June 11, 2008 — Further evidence that vitamin-D deficiency may increase the risk of heart disease has come from a new case-control study [1].

The study, published in the June 9, 2008 issue of the Archives of Internal Medicine, found that low levels of 25-dihydroxyvitamin-D (25[OH]D) were associated with a higher risk of myocardial infarction (MI) in a graded manner, even after researchers controlled for factors known to be associated with coronary artery disease.

The authors, led by Dr Edward Giovannucci (Harvard School of Public Health, Boston, MA), note that in most populations studied, the rate of cardiovascular death is elevated at higher latitudes, increases during the winter months, and is lower at high altitudes, a pattern consistent with an adverse effect of low levels of vitamin D, which are more prevalent at higher latitudes, during the winter, and at lower altitudes.

While alternative explanations for these observations are possible, they point out that a variety of plausible biological mechanisms support a role for vitamin D in heart disease. For example, the vitamin-D axis affects vascular smooth-muscle-cell proliferation, inflammation, vascular calcification, the renin-angiotensin system, and blood pressure.

To look at this issue further, they prospectively examined 25(OH)D concentrations in relation to risk of MI in a nested case-control study involving 18,225 men in the Health Professionals Follow-up Study (HPFS). The men were aged 40 to 75 years and were free of diagnosed cardiovascular disease at baseline.

During 10 years of follow-up, 454 men developed nonfatal MI or fatal coronary heart disease (cases), and 900 controls were selected matched for age, date of blood collection, and smoking status.

Results showed that men deficient in 25(OH)D were found to be at increased risk for MI compared with those considered to be sufficient in 25(OH)D (> 30 ng/mL).

Relative risk of nonfatal MI/fatal CHD in men with low levels of 25(OH)D vs those with levels > 30 ng/mL

Level of plasma 25(OH)D at baseline	< 15.0 ng/mL	15.1 - 22.5 ng/mL	22.6 - 29.9 ng/mL	> 30.0 ng/mL	p for trend
Cases/controls (n)	63/87	156/307	165/299	70/207	NA
Analysis 1 (RR, 95% CI)a	2.42 (1.53 - 3.84)	1.65 (1.15 - 2.37)	1.72 (1.22 - 2.42)	1	< 0.001
Analysis 2 (RR, 95% CI)b	2.09 (1.24 - 3.54)	1.43 (0.96 - 2.13)	1.60 (1.10 - 2.32)	1	0.02

a. Matched for age, month and year of blood collection, and smoking status
b. Matched for age, month and year of blood collection, and smoking status and adjusted for family history of MI before age 60, history of diabetes, history of hypertension, alcohol intake, body-mass index, physical activity, region, race, multivitamin use, marine omega-3 intake, fasting status, and high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceride levels

Giovannucci et al emphasize that men with circulating 25(OH)D levels of at least 30 ng/mL had approximately half the risk of MI, independent of other cardiovascular risk factors, and this association was suggestively stronger for fatal CHD, although the number of cases was too small to make definitive conclusions.

They note that only 23% of the men in the HPFS had levels of 25(OH)D of at least 30 ng/mL, which is typical of many populations, and the prevalence of deficiency is even higher in subpopulations such as dark-skinned individuals and elderly persons. In individuals in sun-rich environments, where clothing or cultural practices do not appreciably limit vitamin-D production, 25(OH)D levels of 54 to 90 ng/mL are attained, they report, adding that it is not possible from these data to evaluate whether levels greater than 35 ng/mL would be associated with an even greater MI risk reduction.

While vitamin-D supplementation was not shown to affect cardiovascular risk in the Women's Health Initiative, the authors point out that the range of vitamin-D levels was much narrower in that study, which would have made it more difficult to detect any effect. They say that to increase 25(OH)D levels from 12 to 35.5 ng/mL would require approximately 3000 IU of vitamin D daily, and although such intakes may seem high by current standards, increasing evidence demonstrates no toxic effects at intakes below 10,000 IU/day. Because current sources of vitamin D provide much less (eg, a glass of milk has approximately 100 IU), those who achieve high levels such as 35 ng/mL naturally do so largely through sun exposure, they add.

If the association seen in this study is causal, which remains to be established, the amount of vitamin D required for optimal benefit may be much higher than would be provided by current recommendations (200-600 IU/day), especially in those with minimal sun exposure, Giovannucci et al comment. Thus, the present findings add further support that the current dietary requirements of vitamin D need to be increased to have an effect large enough for potential health benefits, they conclude.

This study was supported by the National Cancer Institute and the National Heart, Lung, and Blood Institute. Two of the study authors have obtained funding. Another study author is a consultant for Diasorin Corp.

Source

1. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men. A prospective study. Arch Intern Med. 2008;168:1174-1180.

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

The rate of cardiovascular disease–related deaths is greater at higher latitudes, lower at higher altitudes, and higher in the winter months — all associations related to vitamin D deficiency. The vitamin D axis affects vascular smooth muscle cell proliferation, inflammation, vascular calcification, the renin-angiotensin system, and blood pressure, all of which affect cardiovascular disease and MI risk, but evidence linking hypovitaminosis D and MI is sparse. Current recommendations for vitamin D are 200 to 600 IU per day, which may be inadequate to prevent cardiovascular disease. However, the largest trial of vitamin D and calcium supplementation, the Women's health Initiative, did not observe a reduction in the risk for MI with supplementation.

This is a nested case-control study within a cohort study of professional men in the HPFS to examine the relationship between serum vitamin D levels measured as 25(OH)D at baseline and the risk for fatal and nonfatal MI at 10 years of follow-up.

Study Highlights

• The HPFS had an inception cohort of 51,529 male healthcare professionals aged 40 to 75 years who returned questionnaires biennially and completed food frequency questionnaires every 4 years.
• Between 1993 and 1995, a blood sample was drawn and 25(OH)D levels measured by EDTA radioimmunoassay in 18,225 men.
• After the blood sample was obtained, a nested cohort of 454 participants with fatal and nonfatal MI were identified and matched to 900 control subjects from the same study without cardiovascular disease.
• The diagnosis of MI was made after self-report on the questionnaires and confirmed with World Health Organization criteria by review of medical records or autopsy findings.
• Deaths were identified from state vital statistics records and the National Death Index or were reported by relatives.
• 352 men had nonfatal and 102 had fatal MI during the follow-up.
• Mean age was 63.8 years, 9% were current smokers, and the majority were white (> 90%) in both the case and control groups.
• Men in the case group had a higher body mass index, lower level of physical activity, and less alcohol intake and were more likely to have a family history of MI before age 60 years vs men in the control group.
• They also had higher levels of total and LDL cholesterol levels and lower HDL cholesterol levels.
• Plasma 25(OH)D levels were significantly lower in men in the case group (23.0 ng/mL) vs men in the control group (24.5 ng/mL; P = .002).
• Men with lower 25(OH)D levels were more likely to be current smokers, less physically active, heavier, and less likely to be white and have a parental history of MI.
• They were less likely to drink alcohol and more likely to live in the northern states.
• The relative risks (RRs) for MI at 10 years of follow-up were significantly increased for men with deficient levels of 25(OH)D, with an unadjusted RR of 2.42 and an adjusted RR of 2.01 (P = .02 for trend).
• The results did not change after the first 2 years of follow-up were excluded.
• Analysis by season-specific quintiles yielded an RR of 1.94 for those in the lowest quintile of 25(OH)D vs those in the highest quintile.
• The risk for MI increased by 2.1% per 1-ng/mL increment in 25(OH)D levels.
• The risk was higher for fatal vs nonfatal MI, but the numbers of cases were not sufficiently high to determine the risks.
• There was no interaction by age, blood pressure, body mass index, alcohol use, LDL cholesterol levels, or triglyceride levels.
• After exclusion of men using statins, the RR for MI in men with hypovitaminosis D remained increased at 2.30.
• Men with circulating 25(OH)D levels of at least 30 ng/mL had half the risk for MI vs those with lower levels independent of other cardiovascular disease risk factors.
• A dose-response pattern was seen, with the lowest levels of 25(OH)D associated with the highest RR for MI (RR of 2.42 for levels < 15.0 ng/mL, 1.65 for levels between 15.1 and 22.5 ng/mL, and 1.72 for levels between 22.6 and 29.9 ng/mL).
• Only 23% of men in the cohort studied had a 25(OH)D level of at least 30 ng/mL.
• The authors noted that the current requirements for vitamin D will need to be increased, especially in those with low sun exposure, to reduce the potential risk for cardiovascular disease among those with hypovitaminosis D.
• For example, to increase 25(OH)D levels from 12.0 to 35.5 ng/mL would require approximately 3000 IU of vitamin D daily.