Vitamin-D Deficiency Now Associated With Increased Mortality
News Author: Sue Hughes
CME Author: Penny Murata, MD
medscape.com
Learning Objectives
Upon completion of this activity, participants will be able to:
Describe the association of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with the risk for cardiovascular mortality.
Describe the association of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with the risk for all-cause mortality.
Authors and Disclosures
Sue Hughes
Disclosure: Sue Hughes has disclosed no relevant financial relationships.
Penny Murata, MD
Disclosure: Penny Murata, MD, has disclosed no relevant financial relationships.
Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.
From Heartwire — a professional news service of WebMD.
June 25, 2008 — 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 Ludwigshafen Risk and Cardiovascular Health (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.
Hazard ratios (95% CI) for all-cause mortality according to 25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D quartiles
Variable Quartile 1 Quartile 2 Quartile 3 Quartile 4
25-hydroxyvitamin D 2.08 (1.60 - 2.70) 1.53 (1.17 - 2.01) 1.24 (0.94 - 1.65) 1 (reference)
1,25-dihydroxyvitamin D 1.61 (1.25 - 2.07) 1.26 (0.97 - 1.64) 1.16 (0.89 - 1.51) 1 (reference)
Adjusted for age, sex, body-mass index, exercise, smoking, diabetes, blood pressure, albumin, cystatin C, triglycerides, N-terminal pro-brain natriuretic peptide, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and use of bronchodilators, aspirin, statins, beta blockers, and angiotensin-converting enzyme (ACE) inhibitors
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 (C-reactive protein [CRP] and interleukin 6 [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."
The LURIC study has received unrestricted grants from sanofi-aventis, Roche, Dade Behring, and AstraZeneca. Two of the study authors have obtained funding.
Source
Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med 2008; 168:1340-1349.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Clinical Context
According to the 13th Workshop Consensus for Vitamin D Nutritional Guidelines reported by Norman and colleagues in the March 2007 issue of the Journal of Steroid Biochemistry and Molecular Biology, the minimum recommended serum level of 25-hydroxyvitamin D is 20 to 30 ng/mL. However, up to 60% of older populations have inadequate vitamin D status. Possible reasons include shifts in demographics, less outdoor activity, air pollution, and decrease in vitamin D production in the skin with age.
In the June 11, 2007, issue of the Archives of Internal Medicine, Martins and colleagues noted that low 25-hydroxyvitamin D levels were associated with cardiovascular risk factors.
Winkelmann and colleagues described the LURIC Study in the February 2001 issue of Pharmacogenomics that investigated the effect of genetic polymorphisms and plasma biomarkers on cardiovascular health status. This prospective cohort study uses the LURIC study population to evaluate the association of endogenous serum vitamin D levels with cardiovascular and all-cause mortality.
Study Highlights
Of 3316 white adults referred to 1 center for coronary angiography, serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were available for 3258 (98.3%) patients.
Mean age was 62 years (SD, 10 years).
Exclusion criteria were acute illness other than acute coronary syndrome, noncardiac chronic disease, and history of malignant neoplasm in the previous 5 years.
78 (2.4%) patients who took vitamin supplements had slightly higher 25-hydroxyvitamin D levels and similar age, parathyroid hormone levels, and 1,25-dihydroxyvitamin D levels vs the rest of the cohort.
The most common indications for coronary angiography were clinical symptoms or myocardial ischemia according to noninvasive test results.
Fasting venous blood specimens were done the morning before angiography.
Classification of death as cardiovascular or noncardiovascular was based on death certificate.
Median follow-up was 7.7 years.
Of 737 deaths, 463 (62.8%) were from cardiovascular causes, 251 (34.1%) were from noncardiovascular causes, and 23 (3.1%) were unclassified.
Of 437 deaths in patients with coronary artery disease, 319 were from cardiovascular causes and 148 from noncardiovascular causes.
On the basis of 202 to 358 measurements obtained each month, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were categorized into quartiles.
The lowest 25-hydroxyvitamin D level occurred in March (mean, 12.0 ng/mL) and the highest level in August (mean, 22.7 ng/mL).
Parathyroid hormone levels increased with increasing 25-hydroxyvitamin D levels of more than 20 ng/mL.
The lowest 25-hydroxyvitamin D quartile group had higher mean age, more women, and more comorbidities.
Analysis included adjustment for age; sex; body mass index; physical exercise level; smoker status; diabetes mellitus; systolic and diastolic blood pressures; albumin, cystatin C, triglyceride, and N-terminal pro-brain natriuretic peptide levels; LDL and HDL cholesterol levels; and use of bronchodilators, aspirin, statins, beta-blockers, and ACE inhibitors.
All-cause mortality was higher in patients in the 2 lowest 25-hydroxyvitamin D quartiles with median levels of 7.6 ng/mL (hazard ratio, [HR], 2.08; 95% confidence interval [CI], 1.60 - 2.70) and 13.3 ng/mL (HR, 1.53; 95% CI, 1.17 - 2.01) vs highest quartile with median level of 28.4 ng/mL.
All-cause mortality was higher in patients in the lowest 1,25-dihydroxyvitamin D quartile with median level of 20.9 pg/mL (HR, 1.61; 95% CI, 1.25 - 2.07) vs highest quartile with median level of 50.8 pg/mL.
Cardiovascular mortality was higher in patients in the 2 lowest 25-hydroxyvitamin D quartiles (HR, 2.22; 95% CI, 1.57 - 3.13 and HR, 1.82; 95% CI, 1.29 - 2.58) vs highest quartile.
Cardiovascular mortality was also higher in patients in the lowest 1,25-dihydroxyvitamin D vs highest quartile.
Correlation between 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels was weak.
2190 (67.3%) patients had significant coronary artery disease, defined by at least 50% stenosis on at least 1 of 15 segments of 3 major coronary arteries.
693 patients had less than 20% stenosis.
All-cause mortality was higher for lower 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D quintiles even in patients with less than 50% or more than 20% stenosis.
Low 25-hydroxyvitamin D quartiles correlated with cardiovascular risk markers:
Inflammatory markers: higher CRP and IL-6 levels
Cell adhesion markers: higher intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 levels
Oxidative stress markers: lower glutathione and phospholipid levels
Pearls for Practice
Adults with levels in the lower 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D quintiles are at increased risk for cardiovascular mortality.
Adults with levels in the 2 lowest 25-hydroxyvitamin D quintiles and the lowest 1,25-dihydroxyvitamin D quintile are at increased risk for all-cause mortality regardless of the extent of coronary artery disease. |
