This is an excellent article from Nature Reviews Cardiology, 18 August 2009, and offers doctors CME 0.75 AMA PRA Category 1 Credits. Click blue link below for complete article.
A short excerpt is included here:
Vitamin D deficiency is common and is primarily caused by a lack of ultraviolet-B (UVB) radiation from reduced sun exposure, and the consequent limiting of vitamin D production in the skin. The vitamin D endocrine system regulates about 3% of the human genome. Observational data support the concept that vitamin D is involved in the pathogenesis of cardiovascular diseases and arterial hypertension. The antihypertensive properties of vitamin D include renoprotective effects, suppression of the renin–angiotensin–aldosterone system, direct effects on vascular cells, and effects on calcium metabolism, including prevention of secondary hyperparathyroidism. The results of clinical studies largely, but not consistently, favor the hypothesis that vitamin D sufficiency promotes lowering of arterial blood pressure. Randomized, placebo-controlled trials are greatly needed to clarify and definitively prove the effect of vitamin D on blood pressure. In general, the antihypertensive effects of vitamin D seem to be particularly prominent in vitamin-D-deficient patients with elevated blood pressure. Thus, in view of the relatively safe and inexpensive way in which vitamin D can be supplemented, we believe that vitamin D supplementation should be prescribed to patients with hypertension and 25-hydroxyvitamin D levels below target values.
- Vitamin D deficiency is common and can be attributed to reduced sun exposure, which limits ultraviolet-B (UVB)-induced vitamin D production in the skin
- Most cells express the vitamin D receptor (VDR) as well as 1-hydroxylase, which underlies several regulatory mechanisms and converts 25-hydroxyvitamin D (25[OH]D; used to classify vitamin D status) to 1,25-dihydroxyvitamin D (1,25[OH]2D)
- 1,25(OH)2D has high affinity for the VDR, but circulates in lower concentrations than 25(OH)D and is more an indicator of calcium homeostasis and kidney function than vitamin D status
- About 3% of the human genome is directly or indirectly regulated by the vitamin D endocrine system
- The antihypertensive effects of vitamin D include renoprotective effects, suppression of the renin–angiotensin–aldosterone system, effects on calcium homeostasis including the prevention of secondary hyperparathyroidism, and vasculoprotection
- Accumulating evidence—from insights into molecular mechanisms to the outcome of randomized trials—favors the hypothesis that vitamin D deficiency contributes to arterial hypertension, but further data are needed
Vitamin D insufficiency affects almost 50% of the population worldwide.1 This pandemic of hypovitaminosis D can mainly be attributed to lifestyle (for example, reduced outdoor activities) and environmental (for example, air pollution) factors that reduce exposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin. Levels of UVB radiation diminish with increasing distance from the earth’s equator, during the winter months, and as a result of air pollution. Black people absorb more UVB in the melanin of their skin than do white people and, therefore, require more sun exposure to produce same amounts of vitamin D.2 Importantly, conditions associated with reduced UVB-induced vitamin D production, such as high latitude, industrialization, and dark skin, have all been associated with increased blood pressure values.2 The logical hypothesis that high UVB-induced vitamin D production is associated with low blood pressure was confirmed by a small trial of 18 patients with untreated essential hypertension.3 The researchers found that systolic and diastolic blood pressure values were reduced by 6 mmHg after 6 weeks of UVB irradiation three times per week. UVB irradiation was also associated with a 162% rise in plasma 25-hydroxyvitamin D (25[OH]D) concentrations, but in hypertensive patients who received UVA irradiation, no significant change in 25(OH)D levels or blood pressure occurred.3
The high prevalence of vitamin D insufficiency is a particularly important public health issue because hypovitaminosis D is an independent risk factor for total mortality in the general population.4 A meta-analysis published in 2007 showed that vitamin D supplementation was associated with significantly reduced mortality.5 Furthermore, vitamin D insufficiency is associated with an increased risk of cardiovascular events, but whether this association reflects a causal relationship remains unclear.6, 7, 8 The effect of vitamin D on blood pressure could be one of the potential mechanisms underlying the link between vitamin D and cardiovascular disease. In this Review, we will summarize the mechanisms that are presumed to underlie the relationship between vitamin D and arterial hypertension, and examine the clinical data for this association.
Vitamin D metabolism
In humans, the primary source of vitamin D is UVB-induced conversion of 7-dehydrocholesterol to vitamin D in the skin.1 Just 10–20% of our vitamin D comes from dietary sources, such as fish, eggs, or vitamin-D-fortified milk (Figure 1).1 Vitamin D is hydroxylated in the liver to 25(OH)D—the main circulating vitamin D metabolite, which is largely bound to vitamin D binding protein in serum, and is used to classify vitamin D status: vitamin D sufficient (25[OH]D 30 ng/ml [or 75 nmol/l]), vitamin D insufficient (25[OH]D 20–30 ng/ml [or 50–75 nmol/l]), and vitamin D deficient (25[OH]D <20 ng/ml [or <50 nmol/l]).1 These cut-points are currently the most commonly used classification of vitamin D status, but some debate about exact threshold values still exists. Some researchers consider 25(OH)D levels of 10–20 ng/ml (25–50 nmol/l) as vitamin D insufficient and levels below 10 ng/ml (25 nmol/l) as vitamin D deficient, whereas others use a cut-off level of 40 ng/ml (100 nmol/l) to define sufficient vitamin D status.9, 10 25(OH)D is transformed by renal or extrarenal 1-hydroxylase into 1,25-dihydroxyvitamin D (1,25[OH]2D), which circulates at much lower serum concentrations than 25(OH)D, but has a much higher affinity to the vitamin D receptor (VDR).11 Serum levels of 1,25(OH)2D are mainly determined by renal 1,25(OH)2D production, which is closely related to calcium homeostasis, and is upregulated by parathyroid hormone, the concentration of which increases when calcium levels are low.1, 12 In addition, other factors such as fibroblast growth factor 23 and Klotho, which suppress 1-hydroxylase expression, have also been shown to regulate the renal conversion of 25(OH)D to 1,25(OH)2D.13 Studies have, however, shown that many other cell types, including those of the vascular wall, express 1-hydroxylase with subsequent intracellular conversion of 25(OH)D to 1,25(OH)2D, which exerts its effects at the level of the individual cell or tissue before being catabolized to biologically inactive calcitroic acid.1, 12, 14 These intracellular tissue levels of 1,25(OH)2D are determined by the concentration of circulating 25(OH)D, which is, therefore considered the best indicator of whole-body vitamin D status. Importantly, extrarenal 1-hydroxylase expression also underlies various regulatory mechanisms. In this context, extrarenal 1,25(OH)2D production in macrophages is stimulated by Toll-like receptor as part of the innate immune response against intracellular bacteria.15 Another example of extrarenal regulation of 1-hydroxylase is the increased production of 1,25(OH)2D by keratinocytes in wounds, which could be induced by transforming growth factor 1.16 25(OH)D serum levels, therefore, provide a good estimate of vitamin D status, but regulation of 1-hydroxylase activity should also be considered.
1,25(OH)2D binds to the VDR and, after forming a heterodimer with the retinoid X receptor (RXR), binds to specific DNA sequences—the so called ‘vitamin D responsive elements’. These sequences are located in the promoter regions of various vitamin-D-dependent genes that are either upregulated or downregulated by the RXR–VDR complex.1, 12, 14 Approximately 3% of the human genome is directly or indirectly regulated by the vitamin D endocrine system, which supports the idea that vitamin D insufficiency has widespread adverse consequences for human health.14 In addition to cardiovascular pathology, vitamin D insufficiency can cause musculoskeletal, malignant, metabolic, or immunological diseases.1, 12, 14
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Vitamin D toxicity
When discussing the beneficial effects of vitamin D on blood pressure, one must consider that pharmacological doses of vitamin D have been shown to cause arterial hypertension, vascular stiffness, and atherosclerosis in rodents; whether this finding has any relevance for humans is unclear.129 In humans, vitamin D toxicity and associated hypercalcemia—which can cause reversible hypertension—is observed when 25(OH)D levels are higher than 150 ng/ml (374.4 nmol/l).1 In clinical trials, vitamin D toxicity was not observed with doses of up to 10,000 IU vitamin D per day, which is approximately the level of vitamin D production that can be achieved by endogenous UVB-induced vitamin D synthesis in the skin.130, 131 Consequently, at 10,000 IU vitamin D per day, and in the absence of increased vitamin D sensitivity (for example, sarcoidosis or tuberculosis), vitamin D supplementation is safe. Presumably there is a wide margin between the level of 25(OH)D needed for vitamin D sufficiency (30 ng/ml [or 75 nmol/l]) and the level of toxicity (>150 ng/ml [or >374.4 nmol/l]).
Vitamin D supplementation
An intake of 1,000 IU (25 g) of vitamin D per day can be generally assumed to result in an increase in 25(OH)D levels of approximately 10 ng/ml (25 nmol/l).132, 133 Evidence indicates that daily, weekly, and monthly vitamin D dosing frequencies can equally increase serum 25(OH)D levels, which have a half-life of about 1 month. In this context, an oral vitamin D intake of 1,500 IU daily, 10,500 IU once weekly, or 45,000 IU once every 28 days has been demonstrated to result in similar increases of 15–16 ng/ml (37.4–40.0 nmol/l) in 25(OH)D levels.134 The dose to correct vitamin D deficiency should be sufficiently high to achieve 25(OH)D levels of at least 30 ng/ml (75 nmol/l). For example, a patient with 25(OH)D levels of 10 ng/ml (25 nmol/l) should receive at least 2,000 IU daily, which corresponds to weekly doses of at least 14,000 IU or monthly doses of at least 56,000 IU. Several authors recommend loading doses in the initial phase of treatment (that is, 50,000 IU weekly for 8 weeks or 50,000 IU daily for 1 week) before starting maintenance therapy (that is, at least 1,000 IU vitamin D for a person with initial 25[OH]D levels of 20 ng/ml [50 nmol/l]).1, 10 Individual response to vitamin D doses does, however, vary widely and certain patients, such as those who are obese or suffer from malabsorption, might require much higher vitamin D doses than individuals without comorbidities.1, 133 Measurements of 25(OH)D levels are, therefore, useful to monitor 25(OH)D levels and to allow for adequate correction of the vitamin D dose. 25(OH)D levels should be reassessed 3–6 months after initiation of vitamin D supplementation. In patients with increased vitamin D sensitivity, such as those with sarcoidosis or tuberculosis, calcium should be measured in the initial phase of treatment. One problem with vitamin D treatment is that, although maintaining 25(OH)D levels above 30 ng/ml (75 nmol/l) is generally recommended, no consensus exists about optimal 25(OH)D levels. At present, many researchers recommend maintaining 25(OH)D levels between 30 and 60 ng/ml (75.0–149.8 nmol/l).1, 10 We do not know whether higher levels than this are beneficial or detrimental. Data from NHANES-III indicate a ‘J-shaped’ association between 25(OH)D levels and mortality, with the highest mortality in persons with the lowest 25(OH)D levels, but with slightly increasing mortality in those with supraphysiological 25(OH)D levels. However, other data indicate that particularly high levels of vitamin D are optimal for cancer prevention.4, 10
Accumulating evidence, ranging from insights into molecular mechanisms to the outcome of randomized controlled trials, favors the hypothesis that vitamin D deficiency contributes to arterial hypertension. The antihypertensive effects of vitamin D are mediated by renoprotective effects, suppression of the RAAS, by beneficial effects on calcium homeostasis, including the prevention of secondary hyperparathyroidism, and by vasculoprotection. However, definitive evidence from appropriately powered, controlled, intervention trials is lacking. Some inconsistent results from studies of the relationship between vitamin D status and arterial hypertension have been reported, possibly because the effects of 25(OH)D on blood pressure are not apparent in normotensive individuals with 25(OH)D levels within the normal range. In general, evidence for the antihypertensive effects of vitamin D is strongest in patients with elevated blood pressure and vitamin D deficiency; these patients would, in our opinion, benefit from vitamin D supplementation. In addition to cardiovascular sequelae, vitamin D deficiency has been associated with autoimmune, malignant, neurological, metabolic, and infectious diseases, as well as with bone fractures.1, 12, 14, 117, 130, 131 In view of the multiple health benefits of vitamin D and the high prevalence of vitamin D deficiency, as well as the easy, safe, and inexpensive ways in which vitamin D can be supplemented, we believe that the implementation of public health strategies for maintaining a sufficient vitamin D status of the general population is warranted.1, 12, 117, 130, 131