This study retrospectively analyzed the association between corrected sCa levels and in-hospital mortality in patients with AMI. To analyze the in-hospital survival of 7284 patients with AMI, we found a U-shaped association between patients' corrected sCa levels on admission and in-hospital mortality. The results suggest that both high and low corrected sCa levels are associated with a higher risk of in-hospital mortality (Corrected sCa < 9.4 mg/dL, OR 0.8, 95% CI 0.7–0.9, P < 0.001; corrected sCa > 9.4 mg/dL, OR 1.5, 95% CI 1.3–1.8, P < 0.001).
Our findings are consistent with Shiyovich A et al.’s recent studies5 reported a significant U-shaped association between corrected sCa and in-hospital death, with corrected sCa ≤ 9.12 mg/dL and ≥ 9.86 mg/dL as independent predictors of significantly increased in-hospital mortality. Shiyovich A et al. retrospectively analyzed the relationship between corrected sCa and in-hospital mortality in 11,446 AMI patients and drew a broken line graph. In addition, multiple studies have found that high serum calcium levels are associated with higher in-hospital mortality10,11,15. Our study draws a precise smooth curve and identifies the inflection point of the curve (corrected sCa = 9.4 mg/dL), which further elucidates the relationship between serum calcium and in-hospital mortality in patients with AMI. A meta-analysis of prospective cohort studies16 found a U-shaped relationship between dietary calcium intake and cardiovascular mortality (Inflection point of calcium intake = 800 mg/day), which may correspond to our study.
The relationship between serum calcium and in-hospital mortality in patients with myocardial infarction remains controversial. In a 2021 study by Timo Schmitz et al., low serum calcium is associated with higher long-term mortality in patients with AMI, whereas high serum calcium was not4. Consistent with Timo Schmitz et al., multiple previous studies have not found that high serum calcium is associated with an increased risk of in-hospital mortality in patients with AMI8,9,17. An eight-year, single-center study in China6 found that higher serum calcium was associated with a lower risk of in-hospital death (N = 1431; Q1: <8.56 mg/dL, Q2: 8.56-9 mg/dL, Q3: 9-9.44 mg/dL, Q4: ≥9.44 mg/dL). Thus, studies that are inconsistent with our study are not uncommon. We speculate that the main reasons for the different results are: (1) the study population is different; (2) the adjusted variables are different; (3) the statistical methods used are different. However, it is worth noting that our data include more hypercalcemia patients (Q4: corrected serum calcium ≥ 10.5 mg/dL, N = 296) because our study mainly focused on severe cases from American ICU. Therefore, our data may be more representative.
The mechanism responsible for the U-shaped relationship between serum calcium levels and in-hospital mortality in AMI patients is unclear. Several mechanisms may explain that low serum calcium is associated with higher in-hospital mortality in patients with AMI: (1) Serum calcium levels are directly related to the electrophysiological characteristic of the cardiomyocyte membrane. Low serum calcium may cause delayed closure of calcium channels, leading to prolonged plateaus17. In addition, patients with low serum calcium levels are more prone to ventricular arrhythmias and cardiac arrest18,19. (2) Low serum calcium is associated with multiple cardiovascular risk factors such as hypertension and left ventricular systolic dysfunction20,21. (3) Low calcium may lead to reversible heart failure and cardiomyopathy22,23. The mechanisms by which hypercalcemia leads to higher in-hospital mortality in patients with AMI may include the following: (1) High serum calcium levels may lead to subendothelial calcium deposition, leading to atherosclerosis1,24. (2) High serum calcium is associated with vascular calcification by binding to calcium-sensing receptors and inducing mineralization of smooth muscle cells5,25. (3) High serum calcium level increases the risk of heart failure, stroke, and type 2 diabetes mellitus10,20,26,27. One possibility deserves our attention: AMI leads to changes in serum calcium. However, this possibility is minimal because many prospective studies have found an association between serum calcium and in-hospital mortality in patients with AMI28–30.
Whether calcium supplementation can improve prognosis in patients with AMI remains controversial3,31−34. However, it is worth noting that research in recent years has shown that calcium intake from the diet can benefit cardiovascular health. A geospatial analysis found an inverse association between high calcium spring water and cardiovascular mortality, citing waters with high calcium content as cardiovascular protective35. Multiple studies on drinking water have found the same result36,37. A meta-analysis found a U-shaped relationship between dietary calcium intake and cardiovascular mortality, and calcium intake ≥ 800 mg/d is associated with increased cardiovascular risk. Therefore, supplementing calcium in the diet may be beneficial, but only in moderation. In contrast, calcium intake from calcium supplements was seemly associated with an increased risk of cardiovascular death24,38−40. An IVUS study by Najdat Bazarbashi et al. found that oral calcium supplements may increase calcium deposition in coronary vessels, leading to poor prognosis41. The mechanism of oral calcium supplements increasing cardiovascular risk is unclear, likely associated with the sudden increase in serum calcium. However, it is worth noting that the symptoms of severe AMI patients with low serum calcium significantly improved after calcium supplementation5. Based on these controversies, our study has great clinical value for managing patients with AMI. For the first time, our study demonstrated the U-shaped association between corrected serum calcium and in-hospital mortality in AMI patients with a smooth curve and identified the inflection point of the curve (corrected sCa = 9.4 mg/dL). Clinicians can refer to our findings to formulate calcium supplementation strategies for AMI patients, thereby reducing patient mortality.
This study has the following advantages: (1) The sample size is relatively large, and the serum calcium level of the patients was corrected using albumin, which makes the results more reliable; (2) The population of this study is critically ill patients from the ICU of the United States including more patients with abnormal serum calcium; therefore, our data are more representative; (3) This study is the first time to show the relationship between serum calcium and in-hospital death in AMI patients with a smooth curve and to determine the inflection point of the curve, which has an immense clinical value. However, this study excluded patients other than AMI and may not apply to all populations. In addition, due to the nature of observational studies, we can only observe associations, not causality. Our data come from critically ill patients in US ICUs with complex conditions. Although we have adjusted for confounders that may have been associated with the results, we cannot rule out some undocumented confounders confounding the results. Therefore, it is necessary to conduct higher-level clinical studies in more populations in the future to validate our findings.