In this community-based cohort of ambulatory older adults without clinical cardiovascular disease, lower serum 25-OHD concentrations were associated with all-cause mortality and incident myocardial infarction, whereas higher serum PTH concentrations were associated with incident heart failure. We did not detect an interaction of 25-OHD and PTH on cardiovascular outcomes in this study population. This study has several important strengths, which include a generally healthy study population that was free of clinical cardiovascular disease at baseline, more than twice the length of follow-up compared to previous studies, a large number of adjudicated cardiovascular events and cardiovascular causes of death, and the use of standardized methods to assess mineral metabolism markers, cardiovascular risk factors, kidney function, and co-morbid conditions.
In middle-aged populations, lower 25-OHD concentrations are associated with incident myocardial infarction and all cause mortality.20, 25, 26
Associations of lower 25-OHD concentrations with cardiovascular death, defined using administrative codes, have recently been reported in older populations from the United States and Europe.27, 28
However, diagnosis codes and/or death certificate data are known to misclassify cardiovascular events and causes of death in older people.29, 30
We found higher serum PTH levels to be associated with an estimated 18% greater risk of cardiovascular death; however, this result was not statistically significant (95% confidence interval 0.92, 1.50). In contrast, Hagström et al
. reported a statistically significant association of higher PTH concentrations with cardiovascular death among older Swedish men.31
The relatively healthy make-up of our study populations and more specific definition of cardiovascular death in CHS may have reduced study power to detect associations with this outcome.
Lower serum 25-OHD concentrations represent decreased vitamin D stores, whereas serum PTH excess reflects, in part, inadequate biologic vitamin D activity.5, 32, 33
Based on these relationships, we hypothesized that associations of lower 25-OHD concentrations with cardiovascular outcomes would be strongest in the presence of concomitant PTH excess. However, our findings do not support such an interaction. Moreover, 25-OHD and PTH concentrations tended to be associated with different cardiovascular outcomes in this study. These findings are more compatible with the hypothesis that 25-OHD and PTH might influence cardiovascular risk through divergent pathways.
The biologic actions of 25-OHD and PTH may explain their associations with myocardial infarction and heart failure. In previous studies, lower 25-OHD concentrations are associated with metabolic risk factors for atherosclerosis, including diabetes, hypertension, and inflammation.34–36
Cell culture studies and in vivo
animal models demonstrate immunomodulatory actions of vitamin D,8, 37
and vitamin D increases insulin receptor expression and insulin responsiveness for glucose transport in cultured human promonocytic cells.38
Hyperparathyroidism a state of chronic PTH excess, has been linked with arterial stiffness and hypertension. The prevalence of hypertension among individuals with primary hyperparathyroidism ranges from 30 to 70%, and blood pressure decreases following surgical parathyroidectomy.39–41
PTH exerts a trophic effect on cardiomyocytes, with an increase in total cellular mass, and higher serum PTH concentrations are associated with left ventricular hypertrophy in the general population.11, 42
These observational data cannot prove that 25-OHD deficiency or PTH excess play causal roles in the development of cardiovascular disease. These serologic markers may be indicators of health status, in particular 25-OHD deficiency, which may reflect co-morbidity, less time spent outdoors, and inadequate nutrient intake. We attempted to address potential confounding in this study by excluding individuals with pre-existing cardiovascular diseases and by adjusting for lifestyle factors, co-morbidity, and cardiovascular risk factors that were measured using uniform methods. Adjusted models included some factors that could reside on the hypothesized causal pathway between mineral metabolism disturbances and cardiovascular events, such as hypertension, diabetes, and inflammation. Adjustment for estimated GFR using cystatin C levels was particularly important for appreciating the confounding influence of kidney function on the associations of PTH with cardiovascular mortality. A rise in serum PTH is one of the first detectable mineral metabolism disturbances of chronic kidney disease,43
which is highly prevalent in older adults and may be difficult to detect using traditional serologic markers.
A second limitation of this study is the use of a single measurement of 25-OHD and PTH later in life. Biologic variation in these markers within an individual over time is expected. The prospective design of this study favors non-differential misclassification of 25-OHD and PTH concentrations, which would be expected to dilute the observed associations. Future studies of mineral metabolism markers and cardiovascular disease outcomes would benefit from multiple measurements within an individual over time. CHS focused exclusively on older adults; associations of mineral metabolism markers with cardiovascular events may differ in younger and more ethnically diverse populations.
Consistent associations of 25-OHD concentrations with cardiovascular outcomes across multiple cohort studies and compelling biologic evidence for a beneficial effect of vitamin D on cardiovascular health support clinical trials of vitamin D therapy as the next step to test whether observed associations are truly causal. Associations of PTH excess with cardiovascular diseases are emerging and motivate further epidemiological work in diverse populations to better understand functional relationships and to determine specific populations in which associations may be strongest.