Vitamin D and Cardiovascular Disease

Vitamin D Physiology and Safety

Vitamin D is unique for humans because it can be produced in the skin, provided that skin exposure to ultraviolet (UV) B radiation is sufficient. Dietary intake is a second, less important, vitamin D source. Because of the ability of the skin to produce vitamin D, many clinicians consider vitamin D a pro-hormone rather than a vitamin.

Skin synthesis of vitamin D has two advantages: it is very effective and toxic effects are usually impossible, since daily skin synthesis of vitamin D reaches a plateau when 15% of the vitamin D precursor, 7-dehydrocholesterol, is converted into vitamin D. Thereafter, vitamin D-inactive substances such as lumisterol and tachysterol are produced. However, in various population groups such as indoor workers, institutionalized patients, veiled women and dark-skinned people living at high geographic latitude skin synthesis of vitamin D is limited or even absent. In these cases, oral vitamin D intake is essential for humans. Due to the increasing number of most of the aforementioned groups, it is likely that in future the vitamin character of vitamin D moves to the forefront of interest.

Generally, essential nutrients like vitamin D show a U-shaped association between oral intake and its biological response (Figure 1): Briefly, an adequate intake guarantees normality of those functions, which depend on the specific nutrient, whereas deficient intake can cause harm. Above the adequate intake range toxic effects may begin to manifest and risk of harm rises again. In case of excessive oral vitamin D intake, the unregulated intestinal vitamin D uptake in combination with the weakly-regulated hepatic 25-hydroxylation of vitamin D can lead to toxic circulating 25-hydroxyvitamin D (25OHD) levels. In extreme cases both deficient vitamin D supply and excess intake can be fatal.

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Figure 1.

Dose-response curve for nutrients.

Vitamin D status can best be assessed by measuring circulating 25OHD levels. The Institute of Medicine (IOM) has classified circulating 25OHD levels of 50 to 125 nmol/l as adequate (divide by 2.496 to convert into ng/ml), levels between 30 and 49.99 as inadequate and levels below 30 nmol/l as deficient, whereas levels >125 nmol/l are classified as potentially harmful (1). Although 1,25-dihydroxyvitamin D (1,25[OH]₂D) is the active hormonal form of vitamin D, which is primarily produced in the kidney but also in various extra-renal tissues, circulating 1,25(OH)₂D levels are usually homeostatically-regulated and are therefore less valid in assessing human vitamin D status. However, in case of inadequate or deficient vitamin D status, circulating 1,25(OH)₂D levels become substrate-dependent, i.e. dependent on circulating 25OHD levels (2).

To guarantee an adequate vitamin D supply, the IOM recommends beyond infancy and up to an age of 70 years a daily vitamin D intake of 600 international units (IU; divide by 40 to convert into μg) and for people >70 years, 800 IU daily. The IOM has set the upper tolerable intake level at 4,000 IU daily.

The pivotal role of vitamin D for mineral homeostasis and skeletal health is well-established. The present article gives an overview of vitamin D and cardiovascular disease (CVD) and provides evidence that both vitamin D deficiency and excess supply can cause CVD.

History

The biphasic effect of vitamin D on tissue calcification has long been known: Nearly a century ago, the essential role of vitamin D for bone mineralization and its preventive effect on bone diseases such as rickets and osteomalacia became obvious. Shortly after the discovery of vitamin D it also became evident that oral vitamin D excess is responsible for soft tissue calcification in experimental animals and infants (3). Vitamin D intoxication has been related to infantile hypercalcemia with supravalvular aortic stenosis, mental retardation and craniofacial malformation. Correlative pathological studies also suggested that the intermittently high doses of vitamin D given in former decades for the prevention of rickets were responsible for vascular childhood calcinosis (4). However, in the 1980s a paradigm shift occurred with the observation that UVB radiation, through vitamin D formation, may protect against cardiovascular disease (CVD) (5). The hypothesis was based on ecological data indicating seasonality in coronary heart disease and stroke mortality in Australia, with the highest mortality incidence occurring during wintertime, when skin synthesis of vitamin D is low or even absent. In addition, it became obvious that in the United States mortality from CVD was lowest at high geographic altitude, where UVB radiation is considerable higher compared with sea level. In the 1990s an inverse association between circulating 1,25(OH)₂D levels and vascular calcification was reported in two human populations at high and moderate risk for coronary heart disease (6). The hypothesis of cardio-protective vitamin D actions was later on extended to the effect that several apparent paradoxes in the pathogenesis of CVD could be explained by differences in vitamin D status (7). These paradoxes include a low CVD mortality risk despite (i) a high intake of saturated fatty acids, (ii) a high prevalence of cigarette smoking or (iii) a low socioeconomic status. By contrast, a high CVD mortality risk has been reported in populations without the expected risk indicators or despite a very low fat intake.

Experimental Data

It has been hypothesized that vitamin D excess can cause vascular calcification by vascular smooth muscle cell (VSMC) differentiation into osteoblast-like cells either directly or indirectly via hypercalcemia and hyperphosphatemia (8). Similarly, it has been assumed that vitamin D deficiency may promote vascular calcification by suppression of inhibitors of VSMC differentiation into osteoblast-like cells (8).

The assumption of a biphasic vitamin D effect on CVD risk is supported by several experimental studies: Briefly, supra-physiological doses of the parent vitamin D substance as well as high doses of 1,25(OH)₂D₃ (i) result in a marked increase in aortic calcium and phosphate content, (ii) accelerate cell migration and promote the transition of contractile VSCMs into the osteoblast-like phenotype, (iii) lead to vascular calcification, destruction of elastic fibers, arterial stiffness and (iv) induce left ventricular hypertrophy (9-12). Importantly, studies in fibroblast growth factor-23 (fgf-23) null mice (13) demonstrate that phosphate overload seem to be critical for the process of vascular calcification. In these animals, markedly elevated 1,25(OH)₂D levels on a phosphate deficient diet had no apparent adverse effects on vascular calcification. The pivotal role of phosphate overload is supported by results in double knockout mice of klotho- and the sodium/phosphate co-transporters (14). These animals have normal phosphate levels and also a low risk of vascular calcification, despite the presence of significantly elevated serum calcium and 1,25(OH)₂D levels.

In line with the hypothesis of a biphasic effect of vitamin D on CVD, vitamin D receptor (vdr) knockout mice also show several features of premature aging including ectopic calcification and a short lifespan (15). Likewise, vascular calcification can be induced in uremic rats, an experimental model of chronic kidney disease, which is associated with markedly suppressed 1,25(OH)₂D levels and supra-physiological parathyroid hormone (PTH) levels (16). Intriguingly, 1,25(OH)₂D₃ can inhibit tumor necrosis factor alpha (TNFα) converting enzyme, an enzyme that produces secondary hyperparathyroidism, fibrotic and inflammatory lesions to the renal parenchyma and systemic inflammation, which is known to aggravate renal and cardiovascular lesions and enhance the risk of vascular calcification and cardiovascular mortality (17). Notably, vascular calcification and expression of vascular osteoblast differentiation factors can also be induced in low-density lipoprotein receptor (ldl-r)-null mice by feeding a vitamin D deficient diet (18). Similar results were obtained in ApoE-null mice on a vitamin D deficient diet (19).

Vitamin D deficiency may not only influence vascular calcification but also other cardiovascular risk factors: 1,25(OH)₂D₃ is a negative endocrine regulator of the renin-angiotensin system. The vdr-null mice show renin and angiotensin II overexpression leading to hypertension, cardiac hypertrophy and increased water intake (20). Even selective deletion of the vdr gene in cardiac myocytes leads to left ventricular hypertrophy despite normal calcium homeostasis and normal PTH concentrations (21). Another potentially protective vitamin D effect has been reported in macrophages of patients with type 2 diabetes mellitus. In these cells, 1,25(OH)₂D₃ administration decreases cholesterol uptake and inhibits foam cell formation (22).

Epidemiology

Recently, Wang et al. (23) published a meta-analysis of prospective studies on circulating 25OHD and CVD. The analysis included a total number of 19 independent studies, published between 2005 and 2012, with 6,123 CVD cases in 65,994 participants. Comparing the lowest to the highest 25OHD categories, the pooled relative risks was 1.52 (95% confidence interval [CI]: 1.30-1.77) for total CVD, 1.42 (95% CI: 1.19-1.71) for CVD mortality, 1.38 (95% CI: 1.21-1.57) for coronary heart disease and 1.64 (95% CI: 1.27-2.10) for stroke. The CVD risk increased across decreasing 25OHD below approximately 60 nmol/l, with a relative risk of 1.03 (95% CI: 1.00-1.06) per 25 nmol/l decrement in 25OHD. Especially at deficient circulating 25OHD levels, i.e. levels below 30 nmol/l, a non-linear increase in CVD risk became obvious. However, there was no clear increase or decrease in CVD risk with 25OHD over 60 nmol/l, based on the few data points. A more recent prospective cohort study in cardiac surgery patients (24) also showed a nonlinear increase of major adverse cardiac and cerebrovascular events (MACCE) until discharge in patients with inadequate and deficient circulating 25OHD levels, respectively, as compared with 25OHD levels of 75 to 100 nmol/l. In detail, compared with the reference group the multivariable-adjusted odds ratio of MACCE was 1.73 (95% CI: 1.01–2.96) at 25OHD levels of 30 to 50 nmol/l and 2.23 (95%CI: 1.31-3.79) at levels below 30 nmol/l. However, at 25OHD levels >100 nmol/l, the odds ratio was again 2.34 (95% CI: 1.12-4.89), indicating a U-shaped association between circulating 25OHD and MACCE. Possible causes for adverse vitamin D effects on the cardiovascular system at 25OHD levels above 100 nmol/l are not well understood. It has been speculated that high circulating 25OHD levels (i) may result in excessive amounts of absorbed calcium leading to an increased risk of CVD events, (ii) may sometimes only reflect low availability of the active vitamin D hormone 1,25(OH)₂D leading to deficient rather than excessive vitamin D actions or (iii) may be associated with specific gene variants, which increase the CVD risk independent of vitamin D and may thus only be indicative of an increased CVD risk but not causally related to it (24). Notably, the U-shaped association between circulating 25OHD and clinical outcome in cardiac surgery patients is in general agreement with a huge Israeli data analysis (25). This particular investigation demonstrated an inverse J-shaped association of circulating 25OHD with acute coronary syndrome and mortality. Morbidity and mortality were lowest at 25OHD levels between 50 and 90 nmol/l.

It has been argued that circulating 25OHD levels are only an indicator of solar UVB exposure and not causally linked to CVD risk. Therefore, it is important that in a study by Gotsman et al. (26), during a median clinical follow-up of 518 days, vitamin D supplement use was independently associated with reduced mortality in heart failure patients. The inverse association of vitamin D supplement use with mortality was most pronounced in patients with 25OHD levels <25 nmol/l. In another study where patients were followed-up in a cardiovascular practice at a large US academic medical center (27), there was substantial survival benefit among individuals who were on vitamin D supplementation (odds ratio for death 0.39 (95%CI: 0.28-0.53) compared to vitamin D non-users.

Randomized Controlled Trials

During recent years, various randomized controlled trials (RCTs) (28-37) have investigated the effects of daily vitamin D supplements on biochemical cardiovascular risk markers such as lipid parameters and inflammatory markers, endothelial function measured by brachial artery flow-mediated vasodilation and cardiac function measured by left ventricular ejection fraction and New York heart association functional class (Table I). Daily vitamin D doses ranged between 200 and 5,000 IU/d (5-125 μg/d). Generally, results are mixed. Beneficial effects were reported in 5 out of 10 studies (50%). Five out of 6 studies with initial 25OHD levels ≤ 40 nmol/l demonstrated beneficial vitamin D effects on CVD risk markers, whereas none of the studies with initial 25OHD >40 nmol/l reported such an effect. Most importantly, with the exception of one study in HIV-infected patients that reported an impaired insulin sensitivity in the vitamin D group compared with the placebo group (32), none of the other studies reported any risks or adverse effects of the vitamin D supplements. It cannot be ruled-out that the vitamin D effect on insulin sensitivity in HIV-infected patients was a chance finding, since the mean increment in 25OHD in the vitamin D group was only 12.5 nmol/l and thus rather low. However, it may also be that the disease has influenced the vitamin D effect on glucose metabolism.

Table II summarizes the results of studies where bolus administration or UVB exposure was used to assess the vitamin D effect on biochemical risk markers and endothelial function (38-51). Bolus doses ranged from 20,000 IU weekly up to 300,000 IU monthly. Again, results are mixed. Four out of 13 studies (31%) reported beneficial effects. In all 4 studies, initial 25OHD levels were ≤40 nmol/l. One of two other studies with initial 25OHD levels ≤40 nmol/l reported no beneficial effect and the other study reported mixed results. None of the 13 studies reported any risk or adverse vitamin D effect.

There is, however, some evidence that bolus administration of vitamin D should be used cautiously in patients without deficient 25OHD levels: In a pooled data analysis in 928 subjects receiving vitamin D supplements of 20,000-40,000 IU per week or placebo for 6-12 months (52), baseline circulating 25OHD level in those given vitamin D was 55.9 nmol/l and the mean increase was 82.4 nmol/l. Compared to the placebo group there was in the vitamin D group at the end of the studies a slight, but significant increase in hemoglobin A_1C, C-reactive protein and in those with low baseline high-density lipoprotein-cholesterol and circulating 25OHD levels less than 50nmol/l a slight decrease in serum HDL-cholesterol, demonstrating that vitamin D bolus administration does not improve biochemical markers of CVD risk in subjects without vitamin D deficiency. If anything, the effect of 20,000-40,000 IU vitamin D weekly bolus administration was negative.

One of the most important CVD risk factors is hypertension (53). In 2009, Witham et al. (54) performed a meta-analysis of RCTs on vitamin D and blood pressure. They came to the conclusion that in patients with initial systolic blood pressure >140 mmHg vitamin D decreased systolic blood pressure non-significantly by −3.65 mmHg (95%CI:−8.00; 0.74) and diastolic blood pressure significantly by −3.05 (95%CI:−5.50; −0.60). However, this meta-analysis has the limitation that the number of included patients was small (n=445). A more recent meta-analysis (55), which was based on more than 1,700 patients, reported a non-significant reduction in systolic and diastolic blood pressure of only −0.94 mmHg (95%CI:−2.98; 1.10) and −0.52 mmHg (95%CI:−1.18; 0.14), respectively. Unfortunately however, this meta-analysis was not restricted to patients with elevated blood pressure.

While RCTs on risk markers may give important insights into potential mechanisms of vitamin D actions on the cardiovascular system, only those RCTs which investigate clinically relevant end-points can demonstrate whether or not vitamin D is effective in preventing CVD events. An update of a Cochrane collaboration review (56) came to the conclusion that in RCTs with predominantly elderly people (>70 years) vitamin D supplement use is able to reduce total mortality by 6% (95%CI: 2%-9%). However, this effect was primarily based on the reduction of cancer mortality, whereas no significant effect was observed on CVD mortality (relative risk: 0.98, 95%CI: 0.90-1.07). More recently (57), it has been suggested that vitamin D supplementation does not reduce clinical outcomes, including CVD risk, in unselected community-dwelling individuals by more than 15% and that future trials with similar designs are unlikely to alter these conclusions (57). Nonetheless, we should bear in mind that many RCTs on vitamin D and CVD have important limitations: First, many RCTs and meta-analyses of RCTs do not, or not adequately, take study adherence into account, although poor study adherence is of clinical relevance and may influence study results substantially (58). Second, many patients included in vitamin D supplementation trials were not vitamin D deficient (i.e. circulating 25OHD levels not below 30 nmol/l). Therefore, a strong vitamin D effect on CVD prevention cannot be expected. Third, vitamin D is a negative endocrine regulator of the renin-angiotensin aldosterone system (20). In Western societies, medications such as diuretics and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers are frequently prescribed to patients who are at an increased risk for CVD events and may thus interact with vitamin D actions on CVD risk. In addition, statins, which are also frequently prescribed in Western societies, are considered to have vitamin D agonistic effects (59) and may thus influence potential CVD effects of vitamin D supplements. Fourth, many control groups cannot be considered as real placebo groups since most individuals in the control groups are able to get their vitamin D by skin synthesis. Fifth, in several RCTs the vitamin D group was also supplemented with high amounts of calcium. There is however convincing evidence that high amounts of supplemental calcium may increase CVD risk (60-62) and may thus adversely affect potentially beneficial vitamin D effects on CVD risk (63). Finally, many RCTs do not take physical activity into account, although it is well known that calcium and vitamin D metabolism differ markedly in physically active and inactive individuals (64), which may also influence CVD risk.

Given the various limitations of published RCTs, the potential of vitamin D in reducing CVD outcomes may be more pronounced than currently assumed, at least in specific subgroups. Results of adequately designed RCTs with sufficient statistical power are therefore still warranted.

Outlook

There are currently several ongoing trials with CVD as one of the main outcomes. In total, more than 40,000 participants aged 50 years and over will be included in these studies, which are performed in the United States, New Zealand and Europe (65). First results can be expected in 2017. Hopefully, these studies will provide more clarity about the role of vitamin D on CVD risk.