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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
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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).
Table Supplementary Table S1. Univariable Analysis for Other Secondary Endpoints
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 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).
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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.
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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].
doi: 10.3967/bes2019.035
Prognostic Values of Serum Chloride and Sodium Levels in Patients with Three-vessel Disease
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Abstract:
Objective Identification of new risk factors is needed to improve prediction of adverse outcomes in patients with three-vessel disease (TVD). The present study aimed to evaluate the prognostic values of serum chloride and sodium levels in patients with TVD. Methods We used data from a prospective cohort of consecutive patients with angiographically confirmed TVD. The primary endpoint was all-cause death. Cox proportional hazard regression was used to analyze the relationship of serum chloride and sodium levels with long-term outcomes of TVD patients. Results A total of 8, 318 participants with available serum chloride and sodium data were included in this analysis. At baseline, patients in the low tertiles group of serum chloride level (≤ 102.0 mmol/L) or serum sodium level (≤ 139.0 mmol/L) had more severe disease conditions. During a median follow-up of 7.5-year, both low serum chloride level and low serum sodium level were found to be associated with an increased risk for mortality in univariate analysis. However, when both parameters were incorporated into a multivariate model, only low serum sodium level remained to be an independent predictor of all-cause death (hazard ratio:1.16, 95% confidence interval:1.01-1.34, P=0.041). Modest but significant improvement of discrimination was observed after incorporating serum sodium level into the Synergy between percutaneous coronary intervention (PCI) with Taxus and Cardiac Surgery score. Conclusion Serum sodium level is more strongly associated with long-term outcomes of TVD patients compared with serum chloride level. Low serum sodium level is an independent risk factor for mortality, but only provides modest prognostic information beyond an established risk model. -
Key words:
- Coronary disease /
- Prognosis /
- Biomarkers
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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.
Table 1. Baseline Characteristics of the Study Population
Table 2. Long-Term Clinical Outcomes of the Study Population
Supplementary Table S1. Univariable Analysis for Other Secondary Endpoints
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 3. Univariable and Multivariable Analysis for Mortality and MACCE
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[1] Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med, 2010; 362, 886-95. doi: 10.1056/NEJMoa0907272 [2] Bradley SM, Spertus JA, Kennedy KF, et al. Patient selection for diagnostic coronary angiography and hospital-level percutaneous coronary intervention appropriateness:insights from the National Cardiovascular Data Registry. JAMA Intern Med, 2014; 174, 1630-9. doi: 10.1001/jamainternmed.2014.3904 [3] Sorajja P, Gersh BJ, Cox DA, et al. Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. Eur Heart J, 2007; 28, 1709-16. doi: 10.1093/eurheartj/ehm184 [4] Park DW, Clare RM, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA, 2014; 312, 2019-27. doi: 10.1001/jama.2014.15095 [5] Min JK, Dunning A, Lin FY, et al. Age-and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes:An International Multicenter Registry) of 23, 854 patients without known coronary artery disease. J Am Coll Cardiol, 2011; 58, 849-60. doi: 10.1016/j.jacc.2011.02.074 [6] Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med, 2009; 360, 961-72. doi: 10.1056/NEJMoa0804626 [7] Grodin JL, Simon J, Hachamovitch R, et al. Prognostic Role of Serum Chloride Levels in Acute Decompensated Heart Failure. J Am Coll Cardiol, 2015; 66, 659-66. doi: 10.1016/j.jacc.2015.06.007 [8] Goldberg A, Hammerman H, Petcherski S, et al. Prognostic importance of hyponatremia in acute ST-elevation myocardial infarction. Am J Med, 2004; 117, 242-8. doi: 10.1016/j.amjmed.2004.03.022 [9] Goldberg A, Hammerman H, Petcherski S, et al. Hyponatremia and long-term mortality in survivors of acute ST-elevation myocardial infarction. Arch Intern Med, 2006; 166, 781-6. doi: 10.1001/archinte.166.7.781 [10] Singla I, Zahid M, Good CB, et al. Effect of hyponatremia (< 135 mEq/L) on outcome in patients with non-ST-elevation acute coronary syndrome. Am J Cardiol, 2007; 100, 406-8. doi: 10.1016/j.amjcard.2007.03.039 [11] Burkhardt K, Kirchberger I, Heier M, et al. Hyponatraemia on admission to hospital is associated with increased long-term risk of mortality in survivors of myocardial infarction. Eur J Prev Cardiol, 2015; 22, 1419-26. doi: 10.1177/2047487314557963 [12] Choi JS, Kim CS, Bae EH, et al. Prognostic impact of hyponatremia occurring at various time points during hospitalization on mortality in patients with acute myocardial infarction. Medicine (Baltimore), 2017; 96, e7023. doi: 10.1097/MD.0000000000007023 [13] Klein L, O'Connor CM, Leimberger JD, et al. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure:results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study. Circulation, 2005; 111, 2454-60. doi: 10.1161/01.CIR.0000165065.82609.3D [14] Gheorghiade M, Abraham WT, Albert NM, et al. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure:an analysis from the OPTIMIZE-HF registry. Eur Heart J, 2007; 28, 980-8. doi: 10.1093/eurheartj/ehl542 [15] Grodin JL, Verbrugge FH, Ellis SG, et al. Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure. Circ Heart Fail, 2016; 9, e2453. http://cn.bing.com/academic/profile?id=7d2d69c5e36a7608ff5e524fcf09e038&encoded=0&v=paper_preview&mkt=zh-cn [16] Testani JM, Hanberg JS, Arroyo JP, et al. Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure. Eur J Heart Fail, 2016; 18, 660-8. doi: 10.1002/ejhf.2016.18.issue-6 [17] Ferreira JP, Girerd N, Duarte K, et al. Serum Chloride and Sodium Interplay in Patients With Acute Myocardial Infarction and Heart Failure With Reduced Ejection Fraction:An Analysis From the High-Risk Myocardial Infarction Database Initiative. Circ Heart Fail, 2017; 10, e003500. http://cn.bing.com/academic/profile?id=e29c57fe7f8427f0ad12f88140fadca5&encoded=0&v=paper_preview&mkt=zh-cn [18] Xu JJ, Jiang L, Xu LJ, et al. Association of CDKN2B-AS1 Polymorphisms with Premature Triple-vessel Coronary Disease and Their Sex Specificity in the Chinese Population. Biomed Environ Sci, 2018; 31, 787-96. http://d.old.wanfangdata.com.cn/Periodical/bes201811001 [19] Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol, 2011; 58, e44-122. doi: 10.1016/j.jacc.2011.08.007 [20] Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol, 2011; 58, e123-210. doi: 10.1016/j.jacc.2011.08.009 [21] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron, 1976; 16, 31-41. doi: 10.1159/000180580 [22] Girasis C, Garg S, Raber L, et al. SYNTAX score and Clinical SYNTAX score as predictors of very long-term clinical outcomes in patients undergoing percutaneous coronary interventions:a substudy of SIRolimus-eluting stent compared with pacliTAXel-eluting stent for coronary revascularization (SIRTAX) trial. Eur Heart J, 2011; 32, 3115-27. doi: 10.1093/eurheartj/ehr369 [23] Zhang YJ, Iqbal J, Campos CM, et al. Prognostic value of site SYNTAX score and rationale for combining anatomic and clinical factors in decision making:insights from the SYNTAX trial. J Am Coll Cardiol, 2014; 64, 423-32. doi: 10.1016/j.jacc.2014.05.022 [24] Farooq V, van Klaveren D, Steyerberg EW, et al. Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients:development and validation of SYNTAX score Ⅱ. Lancet, 2013; 381, 639-50. doi: 10.1016/S0140-6736(13)60108-7 [25] Sotomi Y, Cavalcante R, van Klaveren D, et al. Individual Long-Term Mortality Prediction Following Either Coronary Stenting or Bypass Surgery in Patients With Multivessel and/or Unprotected Left Main Disease:An External Validation of the SYNTAX Score Ⅱ Model in the 1, 480 Patients of the BEST and PRECOMBAT Randomized Controlled Trials. JACC Cardiovasc Interv, 2016; 9, 1564-72. doi: 10.1016/j.jcin.2016.04.023 [26] Cavalcante R, Sotomi Y, Mancone M, et al. Impact of the SYNTAX scores Ⅰ and Ⅱ in patients with diabetes and multivessel coronary disease:a pooled analysis of patient level data from the SYNTAX, PRECOMBAT, and BEST trials. Eur Heart J, 2017; 38, 1969-77. doi: 10.1093/eurheartj/ehx138 [27] Wannamethee SG, Shaper AG, Lennon L, et al. Mild hyponatremia, hypernatremia and incident cardiovascular disease and mortality in older men:A population-based cohort study. Nutr Metab Cardiovasc Dis, 2016; 26, 12-9. doi: 10.1016/j.numecd.2015.07.008 [28] Kumar S, Berl T. Sodium. Lancet, 1998; 352, 220-8. doi: 10.1016/S0140-6736(97)12169-9 [29] Palevsky PM, Bhagrath R, Greenberg A. Hypernatremia in hospitalized patients. Ann Intern Med, 1996; 124, 197-203. doi: 10.7326/0003-4819-124-2-199601150-00002 [30] Lilly LS, Dzau VJ, Williams GH, et al. Hyponatremia in congestive heart failure:implications for neurohumoral activation and responses to orthostasis. J Clin Endocrinol Metab, 1984; 59, 924-30. doi: 10.1210/jcem-59-5-924 [31] Hanberg JS, Rao V, Ter Maaten JM, et al. Hypochloremia and Diuretic Resistance in Heart Failure:Mechanistic Insights. Circ Heart Fail, 2016; 9, e003180. http://cn.bing.com/academic/profile?id=6b7bfa7aefa45530707f4a8d0cebe553&encoded=0&v=paper_preview&mkt=zh-cn [32] Palmer BR, Pilbrow AP, Frampton CM, et al. Plasma aldosterone levels during hospitalization are predictive of survival post-myocardial infarction. Eur Heart J, 2008; 29, 2489-96. [33] Ivanes F, Susen S, Mouquet F, et al. Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure. Eur Heart J, 2012; 33, 191-202. doi: 10.1093/eurheartj/ehr176 [34] Swedberg K, Eneroth P, Kjekshus J, et al. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation, 1990; 82, 1730-6. doi: 10.1161/01.CIR.82.5.1730 [35] Ter Maaten JM, Damman K, Hanberg JS, et al. Hypochloremia, Diuretic Resistance, and Outcome in Patients With Acute Heart Failure. Circ Heart Fail, 2016; 9, e003109. http://cn.bing.com/academic/profile?id=b6e57a3d3e8286fa7fbc4462d42b01b3&encoded=0&v=paper_preview&mkt=zh-cn [36] Neuberg GW, Miller AB, O'Connor CM, et al. Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J, 2002; 144, 31-8. doi: 10.1067/mhj.2002.123144 [37] Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease:a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol, 2012; 60, e44-164. doi: 10.1016/j.jacc.2012.07.013