Association between serum calcium level and in-hospital mortality in patients with acute myocardial infarction: a retrospective cohort study

DOI: https://doi.org/10.21203/rs.3.rs-2099763/v1

Abstract

The association between serum calcium levels and the prognosis of patients with acute myocardial infarction (AMI) remains controversial.  This study aimed to explore the association between serum calcium and in-hospital mortality in patients with AMI.  A total of 7284 patients were eventually enrolled in this study, of which 799 (10.97%) died during hospitalization.  For each patient, serum calcium, corrected to albumin, was calculated and categorized into four groups: Q1 ≤8.5, Q2 8.5-9.5, Q3 9.5-10.5, and Q4 >10.5 mg/dL.  Multivariate analysis demonstrated that corrected sCa was an independent predictor of in-hospital death (Q2 vs. Q1, OR 0.5, 95% CI 0.4-0.7, P<0.001; Q3 vs. Q1, OR 0.8, 95% CI 0.6-1.0, P=0.035; Q4 vs. Q1, OR 1.6, 95% CI 1.1-2.3, P=0.008). The association remained stable in the fully adjusted model. A significant U-shaped association between corrected serum calcium and in-hospital mortality was observed in piecewise linear regression model (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). In conclusion, both decreased and increased corrected serum calcium is associated with increased in-hospital mortality in patients with AMI, and patients may have the lowest risk of in-hospital death when corrected serum calcium is 9.4 mg/dL (2.35mmol/L).

Backgrounds

Calcium is the most abundant mineral in the human body, 99% of which is stored in bones and teeth1,2. Calcium homeostasis is critical for maintaining normal muscle contractility, vascular tone, and electrical signaling1. An increasing number of people take calcium supplements as they are able to prevent osteoporosis and fractures3. Recently, a rising body of studies has suggested that serum calcium levels are associated with cardiovascular disease, and low serum calcium is associated with higher mortality in patients with acute myocardial infarction (AMI)4–7. However, the relationship between high serum calcium and mortality in patients with AMI is controversial5,6,8−11. The clear association between serum calcium levels and in-hospital mortality in patients with AMI has not been identified. This study further explored the association between serum calcium and in-hospital mortality in a large cohort of patients with AMI. For the first time, we presented a U-shaped relationship between corrected serum calcium levels and in-hospital mortality in patients with AMI in the form of a smooth curve and identified the inflection points of the curve.

Methods

Data source

The data of this study were extracted from the eICU Collaborative Research Database. The database was a multi-center intensive care unit (ICU) database for over 200,000 admissions in 2014 and 2015 from 335 ICUs in 208 hospitals in America12. This database consists of vital sign measurements, care plans, the severity of illness measures, laboratory tests, diagnosis information, treatment information, and more. In order to access the eICU Collaborative Database, you must first register. After the registration application has been approved, the data will be disclosed. If the protocol is approved, the data can be directly downloaded from the eICU Collaborative Database (http://eicu-crd.mit.edu). The Massachusetts Institute of Technology (Cambridge, MA) approved this data collection and waived informed consent requirements. This study's first author (Dingfeng Fang) has approved access to the eICU Collaborative Database (certification number: 50924352). The authors are grateful to the original study group for providing data for the current analysis. The study report follows the broad EQUATOR guidelines13. All methods in our study were performed under the Declaration of Helsinki.

Study design and participants

This study is a retrospective cohort study based on the eICU Collaborative Research Database (N = 200859). Patients with a diagnosis of AMI were included (N = 9884). All AMI patients were continuously enrolled unless: (1) serum calcium level was unrecorded; (2) albumin level was unrecorded. 7284 AMI patients were included in the final data analysis. The details of inclusions and exclusions were showed in Fig. 1.

Outcome and data collection

The primary clinical outcome of this study was all-cause in-hospital death. To make the data more reliable, serum calcium (mg/ml) was corrected to albumin (g/dL) using the Payne formula: corrected serum calcium (corrected sCa) = Serum calcium + 0.8×(4.0 - albumin)14. Demographic data, medical history, laboratory tests, and treatment information were extracted from the database.

Statistical analyses

Each patient's corrected sCa was calculated and categorized into four groups: ≤8.5, 8.5–9.5, 9.5–10.5, and > 10.5 mg/dL. Normally distributed continuous variables were presented as mean ± SD. Skewed distributed continuous variables were presented as median [interquartile range]. The categorical variables were presented as numbers (n) and percentages (%). The characteristics of this study population according to the corrected serum calcium levels were compared using a Kruskal–Wallis test or one-way analysis of variance (ANOVA) for continuous variables and a Chi-Square test for categorical variables.

We performed a univariate analysis to detect the possible risks associated with in-hospital death. Multiple logistic regression models were performed to evaluate the association between corrected calcium and in-hospital death. Multivariate adjusted models were applied as well as non-adjusted models. The adjusted confounders were selected basis on their association with the primary outcome. Different stratification was adjusted for different numbers of confounding variables. Furthermore, the threshold effect of corrected sCa on in-hospital death was explored using piecewise linear regression according to the smoothing plot.

A P value less than 0.05 was considered significant for all tests. Analysis was performed using the statistical software packages R (http://www.Rproject.org, The R Foundation) and Empower Stats (http://www.empowerstats.com, X&Y Solutions, Inc., Boston, MA).

Results

Baseline characteristics of the study population

As shown in Fig. 1, among the 200859 patients from the eICU Collaborative Research Database, 193575 patients were excluded based on exclusion criteria. A total of 7284 patients were eventually enrolled in our study, of which 799 (10.97%) died in hospital. Patients were classified into four groups according to corrected sCa: Q1 (≤ 8.5 mg/dL), Q2, (8.5-≤9.5 mg/dL), Q3 (9.5-≤10.5 mg/dL), Q4 (> 10.5 mg/dL). Table 1 describes the baseline data for all patients and patients stratified by corrected sCa levels. Participants with higher corrected sCa levels were older, female predominant, and more likely to have atrial fibrillation, chronic renal insufficiency, COPD, and diabetes, while the patients with lower corrected sCa were more likely to have a cardiac arrest.

Table 1

Characteristics of study patients

Characteristics

  

Corrected serum calcium, mg/dL

Overall

Q1, ≤ 8.5

Q2, 8.5-≤9.5

Q3, 9.5-≤10.5

Q4, > 10.5

P-value

N

7284

599

4099

2290

296

  

In-hospital death, n (%)

799 (10.97%)

92 (15.5%)

362 (8.9%)

278 (12.2%)

67 (22.7%)

< 0.001

STEMI, n (%)

3305 (45.4%)

286 (47.7%)

1839 (44.9%)

1050 (45.9%)

130 (43.9%)

0.846

Demographics

Age, years

66.8 ± 13.3

64.3 ± 13.3

66.1 ± 13.4

68.5 ± 13.0

69.6 ± 12.2

< 0.001

Female, n (%)

2736 (37.6%)

196 (32.7%)

1356 (33.1%)

1028 (44.9%)

156 (52.7%)

< 0.001

BMI, kg/m2

27.5 ± 7.0

27.8 ± 6.8

27.5 ± 6.9

27.4 ± 7.2

26.6 ± 7.8

0.118

Medical history

Atrial fibrillation, n (%)

706 (9.7%)

69 (11.5%)

339 (8.3%)

261 (11.4%)

37 (12.5%)

< 0.001

Cardiac arrest, n (%)

544 (7.5%)

100 (16.7%)

281 (6.9%)

136 (5.9%)

27 (9.1%)

< 0.001

Cardiac surgery, n (%)

547 (7.5%)

53 (8.8%)

319 (7.8%)

157 (6.9%)

18 (6.1%)

0.234

CRI, n (%)

130 (1.8%)

6 (1.0%)

64 (1.6%)

44 (1.9%)

16 (5.4%)

< 0.001

COPD, n (%)

491 (6.7%)

40 (6.7%)

240 (5.9%)

180 (7.9%)

31 (10.5%)

0.001

Hypertension, n (%)

1149 (15.8%)

78 (13.0%)

648 (15.8%)

389 (17.0%)

34 (11.5%)

0.018

Diabetes mellitus, n (%)

1112 (15.3%)

76 (12.7%)

559 (13.6%)

422 (18.4%)

55 (18.6%)

< 0.001

Stroke, n (%)

214 (2.9%)

19 (3.2%)

113 (2.8%)

76 (3.3%)

6 (2.0%)

0.455

Tumour, n (%)

52 (0.7%)

2 (0.3%)

27 (0.7%)

20 (0.9%)

3 (1.0%)

0.459

Laboratory tests

Serum calcium, mg/dL

8.8 ± 0.8

7.5 ± 1.1

8.7 ± 0.6

9.2 ± 0.6

10.2 ± 1.0

< 0.001

Albumin, g/dL

3.4 ± 0.7

3.3 ± 0.7

3.5 ± 0.6

3.2 ± 0.7

2.8 ± 0.7

< 0.001

Corrected sCa, mg/dL

9.3 ± 0.7

8.0 ± 0.8

9.1 ± 0.3

9.9 ± 0.3

11.1 ± 0.9

< 0.001

Hemoglobin, g/dL

12.7 ± 2.6

12.3 ± 2.6

12.9 ± 2.5

12.6 ± 2.6

11.9 ± 2.8

< 0.001

TC, mg/dL

159.7 ± 48.2

150.4 ± 47.6

161.0 ± 47.3

159.8 ± 49.9

153.2 ± 48.8

< 0.001

LDL-C, mg/ml

87.9 ± 34.0

81.7 ± 34.3

89.6 ± 34.0

86.8 ± 34.0

80.4 ± 33.5

0.002

HDL-C, mg/ml

39.9 ± 14.0

37.4 ± 14.3

40.0 ± 13.6

40.3 ± 14.5

40.6 ± 15.1

0.015

Treatment

Lipid-lowering drugs, n (%)

853 (11.7%)

66 (11.0%)

503 (12.3%)

259 (11.3%)

25 (8.4%)

0.177

Antiplatelet, n (%)

2304 (31.6%)

183 (30.6%)

1347 (32.9%)

709 (31.0%)

65 (22.0%)

< 0.001

Anticoagulants, n (%)

1594 (21.9%)

100 (16.7%)

928 (22.6%)

516 (22.5%)

50 (16.9%)

0.001

Nitroglycerin, n (%)

1348 (18.5%)

83 (13.9%)

778 (19.0%)

451 (19.7%)

36 (12.2%)

< 0.001

Mechanical ventilation, n (%)

1716 (23.6%)

231 (38.6%)

898 (21.9%)

507 (22.1%)

80 (27.0%)

< 0.001
STEMI, ST-segment elevation myocardial infarction; BMI, body mass index; CRI, chronic renal insufficiency; COPD, chronic obstructive pulmonary disease; Corrected sCa, corrected serum calcium; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

 

The association between serum calcium and mortality

The details of univariate analysis in Table 2 showed that age, being female, BMI, hemoglobin, TC, LDL-C, HDL-C, history of atrial fibrillation, cardiac arrest, CRI, COPD, hypertension, diabetes mellitus, stroke or tumor, and treatment with antiplatelet, nitroglycerin or mechanical ventilation were strongly correlated with the in-hospital death. Table 3 illustrated that multivariate analysis demonstrated that corrected sCa was an independent predictor of in-hospital death. In the Model 1 (non-adjusted model), the risk of in-hospital mortality first decreased and then increased with increasing corrected sCa (categorical variable: Q2 vs. Q1, OR 0.5, 95% CI 0.4–0.7, P < 0.001; Q3 vs. Q1, OR 0.8, 95% CI 0.6-1.0, P = 0.035; Q4 vs. Q1, OR 1.6, 95% CI 1.1–2.3, P = 0.008). After adjusting for age, sex, BMI, and chronic renal insufficiency, the association between corrected sCa and in-hospital death was consistent with Model 1 (categorical variable: Q2 vs. Q1, OR 0.5, 95% CI 0.4–0.7, P < 0.001; Q3 vs. Q1, OR 0.7, 95% CI 0.5–0.9, P = 0.003; Q4 vs. Q1, OR 1.2, 95% CI 0.8–1.7, P = 0.425). Furthermore, this association remained stable when age, sex, BMI, chronic renal insufficiency, COPD, diabetes mellitus, stroke, tumor, hemoglobin, TC, LCL-C, HDL-C, lipid-lowering drugs, antiplatelet, anticoagulants, and nitroglycerin were adjusted in Model 3 (categorical variable: Q2 vs. Q1, OR 0.4, 95% CI 0.2–0.7, P = 0.001; Q3 vs. Q1, OR 0.5, 95% CI 0.5–0.5, P = 0.009; Q4 vs. Q1, OR 0.9, 95% CI 0.4-2.0, P = 0.732).

Table 2

Univariate analysis
 

Statistics

OR (95%CI)

P-value

STEMI

3305 (45.4%)

1.0 (0.8, 1.1)

0.737

Cardiac arrest

544 (7.5%)

5.9 (4.8, 7.1)

< 0.001

Age

66.8 ± 13.3

1.0 (1.0, 1.0)

< 0.001

Female

2736 (37.6%)

1.4 (1.2, 1.6)

< 0.001

BMI

27.5 ± 7.0

1.0 (1.0, 1.0)

< 0.001

Atrial fibrillation

706 (9.7%)

2.1 (1.7, 2.6)

< 0.001

Cardiac arrest

544 (7.5%)

5.9 (4.8, 7.1)

< 0.001

Cardiac surgery

547 (7.5%)

0.8 (0.6, 1.0)

0.087

CRI

130 (1.8%)

2.3 (1.5, 3.5)

< 0.001

COPD

491 (6.7%)

1.6 (1.3, 2.1)

< 0.001

Hypertension

1149 (15.8%)

0.7 (0.5, 0.9)

< 0.001

Diabetes mellitus

1112 (15.3%)

1.3 (1.1, 1.6)

0.005

Stroke

214 (2.9%)

3.2 (2.4, 4.4)

< 0.001

Tumor

52 (0.7%)

2.5 (1.3, 4.8)

0.006

Serum calcium

8.8 ± 0.8

0.6 (0.6, 0.7)

< 0.001

Albumin

3.4 ± 0.7

0.3 (0.3, 0.3)

< 0.001

Corrected sCa

9.3 ± 0.7

1.2 (1.1, 1.3)

< 0.001

Hemoglobin

12.7 ± 2.6

0.8 (0.8, 0.9)

< 0.001

TC

159.7 ± 48.2

1.0 (1.0, 1.0)

< 0.001

LDL-C

87.9 ± 34.0

1.0 (1.0, 1.0)

< 0.001

HDL-C

39.9 ± 14.0

1.0 (1.0, 1.0)

< 0.001

Lipid-lowering drugs

853 (11.7%)

0.9 (0.7, 1.2)

0.564

Antiplatelet

2304 (31.6%)

0.6 (0.5, 0.8)

< 0.001

Anticoagulants

1594 (21.9%)

0.9 (0.8, 1.1)

0.406

Nitroglycerin

1348 (18.5%)

0.4 (0.3, 0.5)

< 0.001

Mechanical ventilation

1716 (23.6%)

5.8 (5.0, 6.8)

< 0.001
STEMI, ST-segment elevation myocardial infarction; BMI, body mass index; CRI, chronic renal insufficiency; COPD, chronic obstructive pulmonary disease; Corrected sCa, corrected serum calcium; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

 

Table 3

Association of corrected serum calcium and the incidence of in-hospital mortality
 

Model 1

Model 2

Model 3
 

Odds ratio (95%)

P Value

Odds ratio (95%)

P Value

Odds ratio (95%)

P Value

Q1, ≤ 8.5

Ref.

Ref.

Ref.

Q2, 8.5-≤9.5

0.5 (0.4, 0.7)

< 0.001

0.5 (0.4, 0.7)

< 0.001

0.4 (0.2, 0.7)

0.001

Q3, 9.5-≤10.5

0.8 (0.6, 1.0)

0.035

0.7 (0.5, 0.9)

0.003

0.5 (0.3, 0.8)

0.009

Q4, > 10.5

1.6 (1.1, 2.3)

0.008

1.2 (0.8, 1.7)

0.425

0.9 (0.4, 2.0)

0.732
Model 1 adjust for: none. Model 2 adjust for: age; sex; BMI; chronic renal insufficiency. Model 3 adjust for: age; sex; BMI; chronic renal insufficiency; COPD; diabetes mellitus; stroke; tumor; hemoglobin; TC; LDL-C; HDL-C; lipid-lowering drugs; antiplatelet; anticoagulants; nitroglycerin.

 

Piecewise linear regression model

After the possible factors related to in-hospital death were adjusted, a U-shaped relationship between corrected serum calcium levels and in-hospital mortality in patients with AMI was observed (Table 4; Fig. 2). The occurrence of in-hospital death decreased with an increase in corrected sCa when the corrected sCa < 9.4 mg/dL (OR 0.8, 95% CI 0.7–0.9, P < 0.001). The occurrence of in-hospital death increased with an increase in corrected sCa when the corrected sCa > 9.4 mg/dL (OR 1.5, 95% CI 1.3–1.8, P < 0.001).

Table 4

Threshold effect analysis of serum calcium on in-hospital mortality.

Serum calcium

In-hospital death

OR (95%CI)

P value

< 9.4

0.8 (0.7, 0.9)

< 0.001

> 9.4

1.5 (1.3, 1.8)

< 0.001
Adjust for: age, sex; BMI; chronic renal insufficiency; COPD; diabetes mellitus; stroke; tumor; hemoglobin; lipid-lowering drugs; antiplatelet; anticoagulants; nitroglycerin.

Discussion

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.

Conclusions

The corrected serum calcium level is an independent prognostic marker of in-hospital mortality in patients with AMI with a U-shaped association (inflection point: corrected sCa = 9.4 mg/dL). It is necessary to carry out clinical studies with a higher level of evidence to validate our findings in the future.

Declarations

Acknowledgements

Not applicable.

Author contributions

DF and HC designed the research and analyzed the data; DF wrote the paper. All authors reviewed the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the Seed Funding for Young Individual Research of Shenzhen Second People's Hospital (4001019). The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and writing the manuscript.

Availability of data and materials

All data generated or analyzed during this study are included in this published article. After completing relevant training and registration, the raw data are available in the eICU Collaborative Research Database. [https://eicu-crd.mit.edu/]. You can visit PhysioNet for detailed data acquisition steps (https://physionet.org/content/eicu-crd/2.0/).

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflicting interest

The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Michos, E. D., Cainzos-Achirica, M., Heravi, A. S. & Appel, L. J. Vitamin D, Calcium Supplements, and Implications for Cardiovascular Health: JACC Focus Seminar. J Am Coll Cardiol 77, 437–449, doi:10.1016/j.jacc.2020.09.617 (2021).
  2. Baird, G. S. Ionized calcium. Clin Chim Acta 412, 696–701, doi:10.1016/j.cca.2011.01.004 (2011).
  3. Tankeu, A. T., Ndip Agbor, V. & Noubiap, J. J. Calcium supplementation and cardiovascular risk: A rising concern. J Clin Hypertens (Greenwich) 19, 640–646, doi:10.1111/jch.13010 (2017).
  4. Schmitz, T. et al. Low serum calcium is associated with higher long-term mortality in myocardial infarction patients from a population-based registry. Sci Rep 11, 2476, doi:10.1038/s41598-021-81929-7 (2021).
  5. Shiyovich, A., Plakht, Y. & Gilutz, H. Serum calcium levels independently predict in-hospital mortality in patients with acute myocardial infarction. Nutr Metab Cardiovasc Dis 28, 510–516, doi:10.1016/j.numecd.2018.01.013 (2018).
  6. Lu, X. et al. Association of admission serum calcium levels and in-hospital mortality in patients with acute ST-elevated myocardial infarction: an eight-year, single-center study in China. PLoS One 9, e99895, doi:10.1371/journal.pone.0099895 (2014).
  7. Janmaat, C. J. et al. Lower serum calcium is independently associated with CKD progression. Sci Rep 8, 5148, doi:10.1038/s41598-018-23500-5 (2018).
  8. Chen, Q. et al. Associations between serum calcium, phosphorus and mortality among patients with coronary heart disease. Eur J Nutr 57, 2457–2467, doi:10.1007/s00394-017-1518-8 (2018).
  9. Gu, X. et al. Usefulness of Serum Calcium in the Risk Stratification of Midterm Mortality among Patients with Acute Coronary Syndrome. Biomed Res Int 2019, 9542054, doi:10.1155/2019/9542054 (2019).
  10. Foley, R. N., Collins, A. J., Ishani, A. & Kalra, P. A. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 156, 556–563, doi:10.1016/j.ahj.2008.05.016 (2008).
  11. Lundgren, E. et al. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years. Surgery 130, 978–985, doi:10.1067/msy.2001.118377 (2001).
  12. Pollard, T. J. et al. The eICU Collaborative Research Database, a freely available multi-center database for critical care research. Sci Data 5, 180178, doi:10.1038/sdata.2018.178 (2018).
  13. Simera, I., Moher, D., Hoey, J., Schulz, K. F. & Altman, D. G. A catalogue of reporting guidelines for health research. Eur J Clin Invest 40, 35–53, doi:10.1111/j.1365-2362.2009.02234.x (2010).
  14. Payne, R. B., Little, A. J., Williams, R. B. & Milner, J. R. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J 4, 643–646, doi:10.1136/bmj.4.5893.643 (1973).
  15. Grandi, N. C. et al. Calcium, phosphate and the risk of cardiovascular events and all-cause mortality in a population with stable coronary heart disease. Heart 98, 926–933, doi:10.1136/heartjnl-2011-300806 (2012).
  16. Wang, X. et al. Dietary calcium intake and mortality risk from cardiovascular disease and all causes: a meta-analysis of prospective cohort studies. BMC Med 12, 158, doi:10.1186/s12916-014-0158-6 (2014).
  17. Yan, S. D. et al. Admission Serum Calcium Levels Improve the GRACE Risk Score Prediction of Hospital Mortality in Patients With Acute Coronary Syndrome. Clin Cardiol 39, 516–523, doi:10.1002/clc.22557 (2016).
  18. Husain, A., Simpson, R. J., Jr. & Joodi, G. Serum Calcium and Risk of Sudden Cardiac Arrest in the General Population. Mayo Clin Proc 93, 392, doi:10.1016/j.mayocp.2017.12.022 (2018).
  19. Thongprayoon, C. et al. Hospital mortality and long-term mortality among hospitalized patients with various admission serum ionized calcium levels. Postgrad Med 132, 385–390, doi:10.1080/00325481.2020.1728980 (2020).
  20. Lutsey, P. L. et al. Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 100, 756–764, doi:10.3945/ajcn.114.085167 (2014).
  21. Wang, Y. et al. Low serum calcium is associated with left ventricular systolic dysfunction in a Chinese population with coronary artery disease. Sci Rep 6, 22283, doi:10.1038/srep22283 (2016).
  22. Hurley, K. & Baggs, D. Hypocalcemic cardiac failure in the emergency department. J Emerg Med 28, 155–159, doi:10.1016/j.jemermed.2004.06.014 (2005).
  23. Suzuki, T., Ikeda, U., Fujikawa, H., Saito, K. & Shimada, K. Hypocalcemic heart failure: a reversible form of heart muscle disease. Clin Cardiol 21, 227–228, doi:10.1002/clc.4960210319 (1998).
  24. Anderson, J. J. et al. Calcium Intake From Diet and Supplements and the Risk of Coronary Artery Calcification and its Progression Among Older Adults: 10-Year Follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Heart Assoc 5, doi:10.1161/jaha.116.003815 (2016).
  25. Reid, I. R. & Bolland, M. J. Does widespread calcium supplementation pose cardiovascular risk? Yes: the potential risk is a concern. Am Fam Physician 87, Online (2013).
  26. Rooney, M. R. et al. Serum calcium and incident type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Am J Clin Nutr 104, 1023–1029, doi:10.3945/ajcn.115.130021 (2016).
  27. Lind, L., Skarfors, E., Berglund, L., Lithell, H. & Ljunghall, S. Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol 50, 967–973, doi:10.1016/s0895-4356(97)00104-2 (1997).
  28. Larsson, T. E. et al. Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community. Arterioscler Thromb Vasc Biol 30, 333–339, doi:10.1161/atvbaha.109.196675 (2010).
  29. Tantry, U. S. et al. Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study. Platelets 21, 360–367, doi:10.3109/09537100903548903 (2010).
  30. Welsh, P. et al. Circulating 25OHD, dietary vitamin D, PTH, and calcium associations with incident cardiovascular disease and mortality: the MIDSPAN Family Study. J Clin Endocrinol Metab 97, 4578–4587, doi:10.1210/jc.2012-2272 (2012).
  31. Reid, I. R., Birstow, S. M. & Bolland, M. J. Calcium and Cardiovascular Disease. Endocrinol Metab (Seoul) 32, 339–349, doi:10.3803/EnM.2017.32.3.339 (2017).
  32. Al-Delaimy, W. K., Rimm, E., Willett, W. C., Stampfer, M. J. & Hu, F. B. A prospective study of calcium intake from diet and supplements and risk of ischemic heart disease among men. Am J Clin Nutr 77, 814–818, doi:10.1093/ajcn/77.4.814 (2003).
  33. Samelson, E. J. et al. Calcium intake is not associated with increased coronary artery calcification: the Framingham Study. Am J Clin Nutr 96, 1274–1280, doi:10.3945/ajcn.112.044230 (2012).
  34. Chung, M., Tang, A. M., Fu, Z., Wang, D. D. & Newberry, S. J. Calcium Intake and Cardiovascular Disease Risk: An Updated Systematic Review and Meta-analysis. Ann Intern Med 165, 856–866, doi:10.7326/m16-1165 (2016).
  35. Dore, M. P., Parodi, G., Portoghese, M., Errigo, A. & Pes, G. M. Water Quality and Mortality from Coronary Artery Disease in Sardinia: A Geospatial Analysis. Nutrients 13, doi:10.3390/nu13082858 (2021).
  36. Yang, C. Y., Chang, C. C., Tsai, S. S. & Chiu, H. F. Calcium and magnesium in drinking water and risk of death from acute myocardial infarction in Taiwan. Environ Res 101, 407–411, doi:10.1016/j.envres.2005.12.019 (2006).
  37. Rubenowitz, E., Axelsson, G. & Rylander, R. Magnesium and calcium in drinking water and death from acute myocardial infarction in women. Epidemiology 10, 31–36 (1999).
  38. Xiao, Q. et al. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP diet and health study. JAMA Intern Med 173, 639–646, doi:10.1001/jamainternmed.2013.3283 (2013).
  39. Bolland, M. J. et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. Bmj 336, 262–266, doi:10.1136/bmj.39440.525752.BE (2008).
  40. Yang, C. et al. The Evidence and Controversy Between Dietary Calcium Intake and Calcium Supplementation and the Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Cohort Studies and Randomized Controlled Trials. J Am Coll Nutr 39, 352–370, doi:10.1080/07315724.2019.1649219 (2020).
  41. Bazarbashi, N. et al. Oral Calcium Supplements Associate With Serial Coronary Calcification: Insights From Intravascular Ultrasound. JACC Cardiovasc Imaging 14, 259–268, doi:10.1016/j.jcmg.2020.06.030 (2021).