L-arginine and coronary outcomes
Prior DL, Jennings GLR, Chin-Dusting JPF. Transient improvement of acetylcholine responses after short-term oral L-argininen in forearms of human heart failure. J Cardiovascular Pharmacology. 2000; 36: 3-37.
To determine whether conflicting results observed between oral and intraarterial administration of L-arginine in heart failure patients were attributable to a short-lived effect of the drug.
Heart failure (New York Heart Assocation Functional Class Two and Three).
- Subjects were excluded if they had conditions reported to cause abnormal endothelium-dependent vascular responses independent of the presence of heart failure including smoking
- Drinking more than three standard alcoholic drinks per day
- Systolic blood pressure over 140mmHg
- Diastolic blood pressure over 90mmHg
- Total serum cholesterol levels more than 6.2mMsaf
- Recruitment: Patients who were being assessed for or who were awaiting cardiac transplantation.
- Blood flow measurement was performed by using forearm venous occlusion plethysmography
- The blood flow to the hand was excluded by using a cuff placed at the wrist, which was inflated at the time of blood flow measurements
- Venous occlusion was achieved with a brachial cuff and rapid cuff inflator.
- Baseline measurements: Basal blood flow measurements were taken
- The brachial cuff was inflated to produce forearm ischemia for five minutes
- On release of the cuff, the post-ischemia hyperemic response was recorded for three minutes
- Complete data was obtained in 13 patients
- Responses to intrarterial infusion of acetylcholine and sodium nitroprusside were then obtained (N=18), followed by responses to norepinephrine (N=10).
- Basal blood flow, hyperemic response to ischemia and responses to acetylcholine, sodium nitroprusside and norepinephrine were then measured at 60, 120 and 180 minutes after dosage of L-arginine or placebo. Patients were crossed over 14 days later.
All patients received 20g of L-arginine or placebo orally in 60ml of aromatic syrup.
- Data presented as mean±SEM
- Comparison between measurements at baseline pre-arginine vs. pre-placebo were made by students' paired T-test
- Measurements made at different timepoints after drug administration were compared by two-way repeated-measures analysis of variance
- Post-hoc analysis of significant differences between placebo and l-arginine visits was made by using a paired T-test.
- A two-tailed P-value of under 0.05 was considered significant.
Timing of Measurements
- Before and after infusion of test drug
- Crossover 14 days later.
- Plasma L-arginine levels at baseline and at 60, 120 and 180 minutes after oral supplementation
- Resting forearm blood and mean arterial blood pressure at baseline and 60, 120 and 180 minutes after oral supplementation
- Plasma nitriate and nitrite levels before and after treatment
- Blood flow response to ischemia measured as the area under the curve (AUC) for the three-minute period from the peak response at baseline and after supplementation with L-arginine or placebo
- Blood flow responses to infusions of acetylcholine before and after treatment
- Blood flow responses to infusions of sodium nitroprusside and norepinephrine before and after treatment, etc.
20g of L-arginine orally in 60ml of aromatic syrup.
20g of placebo orally in 60ml of aromatic syrup.
- Initial N: 18
- Attrition (final N): Varied by test
- Age: Mean age was 51.1±2.3 years
- Ethnicity: Not noted
- Other relevant demographics: 13 men, five women
- Location: Australia.
Statistical Significance of Group Difference
Baseline Forearm Blood Flow
Pre-Treatment L-arginine Levels
Response to Acetylcholine at 60 Minutes
Response to Acetylcholine at 180 Minutes
Blood L-arginine levels increased four-fold with arginine infusion and remained high throughout the test, but the increased response to acetylcholine was not significantly different by 120 minutes.
- Short-term oral supplementation of L-arginine in heart failure results in a marked increase in plasma L-arginine levels, which is sustained for a period of 180 minutes
- Brief oral supplementation improves forearm vasodilator responses to acetylcholine
- The enhanced vasodilator response is only transient and no longer present after 180 minutes, despite persistent elecvation of plasma L-arginien levels.
|Government:||national health and medical research council of australia|
- This clinical significance of transient improvements in forearm vasodilator response to acetylcholine remains to be proven
- The study N was smaller for some tests (e.g. norepinephine, N=10), with no explanation.
The study protocol states that nitrate-containing medications were withheld for 24 hours before each study and all other medications except diuretics were withheld on the day of the study.
Quality Criteria Checklist: Primary Research
|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|
|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?||N/A|
|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?||???|
|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)||Yes|
|3.2.||Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?||Yes|
|3.3.||Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)||Yes|
|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?||???|
|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%.)||No|
|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?||N/A|
|5.||Was blinding used to prevent introduction of bias?||N/A|
|5.1.||In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?||Yes|
|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?||Yes|
|6.||Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?||N/A|
|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?||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?||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?||???|
|8.||Was the statistical analysis appropriate for the study design and type of outcome indicators?||N/A|
|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?||N/A|
|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?||N/A|
|10.1.||Were sources of funding and investigators' affiliations described?||Yes|
|10.2.||Was the study free from apparent conflict of interest?||Yes|