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European Journal of Heart Failure 2005 7(5):815-819; doi:10.1016/j.ejheart.2004.10.013
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© 2004 European Society of Cardiology

Echocardiographic ejection fraction in patients with acute heart failure: correlations with hemodynamic, clinical, and neurohormonal measures and short-term outcome

Nir Uriela, Guillermo Torre-Amioneb, Olga Miloa, Edo Kaluskia, Loïc Perchenetc, Alex Blatta, Isaac Kobrinc, Arkadi Turnovskia, Shoshana Kaplana, Maurizio Rainisioc, Aline Freyc, Zvi Vereda and Gad Cotterd,*

a The Cardiology Department Assaf-Harofeh Medical Center, 70300, Zerifin, Israel
b Baylor College of Medicine Houston, TX, USA
c Actelion Pharmaceuticals Ltd Switzerland
d Duke University Medical Center Durham, NC, USA

* Corresponding author. Tel.: +972 8 9779778; fax: +972 8 9779779. E-mail address: cotterg{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
 References
 
Background: Although echocardiographic ejection fraction (EF) is frequently used for the estimation of left ventricular contractility in patients with acute heart failure, its exact role and correlations with clinical, hemodynamic, and neurohormonal variables of cardiac contractility is not known.

Methods: Patients (343) with acute heart failure, enrolled into two prospective placebo-controlled hemodynamic studies of tezosentan, and in whom EF was available at baseline, were included. Outcome was evaluated in a subset of 94 patients who were enrolled in the placebo arms of the studies.

Results: Higher echocardiographic EF was correlated with older age, increased incidence of hypertension and atrial fibrillation, and female gender. We observed weak correlation between EF and cardiac output or cardiac power and no correlation with wedge pressure, and the change in hemodynamic variables over time. Higher EF was correlated with more baseline leukocytosis and higher plasma levels of endothelin-1 and blood urea nitrogen, while lower EF was related to higher baseline B-type natriuretic peptide (BNP). We observed no overall correlations between EF and outcome.

Conclusions: In patients with acute heart failure, echocardiographic EF is weakly correlated with hemodynamic measures of left ventricular contractility and outcome; hence, it should be interpreted cautiously when evaluating patients admitted due to acute heart failure.

Key Words: Acute heart failure • Ejection fraction • Left ventricular contractility

Received July 14, 2004; Revised August 5, 2004; Accepted October 14, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
 References
 
Acute heart failure is the most common cause for hospital admission in patients older than 65 years [1,2]. Although many clinical and laboratory parameters have been found to correlate with the prognosis of acute heart failure, the role of echocardiographic left ventricular ejection fraction (EF) in estimation of left ventricular systolic dysfunction and hence the pathogenesis and risk stratification of acute heart failure has not been determined. In previous studies, it has been suggested that as many as 40–55% of patients with signs and symptoms of heart failure have preserved systolic function [3–5]. These patients have a distinct background; they tend to be older, female, suffer from hypertension and are less likely to have a history of myocardial infarction [6,7]. Also, it was demonstrated that their long-term prognosis is somewhat better than for patients with heart failure and reduced EF. In this study, we examined the relationship between EF measured by echocardiography and clinical features, invasive hemodynamic parameters, neurohormonal factors, and short-term outcome in a cohort of patients admitted to the hospital due to acute heart failure, who were monitored using Swan-Ganz catheters.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
 References
 
The present cohort was based on analysis of patients included in two major double-blind, prospective randomized hemodynamic studies examining the effect of tezosentan (an endothelin antagonist) in patients with acute heart failure during the years 2000 to 2002 [8,9]. Out of the 414 patients enrolled in the studies, the following analysis included 349 patients in whom echocardiographic EF was available at baseline. EF was measured by the method commonly used in the centers, without central standardization. Patients with heart failure of ischemic or nonischemic origin, admitted due to acute heart failure persisting despite initial treatment, who had dyspnea at rest or mild exertion requiring intravenous treatment, and right heart catheterization for their acute heart failure episode were included. Patients were required to have CI<2.5 l/min/M2 and wedge pressure =15 mm Hg. Hemodynamic measures included pulmonary arterial pressure, wedge pressure, right atrial pressure, and cardiac output (CO; determined by the thermodilution technique). We also measured weight, height, and mean blood pressure (MAP) and calculated cardiac index [CI; calculated by CO divided to the body surface area (BSA)], cardiac power index [cardiac power index (Cpi)=MAPxCIx0.0022] and systemic vascular resistance [SVR; calculated as 80x(MAP–right atrial pressure)/CO]. Neurohormonal measurements were performed in 64 patients and included B-type natriuretic peptide (BNP) and endothelin 1(ET-1).

2.1. Outcome
We evaluated the rate of recurrent worsening heart failure at 7 and 30 days in a subset of 94 patients who were randomized to placebo treatment. Worsening heart failure was defined as either failure to improve (persistent symptoms and signs of acute heart failure during the first 24 h of treatment) or recurrent symptoms or signs of acute heart failure, pulmonary edema, or cardiogenic shock after initial stabilization, either of which required the initiation of appropriate intravenous therapy or implantation of mechanical circulatory or ventilatory support to treat the event. Furthermore, we collected data on the incidence of death up to 6 months from enrolment in a subset of 75 patients, for whom these data were available.

2.2. Statistical methods
The association between EF and baseline level and change in various clinical parameters was examined in two ways: first, Pearson correlation coefficients were calculated between levels of EF and the other parameters. Second, patients were divided into four subgroups based on their EF: <20%, 20–29%, 30–39%, 40%+. Comparison between these subgroups with regard to the above clinical parameters was performed using a one-way analysis of variance. Both parametric and nonparametric tests were used. A logistic regression model was applied to calculate odds ratio and confidence intervals for the association between EF levels and death and recurrent worsening heart failure. The SAS system for Windows version 8.01 was used for statistical analysis. P values <0.05 were considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Limitations
 6. Conclusions
 References
 
A total of 349 patients with acute heart failure were included in this analysis.

3.1. Baseline characteristics and their relationship with EF
Table 1 shows the baseline characteristics of the patients by baseline echocardiographic EF. Patients with higher EF were older and more were female. The incidence of hypertension and atrial fibrillation was higher in patients with higher EF. Furthermore, patients who developed acute heart failure with higher EF had higher blood urea nitrogen (BUN) and more leukocytosis on admission.


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  		Table 1 Baseline characteristics and laboratory findings by EF

 
3.2. Hemodynamic measurements and EF
The correlation between hemodynamic variables at baseline and EF is presented in Table 2. We found weak correlations between hemodynamic measures obtained at baseline and EF. CI was correlated with EF (R=0.25, p=0.0003). However, for each 10% increase in EF, we observed an increase of only 0.08 l/min/M2 in CI (Fig. 1). Cpi was also correlated with EF (R=0.38, p<0.0001). Again, for each 10% increase in EF, we observed only a 0.03 W/M2 increase in Cpi. There was no correlation between EF and wedge pressure or SVR. In the subset of patients randomized to placebo treatment, there were no interactions between EF and changes in hemodynamic variables over time.


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  		Table 2 Baseline cardiac hemodynamic and neurohormonal measures by EF

 


Figure 1
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  		Fig. 1 Mean cardiac index by echocardiographic EF.

 
3.3. Neurohormonal measures at baseline and EF (Table 2)
Neurohormonal measures were available at baseline in a subset of 64 patients. Their baseline characteristics were similar to the whole patient cohort. We observed an inverse correlation between EF and BNP at baseline (R=–0.29, p=0.04). For each 10% decrease in EF, we observed a 76 pg/ml increase in plasma BNP. Curiously, we observed a positive correlation between EF and ET-1 at baseline (R=0.33, p=0.008). For each 10% increase in EF, we observed a concomitant 0.4 pg/ml increase in plasma ET-1 levels.

3.4. EF and outcome
This analysis was performed in a subset of 94 patients who were included in the placebo arms of the two original studies. Their baseline characteristics were similar to the whole cohort. There was no correlation between EF and the rate of recurrent episodes of heart failure at 7 and 30 days or death at 30 days. However, we observed a trend toward higher mortality at 6 months in patients with EF <20%, 20–40%, and >40% (19% vs. 10% and 5%, respectively, p=0.3). This trend did not reach statistical significance probably due to the small size of the cohort.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Limitations
 6. Conclusions
 References
 
The results of this study demonstrate that in patients admitted due to acute heart failure, echocardiographic EF is only weakly correlated with hemodynamic measures of cardiac contractility and short-term outcome. This finding is in contrast to data in patients with chronic heart failure where EF is better correlated with long-term outcome [10]. However, these data are in agreement with a recent study by Cohen-Solal et al. [11], showing no correlation between outcome and EF in patients admitted with acute heart failure. There are a few possible explanations for this discrepancy.

  1. EF is not an accurate measure of left ventricular systolic contractility: The result of this study demonstrates that EF is only weakly correlated with hemodynamic measures of left ventricular contractility. This observation is in concordance with echocardiographic studies demonstrating that EF is only a crude measure of left ventricular contractility, and that more subtle measures, such as systolic and diastolic velocities by tissue doppler, are better correlated with left ventricular contractility [12]. Such measures demonstrate contractility impairment even in patients with heart failure and preserved echocardiographic EF [13], in concordance with our results showing low cardiac power in some patients with preserved EF.
  2. (2) EF vs. inflammatory and neurohormonal mechanisms in the pathogenesis of acute heart failure: The discrepancy between the low predictive value of EF in acute heart failure versus its high predictive value in chronic heart failure [14] might be explained, at least partially, by different pathophysiological mechanisms of acute versus chronic heart failure. We have previously suggested that other factors, i.e., SVR increase [15] and inflammatory-neurohormonal activation [16] might have more significant roles in the specific pathogenesis of acute heart failure. In support of this hypothesis, in this study, we have found a positive correlation between higher EF and increased leukocytosis, as well as higher plasma ET-1 and BUN at admission. Therefore, if failure (increased BUN), inflammatory (increased leukocytosis) and endothelial activation (increased ET-1) have a specific independent role in the pathogenesis of acute heart failure, than left ventricular contractility of which EF is only a crude measure may have a lesser role.
  3. (3) Systolic versus diastolic left ventricular function: It has been suggested previously that acute heart failure is related to changes in diastolic rather than systolic factors. In a previous study, Gandhi et al. [17] performed extensive echocardiographic evaluation of patients with acute heart failure at admission and recovery. The authors demonstrated that no changes occurred in the EF of these patients during the acute heart failure episode, while measures of diastolic dysfunction were more impaired at admission than at recovery. Cohen-Solal et al. [11] demonstrated that severity of diastolic dysfunction, but not EF, is correlated with outcome in patients admitted with acute heart failure. Hence, it is possible that acute diastolic rather than systolic dysfunction plays a major role in the pathogenesis of acute heart failure, explaining the reduced correlation between EF and short-term outcome. Regretfully, echocardiographic measures of diastolic dysfunction were not available in the present cohort.

Finally, the results of this study, in concordance with previous ones, show that indeed, patients with heart failure and preserved EF have different background characteristics: they are older, tend to be of female sex, and suffer more from hypertension and atrial arrhythmias. However, despite these differences, the short-term outcome of these patients is remarkably similar to patients with more preserved EF, again emphasizing the fact that other, undetermined mechanisms may have a critical and overriding role in the pathophysiology of acute heart failure, determining its short-term outcome.


   5. Limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
6. Conclusions
 References
 
This study is a retrospective analysis of data from patients with acute heart failure. The echocardiographic data were not collected prospectively and were determined at the different centers using different methods. Other measures of systolic and diastolic dysfunction are not available. However, this study represents "real-life" echocardiographic assessment of patients with acute heart failure and hence is important in determining its value in the context of everyday practice. Furthermore, this study included hemodynamically monitored patients with acute heart failure. The need for such hemodynamic monitoring biases the study population toward sicker patients.


   6. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
References
 
In this study, we observed a weak correlation between echocardiographic EF and hemodynamic measures of cardiac contractility and short-term outcome. This weak correlation could be explained by either the inaccuracy of EF in estimating left ventricular contractility or the overriding role of other factors, such as inflammatory and neurohormonal activation, renal failure, atrial tachyarrythmias, and diastolic dysfunction in the pathogenesis of acute heart failure. Hence, EF should be interpreted cautiously when evaluating patients admitted due to acute heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusions
 References
 

  1. American Heart Association. Heart disease and stroke statistics: 2003 updates. (2002) Dallas, TX: American Heart Association.
  2. Jessup M., Brozena S. Heart failure. N Engl J Med (2003) 348:2007–2018.[Free Full Text]
  3. Dauterman K.W., Massie B.M., Gheorghiade M. Heart failure with preserved systolic function: a common and costly clinical entity. Am Heart J (1998) 135:S310–S319. [Suppl.].[CrossRef][Web of Science][Medline]
  4. Cleland J.G.F., Swedberg K., Follah F., Komajda M., Cohen-Solal A., Aguilar J.C., et al. The EuroHeart survey program—a survey of the quality of care among patients with heart failure in Europe: Part 1. Patient characteristics and diagnosis. Eur Heart J (2003) 24:442–463.[Abstract/Free Full Text]
  5. Lee D.S., Austin P.C., Rouleau J.L., Liu P.P., Naimark D., Tu J.V. Predicting mortality among patients hospitalized for heart failure. Derivation and validation clinical model. JAMA (2003) 290:2581–2587.[Abstract/Free Full Text]
  6. Yusuf S., Pfeffer M.A., Swedberg K., Granger C.B., Held P., McMurray J.J., et al. Effect of Candesartan in patients with chronic heart failure and preserved left ventricular systolic function: the CHARM-preserved Trial. Lancet (2003) 362:777–781.[CrossRef][Web of Science][Medline]
  7. Klapholz M., Maurer M., Lowe A.M., Messineo F., Meisner J.S., Mitchell J., et al. New York Heart Failure Consortium. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York Heart Failure Registry. J Am Coll Cardiol (2004 Apr 21) 43(8):1432–1438.[CrossRef]
  8. Torre-Amione G., Young J.B., Colucci W., Lewis B.S., Pratt C., Cotter G., et al. Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized because of acute decompensated heart failure. J Am Coll Cardiol (2003) 42:140–147.[Abstract/Free Full Text]
  9. Cotter G., Kaluski E., Stangl K., Pacher K., Richter C., Perchenet L., et al. Significantly lower doses of tezosenatn are effective in the treatment of acute heart failure: an interaction with endothelin-1 levels? Eur Heart J (2003) 24:25. [Abstract].
  10. Parameshwar J., Keegan J., Sparrow J., Sutton G.C., Poole-Wilson P.A. Predictors of prognosis in severe chronic heart failure. Am Heart J (1992) 123:421–426.[CrossRef][Web of Science][Medline]
  11. Logeart D., Thabut G., Jourdain P., Chavelas C., Beyne P., Beauvais F., et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol (2004) 43:635–641.[Abstract/Free Full Text]
  12. Greenberg N.L., Firstenberg M.S., Castro P.L., Main M., Travaglini A., Obadashian J.A., et al. Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility. Circulation (2002) 105:99–105.[Abstract/Free Full Text]
  13. Bruch C., Gradaus R., Gunia S., Breithardt G., Wichter D. Doppler tissue analysis of mitral annular velocities: evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr (2003) 16:1031–1036.[CrossRef][Web of Science][Medline]
  14. Lee D.S., Austin P.C., Rouleau J.L., Liu P.P., Naimark D., Tu J.V. Predicting mortality among patients hospitalized for heart failure. Derivation and validation of a clinical model. JAMA (2003) 290:2581–2587.[Abstract/Free Full Text]
  15. Cotter G., Moshkovitz Y., Milovanov O., Salah A., Blatt A., Krakover R., et al. Acute congestive heart failure: a novel approach to its pathogenesis and treatment. Eur J Heart Fail (2002) 4:227–234.[Abstract/Free Full Text]
  16. Milo O., Cotter G., Kaluski E., Blatt A., Krakover R., Vered Z., et al. Inflammatory and neurohormonal activation in cardiogenic pulmonary edema: implications on the pathogenesis and outcome of acute ischemic versus non-ischemic acute heart failure. Am J Cardiol (2003) 92:222–226.[Web of Science][Medline]
  17. Gandhi S.K., Powers J.C., Nomier A.M., Fowle K., Kitzman D.W., Rankin K.M., et al. The pathogenesis of acute pulmonary edema associated with hypertension. New Engl J Med (2001) 344:17–22.[Abstract/Free Full Text]

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