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16 Οκτ 2012

Are Vitamin D Levels and Cardiovascular Risk Related?

Are Vitamin D Levels and Cardiovascular Risk Related?

Charles P. Vega, MD, FAAFP


Associate Professor and Residency Director, Department of Family Medicine, University of California-Irvine, Irvine
Clinical Context

Calcium and vitamin D supplements are routinely used to prevent osteoporosis among adults. However, these supplements might have important cardiovascular effects as well. A meta-analysis by Wang and colleagues, which was published in the March 2, 2010, issue of Annals of Internal Medicine, examined the effects of calcium and vitamin D supplementation on incident cardiovascular events. They found that vitamin D supplements were associated with a slight reduction in the risk for cardiovascular disease, although this effect was limited to moderate to high doses of vitamin D (1000 IU/day). Calcium supplementation and combination supplements including both calcium and vitamin D did not affect the risk for cardiovascular events.
The association between lower vitamin D levels and increased cardiovascular risk has been demonstrated in some previous studies, but the collective research into this subject is limited by variations in study population, follow-up time, and means of measurement of vitamin D levels. The current population-based study and meta-analysis by Brøndum-Jacobsen and colleagues was designed to bring the issue of vitamin D levels and cardiovascular risk into sharper focus.

Study Synopsis and Perspective

There is a firm association between low levels of vitamin D and higher rates of ischemic heart disease, myocardial infarction (MI), and early death, according to the largest epidemiological study to date to examine this issue [1]. And the researchers, led by Dr Peter Brøndum-Jacobsen (Copenhagen University Hospital, Denmark), further confirmed this finding by performing a meta-analysis of all such studies to date, published in their paper in Arteriosclerosis, Thrombosis, and Vascular Biology.
"People with low levels of vitamin D have an increased risk of heart attack, of dying early on from cardiovascular disease, and this is an important message," senior author Dr Børge G Nordestgaard (Copenhagen University Hospital) told heartwire.
People with low levels of vitamin D have an increased risk of heart attack, of dying early on from cardiovascular disease, and this is an important message.
Nordestgaard stresses, however, that the findings don't prove cause and effect--while low vitamin-D levels may lead directly to heart disease and death, it's also possible that vitamin-D deficiency is a marker for poor health generally, he says. Nevertheless, he believes that advice regarding sun exposure needs to be modified.
"The cheapest and easiest way to get enough vitamin D is to let the sun shine on your skin at regular intervals. There's been a lot of focus on trying to avoid people getting too much sun, but maybe this has not been balanced. Cardiovascular disease kills many more people than skin cancer does," he notes. This is particularly important in countries where food is not fortified with vitamin D, he adds. He cautions, however, that "it is, of course, still important to avoid getting sunburned."
Increased Risk of CVD With Lowest Levels of Vitamin D Compared With Optimum
Brøndum-Jacobsen and colleagues measured baseline plasma 25-hydroxyvitamin D levels in 10 170 men and women from the Copenhagen City Heart Study from 1981–1983. Participants were then followed in nationwide Danish registries to the present. During approximately 29 years of follow-up, 3100 people developed ischemic heart disease, 1625 had an MI, and 6747 had died.
The scientists compared the 5% lowest levels of vitamin D (<5 nmol/L) with the 50% highest levels (>50 nmol/L). In Denmark--where foods are not fortified with vitamin D--it is currently recommended to have a vitamin-D status of at least 50 nmol/L, they note.
Following multivariate adjustment, they found a stepwise increase in risk: those with the lowest levels of vitamin D had a 40% increased risk of ischemic heart disease, a 64% higher chance of an MI, a 57% increased risk of early death, and an 81% higher likelihood of fatal ischemic heart disease/MI.
The meta-analysis gives exactly the same result as our study, so the results are quite robust when you look at the totality of the evidence.
To see whether this was a true finding, the researchers also performed a meta-analysis of all prior published population-based prospective studies on the association between plasma 25-hydroxyvitamin-D levels and risk of ischemic heart disease and early death until January 2012.
They identified 17 studies and performed the analysis with these, then also added in their own study. For both analyses, the risk of ischemic heart disease and early death were increased by 39% and 46% for lowest vs highest quartiles of vitamin D level.
In the meta-analysis, the increase in risk of heart disease and death with decreasing levels of vitamin D was seen independently of the fortification of food with vitamin D, the researchers note.
"The meta-analysis gives exactly the same result as our study, so the results are quite robust when you look at the totality of the evidence," Nordestgaard commented to heartwire.
Trial Results Needed Before Vitamin-D Supplements Can Be Recommended
Interest is high in vitamin D as a possible way to reduce the risk of cardiovascular disease, following the failure of many other vitamins to have an impact on CVD morbidity or mortality. But there is concern that many patients are taking vitamin-D supplements and/or doctors are prescribing them without any real evidence of benefit, effectively carrying out a massive uncontrolled experiment.
Nordestgaard says he does not advise taking vitamin-D supplements. "We need evidence that this is beneficial first," he observes.
There are two large, ongoing trials examining this issue--the 20 000-patient US Vitamin D and Omega-3 Trial (VITAL) study, results of which won't be available until 2016 or 2017, and the UKVitamin D and Longevity (VIDAL) trial.
The authors report no conflicts of interest.
References
  1. Brøndum-Jacobsen P, Benn M, Jensen GB, et al. 25-hydroxyvitamin D levels and risk of IHD, MI and early death. Population based study and meta-analyses of 18 and 17 studies. Aterioscler Thromb Vasc Biol 2012; DOI:10.1161/ATVBAHA.112.248039. Available at: http://atvb.ahajournals.org. Abstract

Study Highlights

  • The Copenhagen City Heart Study initially enrolled participants in 1976 to 1978, and these individuals completed 4 follow-up examinations, the last in 2001 to 2003. At each time point, participants underwent a history and physical examination along with laboratory analysis.
  • The current study focuses on 10,170 participants without baseline cardiovascular disease who completed an assessment for plasma 25-hydroxyvitamin D levels.
  • Researchers examined the study cohort for the outcomes of angina pectoris and MI, along with early death. These data were collected from national registry data for disease and mortality.
  • The main study outcome was the relationship between 25-hydroxyvitamin D levels and the risk for cardiovascular events. This outcome was adjusted to account for demographic and lifestyle factors that might promote cardiovascular disease, as well as the presence of diabetes, hypertension, and renal disease.
  • The average age of the 10,170 participants was 57 years, and 56% were women. Most participants had some history of smoking, and the baseline mean systolic blood pressure was elevated at 141 mm Hg.
  • During a maximum of 29 years of follow-up of the study cohort, 3100 ischemic heart disease events were recorded, along with 1625 cases of MI and 6747 deaths.
  • Decreased 25-hydroxyvitamin D levels were associated with a stepwise increase in the risks for ischemic heart disease, MI, and early death.
  • In comparing participants in the first to fourth percentiles of concentration of 25-hydroxyvitamin D (7.5 - 12 nmol/L) vs participants in the 50th to 100th percentiles, the adjusted risk ratios for ischemic heart disease and early death were 1.40 (95% confidence interval [CI], 1.14 - 1.72) and 1.57 (95% CI, 1.38 - 1.78), respectively. The adjusted risk ratio for fatal MI/ischemic cardiac disease was 1.81 (95% CI, 1.40 - 2.35).
  • 25-hydroxyvitamin D levels were not significantly associated with nonfatal ischemic heart disease or nonfatal MI. This finding suggests that vitamin D levels may be a marker of poor general health as opposed to having a specific effect on coronary heart disease.
  • Researchers also performed a meta-analysis of the effects of vitamin D levels on the risk for ischemic heart disease and early death in 18 prospective studies.
  • In this collective research, the risk ratio for ischemic heart disease in comparing the lowest vs the highest quartiles of 25-hydroxyvitamin D levels was 1.39 (95% CI, 1.25 - 1.54). The respective risk ratio for early death was 1.46 (95% CI, 1.31 - 1.64).
  • The association between lower vitamin D levels and higher risks for ischemic heart disease and early death remained consistent in subgroup analyses on the basis of race, geographic location, and the fortification of foods with vitamin D.

Clinical Implications

  • A previous meta-analysis by Wang and colleagues found that supplementation with moderate to high doses of vitamin D may slightly reduce the risk for cardiovascular disease, but supplementation with calcium alone or calcium plus vitamin D did not significantly affect the risk for cardiovascular disease.
  • In the current study and meta-analysis by Brøndum-Jacobsen and colleagues, low plasma levels of vitamin D were associated with higher risks for fatal cardiovascular disease and early death but were not linked with nonfatal MI.