CONTEXT: Cardiovascular disease is the major cause of death in the Western World, but the association between 25-hydroxyvitamin D levels and the risk of cardiovascular disease mortality remains unclear OBJECTIVE: To determine the association between cardiovascular, stroke and acute myocardial infarct mortality and serum levels of 25(OH)D DESIGN: Observational cohort study, the CopD Study, data from a single laboratory center in Copenhagen, Denmark. Follow-up 2004 to 2011 SETTING: Serum 25(OH)D was analyzed from 247,574 subjects from the Copenhagen general practice sector PARTICIPANTS: Examination of the association 25-hydroxyvitamin D levels and mortality from cardiovascular disease, stroke and acute myocardial infarct among 161,428 women and 86,146 men MAIN OUTCOME MEASURES: Multivariate Cox regression analysis was used to compute hazard ratios for cardiovascular, stroke and acute myocardial infarct mortality.

RESULTS: Out of 247,574 a total of 16.645 subjects died in the ensuing 0-7 years. 5,454 died from cardiovascular disease including 1,574 from stroke and 702 acute myocardial infarct. 25-hydroxyvitamin D level of 70 nmol/L was associated with the lowest cardiovascular disease mortality risk. Compared to that level the hazard ratio for cardiovascular disease mortality was 2.0(95% CI 1.8-2.1) at the lower extreme (∼12.5 nmol/L) with higher risk for men 2.5(95% CI 2.2-2.9), than for women 1.7(95% CI 1.5-1.9). At the higher extreme (∼125 nmol/L), the hazard ratio of cardiovascular disease mortality was 1.3(95% CI 1.2-1.4), with similar risk among men and women. Results were similar for stroke and acute myocardial subgroups CONCLUSIONS: In this large observational study low and high levels of 25-hydroxyvitamin D were associated with cardiovascular disease, stroke and acute myocardial mortality in a non-linear, reverse J-shaped manner, with highest risk at lower levels. Whether this was a causal or associational finding cannot be determined from our data. There is a need for randomized clinical trials which include information on the effects of 25-hydroxyvitamin D levels above 100 nmol/L.