Heart Failure

L-arginine and coronary outcomes


Kanaya Y, Nakamura M, Kobayashi N, Hiramori K. Effects of L-arginine on lower limb vasodilator reserve and exercise capacity in patients with chronic heart failure. Heart. 1999; 81: 512-517.

Study Design:
Before-After Study
D - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:

To determine whether the reactive hyperaemic response of the lower limb increases with improved exercise capacity after acute supplementation with L-arginine.

Inclusion Criteria:

Adults with chronic heart failure.



Exclusion Criteria:

Valvular stenotic lesions.

Description of Study Protocol:
  • Recruitment: Not noted.


  • Rest calf blood flow and femoral-occlusion-induced calf blood flow changes were measured by venous occlusion plethysmogrpahy before and after IV infusion of 10% L-arginine infusion (ml per kg for 30 minutes or placebo)
  • Post-exercise calf blood flow and exercise capacity indices were determined after the infusion
  • During both post-infusion periods, several exercise capacity indices were determined by a symptom-limited cardiopulmonary exercise test, using a bicycle ergometer.

Blinding Used

Single-blind crossover design.


IV infusion of 10% L-arginine solution

Statistical Analysis

  • Differences in calf blood flow, blood pressure pulse rate, biochemical data and paired T-tests or two-way analysis of variance for repeated measurements
  • All calculated P-values were two-tailed, and a value of <0.05 was considered significant.
Data Collection Summary:


Timing of Measurements


  • Baseline and post-infusion measurements were taken immediately before and after infusion
  • Time between experimental and placebo infusions was between one and two weeks.


Dependent Variables

  • Variable One: Occlusion induced blood flow response measured by venous occlusion plethysmography
  • Variable Two: Calf blood flow response after exercise
  • Variable Three: Peak oxygen uptake in exercise continuously measured using respiromonitor system
  • Variable Four: Anaerobic threshold, using respiromonitor system
  • Variable Five: Exercise time.

Independent Variables

Infusion of 10% L-arginine (experimental exposure).

Control Variables

5% dextrose solution (placebo).

Description of Actual Data Sample:
  • Initial N: 19 patients
  • Attrition (final N): 19 patients.


  • Range: 29-74 year
  • Mean: 57±3 years.


Not noted.

Other Relevant Demographics

  • 13 males, six females
  • Five current smokers
  • Two were NYHA Functional Class I; 12 were Class II; five were Class III
  • LV ejection fraction averaged 41 (3%)
  • Medications
    • 11 of the 19 patients were being treated with angiotensin-converting enzyme inhibitors
    • Five were using glyceryl trinitate
    • 14 were on digitalis
    • 11 were on diuretics
    • Administration of drugs was discontinued at least 12 hours before the start of the study.


  • Eight healthy age and sex matched volunteers (mean age, 58 years)
  • 37.5% smokers
  • Control group in this instance played no role in the evaluation of the results.


Anthropometrics not noted.



Summary of Results:


L-Arginine Measures and Confidence Intervals (Mean±SEM)

Measures and Confidence Intervals

Statistical Significance of Group Difference

Calf Blood Flow Response Baseline (Pre-Infusion)




Calf Blood Flow Response Post-Infusion



Arginine pre vs. post, P<0.01
Placebo pre vs. post, NS
Post-arginine vs. post-placebo, P<0.0001

Calf Blood Response After Exercise




Peak Oxygen Uptake




Anaerobic Threshold

10.5±0.6 ml/min/kg

10.4±0.7 ml/min/kg


Exercise Time

296±23 seconds

283±22 seconds


Other Findings

L-arginine infusion had no effect on baseline calf blood flow or on resting and exercise-induced systemic blood pressure and heart rate (Table One).

Author Conclusion:

Acute supplementation with the nitric oxide precursor L-arginine increased lower limb reactive hyperaemia, but did not lead to any significant improvement in exercise capacity in patients with chronic heart failure.

Funding Source:
Government: Japanese Ministry of Education, Science and Culture
Foundation associated with industry:
Reviewer Comments:
  • Unclear from discussion whether this sample is representative of CHF patients in general, although level of disability is described
  • The use of 5% dextrose as a placebo could have had some effect on study outcomes vs. 10% arginine. For example, insulin response is higher because load of arginine is higher. It might have been preferable to use another amino acid as a placebo at a similar load level.
  • Control group in this instance played no role in the evaluation of the results
  • The researchers were not blinded as to the therapies. Could that have influenced the outcome?
  • Clinical significance of this would appear limited, given the fact that there was no effect on exercise tolerance and the fact that arginine taken orally may not have the same effect as arginine delivered via forearm catheter.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? No
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? ???
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? ???
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? ???
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? ???
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? Yes