ratio.
Arginine levels can be insufficient under catabolic conditions in
which arginase catalyses arginine. Interestingly, increased extra-
cellular arginine can be taken up by endothelial cells and can con-
tribute to NO synthesis. Therefore, arginine supplementation,
especially by infusion, seems beneficial under conditions of
cardiac dysfunction without inflammation. The impact of the argi-
nine precursors citrulline and glutamine is less apparent. More
research is needed to investigate the ability of nutritional therapies
to increase the arginine/ADMA ratio directly or indirectly via its
degrading enzymes arginase and DDAH, respectively, which
might enhance NO availability with a concomitant improvement
in cardiac function.
Supplementary material is available at EURJHF online.
M.V. was supported by the Egbers Foundation.
Conflict of interest: none declared.
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