Am J Cardiovasc Drugs DOI 10.1007/s40256-014-0080-5

REVIEW ARTICLE

Could Vitamin D Supplements Be a New Therapy for Heart Failure? Possible Pathogenic Mechanisms from Data of Intervention Studies Andrea Dalbeni • Pietro Delva • Pietro Minuz

Ó Springer International Publishing Switzerland 2014

Abstract Vitamin D deficiency may play a role in the pathogenesis of chronic heart failure (HF), but whether giving patients supplements to raise vitamin D into the normal range improves their survival is not clear. It has been demonstrated that vitamin D deficiency is common in patients with HF, especially the elderly, in obese and in dark skinned people, and that low vitamin D levels are associated with adverse outcome. The epidemiological data have been confirmed by experimental data, which show that knockout mice for the vitamin D receptor developed myocardial hypertrophy and dysfunction. Data from interventional studies are scarce and discordant, and more research is urgently needed to confirm whether add-on supplementation therapy with vitamin D has a role in the management of patients with chronic HF.

Key Points Various pathogenic mechanisms could explain the effects of vitamin D supplementation on heart failure. Few trials in humans show mixed results.

A. Dalbeni (&)  P. Delva  P. Minuz Section of Internal Medicine, Department of Biomedical and Surgical Science, University of Verona, Policlinico ‘‘GB Rossi’’, P.le Scuro 1, 37134 Verona, Italy e-mail: [email protected]

1 Introduction Heart failure (HF) is a major medical problem in the Western world, with an increasing incidence and prevalence. In fact recent data show that approximately 1–2 % of the adult population in developed countries has HF, with the prevalence rising to C10 % among people 70 years of age or older [1] and in people with obesity, especially with metabolic syndrome [2]. Furthermore, African Americans (AAs) are specifically at increased risk for cardiovascular diseases, including HF [3], but contrary to whites, HF occurs at an earlier age. Also vitamin D deficiency is more common in elderly patients in developed countries, in patients with an increased body mass index (BMI) or with a dark skin pigmentation, and, for this reason, some authors have recently assumed that there might be a link between HF and vitamin D deficiency. Actually, epidemiological data show that vitamin D levels are substantially decreased in patients with HF, compared with controls [4, 5]. In different cohorts, it was confirmed that higher vitamin D levels are associated with more favored outcomes in patients with HF [6, 7]. Vitamin D deficiency is commonly observed in developed countries and especially in older people. The reason behind this is that people who live in developed countries are located above the Northern or under the Southern tropic. In fact, in these areas, the sun exposure, which induces vitamin D production in the skin, is insufficient to ensure adequate amounts of vitamin D [8]. Moreover, old people have low vitamin D levels because of the limited sun exposure, typical of housebound patients. In an observation study published in The Lancet in 1995, surprisingly, the lowest mean vitamin D concentrations were seen in southern European countries, but low vitamin D

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concentrations could largely be explained by home daily living activities and wearing clothes with long sleeves during winter periods [9]. Not only does their skin have a reduced capacity to produce vitamin D, but malnutrition in elderly people plays an important role as well. Vitamin D levels are also reduced in people with high BMI because of their sedentary life without sun exposure and because vitamin D is stored in fatty cells, and therefore is not bioavailable. Additionally, vitamin D deficiency is commonly observed in AAs, where melanin is a natural sunscreen that raises the time requirement for sunlight exposure and could cause hypovitaminosis D. More recently, it has been shown that in patients with renal failure, the new active hormone fibroblast growth factor 23 (FGF23) aggravates 1,25-2OH vitamin D deficiency and the consequent secondary hyperparathyroidism. In a 1,432-participant study, increased left ventricular mass (LVM) and cavity dilatation were observed with low 25-hydroxyvitamin D [25(OH)D] and high FGF23 [10]. Epidemiological data are supported by experimental data showing that the nuclear vitamin D receptor (VDR) is expressed in vascular smooth muscle cells, renal juxtaglomerular cells and cardiac myocytes [11]. In laboratory experiments, mice VDR-/- (without VDR receptor) showed development of hypertension and cardiac remodeling [12]. Moreover, vitamin D may also act rapidly through intracellular non-genomic receptors that alter cardiac contractility. In mice models, the correction of vitamin D deficiency was associated with a reduction in ventricular hypertrophy and attenuation of hypertension [13, 14]. Unfortunately, the few prospective and randomized vitamin D supplementation trials in humans show mixed results. With the present review, we aim to provide an overview of the intervention studies supplying vitamin D active metabolites and the effects of these vitamin D supplements.

2 Vitamin D Deficiency and Heart Failure: The Possible Pathophysiological Pathways In patients with HF, characterized by left ventricular (LV) systolic dysfunction, the maladaptive changes occurring in surviving myocytes and extracellular matrix after myocardial injury (e.g., myocardial infarction) lead to pathological ‘remodeling’ of the ventricle with dilatation and impaired contractility, which is mirrored by a reduction in the ejection fraction (EF) [15]. What characterizes the untreated systolic dysfunction is a progressive worsening of these changes over time, with increasing enlargement of the left ventricle and decline in EF, even though the patient initially may be symptom free. This progression might be

caused by two mechanisms: the occurrence of further events leading to additional myocyte death (e.g., recurrent myocardial infarction) and the systemic response induced by the decline in systolic function, particularly, neurohumoral activation. The two key neurohumoral systems activated in HF are the renin–angiotensin–aldosterone (RAA) system and the sympathetic nervous system. In addition to causing further myocardial injury, systemic responses have detrimental effects on the blood vessels, kidneys, muscles, bone marrow, lungs and liver, and create a pathophysiological ‘vicious cycle,’ accounting for many of the clinical features of the HF syndrome, including myocardial electrical instability. The interruption of these two key processes is the basis of the most effective treatments of HF [15, 16]. Vitamin D, through its genomic pathway (binding to VDR) and its non-genomic pathway, through non-nuclear receptors via putative membrane vitamin D receptors (mVDRs) that modulate a complex signaling system involving the rapid opening of Ca2? channels, can have antihypertrophic effects, can increase cardiac contractility, modulating differentiation and proliferation of cardiomyocytes, and can have an effect on neurohumoral systems [17]. Therefore, the major potential mechanism (Fig. 1) that may explain a direct protective effect of vitamin D against HF includes effects on myocardial contractile function, regulation of natriuretic hormone secretion, regulation of the renin system, regulation of blood pressure (BP) effects, heart remodeling and reduced LV hypertrophy, and the regulation of inflammatory cytokines. Indirectly, vitamin D can also affect cardiac function by altering parathyroid hormone (PTH) and serum calcium levels.

3 Antihypertrophic Activity Several studies have demonstrated the presence of VDR located in the nucleus or adjacent to the t-tubules in cardiac myocytes [11]. Also, cardiac fibroblasts express the VDR. Vitamin D inhibits myocyte proliferation, induces hypertrophy and regulates expression of the fetal myocyte specific gene [18].

4 Renin–Angiotensin System Animal studies first showed vitamin D to inhibit the RAA system, activation of which contributes to salt and water retention in HF. Epidemiological data showed that vitamin D levels are inversely associated with renin levels [19]. Vitamin D binding VDRs could suppress renin transcription [20].

Could Vitamin D Supplements Be a New Therapy for Heart Failure? Fig. 1 Possible direct and indirect effects of vitamin D on the heart. ANP atrial natriuretic peptide, BNP brain natriuretic peptide, PTH parathyroid hormone, RAA renin– angiotensin–aldosterone

5 Blood Pressure BP is a major risk factor for HF. Epidemiological studies show a link between vitamin D levels and hypertension. One study included 1,181 normotensive patients who were tracked for 4 years. When compared with 25(OH)D levels of [30 nmol/L (12 ng/mL), levels of vitamin D under 15 nmol/L were associated with a relative risk of developing hypertension of 2.67 [95 % confidence interval (CI) 1.05–6.67] [21]. On the other side, the prospective multiethnic study cohort of atherosclerosis did not show any association with hypertension. In this study, however, the mean vitamin D level was higher (26.3 ± 11.2 ng/mL) [22]. Few intervention studies consistently suggest that vitamin D supplementation may lower BP through the inhibition of renin release and inhibition of smooth muscle cells proliferation. Two small, short-term intervention studies [23, 24] support this hypothesis; in particular, a double-bind randomized controlled trial [23] including 148 women showed that supplementation with vitamin D and calcium resulted in a significant increase in 25(OH)D levels (72 %) and decreased serum PTH levels (17 %), along with significant decreases in systolic BP compared with calcium supplementation alone. Meanwhile, the Women’s Health Initiative randomized trial [25], including 36,282 women, showed that vitamin D3 supplementation neither reduced BP nor the risk of developing hypertension over 7 years of follow-up. In a recent double-blind study by Larsen et al. [26], cholecalciferol supplementation did not reduce 24-h BP, although central systolic BP decreased

significantly. In a post hoc subgroup analysis of 92 subjects with baseline 25(OH)D levels of \32 ng/mL, significantly decreased 24-h systolic and diastolic BP occurred during cholecalciferol supplementation. In a recent [27] double-blind randomized controlled trial, 82 hypertensive patients received randomly 400,000 UI/1 year vitamin D supplements or placebo. No significant change in pressure was observed. In this study, however, the mean baseline level was 18 ng/mL, and the increase in vitamin D serum level was only ?8 ng/mL, hinting that few patients had reached the normal range.

6 Cytokines Proinflammatory and anti-inflammatory cytokines are implicated in HF, in particular, high levels of interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-a, and reduced levels of IL-10 [28, 29]. Experimental studies show that the vitamin D hormone calcitriol suppresses the release of TNF-a by inhibiting nuclear factor jB [30]. Moreover, calcitriol effectively regulates the synthesis of the anti-inflammatory IL-10 and induces the downregulation of IL-10 receptor in vitro [31]. 6.1 Atrial Natriuretic Peptides The atrial and brain natriuretic peptides (ANP/BNP/NTproBNP) function as part of the RAA system and are widely used as biomarkers of HF. They are normally

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secreted by cardiomyocytes in response to volume overload and increased atrial and/or ventricular pressure. A recent study in a large cohort of patients referred to coronary angiography suggested that vitamin D levels remained independently associated with brain natriuretic peptides (NT-proBNP) levels in a multivariable model [32]. 6.2 Calcium Influx Traditionally, the role of vitamin D is to achieve normal concentrations of ionized calcium and phosphorus. Calcium flux is crucial for the electrophysiology and contractility of the heart. Vitamin D increases calcium uptake in myocardiocytes and influences calcium influx via nongenomic actions [33]. The administration of calcitriol caused an accelerated relaxation in cardiomyocytes and showed that protein kinase C mediated the phosphorylation of troponin T, which decreased myofilament calcium sensitivity and phospholamban, which increases calcium sequestration into the sarcoplasmatic reticulum [34]. Calcitriol also activates adenylate cyclase, thus mimicking the effects of b-adrenergic stimulation on myocardial contractility [35]. 6.3 Parathyroid Hormone PTH is often elevated in vitamin D insufficiency; this is in response to low vitamin D levels and also to low serum calcium levels. PTH has been involved in myocardial fibrosis and LV hypertrophy [36]. In a recent study, the higher PTH concentrations were associated with greater LV mass and lower systolic function [37].

7 Vitamin D Supplementation It is well established that vitamin D is critical for skeletal mineralization, and numerous observational studies have linked low levels of 25(OH)D to fractures. Defining level of serum 25(OH)D as low or insufficient depends on what level is defined as normal. The World Health Organization (WHO) defined levels below 10 ng/ mL as deficient and levels below 20 ng/mL as insufficient [38]. However, with the recent changes in laboratory reference ranges, a normal level is now defined as a serum level of 30–76 ng/mL (75–190 nmol/L) [39]. The estimated prevalence of vitamin D insufficiency is as high as 50–80 % in the general population. An international workshop on vitamin D held in 2007, based on observational data, indicated that the minimum desirable serum level of vitamin D was 20 ng/mL. In 2010, Osteoporosis Canada issued a report stating that the vitamin D level should be at least 30 ng/mL. In the same year,

the International Osteoporosis Foundation recommended a 25(OH)D serum level of 30 ng/mL in all elderly people and stated that vitamin D intakes as high as 2,000 IU per day may be necessary in these people. Contrarily, the Institute of Medicine (IOM) report [40], based on evidence from observational studies and recent randomized trials, suggests that a 20 ng/mL vitamin D level protects 97 % of the population against adverse skeletal outcomes. Vitamin D insufficiency is typically treated with 800–1,000 IU of vitamin D a day, whereas deficiency requires 50,000 UI a week for 6–8 weeks followed by 1,000 UI per day. Studies confirmed the superiority of cholecalciferol (vitamin D3) compared with ergocalciferol (vitamin D2), which is metabolized more quickly and cannot maintain adequate plasma levels of 25(OH)D, unlike vitamin D3. Therefore, cholecalciferol (D3) should be preferentially used. Currently, it is not clear if low levels of vitamin D could contribute to the progression of HF and it is unknown whether supplementation of vitamin D, and at what dose, could generate a positive effect on the heart.

8 Intervention Studies with Active Vitamin D Supplements A few studies have been performed to investigate the effect of vitamin D supplementation on cardiac function and possible pathophysiological pathways that could explain the benefit of this ‘‘new therapy’’ (Table 1). The earliest studies involved patients with renal failure and dialysis treatments. In the prospective open study by Park et al. [41], 15 patients with hyperparathyroidism received 2 lg calcitriol twice a week for 15 weeks, while ten untreated patients were taken as controls. After 15 weeks of treatment, echocardiograms showed reductions in interventricular wall thickness (13.9 ± 3.6 to 12.8 ± 3.10 mm, p = 0.01), in posterior wall thickness (12.5 ± 2.4 to 11.3 ± 1.8 mm, p \ 0.05) and left ventricle mass (LVM) index (178 ± 73 to 155 ± 61 g/m2, p \ 0.01). In addition, PTH, plasma renin, angiotensin II and ANP levels significantly decreased in the treatment group. Vitamin levels were not measured in this study [41]. Lemmilla¨ et al. [42] demonstrated in five patients on hemodialysis an improvement in LV dimensions and systolic function (fractional shortening [FS%] from 33 ± 4 to 42 ± 3, p = 0.03) after calcitriol intravenous administration. That study compared ten patients treated with calcitriol with a control group pair-matched for age and gender. Also in this case, vitamin D levels were not measured, only PTH levels before and after treatment. A more recent prospective study conducted by Bucharles et al. [43] in 2012 showed in 30 hemodialysis patients without

Reference

42

41

44

28

48

45

49

Author

Lemmila¨

Park

Witte

Schleithoff

Hisia

Witham

Zia

2011

2010

2007

2006

2005

1999

1998

Year

Prospective study

Randomized controlled trial

Randomized controlled trial

Double-blind randomized placebocontrolled trial

Double-blind randomized study

Prospective study

Prospective study

Kind of study

14 (51 age); all recived supplements

105 (79 age); 53 vitamin D/52 placebo

36.282 (62 age); 18.176 calcium/ vitamin D 18.106 placebo

123 (51 age); 61 vitamin D/62 placebo

28 (75 age); 14 vitamin D/14 placebo

15 (all received supplements)

10 (all received supplements)

Number of patients enrolled (n/ mean age)

Adult Afro American population with HF, no ranal impairment

Elderly patients with HF, no renal impairment

Adult population with cardiovascular risk

Adult population with HF

8-Isoprostane; EF%

QoL, BNP, TNF

Cardiovascular events

Cardiovascular events, BNP e cytokines

EF%, cytokines and QoL

PTH and neurormonal assessments

Patients with severe renal insufficiency on hemodialysis

Elderly patients with HF, no renal impairment

Cardiac function

Outcomes

Patients with severe renal insufficiency on hemodialysis

Kind of population

Table 1 Intervention studies investigating vitamin D supplement benefits

14 weeks

10 and 20 weeks

7 years

9 months

9 months

15 weeks

4.5 months

Weeks of intervention

PTH decreased; IVS 13.9 ± 3.6 vs 12.8 ±3.1 mm; PW 12.5 ± 2.4 vs 11.3 ± 1.8; LVMass 178 ± 73 vs 155 ± 61 g/m2; renin 18.5 ± 12.7 vs 12.3 ± 11 pg/mL; BNP 16.6 ± 9.7 vs 12.2 ± 4.4 pg/mL

Calcitriol 2 lg week

400 UI vitamin D/500 mg calcium daily

100,000 UI 2 twice in 20 weeks 50,000 UI once week for 8 weeks, than 1,000 UI plus calcium daily

\20 ng/mL

\20 ng/mL

2.000 UI day

Vitamin D 14.4–30.9 ng/mL; 8-Isoprostane 136.1 ± 8.8 to 117.8 ± 7.8 pg/mL; EF% 24.3 ± 1.7 to 31.1 ± 4.3 %

Vitamin D ?19.5 nmol/L vs. placebo group; BNP -34 pg/mL vs. placebo group; no other changes

No differences between two groups. HF 394 vs. 407; p = 0.5

Vitamin D 14.4 incrementation ?26.8 ng/ mL; TNF-a -2 pg/mL; IL10 ?0.24 pg/mL; no change in EF%

EF% 25.6 ± 6.9 to 30.9 ± 7.1 %; best QoL in treatment group; TNF-a no change

Reduced PTH; FS% 33 ± 4 to 42 ± 3 %

2 lg weekly

Different micronutrients (vitamin D 10 lg)

Results

Dose

Not required

Not declared (all patients were \20 ng/ mL)

Not required

Not required

Not required

Vitamin D level for enrollment

Could Vitamin D Supplements Be a New Therapy for Heart Failure?

43

51

46–47

52

53

Bucharles

Shedeed

Boxer

Schroten

Dalbeni

2014

2013

2013/ 2014

2012

2012

Year

Randomized controlled trial

Open label, blinded end point, randomized prospective trial

Randomized controlled trial

Double bind placebocontrolled intervention study

Prospective study

Kind of study

23 (13 vitamin D/10 placebo)

101 (63.5 age); 51 vitamin D/50 placebo

64 (65.9 age); 31 vitamin D?Ca/ 33 palcebo?Ca

80 (1 year old); 42 vitamin D/38 placebo

30 (all recived supplements)

Number of patients enrolled (n/ mean age)

Elderly patients with HF, no renal impairment

Adult population with stable chronic heart failure. No renal impairment

Adult population with HF, no ranal impairment

Infant patients with HF, no renal impairment

Patients with severe renal insuficiency on hemodialysis

Kind of population

EF%

6 months

6 weeks

6 months

peak VO2/ aldosterone

PRA ng/mL

12 weeks

24 weeks

Weeks of intervention

Evaluation of cytokines (pro and antinfiammatory) and echocardiographic measure

Inflammation markers and LV mass index

Outcomes

1,000 UI/day

\30 ng/mL

2,000 UI daily

800,000 UI in 6 months

Not necessary

\0 ng/mL

50,000 IU weekly

50,000 UI 12 weeks, then 20,000 UI

\30 ng/mL

B37,5 ng/ mL

Dose

Vitamin D level for enrollment

Vitamin D 15.51 vs. -1.40 ng/ mL, p \ 0.001) and plasma calcium (from 9.3 to 9.6 mmol/L, p \ 0.005); DEF increased 6.71 vs. -4.3 %; p \ 0.001)

Vitamin D 48 to 80 nmol/L. PRA 6.5 ng/ml/h–5.2 ng/ml/ h; no changes in BNP and fibrosis marker

Vitamin D 61.7 ± 20.3 vs. 17.4 ± 9.8. No change in peak VO2, 6MW, TGUG or isokinetic muscle strenght, renin and echocardiographic measures. Aldosterone decreased 10.0 to 6.2 ng/mL

Vitamin D 13.4 ± 2.21 to 32.89 ± 2.3 ng/mL; EF% 36.4 ± 2.2 to 52.2 ± 4.7 %; IL-10 1.25 ± 0.2 to 1.85 ± 0.3 pg/mL; IL-6 30.4 ± 4.62 to 16.7 ± 4.62 pg/mL; TNF-a 13.42 ± 0.9 to 12.6 ± 0.9 ng/mL; p \ 0.0001

Vitamin D 18.1 ± 6.6 to 40.4 ± 10.4 ng/mL; Ca 9 ± 0.6 to 9.4 ± 0.6 mg/dL; HS-PCR 0.62 to 0.32 mg/L ; IL-6 6.44 vs 3.83 pg/mL; LV mass reduction 175 ± 63 to 159 ± 55 g/m2

Results

PTH, parathyroid hormone; FS%, fractional shortening; IVS, interventricular septum; PW, posterior wall; LV, left ventricular; EF%, ejection fraction; DEF, delta ejection fraction; QoL, Quality of Life; 6MW, 6 minutes walking test; PRA, plasma renin activity

Reference

Author

Table 1 continued

A. Dalbeni et al.

Could Vitamin D Supplements Be a New Therapy for Heart Failure?

hyperparathyroidism, but with 25(OH)D levels \30 ng/mL at baseline, a statistically significant decrease in high sensitivity C reactive protein and a reduction of IL-6 levels after 6 months of cholecalciferol supplements; LV mass index was significantly reduced at the end of supplementation (159 ± 55 g/m2 from 175 ± 63 g/m2, p = 0.03). In that study, the vitamin D levels were analyzed at the baseline, after 3 months and after 6 months. The major study limitation is that a control group was not included. Therefore, the effect of the vitamin D treatment could have been overestimated. The first double-blind randomized study by Witte et al. [44] tested the effect of multivitamin supplements, including vitamin D, in elderly patients with HF and found significant improvement in EF and quality of life compared with the placebo group. Because of the study design, the contribution of 400 UI daily vitamin D administration to the described improvements is not dissectible from the potentially synergistic components of the multivitamin preparation; also, levels of vitamin D were not investigated. In another double-blind randomized study, by Schleithoff et al. [24] in 2006, 123 patients with HF (New York Heart Association or NYHA class I–IV) received either a daily dose of vitamin D, 2,000 UI, or a placebo for 9 months. In that study, a predefined plasma vitamin D level at baseline was not required. However, from the baseline data, it can be estimated that plasma levels of vitamin D were below the range of normality in all the patients [treatment group 14.4 ng/mL (95 % CI 11.5–22.1); placebo group 15.3 (95 % CI 12.7–22.8)]. The group of patients actively treated with vitamin D showed increased plasma 25(OH)D levels and a statistically significant decrease in anti-inflammatory cytokine IL-10 plasma levels. In addition, TNF-a increased significantly in the placebo group. However, the observed change in inflammatory markers was not associated with any significant change in echocardiographic parameters or level of natriuretic peptides. In a randomized double-blind controlled trial by Witham et al. [45], 105 elderly patients with HF (aged over 70 years) received twice in 10 weeks an oral dose of 100,000 UI vitamin D or a placebo. Participants were required to be screened for 25(OH)D levels lower than 20 ng/mL to enter in the study. The primary outcome was the 6-min walk test, a measure of submaximal exercise capacity. No significant benefits were observed from the results of either that test or the Timed Up and Go test. No changes were observed in TNF-a, aldosterone or renin levels, while BNP significantly decreased in the treatment group arm (-22 vs. ?78 pg/mL at 10 weeks, p = 0.04). However, in this study, 25(OH)D levels, measured at the beginning and at the end of the study, failed to reach 75 nmol/L or 30 ng/mL, the lower limit of the normality

range, and echocardiographic parameters were not evaluated [45]. Boxer et al. in 2013 [46] conducted a randomized trial with a high dose of vitamin D (50,000 UI weekly), achieving an important increase in vitamin D plasma levels (19.1 ± 9.3 to 61.7 ± 20.3 ng/mL) after only 6 months, without differences in adverse effects in the two groups. However, the 64 patients in the vitamin D group did not improve physical performance. This study had some limitations: the small number of patients, the high number of excluded patients and the short follow-up period. Other data from the same population were published by Boxer et al. [47] in 2014. In this work, there were no differences between groups in renin, echocardiographic measures or health status, while vitamin D supplements showed a decrease in aldosterone levels. Hsia et al. [48], in a double-blind trial, randomized 36,282 post-menopausal women to receive a daily dose of 400 UI vitamin D daily plus calcium 1,000 mg/day or a placebo. One of the secondary end points of that study was the incidence of HF during the 7-year follow-up; no differences were observed between groups. However, no echocardiographic measurements were taken and subjects were permitted to take concurrent vitamin D supplements [48]; no vitamin D levels were analyzed at the beginning of, during or at the end of the study. Another recent study, by Zia et al. [49], involved a small group of 14 AA patients with HF and vitamin D deficiency (\20 ng/mL). That study demonstrated an improvement in the EF (from 24.3 ± 1.7 to 31.3 ± 4.3 %, p \ 0.05) after 50,000 UI vitamin D given orally for 8 weeks, and 2,000 UI per day for 6 additional weeks. Also plasma 8-isoprostane levels were reduced at 14 weeks. Also in that study, a control group was not recruited [49]. A recent large prospective study evaluating the effect of post-menopausal hormone therapy by Schierbeck et al. [50], documented in 2012, showed in postmenopausal women with vitamin D deficiency an increased risk for adverse cardiovascular consequences. Vitamin D deficiency was defined as serum 25(OH)D \25 ng/mL at the baseline. Vitamin D and calcium intake as well as serum levels of different forms of vitamin D were documented in this study. Approximately 39 % of women had vitamin D deficiency at baseline. The composite end point including HF was experienced by 243 women: 118 with vitamin D deficiency and 125 who were vitamin D replete. The incidence of HF did not differ between treated and untreated subjects [1.3 vs. 0.7 %; hazard ratio 1.97 (95 % CT 0.78–4.99); p = 0.15] [50]. In 2011, Shedeed et al. [51] published the results of a double-blind, placebo-controlled intervention study preformed in a pediatric HF population. The vitamin D levels were analyzed at baseline and at weeks 6 and 12 after the beginning of the study. All the patients had vitamin D

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depletion. In the intervention group, a significant improvement in HF score, LV end diastolic diameter, and LV EF (36.4 ± 2.2 to 52.2 ± 4.73 %, p \ 0.001) was observed, along with an increase in IL-10 and a decrease in PTH, IL-6 and TNF-a. This positive finding may not be transferable to the adult population [51]. In a very shortterm (6 weeks) vitamin D supplementation study, high plasma renin activity (PRA) decreased significantly in the vitamin D group [52]. In another recent study [53], in a few cohorts of patients, we demonstrated that high dose, active vitamin D supplementation can achieve a normal vitamin D plasma range and increase the EF (%). In 13 patients under active treatment for 6 months, mean plasma 25(OH)D concentrations (15.51 vs. -1.40 ng/mL, p \ 0.001) and plasma calcium (from 9.3 to 9.6 mmol/L, p \ 0.05) increased significantly. However, other biomarkers of bone metabolism did not differ between the treatment and placebo groups. EF increased significantly in the intervention group (6.71 vs. -4.3 %. p \ 0.001), and the serum concentration of carboxyterminal propeptide of procollagene (PIP) increased only in the placebo group after 6 months (1,140.98 vs. -145 lg/L, p \ 0.05). Systolic BP was lower after 6 months of cholecalciferol treatment (from 129.6 to 122.7 mmHg, p \ 0.05). A search of the current controlled trial (ISRCTN) Register of the major clinical trials identified 14 randomized trials with vitamin D supplements in HF, just planned or ongoing. Also, a large prospective placebocontrolled trial, the Vitamin D and Omega 3 Trial (VITAL trial), aims to recruit 20,000 patients to examine the effect of vitamin D and omega 3 fatty acids on cardiovascular events and HF.

9 Conclusion The observational studies show an association between low vitamin D levels and cardiovascular disease. These findings are supported by several mechanistic studies, especially in vitro, indicating that vitamin D may interact with pathophysiological mechanisms of HF. A recent meta-analysis [54] of 11 randomized controlled trials (until 2008) showed that calcium or vitamin D supplementation did not have an effect on major cardiovascular events (including HF), myocardial infarction or stroke. However, few interventional studies are available to date, and those that are have conflicting results. New randomized placebo-controlled intervention trials with long-period follow-up and including a large number of patients are needed to understand if vitamin D supplements may prevent or improve cardiovascular diseases such as HF.

To understand if a direct correlation between vitamin D levels and heart performance exists, echocardiographic parameters like EF and measurement of interventricular septum or LV mass index should necessarily be evaluated. This is necessary both to identify the correct dosage required to improve heart contractility and to understanding if vitamin D therapy could synergize with the traditional HF drugs. Additional data are also necessary to verify possible relationships between vitamin D levels and biomarkers like natriuretic peptides, lipid profile, insulin resistance, pro- and anti-inflammatory cytokines, PTH or BP. In fact, vitamin D could find a role, in addition to traditional drugs, in the treatment of risk factors responsible for HF. Conflict of interest None of the authors have any potential conflicts relevant to the contents of this article.

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Could vitamin D supplements be a new therapy for heart failure? Possible pathogenic mechanisms from data of intervention studies.

Vitamin D deficiency may play a role in the pathogenesis of chronic heart failure (HF), but whether giving patients supplements to raise vitamin D int...
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