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Heart Failure

L-arginine and coronary outcomes

Citation:

Koifman B, Wollman Y, Bogomolny N, Chernichowsky T, Finkelstein A, Peer G, Scherez J, Blum M, Laniado S, Iaina A, Keren G. Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol. 1995 Nov 1; 26 (5): 1,251-1,256.

 
Study Design:
Time Study
Class:
C - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
  • The purpose of this study was to evaluate the hemodynamic effect of L-arginine infusion in patients with congestive heart failure
  • The hypothesis was that administration of L-arginine in patients with congestive heart failure may increase nitric oxide production and have a beneficial hemodynamic effect.
Inclusion Criteria:
  • Patients with congestive heart failure, due to ischemic heart disease and previous myocardial infarction, without clinical or echocardiographic evidence of primary valvular heart disease
  • All had New York Heart Association Functional Class II or III heart failure
  • Left ventricular ejection fractions at baseline varied from 8% to 30%.

Medications

  • All patients were treated with furosemide and digitalis, which were withheld on the day of the study
  • Nine patients were receiving angiotensin-converting enzyme inhibitors and none of the 12 had been given any vasodilators for 24 hours before the study.
Exclusion Criteria:
  • Active anginal syndrome
  • Recent myocardial infarction
  • Coronary artery bypass surgery
  • Systemic chronic disease.
Description of Study Protocol:
  • Recruitment: Not noted.

Design

  • 12 patients were given 20g of L-arginine by intravenous infusion over one hour at a constant rate
  • Stroke volume, cardiac output and left ventricular ejection fraction were determined with Doppler echocardiography at baseline, at 30 and 60 minutes and one hour after end of infusion
  • Blood and urinary levels of nitrite/nitrate (NO2/NO3) stable metabolites of nitric oxide were measured and clearance was calculated.

Blinding Used

Doppler and echocardiographic operators were blinded as to which stage of the study the reading was obtained.

Intervention

IV infusion of 20g of L-arginine over one hour.

Statistical Analysis

  • Results expressed as mean value ±SD
  • Analysis of variance with repeated measurements for the changes in the variables was performed
  • Differences were considered statistically significant at P<0.0
  • Paired Student's T-test with Bonferroni correction was used to compare two time data points of the same variable.
Data Collection Summary:

Timing of Measurements

Stroke volume, heart rate, cardiac output, mean blood pressure, total peripheral resistance and LV ejection fraction were measured at baseline, 30 minutes, 60 minutes (during infusion) and 120 minutes after infusion.

Dependent Variables

  • Variable One: Stroke volume
  • Variable Two: Heart rate
  • Variable Three: Cardiac output
  • Variable Four: Mean blood pressure
  • Variable Five: Total peripheral resistance (or systemic vascular resistance); SVR=(MBP-JVP)x80/CO in dynes.s.cm-5
  • Variable Six: Ejection fraction
  • Variable Seven: Blood NO
  • Variable Eight: Urinary NO (NO2+NO3)
  • Variable Nine: NO2+NO3 clearance.

Independent Variables

Infusion of 5% glucose mixed with 100ml of 20% L-arginine hydrochloride (total 20g).

Control Variables

N/A.

Description of Actual Data Sample:
  • Initial N: 12 patients
  • Attrition: N/A
  • Age range: 55 to 78 years
  • Ethnicity: Not indicated
  • Other relevant demographics: 11 men, one woman
  • Location: Israel.
Summary of Results:

 

 

Baseline

30 Minutes

60 Minutes

After Infusion (120 Minutes)

Statistical Significance

Stroke Volume (ml)

68±18

74±20*

76±23*

73±26

*Significant difference from baseline by paired T-test
NS ANOVA

Heart Rate (BPM)

60±7

61.6±9

61.2±9

60.5±8

NS

Cardac Output (Liters/Minute)

4.07±1.22

4.54±1.44*

4.7±1.42*

4.4±1.57

*Significant difference from baseline by paired T-test; P=0.014
ANOVA

Mean Blood Pressure (mmHg)

102±11

90±13

89±9.5*

101±11*

*Significant difference from baseline by paired T-test; P<0.0001
ANOVA

Total Peripheral Resistance (dynes-s-cm -5)

1,926±515

1,521±420*

1,452±367*

1,834±637

*Significant difference from baseline by paired T-test; P<0.0001 ANOVA

Ejection Fraction (Percentage)

33±6

35±4.5

36±4.8

34±4.4

NS

Blood NO mmol/mg Creatinine

53.7±18.1

 

48.2±15.4

52.2±13.6

NS

Urinary NO umole/Liter

0.84±0.42

 

1.48±1.09*

1.37±1.31

*Significant difference from baseline by paired T-test; P<0.042
ANOVA

NO2+NO3
Clearance ml/Minute

13.28±0.42

 

29.97±1.09*

17.73±1.31

*Significant difference from baseline by paired T-test; P<0.0001
ANOVA

Other Findings

  • One hour of infusion resulted in a significant increase in stroke volume and cardiac output without a change in heart rate
  • Mean arterial blood pressure and systemic vascular resistance decreased significantly
  • Within one hour of cessation of infusion, all parameters were not significantly different from baseline.
Author Conclusion:

Infusion of L-arginine in patients with congestive heart failure results in increased production of nitric oxide, peripheral vasodilation and increased cardiac output, suggesting a beneficial hemodynamic and possibly therapeutic profile.

Funding Source:
Government: Isreali Ministry of Health
Reviewer Comments:

These data suggest the need for further research evaluating the effects of long-term oral therapy with L-arginine.

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? Yes
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? N/A
  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? ???
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? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  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%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? No
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? N/A
  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? Yes
  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? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  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? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
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? N/A
  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)? N/A
  8.6. Was clinical significance as well as statistical significance reported? No
  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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes