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Vitamin D and Heart Failure
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Accumulating evidence suggests that vitamin D deficiency (serum levels <20 ng/mL) and insufficiency (serum levels between 20 ng/mL and 30 ng/mL) may play a role in the development of a variety of conditions, including HF. Several studies have demonstrated an association between low vitamin D levels and worse outcomes among patients with HF. The prevalence of hypovitaminosis D is high, with as much as 57% of the U.S. adult population affected. This has potentially far-reaching implications for the optimal management of patients with HF.
There are many risk factors for the development of vitamin D deficiency. Some of the more common include: lack of sun exposure, pigmented skin, older age, institutionalization, obesity, kidney and liver disease, and the use of certain drugs (eg, anticonvulsants, glucocorticosteroids).
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One major source of vitamin D is sunlight. Photosynthesis in the epidermis results in the conversion of endogenous 7-dehydrocholestol to cholecalciferol (vitamin D3). Vitamin D can also be obtained through the diet or by supplementation. The two major forms of dietary (or supplementary) vitamin D are ergocalciferol (vitamin D2) and cholecalciferol. Vitamins D2 and D3 are precursors of the hormonally active form known as 1,25-dihydroxycholecalciferol (ie, calcitriol), which plays an important role in CVD.
Low levels of calcitriol have been associated with activation of the renin-angiotensin aldosterone system, elevated levels of proinflammatory cytokines such as tumor necrosis factor alpha, and an increase in parathyroid hormone, all of which may increase the risk for CVD. Besides these systemic effects, there may be local implications as well. The vitamin D receptor, which is widely distributed throughout human tissues, has been identified in human cardiomyocytes, where it regulates many important physiologic processes, including calcium influx and myocyte proliferation and hypertrophy. In addition, enzymes necessary for the conversion of vitamin D precursors to calcitriol have been isolated in heart tissue.
Vitamin D trials
Many observational studies and some randomized trials have been performed to further elucidate the role of vitamin D in HF. One of the first human studies demonstrating the possible benefit of vitamin D supplementation in HF involved a randomized, controlled trial among 123 patients treated for 9 months with cholecalciferol 2,000 IU daily vs. placebo. Although results demonstrated no differences in survival rates in this relatively small, short-term study, patients who received cholecalciferol achieved significant reductions in parathyroid hormone and tumor necrosis factor alpha, as well as significant increases in the anti-inflammatory cytokine interleukin-10. As expected, serum vitamin D levels increased in the treatment group by 26.8 ng/mL.
In another more recent trial, investigators examined the relationship between vitamin D deficiency and various assessments associated with HF, including HF mortality. In this study, 3,299 patients who had been referred for cardiac angiography had baseline serum vitamin D levels measured. They were categorized into four groups based on vitamin D status: severe deficiency (<10 ng/mL), moderate deficiency (10 to 19.99 ng/mL), insufficiency (20 to 29.99 ng/mL) and optimal (≥30 ng/mL). During the 7.7-year follow-up period, there were significantly more HF-related deaths among those with severe vitamin D deficiency (6.6%) vs. those with optimal levels (1.8%). Even after adjusting for multiple potential confounders, the HR remained significant at 2.84 for those with severe deficiency. Other findings included a significant negative correlation between vitamin D serum levels and N-terminal pro-B-type natriuretic peptide, as well as significant inverse associations between vitamin D levels and impaired left ventricular function and NYHA functional classification.
Although currently available evidence does not support widespread vitamin D screening for all patients with HF, consideration should be given for assessment in some HF subgroups. Clearly, those with concomitant disease states necessitating optimal vitamin D levels (eg, osteoporosis) should be screened and treated. Other patients with HF who may benefit from screening include those with multiple risk factors for deficiency and those with persistent HF-related symptoms despite the use of optimal drug therapy (eg, ACE inhibitors/angiotensin receptor blockers, beta-blockers). Although calcitriol is the active form of vitamin D, the most reliable predictor of bodily stores is 25-hydroxyvitamin D (25-OH vitamin D) and is thus the preferred method for assessing vitamin D status.
Repletion regimens
For patients with vitamin D deficiency or insufficiency, there are a variety of repletion regimens that have been used. Dosing should be individualized based on a given patient’s 25-OH vitamin D level and risk factors. Vitamin D supplements are available in two forms: plant-derived ergocalciferol, and cholecalciferol, which is animal-based. Although some experts favor the use of cholecalciferol because of greater potency, once consumed, both forms are ultimately converted to 25-OH vitamin D. One strategy for replacement in deficiency includes ergocalciferol 50,000 IU orally once weekly for 8 to 12 weeks. Insufficiency can generally be treated for shorter durations or with lower daily doses (eg, cholecalciferol 1,000 IU by mouth daily). Depending on the cause, most patients with deficiency will likely require long-term, lower daily dosing to maintain body stores. As with all drug therapy, patients should receive appropriate monitoring to ensure safety. Although rare, hypercalcemia and hyperphosphatemia may occur and could be measured, along with a repeat 25-OH vitamin D level after replacement.
Data from future randomized, controlled trials will help to establish more definitive guidelines regarding vitamin D supplementation in patients with HF or other CV and renal diseases. According to ClinicalTrials.gov, there are currently at least eight studies in various stages examining the effects of vitamin D in patients with HF, and many other ongoing vitamin D trials in patients with heart disease and/or chronic kidney disease. One of the largest is the Paricalcitol Capsules Benefits in Renal Failure-Induced Cardiac Morbidity in Chronic Kidney Disease (PRIMO) trial. This study will randomly assign 220 patients with chronic kidney disease to treatment with paricalcitol (an activated vitamin D analogue) vs. placebo for 48 weeks to assess the potential effects of paricalcitol on LV hypertrophy. An even larger trial, the Vitamin D and Omega-3 Trial (VITAL) is a 5-year study that will enroll 20,000 patients and will measure several important outcomes, including CVD, stroke and cancer. Results from studies such as PRIMO, VITAL and others will help further clarify the role of vitamin D in many high-risk conditions.
Charley Hepfinger, PharmD, is a clinical pharmacy specialist for the Phoenix VA Health Care System in Arizona.
For more information:
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