A total of 8, 318 (93%) participants with available serum chloride and sodium values were included in the present analysis. The mean levels of serum chloride and sodium were 103.5 ± 3.5 mmol/L and 139.9 ± 3.1 mmol/L, respectively. The correlation between serum chloride level and serum sodium level was modest (r = 0.41, P < 0.001).
Baseline characteristics of the participants grouped by tertiles of serum chloride and sodium levels are presented in Table 1. Patients in the low chloride tertiles group (≤ 102.0 mmol/L) were younger, had higher rates of diabetes and MI, lower LVEF and serum sodium level, higher creatinine clearance, and received MT more frequently. Patients in the low sodium tertiles group (≤ 139.0 mmol/L) showed a higher prevalence of diabetes, chronic kidney disease and MI, with lower LVEF and serum chloride level, and were more likely to receive MT.
Table 1. Baseline Characteristics of the Study Population
During the median follow-up of 7.5 years, deaths from any cause were observed in 1, 249 patients (15.0%), including 643 deaths from cardiac causes (7.7%). Most all-cause deaths, cardiac deaths and MACCE occurred in patients in the low tertiles group of serum chloride or sodium level (Table 2).
Table 2. Long-Term Clinical Outcomes of the Study Population
In univariate analyses, patients in the low tertiles group of serum chloride level had a higher risk for all-cause death (HR: 1.25, 95% CI: 1.09-1.43, P = 0.001), cardiac death (HR: 1.52, 95% CI: 1.26-1.84, P < 0.001), and MACCE (HR: 1.13, 95% CI: 1.03-1.24, P = 0.012), but not for MI, stroke or unplanned revascularization, compared with those in the high tertiles group (Table 3 and Supplementary Table S1 available in www.besjournal.com). Comparable findings were also observed in patients in the low tertiles group of serum sodium level (Table 3 and Supplementary Table S1). Kaplan-Meier estimates of all-cause death, cardiac death and MACCE were significantly different across tertiles groups of serum chloride and sodium levels (log-rank P < 0.05 for all) (Figure 1A-F).
Variable Myocardial Infarction Stroke Unplanned Revascularization HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value Chloride ≤ 102.0 mmol/L 0.92 (0.74-1.15) 0.451 1.03 (0.85-1.25) 0.752 1.03 (0.86-1.23) 0.780 Chloride > 102.0 to ≤ 105.1 mmol/L 0.99 (0.80-1.23) 0.944 0.86 (0.70-1.05) 0.127 1.00 (0.84-1.20) 0.977 Chloride > 105.1 mmol/L Reference Reference Reference Sodium ≤ 139.0 mmol/L 0.94 (0.76-1.16) 0.550 1.01 (0.83-1.22) 0.940 0.88 (0.74-1.06) 0.173 Sodium > 139.0 to ≤ 141.0 mmol/L 0.93 (0.74-1.17) 0.520 1.00 (0.81-1.23) 0.994 1.00 (0.83-1.20) 0.989 Sodium > 141.0 mmol/L Reference Reference Reference Note. CI, confidence interval; HR indicates hazard ratio.
Table Supplementary Table S1. Univariable Analysis for Other Secondary Endpoints
Table 3. Univariable and Multivariable Analysis for Mortality and MACCE
Figure 1. Kaplan-Meier curves for all-cause death (A, D), cardiac death (B, E) and major adverse cardiac and cerebrovascular events (MACCE; C, F) across tertiles of chloride and sodium. Cl, serum chloride level, mmol/L; Na, serum sodium level, mmol/L.
When both chloride and sodium were simultaneously integrated into the base model, low sodium level (≤ 139.0 mmol/L) remained significantly associated with an increased risk for all-cause death (HR: 1.16, 95% CI: 1.01-1.34, P = 0.041) and cardiac death (HR: 1.26, 95% CI: 1.03-1.55, P = 0.027), while serum chloride level was no longer significantly associated with the outcomes (Table 3). There was no interaction of serum chloride and sodium levels with all-cause or cardiac death (P = 0.705 and 0.618, respectively).
The relationship of serum sodium level with all-cause death was relatively consistent across the subgroups of age, sex, diabetes, presentation, left main disease, LVEF, SYNTAX score or procedure (Figure 2). There was no significant interaction of tertiles of sodium and these covariates (interaction P-value > 0.05 for all subgroups).
Figure 2. Associations of tertiles of serum sodium with risk of all-cause death across subgroups. AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; MT, medical therapy; PCI, percutaneous coronary intervention; SAP, stable angina pectoris; UAP, unstable angina pectoris. *Multivariable Cox regression was used to determine mortality risk of patients in low sodium tertile (≤ 139.0 mmol/L) compared with patients in high sodium tertile (> 141.0 mmol/L). †The interaction between sodium tertiles and each covariate was tested using multivariable Cox regression hazard model.
Since serum sodium level was more strongly associated with outcomes compared with serum chloride, tertiles of serum sodium level were combined with SYNTAX score for prediction of mortality to evaluate its incremental information. There was a modest but significant improvement for AUC values between the two prediction sets [SYNTAX score: 0.570 (0.552-0.588) vs. SYNTAX score with serum sodium level 0.586 (0.568-0.603), P = 0.011].