Posted Feb 10, 2010
Vitamin D has a well-established role in calcium and phosphorus metabolism and bone mineralization. Vitamin D deficiency causes rickets in children, and in adults can lead to osteomalacia, resulting in muscle and bone weakness. Data are emerging that link hypovitaminosis D, as assessed by measurement of 25-hydroxyvitamin D [25(OH)D], with cardiovascular pathology. Vitamin D deficiency has been associated with hypertension, some inflammatory markers, and metabolic syndrome. More recently, low serum 25(OH)D has been associated with increased incidence of cardiovascular events and all-cause mortality. In this review, we discuss the role of vitamin D in health, and describe recent evidence linking hypovitaminosis D to cardiovascular disease. We describe controversies surrounding recommended daily intake and optimal serum levels, as well as discuss the need for further research relating vitamin D deficiency with cardiovascular disease.
Vitamin D deficiency
Vitamin D, which has also been referred to as the “sunshine vitamin” is a lip id-soluble vitamin obtained from both exogenous and endogenous sources. Some foods, such as eggs, fatty fish, and liver naturally contain vitamin D, but other dietary sources of vitamin D are from fortified foods, like milk and cereals, or from nutritional supplements1. Most of the body’s vitamin D is produced endogenously following exposure of skin to sunlight, thus geography, season, skin tone, and sun exposure are primary predictors of vitamin D nutritional status2. Vitamin D obtained from sun is in the form of vitamin D3 (cholecalciferol), while vitamin D2 (ergocalciferol) or D3 may be obtained from dietary sources. Vitamin D2 differs from vitamin D3 in that it is derived from dietary ergosterol; it contains a double bond between carbon 22 and 23 and it has an additional methanol group at position 24, while vitamin D3 is produced by the action of sunlight on 7-dehydrocholesterol. Both Vitamin D2 and D3 are biologically inactive and are activated by two hydroxylation reactions, the first occurring in the liver to form 25(OH)D and the second occurring in the kidney to form the biologically active 1,25-dihydroxyvitamin D [1,25 (OH^D] (see Figure 1). Since only the hydroxylated forms are active and because these active molecules are produced within the body and have effects in multiple tissues and cell types, it is more accurate to consider 25(OH)D and 1,25(OHz)D as hormones rather than vitamins.
The main function of vitamin D is to promote calcium absorption in the gut and to maintain adequate blood levels of calcium and phosphorus. If the body is deficient in vitamin D, normal bone mineralization is compromised and bones may become thin and brittle. Severe deficiency can lead to rickets, with associate skeletal deformities, in children and osteomalacia in adults, which results in both weak bones and muscles. Despite the clear association between vitamin D deficiency and bone disease, much controversy still exists regarding appropriate vitamin D doses needed to avoid disease. Currently, the US Institute of Medicine-National Academy of Sciences recommends a daily intake of 200 IU (5 mg) for individuals < 50 years of age, 400 IU (10 mg) for those 50 to 60 years, and 600 IU (15 mg) for those over 70 years of age.3 However, many experts are recommending that higher daily intakes would be beneficial to most adults. A meta-analysis of 13 randomized placebo controlled studies for hip fracture and non-vertebral fracture risk demonstrated that vitamin D supplementation between 700-800 IU/day reduced the risk of fractures while a dose of 400 IU/day was not sufficient for fracture prevention.4
The current upper limit of vitamin D intake is 2000 IU/day due to toxicities that may occur at higher doses. Toxicities are rare but are associated with symptoms caused by marked hypercalcemia. Many have also suggested that the 2000 IU/day recommendation is too conservative. A review of recent clinical trials by Hathcock, et.al.5, applying risk assessment methodology used by the Food and Nutrition Board, demonstrated an absence of toxicity in trials conducted on healthy individuals using a vitamin D dose of > 10,000 IU/day. The authors suggested this value could be used as the upper limit. However concerns about possible toxicity lead most patients and clinicians to use more conservative dosing regimens. Vitamin D intoxication has been clearly documented in experimental studies in animals and in human case reports.6 Hypervitaminosis D is associated with increased absorption of calcium and phosphorus, which can lead to hypercalcemia, hypercalciuria, vascular calcification, renal, and even renal failure. It is important to note that most case reports of vitamin D toxicity have resulted calcification from vitamin D intake far above 10,000 IU/day (5).
Most of the attention concerning vitamin D has been generated over the assessment of vitamin D deficiency. Vitamin D nutritional status is best determined by measurement of 25(OH)D.7 At the 13th workshop consensus for vitamin D nutritional guidelines in 2007, studies were summarized indicating that adults should maintain a blood 25(OH)D concentration of approximately 75 nmol/L (30 ng/mL).8 There was general consensus that serum vitamin D concentration should meet, or hopefully exceed a minimum desirable concentration of 50 nmol/L (20 ng/mL). Using these levels, it has been estimated that as many as half of the elderly persons in North America are not getting adequate vitamin D to facilitate healthy bone density.8
In addition to its primary action on bone metabolism, it is now clear that vitamin D has many non-skeletal actions, and that vitamin D deficiency may be associated with chronic diseases including cancer, autoimmune disease, cardiovascular disease and even psychological illnesses such as schizophrenia and depression.9 Here we describe some of the more recent findings associating vitamin D deficiency with various aspects of cardiovascular disease. Vitamin D deficiency has been associated with hypertension, inflammatory markers, diabetes, and the metabolic syndrome, and has recently been associated with increased cardiovascular events and all cause mortality.
Vitamin D and Hypertension
It is well documented that hypertension is a risk factor for cardiovascular disease. For most individuals with hypertension, the cause is unknown and its origin is likely multifaceted. It has been hypothesized that vitamin D deficiency is associated with hypertension, possibly through activation of the renin-angiotensin system. This is due to the finding that l,25(OH)2D is a negative endocrine regulator of the renin-angiotensin system.10 A study describing data from the third National Health and Nutrition Examination Survey (NHANES, 1988-1992) including 16,135 participants > 19 years of age, found that systolic blood pressure (SBP) is inversely associated with serum vitamin D concentrations in nonhypertensive white persons in the United States.11 Although adjusting for age resulted in loss of significance for the association, concentrations of 25(OH)D > 80 nmol/L decreased the age-related increase in SBP by 20% compared with individuals having 25(OH)D < 50 nmol/L. The authors suggest that future studies should be undertaken to determine the effects of vitamin D supplementation on hypertension.11
Vitamin D, Diabetes, and the Metabolic Syndrome
The association between diabetes and cardiovascular disease is well-established and the presence of diabetes is considered as a coronary heart disease risk equivalent in the National Cholesterol Education Program Adult Treatment Panel III guidelines.12 A body of research now indicates that vitamin D may play a role in insulin resistance13 and diabetes.14 Although many studies have been published, a few will be highlighted here. Hypp