Circulating levels of vitamin D had no apparent influence on overall risk for cardiovascular disease in older men….
However, there was some evidence for an elevated risk for cerebrovascular events among those with low levels, Eva S. Schernhammer, MD, DPH, of Harvard Medical School, and colleagues reported.
For men whose serum 25(OH) vitamin D levels were below 20 ng/mL, the hazard ratio for any cardiovascular disease event in a fully adjusted model was 0.91 (95% CI 0.73-1.13), while the hazard ratio for coronary artery disease was 0.81 (95% CI 0.61-1.07).
However, among men not taking vitamin D supplements whose levels were beneath that cutoff, the multivariate hazard ratio for a cerebrovascular event was 1.70 (95% CI 1.02-2.83).
Observational studies and meta-analyses have suggested a possible link between vitamin D levels and cardiovascular disease. For instance, in a meta-analysis that included 19 prospective studies and almost 66,000 participants, those with low levels of 25(OH) vitamin D had greater risks of cardiovascular disease, stroke, and coronary heart disease, as well as cardiovascular death. In addition, several lines of evidence support a preventive role for the vitamin, such as through effects on endothelial cells and cardiac myocytes.
The active metabolite of vitamin D is also known to be a negative regulator of the renin-angiotensin system via a vitamin D receptor-regulated mechanism altering renin gene transcription.
The researchers previously found no association among 813 men enrolled in the prospective Osteoporotic Fractures in Men (MrOS) study, which involved almost 6,000 men from six different sites.
In their previous analysis, which followed the men for a median of 4.4 years, those whose circulating vitamin D levels were in the bottom quartile had a hazard ratio of 1.18 (95% CI 0.69-2.03) for developing cardiovascular disease when compared with the top quartile, after adjustment for variables such as age and other cardiovascular risk factors.
The researchers now have extended the analysis to include 3,019 men age 65 and older who had baseline vitamin D levels available and who were followed for a mean of 5.9 years.
In this report, they also conducted secondary analyses to examine the effects of vitamin D supplementation and having a history of cardiovascular disease at the time of enrollment. Vitamin D levels were categorized as being below 20 ng/mL, which represents "the generally accepted definition for vitamin D deficiency," versus 20 ng/mL or higher. Participants’ mean age was 77, and 90% were white.
A total of 2,603 had serum 25(OH) vitamin D levels of 20 ng/mL or higher, while the remaining 416 had levels below this cutoff. Almost half had a history of hypertension, and nearly two-thirds were using supplementary vitamins.
Body mass index was higher in men with low vitamin D levels (28 versus 27 kg/m2, P<0.001), and a history of diabetes was more common (19% versus 12%, P<0.001).
During the follow-up period, 749 of the participants had at least one cardiovascular disease-related event, 503 had one or more events related to coronary heart disease, and 214 had a cerebrovascular event.
Cardiovascular disease events included any incident coronary heart disease, cerebrovascular disease, or peripheral vascular disease. Coronary heart disease events included acute myocardial infarction, congestive heart failure, revascularization, coronary artery bypass surgery, unstable angina requiring hospital admission, and sudden death. Cerebrovascular events were transient ischemic attacks or strokes.
In a model adjusted only for age, race, study site, season, and laboratory batch, no significant association was found for low vitamin D and incident cardiovascular disease, with a hazard ratio of 1.03 (95% CI 0.83-1.27). Similarly, in this minimally adjusted model, no increased risk was seen with vitamin D levels below 20 ng/mL for coronary heart disease compared with the higher range, for a hazard ratio of 0.95 (95% CI 0.73-1.25).
However, a "borderline statistically significant positive association" in this model was seen for cerebrovascular events for men considered to be deficient in circulating vitamin D (HR 1.44, 95% CI 1-2.08). But the association with cerebrovascular events was attenuated in a multivariate analysis (HR 1.34, 95% CI 0.92-1.95). Only in the multivariate analysis excluding men who reported taking vitamin D supplements was there statistical significance.
In contrast, in a multivariate analysis excluding men who used supplements, no association was seen with low vitamin D levels and cardiovascular disease or coronary heart disease (, the researchers reported. They also looked at stroke specifically, finding no significant association even after excluding supplement users. Furthermore, on sensitivity analyses using cutoffs other than 20 ng/mL, neither deficient levels below 20 nor "insufficient" levels between 20 and 30 ng/mL showed an increased risk of cardiovascular events.
And even with severe deficiencies of 12 ng/mL or less, there was no significant elevation of cardiovascular disease compared with levels of 20 ng/mL or higher.
Moreover, no association was found on the multivariate analysis after excluding the 1,265 men who had a history of cardiovascular disease at the time of enrollment.
The finding that there appeared to be a higher risk for cerebrovascular events in men with low vitamin D levels could have been a chance finding, according to the researchers. It’s also possible that the men who reported use of vitamin D may have been taking it as a component of a multivitamin or were also taking other supplements that might lower risk for cerebrovascular disease.
"Vitamin D-containing supplement use could also be a marker of other health behaviors that we did not measure, or measure adequately, that might alter the risk for cerebrovascular events," they wrote.
As to why their results should differ markedly from what was seen in the large meta-analysis, they noted, "As is expressed by the study authors, the meta-analysis is limited by publication bias: positive results are more likely to be published than papers, like ours, showing null findings."
Schernhammer added that, "While our study does not support an association between serum vitamin D levels and risk for cardiovascular events, the significantly higher risk of cerebrovascular disease among men with mild to moderate vitamin D deficiency not using vitamin D supplements warrants further exploration."
- The modest association between low Vitamin D levels and cerebrovascular disease will need to be validated in other studies.
- Note that this large observational cohort study failed to demonstrate a significant association between low vitamin D levels and cardiovascular outcomes.