Plasma Ionized Calcium and Risk of Cardiovascular Disease: 106 774 Individuals from the Copenhagen General Population Study

BACKGROUND: Circulating total calcium or albumin-adjusted calcium is a risk factor for cardiovascular disease. As the biologically active ionized calcium is a physiologically more relevant measure and its association with cardiovascular disease is poorly understood, we tested the hypothesis that high plasma ionized calcium is associated with higher risk of myocardial infarction and ischemic stroke in individuals in the general population.

METHODS: We included 106 774 individuals from the Copenhagen General Population Study, and defined hypocalcemia and hypercalcemia by the lowest and highest 2.5 percentiles, respectively, using the central 95% reference interval. Information on myocardial infarction and ischemic stroke was from registries and risks calculated using Cox regression and Fine and Gray competing-risks regression.

RESULTS: During a median follow-up of 9.2 years, 4932 individuals received a diagnosis of either myocardial infarction or ischemic stroke. Hypercalcemia was associated with subdistribution hazard ratios of 1.67 (95%CI: 1.05-2.67) for myocardial infarction, 1.28 (0.81-2.02) for ischemic stroke, and of 1.54 (1.10-2.15) for the combined endpoint compared to individuals with plasma ionized calcium within the reference interval; hypocalcemia was not associated with cardiovascular disease. In models using plasma ionized calcium as a continuous variable, the associations were nonlinear; above the median, each 0.1 mmol/L higher plasma ionized calcium was associated with a hazard ratio of 1.31(1.02-1.68) for myocardial infarction, 1.21 (0.95-1.54) for ischemic stroke, and of 1.28 (1.08-1.53) for the combined endpoint.

CONCLUSIONS: High plasma ionized calcium is associated with higher risk of myocardial infarction and ischemic stroke compared to plasma ionized calcium within the reference interval.