Author + information
- Received July 11, 2012
- Revision received November 14, 2012
- Accepted November 21, 2012
- Published online February 1, 2013.
- Rebecca S. Boxer, MD, MS∗∗ (, )
- Anne M. Kenny, MD†,
- Brian J. Schmotzer, MS‡,
- Marianne Vest, MA, BSN, RN∗,
- Justin J. Fiutem, MS§ and
- Ileana L. Piña, MD, MPH‖
- ↵∗Reprint requests and correspondence:
Dr. Rebecca S. Boxer, Case Western Reserve University, Department of Medicine, 11100 Euclid Avenue, Cleveland, Ohio 44106.
Objectives The aim of this study was to investigate the effect of vitamin D3 on physical performance in patients with heart failure (HF).
Background HF is associated with functional decline and frailty. Vitamin D deficiency is associated with loss of muscle strength and poor outcomes in patients with HF.
Methods Sixty-four patients participated in a 6-month parallel-design, double-blind randomized controlled trial to test the hypothesis that oral vitamin D3 would improve physical performance. Vitamin D3 50,000 IU or placebo was given weekly; all patients received daily calcium. Patients were included, regardless of ejection fraction, if they had 25 hydroxyvitamin D (25[OH]D) levels ≤37.5 ng/ml. The primary outcome was peak oxygen uptake, and secondary outcomes were 6-min walk distance, timed get up and go, and knee isokinetic muscle strength. Between-group comparisons were made using analysis-of-covariance models that adjusted for baseline measures.
Results Patients’ mean age was 65.9 ± 10.4 years, 48% were women, 64% were African American, the mean ejection fraction was 37.6 ± 13.9%, 36% were in New York Heart Association functional class III, and the remainder were in functional class II. At baseline, the vitamin D group’s mean 25(OH)D level was 19.1 ± 9.3 ng/ml and increased to 61.7 ± 20.3 ng/ml; in the placebo group, the mean baseline 25(OH)D level was 17.8 ± 9.0 ng/ml and decreased to 17.4 ± 9.8 ng/ml at 6 months (between-groups p < 0.001). There was no significant change from baseline to 6 months in peak oxygen uptake, 6-min walk distance, timed get up and go, or isokinetic muscle strength.
Conclusions Vitamin D3 did not improve physical performance in patients with HF despite a robust increase in serum 25(OH)D levels. Vitamin D repletion in patients with HF should conform to standard adult guidelines for vitamin D supplementation. (A Trial of Vitamin D Therapy in Patients With Heart Failure; NCT01125436)
Heart failure (HF) is a complex syndrome that results in exercise intolerance and disability. Unraveling the mechanisms for the loss of physical function is complex because the failing heart results in a cascade of neurohormonal and peripheral muscle effects. HF adversely affects the function and strength of peripheral skeletal muscle and is strongly associated with frailty (1,2). Strategies to improve the function of peripheral skeletal muscle are important for older adults with HF to improve aerobic capacity (3) and maintain independence.
Vitamin D deficiency is known to cause muscle weakness and myopathy (4). In older adults with and without HF, vitamin D deficiency is associated with reduced physical performance and frailty (5–8). Vitamin D repletion has been shown to result in improvements in strength and balance and reduced risk for falls (9–11). Higher vitamin D concentrations are associated with improved lower extremity function, including skeletal muscle function and strength (9,12,13). HF and vitamin D deficiency are both common in older adults (14,15). It is unknown if these 2 conditions are additive in worsening functional decline. Repletion of vitamin D may have particular benefit in patients with HF who are at risk for muscle weakness and falls (16).
Vitamin D deficiency is common in patients with HF (17). A recent trial randomized patients with HF to vitamin D or placebo, without a change in physical performance (18). Although the results of that trial were neutral, 2 questions remain: First, if the achieved serum level of 25 hydroxyvitamin D (25[OH]D) were higher, would an effect on physical performance have been identified? Second, if vitamin D were administered over a longer period of time, would the patients have had improvements in physical function? To address these 2 questions, we report a trial of patients with HF randomized to vitamin D3 50,000 IU or weekly placebo for 6 months. The 6-month time period was chosen because it would be more than adequate time to increase serum 25(OH)D to ≥40 ng/ml. We hypothesized that achieving 25(OH)D concentrations well into the normal range would improve functional capacity, as measured by peak oxygen uptake (Vo2), 6-min walk distance (6MWD), and knee isokinetic muscle strength.
This study was a parallel-design, randomized, double-blind, placebo-controlled trial conducted at an academic medical center. Sample-size planning included 30 subjects per group plus 20% inflation for attrition. At the time of planning for the study, there were no trials of vitamin D treatment in patients with HF. Therefore, the sample size was based on standard deviation estimates from a study of exercise in patients with HF by Belardinelli et al. (19) in a similar HF population for the ventilatory threshold endpoint and on an expected standardized effect size of 0.8.
The institutional review board at University Hospitals, Case Medical Center, approved the trial. Eligible subjects were consented and randomly assigned in a 1:1 ratio to receive vitamin D3 50,000 IU or matching placebo. Both groups received calcium citrate 400 mg twice daily.
Randomization and allocation
Patients were randomized in a permuted block scheme according to race, age, and sex. Group assignment remained concealed from study staff members, participants, and investigators until data collection was complete.
Patients age ≥50 years, regardless of ejection fraction, in New York Heart Association functional classes II to IV were recruited. Patients were receiving maximum tolerated doses of evidence-based HF medications per their cardiologists. The required serum 25(OH)D level was ≤37.5 ng/ml. Exclusion criteria were primary hyperparathyroidism, sarcoid, hypercalcemia, nephrolithiasis, osteoporosis, creatinine >2.5 mg/dl, vitamin D supplementation >400 IU/day, corticosteroids, parathyroid hormone, androgen or estrogen, current illicit drug use or ≥3 alcoholic drinks daily, advanced cancer, or myocardial infarction in the preceding 6 months. Patients using medications known to lower serum 25(OH)D or the bioavailability of oral vitamin D (ketoconazole, colestipol, cholestyramine, mineral oil, phenobarbital, and phenytoin) were also excluded.
Cardiopulmonary Stress Testing
Aerobic capacity was measured at baseline and 6 months using a modified Naughton protocol. Breath-by-breath online gas measurements (Medical Graphics, St. Paul, Minnesota) were obtained at rest and throughout exercise. Peak Vo2 was defined as the highest Vo2 in the last minute of symptom-limited exercise. Ventilatory threshold was determine using the V-slope method (20). The Borg rating of perceived exertion was used to assess patient effort. Patients were encouraged to exercise to a rating of perceived exertion >15 (hard) (21) and a respiratory exchange ratio (carbon dioxide output/Vo2) >1.05. The electrocardiogram was continuously monitored, and blood pressure was obtained at rest and at the end of each exercise stage.
Timed Get Up and Go (TGUG)
TGUG was assessed at baseline and 6 months. It is a reliable and valid test of basic mobility maneuvers, including balance, gait speed, strength, and functional ability (22). Subjects were instructed to rise from a chair, walk 3 m, turn around, and return to the chair. The test was timed. If subjects normally used walking aids (canes or walkers), they were encouraged to use these during the test.
Six-minute walk tests were performed at baseline and at 3 and 6 months in a pre-measured hallway (23). Patients were permitted to use walking aids and instructed to walk at their own pace from the start point to the turnaround point as many times as possible in 6 min. Patients were permitted to slow their pace or rest as needed but were encouraged to resume walking when possible.
Isokinetic Muscle Testing
Isokinetic muscle strength was measured by peak torque in newton-meters and peak torque/body weight in newton-meters per kilogram at baseline and 6 months in the dominant leg using the Biodex System 3 Pro isokinetic dynamometer (Biodex, Shirley, New York). The protocol was designed for older adults. Each patient was instructed on how to breathe during testing to avoid Valsalva breath holding. Patients sat upright on the Biodex chair and were secured using torso, pelvic, thigh, and ankle straps to avoid extraneous movements and provide stability. The lateral femoral epicondyle was used as the bony landmark for matching the axis of rotation of the knee joint with the axis dynamometer resistance adapter. All tests were performed using the same positioning standards for reproducibility. Ranges of motion were determined before warm-up. Gravity correction was obtained by measuring the torque applied to the resistance arm with the leg completely relaxed at the terminal extension position. Patients were familiarized with the dynamometer resistance adapter and given a chance to perform 10 repetitions of a warm-up set before performing the test, followed by a 5-min recovery period before starting the test protocol. Quadriceps strength during knee extension and hamstring strength during knee flexion were measured over a range of motion of about 90° using speeds of 60°/s and 120°/s. Verbal encouragement was given to achieve maximal efforts.
Blood was stored at 2°C to 8°C. Serum 25(OH)D was measured using chemiluminescence immunoassay (ARUP, Salt Lake City, Utah), with an intra-assay coefficient of variation of 3% to 6% and between-assay variability of 6% to 11%. Parathyroid hormone was measured by chemiluminometric technology (Siemens Dimension Vista Systems, Newark, DE) at the University Hospitals clinical laboratory. Creatinine, blood urea nitrogen, albumin, and calcium were measured at the University Hospitals clinical laboratory. High-sensitivity C-reactive protein was measured by nephelometry (Siemens Dimension Vista Systems) at the University Hospitals clinical laboratory.
Baseline demographics are summarized as means and standard deviations for continuous variables and as frequencies and proportions for categorical variables within study groups. Vo2 was reported by sex because of expected differences in performance between men and women. The treatment effect (vitamin D vs. placebo) was evaluated for each endpoint using an analysis-of-covariance model that adjusted for baseline endpoint. An extended model was considered that additionally included race, sex, and ejection fraction as covariates (results not shown). A separate extension of the simple analysis-of-covariance model additionally included baseline serum vitamin D level as a covariate. Rates of adverse events were compared using a test of incidence rates between the treatment groups for each category of adverse events. All statistical analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria).
Recruitment, retention, and adherence
Patients were recruited from May 2007 to April 2011. Three hundred forty patients were screened for study inclusion, and 276 did not meet entry criteria (Fig. 1). Sixty-four were randomized and their data included in the analysis. On the basis of monthly pill counts, adherence was 100% in the vitamin D group and 99.5% in the placebo group. The vitamin D group had 90.7% and the placebo group 90.8% adherence to the calcium pills.
The mean age of the participants in the intervention group was 65.8 ± 10.6 years, 51.6% were women, and 61.3% were African American. For the placebo group, the mean age was 66.0 ± 10.4 years, 45.5% were women, and 66.7% were African American (Table 1).
Serum vitamin D concentrations
At 6 months, the mean serum 25(OH)D level had increased by 42.3 ± 16.4 ng/ml in the treatment group and by 0.2 ± 6.6 ng/ml in the placebo group (between-groups p < 0.001). Serum parathyroid hormone declined by 23.1 ± 40.0 pg/ml in the treatment group and by 3.1 ± 38.1 pg/ml in the placebo group (p = 0.014).
Aerobic capacity and muscle strength
The changes in peak Vo2, 6MWD, TGUG, and isokinetic muscle strength did not differ between groups (Table 2). Adjustments for race, sex, and ejection fraction had no effect on outcomes (results not shown). Further analysis was performed to assess if low baseline serum 25(OH)D was associated with more improvement in peak Vo2, 6MWD, or TGUG. Data showed that those with higher baseline 25(OH)D levels had more improvement in peak Vo2 than those with low baseline levels, regardless of group (i.e., for each 5-IU increase in 25[OH]D, peak Vo2 increased by 0.3 ml/kg/min), although this did not reach statistical significance (p = 0.06). No association was found between baseline 25(OH)D and improvement in either 6MWD or TGUG (p = 0.70 for both) (Fig. 2).
Vitamin D and calcium were well tolerated. Adverse events were not significantly different between groups, except for an increased number of infections in the vitamin D group compared with the placebo group (Table 3).
Older adults with HF who were treated with high-dose vitamin D3 and calcium for 6 months had no changes in aerobic capacity or skeletal muscle strength compared with those taking placebo plus calcium. This finding is noteworthy because those in the vitamin D group increased 25(OH)D levels by an average of 45%, with appropriate decreases in parathyroid hormone. Our trial was unique in that it included a diverse study population with a strong representation of women, predominantly African American, and with either reduced or preserved systolic failure. Patients were receiving appropriate HF medications per evidence-based guidelines (24). Both types of HF were included under the premise that skeletal muscle is affected and deconditioning occurs regardless of ejection fraction.
In 2006, Schleithoff et al. (25) randomized 123 patients with systolic HF to vitamin D3 2,000 IU/day versus placebo, both with calcium 500 mg for 9 months. Concentrations of 25(OH)D increased by a median of 26.8 ng/ml, significantly more than the median increase in the placebo group of 3.6 ng/ml. Peak Vo2 as a secondary outcome (levels of proinflammatory cytokines were the primary outcome) was not significantly different between the vitamin D and placebo groups. Witham et al. (18) gave 2 doses of 100,000 IU of vitamin D2 (at baseline and 10 weeks) to patients with systolic HF and also showed no significant change in 6MWD or TGUG at both 10 and 20 weeks. Our trial, with confirmed high serum levels of 25(OH)D, adds to the growing body of evidence that therapy with vitamin D does not affect aerobic capacity or functional performance in patients with HF. Our duration of therapy was shorter than in the trial by Schleithoff et al. but longer than that in the trial by Witham et al. We achieved the highest serum concentration of 25(OH)D published to date, but with no measurable effect.
Baseline 25(OH)D concentrations, regardless of group, showed a relationship with the change in peak Vo2, although not statistically significantly. This finding mirrors what has been seen in observational studies in which an association of worse physical performance with low 25(OH)D has been reported (6,8,26). This may indicate that vitamin D is a marker of poor function rather than a modulator. Alternatively, because both groups received calcium, we cannot rule out the possibility that calcium affected both groups equally, regardless of 25(OH)D level.
Results from clinical trials of vitamin D treatment that measured muscle strength have been mixed, with some demonstrating benefit (9,11,27) while others have not (28,29). In a meta-analysis that examined physical performance with vitamin D, smaller, more frequent dosing (800 to 1,000 IU/day) and vitamin D with calcium had the most consistent benefit. However, benefit was shown only for TGUG and tests of balance, not for distance walked (12). In our trial, vitamin D and calcium were administered, but it is possible that the dose given was too high compared with the doses used in these other trials. Optimal dosing and the target for serum 25(OH)D have been under intense debate, especially because a 1-time high dose of vitamin D3 increased the risk for falls in older women (30). Optimal dosing, frequency, and serum target to decrease events and modulate different disease states require further study.
The myopathy of vitamin D deficiency is hallmarked by muscle weakness and fatigue. Skeletal muscle biopsies of those who are severely deficient in vitamin D show selective atrophy of type II fibers and fat infiltration and fibrosis (31). The change in fiber type is in contrast to the myopathy of HF, in which there is an increase of type II skeletal muscle fibers and a loss of type I fibers. The vitamin D receptor present on skeletal muscle has many polymorphisms and variable expression with aging. There are both genomic and nongenomic pathways that influence protein transcription and calcium metabolism (32). If vitamin D has an opportunity to improve physical performance in those with HF, further characterization of the vitamin D receptor and intrinsic muscle changes may help target the population of patients who may benefit the most.
Adverse events in our patients were expected and equal between groups. One exception, however, was the report of more infections in the vitamin D group than in the placebo group, which was statistically significant. This finding is contrary to the expected higher risk for infection in those who are deficient in serum 25(OH)D, because vitamin D is theorized to reduce the risk for infection and inflammation (33). Additionally, this finding may be spurious and due to the small sample size or to multiple comparisons.
The study was limited by a short duration of 6 months and a relatively small sample size, which may have affected our ability to show a difference between groups (type II error).
The findings of this study do not support the use of vitamin D and calcium to improve functional performance in older adults with HF. Vitamin D may still be a good candidate to help break the cycle of frailty and functional decline in patients with HF, because benefit has been demonstrated in older adults in nondiseased base studies (12). A trial of exercise combined with vitamin D as the intervention may have the greatest chance to demonstrate benefit from vitamin D for patients with HF.
Dr. Boxer and this work are supported by the NIHKL2RR024990 (CWRU) and by the American Heart Association Scientist Development Grant 0635055N and the Joan C. Edwards Fund. This publication was made possible by the Clinical Translational Science Center of Cleveland, grant UL1TR000439 from the National Center for Advancing Translational Science of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- heart failure
- 6-min walk distance
- timed get up and go
- 25 hydroxyvitamin D
- oxygen uptake
- Received July 11, 2012.
- Revision received November 14, 2012.
- Accepted November 21, 2012.
- American College of Cardiology Foundation
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