3.1. Baseline demographic and clinical characteristics of the study participants stratified by serum calcium concentration on admission
A total of 3780 patients with AMI met the criteria for inclusion in our study. Among these 3780 patients, 188 (4.97%) died during hospitalization. The mean age of all our study patients was 58.9 years (SD, 10.6 years), and 2798 patients (74.0%) were male. A total of 1608 patients (42.5%) had hypertension, 759 (20.1%) had a history of diabetes mellitus, and 311 (8.2%) had a history of stroke. Most patients had STEMI (2614/3780, 69.2%), and more than half were current smokers (2030/3780, 53.7%).
Serum calcium concentration (measured in each patient at the time of hospital admission) approximated to a normal distribution (Supplemental Figure S1) with a mean level of 2.26 mmol/L (SD, 0.15 mmol/L) and a median level of 2.26 mmol/L (IQR, 2.19–2.33 mmol/L). The distribution of DTR exhibited slight positive skewness (Supplemental Figure S2) with a mean temperature difference of 10.26°C (SD, 3.56°C) and a median temperature difference of 9.90°C (IQR, 7.69–12.60°C).
Based on the admission serum calcium concentrations, the patients were stratified into quartiles: Ca-Q1 (serum calcium concentration <2.19 mmol/L), n = 892; Ca-Q2 (serum calcium concentration 2.19–2.26 mmol/L), n = 997; Ca-Q3 (serum calcium concentration 2.27–2.33 mmol/L), n = 883; and Ca-Q4 (serum calcium concentration >2.33 mmol/L), n = 1008. The clinical characteristics of the patients in each of the serum calcium quartiles are shown in Table 1. Age, BUN, HDL-C, serum creatinine, uric acid, serum phosphate, serum magnesium, serum chloride and left atrial diameter (LAD) were significantly higher in patients with low serum calcium levels than in patients with elevated levels of serum calcium (all P < 0.05; Table 1).
3.2. Association between serum calcium concentration and in-hospital mortality
Patients in the lowest serum calcium quartile exhibited the highest incidence of in-hospital mortality (Table 1). As shown in Figure 1, in-hospital mortality progressively increased with a decrease in the tertile/quartile/quintile of serum calcium concentration (P for trend < 0.001).
Univariate logistic regression analysis found that age, gender, current smoking, current alcohol use, diabetes mellitus, HDL-C, uric acid, serum phosphate, serum potassium, left ventricular ejection fraction (LVEF), LAD and serum calcium concentration were factors significantly associated with in-hospital mortality (Supplemental Table S1). However, multivariate logistic regression analysis revealed that only age, gender, diabetes mellitus, HDL-C, uric acid, serum phosphate, LVEF and serum calcium concentration were independently associated with in-hospital mortality (Supplemental Table S2).
As shown in Table 2, the odds of in-hospital mortality were significantly lower among study patients with serum calcium concentration in the highest quartile (>2.33 mmol/L) than among those with serum calcium concentration in the lowest quartile (<2.19 mmol/L) in model 1 (unadjusted; OR, 0.53; 95%CI, 0.45–0.63; P for trend < 0.001), model 2 (adjusted for age and gender; OR, 0.57; 95%CI, 0.48–0.68; P for trend < 0.001) and model 3 (adjusted for all significant factors in the univariate analysis; OR, 0.56; 95%CI, 0.47–0.67; P for trend < 0.001).
3.3. Moderating effect of DTR on the association between serum calcium concentration and in-hospital mortality
The patients were stratified into quartiles based on admission DTR: DTR-Q1 (DTR <7.7ºC), n = 945; DTR-Q2 (DTR 7.7–9.9ºC), n = 910; DTR-Q3 (DTR 10.0–12.6ºC), n = 972; and DTR-Q4 (DTR >12.6ºC), n = 953. Logistic regression analysis showed that DTR was not independently associated with in-hospital mortality (Supplemental Table S3). However, subgroup analyses revealed that the association between serum calcium concentration and in-hospital mortality was moderated by different quartiles of admission DTR (Table 3). Although the association between serum calcium concentration and in-hospital mortality was significant in most of the subgroups analyzed (Table 3), only DTR was observed to interact significantly with serum calcium concentration (P-interaction = 0.020).
All analyses were adjusted for the same variables as model 3 in Table 2, except for the stratification variable. Ca-Q1: serum calcium concentration <2.19 mmol/L; Ca-Q2: serum calcium concentration 2.19–2.26 mmol/L; Ca-Q3: serum calcium concentration 2.27–2.33 mmol/L; Ca-Q4: serum calcium concentration >2.33 mmol/L; DTR-Q1: diurnal temperature range <7.7ºC; DTR-Q2: diurnal temperature range 7.7–9.9ºC; DTR-Q3: diurnal temperature range 10.0–12.6ºC; DTR-Q4: diurnal temperature range >12.6ºC. NA: not available due to limited sample size. Abbreviations: ACEI, angiotensin converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; DTR, diurnal temperature range; CI, confidence interval; NSTEMI, non-ST-segment elevation myocardial infarction; OR, odds ratio; STEMI, ST-segment elevation myocardial infarction.
Patients with low serum calcium levels in the highest quartile of admission DTR (>12.6ºC) had a notably increased risk of in-hospital mortality compared with patients in the lowest quartile of DTR (<7.7ºC) after adjustment for potential confounders (Q4:Q1 OR, 0.03; 95%CI, 0.01–0.20; P for trend < 0.001). This strong negative association of DTR with in-hospital mortality was consistent between different regression models and the various quartiles of serum calcium concentration. A model of the moderating effect of DTR, built based on a multivariate logistic regression model, is shown in Figure 2. The ORs per 1-SD increment of serum calcium concentration for patients in the second and third quartiles of DTR were 0.16 (95%CI, 0.05–0.55; P for trend = 0.004) and 0.14 (95%CI, 0.04–0.50; P for trend = 0.007), respectively. However, there were no statistically significant associations with the lowest quartile of DTR (P for trend = 0.150). Smooth curve fitting showed that for the third and fourth quartiles of DTR, the relationship between serum calcium concentration and in-hospital mortality was L-shaped, and the in-hospital mortality progressively decreased with increasing serum calcium concentration up to ~2.45 mmol/L (Figure 3).
3.4. The value of serum calcium concentration for the prediction of in-hospital mortality
The value of serum calcium concentration for the prediction of in-hospital mortality in different quartiles of DTR is shown in Figure 4. Compared with other quartiles of DTR, the independent ROCAUC for serum calcium concentration in the highest quartile of DTR was 0.72 (95%CI, 0.69–0.75; P < 0.001). Among patients in the highest quartile of DTR, the combined predictive values in the risk factor models with and without serum calcium concentration were 0.81 (95%CI, 0.76–0.84; P < 0.001) and 0.76 (95%CI, 0.72–0.79, P < 0.001), respectively.
In addition, we also performed NRI analyses to reveal whether the inclusion of serum calcium concentration would improve the reclassification ability of the model. Among patients in the highest quartile of DTR, the results showed that 2.9% of the individuals who survived and 28.6% of those who died in hospital would be correctly reclassified when the clinical model (including the above risk factors) included serum calcium concentration (Table 4). These reclassification rates led to an estimated NRI of 20.2% (95% CI, 7.5–32.9; P = 0.001). In addition, statistically significant NRI was not observed among patients in other quartiles of DTR.