Graz, Austria - Another study suggesting a link between low levels of vitamin D and cardiac risk has been published, this time showing that vitamin-D deficiency is associated with both cardiovascular mortality and all-cause mortality [1].

The study, published in the June 23, 2008 issue of the Archives of Internal Medicine, was conducted by a group led by Dr Harald Dobnig (Medical University of Graz, Austria).

They note that it has been estimated that 50% to 60% of people do not have satisfactory vitamin-D status, and this is probably related to factors such as urbanization, demographic shifts, decreased outdoor activity, air pollution and global dimming, and decreases in the cutaneous production of vitamin D with age.

The minimum desirable serum level of 25-hydroxyvitamin D has been suggested to be 20 to 30 ng/mL, and levels lower than this are clearly related to compromised bone-mineral density, falls, and fractures and more recently have also been linked to cancer and immune dysfunction, as well as cardiovascular disease, hypertension, and metabolic syndrome, the authors report.

They point out that recent studies have shown an association of low 25-hydroxyvitamin-D levels with important cardiovascular risk factors, supporting previous findings that demonstrated positive effects of vitamin D and its analogs on fibrinolysis, blood lipids, thrombogenicity, endothelial regeneration, and smooth-muscle-cell growth. "Together, these findings strongly suggest that 25-hydroxyvitamin D has beneficial effects, some involving the cardiovascular system, that are independent of calcium metabolism," they comment.

Noting that there are few large studies addressing associations of endogenous serum vitamin-D levels with overall and cardiovascular mortality, they set to look at this issue in a large cohort of patients referred for coronary angiography in the LURIC study. All patients underwent detailed baseline examinations, which allowed adjustment for possible confounders.

The 3258 patients included were followed for a median of 7.7 years, during which time 737 patients (22.6%) died, including 463 from cardiovascular causes. Results showed patients in the lower two 25-hydroxyvitamin-D quartiles at baseline (median, 7.6 and 13.3 ng/mL) and those in the lowest 1,25-dihydroxyvitamin-D quartile had a significantly higher risk of all-cause mortality during follow-up.

Similar results were seen for cardiovascular mortality, which was approximately doubled in patients in the lowest quartiles compared with those in the highest quartiles.

Low 25-hydroxyvitamin-D levels were also significantly correlated with markers of inflammation (CRP and IL-6), oxidative burden (serum phospholipid and glutathione levels), and cell adhesion (vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 levels).

Dobnig et al say that these results show that a low 25-hydroxyvitamin-D level can be considered a strong risk indicator for all-cause mortality in women and in men.

They note that while the percentage of patients with low 25-hydroxyvitamin-D values in this study may seem unexpectedly high, with roughly two-thirds of those included having levels below 20 ng/mL, they point out that the mean value of 17.3 ng/mL compares well with values reported from other large trials performed in middle European countries such as France, Italy, and Germany.

The authors also report that the increase in risk of all-cause mortality with lower levels of vitamin D was seen regardless of the degree of coronary artery disease seen on angiography, and they comment: "Low 25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D levels seem to be important mediators of mortality even when there is little or no indication of overt vascular disease."

They say they are unable to tell, based on these results, whether the association between low 25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D levels and mortality is causal or not. But they believe there are a few indications pointing to a possible link. These include the association with elevated inflammatory markers, which suggests these compounds may have anti-inflammatory properties, and the effects related to oxidative stress and increased cell adhesion suggest that low levels of vitamin D may detrimentally affect vascular biologic function in multiple ways.

They add that other mechanisms whereby low vitamin-D levels may be associated with mortality include effects on matrix metalloproteinases, which have been shown to affect plaque production and stability, increased susceptibility to arterial calcification, or an increase in renin messenger-RNA expression.

They conclude: "This prospective cohort study demonstrates for the first time, to our knowledge, that low 25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D levels are associated with increased risk in all-cause and cardiovascular mortality compared with patients with higher serum vitamin-D levels. Both vitamins seem to have synergistic biologic action that is largely independent of each other. . . . Based on the findings of this study, a serum 25-hydroxyvitamin-D level of 20 ng/mL or higher may be advised for maintaining general health."