From the Department of Internal Medicine and Division of Cardiovascular
Diseases, Mayo Clinic and Foundation, Rochester, Minn.
Correspondence to Amir Lerman, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail lerman.amir{at}mayo.edu
Methods and Results—Twenty-six patients without significant
coronary artery disease on coronary angiography and
intravascular ultrasound were blindly randomized to either oral
L-arginine or placebo, 3 g TID.
Endothelium-dependent coronary blood flow
reserve to acetylcholine (10-6 to 10-4 mol/L)
was assessed at baseline and after 6 months of therapy. There was no
difference between the two study groups in clinical characteristics or
in the coronary blood flow in the response to acetylcholine at
baseline. After 6 months, the coronary blood flow in response
to acetylcholine in the subjects who were taking L-arginine
increased compared with the placebo group (149±20% versus 6±9%,
P<0.05). This was associated with a decrease in plasma
endothelin concentrations and an improvement in patients' symptoms
scores in the L-arginine treatment group compared with the
placebo group.
Conclusions—Long-term oral L-arginine supplementation
for 6 months in humans improves coronary small-vessel
endothelial function in association with a significant
improvement in symptoms and a decrease in plasma endothelin
concentrations. This study proposes a role for L-arginine
as a therapeutic option for patients with coronary
endothelial dysfunction and nonobstructive
coronary artery disease.
Previous studies in experimental animals and humans that used either
feeding or intravenous infusion of L-arginine
have shown that L-arginine improves peripheral
endothelium-dependent dilatation, inhibits platelet
aggregation, and may reduce
atherosclerosis.8 9 10 11 Moreover,
short-term intracoronary administration of
L-arginine improves coronary
endothelial response to acetylcholine in
hypercholesterolemic subjects.12
Supplemental oral L-arginine in patients with heart failure
resulted in improvement in symptoms in association with a decrease in
plasma endothelin concentrations.13 To date, the
effect of long-term administration of L-arginine on
coronary endothelial function is unknown. Thus,
the present study was designed to test the hypothesis that
long-term oral L-arginine supplementation for 6 months
reverses coronary endothelial dysfunction in
response to acetylcholine in humans with nonobstructive
coronary artery disease. Moreover, the effect on plasma
endothelin concentrations and symptoms was also assessed.
Drug Infusion
The determination of endothelium-dependent and
endothelium-independent CFR was performed as previously
described.7 14 Additional intravenous
heparin (5000 to 7500 U) was administered before instrumentation. Heart
rate and mean arterial pressure were continuously
monitored. A Doppler guidewire (FloWire, Cardiometrics Inc) 0.014
in. in diameter within a 2.2F coronary infusion catheter
(Ultrafuse, SciMed Life System) was advanced and positioned in the
middle portion of the LAD, 2 to 3 mm distal to the tip of the
infusion catheter. Baseline average peak velocity as measured by
Doppler echocardiography was recorded.
Intracoronary bolus injections of incremental doses (18 to 36
µg) of adenosine (Fujisawa), an
endothelium-independent vasodilator, were administered
into the guiding catheter positioned in the ostium of the left main
coronary artery until maximal hyperemia was achieved in
all of the patients, and the maximal average peak velocity was
recorded (in only 4 patients, or 13%, a dose >24 µg was
required to achieve maximal
hyperemia).14 15 To ensure that the
increase in CBF did not merely reflect the forces of
intracoronary bolus injection, CFR in response to normal saline
(3 to 6 mL) was measured before adenosine injection and served
as control.
The assessment of the endothelium-dependent CFR was
performed by selective infusion of acetylcholine into the LAD. After a
5-minute equilibration period, baseline average peak velocity was
recorded, followed by coronary angiography using nonionic
contrast medium (Omnipaque, Winthrop Laboratories). Acetylcholine
(Iolab Pharmaceuticals) at concentrations of
10-6, 10-5, and
10-4 mol/L (to achieve estimated final blood
concentrations in the coronary bed of
10-8, 10-7, and
10-6 mol/L) was infused with a Harvard pump for
3 minutes at each concentration. Hemodynamic data
(heart rate and mean arterial pressure), Doppler
measurements, and coronary angiography were obtained after each
infusion. The infusion was terminated when the largest dose of
acetylcholine (10-4 mol/L) was reached.
Nitroglycerin (Abbott Laboratories) was then injected
as an intracoronary bolus (200 µg) through the guiding
catheter.
At each time interval, average peak velocity was recorded, followed
by coronary angiography. The angles, skew rotation, and table
height were kept constant during the procedure. In addition, the
distances between the patient and the image intensifier and x-ray tube
were kept constant. Coronary artery diameter was measured at
three sites (proximal, middle, and distal) in three
end-diastolic frames and averaged by an independent
investigator unaware of the Doppler flow data using a
computer-based image analysis system, as previously
described.16 For the calculation of CBF, the
measurements were performed in a 1-cm segment 5 mm distal to the
tip of the Doppler wire. For each time interval, the diameter was
measured in the same segment. CBF was calculated from the
Doppler-derived time-velocity integral and vessel
diameter17,18: CBF=
After the intracoronary infusions, IVUS of the LAD was
performed with a Hewlett-Packard imaging system, as described
previously,19 to confirm the absence of
significant obstructive coronary artery disease. Continuous
images were recorded throughout the LAD on a 0.5-in videotape for
off-line analysis. A special effort was made to keep the IVUS
catheter parallel to the long axis of the vessel lumen. Five or six
segments of the LAD were identified in the videotape recording
of the IVUS images by the digital counter, and the exact position of
the IVUS catheter in relation to the artery was recorded on cine
film at each position. The location of the catheter seen on the cine
film of each segment was used to correlate the identified IVUS image
with the angiographic segment.
An off-line computer-interactive analysis system was used to
digitize the intracoronary IVUS video images onto a
256x256-bit matrix. Standard calibration markers obtained directly
from the IVUS images were used for calibration of absolute
measurements. All measurements were made in end diastole
and measured at the media-adventitia interface. Measurements of
coronary artery diameters and areas were averaged from two
orthogonal planes. All measurements were made by an observer blinded to
the Doppler or angiographic findings.
After the procedure, patients with coronary
endothelial dysfunction, defined as an attenuated
increase (<50%) or a decrease in CBF in response to graded infusion
of acetylcholine12 and normal CFR in response to
adenosine (CFR >2.5), were recruited into the study and
randomized. Oral L-arginine was given at a dose of 1 g
TID for week 1, 2 g/d for week 2, and at the target dose of 3 g
TID beginning in week 3. Both the active drug and the placebo were
prepared as identical capsules and supplied by Triage Pharmaceuticals
Inc. This dose has previously been shown to improve
endothelial function in
hypercholesterolemic subjects.8 10 11 The patients were instructed to avoid taking other
medication, over-the-counter vitamins, or amino acids. The patients
were thereafter contacted, in a blinded fashion, weekly for month 1 and
monthly for the remainder of the 6-month study duration for monitoring
of any side effects and to ensure compliance with treatment
instructions. During these interviews, the patients were also
questioned about their symptoms of chest pain. Their symptoms were
scored as follows: 0, no symptoms; 0.5, improvement in their symptoms;
and 1.0, no change or worsening of their symptoms.
One week before the repeat angiogram, all medications except for the
study drug were discontinued. The study drug was continued until the
evening before the repeat study. During the repeat angiogram at 6
months, the entire intracoronary infusion protocol was repeated
by the investigator, who was blinded to the randomization. The same
angles, skew rotation, and table height as in the baseline study were
used. There were no complications at the baseline or follow-up
procedures, and all patients tolerated the entire procedures without
side effects.
Biochemical Studies
Statistics
Of the remaining patients, 23% from group 1 (L-arginine)
and 31% from group 2 (placebo) received calcium channel blockers for
treatment of hypertension. None of the patients received nitrates,
ß-blockers, ACE inhibitors, or
cholesterol-lowering drugs. All the patients were referred
for the evaluation of stable exertional chest pain suspected to be of
cardiac origin. Before the coronary angiogram, 10 patients
(77%) from each group underwent a noninvasive functional test, which
was positive and consistent with myocardial ischemia in
6 patients from group 1 and 5 patients from group 2.
The demographic and clinical characteristics of the two groups at
baseline are outlined in Table 1
At baseline, the two groups also had similar resting CBF, CFR in
response to adenosine, and CBF response to graded infusion of
acetylcholine (peak response to 10-4 mol/L:
group 1, 10±8% versus group 2, 5±6%) (Tables 2
In the subjects who were taking L-arginine for 6 months,
there was a significant improvement in CBF (149±20% versus 6±9%,
P<0.05) and epicardial coronary artery diameter
(16±1.4% versus -25.9±1.8%, P<0.05) in response to
acetylcholine compared with the placebo group (Table 3
A significant improvement of the symptoms score was observed in the
group that was treated with L-arginine compared with the
placebo group (Figure 2
The endothelium is an important modulator of
coronary vascular tone through the release of
endothelium-derived relaxing factors such as NO and
endothelium-derived vasoconstrictors such as
endothelin.2 Early coronary
atherosclerosis is associated with coronary
endothelial dysfunction, which is characterized by an
attenuated or absent endothelium-dependent
vasodilatation, such as the response to intracoronary
administration of acetylcholine.3 4 5 The
significance of coronary endothelial
dysfunction is underscored by its implications as a mechanism of
exercise-induced myocardial ischemia6 and
by its association with myocardial perfusion defects, as recently
observed in our laboratory.20
A growing body of evidence suggests that dietary supplementation of
arginine improves endothelial function in experimental
animals and in humans. Short-term administration of
intracoronary L-arginine restored the impaired
endothelium-dependent dilatation in
hypercholesterolemic patients.12
Recently, Clarkson and colleagues8 reported that
a 4-week regimen of oral L-arginine improved
peripheral endothelium-dependent dilation
in hypercholesterolemic subjects, and Rector and
colleagues13 demonstrated beneficial effects of
oral L-arginine in patients with heart failure. The
present study extends these previous observations and demonstrates
that long-term L-arginine improves coronary
endothelial function in humans.
The patients treated with L-arginine demonstrated a
significant improvement in symptoms compared with the placebo group.
This observation may support the hypothesis that their symptoms were
related to their abnormalities in coronary
endothelial function. This observation is also in
accord with previous studies that demonstrated an improvement in
symptoms in patients with heart failure subsequent to
L-arginine treatment13 and with a
recent report that oral L-arginine supplementation has a
beneficial effect on exercise capacity in patients with stable
angina.21
The mechanism by which L-arginine improves
endothelial function may be multifactorial.
L-Arginine is the substrate for NO synthase, the enzyme
that catalyzes the production of NO in vascular
endothelial cells.1 NO
contributes to the resting epicardial and the coronary
microvascular tone. Moreover, the acetylcholine-induced increase in CBF
is largely due to release of NO from the coronary epicardial
and microvascular bed.22 Thus, one possible
mechanism for the beneficial effect of L-arginine is the
enhanced production of NO from the coronary
endothelium. This mechanism was recently challenged
because the intracellular concentration of L-arginine far
exceeds the Km of the NO
synthases,22 23 and L-arginine did
not improve relaxation to acetylcholine in aortic rings from
hypercholesterolemic rabbits in
vitro.24 However, the composition of the buffer
solution in the in vitro studies may have contributed to this
discrepancy, because when L-glutamine was added to the
solution, L-arginine did enhance
endothelium-dependent vascular
relaxation.22 23 Another hypothetical mechanism
whereby L-arginine administration could directly affect the
activity of the endothelial NO synthase may be
uncovered by a recent observation that an endogenous
inhibitor of NO synthase, asymmetric dimethylarginine,
accumulates in the serum of cholesterol-fed rabbits and
might antagonize the normal intracellular concentrations of
L-arginine.25 Although we did not
measure the levels of asymmetric dimethylarginine in the present
study, it may be speculated that large doses of L-arginine
might overcome this effect.
An additional, indirect mechanism by which L-arginine may
improve endothelial function is through other
vasoactive factors, such as endothelin-1. Indeed, in the present
study, plasma endothelin concentration decreased after 6 months of
L-arginine supplementation, and this observation is
supported by a previous study that demonstrated a beneficial effect of
oral L-arginine in patients with heart failure in
association with a decrease in plasma endothelin-1
concentrations.13 The increase in NO activity by
L-arginine may decrease endothelin production,
because endothelium-derived NO inhibits the
production of endothelin via a cGMP-dependent
pathway.26 Moreover, we recently reported that
experimental hypercholesterolemia, which is
associated with coronary endothelial
dysfunction and a decrease in endogenous coronary
NO activity, is characterized by an enhanced coronary
vasoconstrictive response to
pathophysiological doses of
endothelin-1.27 Thus, a decrease in plasma
endothelin concentration may both directly and indirectly contribute to
the improvement in coronary endothelial
function by decreasing the sensitivity of the coronary
circulation to other vasoconstrictor factors, such as
angiotensin II and
norepinephrine.28 29 Indeed, recent
studies have demonstrated a clear benefit of pharmacological therapy,
such as ACE inhibitors, on coronary
endothelial dysfunction.30
We previously reported that plasma and circulating endothelin
concentrations are increased in patients with coronary
endothelial dysfunction.7 The
decrease in circulating endothelin-1 in the present study in
association with an improvement in coronary
endothelial function further supports the hypothesis
that in early coronary atherosclerosis, an
imbalance between production and release of NO and endothelin
occurs that leads to augmented coronary vasoconstriction.
Because endothelin and NO act primarily as local, paracrine/autocrine
factors, it seems reasonable to assume that the circulating levels of
endothelin underrepresent the local and tissue concentrations
in the coronary circulation.
An increasing body of evidence suggests that dietary supplementation of
arginine inhibits atherogenesis.31 Aji and
colleagues9 recently reported that oral
L-arginine for 6 months prevented xanthoma development and
inhibited atherosclerosis in LDL
cholesterol receptor knockout mice, suggesting that this
response may be mediated by NO. Moreover, long-term administration of
supplementary dietary arginine markedly inhibits intimal lesion
formation in hypercholesterolemic
rabbits32 and preserves
endothelium-dependent
vasodilatation.33 NO can inhibit monocyte
adhesion to the endothelium1 31
and may also inhibit the production of superoxide anion by
activated neutrophils.34 Thus, it may be
speculated that long-term L-arginine
administration improves coronary endothelial
function by attenuating the progression of coronary
atherosclerosis.35 In the
present study, a small number of selected patients were studied,
and the results may be influenced by altered
hemodynamics or other mechanisms. Moreover, we did not
measure biochemical markers to evaluate the NO pathways, such as
urinary nitrogen oxides or cGMP.36 Thus, a
larger, comprehensive study may be required before the therapeutic role
for L-arginine and the mechanism of its
beneficial effect can be elucidated.
In summary, this study demonstrated that oral L-arginine
supplementation for 6 months improves coronary
endothelial function in association with improvement in
symptoms. This study proposes a therapeutic role for
L-arginine in patients with chest pain and coronary
endothelial dysfunction.
Received October 14, 1997;
revision received January 21, 1998;
accepted January 23, 1998.
2.
Lerman A, Burnett JC Jr. Intact and altered
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Egashira K, Inou T, Hirooka Y, Yamada A, Maruoka Y,
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Aji W, Ravalli S, Szabolcs M, Jiang X, Sciacca RR,
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Bell MR, Britson PJ, Chu A, Holmes DR Jr, Bresnahan JF,
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A. Beyond the coronary angiogram: further evaluation of the
coronary vasculature and endothelial function.
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18.
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Nishimura RA, Lerman A, Chesebro JH, Ilstrup DM, Hodge
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© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Long-term L-Arginine Supplementation Improves Small-Vessel Coronary Endothelial Function in Humans
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Coronary
endothelial dysfunction is characterized by an
imbalance between endothelium-derived vasodilating and
vasoconstricting factors and coronary vasoconstriction in
response to the endothelium-dependent vasodilator
acetylcholine. Thus, the present double-blind, randomized study was
designed to test the hypothesis that long-term, 6-month supplementation
of L-arginine, the precursor of the
endothelium-derived vasodilator NO, reverses
coronary endothelial dysfunction to
acetylcholine in humans with nonobstructive coronary
artery disease.
Key Words: vessels • endothelium • arginine
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
The coronary
vascular endothelium modulates vascular tone through
release of vasodilating and vasoconstricting substances. The
endothelium-derived relaxing factor NO is synthesized
from the amino acid L-arginine by a family of
enzymes, the NO synthases, through a metabolic route,
namely the L-arginine–NO
pathway.1 NO mediates vascular smooth muscle cell
relaxation and inhibits platelet aggregation and adhesion and
smooth muscle cell proliferation.1 2
Endothelin-1, on the other hand, is an
endothelium-derived peptide that produces
coronary vasoconstriction at
pathophysiological concentrations by binding to
specific receptors on the vascular smooth
muscle.2 Repeated studies have established that
coronary endothelial dysfunction is present
in early atherosclerosis and is characterized by a
coronary vasoconstriction in response to the
endothelium-dependent vasodilator
acetylcholine.3 4 5 Indeed, Zeiher and
colleagues6 have suggested that coronary
endothelial dysfunction may be a mechanism of
exercise-induced myocardial ischemia in patients with effort
angina and normal coronary arteriogram. We recently
demonstrated that coronary endothelial
dysfunction in humans is characterized by increased coronary
and circulating endothelin and decreased production of the
second messenger of NO, cGMP.7 These studies
underscore that endothelial dysfunction is
characterized by an imbalance between
endothelium-derived vasodilating and vasoconstricting
factors.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
The study protocol was approved by the Mayo Clinic Institutional
Review Board. All patients gave written informed consent to participate
in the study and were referred for coronary angiography because
of recurrent chest pain. Exclusion criteria included 
40% diameter
stenosis of any coronary artery, prior myocardial
infarction, unstable angina pectoris, uncontrolled hypertension,
peripheral vascular disease, ejection fraction <55%, left
ventricular hypertrophy, active smoking,
diabetes mellitus, and significant endocrine, hepatic, renal, or
inflammatory disease. None of the patients had a left-dominant
system.
Patients were brought to the cardiac
catheterization laboratory between 8 AM and
10 AM in the fasting state after all
cardiovascular medications had been discontinued for at
least 72 hours. None of the patients were receiving lipid-lowering
drugs. Diagnostic coronary angiography was
performed via the percutaneous femoral approach without
prior administration of nitrates or calcium channels blockers. The
coronary angiogram was reviewed before the infusion of drugs;
severity of stenosis was assessed by on-line quantitative
coronary angiography. Patients with significantly obstructive
coronary artery disease (40% diameter stenosis of
any coronary artery) or diffuse disease were excluded from
further studies. 
(average peak
velocity/2)(coronary artery
diameter/2).2
Venous blood samples were collected before the baseline
procedure and after the 6 months of treatment. Fasting lipid
analyses were performed for total cholesterol, HDL
cholesterol, and triglycerides; LDL was
measured in the Mayo Clinic Immuno Chemistry Laboratory by use of the
Roch reagent, a colorimetric assay on the COBAS Mira
System. The concentration of free L-arginine was
analyzed with an automated amino acid analyzer by the
Mayo Clinic laboratory, the normal range being from 20 to 180
µmol/L. Plasma endothelin was determined by the
ET-1,2[125I] assay system (Amersham), as
previously described from our laboratory.7 The
recovery of the extraction procedure is 81%, as determined by addition
of synthetic endothelin to plasma, and interassay and intra-assay
variations are 9% and 5%, respectively. The minimal level of
detection is 0.5 pg per tube. The cross-reactivities of endothelin-2,
endothelin-3, and proendothelin in this assay are <5%, <3%, and
<37%, respectively.
Continuous variables are presented as mean±SEM. The
effect of acetylcholine infusion is expressed as percent change
(mean±SEM) in CBF during the infusion of 10-4
mol/L relative to baseline. The effect of adenosine is
expressed as the maximal ratio between the coronary flow
velocities after and immediately before the bolus injection. The
differences within the groups were analyzed by
repeated-measures ANOVA, and the differences between groups were
analyzed by ANOVA and Student's unpaired t test and
the 
2 test. A value of P<0.05 was
accepted as significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Of the 52 patients screened, 30 subjects fulfilled the selection
criteria and were randomized. However, during the 6-month study, 4
patients discontinued the study. One patient from each group
discontinued the study secondary to minor gastrointestinal side effects
and 1 from each group secondary to personal preference. The remaining
26 participants completed the study (L-arginine, group 1,
n=13, and placebo, group 2, n=13). 
. There was no difference
between the study groups in age, sex, or coronary artery
disease risk factors. Nor was there any difference between groups 1 and
2 in the extent of coronary artery
atherosclerosis as determined by IVUS (maximal area
stenosis, 35±11% and 37±9%, respectively) or in the left
ventricular ejection fraction (68±3% and 67±5%,
respectively).
View this table:
[in a new window]
Table 1. Demographic Characteristics of the Study
Population and 3).
View this table:
[in a new window]
Table 2. Coronary Hemodynamics and Biochemical Results of
Study Groups at Baseline and at 6
Months
View this table:
[in a new window]
Table 3. Dose Response to
Acetylcholine 
, Figure 1). This change was associated in group 1
with a significant decrease in plasma endothelin concentrations
(35±5%) and a mild but significant increase in plasma
L-arginine levels (33±8%), which remained unaltered in
group 2 (Table 2). There was no correlation between the decrease in
plasma endothelin concentrations and the CBF response to acetylcholine.
There was no difference in the response to L-arginine
between the hypertensive and normotensive patients. There was no
significant difference between the subjects on L-arginine
or placebo in respect to mean arterial pressure, plasma
cholesterol, CFR in response to adenosine, and CBF
in response to intracoronary nitroglycerin
(Table 2). Also, there was no difference between the groups in the
extent of coronary artery atherosclerosis at
follow-up angiogram.
View larger version (12K):
[in a new window]
Figure 1. Percent changes in CBF in response to
10-4 mol/L of acetylcholine at baseline and at 6-month
follow-up in two study groups (solid bars, group 1,
L-arginine; hatched bars, group 2, placebo;
*P<0.05 between groups and compared with
baseline). ) after 1 week and
persisted for the 6-month study.
View larger version (38K):
[in a new window]
Figure 2. Symptoms scores at 1-week, 1-month, and 6-month
follow-up in two study groups (solid bars, group 1,
L-arginine; hatched bars, group 2, placebo;
*P<0.05 between groups and compared with
baseline).
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The present study demonstrates that long-term oral
L-arginine supplementation for 6 months in humans with
nonobstructive coronary artery disease improves
coronary small-vessel endothelial function in
response to acetylcholine in association with a significant improvement
in their symptoms. The group that received L-arginine
demonstrated an improvement in endothelial function at
the level of both the epicardial and small coronary vessels.
This improvement in coronary endothelial
function was associated with a decrease in plasma endothelin
concentrations. This study proposes a role for
L-arginine as a therapeutic option for patients
with coronary endothelial dysfunction and
nonobstructive coronary artery disease.
Selected Abbreviations and Acronyms
CBF
=
coronary blood flow
CFR
=
coronary flow reserve
IVUS
=
intravascular ultrasound
LAD
=
left anterior descending coronary artery
Acknowledgments
This study was supported by the National Institutes of Health
(HL-03180–01), the Miami Heart Research Institute, The Bruce and Ruth
Rappaport Vascular Biology Program, and the Mayo Foundation.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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