Plasma Calcium as a Predictor of Cardiovascular Disease
Objective Primary hyperparathyroidism and calcium supplementation have been linked to cardiovascular outcomes. The study objective was to examine plasma calcium as a predictor of cardiovascular disease in the general population, as results from previous cohort studies are conflicting.
Design, participants and measurements Plasma calcium was measured in 4003 participants (aged 25–84 years) in the 1994/1995 Busselton Health Survey. Using a Cox proportional hazards model, we examined albumin-corrected calcium as a predictor of total mortality, cardiovascular mortality and cardiovascular events up to the end of 2010.
Results At baseline, there were significant positive relationships between plasma calcium and each of body mass index, systolic and diastolic blood pressure, glucose and total cholesterol. During the follow-up period, 666 participants died (278 from cardiovascular disease) and 652 had incident cardiovascular events. After adjustment for age and sex, each additional 0·1 mm of albumin-corrected calcium at baseline was associated with a hazard ratio (HR) of 1·09 [95% confidence interval (CI) 0·99, 1·20; P = 0·062] for total mortality, 1·06 (95% CI 0·92, 1·23;P = 0·41) for cardiovascular mortality and 1·13 (95% CI 1·03, 1·24; P = 0·012) for cardiovascular events. These associations were attenuated by further adjustment for standard cardiovascular risk factors with HR 1·03 (95% CI 0·94, 1·14), 0·99 (95% CI 0·86, 1·16) and 1·05 (95% CI 0·95, 1·15), respectively.
Conclusion After adjustment for age and sex, plasma calcium is a predictor of cardiovascular events. This appears to be mediated by conventional cardiovascular risk factors, and calcium is not an independent predictor of cardiovascular disease.
In healthy individuals, circulating concentrations of calcium are tightly regulated by homeostatic mechanisms involving the calcium-sensing receptor, parathyroid hormone and 1,25-dihydroxyvitamin D, and disorders of calcium homeostasis are associated with a range of adverse clinical outcomes, including cardiovascular disease. Hypercalcaemia caused by primary hyperparathyroidism is associated with hypertension and cardiovascular dysfunction, and several cohort studies (though not all) report an increased risk of cardiovascular disease. In cohort studies of patients with end-stage renal failure, serum calcium is a predictor of cardiovascular outcomes, such that each additional 0·25 mm of calcium at baseline is associated with a 15% increase in cardiovascular mortality. The pathophysiology of chronic kidney disease is complex, however, and the contribution of circulating calcium to cardiovascular risk is difficult to tease out from those of phosphate, vitamin D and parathyroid hormone.
It is uncertain whether circulating calcium concentrations are a predictor of cardiovascular risk in the general population, and in particular, whether the small differences in calcium which exist between normocalcaemic individuals are associated with differing risks of cardiovascular disease. Cohort studies have yielded conflicting results: in three studies of Swedish men, plasma calcium was a predictor of total mortality, cardiovascular mortality and myocardial infarction, whereas in the Framingham Study and the Atherosclerosis Risk in Communities (ARIC) Study, calcium was not a predictor of cardiovascular disease in age- and sex-adjusted or multivariable-adjusted models. The conflicting results from these studies may reflect demographic differences between participants or differences in analysis, such as adjustment for covariates. The latter is important because plasma calcium is significantly associated with cardiovascular risk factors including body mass index (BMI), blood pressure, glucose, cholesterol and insulin resistance.
Interest in this area has been rekindled by two meta-analyses suggesting that calcium supplementation increases the risk of cardiovascular disease in older women, although this remains controversial. The putative mechanism includes an increase in circulating calcium concentrations after ingestion of calcium supplements, and in a recent study of women who were all taking calcium and vitamin D supplements, serum calcium was an independent predictor of cardiovascular events. In view of the conflicting evidence as to whether plasma calcium is a predictor of cardiovascular outcomes in the general population, we examined this in a well-characterized, community-based cohort.
Abstract and Introduction
Abstract
Objective Primary hyperparathyroidism and calcium supplementation have been linked to cardiovascular outcomes. The study objective was to examine plasma calcium as a predictor of cardiovascular disease in the general population, as results from previous cohort studies are conflicting.
Design, participants and measurements Plasma calcium was measured in 4003 participants (aged 25–84 years) in the 1994/1995 Busselton Health Survey. Using a Cox proportional hazards model, we examined albumin-corrected calcium as a predictor of total mortality, cardiovascular mortality and cardiovascular events up to the end of 2010.
Results At baseline, there were significant positive relationships between plasma calcium and each of body mass index, systolic and diastolic blood pressure, glucose and total cholesterol. During the follow-up period, 666 participants died (278 from cardiovascular disease) and 652 had incident cardiovascular events. After adjustment for age and sex, each additional 0·1 mm of albumin-corrected calcium at baseline was associated with a hazard ratio (HR) of 1·09 [95% confidence interval (CI) 0·99, 1·20; P = 0·062] for total mortality, 1·06 (95% CI 0·92, 1·23;P = 0·41) for cardiovascular mortality and 1·13 (95% CI 1·03, 1·24; P = 0·012) for cardiovascular events. These associations were attenuated by further adjustment for standard cardiovascular risk factors with HR 1·03 (95% CI 0·94, 1·14), 0·99 (95% CI 0·86, 1·16) and 1·05 (95% CI 0·95, 1·15), respectively.
Conclusion After adjustment for age and sex, plasma calcium is a predictor of cardiovascular events. This appears to be mediated by conventional cardiovascular risk factors, and calcium is not an independent predictor of cardiovascular disease.
Introduction
In healthy individuals, circulating concentrations of calcium are tightly regulated by homeostatic mechanisms involving the calcium-sensing receptor, parathyroid hormone and 1,25-dihydroxyvitamin D, and disorders of calcium homeostasis are associated with a range of adverse clinical outcomes, including cardiovascular disease. Hypercalcaemia caused by primary hyperparathyroidism is associated with hypertension and cardiovascular dysfunction, and several cohort studies (though not all) report an increased risk of cardiovascular disease. In cohort studies of patients with end-stage renal failure, serum calcium is a predictor of cardiovascular outcomes, such that each additional 0·25 mm of calcium at baseline is associated with a 15% increase in cardiovascular mortality. The pathophysiology of chronic kidney disease is complex, however, and the contribution of circulating calcium to cardiovascular risk is difficult to tease out from those of phosphate, vitamin D and parathyroid hormone.
It is uncertain whether circulating calcium concentrations are a predictor of cardiovascular risk in the general population, and in particular, whether the small differences in calcium which exist between normocalcaemic individuals are associated with differing risks of cardiovascular disease. Cohort studies have yielded conflicting results: in three studies of Swedish men, plasma calcium was a predictor of total mortality, cardiovascular mortality and myocardial infarction, whereas in the Framingham Study and the Atherosclerosis Risk in Communities (ARIC) Study, calcium was not a predictor of cardiovascular disease in age- and sex-adjusted or multivariable-adjusted models. The conflicting results from these studies may reflect demographic differences between participants or differences in analysis, such as adjustment for covariates. The latter is important because plasma calcium is significantly associated with cardiovascular risk factors including body mass index (BMI), blood pressure, glucose, cholesterol and insulin resistance.
Interest in this area has been rekindled by two meta-analyses suggesting that calcium supplementation increases the risk of cardiovascular disease in older women, although this remains controversial. The putative mechanism includes an increase in circulating calcium concentrations after ingestion of calcium supplements, and in a recent study of women who were all taking calcium and vitamin D supplements, serum calcium was an independent predictor of cardiovascular events. In view of the conflicting evidence as to whether plasma calcium is a predictor of cardiovascular outcomes in the general population, we examined this in a well-characterized, community-based cohort.
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