Serum 25-hydroxyvitamin D as a Predictor of Mortality and Cardiovascular Events

A 20-Year Study of a Community-Based Cohort

Kun Zhu; Matthew Knuiman; Mark Divitini; Joseph Hung; Ee Mun Lim; Brian R. Cooke; John P. Walsh


Clin Endocrinol. 2018;88(1):154-163. 

In This Article

Abstract and Introduction


Objective Prospective studies, mostly from Europe and North America, suggest that serum 25-hydroxyvitamin D (25(OH)D) is inversely associated with mortality and cardiovascular disease (CVD) risk. Data from other regions are limited, and threshold levels for adverse cardiovascular outcomes are uncertain. We examined serum 25(OH)D as a predictor of total mortality and cardiovascular outcomes in an Australian cohort.

Design A 20-year, community-based cohort study.

Patients Participants in the 1994/1995 Busselton Health Survey (n = 3946, baseline age 25–84 years).

Measurements Baseline serum 25(OH)D and mortality and cardiovascular outcomes to 2014 obtained by record linkage.

Results The mean serum 25(OH)D concentration was 60.6 ± 18.0 nmol/L. During 20-year follow-up (excluding the first 2 years), 889 participants died (including 363 from CVD) and 944 experienced a CVD event (including 242 with heart failure). In the full cohort, controlling for Framingham risk score variables, higher baseline 25(OH)D was associated with significantly reduced all-cause mortality (adjusted HR 0.83 per SD increment of 25(OH)D, 95% CI 0.77–0.90), CVD death (HR 0.85, 95% CI 0.74–0.96) and heart failure (HR 0.81, 95% CI 0.69–0.94), but not CVD events (HR 0.99, 0.92–1.07). In restricted cubic spline regression models, serum 25(OH)D below 65 and 55 nmol/L was associated with higher total mortality and higher CVD mortality/heart failure, respectively. In participants without CVD at baseline (n = 3220), results were similar, but hazard ratios were attenuated and associations with CVD mortality no longer significant.

Conclusions In an Australian community-based cohort, baseline vitamin D levels below 55–65 nmol/L are predictive of all-cause mortality, CVD death and heart failure.


The pivotal role of vitamin D in calcium homoeostasis and bone health is well known. Vitamin D may also have anti-inflammatory and immune-modulating effects, and vitamin D receptors are expressed in many tissues related to cardiovascular health.[1] Several previous cohort studies have shown that low vitamin D status, usually defined as serum 25-hydroxyvitamin D (25(OH)D) below 30 or 50 nmol/L, is associated with increased all-cause mortality.[2–5] Cohort studies of 25(OH)D as a predictor of cardiovascular disease (CVD) mortality and events have been less consistent, with some[2,3] but not others[6,7] finding an association; however, two recent meta-analyses did report a significant association between vitamin D and CVD outcomes.[5,8] For the most part, randomized controlled trials (RCTs) of vitamin D supplementation have reported no effect on cardiovascular risk factors such as blood pressure, arterial stiffness, carotid intima medial thickness or endothelial function.[9] To date, RCTs of vitamin D (alone or with calcium supplementation) have shown no protective effects on CVD events or death.[9–11] However, a number of RCTs had significant limitations which hamper interpretation, including being designed to detect musculoskeletal outcomes such as falls and fracture rather than CVD outcomes, inclusion of participants who were vitamin D replete or did not measure 25(OH)D at baseline, and the heterogeneity in the supplementation dose and interval.[10,12]

It is also possible that vitamin D level is more relevant to particular types of CVD, such as heart failure. In the RECORD trial, where participants received 800 IU vitamin D or placebo daily for 3 years then followed up for a further 3 years, vitamin D supplementation was related to lower risk for cardiac failure, but not MI and stroke.[11] Cardiomyocytes express vitamin D receptors, and there is experimental evidence that vitamin D deficiency results in maladaptive cardiac remodelling and dysfunction.[1,13] However, there have been few longitudinal community-based cohort studies on the association between vitamin D status and heart failure. In addition, most previous studies on vitamin D level and CVD have been carried out in Europe and North America, and there are no previous large prospective studies in the Australian population. The "dose–response" relationship between serum 25(OH)D level and CVD risk is also not well-characterized, and threshold levels for risk are uncertain. Previous studies have suggested a no-linear association and in some cases a reverse J-shaped relationship between vitamin D status and all-cause[14] and cardiovascular mortality,[15] with increased risk at both low and high serum 25(OH)D values, but this remains controversial.

In the Busselton Health 1994/1995 survey cohort of adults aged 25–84 at baseline,[16] complete hospital morbidity and death records for 20 years after the baseline survey are available from the Western Australian Data Linkage System. The aim of this study was to investigate serum 25(OH)D as a predictor of all-cause and CVD mortality, incident CVD and heart failure in this well-characterized general community Australian adult cohort, and to evaluate the "dose–response" relationship between vitamin D status and outcomes.