Clinical Nutrition 40 (2021) 3037e3044

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Randomized Control Trials

Effect of L-arginine on cardiac reverse remodeling and quality of life in

patients with heart failure
Mahnaz Salmani a, Elham Alipoor b, Hossein Navid c, Payam Farahbakhsh d,
Mehdi Yaseri e, Hossein Imani a, *
a
Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
b
Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
c
Department of Heart Failure and Heart Transplantation, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
d
Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
e
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: Heart failure (HF), as a major cardiac disease, is associated with considerable
Received 17 September 2020 mortality, morbidities and poor quality of life. The aim of this study was to investigate the effect of L-
Accepted 29 January 2021 arginine supplementation on cardiac outcomes and quality of life in patients with ischemic HF.
Methods: This double-blind randomized controlled clinical trial was conducted in 50 patients with
Keywords: ischemic HF. Patients were randomly assigned to receive either 3 gr/d L-arginine or placebo, for 10 weeks.
Heart failure
Cardiac function (based on echocardiography and six-minute walk test), blood pressure, and quality of
L-arginine
life (based on the Minnesota living with heart failure questionnaire) were assessed.
Ejection fraction
Cardiac reverse remodeling
Results: The results showed significant improvements in ejection fraction (
6.5 ± 8.7 vs.
0.7 ± 7.8%,
Quality of life P ¼ 0.037), left ventricular function (P ¼ 0.043), diastolic dysfunction (P ¼ 0.01) and marginally
improvement in changes of left ventricular dimension during diastole (LVDd) (4 ± 6 vs. 0.3 ± 6.9 mm,
P ¼ 0.065) in the L-arginine compared to the placebo group. At the end of the study, physical aspect
(5.7 ± 3.3 vs. 1.2 ± 6.1, P ¼ 0.002) and total score (10 ± 6.7 vs. 4.1 ± 9.4, P ¼ 0.011) of quality of life
improved significantly in the L-arginine compared with the placebo group. Additionally, pre-to post-
values of diastolic blood pressure, mean arterial pressure, LVDd, LV ejection fraction, left ventricular
function, diastolic dysfunction as well as physical and total scores of quality of life improved significantly
within the intervention, but not the placebo, group (all P < 0.05).
Conclusion: This study showed that 3 gr/d L-arginine supplementation for 10 weeks could improve
cardiac recovery and function, and quality of life in patients with HF.
This study was registered at the Iranian Clinical Trial Registration Center (www.irct.ir) with
IRCT20170202032367N4 code.
© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction About 25% of patients with HF need re-admission within 30 days of

Heart failure (HF), which is known a major cardiac disease, is
associated with considerable mortality, morbidity and disabilities,
and consequent poor quality of life [1]. HF has been introduced as
the leading cause of hospitalization among elderly people [2].
* Corresponding author. School of Nutritional Sciences and Dietetics, Tehran
University of Medical Sciences, No#44, Hojjatdoust St., Naderi St., Keshavarz Blvd.,
Tehran, Iran.Fax: þ982188984861.
E-mail address: h-imani@sina.tums.ac.ir (H. Imani).
hospital discharge [3].
Ventricular remodeling, which is defined as changes in cardiac
geometry, structure and function, is the main process in HF that
correlates with reduced ejection fraction and progression of disease
[4]. Left ventricular remodeling has a close relationship with clin-
ical outcomes [4]; thus it may be targeted as an important endpoint
of therapies.
Myocardial ischemia is one of the leading causes of HF [5].
Endothelial dysfunction is a principle cause of ischemic heart
disease, which is known as a result of imbalance between the
vasodilator (such as nitric oxide (NO) and prostacyclin) and

https://doi.org/10.1016/j.clnu.2021.01.044
0261-5614/© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
M. Salmani, E. Alipoor, H. Navid et al.
vasoconstrictor (such as endothelins and thromboxane A2) me-
diators [6]. Reduction in NO synthesis is associated with higher
vascular adhesion and proliferation of vascular smooth muscle
cells [7].
L-arginine, as a conditionally essential amino acid, is the pre-
cursor of NO synthesis. The main effects of L-arginine on vascula-
ture are predominantly mediated through NO. However, it can also
affect cardiovascular system independent of NO and through
antihypertensive and antioxidant properties, decreasing blood
viscosity, inhibiting the angiotensin converting enzyme activity, as
well as influencing the metabolism of macronutrients [8]. Previous
studies indicated the beneficial effects of L-arginine on endothelial
dysfunction in both coronary microvasculature and epicardial cor-
onary arteries of patients with heart transplantation [9]. Some
studies have suggested the advantageous effects of L-arginine on
stroke volume and cardiac output [10,11], blood pressure (BP)
[10,12], and ejection fraction [12]. However, these studies were
mainly nonrandomized and/or uncontrolled trials in small number
of patients using large doses of L-arginine, and the older studies
mainly administered short term injections of the supplement. It
seems that very few data are available on the effects of L-arginine
on important cardiac variables such as left ventricular (LV) function,
LV dimensions, and diastolic dysfunctions in HF.
The chronic, progressive, and generally irreversible nature of HF
are important determinants of low quality of life in these patients
[13]. Quality of life decreases with worsening the class of HF [14].
Some old data have shown the potential positive effect of large
doses of L-arginine on overall quality of life in small group of pa-
tients with HF [15]; however, this finding has not been further
assessed considering the changes of cardiac function.
Thus due to the proposed beneficial effects of L-arginine on
cardiovascular disorders, and lack of strong evidence on cardiac
function and other outcomes in HF, this study was conducted to
investigate the effect of L-arginine on clinical outcomes and quality
of life in patients with HF.
2. Methods
This double-blind parallel-design randomized controlled clin-
ical trial (RCT) was conducted in 50 patients with ischemic HF. The
inclusion criteria of the study were age between 35 and 65 years,
ejection fraction less than 40% (based on echocardiography test),
and cardiac functional level of 2 or 3 based on the classification of
the New York heart association. The exclusion criteria were a his-
tory of angina pectoris, myocardial infarction or stroke, untreated
arrhythmias, taking medications including glucocorticoids, anti-
arrhythmic drugs, chemotherapy agents, non-steroidal anti-in-
flammatory drugs (NSAIDs), diltiazem, verapamil, thiazolidine-
diones, and being unable to perform the 6-min walking test
(6MWT). Smoking, drinking alcohol, pregnancy and lactation, a
history of drug sensitivity or allergy, chronic kidney or liver dis-
eases, chronic inflammatory diseases, and thyroid diseases during
the past year, and consumption of L-arginine supplement were
other exclusion criteria. All patients continued their routine treat-
ment by the cardiologist during the study period.
Eligible patients were randomly assigned to two groups of L-
arginine (n ¼ 25) or placebo (n ¼ 25) by an independent colleague
not involved in the study procedure. The sequence of the
randomization was determined using a random allocation soft-
ware. Patients in the intervention group received 3 g L-arginine,
1000 mg tablets thrice daily (Karen Company, Yazd, Iran), and
placebo group received 3 g Maltodextrin, 1000 mg tablets thrice
daily, after breakfast, lunch and dinner, for 10 weeks. The L-arginine
and placebo tablets were identical in size, shape, and color. All
tablets were put in similar boxes and coded as A and B by an
3038
Clinical Nutrition 40 (2021) 3037e3044
independent colleague. Participants were asked to not change their
usual diet and physical activity during the study and to avoid any
new dietary supplement. Patients were contacted once a week.
They were asked to bring the empty boxes at the end of the study
and those who did not take more than 15% of the tablets during 10
weeks were excluded from the study.
This study was approved by the Ethics Committee of the Tehran
University of Medical Sciences. All patients completed a written
informed consent.
2.1. Measurements
All measurements were performed at baseline and after 10
weeks of the study by a trained researcher. The body weight was
measured wearing light clothing and barefoot using a scale (SECA,
Germany) with a sensitivity of 0.1 kg. Height was measured in
standing position without shoes using a tape measure to the
nearest 0.5 cm. The Body mass index (BMI) was calculated by
dividing weight (in kg) by the square of height (in meters). Waist
circumference (WC) was measured (between the lower margin of
the last palpable rib and the top of the iliac crest) in standing po-
sition with a tape measure to the nearest 0.5 cm.
Systolic blood pressure (SBP) and diastolic blood pressure (DBP)
were measured by a trained and experienced technician unaware of
the study aim and type of the intervention, using a sphygmoma-
nometer with an accuracy of 2 mmHg. The measurements were
performed in sitting position in a quiet room after a 10-min rest. All
patients were asked to avoid exercise, eating, drinking except for
water, and smoking prior to the measurement. The mean arterial
pressure (MAP) was calculated based on the suggested formula:
MAP ¼ (SBP þ 2 DBP)/3. The sphygmomanometer was calibrated
before each measurement to enhance the accuracy of the
measurements.
A three-day 24-h dietary recall was obtained from all partici-
pants by a trained researcher at baseline and following the inter-
vention. Dietary reported intakes were analyzed using Nutritionist
IV software (N Squared Computing, San Bruno, CA, USA) modified
for some local foods.
The 6MWT was performed in accordance with the American
Thoracic Society's guidelines [16] at the beginning and at the end of
the intervention. The 6MWT is a simple and well-tolerated test that
measures the distance a person can walk within 6 min, and only
requires a 30-m corridor with flat surface and does not need any
special equipment or expert person. This test provides data about
the functional capacity and the efficacy of treatments in different
cardiopulmonary conditions, as it simultaneously evaluate the
function of many respiratory, cardiovascular, and muscular sys-
tems. All patients underwent echocardiography, as the most useful
diagnostic test in patients with HF, based on the American College
of Cardiology/American Heart Association (ACC/AHA) guidelines
[17]. The test was performed by a two-dimensional echocardio-
graph in the supine position by the cardiologist at the beginning
and at the end of the intervention. LV ejection fraction, LV dimen-
sion during diastole (LVDd) and LV dimension during systole
(LVDs), left ventricular function, systolic function, and diastolic
dysfunction were assessed with echocardiography. Ejection frac-
tion and systolic and diastolic functions were assessed using
biplane Simpson's method. Diastolic dysfunction has been catego-
rized according to the pattern of diastolic filling as: 1- mild
dysfunction; relaxation impairment with normal filling pressure, 2-
moderate dysfunction; pseudonormal mitral input pattern, and 3-
Severe and reversible performance disorder; reversible limit with
high filling pressure [18].
Quality of life has been investigated using Minnesota living with
heart failure questionnaire. This questionnaire, reflects the quality
M. Salmani, E. Alipoor, H. Navid et al.
of physical, socioeconomic, and psychological aspects of patients
living with HF. The total score indicates the effects of HF and
treatments on overall quality of life. The questionnaire includes 21
questions, each ranges between 0 (no effect on life) to 5 (a very
large impact on life). The overall score ranges between 0 and 105,
with lower scores indicating the lower impact of the disease on
patients’ quality of life [19].
2.2. Statistical analysis
The sample size was determined based on expected changes in
ejection fraction as the primary outcome using the relevant for-
mula. It was calculated that 22 patients in each group would allow a
power of 85% to detect a 7% change in ejection fraction, with a type I
error of 0.05, and a ‘drop-out’ rate of ~20%. The normality of the
variables was determined using the KolmogoroveSmirnov test.
Comparisons of baseline characteristics were performed using
ChieSquare test, Student's t-tests, and ManneWhitney test, where
appropriate. Paired t-test and Wilcoxon singed rank test were
applied for within group comparisons (pre-to post-changes in each
study group). The effect of the intervention was investigated by
ANCOVA test adjusted for baseline values and other potential
confounders. All statistical analyses were conducted using SPSS
software (IBM Corp. Released 2013. IBM SPSS Statistics for Win-
dows, Version 22.0. Armonk, NY: IBM Corp.), and P-value < 0.05
was considered to be statistically significant.
3. Results
3.1. General characteristics
The study procedure has been shown in Fig. 1. During the study,
2 patients were excluded from the L-arginine group (due to poor
adherence) and 4 patients from the placebo group (poor adherence
(n ¼ 2), death (n ¼ 1) and smoking (n ¼ 1)). No adverse effects has
been reported by the study participants. Finally, the data of 23
patients in the L-arginine group and 21 patients in the placebo
group was analyzed (Fig. 1).
There were no significant differences in sex, age, disease
duration, diabetes and medications between two study groups
Fig. 1. CONSORT flow diagram of the study population.
3039
Clinical Nutrition 40 (2021) 3037e3044
(Table 1). The findings showed no significant differences in
energy and protein intake between the L-arginine and placebo
groups at baseline (1561.6 ± 394.9 vs. 1656 ± 602.4 kcal/d,
P ¼ 0.924 and 60.5 ± 18.4 vs. 68.9 ± 37.5 g/d, P ¼ 0.342,
respectively) or at the end of the study (1531.4 ± 402.4 vs.
1692 ± 351.2 kcal/d, P ¼ 0.175 and 63.7 ± 22.6 vs. 65.5 ± 15 g/
d, P ¼ 0.760, respectively).
3.2. Blood pressure
There were no significant differences in mean SBP, DBP and MAP
between the two groups at baseline. At the end of the study, DBP
(77.7 ± 12.8 to 71 ± 9.6 mmHg, P ¼ 0.006) and MAP (91.9 ± 14.8 to
86.4 ± 12.7 mmHg, P ¼ 0.024) decreased significantly in the L-
arginine, but not the placebo, group compared to the baseline
values (Table 2).
3.3. Cardiac function based on echocardiography
There were no significant differences in parameters of cardiac
function between the two groups at baseline. At the end of the
study, statistically significant improvements were observed in
changes of LV ejection fraction (
6.5 ± 8.7 vs.
0.7 ± 7.8%,
P ¼ 0.037), left ventricular function (P ¼ 0.043), diastolic
dysfunction (P ¼ 0.01) and there was also statistically marginal
improvement in changes of LVDd (4 ± 6 vs. 0.3 ± 6.9 mm,
P ¼ 0.065) in the L-arginine compared to the placebo group.
Additionally, pre-to post-values of LVDd, LVDs, LV ejection frac-
tion, left ventricular function, and diastolic dysfunction improved
significantly only in the intervention group (P < 0.05) (Tables 3
and 4).
3.4. Six-minute walk test
No significant differences were observed in 6MWT variables at
baseline or at the end of the study between the two groups. Both
groups showed significant improvement in total walking distance
compared to the baseline (Table 5).
M. Salmani, E. Alipoor, H. Navid et al. Clinical Nutrition 40 (2021) 3037e3044

Table 1
Baseline characteristics of the study participants.

Placebo L-arginine P
(n ¼ 21) (n ¼ 23)

Age (year) 55.8 ± 7.9 56.6 ± 3.3 0.289a

Disease duration (year) 4.5 ± 3.8 6.62 ± 4.1 0.082b
Sex (male) 15 (71.4) 16 (69) 0.892b
Diabetes 11 (52.4) 9 (39.1) 0.442b
Medications Beta Blocker 20 (95.2) 22 (95.7) 0.999b
ACEI 17 (81) 22 (95.7) 0.176b
Loop Diuretic 21 (100) 22 (95.7) 0.999b
Anticoagulant 20 (95.2) 22 (95.7) 0.999b
Statins 21 (100) 22 (95.7) 0.236b
Anti-diabetic 5 (23.8) 6 (26.1) 0.862b
Insulin 4 (19) 3 (13) 0.543b

Values were presented as Mean ± SD or frequency (%).

a
Based-on t-test.
b
Based on ChieSquare test.

Table 2
Blood pressure before and after 10 weeks supplementation with L-arginine in patients with HF.

Placebo L-arginine Mean 95% CI P

(n ¼ 21) (n ¼ 23) Difference
Lower Upper

SBP (mmHg) Before 120 ± 22.1 120.3 ± 22.8
0.2
13.9 13.5 0.976a
After 117.6 ± 17.3 117.3 ± 21.2 0.3
11.5 12.2 0.913b
Change 2.6 ± 15.3 3 ± 15.7
0.5
10 8.9 0.913a
P withinc 0.451 0.355
DBP (mmHg) Before 71.7 ± 12.1 77.7 ± 12.8
5.9
13.5 1.7 0.123a
After 69.2 ± 10.2 71 ± 9.6
1.85
7.9 4.2 0.718b
Change 2.5 ± 10.5 6.6 ± 10.4
4.1
10.4 2.3 0.201a
P withinc 0.283 0.006
MAP (mmHg) Before 87.85 ± 14.7 91.9 ± 14.8
4
13 5 0.372a
After 85.3 ± 12.1 86.4 ± 12.7
1.1
8.7 6.4 0.666b
Change 2.5 ± 11.1 5.4 ± 10.7
2.9
9.5 3.7 0.383a
P withinc 0.306 0.024
a
Based-on t-test.
b
Adjusted for baseline values based on Analysis of Covariance (ANCOVA).
c
Based-on Paired Samples t-test.

Table 3
Left ventricular ejection fraction and dimensions during diastole and systole based on echocardiography before and after 10 weeks supplementation with L-arginine in patients
with HF.

Placebo L-arginine Mean 95% CI P

(n ¼ 21) (n ¼ 23) Difference
Lower Upper

LVDd (mm) Before 57.2 ± 9.9 58.7 ± 7.2
1.5
6.7 3.8 0.557a
After 56.9 ± 9.1 54.7 ± 6.2 2.3
2.5 7 0.074b
Change 0.3 ± 6.9 4±6
3.7
7.7 0.2 0.065a
P withinc 0.828 0.004
LVDs (mm) Before 44.1 ± 13 44.8 ± 10.8
0.7
8.0 6.5 0.68a
After 36 ± 11.7 34.2 ± 7.6 1.7
4.2 7.9 0.58b
Change 8.2 ± 10.8 10.6 ± 11.9
2.5
9.4 4.5 0.533d
P withine 0.003 0 < 0.001
LV Ejection fraction (%) Before 29.5 ± 7.9 27.1 ± 7.4 2.4
2.3 7 0.327d
After 30.2 ± 9.9 33.7 ± 8.7
3.5
9.1 2.2 0.046b
Change
0.7 ± 7.8
6.5 ± 8.7 5.8 0.8 10.9 0.037d
P withine 0.623 0.004
a
Based on t-test.
b
Adjusted for the baseline values based on Analysis of Covariance (ANCOVA).
c
Paired Samples t-test.
d
ManneWhitney test.
e
Wilcoxon singed rank test.

3.5. Quality of life
There were no significant differences in baseline scores of the
physical, socioeconomic, psychological and total scores of quality of
life based on Minnesota questionnaire. Following the supplementa-
tion, physical aspect (5.7 ± 3.3 vs. 1.2 ± 6.1, P ¼ 0.002) and total score
of quality of life (10 ± 6.7 vs. 4.1 ± 9.4, P ¼ 0.011) improved signifi-
cantly in the L-arginine compared with the placebo group. Significant
pre-to post-reductions were occurred in all subscales and total score
of quality of life in the intervention group (P < 0.05). Socioeconomic
(P ¼ 0.028) and psychological (P ¼ 0.030) aspects were also improved
in the placebo group compared to the baseline (Table 6).

3040
M. Salmani, E. Alipoor, H. Navid et al. Clinical Nutrition 40 (2021) 3037e3044

Table 4
Diastolic dysfunction, left ventricular and systolic functions based on echocardiography before and after 10 weeks supplementation with L-arginine in patients with HF.

Placebo (n ¼ 21) L-arginine (n ¼ 23) p

Normal Mild Moderate Severe Normal Mild Moderate Severe

Left Ventricular Function (n) Before 10 (50) 5 (25) 2 (10) 3 (15) 9 (39.1) 6 (26.1) 5 (21.7) 3 (13) 0.511a
After 15 (71.4) 4 (19) 0 2 (9.5) 19 (82.6) 4 (17.4) 0 0 0.043b
P withinc 0.078 <0.001
Systolic Function (n) Before 1 (4.8) 2 (9.5) 7 (33.3) 11 (52.4) 1 (4.3) 0 9 (39.1) 13 (56.5) 0.615a
After 1 (4.8) 2 (9.5) 4 (19) 14 (66.7) 2 (8.7) 3 (13) 6 (26.1) 12 (52.2) 0.281b
P withinc 0.378 0.59

Mild Moderate Severe Mild Moderate Severe p

Diastolic dysfunction (n) Before 14 (70) 6 (30) 0 14 (60.9) 9 (39.1) 0 0.536a

After 8 (38.1) 11 (52.4) 2 (9.5) 16 (69.6) 7 (30.4) 0 0.01b
P withinc 0.727 0.031
a
ManneWhitney test.
b
Adjusted for the baseline values based on Analysis of Covariance (ANCOVA).
c
Wilcoxon singed rank test.

Table 5
Six-minute walk test before and after 10 weeks supplementation with L-arginine in patients with HF.

Placebo L-arginine Mean 95% CI P

(n ¼ 21) (n ¼ 22) Difference
Lower Upper

Total distance (m) Before 440.5 ± 120.4 458.6 ± 108
18.2
88.6 52.2 0.605a
After 476.2 ± 136 496.8 ± 1
20.6
99.8 58.6 0.746b
Change
35.7 ± 51
41.4 ± 47.6 5.7
25.1 36.5 0.710a
P withinc 0.004 0.001
O2 MAX Saturation (%) Before 95.1 ± 1.6 94.3 ± 1.9 0.8
0.3 1.9 0.136a
After 95.1 ± 2 94.2 ± 3 0.9
0.7 2.5 0.251b
Change 0 ± 2.1 0.2 ± 2.3
0.24
1.6 1.1 0.728a
P withinc 0.999 0.637
End SBP (mmHg) * Before 139.6 ± 17.1 135.1 ± 18.9 4.4
6.7 15.6 0.425a
After 139 ± 17.9 130.8 ± 19.5 8.3
3.3 19.8 0.321b
Change 0.5 ± 16.2 3.5 ± 16.1
3
13.1 7.1 0.551a
P withinc 0.884 0.328
End DBP (mmHg)** Before 80.1 ± 10.6 77.4 ± 13.3 2.8
4.7 10.2 0.455a
After 80.1 ± 9.9 75.3 ± 10.2 4.7
1.5 10.9 0.308b
Change 0.1 ± 12 0.95 ± 10.7
0.9
8 6.2 0.808d
P withine 0.971 0.687
Maximum Heart rate (bpm) Before 108.1 ± 14.7 108.8 ± 16.9
0.7
10.1 8.8 0.886a
After 107 ± 13.7 112.1 ± 14.1 0.1
8.6 8.9 0.843b
Change
4.1 ± 12.6
2.9 ± 16.1
1.2
10.3 7.8 0.545d
P withine 0.148 0.418

*End SBP: Systolic blood pressure at the end of the 6-min walk test.
**End DBP: Diastolic blood pressure at the end of the 6-min walk test.
a
Based on t-test.
b
Adjusted for the baseline values based on Analysis of Covariance (ANCOVA).
c
Paired Samples t-test.
d
ManneWhitney test.
e
Wilcoxon singed rank test.

3.6. Anthropometric parameters
There were no statistically differences in body weight
(82.2 ± 11.8 vs. 83 ± 15.7 kg P ¼ 0.859), WC (103.7 ± 11.4 vs.
99 ± 21.8 cm, P ¼ 0.796), and BMI (29.1 ± 4.2 vs. 28 ± 4 kg/m2,
P ¼ 0.437) between the intervention and placebo groups, respec-
tively, at baseline. Additionally, there were not statistically signifi-
cant differences in body weight (83.2 ± 11.1 vs. 83 ± 16.2 kg,
P ¼ 0.140), WC (106.2 ± 9.3 vs. 105.3 ± 9.6, P ¼ 0.862), and BMI
(29.5 ± 3.8 vs. 28 ± 4 kg/m2, P ¼ 0.084) between the intervention
and Placebo groups, respectively, following supplementation.
4. Discussion
The results of the current study showed the beneficial effects of
L-arginine supplementation on improving ejection fraction, left
ventricular function, diastolic dysfunction, and LVDd, as well as
3041
physical and total scores of quality of life compared with the pla-
cebo group in patients with HF. Additionally, DBP, MAP, LVDd,
ejection fraction, left ventricular function, diastolic dysfunction,
and physical and total scores of quality of life improved significantly
in the L-arginine, but not the placebo, group compared to the
baseline.
Echocardiography, which is the most informative diagnostic test
for HF, showed significant improvement in LV function recovery in
this trial. A nonrandomized and uncontrolled study in 12 patients
with HF showed significant improvements in stroke volume and
cardiac output and non-significant increase in ejection fraction
following intravenous (IV) infusion of 20 g L-arginine, compared to
baseline. This effects were transient and one hour after the termi-
nation of L-arginine infusion these variables were not different with
baseline anymore [10]. The other study in 7 patients with severe HF
showed an improvement in cardiac output and stroke volume with
30 gr L-arginine IV infusion [11]. An uncontrolled trial with oral L-
M. Salmani, E. Alipoor, H. Navid et al. Clinical Nutrition 40 (2021) 3037e3044

Table 6
Quality of life based on Minnesota questionnaire before and after 10 weeks supplementation with L-arginine in patients with HF.

Placebo L-arginine Mean %95 CI P

(n ¼ 21) (n ¼ 23) Difference
Lower Upper

Physical score Before 26 ± 5.2 25 ± 4.4 0.3
2.6 3.3 0.888a

After 24.8 ± 6.7 19.9 ± 4.6 4.8 1.4 8.3 0.002b
Change 1.2 ± 6.1 5.7 ± 3.3
4.5
7.5
1.5 0.002a
P withinc 0.420 <0.001
Socioeconomic score Before 15 ± 2.6 16 ± 3.3
1.0
2.9 0.8 0.126a
After 13.8 ± 2.5 14 ± 3.1
0.2
2 1.5 0.515b
Change 1.3 ± 2.4 2 ± 2.3
0.8
2.2 0.6 0.346a
P withinc 0.028 <0.001
Psychological score Before 23.2 ± 3 22.6 ± 3.6 0.7
1.4 2.7 0.332a
After 21.7 ± 3.4 20.4 ± 3 1.2
0.7 3.2 0.272b
Change 1.5 ± 2.7 2±2
0.5
1.9 1 0.393a
P withinc 0.030 0.001
Total score Before 64.3 ± 9.2 64.3 ± 10.1
0.0
5.9 5.9 0.805a
After 60.2 ± 10.8 54.4 ± 9.4 5.8
0.3 12 0.015b
Change 4.1 ± 9.4 10 ± 6.7
5.9
10.8
0.9 0.011a
P withinc 0.079 <0.001
a
ManneWhitney test.
b
Adjusted for the baseline values based on Analysis of Covariance (ANCOVA).
c
Wilcoxon singed rank test.

arginine supplementation, 8 gr/d for 2 months, showed significant
improvement in right ventricular ejection fraction and duration on
treadmill compared to baseline in 15 patients with right HF [12]. L-
arginine did not change LV elastance or other functional parame-
ters, which reported in our trial, in the mentioned studies. It should
be considered that these studies were uncontrolled and had
different route of supplementation and/or higher doses of L-argi-
nine in small groups of patients. In a rat model of acute myocardial
infarction, myocardial eNOS protein level increased significantly
following 100 mg/kg gavage of L-arginine for 4 weeks. L-arginine
supplementation did not improve LV ejection fraction and LV end-
systolic and end-diastolic dimensions, but its coadministration
with intramyocardial placental growth factor showed a pro-
nounced protective effect on myocardial protection [20].
Ventricular remodeling is a pivotal disorder in the progression
of HF. The concept of stopping or reversing the progression of
remodeling is a main target in HF treatment. One study has defined
reverse remodeling as  15% increase in LV ejection fraction or
10% increase in LV ejection fraction plus improvements in LV end-
systolic parameters, for one year [21]. Others indicated every HF
therapy with positive long-term clinical outcome in the sense of
reduction in end-systolic and end-diastolic volumes has induced
reverse remodeling [22]. A very recent expert panel documented
HF with recovered ejection fraction as 1) a decreased LV ejection
fraction <40% at baseline, as well as 2) 10% improvement in LV
ejection fraction, and 3) a second assessment of LV ejection fraction
>40% [23]. In the current study, significant improvements including
about 24% increase in LV ejection fraction, about 7% decrease in
LVDd, as well as more patients with normal left ventricular function
and mild diastolic dysfunction in the L-arginine group were
observed following supplementation. However, duration of this
trial was 10 week and long-term efficacy of these changes needs to
be investigated.
The effects of different nutraceuticals such as L-carnitine, car-
nosine, coenzyme Q10, n-3 PUFAs and beetroot nitrates have been
recently reviewed in HF [24], which could be compared with the
efficacy of the current trial. Pooled data meta-analysis of 17 RCTs
examining the effects of L-carnitine supplementation in patients
with HF has reported 4.14% improvement in LV ejection fraction,
0.88 L/min improvement in cardiac output, significant decreases in
LV end-systolic and end-diastolic dimensions as well as circulating
BNP and NT-proBNP, and no significant change in 6MWT [25].
3042
Although L-arginine supplementation led to a substantial increase
in LV ejection fraction (24%) in the current study, its efficacy could
not be directly compared with L-carnitine as a range of doses
(1.5e6 g/d) and follow-up periods (7 dayse3 years) were analyzed
in this meta-analysis [25]. One RCT in patients with systolic HF,
showed about 20% increase in LV ejection fraction, compared to the
control group following 3 g/d oral L-citrulline supplementation for
4 months [26]. It has been shown that there is an essential and
efficient recycling of L-citrulline to L-arginine, as part of the
citrulline-NO cycle, to produce endothelial NO [27]. Some experi-
mental studies have proposed more efficiency of citrulline
compared with arginine supplementation in increasing arginine
levels [28,29], especially in compromised intestinal function as
intestine is the main site of citrulline production and also because
arginine is largely metabolized by the liver [30]. However, L-argi-
nine supplementation in the current study led to better improve-
ment of LV ejection fraction (24% vs. 20%) in a shorter duration (10
weeks vs. 4 months) compared to similar dose of L-citrulline [26]. In
a randomized double-blind cross-over trial, supplementation with
2 g/d omega-3 fatty acids for 8 weeks improved LV ejection fraction
about 4% in ischemic HF [31], which is much lower compared to
24% increase in LV ejection fraction in the present study. Acute
consumption of dietary inorganic nitrate (NO3-) in the form of a
single dose of 140 mL concentrated beetroot juice (11.2 mmol of
NO3-) in a small placebo-controlled double-blind crossover study
of HF patients with reduced ejection fraction resulted in a consid-
erable increase in VO2 peak and time to fatigue, as well as circu-
lating and breath NO metabolites, but not efficiency and ventilation
during exercise [32]. Cardiac functional tests were not assessed in
this study probably due to its short duration.
The beneficial effects of L-arginine may be partly due to NO-
cGMP signaling. NO has a protective effect against stress-induced
cardiac remodeling and dysfunction [33]. An experimental study
showed that elevated endothelial NO synthase (NOS) expression
declined LV remodeling and cardiac dysfunction and increased
survival in mice with myocardial infarction [34]. cGMP production
and activation of protein kinase G are main mediators of NO
signaling, which could in turn affect different proteins involved in
cardiac contractility, hypertrophy and remodeling [33].
Blood pressure did not differ between the two groups neither at
baseline nor at the end of this trial. Hypertension has been tradi-
tionally recognized as one of the most important risk factors in HF
M. Salmani, E. Alipoor, H. Navid et al.
progression and its effective treatment may prevent further cardiac
complications [35]. Thus, decrease in DBP (6.6 vs. 2.5 mmHg) and
MAP (5.4 vs. 2.5 mmHg), in the L-arginine and placebo groups,
although are not statistically different, seems to be clinically of
importance. Additionally, DBP and MAP decreased significantly in
the L-arginine group compared to baseline values. Similarly, IV
infusion of 30 gr L-arginine in 7 patients and 20 g L-arginine in 12
patients with HF decreased MAP and systemic vascular resistance
compared to baseline [10,11]. An oral L-arginine trial, 8 gr/d for 2
months, showed significant decrease in SBP and DBP compared to
baseline in 15 patients with right HF [12]. Studies in other cardio-
vascular disorders have shown a decrease in DBP with 6.4 gr L-
arginine supplementation for 6 months in 30 patients with aorto-
coronary bypass [36] and a decrease in DBP and MAP with 12 gr L-
arginine supplementation for 3 weeks in 16 patients with hyper-
cholesterolemia [37].
These beneficial effects were also seen for SBP and DBP with 8.3
gr L-arginine consumption for 3 weeks in 33 obese, insulin-
resistant type 2 diabetic patients [38], and with 8 gr L-arginine
consumption for 6 months in 28 patients with polycystic ovary
syndrome [39]. These studies have generally low sample sizes and
used considerably higher doses of L-arginine compared to the cur-
rent study. In this regard, 3 months supplementation with 3 gr/d L-
arginine did not improve BP in patients with diabetes, while the
dose of 6 gr/d significantly reduced SBP and DBP in these patients
[40]. Thus, the current study improved BP with lower doses of L-
arginine in a reasonable period.
L-arginine could affect BP through NO production that, in turn,
acts through increasing cGMP and modulation of calcium and po-
tassium channels; the pathways which ultimately lead to vascular
relaxation [41]. Additionally, this amino acid is an inhibitor of
angiotensin-converting enzyme, and could decrease circulating
angiotensin II [42].
The 6MWT did not improved significantly in this study. L-argi-
nine IV infusion, 5 mg/kg for 30 min, did not also improve exercise
capacity and time, heart rate and BP compared to the control group
in 19 patients with HF [43]. However, oral L-arginine, 9 g/d for 7
days, increased exercise duration in 21 patients with HF [44].
Additionally, oral L-arginine, 5.6e12.6 g/d for 6 weeks, increased
distance in 6MWT in 17 patients with HF [15]. A direct relationship
has been reported between L-arginine/asymmetric dimethylargi-
nine (ADMA) ratio with maximum workload and the 6-min walk
test in HF patients with preserved ejection fraction [45]. ADMA is
an inhibitor of NOS, which reduces the bioavailability of NO, and
could in turn, impair vasodilatation, and disturb antithrombotic,
anti-inflammatory, and anti-apoptotic functions [46].
Probably, the threshold of L-arginine dosage and the duration of
therapy should be higher to improve 6MWT components compared
with other functional parameters, which improved significantly in
this study.
In the current study, physical and total scores of quality of life
improved significantly in the intervention compared with the
placebo group and also compared with the baseline values,
simultaneously with cardiac recovery. Oral L-arginine, 5.6e12.6 g/
d for 6 weeks, increased overall quality of life score in 17 patients
with HF [15], while another study failed to show any significant
difference in quality of life with 2 g tid L-arginine supplementation
for 3 months compared to the placebo group [47]. It has been re-
ported that depressive symptoms (based on Beck questionnaire)
were correlated with a lower L-arginine/ADMA ratio; the ratio
which indicates NO dysregulation and low bioavailability in pa-
tients with HF [48]. Inflammatory pathways are suggested as key
pathways involved in fatigue, pain, and overall QoL [49]. Some
studies proposed the anti-inflammatory properties of L-arginine
[50]. However, due to lack of studies, the mechanism of action of L-
3043
Clinical Nutrition 40 (2021) 3037e3044
arginine in improving quality of life could not be completely
established currently.
Oral L-arginine has generally been proposed to be safe about 20
gr/d [51]. However, adverse gastrointestinal symptoms such as
nausea, vomiting and diarrhea can be problematic in some in-
dividuals (especially > 15 gr/d), which seems to be dose dependent
and attenuate if divided doses are consumed [52]. Additionally,
cautions are recommended for individuals with or at risk of cancer
[51] and critically ill patients [53]. Thus, more experimental and
clinical data are required to evaluate safety and efficacy of this
amino acid. The dosage used in this trial was considerably lower
than the upper limits proposed for L-arginine and no adverse effect
was reported by the study participants. Taken as a whole, this study
has suggested that oral moderate doses of L-arginine supplemen-
tation is a valuable safe and effective adjunctive treatment in pa-
tients with ischemic HF, which could affect cardiac reverse
remodeling and recovery as well as quality of life.
4.1. Limitations
This study had some limitations that should be noted. This was a
10-week clinical study. As every other method targeting reverse
remodeling the clinical efficacy of this trial should also be investi-
gated in long term period. We studied a relatively small number of
patients, which may hinder to detect some advantageous of L-
arginine for example improvements in blood pressure and 6MWT
compare with the control group. However, the sample size was
generally larger than similar studies and was adequate to detect
changes in our primary outcome LV ejection fraction.
4.2. Future directions
Changes in clinical outcomes were the main practical target of
this trial; however, investigating biochemical and cellular pathways
should be considered in future studies to better clarify the mech-
anisms of L-arginine function in HF. Additionally, future large and
long-term well-designed clinical trials should investigate probable
doseeresponse or duration-dependent effects of L-arginine on
parametres of cardiac functional tests such as echocardiography or
6MWT.
5. Conclusion
The results of the current trial showed 10-week 3 gr/d L-arginine
supplementation in patients with ischemic HF improved ejection
fraction, left ventricular function, diastolic dysfunction, as well as
physical and overall quality of life scores compared with the pla-
cebo group. Additionally, pre-to post-values of DBP, MAP, LVDd,
ejection fraction, left ventricular function, diastolic dysfunction,
and physical and total scores of quality of life improved significantly
within the L-arginine, but not the placebo, group.
Funding
This study was supported by Tehran University of Medical Sci-
ences and Health Services with the grant 38436.
Conflicts of interest
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.clnu.2021.01.044.
M. Salmani, E. Alipoor, H. Navid et al. Clinical Nutrition 40 (2021) 3037e3044

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