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Prognostic impact of small pericardial effusion in acute heart failure

      Abstract

      Background

      The relationship between small pericardial effusion (SPE) and outcomes has not been well studied in patients with heart failure. Therefore, we aimed to investigate the prevalence and importance of SPE in acute heart failure (AHF).

      Methods

      A total of 398 hospitalized patients with AHF were retrospectively reviewed. Patients’ baseline demographic, clinical, echocardiographic, and laboratory characteristics were noted. SPE was defined as the presence of a pericardial effusion <10 mm. The primary outcome was one-year mortality.

      Results

      SPE was noted in 54 (13.6%) of the patients. Mortality at one year was greater for patients with a small effusion compared with those without SPE (44.4 vs. 11.4%, respectively; p < 0.001), and the one-year mortality rate for the whole group was 15.8%. Age (HR = 1.12, 95% CI 1.054–1.854, p = 0.024), N-terminal pro-B-type natriuretic peptide >4800 pg/ml (HR = 1.628, 95% CI 01.102–4.805, p = 0.001), left ventricular ejection fraction <30% (HR = 1.878, 95% CI 1.154–4.524, p = 0.001), and presence of SPE (HR = 1.567, 95% CI 1.122–2.991, p = 0.005) were independent predictors of one-year mortality on multivariate analysis.

      Conclusions

      The presence of SPE on admission was an independent predictor of one-year mortality in AHF.

      Keywords

      Introduction

      The prognosis of moderate or large pleural and pericardial effusion is associated with the etiology of the effusion in various diseases.
      • Vakamudi S.
      • Ho N.
      • Cremer P.C.
      Pericardial effusions: causes, diagnosis, and management.
      ,
      • Yusuf S.W.
      • Hassan S.A.
      • Mouhayar E.
      • et al.
      Pericardial disease: a clinical review.
      However, the clinical importance of trivial and hemodynamically insignificant pericardial effusion has not been well studied in different patient populations. In heart failure, the main cause of pleural effusion is increased left heart filling pressure, increased right heart filling pressure, or both, whereas pericardial effusion is generated only if the filling pressures of the right heart are increased.
      • Natanzon A.
      • Kronzon I
      Pericardial and pleural effusions in congestive heart failure-anatomical, pathophysiologic, and clinical considerations.
      Therefore, pericardial effusions are less common than pleural effusions in chronic heart failure (CHF).
      • Imazio M.
      • Adler Y.
      Management of pericardial effusion.
      However, small pericardial effusion (SPE) is not an uncommon finding for patients with acute heart failure (AHF) or chronic heart failure (CHF) in real-life clinical practice.
      • Maisch B.
      Pericardial diseases, with a focus on etiology, pathogenesis, pathophysiology, new diagnostic imaging methods, and treatment.
      Previous studies showed that presence or development of SPE was associated with adverse events in patients with lung cancer,
      • Kato R.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Prognostic impact of minimal pericardial effusion in patients with advanced non-small cell lung cancer.
      acute ischemic stroke,
      • Biteker M.
      • Tekkeşin A.I.
      • et al.
      A novel prognostic marker in acute ischemic stroke: small pericardial effusion.
      human immunodeficiency virus infection,
      • Heidenreich P.A.
      • Eisenberg M.J.
      • Kee L.L.
      • et al.
      Pericardial effusion in AIDS. Incidence and survival.
      and pneumonia,
      • Biteker F.S.
      • Biteker M.
      • Başaran Ö.
      • et al.
      A small pericardial effusion is a marker of complicated hospitalization in patients with community-acquired pneumonia.
      as well as in heart transplant patients
      • Stämpfli S.F.
      • Özkartal T.
      • Hagenbuch N.
      • et al.
      Pericardial effusion unrelated to surgery is a predictor of mortality in heart transplant patients.
      and patients undergoing hip fracture surgery.
      • Açan A.E.
      • Gültaç E.
      • Kılınç C.Y.
      • et al.
      Preoperative mild pericardial effusion is associated with perioperative complications in elderly patients following hip fracture surgery.
      Although the prevalence of SPE varied from 12 to 20% in patients with heart failure,
      • Kataoka H.
      Pericardial and pleural effusions in decompensated chronic heart failure.
      ,
      • Kessler K.M.
      • Rodriguez D.
      • Rahim A.
      • et al.
      Echocardiographic observations regarding pericardial effusions associated with cardiac disease.
      only one study has examined the association between SPE and prognosis in CHF,
      • Fröhlich G.M.
      • Keller P.
      • Schmid F.
      • et al.
      Haemodynamically irrelevant pericardial effusion is associated with increased mortality in patients with chronic heart failure.
      and only one study has investigated the prognostic value of SPE in AHF.
      • Santas E.
      • Sandino J.
      • Chorro F.J.
      • et al.
      Prognostic implications of pericardial effusion in acute heart failure: does size matter?.
      Therefore, the present study aimed to examine the frequency and prognostic relevance of SPE in AHF.

      Methods

      Ethics statement

      The study protocol was approved by the University of Health Sciences, Derince Education and Research Hospital Ethics Committee. Consent was not required due to the retrospective nature of the study. The study was conducted in accordance with the principles of the Declaration of Helsinki.

      Study design

      This was a single-center, retrospective study, including all consecutive patients with AHF hospitalized between December 2016 and March 2019. Patients aged 18 years or older who had undergone transthoracic echocardiography within the first 24 h of admission were eligible for inclusion. Patients with incomplete echocardiographic or laboratory data, patients with a history of chronic inflammatory disease or an active cancer, patients who had undergone cardiac or thoracic surgery within the last 12 months, or patients who had an acute myocardial infarction within the previous six months were excluded from the study. Patients with a pericardial effusion >10 mm and patients with inadequate echocardiographic visualization were also excluded. Demographic information, past medical history, vital signs, and electrocardiographic, echocardiographic, and laboratory data on admission were noted. Transthoracic echocardiography was performed in all patients, and the severity of valvular heart disease was defined according to the current guidelines.
      • Baumgartner H.
      • Falk V.
      • Bax J.J.
      • et al.
      2017 ESC/EACTS Guidelines for the management of valvular heart disease.
      The pericardial effusion was defined as SPE when the maximum pericardial space at end-diastole was <10 mm. Patients with moderate or greater pericardial effusion (>10 mm) were excluded from the study. The primary etiology of AHF was classified as ischemic heart failure, idiopathic dilated cardiomyopathy, hypertensive heart failure, and other reasons. The other reasons were primary valvular heart diseases, alcoholic cardiomyopathy, peripartum cardiomyopathy, infectious cardiomyopathy, diabetic cardiomyopathy, and drug-induced cardiomyopathy. Data for patients’ survival status were collected by phone call or from an electronic database at the end of the first year. The primary outcome was all-cause mortality at 12 months.

      Statistical analysis

      Data were analyzed using SPSS for Windows version 20.0 (IBM, Armonk, NY, USA). The impact of parameters on prognosis was evaluated using univariate and multivariable Cox proportional hazards analyses. Age, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction, comorbid diseases, and presence of SPE were forced in models to adjust the multivariate analysis. Receiver operating characteristic (ROC) curves for independent parameters were drawn, and the areas under the curves were calculated. For a specific parameter, the cutoff level that resulted in the highest sensitivity and specificity was an optimal cutoff value for prognostication. Kaplan-Meier methods were used to estimate rates of death after AHF. For all analyses, p < 0.05 was considered statistically significant.

      Results

      Patient characteristics

      A total of 490 patients were hospitalized with a primary diagnosis of AHF during the study period. However, 92 of the patients were excluded from the study for various reasons (Fig. 1). Therefore, the final study population consisted of 398 patients (mean age 73.4 ± 8.7 years, 51.5% male). The most common cause of AHF was ischemic cardiomyopathy (43.5%), and the most common comorbid disease was hypertension (72.1%) in our study population. The mean left ventricular ejection fraction was 38.1 ± 15.2%, and 105 (26.4%) of the patients had preserved left ventricular ejection fraction at presentation.
      Fig 1
      Figure 1Flowchart of study population selection. Abbreviations: AHF, acute heart failure;,MI, myocardial infarction.
      Fifty-four of the patients (13.6%) had SPE on admission. Comparison of patients with and without SPE is presented in Table 1. There were no significant differences between the two groups in terms of age, gender, smoking, etiology of heart failure, prevalence of diabetes, hypertension, chronic renal or liver disease, and malignancy. However, patients with an effusion were more likely to have coronary artery disease and atrial fibrillation and had lower albumin, higher creatinine, higher NT-proBNP, and higher high-sensitivity C-reactive protein (hsCRP) levels on admission compared with patients without effusion. The left ventricular ejection fraction was similar in the two groups.
      TABLE 1Comparison of patients with and without small pericardial effusion.
      SPE (+) (n = 54)SPE (-) (n = 344)P value
      Gender (male)29 (53.7)176 (51.2)0.875
      Age (years)73.2 ± 10.473.7 ± 12.50.232
      Etiology
      Ischemic25 (46.3)148 (43.0)0.105
      Hypertensive15 (27.8)78 (22.7)
      Idiopathic dilated cardiomyopathy10 (18.5)50 (14.5)
      Other10 (18.5)72 (20.9)
      Comorbidities
      Atrial fibrillation20 (37.1)99 (28.8)0.035
      Smoking9 (16.7)45 (13.0)0.847
      Diabetes mellitus14 (25.9)85 (24.7)0.527
      Hypertension40 (74.1)247 (71.8)0.951
      Chronic renal failure4 (7.4)16 (4.7)0.098
      Chronic liver disease2 (3.7)8 (2.3)0.711
      Malignancy4 (7.4)18 (5.2)0.621
      Coronary artery disease32 (59.3)175 (50.9)0.012
      Laboratory results
      NT-proBNP (pg/ml)4241 (1799–12,371)3678 (1491–11,629)0.002
      Hemoglobin (g/dL)13.1 ± 2.413.2 ± 2.20.613
      Albumin (g/dL)3.58 ± 0.353.70 ± 0.390.041
      Creatinine (mg/dL)1.39 ± 1.231.32 ± 1.120.042
      hsCRP (mg/dl)1.52 (0.44–6.72)0.86 (0.38–3.34)<0.001
      Echocardiography
      ≥Moderate mitral regurgitation25 (46.3)80 (23.3)<0.001
      ≥Moderate tricuspid regurgitation30 (55.6)150 (43.6)0.036
      Pulmonary systolic pressure (mmHg)34.6 ± 8.330.8 ± 4,30.025
      Left ventricle ejection fraction (%)37.8 ± 14.938.5 ± 14.60.082
      Mortality24 (44.4)39 (11.4)0.001
      Values are given as mean ± SD or number (percentage)
      Abbreviations: SPE, small pericardial effusion; NT-proBNP, N-terminal pro B-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein.

      One-year mortality

      The one-year mortality rate was 15.8%. Results of univariate comparison of baseline clinical, demographic, and laboratory parameters between the two groups (deceased and survivors) are listed in Table 2. Patients who died were older and more often had coronary artery disease, diabetes, or chronic renal failure. There were no differences in medications at discharge between the two groups. Deceased patients had higher levels of creatinine, hsCRP, and NT-proBNP but lower levels of albumin at presentation. Prevalence of the ischemic etiology was more common in deceased patients, whereas the hypertensive etiology was more common in the survivors. Non-survivors had a lower left ventricular ejection fraction and were more likely to have mitral regurgitation at presentation. Mortality at one year was higher in patients with SPE compared with those without pericardial effusion (44.4 vs. 11.4%, respectively; p < 0.001) (Fig. 2).
      TABLE 2Patient characteristics by vital status at 12 months.
      Alive (n = 335)Deceased (n = 63)P value
      Gender (male)172 (51.3)33 (52.4)0.165
      Age (years)72.4 ± 8.976.8 ± 8.5<0.001
      Etiology
      Ischemic140 (41.8)33 (52.4)0.003
      Hypertensive85 (25.4)8 (12.7)
      Idiopathic dilated cardiomyopathy50 (14.9)10 (15.9)
      Other61 (18.2)21 (33.3)
      Comorbidities
      Atrial fibrillation105 (31.3)14 (22.2)0.089
      Smoking44 (13.1)10 (15.9)0.447
      Diabetes mellitus80 (23.9)19 (30.2)0.045
      Hypertension250 (74.6)37 (58.7)0.001
      Chronic renal failure13 (3.8)7 (11.1)0.036
      Chronic liver disease7 (2.1)3 (4.8)0.166
      Malignancy17 (5.1)5 (7.9)0.411
      Coronary artery disease165 (49.3)43 (68.3)0.002
      Medication at discharge
      ACEI or ARB260 (77.6)49 (77.8)0.865
      Loop diuretics314 (93.7)60 (95.2)0.362
      Thiazides44 (13.1)7 (11.1)0.102
      Beta blockers290 (86.6)55 (87.3)0.754
      MRA230 (68.6)42 (66.7)0.512
      Laboratory results
      NT-proBNP (pg/ml)2564 (1491–8697)5247 (1854–12,391)<0.001
      Hemoglobin (g/dL)13.2 ± 2.313.2 ± 2.40.748
      Albumin (g/dL)3.77 ± 0.463.74 ± 0.410.102
      Creatinine (mg/dL)1.32 ± 1.211.42 ± 1.320.002
      hsCRP (mg/dl)0.75 (0.38–5.31)1.12 (0.51–6.72)0.001
      Echocardiography
      ≥ Moderate mitral regurgitation81 (24.2)24 (38.1)0.025
      ≥ Moderate tricuspid regurgitation150 (44.8)30 (47.6)0.965
      Pulmonary systolic pressure (mmHg)31.6 ± 9.334.8 ± 10.20.085
      Left ventricle ejection fraction (%)38.6 ± 13.935.5 ± 11.60.001
      Small pericardial effusion30 (8.9)24 (38.1)<0.001
      Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker, MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro B-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein.
      Fig 2
      Figure 2Kaplan-Meier curves for all-cause one-year mortality in acute heart failure patients with or without small pericardial effusion (SPE).

      Predictors of one-year mortality

      In univariate analysis, age, diabetes mellitus, coronary artery disease, chronic renal failure, ischemic etiology of AHF, NT-proBNP, creatinine, hsCRP, left ventricular ejection fraction, mitral regurgitation, and presence of SPE were associated with higher one-year mortality rates. However, age (HR = 1.12, 95% CI 1.054–1.854, p = 0.024), NT-proBNP >4800 pg/ml (HR = 1.628, 95% CI 01.102–4.805, p = 0.001), left ventricle ejection fraction <30% (HR = 1.878, 95% CI 1.154–4.524, p = 0.001), and presence of SPE (HR = 1.567, 95% CI 1.122–2.991, p = 0.005) were independent predictors of one-year mortality on multivariate analysis (Table 3).
      TABLE 3Multivariate analysis for the prediction of all-cause mortality at 12 months.
      OR95% ClP
      Age (per 10 y)1.1251.054–1.8540.024
      Ischemic etiology1.0860.985–1.4120.205
      Coronary artery disease (presence vs absent)1.0740.741–3.3770.903
      Hypertension (presence vs absent)0.8750.758–1.1150.125
      Chronic renal disease (presence vs absent)1.1020.848–1.4320.334
      NT-proBNP > 4800pg/ml1.6281.102–4.8050.001
      High-sensitivity C-reactive protein1.0860.913–1.4120.504
      Left ventricle ejection fraction <30%1.8781.154–4.5240.001
      ≥ Moderate mitral regurgitation1.1100.921–1.4120.223
      Small pericardial effusion (presence vs absence)1.5671.122–2.9910.005
      Abbreviation: NT-proBNP, N-terminal pro B-type natriuretic peptide.

      Discussion

      Our study showed that SPE was present in 13.6% of the patients with AHF, and the presence of SPE on admission was associated with a greater risk of one-year mortality in AHF. However, the prevalence and significance of SPE have not been well studied in various cardiovascular conditions. Fröhlich and colleagues analyzed the data of 897 patients with CHF to identify the prognostic value of hemodynamically irrelevant pericardial effusion for one-year mortality.
      • Fröhlich G.M.
      • Keller P.
      • Schmid F.
      • et al.
      Haemodynamically irrelevant pericardial effusion is associated with increased mortality in patients with chronic heart failure.
      They found that 73 (8.1%) of the patients had SPE, and it was independently associated with increased mortality at one year.
      • Fröhlich G.M.
      • Keller P.
      • Schmid F.
      • et al.
      Haemodynamically irrelevant pericardial effusion is associated with increased mortality in patients with chronic heart failure.
      Similar to our findings, they also found that patients with SPE had higher C-reactive protein and NT-proBNP levels at presentation. Santas et al. included 1827 patients with AHF to find the association between pericardial effusion and the risk of one-year mortality.
      • Santas E.
      • Sandino J.
      • Chorro F.J.
      • et al.
      Prognostic implications of pericardial effusion in acute heart failure: does size matter?.
      The prevalence of mild, moderate, and severe pericardial effusion was 11.6%, 1.9%, and 0.9%, respectively, in the study cohort. In multivariate analysis, patients with moderate and severe effusion were at increased risk for mortality compared with those without pericardial effusion. However, AHF patients with SPE showed similar mortality risk with no pericardial effusion.
      • Santas E.
      • Sandino J.
      • Chorro F.J.
      • et al.
      Prognostic implications of pericardial effusion in acute heart failure: does size matter?.
      In contrast to the findings of Santas et al., all-cause mortality at one year was greater for patients with SPE compared with those without an effusion (44.4% vs. 11.4%, p = 0.001) in our study. The main difference in our study was the lower mean left ventricular ejection fraction (38.1%) compared with Santas and colleagues’ study (49.6%).
      Another important finding of our study was that mortality was lower among those with a hypertensive etiology than among those with other causes. Similar to our data, Pecini et al. found that heart failure attributed to hypertensive heart disease had a significantly better prognosis than that attributed to ischemic heart disease, valvular heart disease, dilated cardiomyopathy, or unknown/mixed etiology.
      • Pecini R.
      • Møller D.V.
      • Torp-Pedersen C.
      • et al.
      Heart failure etiology impacts survival of patients with heart failure.
      The pathophysiology of pericardial effusion is unclear in AHF, but increased right heart pressures causing congestion and increased systemic inflammatory response could have an impact on the accumulation of fluid in the pericardial space. The reasons for the increased mortality in patients with SPE are also unclear, but higher burden of comorbid diseases such as atrial fibrillation and coronary artery disease and more severe mitral and tricuspid valve regurgitation are all thought to play a role.

      Study limitations

      Due to the retrospective design of the study, serial changes in SPE could not be assessed by serial echocardiography. Other limitations of this study include the single-center study design, the lack of invasive hemodynamic data, and chest X-ray findings.
      Definitive causes of SPE could not be identified due to lack of pericardial fluid analysis. However, because pericardiocentesis is reserved for hemodynamically significant or large effusions, it cannot be performed in patients with SPE. This was a single-center study, and only hospitalized patients were included. Therefore, our results cannot be directly applied to all patients with AHF. Prospective studies are needed to elucidate the prognostic value of SPE in AHF.

      Conclusions

      We found that 13.6% of the AHF patients had SPE at presentation, and SPE was an independent predictor of mortality at one year.

      Declaration of Competing Interest

      The authors declare that there is no conflict of interest.

      Funding

      This research received no grant from any funding agency in the public, commercial or not-for-profit sectors.

      Appendix. SUPPLEMENTARY MATERIALS

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