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B-Vitamin Deficiency in Hospitalized Patients with Heart Failure
RESEARCH Perspectives in Practice
B-Vitamin Deficiency in Hospitalized Patients with Heart Failure MARY E. KEITH, PhD, RD; NATALIE A. WALSH, MSc; PAULINE B. DARLING, PhD, RD; STACY A. HANNINEN, MSc, RD; SUBARNA THIRUGNANAM, MD; HOWARD LEONG-POI, MD; AIALA BARR, PhD; MICHAEL J. SOLE, MD, FRCPC, FACC
ABSTRACT The impact of heart failure and its treatment on specific nutrient requirements is unknown. Furthermore, depletion of water-soluble B vitamins that play key roles in the production of cellular energy in patients with heart failure can contribute to depletion of energy reserves observed in the failing heart. A cross-sectional study recently reported that approximately one third of hospitalized patients with heart failure had tissue levels suggestive of thiamin deficiency (vitamin B-1). Riboflavin (vitamin B-2) and pyridoxine (vitamin B-6) are similar to thiamin in that they are water-soluble, subject to renal excretion, have limited tissue storage, and are dependent M. E. Keith is coordinator of Nutrition and Dietetic Education, adjunct scientist in the Keenan Research Centre in the Li Ka Shing Knowledge Institute, and assistant professor, Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada. N. A. Walsh is a dietetic intern, St Michael’s Hospital, Toronto, Ontario, Canada. P. B. Darling is coordinator of Nutrition and Dietetic Research, adjunct scientist in the Keenan Research Centre in the Li Ka Shing Knowledge Institute, and assistant professor, Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada. S. A. Hanninen is a clinical dietitian, Heart and Vascular Program, St Michael’s Hospital, Toronto, Ontario, Canada. S. Thirugnanam is a resident, Division of Cardiology, St Michael’s Hospital, Toronto, Ontario, Canada. H. Leong-Poi is director of the Echocardiography Laboratory, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, Division of Cardiology, and Heart and Vascular Program, St Michael’s Hospital, Toronto, Ontario, Canada. A. Barr is a statistical consultant, Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada. M. J. Sole is professor of Medicine and Physiology, University of Toronto, Division of Cardiology, University Health Network, Toronto, Ontario, Canada, and Heart and Stroke/ Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada. Address correspondence to: Mary E. Keith, PhD, RD, Department of Nutrition, 6 Cardinal Carter Wing, Suite 6-056d, Toronto, Ontario M5B 1W8. E-mail: keithm@ smh.toronto.on.ca Manuscript accepted: January 26, 2009. Copyright © 2009 by the American Dietetic Association. 0002-8223/09/10908-0009$36.00/0 doi: 10.1016/j.jada.2009.05.011
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on intake. Therefore, it was hypothesized that the status of these B vitamins may also be adversely affected by heart failure. As a result, the prevalence of patients at risk of vitamin B-2 (erythrocyte glutathione reductase activity coefficient ⱖ1.2) and B-6 deficiency (plasma B-6 ⱕ20 nmol/L) was determined in a cross-section of 100 patients hospitalized with heart failure between April 2001 and June 2002 as well as in a group of volunteers without heart failure. Twenty-seven percent of patients with heart failure had biochemical evidence of vitamin B-2 deficiency, while 38% had evidence of B-6 deficiency. These prevalence rates were significantly higher than those observed in the volunteers without heart failure (2% and 19%, respectively; Pⱕ0.02). Use of common B-vitamin⫺containing supplements by patients with heart failure did not significantly reduce deficiency rates in comparison with those who did not use supplements (B-2 P⫽0.38 or B-6 P⫽0.18)). Finally, while 80% of patients with heart failure took diuretics, neither the dose nor the duration of furosemide use was related to the presence of either B-2 or B-6 deficiency. Given the physiologic importance of these vitamins, further investigations aimed at determining the effect of heart failure on specific nutrient requirements as well as the safety and efficacy of B-vitamin supplementation are warranted. J Am Diet Assoc. 2009;109:1406-1410.
A
norexia, malnutrition, advanced age, and frequent hospitalization are all factors that have been identified as contributing to the increased risk of nutrient deficiencies in patients with congestive heart failure (1-5). Furthermore, diuretic medications used for the management of fluid overload have been linked with biochemical and clinical markers of thiamin (vitamin B-1) deficiency, suggesting inappropriate diuretic-induced losses of water-soluble vitamins in this population (6-8). A recent cross-sectional study reported that 33% of hospitalized patients with heart failure have erythrocyte thiamin pyrophosphate levels suggestive of thiamin deficiency (9). Riboflavin (vitamin B-2) and pyridoxine (vitamin B-6) play critical roles in production of red blood cells and are essential cofactors in cellular energy production. Therefore, deficiency of these vitamins may contribute to depletion of energy reserves observed in the failing heart. Vitamins B-2 and B-6 are similar to thiamin because they are water-soluble, subject to renal excretion, have limited tissue storage, and are dependent on intake. Therefore, it was hypothesized that the status of these B vitamins may also be adversely affected by heart failure. As a result, prevalence of vitamin B-2 and B-6 deficiency in a cross-
© 2009 by the American Dietetic Association
section of hospitalized patients with heart failure was evaluated as well as the relationships between deficiency and various clinical and demographic factors. METHODS Study Subjects Vitamin B-2 and B-6 status was determined in 100 consecutive patients hospitalized with heart failure between April 2001 and June 2002 and compared with 50 age- and sex-matched volunteers without heart failure. Diagnosis of heart failure was made by the attending physician and confirmed based on the Framingham criteria (10). Patients were excluded if they had a history of alcohol abuse, were prescribed medications undergoing research evaluation, or were unable to provide informed consent. Volunteers without heart failure were recruited by the coordinator (a clinical registered dietitian) and were comprised of outpatients attending the cardiac rehabilitation program (n⫽12), volunteers or spouses of participants with heart failure (n⫽6), day patients undergoing cardiac investigations (n⫽18), and staff (n⫽14) who responded to either paper or electronic advertisements. Volunteers without heart failure were excluded if they were known to have any conditions affecting B-vitamin status, such as heart failure, alcoholism, cirrhosis, poorly controlled diabetes, wasting diseases (acquired immunodeficiency syndrome, cancer, or recent myocardial infarction), or if they used diuretics or supplements containing B vitamins. Data Collection Demographic and detailed clinical data, including heart function data, medications and doses (particulary diuretics), medical history, and etiology of heart failure were collected from the participants’ medical charts. Patients with heart failure were categorized as having heart failure with normal ejection fraction if their ejection fraction was determined to be ⱖ45% using standardized echocardiographic criteria (11). The nutritional status of all patients with heart failure was assessed by a trained, registered dietitian using Subjective Global Assessment (SGA) (12). Subsequently, patients were categorized as normally nourished (A), moderately malnourished (B), or severly malnourished (C). A modified semi-quantitative food frequency questionnaire was used to assess habitual dietary intake in the month prior to admission (13,14). Nutrient intakes from food were determined using the Windows version of the Nutriwatch software program (1981-2001, Elizabeth Warwick, Long Creek, Cornwall, Prince Edward Island, Canada) containing the 1997 Canadian Nutrient File and compared with the estimated average requirement (EAR) (15). Total B-6 intake was calculated by adding the dietary intake of B-6 to a corrected intake of B-6 from supplements because of the increased bioavailability of B-6 from supplements (1.27⫻ mg/day pyridoxine hydrochloride) (15). A fasting blood sample was collected from all patients with heart failure within 48 hours of admission. Blood samples from non– heart failure volunters were collected in the morning after an overnight fast as described previously (9). All participants in this study provided informed consent. The research proposal was approved by the Institutional Research Ethics Board.
Analysis of Samples and Definition of Deficiency Blood samples were centrifuged for 10 minutes at 1,080g. Plasma and red blood cells were separated, red blood cells washed, and stored at ⫺70°C until analyzed. Erythrocyte B-2 was determined by measuring the activity of the enzyme erythrocyte glutathione reductase with and without the addition of flavin adenine dinucleotide and is expressed as an activity coefficient. An erythrocyte glutathione reductase activity coefficent ⬍1.2 reflects complete tissue saturation with riboflavin (15-17), whereas an erythrocyte glutathione reductase activy coefficent of ⱖ1.2 suggests deficiency (15,18). Plasma B-6 concentration, measured as pyridoxal-5=-phosphate, was determined by radioimmunoassay according to the protocol of the American Laboratory Products Company (ALPCO Diagnostics, Windham, NH), and deficiency was defined as ⱕ20 nmol/L plasma (15,19). Statistics As the data were not normally distributed, continuous data are presented as the median (25th and 75th percentiles) and categorical data as frequencies and percentages unless otherwise noted. Categorical data were compared using either the Pearson 2 test or Fisher’s exact test when the counts in any one cell were less than five. Relationships between continuous variables were made using Spearman’s rank correlation. Comparisons between deficient and nondeficient groups for continuous variables were made using Mann-Whitney U test. The association of potential predictors with vitamin B-2 or B-6 deficiency were analyzed using logistic regression. Crude odds ratios (OR) and 95% confidence intervals (CI) were calculated using univariate analysis on the heart failure population (20). Statistical analyses were performed using SPSS for Windows software (version 13, 2004, Statistical Package for the Social Sciences, Chicago, IL). All P values were two-tailed and significance was set at a value of 0.05. RESULTS AND DISCUSSION Overall, 27% of a cross-section of hospitalized patients with heart failure had biochemical evidence of vitamin B-2 deficiency, whereas 38% had evidence of B-6 deficiency. Prevalence rates of B-2 and B-6 deficiency were significantly higher that those found in volunteers without heart failure (2.2%; P⬍0.001 and 19%; P⫽0.02, respectively). Furthermore, 68% of patients with heart failure had biochemical evidence of deficiency for at least one B vitamin in comparison with 42% of volunteers without heart failure (P⫽0.007). Approximately one fifth of patients with heart failure used B-vitamin⫺containing supplements (n⫽19), which were either multivitamins or B-complex vitamins consumed daily containing 1.6 to 50 mg B-2 (mean dose⫽13⫾21 mg/day) and 2 to 400 mg B-6 (mean dose⫽36⫾93 mg/day) prior to hospitalization. Use of B-vitamin⫺containing supplements resulted in approximately a 50% reduction in deficiency rates (17.6% for vitamin B-2 and 22% for vitamin B-6). Despite this reduction, the prevalence of B-2 and B-6 deficiency in heart failure supplement users was not significantly different from those who did not use supplements (B2 P⫽0.38 or B6 P⫽0.18).
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Table 1. Characteristics of study subjects—Hospitalized patients with acute heart failure and age-matched volunteers without heart failure Characteristics Age (y) Body mass indexa Male sex Use of B-vitamin–containing supplementsb Use of other supplementsc Erythrocyte glutathione reductase activity coefficient Plasma vitamin B-6 (nmol/L) Left ventricular systolic function Normal (LVEFi⬎60%) Mildly reduced (LVEF 40%-60%) Moderately reduced (LVEF 20%-40%) Severely reduced (⬍20%) Diastolic heart failure (LVEF⬎45%)
Heart failure (nⴝ100)
Volunteers (nⴝ50)
4™™™™™™™ mean⫾standard deviation ™™™™™™™3 67.1 ⫾ 10.1 61.1 ⫾ 11.1 27.3 ⫾ 5.5 27.2 ⫾ 4.7 4™™™™™™™™™™™™™™™ n (%) ™™™™™™™™™™™™™™™3 58 (58) 24 (48) 19 (19) 0 41 (41) 9 (18) 4™™™™™™ median (25th, 75th percentile) ™™™™™™3 1.09 (1.04, 1.21)e 1.06 (1.02, 1.09)f g 25.1 (13.2, 41.8) 33.7 (21.8, 68.3)h n
P value 0.001 0.8 0.3 0.001d 0.01 0.01
21 26 27 26 33
a
Calculated as kg/m2. Congestive heart failure patients taking B-vitamin⫺containing supplements (eg, multivitamin or B-complex) prior to admission and/or during hospital admission. c Includes vitamin supplements other than B-vitamin⫺containing supplements and herbal remedies. d Fisher’s exact test. e n⫽96. f n⫽46. g n⫽98 heart failure. h n⫽48 volunteers. i LVEF⫽left ventricular ejection fraction. b
Demographic Variables, Left Ventricular Function, and B-Vitamin Deficiency Despite attempts to age-match volunteers to the patients with heart failure, the allowed variance (⫾5 years), and the fact that we recruited in a 2:1 ratio resulted in patients with heart failure being significantly older than those in the comparison group (P⫽0.001) (Table 1). While this is a limitation of the study, the impact is minimized by the observed lack of relationship between either B-2 or B-6 deficiency and age using logistic regression analyses (P⫽0.36 and P⫽0.54, respectively). There was a tendency for females to have a higher rate of B-6 deficiency when compared with males (54% vs 46%; P⫽0.06) (Table 2). However, no such relationship was observed for vitamin B-2. Heart failure severity (measured by the left ventricular ejection fraction) was not associated with vitamin B-2 deficiency (P⫽0.5). However, patients with moderate or severe left ventricular systolic dysfunction were 0.44 times (95% CI: 0.19 to 1.00) less likely to be vitamin B-6⫺deficient (Table 2). Nutritional Factors and B-Vitamin Deficiency Determination of the SGA score revealed that 50% of patients with heart failure were at risk of being malnourished (SGA B or C). While no relationship was observed between vitamin B-2 deficiency and the presence of malnutrition (P⫽0.24), patients with SGA class A (well-nourished) were more likely to be B6-deficient (OR⫽2.3; 95% CI: 0.99 to 5.32).
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These data support a link between vitamin status and total vitamin intake (B-2 rs⫽⫺0.38; P⬍0.001 and B-6 rs⫽0.25; P⫽0.01). Failing to meet the B-2 EAR was significantly related to the presence of B-2 deficiency (OR⫽0.16; 95% CI: 0.04 to 0.62; P⫽0.008). On the other hand, no relationship was observed between not meeting the B-6 EAR and B-6 deficiency (P⫽0.63) (Table 2). A considerable proportion of patients with heart failure were considered deficient, despite having intakes that met or exceeded the EAR for the habitual intake of these vitamins for the healthy population (88% B-2, 81% B-6), suggesting that current recommended intakes may be insufficient to meet the needs of this population. This finding is supported by a recent, large epidemiological study of B-6 deficiency in the United States, which found low plasma pyridoxal-5=-phosphate levels even at intake levels above the Recommended Dietary Allowances (21). Surprisingly, use of commonly found B complex or multivitamin supplements was insufficient to prevent development of B-vitamin deficiency, although these data are limited by the small number of supplement users (n⫽19) in this sample. Kidney Function and Diuretic Use There were no significant relationships observed between any of the common medications used by the patients with heart failure and B-vitamin deficiency (Table 2). Previous studies have suggested that use of loop diuretics, such as furosemide, results in excessive losses of water-soluble
Table 2. Selected clinical and nutritional factors and their relationship with the presence of vitamin B-2 or vitamin B-6 deficiency in a cross section of hospitalized patients with heart failure Factor Age (y) Female sex Moderate/severe left ventricular dysfunction ejection fraction ⬍40% SGAb, A vs B ⫹ C Taking furosemide Taking ⬎1 diuretic Furosemide dose Taking B-vitamin⫺containing supplements Intake meets EARc Creatinine clearance mL/s/SAd
Vitamin B-2 deficiency
P value
Vitamin B-6 deficiency
P value
4™™™™™™™™™™™™ odds ratio (95% confidence interval) ™™™™™™™™™™™™3 0.98 (0.94-1.0) NSa 1.14 (0.76-1.7) 1.96 (0.78-5.0) NS 2.13 (0.97-5.26)
NS 0.06
1.36 (0.55-3.4) 0.57 (0.23-1.4) 0.83 (0.28-2.5) 2.3 (0.86-6.1) 1.0 (0.95-1.03) 0.46 (0.12-1.75) 0.16 (0.04-0.62) 0.72 (0.26-2.0)
0.05 0.05 NS NS NS NS NS NS
NS NS NS NS NS NS 0.008 NS
0.44 (0.19-1.02) 2.3 (0.99-5.3) 1.9 (0.6-5.8) 0.9 (0.35-2.3) 1.0 (0.98-1.04) 0.36 (0.1-1.2) 0.77 (0.26-2.3) 0.78 (0.4-1.5)
a
NS⫽not significant. SGA⫽Subjective Global Assessment. c EAR⫽estimated average requirement. d SA⫽surface area. To convert mL/s creatinine clearance to mL/min, multiply by 60. b
vitamins, in particular thiamin, thereby increasing the risk of nutritional deficiencies (3,6-8). In this study, 80% of patients with heart failure took furosemide daily. Median dose of furosemide was 60 mg/day, which had been taken for a median duration of 14 months. Twenty-seven patients used a combination of diuretics and 3 took more than two diuretics daily. Despite this, no significant relationships were observed between either the dose or duration of diuretic use and B-2 or B-6 deficiency (Table 2). The observed lack of relationship between diuretic use and B-vitamin deficiency remained even when B-supplement users were excluded from the analysis. This finding is supported by others who also failed to find a relationship between thiamin deficiency and diuretic use (1,9,22,23). However, the impact of multiple diuretics on nutrient status remains unclear. As expected, 87% of patients with heart failure had some evidence of impaired kidney function as defined as a corrected creatinine clearance ⬍1.24 mL/s/surface area (⬍74 mL/min). In previous work, impaired renal function was positively related to thiamin status, suggesting a protective effect, possibly by limiting diuretic-induced losses of water-soluble compounds (9). However, in the present study, no substantial relationship was observed between the presence of renal dysfunction and either B-2 or B-6 deficiency, suggesting that kidney dysfunction alone was insufficient to protect against B-vitamin deficiency (Table 2). One limitation in the interpretation of the impact of kidney function is the lack of data on the urinary losses of these B vitamins. Additional limitations of this study include the measurement of B-vitamin status in patients admitted for an acute exacerbation of congestive heart failure and, therefore, may not reflect the prevalence of deficiency in a stable outpatient setting. In addition, there are limitations associated with estimation of habitual dietary intake of B vitamins using the food frequency methodology. However, this tool was believed to give the best estimation of overall intake during the last 3 months in patients
who were unwell and recently admitted to hospital. Finally, urinary riboflavin and B-6 losses were not measured and their relationships with urine volume, B-6 deficiency, or B-2 deficiency could not be analyzed. CONCLUSIONS The findings of this study revealed that approximately one-quarter to one-third of a cross-section of hospitalized patients with heart failure were at risk of vitamin B-2 or B-6 deficiency, respectively. These observations were made in the relative absence of overt malnutrition and in patients, the majority of whom had intakes that met or exceeded the EAR for healthy individuals. Furthermore, use of furosemide over a range of doses was not found to be related to the prevalence of either B-2 of B-6 deficiency, as had been reported previously. Finally, use of commonly consumed B-vitamin supplements appeared to be insufficient to prevent development of B-vitamin deficiency in patients with heart failure. This study also highlights the differences in clinical and nutritional factors that are related to the presence of B-2 and B-6 deficiency. The presence of vitamin B-2 deficiency was strongly related to low vitamin intake, whereas vitamin B-6 deficiency was not. In addition, in contrast to what one might expect, B-6 deficiency was associated with being relatively well-nourished. Finally, the fact that B-6 deficiency was related to diastolic heart failure and not worsening heart function suggests that B-6 deficiency is influenced by differing factors than those associated with vitamin B-2 deficiency or shown previously for vitamin B-1 deficiency despite being part of the same B-vitamin family. Vitamin B-6 plays a critical role in the metabolism of homocysteine and subsequently atherosclerotic heart disease (24,25). Therefore, changes in B-6 status may simply reflect the degree of coronary artery disease and not necessarily the degree of ventricular dysfunction. In addition, vitamin B-6 status has also been linked with markers of inflammation, such as C-re-
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active protein, and thus may be influenced more by the degree of inflammation, thrombogenesis, and endothelial dysfunction than by nutritional factors (26). The high rate of B-2 and B-6 deficiency in this population, together with the important roles of these vitamins in cellular energy metabolism, suggest that the relationship between nutrient requirements and heart failure requires additional investigation. Furthermore, investigations defining the safety and efficacy of B-vitamin supplementation in the heart failure population are warranted, as supplementation may represent a relatively inexpensive adjunctive therapeutic option for heart failure patients in the future. STATEMENT OF POTENTIAL CONFLICT OF INTEREST: No potential conflict of interest was reported by the authors. FUNDING/SUPPORT: This work was supported by a research grant from the Canadian Foundation for Dietetic Research. S. Douglas-Hanninen was supported by a CIHR training grant. ACKNOWLEDGEMENTS: We would like to thank Regina Kurian for conducting the analysis of riboflavin status as well as to Phillip Connelly, PhD, and his laboratory staff for conducting the B6 analysis. Finally, to Joel Ray, MD, for his intellectual contribution. References 1. Brady J, Rock C, Horneffer M. Thiamin status, diuretic medications, and the management of congestive heart failure. J Am Diet Assoc. 1995;95:541-544. 2. Kwok T, Falconer-Smith J, Potter J, Ives D. Thiamin status of elderly patients with cardiac failure. Age Ageing. 1992;21:67-71. 3. Zenuk C, Healey J, Donnelly J, Vaillancourt R, Almalki Y, Smith S. Thiamine deficiency in congestive heart failure patients receiving long-term furosemide therapy. Can J Pharmacol. 2003;10:184-188. 4. Baines M, Davies G. The evaluation of erythrocyte thiamin diphosphate as an indicator of thiamin status in man, and its comparison with erythrocyte transketolase activity measurements. Ann Clin Biochem. 1988;25:698-705. 5. O’Rourke N, Bunker V, Thomas A, Finglas P, Bailer A, Clayton B. Thiamine status of healthy and institutionalized elderly subjects: Analysis of dietary intake and biochemical indices. Age Ageing. 1990; 19:325-329. 6. Seligmann H, Halkin H, Rauchfleisch S, Kaufmann N, Tal R, Motro M, Vered Z, Ezra D. Thiamin deficiency in patients with congestive heart failure receiving long-term furosemide therapy: A pilot study. Am J Med. 1991;91:151-155. 7. Lubetsky A. Urinary thiamine excretion in the rat: Effect of furosemide, other diuretics, and volume load. J Lab Clin Med. 1999;134: 232-7. 8. Rieck J, Halkin H, Almog S, Seligman H, Lubetsky A, Olchovsky D, Ezra D. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med. 1999;134:238-243. 9. Hanninen S, Darling P, Sole M, Barr A, Keith M. The prevalence of
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10. 11.
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thiamin deficiency in hospitalized patients with congestive heart failure. J Am Coll Cardiol. 2006;47:354-361. Ho K, Pinsky J, Kannel W, Levy D. The epidemiology of heart failure: The Framingham study. J Am Coll Cardiol. 1993;4(suppl A):6A-13A. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Chamber Quantification Writing Group, American Society of Echocardiography’s Guidelines and standards Committee, European Association of Echocardiography. Recommendations for Chamber Quantification: A Report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, Developed in Conjunction with the European Association of Echocardiography, a Branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440-1463. Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, Jeejeebhoy KN. What is subjective global assessment of nutritional status. J Parenter Enteral Nutr. 1987;11:8-13. Block G, Dresser C, Hartman A, Carroll M. Nutrient sources in the American diet: Quantitative data from NHANES II: Vitamins and mineral. Am J Epidemiol. 1985;122:13-26. Block G. Block Brief Questionnaire 2000 (unpublished). NutritionQuest Web site. http://www.nutritionquest.com. Accessed January 2001. Institute of Medicine of the National Academies of Science. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Panthothenic Acid, Biotin and Choline. Washington, DC: National Academies Press; 1999:87-120, 150-195. Sauberlich H. Vitamin B2. In: Wolinsky I, ed. Laboratory Tests for the Assessment of Nutritional Status. 2nd ed. Washington, DC: CRC Press; 1999:62-64. Bates C. Riboflavin. Int J Vitam Res. 1993;63:274-277. McCormick DB, Greene HL. Vitamins. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. Philadelphia, PA: Saunders; 1994:999-1028. Lui A, Lumeng L, Aronoff GR, Li TK. Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: Metabolic balance studies in humans. J Lab Clin Med. 1985;106:491-497. Norman G, Streiner D. Biostatistics: The Bare Essentials. 3rd ed. Hamilton, Ontario, Canada: BC Decker Inc; 2008. Morris MS, Picciano MF, Jaques PF, Selhub J. Plasma pyridoxal 5=-phosphate in the US population: The National Health and Examination Survey, 2003-2004. Am J Clin Nutr. 2008;87:1446-1454. Pfitzenmeyer P, Guillard J, d’Athis PH, Petit-Marnier C, Gaudet M. Thiamin status of elderly patients with cardiac failure including the effects of supplementation. Int J Vitam Nutr Res. 1994;64:113-118. Yue Q, Beerman B, Lindstrom B, Nyquist O. No difference in blood thiamin diphosphate levels between Swedish Caucasian patients with congestive heart failure treated with furosemide and patients without heart failure. J Intern Med. 1997;242:491-495. Friso S, Girelli D, Martinelli N, Olivieri O, Lotto V, Bozzini C, Pizzolo F, Faccini G, Beltrame F, Corrocher R. Low plasma vitamin B-6 concentrations and modulation of coronary artery disease risk. Am J Clin Nutr. 2004;79:992-998. Robinson K, Mayer E, Miller DP, Green R, van Lente F, Gupta A, Kottke-Marchant K, Savant SR, Selhub J, Nissen SE, Kutner M, Topol EJ, Jacobsen EJ. Hyperhomocysteinemia and low pyridoxal phosphate: Common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830. Friso S, Jacques PF, Wilson PWF, Rosenberg IH, Selhub J. Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation. 2001;102:2788-2791.
B-Vitamin Deficiency in Hospitalized Patients with Heart Failure MARY E. KEITH, PhD, RD; NATALIE A. WALSH, MSc; PAULINE B. DARLING, PhD, RD; STACY A. HANNINEN, MSc, RD; SUBARNA THIRUGNANAM, MD; HOWARD LEONG-POI, MD; AIALA BARR, PhD; MICHAEL J. SOLE, MD, FRCPC, FACC
ABSTRACT The impact of heart failure and its treatment on specific nutrient requirements is unknown. Furthermore, depletion of water-soluble B vitamins that play key roles in the production of cellular energy in patients with heart failure can contribute to depletion of energy reserves observed in the failing heart. A cross-sectional study recently reported that approximately one third of hospitalized patients with heart failure had tissue levels suggestive of thiamin deficiency (vitamin B-1). Riboflavin (vitamin B-2) and pyridoxine (vitamin B-6) are similar to thiamin in that they are water-soluble, subject to renal excretion, have limited tissue storage, and are dependent M. E. Keith is coordinator of Nutrition and Dietetic Education, adjunct scientist in the Keenan Research Centre in the Li Ka Shing Knowledge Institute, and assistant professor, Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada. N. A. Walsh is a dietetic intern, St Michael’s Hospital, Toronto, Ontario, Canada. P. B. Darling is coordinator of Nutrition and Dietetic Research, adjunct scientist in the Keenan Research Centre in the Li Ka Shing Knowledge Institute, and assistant professor, Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada. S. A. Hanninen is a clinical dietitian, Heart and Vascular Program, St Michael’s Hospital, Toronto, Ontario, Canada. S. Thirugnanam is a resident, Division of Cardiology, St Michael’s Hospital, Toronto, Ontario, Canada. H. Leong-Poi is director of the Echocardiography Laboratory, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, Division of Cardiology, and Heart and Vascular Program, St Michael’s Hospital, Toronto, Ontario, Canada. A. Barr is a statistical consultant, Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada. M. J. Sole is professor of Medicine and Physiology, University of Toronto, Division of Cardiology, University Health Network, Toronto, Ontario, Canada, and Heart and Stroke/ Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada. Address correspondence to: Mary E. Keith, PhD, RD, Department of Nutrition, 6 Cardinal Carter Wing, Suite 6-056d, Toronto, Ontario M5B 1W8. E-mail: keithm@ smh.toronto.on.ca Manuscript accepted: January 26, 2009. Copyright © 2009 by the American Dietetic Association. 0002-8223/09/10908-0009$36.00/0 doi: 10.1016/j.jada.2009.05.011
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on intake. Therefore, it was hypothesized that the status of these B vitamins may also be adversely affected by heart failure. As a result, the prevalence of patients at risk of vitamin B-2 (erythrocyte glutathione reductase activity coefficient ⱖ1.2) and B-6 deficiency (plasma B-6 ⱕ20 nmol/L) was determined in a cross-section of 100 patients hospitalized with heart failure between April 2001 and June 2002 as well as in a group of volunteers without heart failure. Twenty-seven percent of patients with heart failure had biochemical evidence of vitamin B-2 deficiency, while 38% had evidence of B-6 deficiency. These prevalence rates were significantly higher than those observed in the volunteers without heart failure (2% and 19%, respectively; Pⱕ0.02). Use of common B-vitamin⫺containing supplements by patients with heart failure did not significantly reduce deficiency rates in comparison with those who did not use supplements (B-2 P⫽0.38 or B-6 P⫽0.18)). Finally, while 80% of patients with heart failure took diuretics, neither the dose nor the duration of furosemide use was related to the presence of either B-2 or B-6 deficiency. Given the physiologic importance of these vitamins, further investigations aimed at determining the effect of heart failure on specific nutrient requirements as well as the safety and efficacy of B-vitamin supplementation are warranted. J Am Diet Assoc. 2009;109:1406-1410.
A
norexia, malnutrition, advanced age, and frequent hospitalization are all factors that have been identified as contributing to the increased risk of nutrient deficiencies in patients with congestive heart failure (1-5). Furthermore, diuretic medications used for the management of fluid overload have been linked with biochemical and clinical markers of thiamin (vitamin B-1) deficiency, suggesting inappropriate diuretic-induced losses of water-soluble vitamins in this population (6-8). A recent cross-sectional study reported that 33% of hospitalized patients with heart failure have erythrocyte thiamin pyrophosphate levels suggestive of thiamin deficiency (9). Riboflavin (vitamin B-2) and pyridoxine (vitamin B-6) play critical roles in production of red blood cells and are essential cofactors in cellular energy production. Therefore, deficiency of these vitamins may contribute to depletion of energy reserves observed in the failing heart. Vitamins B-2 and B-6 are similar to thiamin because they are water-soluble, subject to renal excretion, have limited tissue storage, and are dependent on intake. Therefore, it was hypothesized that the status of these B vitamins may also be adversely affected by heart failure. As a result, prevalence of vitamin B-2 and B-6 deficiency in a cross-
© 2009 by the American Dietetic Association
section of hospitalized patients with heart failure was evaluated as well as the relationships between deficiency and various clinical and demographic factors. METHODS Study Subjects Vitamin B-2 and B-6 status was determined in 100 consecutive patients hospitalized with heart failure between April 2001 and June 2002 and compared with 50 age- and sex-matched volunteers without heart failure. Diagnosis of heart failure was made by the attending physician and confirmed based on the Framingham criteria (10). Patients were excluded if they had a history of alcohol abuse, were prescribed medications undergoing research evaluation, or were unable to provide informed consent. Volunteers without heart failure were recruited by the coordinator (a clinical registered dietitian) and were comprised of outpatients attending the cardiac rehabilitation program (n⫽12), volunteers or spouses of participants with heart failure (n⫽6), day patients undergoing cardiac investigations (n⫽18), and staff (n⫽14) who responded to either paper or electronic advertisements. Volunteers without heart failure were excluded if they were known to have any conditions affecting B-vitamin status, such as heart failure, alcoholism, cirrhosis, poorly controlled diabetes, wasting diseases (acquired immunodeficiency syndrome, cancer, or recent myocardial infarction), or if they used diuretics or supplements containing B vitamins. Data Collection Demographic and detailed clinical data, including heart function data, medications and doses (particulary diuretics), medical history, and etiology of heart failure were collected from the participants’ medical charts. Patients with heart failure were categorized as having heart failure with normal ejection fraction if their ejection fraction was determined to be ⱖ45% using standardized echocardiographic criteria (11). The nutritional status of all patients with heart failure was assessed by a trained, registered dietitian using Subjective Global Assessment (SGA) (12). Subsequently, patients were categorized as normally nourished (A), moderately malnourished (B), or severly malnourished (C). A modified semi-quantitative food frequency questionnaire was used to assess habitual dietary intake in the month prior to admission (13,14). Nutrient intakes from food were determined using the Windows version of the Nutriwatch software program (1981-2001, Elizabeth Warwick, Long Creek, Cornwall, Prince Edward Island, Canada) containing the 1997 Canadian Nutrient File and compared with the estimated average requirement (EAR) (15). Total B-6 intake was calculated by adding the dietary intake of B-6 to a corrected intake of B-6 from supplements because of the increased bioavailability of B-6 from supplements (1.27⫻ mg/day pyridoxine hydrochloride) (15). A fasting blood sample was collected from all patients with heart failure within 48 hours of admission. Blood samples from non– heart failure volunters were collected in the morning after an overnight fast as described previously (9). All participants in this study provided informed consent. The research proposal was approved by the Institutional Research Ethics Board.
Analysis of Samples and Definition of Deficiency Blood samples were centrifuged for 10 minutes at 1,080g. Plasma and red blood cells were separated, red blood cells washed, and stored at ⫺70°C until analyzed. Erythrocyte B-2 was determined by measuring the activity of the enzyme erythrocyte glutathione reductase with and without the addition of flavin adenine dinucleotide and is expressed as an activity coefficient. An erythrocyte glutathione reductase activity coefficent ⬍1.2 reflects complete tissue saturation with riboflavin (15-17), whereas an erythrocyte glutathione reductase activy coefficent of ⱖ1.2 suggests deficiency (15,18). Plasma B-6 concentration, measured as pyridoxal-5=-phosphate, was determined by radioimmunoassay according to the protocol of the American Laboratory Products Company (ALPCO Diagnostics, Windham, NH), and deficiency was defined as ⱕ20 nmol/L plasma (15,19). Statistics As the data were not normally distributed, continuous data are presented as the median (25th and 75th percentiles) and categorical data as frequencies and percentages unless otherwise noted. Categorical data were compared using either the Pearson 2 test or Fisher’s exact test when the counts in any one cell were less than five. Relationships between continuous variables were made using Spearman’s rank correlation. Comparisons between deficient and nondeficient groups for continuous variables were made using Mann-Whitney U test. The association of potential predictors with vitamin B-2 or B-6 deficiency were analyzed using logistic regression. Crude odds ratios (OR) and 95% confidence intervals (CI) were calculated using univariate analysis on the heart failure population (20). Statistical analyses were performed using SPSS for Windows software (version 13, 2004, Statistical Package for the Social Sciences, Chicago, IL). All P values were two-tailed and significance was set at a value of 0.05. RESULTS AND DISCUSSION Overall, 27% of a cross-section of hospitalized patients with heart failure had biochemical evidence of vitamin B-2 deficiency, whereas 38% had evidence of B-6 deficiency. Prevalence rates of B-2 and B-6 deficiency were significantly higher that those found in volunteers without heart failure (2.2%; P⬍0.001 and 19%; P⫽0.02, respectively). Furthermore, 68% of patients with heart failure had biochemical evidence of deficiency for at least one B vitamin in comparison with 42% of volunteers without heart failure (P⫽0.007). Approximately one fifth of patients with heart failure used B-vitamin⫺containing supplements (n⫽19), which were either multivitamins or B-complex vitamins consumed daily containing 1.6 to 50 mg B-2 (mean dose⫽13⫾21 mg/day) and 2 to 400 mg B-6 (mean dose⫽36⫾93 mg/day) prior to hospitalization. Use of B-vitamin⫺containing supplements resulted in approximately a 50% reduction in deficiency rates (17.6% for vitamin B-2 and 22% for vitamin B-6). Despite this reduction, the prevalence of B-2 and B-6 deficiency in heart failure supplement users was not significantly different from those who did not use supplements (B2 P⫽0.38 or B6 P⫽0.18).
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Table 1. Characteristics of study subjects—Hospitalized patients with acute heart failure and age-matched volunteers without heart failure Characteristics Age (y) Body mass indexa Male sex Use of B-vitamin–containing supplementsb Use of other supplementsc Erythrocyte glutathione reductase activity coefficient Plasma vitamin B-6 (nmol/L) Left ventricular systolic function Normal (LVEFi⬎60%) Mildly reduced (LVEF 40%-60%) Moderately reduced (LVEF 20%-40%) Severely reduced (⬍20%) Diastolic heart failure (LVEF⬎45%)
Heart failure (nⴝ100)
Volunteers (nⴝ50)
4™™™™™™™ mean⫾standard deviation ™™™™™™™3 67.1 ⫾ 10.1 61.1 ⫾ 11.1 27.3 ⫾ 5.5 27.2 ⫾ 4.7 4™™™™™™™™™™™™™™™ n (%) ™™™™™™™™™™™™™™™3 58 (58) 24 (48) 19 (19) 0 41 (41) 9 (18) 4™™™™™™ median (25th, 75th percentile) ™™™™™™3 1.09 (1.04, 1.21)e 1.06 (1.02, 1.09)f g 25.1 (13.2, 41.8) 33.7 (21.8, 68.3)h n
P value 0.001 0.8 0.3 0.001d 0.01 0.01
21 26 27 26 33
a
Calculated as kg/m2. Congestive heart failure patients taking B-vitamin⫺containing supplements (eg, multivitamin or B-complex) prior to admission and/or during hospital admission. c Includes vitamin supplements other than B-vitamin⫺containing supplements and herbal remedies. d Fisher’s exact test. e n⫽96. f n⫽46. g n⫽98 heart failure. h n⫽48 volunteers. i LVEF⫽left ventricular ejection fraction. b
Demographic Variables, Left Ventricular Function, and B-Vitamin Deficiency Despite attempts to age-match volunteers to the patients with heart failure, the allowed variance (⫾5 years), and the fact that we recruited in a 2:1 ratio resulted in patients with heart failure being significantly older than those in the comparison group (P⫽0.001) (Table 1). While this is a limitation of the study, the impact is minimized by the observed lack of relationship between either B-2 or B-6 deficiency and age using logistic regression analyses (P⫽0.36 and P⫽0.54, respectively). There was a tendency for females to have a higher rate of B-6 deficiency when compared with males (54% vs 46%; P⫽0.06) (Table 2). However, no such relationship was observed for vitamin B-2. Heart failure severity (measured by the left ventricular ejection fraction) was not associated with vitamin B-2 deficiency (P⫽0.5). However, patients with moderate or severe left ventricular systolic dysfunction were 0.44 times (95% CI: 0.19 to 1.00) less likely to be vitamin B-6⫺deficient (Table 2). Nutritional Factors and B-Vitamin Deficiency Determination of the SGA score revealed that 50% of patients with heart failure were at risk of being malnourished (SGA B or C). While no relationship was observed between vitamin B-2 deficiency and the presence of malnutrition (P⫽0.24), patients with SGA class A (well-nourished) were more likely to be B6-deficient (OR⫽2.3; 95% CI: 0.99 to 5.32).
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These data support a link between vitamin status and total vitamin intake (B-2 rs⫽⫺0.38; P⬍0.001 and B-6 rs⫽0.25; P⫽0.01). Failing to meet the B-2 EAR was significantly related to the presence of B-2 deficiency (OR⫽0.16; 95% CI: 0.04 to 0.62; P⫽0.008). On the other hand, no relationship was observed between not meeting the B-6 EAR and B-6 deficiency (P⫽0.63) (Table 2). A considerable proportion of patients with heart failure were considered deficient, despite having intakes that met or exceeded the EAR for the habitual intake of these vitamins for the healthy population (88% B-2, 81% B-6), suggesting that current recommended intakes may be insufficient to meet the needs of this population. This finding is supported by a recent, large epidemiological study of B-6 deficiency in the United States, which found low plasma pyridoxal-5=-phosphate levels even at intake levels above the Recommended Dietary Allowances (21). Surprisingly, use of commonly found B complex or multivitamin supplements was insufficient to prevent development of B-vitamin deficiency, although these data are limited by the small number of supplement users (n⫽19) in this sample. Kidney Function and Diuretic Use There were no significant relationships observed between any of the common medications used by the patients with heart failure and B-vitamin deficiency (Table 2). Previous studies have suggested that use of loop diuretics, such as furosemide, results in excessive losses of water-soluble
Table 2. Selected clinical and nutritional factors and their relationship with the presence of vitamin B-2 or vitamin B-6 deficiency in a cross section of hospitalized patients with heart failure Factor Age (y) Female sex Moderate/severe left ventricular dysfunction ejection fraction ⬍40% SGAb, A vs B ⫹ C Taking furosemide Taking ⬎1 diuretic Furosemide dose Taking B-vitamin⫺containing supplements Intake meets EARc Creatinine clearance mL/s/SAd
Vitamin B-2 deficiency
P value
Vitamin B-6 deficiency
P value
4™™™™™™™™™™™™ odds ratio (95% confidence interval) ™™™™™™™™™™™™3 0.98 (0.94-1.0) NSa 1.14 (0.76-1.7) 1.96 (0.78-5.0) NS 2.13 (0.97-5.26)
NS 0.06
1.36 (0.55-3.4) 0.57 (0.23-1.4) 0.83 (0.28-2.5) 2.3 (0.86-6.1) 1.0 (0.95-1.03) 0.46 (0.12-1.75) 0.16 (0.04-0.62) 0.72 (0.26-2.0)
0.05 0.05 NS NS NS NS NS NS
NS NS NS NS NS NS 0.008 NS
0.44 (0.19-1.02) 2.3 (0.99-5.3) 1.9 (0.6-5.8) 0.9 (0.35-2.3) 1.0 (0.98-1.04) 0.36 (0.1-1.2) 0.77 (0.26-2.3) 0.78 (0.4-1.5)
a
NS⫽not significant. SGA⫽Subjective Global Assessment. c EAR⫽estimated average requirement. d SA⫽surface area. To convert mL/s creatinine clearance to mL/min, multiply by 60. b
vitamins, in particular thiamin, thereby increasing the risk of nutritional deficiencies (3,6-8). In this study, 80% of patients with heart failure took furosemide daily. Median dose of furosemide was 60 mg/day, which had been taken for a median duration of 14 months. Twenty-seven patients used a combination of diuretics and 3 took more than two diuretics daily. Despite this, no significant relationships were observed between either the dose or duration of diuretic use and B-2 or B-6 deficiency (Table 2). The observed lack of relationship between diuretic use and B-vitamin deficiency remained even when B-supplement users were excluded from the analysis. This finding is supported by others who also failed to find a relationship between thiamin deficiency and diuretic use (1,9,22,23). However, the impact of multiple diuretics on nutrient status remains unclear. As expected, 87% of patients with heart failure had some evidence of impaired kidney function as defined as a corrected creatinine clearance ⬍1.24 mL/s/surface area (⬍74 mL/min). In previous work, impaired renal function was positively related to thiamin status, suggesting a protective effect, possibly by limiting diuretic-induced losses of water-soluble compounds (9). However, in the present study, no substantial relationship was observed between the presence of renal dysfunction and either B-2 or B-6 deficiency, suggesting that kidney dysfunction alone was insufficient to protect against B-vitamin deficiency (Table 2). One limitation in the interpretation of the impact of kidney function is the lack of data on the urinary losses of these B vitamins. Additional limitations of this study include the measurement of B-vitamin status in patients admitted for an acute exacerbation of congestive heart failure and, therefore, may not reflect the prevalence of deficiency in a stable outpatient setting. In addition, there are limitations associated with estimation of habitual dietary intake of B vitamins using the food frequency methodology. However, this tool was believed to give the best estimation of overall intake during the last 3 months in patients
who were unwell and recently admitted to hospital. Finally, urinary riboflavin and B-6 losses were not measured and their relationships with urine volume, B-6 deficiency, or B-2 deficiency could not be analyzed. CONCLUSIONS The findings of this study revealed that approximately one-quarter to one-third of a cross-section of hospitalized patients with heart failure were at risk of vitamin B-2 or B-6 deficiency, respectively. These observations were made in the relative absence of overt malnutrition and in patients, the majority of whom had intakes that met or exceeded the EAR for healthy individuals. Furthermore, use of furosemide over a range of doses was not found to be related to the prevalence of either B-2 of B-6 deficiency, as had been reported previously. Finally, use of commonly consumed B-vitamin supplements appeared to be insufficient to prevent development of B-vitamin deficiency in patients with heart failure. This study also highlights the differences in clinical and nutritional factors that are related to the presence of B-2 and B-6 deficiency. The presence of vitamin B-2 deficiency was strongly related to low vitamin intake, whereas vitamin B-6 deficiency was not. In addition, in contrast to what one might expect, B-6 deficiency was associated with being relatively well-nourished. Finally, the fact that B-6 deficiency was related to diastolic heart failure and not worsening heart function suggests that B-6 deficiency is influenced by differing factors than those associated with vitamin B-2 deficiency or shown previously for vitamin B-1 deficiency despite being part of the same B-vitamin family. Vitamin B-6 plays a critical role in the metabolism of homocysteine and subsequently atherosclerotic heart disease (24,25). Therefore, changes in B-6 status may simply reflect the degree of coronary artery disease and not necessarily the degree of ventricular dysfunction. In addition, vitamin B-6 status has also been linked with markers of inflammation, such as C-re-
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active protein, and thus may be influenced more by the degree of inflammation, thrombogenesis, and endothelial dysfunction than by nutritional factors (26). The high rate of B-2 and B-6 deficiency in this population, together with the important roles of these vitamins in cellular energy metabolism, suggest that the relationship between nutrient requirements and heart failure requires additional investigation. Furthermore, investigations defining the safety and efficacy of B-vitamin supplementation in the heart failure population are warranted, as supplementation may represent a relatively inexpensive adjunctive therapeutic option for heart failure patients in the future. STATEMENT OF POTENTIAL CONFLICT OF INTEREST: No potential conflict of interest was reported by the authors. FUNDING/SUPPORT: This work was supported by a research grant from the Canadian Foundation for Dietetic Research. S. Douglas-Hanninen was supported by a CIHR training grant. ACKNOWLEDGEMENTS: We would like to thank Regina Kurian for conducting the analysis of riboflavin status as well as to Phillip Connelly, PhD, and his laboratory staff for conducting the B6 analysis. Finally, to Joel Ray, MD, for his intellectual contribution. References 1. Brady J, Rock C, Horneffer M. Thiamin status, diuretic medications, and the management of congestive heart failure. J Am Diet Assoc. 1995;95:541-544. 2. Kwok T, Falconer-Smith J, Potter J, Ives D. Thiamin status of elderly patients with cardiac failure. Age Ageing. 1992;21:67-71. 3. Zenuk C, Healey J, Donnelly J, Vaillancourt R, Almalki Y, Smith S. Thiamine deficiency in congestive heart failure patients receiving long-term furosemide therapy. Can J Pharmacol. 2003;10:184-188. 4. Baines M, Davies G. The evaluation of erythrocyte thiamin diphosphate as an indicator of thiamin status in man, and its comparison with erythrocyte transketolase activity measurements. Ann Clin Biochem. 1988;25:698-705. 5. O’Rourke N, Bunker V, Thomas A, Finglas P, Bailer A, Clayton B. Thiamine status of healthy and institutionalized elderly subjects: Analysis of dietary intake and biochemical indices. Age Ageing. 1990; 19:325-329. 6. Seligmann H, Halkin H, Rauchfleisch S, Kaufmann N, Tal R, Motro M, Vered Z, Ezra D. Thiamin deficiency in patients with congestive heart failure receiving long-term furosemide therapy: A pilot study. Am J Med. 1991;91:151-155. 7. Lubetsky A. Urinary thiamine excretion in the rat: Effect of furosemide, other diuretics, and volume load. J Lab Clin Med. 1999;134: 232-7. 8. Rieck J, Halkin H, Almog S, Seligman H, Lubetsky A, Olchovsky D, Ezra D. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med. 1999;134:238-243. 9. Hanninen S, Darling P, Sole M, Barr A, Keith M. The prevalence of
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thiamin deficiency in hospitalized patients with congestive heart failure. J Am Coll Cardiol. 2006;47:354-361. Ho K, Pinsky J, Kannel W, Levy D. The epidemiology of heart failure: The Framingham study. J Am Coll Cardiol. 1993;4(suppl A):6A-13A. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Chamber Quantification Writing Group, American Society of Echocardiography’s Guidelines and standards Committee, European Association of Echocardiography. Recommendations for Chamber Quantification: A Report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, Developed in Conjunction with the European Association of Echocardiography, a Branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440-1463. Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, Jeejeebhoy KN. What is subjective global assessment of nutritional status. J Parenter Enteral Nutr. 1987;11:8-13. Block G, Dresser C, Hartman A, Carroll M. Nutrient sources in the American diet: Quantitative data from NHANES II: Vitamins and mineral. Am J Epidemiol. 1985;122:13-26. Block G. Block Brief Questionnaire 2000 (unpublished). NutritionQuest Web site. http://www.nutritionquest.com. Accessed January 2001. Institute of Medicine of the National Academies of Science. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Panthothenic Acid, Biotin and Choline. Washington, DC: National Academies Press; 1999:87-120, 150-195. Sauberlich H. Vitamin B2. In: Wolinsky I, ed. Laboratory Tests for the Assessment of Nutritional Status. 2nd ed. Washington, DC: CRC Press; 1999:62-64. Bates C. Riboflavin. Int J Vitam Res. 1993;63:274-277. McCormick DB, Greene HL. Vitamins. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. Philadelphia, PA: Saunders; 1994:999-1028. Lui A, Lumeng L, Aronoff GR, Li TK. Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: Metabolic balance studies in humans. J Lab Clin Med. 1985;106:491-497. Norman G, Streiner D. Biostatistics: The Bare Essentials. 3rd ed. Hamilton, Ontario, Canada: BC Decker Inc; 2008. Morris MS, Picciano MF, Jaques PF, Selhub J. Plasma pyridoxal 5=-phosphate in the US population: The National Health and Examination Survey, 2003-2004. Am J Clin Nutr. 2008;87:1446-1454. Pfitzenmeyer P, Guillard J, d’Athis PH, Petit-Marnier C, Gaudet M. Thiamin status of elderly patients with cardiac failure including the effects of supplementation. Int J Vitam Nutr Res. 1994;64:113-118. Yue Q, Beerman B, Lindstrom B, Nyquist O. No difference in blood thiamin diphosphate levels between Swedish Caucasian patients with congestive heart failure treated with furosemide and patients without heart failure. J Intern Med. 1997;242:491-495. Friso S, Girelli D, Martinelli N, Olivieri O, Lotto V, Bozzini C, Pizzolo F, Faccini G, Beltrame F, Corrocher R. Low plasma vitamin B-6 concentrations and modulation of coronary artery disease risk. Am J Clin Nutr. 2004;79:992-998. Robinson K, Mayer E, Miller DP, Green R, van Lente F, Gupta A, Kottke-Marchant K, Savant SR, Selhub J, Nissen SE, Kutner M, Topol EJ, Jacobsen EJ. Hyperhomocysteinemia and low pyridoxal phosphate: Common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830. Friso S, Jacques PF, Wilson PWF, Rosenberg IH, Selhub J. Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation. 2001;102:2788-2791.