Heart Failure

HF: Folate and B-12 (2007)


Andersson SE, Edvinsson ML, Edvinsson L. Reduction of Homocysteine in Elderly with Heart Failure Improved Vascular Function and Blood Pressure Control but Did Not Affect Inflammatory Activity. Basic & Clin Pharm & Toxicol. 2005; 97: 306-310.

Study Design:
Before-after study
D - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To investigate if vitamin supplementation, with doses used in ordinary health care, has the ability to normalise plasma homocysteine in elderly heart failure patients and furthermore, if this affected endothelial function, vasodilatatory capacity, inflammatory activity and low health quality.   

Inclusion Criteria:

Heart failure (HF), based on symptoms, clinical signs and an elevated plasma level of N-terminal brain natriuretic peptide (NT-proBNP) and plasma homocysteine over 15µM.

Exclusion Criteria:

Presence of tremor or cognitive impairment, which could affect measurements.

Description of Study Protocol:
  • Recruitment: Primarily from outpatients in primary care
  • Design: Before-after study
  • Intervention: Daily dose for six weeks of three mg pyridoxine, 0.8mg folate and 0.5mg vitamin B12

Statistical Analysis

  • Student's two-tailed T-test for paired data
  • Maximal value and relative changes are presented
  • Data are given as mean ±SEM
  • Calculations were preformed using StatView 5.0.
Data Collection Summary:

Timing of Measurements

Baseline and six weeks.

Dependent Variables

  • Variable One
    • Plasma samples for interleukin-6 (IL-6)
    • Soluble interleukin2-receptor (sIL2r)
    • C-reactive protein (CRP, high sensitive method)
    • Cobalamines
    • Folate
    • von Willebrand factor (antigen)
    • HbA1c
    • Creatinine
    • Uric acid.
  • Variable Two
    • Cutaneous blood flow response to the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent dilator sodium nitroprusside (SNP) administered by iontophoresis and to local warming was determined
    • ACh (2%) was administered five times using anodal current, SNP four times using cathodal current. After this, the vasodilatatory response to local warming (44oC for 10 minutes) was determined. 

Independent Variables

  • Pyridoxine
  • Folate
  • Vitamin B12.
Description of Actual Data Sample:
  • Initial N: 14 (12 males, 2 females)
  • Attrition (final N): 14
  • Age: 81±1 years
  • Ethnicity: Not described

Other Relevant Demographics

  • One was an active smoker
  • One used oral tobacco
  • Seven were former smokers (over 20 years ago). 


  • The mean estimated NYHA functional class was 2.8±0.2
  • Mean estimated maximal walking distance, 400 meters; range of 10 meters to 1,000 meters
  • The subjects were on an average of nine different drugs.
Summary of Results:


Before Treatment
(Measures and Confidence Intervals)

After Treatment
(Measures and Confidence Intervals)

Statistical Significance of Group Difference

Mean Plasma Homocystein (µM)




Mean Plasma Folate (nM)




Plasma Cobalamine




Arterial Blood Pressure




Heart Frequency




ACh (Flow Units)








Heat Stimulation




Other Findings

  • Homocysteine levels decreased in all of the subjects, except for one with end stage renal disease, who had an increase. Only four of the individuals had homocysteine levels considered at the upper limit.
  • Four of the patients had subnormal folate levels before treatment
  • Creatinine clearance, uric acid, HbA1c, sIL2r, IL-6, von Willebrand factor and severity of HF (NT-proBMP) were unaffected by the vitamin treatment
  • There wasn't any change in the patient's subjective health quality or walking distance
  • Stimulation with ACh caused a non-significant increase in blood flow and SNP. Local warming induced a non-significant increase in blood flow. There was a significant enhancement of the response to ACh, when it was expressed as relative to the response to heat (P≤0.05), while the repsonse to SNP did not reach statistical significance. These responses did not correlate to homocysteine levels.
Author Conclusion:
  • The present data suggests that the hyperhomocysteinaemia seen in HF is multi-factorial in origin
  • Vitamin supplementation reduces plasma homocysteine in this condition and it is suggested that this treatment could improve the endothelium-dependent vasodilatory capacity and reduce blood pressure
  • We found no improvement of the prothrombotic endothelial function. 
Funding Source:
Government: SMRC, Region Skane (Sweden)
Foundation associated with industry:
Reviewer Comments:

The authors state, "The small number of participants and the open-label design limit the study. Furthermore, the variations in the base-level flow could have influenced the vasodilatory results. These data could also have been affected by the increased compliance to the prescribed drugs."

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? 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? Yes
  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? N/A
  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? No
  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.) No
  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? N/A
  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? ???
  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? 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? 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)? N/A
  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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes