**10. Heart failure**

*Vitamin D Deficiency*

**8. Hypertension**

subgroup analysis is difficult.

levels and hypertension development [51].

pressure was demonstrated [55].

ing incident hypertension [10].

**9. Endothelial dysfunction**

Improvement was seen with vitamin D repletion [58].

assessment [57].

groups [9].

A recent updated meta-analysis, including VITAL and VIDA, with a total of 83,291 patients, indicated that vitamin D supplementation had no benefit on CV health. Only 4 of the 21 trials used CVD as a primary endpoint. It has also been shown that vitamin D supplementation provided no benefit toward the secondary endpoints of MI, stroke, CVD mortality, and all-cause mortality [50]. This metaanalysis, though, lacks complete and specific patient level data and, therefore,

Low vitamin D status has been heavily linked to an increased prevalence of hypertension. A prospective examination of 1,211 non-hypertensive men, over a 15 year follow-up period, demonstrated an inverse association between vitamin D

In addition to the demonstrated link between low vitamin D levels and hypertension development, the Framingham Offspring Study suggested that low vitamin D levels may also increase the risk associated with already existing hypertension,

Contrary to observational evidence, randomized controlled trials of vitamin D repletion have not shown significant changes in blood pressure in vitamin D

In a randomized, double blind trial involving 283 black subjects given either placebo, 1,000, 2,000, or 4,000 IU/day of vitamin D for 3 months, significant modest reductions in systolic blood pressure were seen. Systolic blood pressure decreased by 0.2 mmHg for every 1 ng/mL increase in vitamin D, but no effect on diastolic

In VITdish, another small (N = 159) randomized, double-blind, placebo-controlled trial, there was no effect of vitamin D supplementation on blood pressure or other markers of vascular health in older adults with systolic hypertension [56]. A 6 month study of vitamin D3 supplementation including patients with resistant hypertension showed similar results. Effects on left ventricular hypertrophy were also negligible, although the short follow-up may have limited this

In the VIDA study, with monthly high dose vitamin D supplementation, there were no significant differences between the vitamin D and placebo groups regard-

Lastly and likewise, in the VITAL study using high daily doses of vitamin D, hypertension incidence was not significantly different in the vitamin D and placebo

Vitamin D deficiency has been associated with endothelial dysfunction. A study involving 23 asymptomatic subjects demonstrated impaired brachial artery flow-mediated dilatation (FMD) in subjects with significant vitamin D deficiency.

In contrast, there was no improvement in endothelial-dependent vasodilation with active treatment (ergocalciferol 50,000 IU/week) versus placebo in an 8 week

trial in non-hypertensive, overweight, vitamin D deficient individuals [59].

which may substantially augment the risk of future CV events [52].

deficient individuals with prehypertension or hypertension [53, 54].

**218**

The impact of vitamin D supplementation on patients with heart failure has not been the focus of large randomized trials.

The RECORD trial (Randomized Evaluation of Calcium Or vitamin D) was a trial designed for the secondary prevention of fractures in 5292 participants aged ≥70 years (conducted between 1999 and 2002). Subjects received oral vitamin D3 (800 IU/d) plus calcium (1,000 mg calcium carbonate/d), vitamin D3 alone, calcium alone, or a placebo. An analysis of unpublished data from the trial, suggested that vitamin D supplementation may decrease heart failure events in the elderly. The trial had pre-specified CV endpoints of time to first cardiac failure, time to first MI, time to first stroke, and time to first composite outcome of cardiac failure, MI, or stroke. The trial, though, was not designed as a CV outcomes trial, and outcomes were not subject to an adjudication committee nor verified against medical records. Furthermore, significance for heart failure event reduction was reached only when off-trial data were used [63].

Several small placebo-controlled studies have been conducted to analyze the effects of vitamin D supplementation on differing endpoints in patients with heart failure. Results have been conflicting.

In a small randomized, double-blind, placebo-controlled trial (N = 105) in older adults with vitamin D deficiency (25-vitamin D < 20 ng/mL) and systolic heart failure, subjects were given 100,000 IU of oral vitamin D2 or placebo at baseline and 10 weeks. Functional outcomes, quality of life and biomarkers (B-type natriuretic peptide (BNP) and tumor necrosis factor (TNF alpha)) were measured at baseline, 10 and 20 weeks. BNP was significantly reduced in the active treatment group versus placebo, but TNF alpha was not. Despite reduced BNP levels, physical function, as measured by the 6-minute walk test and the timed get up and go test, did not improve. There was also no change in the Functional Limitations Profile measure in the active versus placebo group. A small, but significant worsening in quality of life with active treatment was noted, despite a non-significant increase in activity level, suggesting a chance finding [64].

Schleithoff et al. examined cytokine profiles with vitamin D3 supplementation in younger patients with heart failure. A dose of 2,000 IU per day reduced the proinflammatory marker TNF-alpha levels and increased the anti-inflammatory cytokine interleukin-10 levels, but no significant effects on BNP levels were seen [20].

A recent randomized, controlled trial assessed the effects of 50,000 IU of weekly vitamin D or placebo for 6 months on various measures of physical performance (primary endpoint: peak VO2; secondary endpoints: 6-Minute Walk test, timed get up and go test, isokinetic muscle strength) in patients with heart failure. The study failed to demonstrate any benefits, despite considerable increases in serum 25(OH)D levels in the active treatment group [65].

In VINDICATE, a double-blind, randomized, placebo-controlled trial, subjects with systolic dysfunction (ejection fraction (EF) ≤ 45%) and vitamin D deficiency (<20 ng/mL) were randomized to 4,000 IU of vitamin D3 or placebo. At 12 months, there was no significant difference in 6-minute walking distance (primary endpoint), but there was significant improvement in left ventricular (LV) systolic function and a reduction in LV end diastolic and end systolic diameter with active supplementation [66].

In the EVITA trial, 400 patients with heart failure were randomized to receive 4,000 IU of vitamin D or placebo daily for 3 years. There was no benefit of supplementation on the primary endpoint of all-cause mortality. Additionally, secondary endpoint analysis suggested that vitamin D supplementation was associated with an increased frequency of implantation of mechanical circulatory support [67].
