Author + information
- Received October 8, 2013
- Revision received December 19, 2013
- Accepted December 24, 2013
- Published online June 1, 2014.
- Nicholas A. McKeag, MB, BCh, PhD∗,†∗ (, )
- Michelle C. McKinley, PhD∗,
- Mark T. Harbinson, MD†,‡,
- Rebecca L. Noad, MB, BCh∗,†,
- Lynn H. Dixon, MSc†,
- Ann McGinty, PhD∗,
- Charlotte E. Neville, PhD∗,
- Jayne V. Woodside, PhD∗ and
- Pascal P. McKeown, MD†,‡
- ∗Centre for Public Health, School of Medicine, Dentistry & Biomedical Sciences, Queen's University, Belfast, Northern Ireland
- †The Heart Centre, Belfast Health & Social Care Trust, Belfast, Northern Ireland
- ‡Centre for Medical Education, School of Medicine, Dentistry & Biomedical Sciences, Queen's University, Belfast, Northern Ireland
- ↵∗Reprint requests and correspondence:
Dr. Nicholas A. McKeag, Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences Block B, Grosvenor Road, Belfast BT12 6BJ, Northern Ireland.
Objectives This study sought to investigate the effect of a multiple micronutrient supplement on left ventricular ejection fraction (LVEF) in patients with heart failure.
Background Observational studies suggest that patients with heart failure have reduced intake and lower concentrations of a number of micronutrients. However, there have been very few intervention studies investigating the effect of micronutrient supplementation in patients with heart failure.
Methods This was a randomized, double-blind, placebo-controlled, parallel-group study involving 74 patients with chronic stable heart failure that compared multiple micronutrient supplementation taken once daily versus placebo for 12 months. The primary endpoint was LVEF assessed by cardiovascular magnetic resonance imaging or 3-dimensional echocardiography. Secondary endpoints were Minnesota Living With Heart Failure Questionnaire score, 6-min walk test distance, blood concentrations of N-terminal prohormone of brain natriuretic peptide, C-reactive protein, tumor necrosis factor alpha, interleukin-6, interleukin-10, and urinary levels of 8-iso-prostaglandin F2 alpha.
Results Blood concentrations of a number of micronutrients increased significantly in the micronutrient supplement group, indicating excellent compliance with the intervention. There was no significant difference in mean LVEF at 12 months between treatment groups after adjusting for baseline (mean difference: 1.6%, 95% confidence interval: −2.6 to 5.8, p = 0.441). There was also no significant difference in any of the secondary endpoints at 12 months between treatment groups.
Conclusions This study provides no evidence to support the routine treatment of patients with chronic stable heart failure with a multiple micronutrient supplement. (Micronutrient Supplementation in Patients With Heart Failure [MINT-HF]; NCT01005303)
Heart failure is a common condition. At 40 years of age, the lifetime risk is approximately 1 in 5 for both men and women in the United States (1). The economic impact of heart failure on health services is therefore considerable, with an estimated combined direct and indirect cost in the United States of $39.2 billion in 2010 (2). Advances in treatment options have led to improvements in outcomes, but overall, the prognosis is poor, with 5-year mortality rates as high as 70% (3).
A growing body of evidence is emerging suggesting that micronutrients (defined as substances needed only in small amounts for normal body function ) play an important role in the setting of heart failure. Observational studies suggest that patients with heart failure have reduced intake and lower concentrations of a number of micronutrients, with the exception of copper status, which tends to be elevated (5). Treatment with intravenous thiamin produced an improvement in left ventricular ejection fraction (LVEF) in a small, randomized, placebo-controlled trial involving 30 patients with heart failure who received long-term furosemide therapy (6). More recently, 2 studies have demonstrated the potential benefits of micronutrient supplementation in patients with chronic stable heart failure. In 30 elderly patients with heart failure secondary to ischemic heart disease (IHD), multiple micronutrient supplementation, including vitamin D at a dose of 10 μg/day, improved LVEF and quality of life with no change in markers of systemic inflammation (7). In 123 patients with heart failure, vitamin D supplementation at a higher dose (50 μg/day) produced a reduction in systemic inflammation but no change in LVEF (8).
The aim of this study was to investigate the effect of multiple micronutrient supplementation (including vitamin D at a dose of 50 μg/day) on LVEF in patients of varying ages with chronic stable heart failure of any etiology.
This was a randomized, double-blind, placebo-controlled, parallel-group study performed at a single center in Belfast, Northern Ireland. The study was approved by the Office for Research Ethics Committee Northern Ireland and conformed to the principles of the Declaration of Helsinki. All patients provided written informed consent. The study was registered on the ClinicalTrials.gov web site (NCT01005303).
Patients with heart failure were recruited from hospital-based heart failure clinics in Northern Ireland between July 2009 and December 2010. Inclusion and exclusion criteria are listed in Table 1.
Randomization and blinding
Patients were randomized to a 12-month period of treatment with a multiple micronutrient supplement (containing 1 Forceval tablet [Alliance Pharmaceuticals, Wiltshire, United Kingdom] [Table 2] and 2 25-μg vitamin D3 tablets [Merck, Serono, Germany]) or placebo (1 tablet containing lactose) daily. Patients were consecutively allocated to a computer-generated random number using block randomization. All study personnel and participants were blinded to the treatment assigned for the duration of the study. The randomization schedule was held and maintained by the clinical trials pharmacist (Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, United Kingdom) until recruitment, data collection, and endpoint analyses were complete.
All endpoints were assessed at baseline and after 12 months of treatment. The primary endpoint was LVEF assessed by cardiovascular magnetic resonance (CMR) imaging or 3-dimensional (3D) transthoracic echocardiography (TTE). Secondary endpoints were quality of life, assessed using the Minnesota Living With Heart Failure Questionnaire; physical functioning, assessed using 6-min walk test distance; blood concentrations of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-6), and an anti-inflammatory cytokine (IL-10); and urinary levels of a marker of oxidative stress (8-iso-prostaglandin F2 alpha [8-iso-PGF2α]).
Compliance was assessed by measuring blood concentrations of a number of micronutrients contained within the multiple micronutrient supplement at baseline and after 12 months.
CMR imaging was performed in a 1.5-T magnetic resonance imaging scanner (General Electric Company, Fairfield, Connecticut) using electrocardiogram gating and a chest coil in the standard position. Standard steady state free precession cine images were obtained based on the Society for Cardiovascular Magnetic Resonance standards (9). Contiguous short-axis slices (thickness 7 mm, 3-mm gaps) were obtained from base/valve plane to cardiac apex; end-diastolic and -systolic frames were used to generate the end-diastolic and -systolic volumes for each slice by manual tracing of the endocardial border. Images were analyzed offline by 1 experienced operator (M.T.H.) using QMass MR Enterprise Solution software (Medis Medical Imaging Systems, Leiden, the Netherlands).
3D transthoracic echocardiography
3D-TTE was performed by 2 experienced clinical physiologists (L.H.D.) on a Philips ie33 Echocardiography System (Koninklijke Philips Electronics, Amsterdam, the Netherlands) with standard and 3D transducers. Standard TTE views were obtained based on the British Society of Echocardiography standards (10). Images were analyzed offline by the clinical physiologist performing the scan. LVEF was estimated using a biplane Simpson's rule for 2-dimensional imaging and using manufacturer's proprietary software for 3D volume sets.
Minnesota living with heart failure questionnaire
The Minnesota Living With Heart Failure Questionnaire is a validated, self-administered questionnaire containing 21 statements to be scored on a 0 to 5 Likert-type scale that measures the effects of symptoms, functional limitations, and psychological distress on an individual's quality of life (11).
6-min walk test
Participants completed a 6-min walk test as described by the American Thoracic Society (12). The total distance walked over 6 min was measured to the nearest meter.
Blood and urine analysis
Serum concentrations of iron, magnesium, phosphate, and calcium were measured using colorimetric assays (Roche Diagnostics, Burgess Hill, United Kingdom). Serum concentrations of NT-proBNP and ferritin were measured using electrochemiluminescence immunoassays (Roche Diagnostics). Serum concentrations of vitamin B12 and folate were measured using chemiluminescent microparticle assays (Roche Diagnostics). Serum vitamin D concentration was measured using Ultra Performance Liquid Chromatography followed by tandem mass spectrometry (13) (Waters Corporation, Milford, Massachusetts). This method measures both 25-hydroxy-vitamin D2 and 25-hydroxy-vitamin D3, and the results are presented as total 25-hydroxy-vitamin D. The serum concentration of vitamin B6 (pyridoxal phosphate) was measured using high-performance liquid chromatography (HPLC) with fluorescence detection (Chromsystems Instruments & Chemicals, Gräfelfing, Germany). Plasma concentrations of vitamin A (β-carotene) and vitamin E (α-tocopherol) were measured using HPLC with diode array detection (Thermo Fisher Scientific, Waltham, Massachusetts). Serum CRP concentration was measured using an immunoturbidimetric assay (Roche Diagnostics). Serum concentrations of TNF-α, IL-6, and IL-10 were measured using an electrochemiluminescence immunoassay (Randox Laboratories, Crumlin, United Kingdom). The urinary concentration of 8-iso-PGF2α was measured using a colorimetric immunoassay (Enzo Life Sciences, Exeter, United Kingdom).
To assess possible changes in dietary intake during the study, all patients completed a modified version of the European Prospective Investigation into Cancer and Nutrition food frequency questionnaire (FFQ) at baseline and after 12 months. This is a semiquantitative FFQ with good reproducibility and modest to good validity when compared with other dietary assessment methods (14,15).
All tests were 2-tailed, and p < 0.05 was considered statistically significant. Results are presented as mean ± SD for continuous variables and number (percentage) for categorical variables. For continuous variables, approximate normality was assessed from histograms. For baseline characteristics, comparisons between groups were performed using the independent samples t test for continuous variables and chi-square test for categorical variables. For all measurements performed at baseline and after 12 months, analysis of covariance (ANCOVA) was used to look for differences between treatment groups (16). The paired samples t test was used to look for differences within groups. All analyses were performed on an intention-to-treat basis. Power was calculated based on an assumed SD of change in LVEF (at 12 months) of 5.2% (estimated from data from a previous similar study ). With a 2-tailed test at the 5% level, approximately 46 patients/group would be required to detect, as significant, a 3 percentage point difference in mean LVEF at 12 months (adjusting for baseline) with 80% power. Analyses were performed with SPSS version 18.0 (SPSS Inc., Chicago, Illinois).
Recruitment and follow-up
A summary of recruitment, randomization, and protocol completion is shown in Figure 1. A total of 274 patients were approached as potential candidates for the study. Of these, 150 patients did not wish to participate and 45 had 1 or more exclusion criteria. Thus, 79 patients were recruited. Five patients were withdrawn from the study prior to randomization (2 patients declined to continue in the study, and a previously unidentified exclusion criterion was identified in 3 patients). Seventy-four patients were randomized to treatment: 38 to the multiple micronutrient supplement and 36 to placebo. Within the multiple micronutrient supplement group, 3 patients did not complete the study protocol (2 developed illnesses during the first 3 months of follow-up, requiring withdrawal from the study, and 1 died approximately 6 months into the study). Within the placebo group, all patients completed the study protocol. All patients were of white European origin.
Baseline characteristics are summarized in Table 3. The mean age of participants was 64.3 years, and 81.1% of the population was male. Overall, the groups were well matched. However, LVEF was significantly lower and the percentage of patients receiving a mineralocorticoid antagonist was significantly higher in the micronutrient supplement group. In addition, there was a trend suggesting that there was more IHD in the micronutrient supplement group. With respect to etiology of heart failure, IHD was twice as common as non-IHD. The majority (78.4%) of patients were within New York Heart Association (NYHA) functional class II. Most patients were receiving the current best drug therapy for heart failure: nearly all were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (97.2%) and beta-blocker (94.6%), and 50.0% were receiving a mineralocorticoid antagonist. In total, 56.7% of patients were receiving device-based therapy: 27.0% had an implantable cardioverter-defibrillator (ICD) only and 29.7% had an ICD with cardiac resynchronization therapy (CRT) functionality. No patients were receiving CRT only. Suboptimal micronutrient status was observed in 69 patients (93.2%) for vitamin D (<75.0 nmol/l), 3 patients (4.1%) for vitamin B6 (<20.0 mmol/l), 5 patients (6.8%) for vitamin B12 (<200.0 ng/l), 4 patients (5.4%) for folate (<2.3 μg/l), and no patients for vitamin E (<11.6 μmol/l).
Compliance was assessed by measuring blood concentrations of iron, ferritin, magnesium, phosphate, calcium, folate, and vitamins D, B6, B12, A, and E at baseline and after 12 months. The results are summarized in Table 4. There was a significant between-group difference in concentrations of ferritin, folate, and vitamins D, B6, B12, and A at 12 months. Within-group analysis revealed a significant increase in concentrations of folate and vitamins D, B6, B12, A, and E in the active treatment group. Figure 2 summarizes changes in vitamin D concentration in both treatment groups.
Primary and secondary endpoints
Primary and secondary endpoint results are summarized in Table 5. There was no significant difference in mean LVEF at 12 months between treatment groups after adjusting for baseline (mean difference: 1.6%, 95% confidence interval: −2.6% to 5.8%, p = 0.441) (Fig. 3). A total of 28 patients (41.2%) underwent CMR imaging (11 patients from the micronutrient supplement group and 17 patients from the placebo group), and 40 patients (58.8%) underwent 3D-TTE (22 patients from the micronutrient supplement group and 18 patients from the placebo group). ANCOVA may be expanded to include adjustment for additional variables. It was therefore possible to include imaging type within the analysis for the primary endpoint. This had no significant impact on the result (mean difference after adjustment: 1.6%, 95% confidence interval: −2.6% to 5.8%, p = 0.449). There was no significant difference in Minnesota Living With Heart Failure Questionnaire score; 6-min walk test distance; blood concentrations of NT-proBNP, CRP, TNF-α, IL-6, or IL-10; or urinary levels of 8-iso-PGF2α at 12 months between treatment groups. A subgroup analysis was undertaken including only patients with an increase in serum vitamin D concentration greater than the median increase. No significant difference was observed in the primary or secondary endpoint results (data not shown).
Anthropometry and dietary intake
Anthropometric measures and dietary intake of participants are summarized in Table 6. There was no significant between-group difference in any of the anthropometric measurements or dietary intake at 12 months.
In this randomized, double-blind, placebo-controlled trial, treatment with a multiple micronutrient supplement had no significant effect on LVEF, Minnesota Living With Heart Failure Questionnaire score, 6-min walk test distance, blood concentrations of NT-proBNP or biomarkers of inflammation, or urinary levels of a biomarker of oxidative stress.
Compliance with the intervention is supported by objective data indicating a significant between-group difference in blood concentrations of ferritin, folate, and vitamins D, B6, B12, and A. There was no significant between-group difference in blood concentrations of magnesium, phosphate, calcium, or vitamin E at 12 months. This can likely be attributed to the fact that, in the case of vitamin E, the dose within the supplement was low. With respect to calcium, blood concentrations are homeostatically maintained within narrow limits and, in the case of phosphate and magnesium, blood status is not necessarily reflective of dietary intake as many factors influence plasma or serum concentrations (17).
The randomization process ensured that the micronutrient supplement and placebo groups were fairly well-matched overall. However, compared with the placebo group, the mean LVEF in the micronutrient supplement group was significantly lower (38.3% vs. 45.1%, p = 0.006) and the percentage of patients receiving a mineralocorticoid antagonist was significantly higher (63.2% vs. 36.1%, p = 0.020) at baseline. These observations suggest that patients in the micronutrient supplement group had more advanced heart failure and could potentially have biased the findings towards the alternative hypothesis. However, it is very unlikely that this chance occurrence had any impact on the results observed because ANCOVA, the statistical test chosen to look for differences between groups at 12 months, accounts for baseline differences (16).
A number of observational studies have demonstrated reduced or suboptimal vitamin D status in heart failure (18–20), and this appears to be associated with an adverse prognosis (21–25). Despite these findings, few randomized controlled trials have investigated the effect of vitamin D supplementation in patients with heart failure. Schleithoff et al. (8) demonstrated a reduction in levels of systemic inflammation (as assessed by blood concentrations of TNF-α and IL-10) in 123 patients with chronic heart failure randomized to receive vitamin D3 (50 μg/day) or placebo for 9 months. No significant change was observed in LVEF, left ventricular end-diastolic volume, or cardiopulmonary stress test performance. In a similar study, Witham et al. (26) randomized 105 patients with chronic heart failure, age ≥70 years, to receive vitamin D2 (2,500 μg) or placebo at baseline and at 10 weeks (26). Treatment with vitamin D resulted in a significant decrease in circulating BNP concentration at 10 weeks (but not at 20 weeks). However, this was not associated with any significant change in 6-min walk test distance or blood concentration of TNF-α, and the mean Minnesota Living With Heart Failure Questionnaire score at 20 weeks increased significantly in the treatment group compared with placebo, suggesting a worsening in quality of life. More recently, in a randomized intervention study involving 101 patients with heart failure, Schroten et al. (27) demonstrated that treatment with vitamin D3 (50 μg daily) was associated with a significant decrease in plasma renin activity without a significant change in circulating NT-proBNP concentration. In a similar intervention study involving 64 patients with heart failure, treatment with vitamin D3 (1,250 μg weekly) was not associated with any significant change in physical performance (28). Only 1 randomized controlled trial has been published examining the effect of multiple micronutrient supplementation alone in patients with chronic heart failure. In this study, Witte et al. (7) randomized 30 patients with chronic heart failure to receive a multiple micronutrient supplement or placebo. Treatment with the micronutrient supplement produced a number of significant changes in heart failure status. LVEF increased significantly, and left ventricular end-diastolic volume decreased significantly, suggesting that there was an improvement in left ventricular systolic function. In addition, mean EuroQol questionnaire score increased significantly, suggesting that there was an improvement in quality of life. No significant change was observed in 6-min walk test distance or blood concentrations of TNF-α. The reason for the difference in results observed between these studies and the present one is not clear. However, a number of differences exist that may be partly responsible. In comparison to the present study, mean LVEF and 6-min walk test distance were substantially lower at baseline in both the studies by Schleithoff et al. (8) and Witte et al. (7). This suggests that patients from these studies had more advanced heart failure. In keeping with this, the study by Schleithoff et al. (8) included a number of patients with NYHA functional class IV. In the present study, 29.7% of patients were receiving CRT and 56.8% had an ICD. In the study by Schleithoff et al. (8), patients receiving CRT were excluded and the number of patients with an ICD was not disclosed. Likewise, no patients in the study by Witte et al. (7) were receiving device-based therapy. This suggests that more patients in the present study were receiving contemporary evidence-based treatment of heart failure. As a consequence, the results presented here may have more relevance to current clinical practice. In addition, all patients in the study by Witte et al. (7) were >70 years of age, compared with a mean age of 64.3 years in the present study. Furthermore, IHD was the cause of heart failure in all patients in the study by Witte et al. (7), whereas non-IHD causes accounted for approximately one-third of heart failure patients in the present study, suggesting a population more representative of the general clinical population. Finally, the micronutrient supplement used in the study by Witte et al. (7) was substantially different, containing much higher doses of thiamin, vitamin B6, folate, and vitamins B12, C, and E than that used in the present study. Unlike the present study, the supplement also contained coenzyme Q10. Coenzyme Q10 is endogenously synthesized from acetyl coenzyme A and is often not considered a micronutrient (29). However, a recent meta-analysis suggests that treatment with coenzyme Q10 may improve LVEF in patients with heart failure (30).
In the FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure) study, treatment with ferric carboxymaltose was associated with an improvement in symptoms, functional capacity, and quality of life in 459 patients with chronic heart failure (31). In the present study, treatment with a multiple micronutrient supplement containing iron had no significant effect on any of the measured endpoints despite evidence of a difference in ferritin levels between groups at 12 months. A possible explanation for this is that patients in the FAIR-HF study had evidence of iron deficiency at baseline, whereas in the present study, at baseline, only 1 patient had a blood ferritin concentration lower than the reference range.
First, this study was a randomized trial with a placebo control group, and both subjects and study investigators were blinded to the treatment type. With the caveat described in the following text, the study population was representative of a typical chronic heart failure population attending secondary care. In particular, most patients were receiving contemporary, evidence-based therapies for heart failure, including a substantial proportion that was receiving device-based therapies. Measurement of blood concentrations of a number of micronutrients contained within the micronutrient supplement indicated excellent compliance with the study medication. Furthermore, analysis of data from the FFQ suggested very little change in dietary intake during the study. On the basis of previously published studies, the duration of follow-up would be expected to be sufficient to detect any beneficial (or detrimental) effects of micronutrient supplementation. Finally, the number of subjects completing the study protocol greatly exceeded that in the only other published clinical trial investigating the effect of multiple micronutrient supplementation in the setting of chronic heart failure (7).
First, it was not possible to achieve the recruitment target. The main reason for this was patient refusal to participate in the study because of difficulties travelling to the hospital for study visits. As such, the study is underpowered with respect to the primary endpoint. With complete follow-up data from 96 patients, the study would have had 80% power to detect as significant (at the 5% level) a 3 percentage point difference in LVEF at 12 months (adjusting for baseline). As previously described, follow-up data for the primary endpoint were available for 68 patients. However, the 95% confidence intervals for the primary endpoint indicate that treatment with the micronutrient supplement compared with placebo was not consistent with a 3% increase in LVEF in the multiple micronutrient supplement group. Overall, it is, therefore, unlikely that this small change in power is of clinical significance. As indicated above, mean LVEF was significantly lower in the micronutrient supplement group, and the percentage of patients receiving a mineralocorticoid antagonist was significantly higher in the micronutrient supplement group at baseline, suggesting that patients in the micronutrient supplement group had more advanced heart failure. An additional study weakness is the proportion of patients with mild heart failure. The majority of patients fell within NYHA functional class II, with a mean baseline LVEF of 41.6% and mean baseline 6-min walk test distance of 427.5 m. This indicates a predominance of individuals with mild heart failure. This would greatly limit the ability of the study to detect beneficial (or detrimental) effects of micronutrient supplementation if these were more likely to occur in individuals with more severe disease.
This study provides no evidence to support the routine treatment of patients with chronic stable heart failure with a multiple micronutrient supplement.
The authors would like to thank Dr. Chris Cardwell for his advice regarding choice of statistical methods and Dr. Sarah Gilchrist, Mr. Cyril McMaster, and Dr. Caroline Mercer for their help with laboratory analysis.
This work was supported by a Northern Ireland Health & Social Care R&D Doctoral Fellowship Award and a Northern Ireland Chest Heart & Stroke Association Grant. Dr. Harbinson has received sponsorship to attend a conference from Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- 8-iso-prostaglandin F2 alpha
- analysis of covariance
- cardiovascular magnetic resonance
- C-reactive protein
- cardiac resynchronization therapy
- food frequency questionnaire
- implantable cardioverter-defibrillator
- ischemic heart disease
- left ventricular ejection fraction
- N-terminal prohormone of brain natriuretic peptide
- New York Heart Association
- tumor necrosis factor
- transthoracic echocardiography
- Received October 8, 2013.
- Revision received December 19, 2013.
- Accepted December 24, 2013.
- American College of Cardiology Foundation
- Lloyd-Jones D.M.,
- Larson M.G.,
- Leip E.P.,
- et al.
- Lloyd-Jones D.,
- Adams R.J.,
- Brown T.M.,
- et al.
- Witte K.K.,
- Nikitin N.P.,
- Parker A.C.,
- et al.
- Schleithoff S.S.,
- Zittermann A.,
- Tenderich G.,
- Berthold H.K.,
- Stehle P.,
- Koerfer R.
- Kramer C.M.,
- Barkhausen J.,
- Flamm S.D.,
- Kim R.J.,
- Nagel E.
- Wharton G.,
- Steeds R.,
- Allen J.,
- et al.
- Rector T.S.,
- Cohn J.N.,
- Pimobendan Multicenter Research Group
- Ocke M.C.,
- Bueno-de-Mesquita H.B.,
- Goddijn H.E.,
- et al.
- Ocke M.C.,
- Bueno-de-Mesquita H.B.,
- Pols M.A.,
- Smit H.A.,
- van Staveren W.A.,
- Kromhout D.
- Vickers A.J.,
- Altman D.G.
- Sauberlich H.
- Zittermann A.,
- Schleithoff S.S.,
- Tenderich G.,
- Berthold H.K.,
- Korfer R.,
- Stehle P.
- Witham M.D.,
- Crighton L.J.,
- Gillespie N.D.,
- Struthers A.D.,
- McMurdo M.E.
- Boxer R.S.,
- Kenny A.M.,
- Schmotzer B.J.,
- et al.
- Fotino A.D.,
- Thompson-Paul A.M.,
- Bazzano L.A.