Prognostic value of serum hyponatremia for outcomes in patients with heart failure with preserved ejection fraction: An observational cohort study
- Authors:
- Published online on: September 17, 2020 https://doi.org/10.3892/etm.2020.9231
- Article Number: 101
-
Copyright: © Su et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Heart failure (HF) is a clinical syndrome associated with poor quality of life, substantial health-care resource utilization and premature mortality (1). Despite the fact that the division of HF with preserved ejection fraction (HFpEF) varies depending on the cut-off point of the left ventricular ejection fraction (LVEF) used, previous studies have reported that HFpEF accounted for ~50% of patients with HF (2). Unlike HF with reduced EF (HFrEF), HFpEF is characterized by heterogenetic pathophysiology processes and various co-morbidities (3).
Hyponatremia, defined as a serum sodium levels of <135 mmol/l, is one of the major electrolyte disorders in acute hospitalized patients (4), and its prevalence in patients with acute HF (AHF) was estimated to be ≤25% (5-7). HF involves fluid retention in the body and diuretics are normally used to induce a negative balance of sodium in patients with HF, and all of this may lead to hyponatremia. A lower serum sodium level in AHF may indicate poor water excretion attributed to cardio-renal insufficiency, which is linked to a worse clinical outcome. Previous studies have revealed that hyponatremia is an independent predictor of mortality and re-hospitalization for patients with HFrEF (7,8) and has been demonstrated in HFpEF populations (9,10). However, there is limited data on the burden of hyponatremia and its complications in patients with HFpEF in China and any other Asian countries.
To the best of our knowledge, the prevalence and factors associated with hyponatremia among patients with HFpEF have not been studied in China or other Asian countries. Therefore, the aim of the present study was to examine the clinical characteristics of subjects with hyponatremia via a prospective observational study with a cohort of patients with HFpEF and examine the prognostic value regarding adverse outcomes.
Materials and methods
Study population
In the present prospective observational study, consecutive symptomatic patients with HF hospitalized for the treatment of decompensated HFpEF from Shanghai 10th People's Hospital, Tongji University School of Medicine (Shanghai, China) between July 2017 and December 2018 were enrolled. The study protocol was approved by the Ethics Committee of Shanghai 10th People's Hospital (Shanghai, China). Written informed consent for medical treatment was provided by each patient on admission. The present study was based on a previously registered clinical trial (NCT04062500). Symptomatic HFpEF was defined based on the Framingham criteria (11) and a left ventricular ejection fraction (LVEF) of >50%. In line with previous studies, patients were ≥18 years of age and met the Framingham criteria for the diagnosis of HF (presence of either two major criteria or combination of one major criterion and two minor criteria). Patients with severe liver disease, trauma, infection and recent surgery were excluded. A flow diagram depicting the movement of the patients throughout the study is presented in Fig. 1.
Blood samples and echocardiography were obtained within 24 h of hospitalization of admission before any treatment was given. Echocardiographic parameters were measured by experienced echocardiographic cardiologists according to the recommendations of the American Society of Echocardiography (12). The left atrial diameter, measured as the diameter from the anterior to the posterior side of the left atrium, the left ventricular end-systolic diameter and the left ventricular end-diastolic diameter were determined in the parasternal long-axis view. The left ventricular ejection fraction was calculated using a biplane methods of disc (modified Simpson's rule) in four-chamber view (13).
The patients' medical history and current medical treatment of angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blocker, β-blockers, aldosterone antagonists, loop diuretics, antiplatelet agents, oral anticoagulants and calcium channel blockers were collected. Cardiac function was evaluated using the New York Heart Association (NYHA) classification (1).
Data preparation and outcome measures
Patients were categorized depending on their level of sodium on first admission to the center. Each patient was assigned to either the hyponatremia group if serum sodium was <135 mmol/l or the non-hyponatremia group if sodium was ≥135 mmol/l. The follow-up period of the patients was 24 months. Clinical events, including all-cause mortality, re-hospitalization for HF and stroke, were recorded via telephone enquiry and searching of the patients' electronic medical records. The prognostic value of hyponatremia for the outcomes of patients with HFpEF was investigated.
Statistical analysis
Continuous, normally distributed variables are presented as the mean ± standard deviation and non-normally distributed data as the median (interquartile range). Data were compared using the independent-samples Student's t-test or by one-way analysis of variance and the Mann-Whitney U-test, as appropriate. Categorical data are presented as n (%) and compared using Pearson's χ2-test.
Univariate logistic regression analysis was used to assess the influence of relevant variables on hyponatremia that were derived from a comparison of baseline characteristics and published literature (14). In addition, multivariate logistic regression analysis was performed to determine whether they have a significant influence on the outcomes. Cumulative survival rates were calculated according to the Kaplan-Meier method with the log-rank test used for comparison between hyponatremia and non-hyponatremia groups, setting statistical power by assuming an event rate of 0.3 for all-cause mortality, re-hospitalization for HF and stroke.
Cox-proportional hazards models were used to calculate the hazard ratio (HR) with corresponding 95% CI for occurrence of the primary study end-points (all-cause mortality, re-hospitalization for HF and stroke) associated with each pattern of hyponatremia development. All-cause mortality was adjusted by age, sex, body mass index (BMI), systolic blood pressure (SBP), hyponatremia, N-terminal pro B-type natriuretic peptide (NT-proBNP), NYHA class, atrial fibrillation history, estimated glomerular filtration rate (eGFR) and hemoglobin. Re-hospitalization for HF was adjusted by age, sex, BMI, SBP, hyponatremia, NT-proBNP, NYHA class, atrial fibrillation history, eGFR and hemoglobin. Furthermore, stroke was adjusted by age, sex, SBP, hyponatremia, D-dimer, atrial fibrillation history, anti-platelet use and statin use.
P<0.05 was considered to indicate statistical significance. All statistical analyses were performed using SPSS v.25 (IBM Corp.).
Results
Baseline clinical characteristics of patients with HFpEF
In total, 496 patients with HFpEF (mean age, 72.8±11.6 years; 53.0% males) were included and the mean serum sodium level was 140.1±4.7 mmol/l. Patients with hyponatremia had a mean sodium level of 131.1±3.6 mmol/l. Baseline characteristics of patients with HFpEF are presented in Table I. The hyponatremia group had a significantly lower blood pressure (SBP, 112.1±13.1 vs. 137.1±22.5 mmHg, P<0.001; diastolic blood pressure (DBP), 67.7±11.6 vs. 76.9±12.4 mmHg, P=0.002) and hemoglobin levels (113.4±14.4 vs. 123.2±22.1 g/l, P<0.001) but higher NT-proBNP [1,168.0 (586.1-3,000.0) vs. 1,046.0 (525.8-2,380.5), P<0.001] and D-dimer levels [0.78 (0.48-1.43) vs. 0.47 (0.27-0.90), P<0.001]. Furthermore, the hyponatremia group contained a larger proportion of patients with a history of atrial fibrillation (49.3 vs. 28.9%, P<0.001). The proportion of patients taking aldosterone antagonists and loop diuretics was higher in the hyponatremia group (59.2 vs. 33.4%, P<0.001; 66.2 vs. 40.2%, P<0.001, respectively). Furthermore, there were no differences in age, sex, percentage of NYHA III-IV, eGFR, lipid profile, blood glucose, echocardiographic parameters and other medications that the patients were taking.
 | Table IBaseline clinical characteristics of patients with heart failure with preserved ejection fraction based on serum sodium status. |
Serum sodium distribution of patients with HFpEF and logistic regression analysis for risk factors of hyponatremia
The distribution of serum sodium levels was analyzed in patients with HFpEF and the majority of patients was within the interval of 141.5-142.4 mmol/l (n=56; Fig. S1).
Univariate logistic regression analyses identified that hyponatremia was positively associated with NT-proBNP >median [odds ratio (OR)=6.045, 95% CI=3.41-10.72], NYHA classification III-IV (OR=2.994, 95% CI=1.714-5.057), atrial fibrillation history (OR=2.100, 95% CI=1.233-3.577), loop diuretics (OR=1.875, 95% CI=1.094-3.215) and spironolactone (OR=1.799, 95% CI=1.058-3.058), but it was negatively associated with β-blockers (OR=0.569, 95% CI=0.331-0.981),SBP (OR=0.946, 95% CI=0.930-0.962) and DBP (OR=0.965, 95% CI=0.945-0.986). Multivariate logistic regression analysis demonstrated that in patients with HFpEF, a higher NT-proBNP (above median, OR=4.521, 95% CI=2.450-9.584) or worse cardiac function (OR=2.275, 95% CI=1.207-4.338) were positively associated with hyponatremia. In addition, a higher SBP (OR=0.942, 95% CI 0.920-0.964) and β-blocker use (OR=0.343, 95% CI=0.186-0.675) were negatively associated with hyponatremia (Table II).
| Table IIUnivariate and multivariate logistic regression analysis for the risk factors of hyponatremia. |
Clinical outcomes of patients with HFpEF
In total, 29 (6%) patients were lost to follow-up, mortality occurred in 71 (15.2%) cases in the first 24 months, 129 (27.6%) patients were re-hospitalized for HF and 77 (16.5%) patients had a stroke. Furthermore, the hyponatremia group had a worse prognosis compared with the non-hyponatremia group. All-cause mortality was 39.1% in the hyponatremia group compared with 11.4% in the non-hyponatremia group (P<0.001). In the hyponatremia group, 40.6% of patients were re-hospitalized for HF, as compared with 25.6% in the non-hyponatremia group (P=0.016). Furthermore, the prevalence of stroke was 28.1% in the hyponatremia group as compared with 14.6% in the non-hyponatremia group (P=0.011; Table III).
| Table IIIOutcomes of patients with HF with preserved ejection fraction based on serum sodium status. |
Survival analysis
The median duration of the follow up of the study participants was 24 months. The number of mortalities in the hyponatremia group was 25 (39.1% of patients) compared with 46 in the non-hyponatremia group (11.4% of patients). Kaplan-Meier survival curves (Fig. 2) indicated that there were significant differences in survival status, re-hospitalization and stroke between the two groups of patients with HFpEF. In addition, patients with sodium levels ≥135 mmol/l had an improved prognosis compared with patients with hyponatremia.
In order to investigate the predictors of adverse events in patients with HFpEF, a multivariate Cox proportion hazard regression model was established for all-cause mortality, re-hospitalization and stroke (Fig. 3). It was indicated that hyponatremia was an independent predictor for three adverse events in patients with HFpEF (all-cause mortality: Adjusted HR=1.54, 95% CI=1.07-2.91, P=0.034; re-hospitalization: Adjusted HR=1.28, 95% CI=1.16-2.47, P=0.013; stroke: Adjusted HR=1.78, 95% CI=1.04-2.89, P=0.016). Another independent predictor for all-cause mortality was older age (adjusted HR=1.07, 95% CI=1.05-1.09, P<0.001). Furthermore, lower SBP (adjusted HR=0.97, 95% CI=0.97-0.98, P<0.001), NT-proBNP >median (adjusted HR=1.62, 95% CI=1.05-3.03, P=0.027), NYHA III-IV (adjusted HR=1.73, 95% CI=1.07-2.81, P=0.021), AF history (adjusted HR=2.69, 95% CI=1.32-3.58, P<0.001) and eGFR<60 ml/min/1.73 m2 (adjusted HR=0.51, 95% CI=0.28-0.91, P=0.024) were significantly associated with all-cause mortality. Other independent predictors for re-hospitalization were older age (adjusted HR=1.04, 95% CI=1.02-1.07, P=0.008), lower SBP (adjusted HR=0.96, 95% CI=0.95-0.99, P=0.001), NT-proBNP >median (adjusted HR=1.24, 95% CI=1.03-2.08, P=0.042), NYHA III-IV (adjusted HR=2.15, 95% CI=2.02-2.46, P=0.001) and additional AF history (adjusted HR=1.48, 95% CI=1.05-2.20, P=0.003). In addition, other independent predictors for stroke were lower SBP (HR=0.99, 95% CI=0.98-0.99, P=0.042), higher D-dimer levels (HR=1.96, 95% CI=1.30-2.59, P=0.025) and atrial fibrillation history (HR=1.34, 95% CI=1.15-2.47, P=0.018).
Discussion
In the present observational study, it was indicated that hyponatremia was associated with higher all-cause mortality and re-hospitalization for HF in a cohort of patients with HFpEF; these results were consistent with those of previous studies (14-16). Furthermore, patients with HFpEF with hyponatremia had lower blood pressure, higher serum levels of NT-proBNP and D-dimer, serious anemia and atrial fibrillation, as well as higher rate of medication used, such as spironolactone and loop diuretics, which suggested that the disease in those patients was more serious and should be actively treated. To the best of our knowledge, the present study was the first to demonstrate that hyponatremia was an independent predictor of the incidence of stroke in a patient population with HFpEF.
HFpEF is an increasingly prevalent phenotype of HF. Unlike those for HFrEF, the diagnosis and treatment of HFpEF are not well-standardized, rendering numerous patients with HFpEF misdiagnosed or underdiagnosed. In this situation, the disease may further progress due to poor appetite and low-sodium diet (insufficient intake), and a high dose of diuretic agents (excessive loss), leading to electrolyte disorders, particularly hyponatremia (16).
Hyponatremia is the most common electrolyte disorder (17) and is frequently encountered in patients with HF. It may either arise from depletion (excessive sodium depletion), which is caused by extensive administration of diuretics as aforementioned, or dilution, which is caused by impaired glomerular filtration. Therefore, dilutional hyponatremia in patients with HF with impaired renal function likely results in volume overload, which deteriorates the condition and subsequently leads to a worse prognosis (16). Thus, hyponatremia is an adverse marker of a significant underlying disease and may enhance the severity and complexity of HF. The present results suggested a high incidence of hyponatremia of 14.3% in hospitalized patients with HF, which is comparable to that reported by other studies on acute decompensated HF (7,18,19).
The causes of hyponatremia are miscellaneous, as the present results suggested that a higher NYHA class and NT-proBNP levels increase the risk, while usage of renin-angiotensin-aldosterone system (RAAS) inhibitor and β-blockers reduce the risk. On one hand, it has been reported that NYHA class and NT-proBNP correlate with the severity of HF (14). While patients with severe HF require a large dosage of diuretics, this will lead to disturbance of homeostasis and pose a higher risk for hyponatremia. The present results support this concept and are consistent with those of previous studies (20). One the other hand, dilutional hyponatremia resulting from concomitant activation of the RAAS and sympathetic nervous system may be counteracted by the use of RAAS inhibitor or β-blockers (21,22). This is also in line with the present results.
Previous studies have reported that hyponatremia was associated with worse short-term, mid-term and long-term outcomes (1,19,23). In the OPTIMIZE-HF (24) and OPTIME-CHF (19) trials, following a drop in serum sodium levels (per 3 mmol/l decrease from 140 mmol/l), the OR of in-hospital mortality, 60-day mortality and 60-90 day mortality was 1.25, 1.18 and 1.10, respectively. In the present study, all-cause mortality was 13.9% in patients with HFpEF, which is lower than the rates obtained in other trials (OPTIME-CHF, 27%; ACTIV-in-CHF, 21%) (5,19). Furthermore, hyponatremia was associated with a 2-fold increased risk of 24-month all-cause mortality. Hence, hyponatremia is a valuable predictor of prognosis in patients with HF.
A number of factors contribute to the poor outcomes in patients with HFpEF with hyponatremia. For instance, HF progression is closely linked to the activation of the neuroendocrine system, which is classically represented by the RAAS. Furthermore, hyponatremia may directly upregulate the activity of RAAS and arginine vasopressin (AVP), which increase the heart rate, vessel constriction and renal urine reabsorption. However, excessive activation of the neuroendocrine system may result in adverse effects, including increased cardiac afterload and myocardial oxygen consumption, cardiac cell death and myocardial fibrosis (25). However, the amount of BNP secreted into the circulation of patients with exacerbation inhibits the release of aldosterone to facilitate natriuresis (26,27).
To the best of our knowledge, the present study was the first to demonstrate that hyponatremia (OR=1.78, 95% CI=1.04, 2.89, P=0.016) was a stronger predictor of stroke in patients with HFpEF. Furthermore, a previous study reported that hyponatremia was associated with stroke (28). Aberrant serum sodium levels are also considered as a complication of cerebrovascular disease (29), and the possible mechanisms are associated with inappropriate secretion of antidiuretic hormone, frequent use of diuretics, as well as blood concentration and viscosity (30).
Since hyponatremia is independently associated with poor outcomes, correcting hyponatremia in a timely and appropriate manner may improve the prognosis of patients with HFpEF. There are different treatment options, the first of which includes a daily fluid allowance of 800-100 ml. As another option, the addition of furosemide with an ACEI is able to significantly improve the sodium concentration. In addition, arginine vasopressin (AVP) receptor antagonists, which have a central role in regulating water retention via these receptors, may be used. It has been revealed that anemia, NT-proBNP and NYHA cardiac function not only have an impact on the risk of mortality, but also on the incidence of hyponatremia (14,31), which should be corrected as soon as possible.
The present study had several limitations. First, it was designed as an observational study and was potentially open to selection bias, as patients with severe liver disease, trauma, infection and recent surgery were excluded. Furthermore, the etiology of hyponatremia was not surveyed in the patients. The present study did not differentiate true hyponatremia from pseudo-hyponatremia and did not analyze depletion and dilution hyponatremia, but the prognosis and treatment were different between them (32). In addition, tolvaptan and AVP receptor antagonists were not widely used in the current cohort and these should be further examined to assess their effect on patients with HFpEF. Due to potential recall bias when performing the subgroup analysis, the present study did not avoid the influence of the history of atrial fibrillation on the incidence of stroke.
In conclusion, the present results indicated that hyponatremia on admission may be a useful prognostic marker for patients with HFpEF. However, larger studies are required to be performed to confirm these results, as well as to elucidate the mechanisms of mortality and stroke associated with hyponatremia and identify the potential benefit of correction of hyponatremia in patients with HFpEF.
Supplementary Material
Frequency distribution of serum sodium levels within the cohort.
Acknowledgements
Not applicable.
Funding
This work was supported by a grant from the National Nature Science Foundation of China (grant no. 81270194).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
Conception and design: YS, YL, CY. Clinical support and acquisition of data: YS, YL, CY. Provision of study materials or patients: YS, YL. Collection and collation of data: YS, MM, HZ, XP, XZ and FZ. Data analysis and interpretation: YS, YL. Manuscript writing: YS, MM, HZ, YL, CY. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The study protocol was approved by the Research Ethical Committee of Shanghai 10th People's Hospital of Tongji University School of Medicine (Shanghai, China) and conducted according to the principles expressed in the Declaration of Helsinki. The data were retrieved from the hospital's medical record system and therefore, no additional informed consent was required. The institutional review board also waived the need for written informed consent from the participants. The privacy of patients' personal data was protected.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, et al: 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC). Developed with the special contribution of the heart failure association (HFA) of the ESC. Eur J Heart Fail. 18:891–975. 2016.PubMed/NCBI View Article : Google Scholar | |
|
Dunlay SM, Roger VL and Redfield MM: Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 14:591–602. 2017.PubMed/NCBI View Article : Google Scholar | |
|
Ge J: Coding proposal on phenotyping heart failure with preserved ejection fraction: A practical tool for facilitating etiology-oriented therapy. Cardiol J. 27:97–98. 2020.PubMed/NCBI View Article : Google Scholar | |
|
Mohan S, Gu S, Parikh A and Radhakrishnan J: Prevalence of hyponatremia and association with mortality: Results from NHANES. Am J Med. 126:1127–1137.e1. 2013.PubMed/NCBI View Article : Google Scholar | |
|
Rossi J, Bayram M, Udelson JE, Lloyd-Jones D, Adams KF, Oconnor CM, Stough WG, Ouyang J, Shin DD, Orlandi C and Gheorghiade M: Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: Insights from the acute and chronic therapeutic impact of a vasopressin antagonist in chronic heart failure (ACTIV in CHF) trial. Acute Card Care. 9:82–86. 2007.PubMed/NCBI View Article : Google Scholar | |
|
Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O'Connor CM, She L, Yancy CW, Young J and Fonarow GC: OPTIMIZE-HF Investigators and Coordinators. 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. 28:980–988. 2007.PubMed/NCBI View Article : Google Scholar | |
|
Gheorghiade M, Rossi JS, Cotts W, Shin DD, Hellkamp AS, Piña IL, Fonarow GC, DeMarco T, Pauly DF, Rogers J, et al: Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial. Arch Intern Med. 167:1998–2005. 2007.PubMed/NCBI View Article : Google Scholar | |
|
Lu DY, Cheng HM, Cheng YL, Hsu PF, Huang WM, Guo CY, Yu WC, Chen CH and Sung SH: Hyponatremia and worsening sodium levels are associated with long-term outcome in patients hospitalized for acute heart failure. J Am Heart Assoc. 5(e002668)2016.PubMed/NCBI View Article : Google Scholar | |
|
Patel YR, Kurgansky KE, Imran TF, Orkaby AR, McLean RR, Ho YL, Cho K, Gaziano JM, Djousse L, Gagnon DR and Joseph J: Prognostic significance of baseline serum sodium in heart failure with preserved ejection fraction. J Am Heart Assoc. 7(e007529)2018.PubMed/NCBI View Article : Google Scholar | |
|
Park JJ, Cho YJ, Oh IY, Park HA, Lee HY, Kim KH, Yoo BS, Kang SM, Baek SH, Jeon ES, et al: Short and long-term prognostic value of hyponatremia in heart failure with preserved ejection fraction versus reduced ejection fraction: An analysis of the Korean acute heart failure registry. Int J Cardiol. 248:239–245. 2017.PubMed/NCBI View Article : Google Scholar | |
|
McKee PA, Castelli WP, McNamara PM and Kannel WB: The natural history of congestive heart failure: The Framingham study. N Engl J Med. 285:1441–1446. 1971.PubMed/NCBI View Article : Google Scholar | |
|
Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al: Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American society of echocardiography and the European association of cardiovascular imaging. J Am Soc Echocardiogr. 28:1–39.e14. 2015.PubMed/NCBI View Article : Google Scholar | |
|
Cabuk AK, Cabuk G, Sayin A, Karamanlioglu M, Kilicaslan B, Ekmekci C, Solmaz H, Aslanturk OF and Ozdogan O: Do we overestimate left ventricular ejection fraction by two-dimensional echocardiography in patients with left bundle branch block? Echocardiography. 35:148–152. 2018.PubMed/NCBI View Article : Google Scholar | |
|
Bavishi C, Ather S, Bambhroliya A, Jneid H, Virani SS, Bozkurt B and Deswal A: Prognostic significance of hyponatremia among ambulatory patients with heart failure and preserved and reduced ejection fractions. Am J Cardiol. 113:1834–1838. 2014.PubMed/NCBI View Article : Google Scholar | |
|
Kusaka H, Sugiyama S, Yamamoto E, Akiyama E, Matsuzawa Y, Hirata Y, Fujisue K, Kurokawa H, Matsubara J, Sugamura K, et al: Low-normal serum sodium and heart failure-related events in patients with heart failure with preserved left ventricular ejection fraction. Circ J. 80:411–417. 2016.PubMed/NCBI View Article : Google Scholar | |
|
Rusinaru D, Buiciuc O, Leborgne L, Slama M, Massy Z and Tribouilloy C: Relation of serum sodium level to long-term outcome after a first hospitalization for heart failure with preserved ejection fraction. Am J Cardiol. 103:405–410. 2009.PubMed/NCBI View Article : Google Scholar | |
|
Upadhyay A, Jaber BL and Madias NE: Incidence and prevalence of hyponatremia. Am J Med. 119 (7 Suppl 1):S30–S35. 2006.PubMed/NCBI View Article : Google Scholar | |
|
Gheorghiade M, Gattis WA, O'Connor CM, Adams KF Jr, Elkayam U, Barbagelata A, Ghali JK, Benza RL, McGrew FA, Klapholz M, et al: Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA. 291:1963–1971. 2004.PubMed/NCBI View Article : Google Scholar | |
|
Klein L, O'Connor CM, Leimberger JD, Gattis-Stough W, Piña IL, Felker GM, Adams KF Jr, Califf RM and Gheorghiade M: OPTIME-CHF Investigators. 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. 111:2454–2460. 2005.PubMed/NCBI View Article : Google Scholar | |
|
Stolfo D, Uijl A, Vedin O, Strömberg A, Faxén UL, Rosano GMC, Sinagra G, Dahlström U and Savarese G: Sex-based differences in heart failure across the ejection fraction spectrum: Phenotyping, and prognostic and therapeutic implications. JACC Heart Fail. 7:505–515. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Baldasseroni S, Urso R, Orso F, Bianchini BP, Carbonieri E, Cirò A, Gonzini L, Leonardi G, Marchionni N and Maggioni AP: IN-CHF Investigators. Relation between serum sodium levels and prognosis in outpatients with chronic heart failure: Neutral effect of treatment with beta-blockers and angiotensin-converting enzyme inhibitors: Data from the Italian network on congestive heart failure (IN-CHF database). J Cardiovasc Med (Hagerstown). 12:723–731. 2011.PubMed/NCBI View Article : Google Scholar | |
|
Lee WH and Packer M: Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation. 73:257–267. 1986.PubMed/NCBI View Article : Google Scholar | |
|
Yoo BS, Park JJ, Choi DJ, Kang SM, Hwang JJ, Lin SJ, Wen MS, Zhang J and Ge J: COAST investigators. Prognostic value of hyponatremia in heart failure patients: An analysis of the clinical characteristics and outcomes in the relation with serum sodium level in asian patients hospitalized for heart failure (COAST) study. Korean J Intern Med. 30:460–470. 2015.PubMed/NCBI View Article : Google Scholar | |
|
Abraham WT, Fonarow GC, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, O'Connor CM, Sun JL, Yancy CW and Young JB: OPTIMIZE-HF Investigators and Coordinators. Predictors of in-hospital mortality in patients hospitalized for heart failure: Insights from the organized program to initiate lifesaving treatment in hospitalized patients with heart failure (OPTIMIZE-HF). J Am Coll Cardiol. 52:347–356. 2008.PubMed/NCBI View Article : Google Scholar | |
|
Vergaro G, Aimo A, Prontera C, Ghionzoli N, Arzilli C, Zyw L, Taddei C, Gabutti A, Poletti R, Giannoni A, et al: Sympathetic and renin-angiotensin-aldosterone system activation in heart failure with preserved, mid-range and reduced ejection fraction. Int J Cardiol. 296:91–97. 2019.PubMed/NCBI View Article : Google Scholar | |
|
Azim A and Jena S: BNP: Is it an ideal marker to assess volume status in patients with hyponatremia and natriuresis? Neurol India. 66:1392–1393. 2018.PubMed/NCBI View Article : Google Scholar | |
|
Tobin G, Chacko AG and Simon R: Evaluation of NT-ProBNP as a marker of the volume status of neurosurgical patients developing hyponatremia and natriuresis: A pilot study. Neurol India. 66:1383–1388. 2018.PubMed/NCBI View Article : Google Scholar | |
|
Wannamethee G, Whincup PH, Shaper AG and Lever AF: Serum sodium concentration and risk of stroke in middle-aged males. J Hypertens. 12:971–979. 1994.PubMed/NCBI | |
|
Zheng B, Qiu Y, Jin H, Wang L, Chen X, Shi C and Zhao S: A predictive value of hyponatremia for poor outcome and cerebral infarction in high-grade aneurysmal subarachnoid haemorrhage patients. J Neurol Neurosurg Psychiatry. 82:213–217. 2011.PubMed/NCBI View Article : Google Scholar | |
|
Writing Group Members. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, et alHeart disease and stroke statistics-2016 update: A report from the American heart association. Circulation. 133:e38–e360. 2016.PubMed/NCBI View Article : Google Scholar | |
|
McGirt MJ, Blessing R, Nimjee SM, Friedman AH, Alexander MJ, Laskowitz DT and Lynch JR: Correlation of serum brain natriuretic peptide with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage. Neurosurgery. 54:1369–1373; discussion 1373-1364. 2004.PubMed/NCBI View Article : Google Scholar | |
|
Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WH and Mullens W: Hyponatremia in acute decompensated heart failure: Depletion versus dilution. J Am Coll Cardiol. 65:480–492. 2015.PubMed/NCBI View Article : Google Scholar |
