Lütfi Öcal1, Aslı Öcal2, Sinan Cerşit1, Hayati Eren3, Ender Özgün Çakmak1, Hakan Çakır1

1Department of Cardiology, Kartal Kosuyolu High Specialization Training and Research Hospital, Istanbul, Turkey
2Department of Internal Medicine, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey
3Department of Cardiology, Elbistan State Hospital, Kahramanmaras, Turkey

Keywords: Sodium; myocardial infarction; mortality.

Abstract

Introduction: There are some conflicting results in the association of serum sodium level with clinical outcomes in patients with acute myocardial infarction. The aim of this study was to investigate the effect of serum sodium levels on in-hospital and long-term outcomes in patients with ST-segment elevation myocardial infarction (STEMI).

Patients and Methods: A total of 1840 patients with STEMI (mean age 57.3 ± 11.8; men 79.7%) who underwent primary percutaneous coronary intervention were included to the study. Baseline characteristics and outcomes were compared among the patients by admission serum sodium level and categorized accordingly; Q1, Q2, Q3 and Q4.

Results: There was not a significant difference regarding in-hospital mortality, cardiogenic shock, ventricular arrhythmia, acute kidney injury and major adverse cardiac events. Furthermore, after a follow-up period of 3-years; there was not a significant difference regarding long-term mortality and major adverse cardiac events.

Conclusion: In this large-scale study, we did not observe a significant association of serum sodium level with in-hospital and long-term clinical outcomes in patients with STEMI.

Introduction

Hyponatremia is recognized as the most common electrolyte disorder. It is a well-known predictor of poor prognosis in certain diseases such as congestive heart failure (CHF), chronic kidney disease, and liver cirrhosis(1-5). In CHF, hyponatremia develops after excessive activation of baroreceptor-mediated hormones including arginine vasopressin (AVP), catecholamines and renin-angiotensin-aldosterone system based on low output rate. This hyponatremia process occurs in CHF after weeks. Moreover, recent studies showed that hyponatremia is a prognostic indicator in patients with acute myocardial infarction (AMI) (6-11). When we consider patients with ST-segment elevation myocardial infarction (STEMI) separately, especially compared to patients with myocardial infarction without ST-segment elevation; it consists of patients with generally low comorbidity and no significant electrolyte imbalance. The development of hyponatremia in these patients generally occurs due to CHF developing during follow-up or due to diuretic treatments. However, hyponatremia (> 130 mg/dL), which is not as severe as in CHF, can be observed in some patients during admission. Studies analyzing STEMI patients, the relationship between inhospital or admission sodium levels and in-hospital events are contradictory and it is still unclear whether hyponatremia has a direct effect on mortality and morbidity in STEMI patients, and previous studies on in-hospital survival in patients with hemodynamically stable have no enough information. The aim of this study was to investigate the effect of serum sodium levels on in-hospital and long-term outcomes in patients with STsegment elevation myocardial infarction (STEMI).

Patients and Methods

Study Population

A total of 2094 consecutive patients who admitted to the emergency service of our tertiary heart center [annual percutaneous coronary intervention > 2500] between January 2014 and December 2017 and who met criteria for STEMI were retrospectively evaluated. A total of 97 patients, who underwent thrombolytic therapy within the last 24 hours and with active infection, recent major surgical procedures or history of trauma, imaging modalities and investigational techniques for detecting systemic inflammatory disease, malignancy, or end-stage renal and liver failure, were excluded from the study. Moreover, 138 patients whose urea, glucose and/or sodium measurements were not studied within 8 hours after admission and 19 patients who did not come to follow-up were excluded from the study. A total of 1840 patients were included in the study. Our study was approved by the local ethics committee in accordance with the declaration of Helsinki.

Clinical, demographic, angiographic and laboratory parameters were taken from the hospital database. The sodium level of each patient was measured within the first 8 hours after admission. Serum sodium level was measured on Roche, Cobas 6000 Biochemistry Auto-Analyzer, USA. According to the sodium level, the patients were ranked from low to high and divided into 4 equal groups (quartile). In-hospital and longterm clinical events, evaluated by 2 independent observers, were compared between these 4 groups. In-hospital and long-term mortality was determined as the primary endpoint of the study.

In-hospital procedures such as primary PCI were performed by experienced interventional cardiologists. Primary PCI was usually performed via the femoral route. Echocardiographic imaging was performed on all patients within the first 12 hours after hospitalization, and left ventricular ejection fraction was measured by the Simpson method. During PCI, iodinated contrast agents with low osmolar content were used in all patients. In-hospital clinical events were evaluated and recorded by an experienced cardiologist. After PCI, patients were followed up in the coronary intensive care unit for observation. The estimated glomerular filtration rate was measured with the Cockcroft-Gault equation. In-hospital and follow-up medical treatments were planned in accordance with the guidelines of the European Society of Cardiology.

Diagnostic Criteria in STEMI

Diagnostic criteria for STEMI are as follows: (a) Typical chest pain lasting more than 30 minutes and (b) with ST segment elevation in at least two leads, minimum 0.2 mV in men or 0.15 mV in women in V2-V3 leads and/or minimum 0.1 mV in other leads or newly developed definite or possible left bundle branch block. The right (V3R-V4R) and posterior (V7-V9) leads were obtained in the indication case(12). Patients who admitted with STEMI within 12 hours from the onset of symptoms and underwent percutaneous coronary intervention (angioplasty and/or stent placement) were included in the study.

Description of In-Hospital and Long-Term Events

Cardiogenic shock; defined as systolic blood pressure below 90 mmHg or vasopressor drug requirement to maintain systolic blood pressure above 90 mmHg and decrease in urine output or the presence of end-organ hypoperfusion results such as sweaty and cold extremities or fluctuation in mental state.

Acute renal failure; defined as a 0.5 mg/dL increase in serum creatinine concentration from baseline or a 50% decrease in creatinine clearance.

Acute respiratory failure; defined as a sudden deterioration in blood oxygenation (PaO2 < 80 mmHg or SpO2 < 90) and shortness of breath in the patient.

Stent thrombosis; defined as increase in biomarker levels after stent placement or a sudden onset of cardiac symptoms with ECG evidence of myocardial damage and the angiographic presence of a flow limiting thrombus within or 5 mm near previously placed stent.

Revascularization; defined as the decision of angioplasty procedure performed due to re-stenosis or occlusion in the infarct-related artery or CABG surgery.

Recurrent MI; defined as an increase in serum CK-MB levels, re-elevation in ST segments or dynamic ECG changes and an association of cardiac symptoms.

Major cardiac event; defined as cardiovascular death, recurrent MI and repeated target vessel revascularization (percutaneous or surgical).

Statistical Analysis

Patients (n= 1840) were ranked by low to high sodium level and divided into quartiles with 4 equal numbers of patients (n= 460). The normality status of continuous variables was evaluated by Kolmogorov-Smirnov test. Continuous variables were shown in the table with mean and standard deviation values. The difference analysis of continuous variables with normal distribution was evaluated using ANOVA, and the difference analysis of variables without normal distribution was evaluated using Kruskal-Wallis test. The categorical variables were indicated as numbers and percentages, and the difference analysis was performed using Pearson’s chi-square or Fisher’s exact test. Out-of-hospital follow-up period was determined as 3 years. P value less than 0.05 was considered statistically significant. All analyzes were performed using SPSS 18.0 software (SPSS; IBM, Armonk, New York, USA).

Results

Basal characteristics of the patients and their values at the time of admission are summarized in Table 1. There was no difference between the groups in age, gender, body mass index, hypertension, diabetes mellitus, hyperlipidemia, smoking, chronic renal failure, previous MI frequency, systolic and diastolic blood pressures at the time of admission, heart rates, Killip classes, percutaneous intervention times and medical treatments. The rates of patients with anterior wall MI were similar, but the left ventricular EF of the patients in groups I and II was slightly lower. When we looked at the laboratory values at admission, the urea and creatinine values of the patients were similar. However, glucose levels of the patients were higher in groups 1 and 2. The patients were analyzed in 4 groups according to their serum sodium levels at admission. The mean sodium levels for group I were 133.77 ± 1.21; 136.54 ± 0.58 for group II; 138.48 ± 0.50 for group III; 141.27 ± 1.64 for group IV. When in-hospital events are analyzed; there was no statistically significant difference between the groups in cardiogenic shock, acute respiratory failure, acute renal failure, stent thrombosis, recurrent MI, major cardiac events and death.

When three-year long-term follow-up results of the patients were analyzed; there was no difference between the groups in stent thrombosis, recurrent MI, revascularization, major cardiac events and death from all causes.

Discussion

In this study; we divided 1840 STEMI patients into quartiles with 4 equal numbers of patients according to their sodium levels at the time of admission and analyzed as-hospital events and three-year follow-up. During the in-hospital period; No significant differences were found in death, cardiogenic shock, ventricular arrhythmia, acute kidney injury, and major cardiac events. Moreover, after 3 years of follow-up; similar results were found in long-term death and major cardiac events. Many factors were also identified such as advanced age, killip class of patient, delay in treatment, treatment strategy, history of MI, diabetes mellitus, renal failure, multiple vascular diseases and low left ventricular ejection fraction that affect the mortality of patients admitting with STEMI(13).

The prognostic importance of hyponatremia in CHF was shown in many studies. The development of hyponatremia in CHF was explained by several mechanisms(12,14-17). These are vasopressin secretion, carotid baroreceptor activation and hypothalamus stimulation that can take 1-2 weeks. STEMI is an acute event. It seems unlikely to be significant hyponatremia (< 130 mg/dL) at the beginning.

When we analyze the studies on sodium levels of STEMI patients, the results are controversial and there is no effect of causes other than sodium for results. In the studies, patients with hyponatremia constitute very little part of the general STEMI patients and this leads to a serious difference in the number of patients in these groups. Goldberg et al. included patients who developed hyponatremia at the time of admission and followup in the study. In the study, hyponatremia was defined as an indicator of 30-day mortality(18). Most patients underwent fibrinolytic therapy and this does not reflect the current age of primary percutaneous intervention. These treatments may be responsible for the poor outcome and developing CHF in these patients. Moreover, a significant rate of patients with hyponatremia is diabetic and involved in the high admission killip class. It seems that the main cause of the mortality of the patients in this hyponatremia group is the patient’s clinic. In the study including the long-term results of hyponatremia by Goldberg et al.; for the same reasons, the results of the study are affected by factors other than hyponatremia such as diabetes mellitus and high admission killip class(19).

Klopotowski et al. stated in their study that hyponatremia increased in-hospital mortality(11). However, in this study; only 96 of 1858 STEMI patients were in the hyponatremia group. No statistically significant difference was found in the group statistics made by dividing into quantile.

In the study of Bozbay et al., it was stated that hyponatremia increased mortality(20). The number of patients in the study (366 patients) is low and the number of patients with hyponatremia (56 patients) constitutes approximately 15% of the patients incompatible with the literature. The hyponatremia group also consists of older patients. It is known that advanced age is associated with mortality in patients with STEMI(13). It is contradictory that it was not found an independent determinant although patients over 65 years of age had 6 times more mortality in this study. The fact that important laboratory values such as creatinine were not examined for independent determinants is an important deficiency of this study. Tatlısu et al. calculated the plasma osmolarity of 3748 STEMI patients(21). They found that high plasma osmolarity was associated with in-hospital and long-term mortality. In the same study, when fasting glucose and blood urea nitrogen, which are a part of plasma osmolarity, were analyzed separately, it was found to be associated with mortality; while sodium was not associated with mortality in this large-scale study in compatible with our study.

Our study has some limitations. First, it is a single center and retrospective observational study. Our study includes only patients with STEMI and this does not cover all patients with AMI. Besides, the instantaneous value of sodium at admission was used for statistical analysis and changes that could be observed during follow-up were ignored.

Consequently; when we analyzed the patients in this study by dividing the number of patients equally into quantiles according to the reference sodium level; we did not find that the admission sodium value is associated with in-hospital and 3-year mortality. When we compared STEMI patients with MI patients without ST elevation, they are patients with less comorbidity and less routine blood values. In our study, patients who firstly admitted with STEMI constitute approximately 80% of the patients. Therefore, the patients in our study are also patients with less comorbid diseases and there is no severe hyponatremia in the sodium values of the patients. Hyponatremia is associated with mortality in chronic heart failure in patients with chronic ischemic heart disease and the time is required for the development of specific hyponatremia. STEMI is an acute event and patients are intervened early in the age of primary percutaneous intervention.

Ethics Committee Approval

The study was approved by the Kartal Dr. Lutfi Kirdar City Hospital Clinical Research Ethics Committee (Decision no: 514/196/5; Date: 24.02.2021).

Peer Review

Externally peer-reviewed.

Author Contributions

Concept/Design - LÖ, AÖ; Analysis/Interpretation - SC, EÇ; Data Collection - LÖ, AÖ; Writing - SC, EÇ; Critical Revision - SC, EÇ; Statistical Analysis - HE, HÇ; Overall Responsibility - LÖ; Final Approval - All of authors.

Conflict of Interest

The authors have no conflicts of interest to declare.

Financial Disclosure

The authors declared that this study has received no financial support.

References

  1. Bae MH, Chae SC. Hyponatremia in acute heart failure: a marker of poor condition or a mediator of poor outcome? Korean J Intern Med 2015;30:450-2. [Crossref]
  2. Lee SE, Choi DJ, Yoon CH, Oh IY, Jeon ES, Kim JJ, et al. Improvement of hyponatraemia during hospitalization for acute heart failure isnot associated with improvement of prognosis: an analysis fromthe Korean Heart Failure (KorHF) registry. Heart 2012;98:1798-804. [Crossref]
  3. Jenq CC, Tsai MH, Tian YC, Chang MY, Lin CY, Lien JM, et al. Serum sodium predicts prognosis in critically ill cirrhotic patients. J Clin Gastroentero 2010;l44:220-6. [Crossref]
  4. Waikar SS, Curhan GC, Brunelli SM. Mortality associated with low serum sodium concentration in maintenance hemodialysis. Am J Med 2011;124:77-84. [Crossref]
  5. Kovesdy CP, Lott EH, Lu JL, Malakauskas SM, Ma JZ, Molnar MZ, et al. Hyponatremia, hypernatremia and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation 2012;125:677-84. [Crossref]
  6. Singla I, Zahid M, Good CB, Macioce A, Sonel AF. Effect of hyponatremia (< 135 mEq/L) on outcome in patients with non-ST-elevation acute coronary syndrome. Am J Cardiol 2007;100:406-8. [Crossref]
  7. Qureshi W, Hassan S, Khalid F, Almahmoud MF, Shah B, Tashman R, et al. Outcomes of correcting hyponatremia in patients with myocardial infarction. Clin Res Cardiol 2013;102:637-44. [Crossref]
  8. Lazzeri C, Valente S, Chiostri M, Attana P, Picariello C, Gensini GF. Usefulness of hyponatremia in the acute phase of ST-elevation myocardial infarction as a marker of severity. Am J Cardiol 2012;110:1419-24. [Crossref]
  9. Havranek S, Belohlavek J, Skulec R, Kovarnik T, Dytrych V, Linhart A. Long-term prognostic impact of hyponatremia in the ST-elevation myocardial infarction. Scand J Clin Lab Invest 2011;71:38-44. [Crossref]
  10. Goldberg A, Hammerman H, Petcherski S, Zdorovyak A, Yalonetsky S, Kapeliovich M, et al. Prognostic importance of hyponatremia in acute STelevation myocardial infarction. Am J Med 2004;117:242-8. [Crossref]
  11. Klopotowski M, Kruk M, Przyluski J, Kalinczuk L, Pregowski J, Bekta P, et al. Sodium level on admission and in-hospital outcomes of STEMI patients treated with primary angioplasty: the ANIN Myocardial Infarction Registry. Med Sci Monit 2009;15:CR477-CR83. [Crossref]
  12. Kumar S, Berl T. Sodium. Lancet 1998;352:220-8. [Crossref]
  13. Ibanez B, James S, Agewall S, ESC Scientific Document group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119-77. [Crossref]
  14. Szatalowicz VL, Arnold PE, Chaimovitz C, Bichet D, Berl T, Schrier RW. Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. N Engl J Med 1981;305:263-6. [Crossref]
  15. Kim JK, Michel JB, Soubrier F, Durr J, Corvol P, Schrier RW. Arginine vasopressin gene expression in chronic cardiac failure in rats. Kidney Int 1990;38:818-22. [Crossref]
  16. Xu DL, Martin PY, Ohara M, St John J, Pattison T, Meng X, et al. Upregulation of aquaporin-2 water channel expression in chronic heart failure rat. J Clin Invest 1997;99:1500-5. [Crossref]
  17. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581-9. [Crossref]
  18. Goldberg A, Hammerman H, Petcherski S, Zdorovyak A, Yalonetsky S, Kapeliovich M, et al. Prognostic importance of hy- ponatremia in acute ST-elevation myocardial infarction. Am J Med 2004;117:242-8. [Crossref]
  19. Goldberg A, Hammerman H, Petcherski S, Nassar M, Zdorovyak A, Yalonetsky S, et al. Hyponatremia and long- term mortality in survivors of acute ST-elevation myocardial infarction. Arch Intern Med 2006;166:781-6. [Crossref]
  20. Bozbay M, Ayhan E, Uyarel H, Çiçek G, Altay S, Işık T, et al. Patients undergoing primary PCI in acute myocardial infarction plasma sodium levels at the time of admission hospital relationship between in-hospital morbidity and mortality. MN Kardiyoloji 2012;19:165-71. [Crossref]
  21. Tatlisu MA, Kaya A, Keskin M, Uzman O, Borklu EB, Cinier G, et al. Can we use plasma hyperosmolality as a predictor of mortality for STsegment elevation myocardial infarction? Coron Artery Dis 2017;28:70-6. [Crossref]

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