Medical Grand Rounds

Vitamin D and the heart: Why we need large-scale clinical trials

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RISK FACTORS FOR LOW VITAMIN D LEVELS

Risk factors for low vitamin D levels include older age, living in northern latitudes, sun avoidance, dark skin pigmentation, obesity, low dietary intake, and various medical conditions, especially malabsorption syndromes. Some of these are also risk factors for cardiovascular disease, cancer, and other chronic diseases, and potentially confound outcomes in many studies. Older age, which is usually adjusted for in multivariate models, is important to recognize as a major risk factor for vitamin D deficiency, owing to reduced absorption and synthesis, less time outdoors, and low dietary intake.

Wearing sunscreen decreases the synthesis of vitamin D in the skin, but because ultra-violet light has been clearly classified as a carcinogen, it is a not advisable to increase sun exposure for the sake of increasing vitamin D levels. That is a poor trade-off, given the high incidence rate of skin cancer and the adverse effects of solar radiation on skin aging.

Obesity is a risk factor for vitamin D deficiency because vitamin D is fat-soluble and becomes sequestered in fat tissue. Vitamin D may also play a role in the differentiation of adipocytes and may affect their function. In observational studies, it is very important for researchers to adjust for body mass index, physical activity (which may be correlated with more time outdoors), and other potential confounders in their analyses.

HOW VITAMIN D MAY LOWER CANCER RISK

Because of the important effect of vitamin D in regulating cell differentiation and cell growth, there are multiple ways that it may affect cancer risk. Laboratory, cell culture, and animal studies suggest that vitamin D may lower cancer risk by inhibiting cell proliferation, angiogenesis, metastasis, and inflammation and inducing apoptosis and cellular differentiation. Several of these mechanisms are also relevant to atherosclerosis and cardiovascular disease. Although VITAL is addressing the role of vitamin D in preventing both cancer and cardiovascular disease, the remainder of this article will focus on cardiovascular outcomes.

HOW VITAMIN D MAY REDUCE CARDIOVASCULAR RISK

Vitamin D may lower cardiovascular risk via several mechanisms:

Inhibiting inflammation. Vitamin D has a powerful immunomodulatory effect: laboratory studies show that it inhibits prostaglandin and cyclooxygenase 2 pathways, reduces matrix metalloproteinase 9 and several proinflammatory cytokines, and increases interleukin 10, all of which result in suppressed inflammation.1

Inhibiting vascular muscle proliferation and vascular calcification. Animal studies indicate that in moderate doses vitamin D decreases calcium cellular influx and increases matrix Gla protein, which inhibits vascular smooth muscle proliferation and vascular calcification. These protective effects contrast with the hypercalcemia associated with a high intake of vitamin D, especially in the context of renal failure or other risk factors, which may lead to increased vascular calcification.1

Regulates blood pressure. Vitamin D decreases renin gene expression and the synthesis of renin, which reduces activity of the renin-angiotensin-aldosterone system, leading to a reduction of blood pressure and a favorable effect on volume homeostasis.1

Regulates glucose metabolism. Limited evidence shows that vitamin D may increase insulin sensitivity and regulate glucose metabolism.1

Vitamin D and cardiac hypertrophy

The vitamin D receptor is present in virtually all tissues, including cardiac myocytes and endothelial cells. Animals with vitamin D deficiency have higher blood pressures, and animals genetically altered to have no vitamin D receptors (knock-out models) develop left ventricular hypertrophy and heart failure.

Animals genetically altered to have no 1-alpha-hydroxylase (so that the most active form of vitamin D is not made) also develop left ventricular hypertrophy. They can be rescued by the administration of 1,25-dihydroxy vitamin D3.1

These findings are consistent with what is observed in patients with end-stage renal disease, who produce very little 1,25-dihydroxyvitamin D3: they often develop left ventricular hypertrophy, diastolic heart failure, atherosclerosis, and vascular calcification.

EVIDENCE FOR CARDIOVASCULAR DISEASE REDUCTION

Wang et al1 recently reviewed available prospective cohort and randomized clinical trials from 1966 to 2009 that examined vitamin D or calcium supplementation and cardiovascular disease. Comparing people with the lowest to the highest levels of serum 25-hydroxyvitamin D3 indicated that a low level is a risk factor for coronary artery disease and cardiovascular death. Unfortunately, most studies were not designed to assess primary effects on cardiovascular outcomes, and so have many potential confounders.

Prospective observational studies

Observational studies suggest that vitamin D deficiency is associated with an increased risk of cardiovascular disease. Some examples:

The Framingham Offspring Study2 followed 1,739 men and women with a mean age of 59 for 5.4 years. The study compared the incidence of cardiovascular events in those with a serum 25-dihydroxyvitamin D level of at least 37.5 nmol/L vs those with lower levels. The risk of cardiovascular disease was 1.62 times higher in those with the lowest levels of vitamin D, a statistically significant difference. However, a threshold effect was apparent (discussed below).

The Health Professionals Follow-up Study3 prospectively evaluated more than 18,000 men ages 40 to 75 for 10 years. The study compared men with a low serum level of vitamin D (< 37.5 nmol/L) to those with a more optimal level (> 75 nmol/L). The incidence of cardiovascular events was 2.09 times higher in men with low levels of vitamin D, a difference that was statistically significant.

The Third National Health and Nutrition Examination Survey (NHANES III) included data for more than 13,300 men and women age 20 years and older. Using a cohort that was followed for 8.7 years, Melamed et al4 compared the quartile with the lowest serum vitamin D level (< 44.4 nmol/L) against the quartile with the highest level (> 80.1 nmol/L). The associations were modest: those with low levels had a 1.20-times higher rate of death from cardiovascular disease and a statistically significant 1.26-times higher rate of death from all causes.

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