Vitamin D Deficiency and Cardiovascular Events in Patients With Coronary Heart Disease: Data From the Heart and Soul Study

Christine C. Welles; Mary A. Whooley; S. Ananth Karumanchi; Tammy Hod; Ravi Thadhani; Anders H. Berg; Joachim H. Ix; Kenneth J. Mukamal


Am J Epidemiol. 2014;179(11):1279-1287. 

In This Article

Abstract and Introduction


A growing body of evidence supports an association between vitamin D and cardiovascular disease. However, the mechanisms underlying this association are unknown. From 2000 to 2002, we identified 946 participants with stable cardiovascular disease in San Francisco, California, and followed them prospectively for cardiovascular events (heart failure, myocardial infarction, stroke, or cardiovascular death). We then examined the extent to which the association was attenuated by adjustment for poor health behaviors, comorbid health conditions, and potential biological mediators. During a median follow-up period of 8.0 years (through August 24, 2012), 323 subjects (34.1%) experienced a cardiovascular event. Following adjustment for sociodemographic factors, season of blood measurement, health behaviors, and comorbid conditions, 25-hydroxyvitamin D levels under 20 ng/mL remained independently associated with cardiovascular events (hazard ratio = 1.30, 95% confidence interval: 1.01, 1.67). However, after further adjustment for potential biological mediators, the independent association was no longer present (hazard ratio = 1.11, 95% confidence interval: 0.85, 1.44). Parathyroid hormone, a potentially modifiable biological factor downstream from 25-hydroxyvitamin D, was responsible for the majority of this attenuation. These findings highlight the need for randomized controlled trials to determine whether vitamin D supplementation in persons with deficiency could be beneficial for the primary or secondary prevention of cardiovascular events.


Vitamin D deficiency is highly prevalent; approximately 25%–57% of the US population[1] and more than 1 billion persons worldwide[2] are either insufficient (defined as serum 25-hydroxyvitamin D (25(OH)D) levels of 20–29.9 ng/mL) or deficient (defined as serum 25(OH)D levels under 20 ng/mL) in vitamin D. Several lines of evidence support the hypothesis that vitamin D deficiency may contribute to cardiovascular disease (CVD).[3] Ecological studies have demonstrated a higher burden of hypertension and CVD at greater distances from the equator.[4,5] Observational studies have shown inverse associations between 25(OH)D levels and hypertension,[6,7] body mass index,[8] congestive heart failure,[9,10] myocardial infarction,[11–13] stroke,[12,14] peripheral arterial disease,[15,16] mortality[13,17] and combined cardiovascular events.[18,19] A recent meta-analysis suggested that vitamin D supplementation at moderate-to-high doses may reduce CVD risk.[20]

However, it is unclear whether vitamin D deficiency is simply a marker for poor health or whether this association is mediated by biological changes that increase risk of cardiovascular events. For example, persons with vitamin D deficiency may have comorbid health conditions or poor health behaviors which cause them to stay indoors. Therefore, vitamin D deficiency could simply be a surrogate for poor health. Alternatively, however, a variety of plausible biological mechanisms (blood pressure elevation,[21] insulin resistance,[22] inflammation,[23] obesity,[8] endothelial dysfunction,[24] or vascular remodeling due to hyperparathyroidism[25]) have been proposed by which vitamin D deficiency may cause cardiovascular events.

A better understanding of the mechanisms underlying the association between vitamin D deficiency and CVD would be informative for determining the potential benefit of vitamin D supplementation. If low 25(OH)D levels simply identify persons with poor overall health, vitamin D supplementation is unlikely to be effective in the primary or secondary prevention of CVD. Alternatively, if low vitamin D levels produce biological changes which mediate CVD risk, repletion of vitamin D could have substantial public health benefit. Such relationships may be particularly beneficial in secondary prevention, as the risks of recurrent CVD and death are much higher in populations with established CVD. Therefore, in a population of outpatients with stable coronary heart disease (CHD), we evaluated the association between 25(OH)D levels and cardiovascular events and sought to elucidate the potential mediators underlying this association.