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European Journal of Heart Failure 2007 9(6-7):610-616; doi:10.1016/j.ejheart.2007.03.001
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© 2007 European Society of Cardiology

Right ventricular dysfunction as an independent predictor of short- and long-term mortality in patients with heart failure

Jesper Kjaergaarda,*, Dilek Akkana, Kasper Karmark Iversena, Lars Købera, Christian Torp-Pedersenb and Christian Hassagera

a Department of Cardiology, The Heart Centre, Copenhagen University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
b Department of Cardiology, Copenhagen University Hospital, Bispebjerg Hospital, Copenhagen, Denmark

* Corresponding author. Tel: +45 3545 3545; fax: +45 3545 2648. E-mail address: jesper.kjaergaard{at}rh.dk


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: The prognostic importance of right ventricular (RV) dysfunction in heart failure (HF) has been suggested in patients with severe systolic heart failure. Tricuspid annular plane systolic excursion (TAPSE) is a simple echocardiographic measure of RV ejection fraction, but may be affected by co-existing chronic obstructive pulmonary disease (COPD).

Aims: To examine the prognostic information from TAPSE adjusted for the potential confounding effects of co-existing cardiovascular and COPD in a large series of patients admitted for new onset or worsening HF.

Methods and results: Eight hundred and seventeen patients screened for participation in a large clinical trial by trans-thoracic echocardiography, including measurement of TAPSE, were followed for a median of 4.1 years (maximum 5.5 years). Decreased TAPSE as well as presence of COPD were independently associated with adverse short- and long-term survival, hazard ratio was 0.74 (p=0.004) for every doubling of TAPSE; and 2.4 (p=0.0001) for the presence of COPD.

Conclusion: Decreased RV systolic function as estimated by TAPSE is associated with increased mortality in patients admitted for HF, and is independent of other risk factors in HF including left ventricular function. The co-existence of COPD is also associated with an adverse prognosis independent of the RV systolic function.

Key Words: Prognosis • Echocardiography • Congestive heart failure • Chronic obstructive pulmonary disease • Right ventricular function

Received August 23, 2006; Revised December 21, 2006; Accepted March 5, 2007


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Reduced left ventricular (LV) function is associated with heart failure (HF), but once HF is present the relationship between LV ejection fraction and mortality is less clear [1]. Accurate prognostic information is important in the management of patients, and therefore the identification of additional risk factors associated with increased mortality in HF is required. Right ventricular (RV) dysfunction in patients with left ventricular HF has been shown to be associated with an adverse outcome in a small series of patients with symptomatic HF [2-5], but studies of RV systolic function as a risk factor are challenging as a result of a lack of clinically applicable methods for the evaluation of RV performance [6,7].

Estimates of RV function using echocardiography are limited by the inability to represent the complex shape of the RV. Based on the observation that the contraction pattern of the RV, unlike the LV, begins at the RV sinus and ends at the infundibulum and RV outflow tract, and that the RV free wall consists predominantly of longitudinal myocardial fibres, the tricuspid annular plane systolic excursion (TAPSE) has been shown to correlate with RV ejection fraction [8]. The prognostic information from TAPSE and related measures of RV plane motion, have been tested in small studies and predominantly in patients with severe, symptomatic HF with reduced left ventricular ejection fraction [4,9,10].

The presence of obstructive pulmonary disease (COPD) affects right ventricular haemodynamics in advanced disease [11], but RV ejection fraction is preserved at least in the earlier stages of disease [12,13]. Furthermore, the risk of cardiovascular events is increased in patients with COPD [14], and thus the co-existence of COPD could be important in the evaluation of RV function as a risk factor in patients with HF.

The present study is a prospective analysis of prognostic information from the echocardiographic estimation of RV ejection fraction by TAPSE in a large series of patients admitted for new onset or worsening HF, adjusted for presence of COPD as a possible confounder.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
The present study is a sub-study based on the population of Danish patients, consecutively screened for participation in the ECHOS trial (EchoCardiography and Heart Outcome Study). To ensure a sample of typical, representative HF patients for the trial, participating centres were required to perform consecutive screening of all patients hospitalised with HF, complying with the following criteria: hospitalised for symptomatic HF, requiring treatment with diuretics, ≥18 years of age, and dyspnoeic (NYHA class II-IV, where class II patients were required to have had at least one episode of dyspnoea corresponding to NYHA III within 1 month prior to screening). Patients were not eligible for screening if an acute myocardial infarction was diagnosed. Screening for the ECHOS trial included a transthoracic echocardiography (TTE) performed at rest in the left lateral position according to a predefined protocol, to ensure that standardized echocardiographic imaging data for the assessment of the left ventricular ejection fraction were available. All centres were encouraged to record echocardiographic views for the evaluation of right ventricular size, systolic pressure and function by RV end-diastolic diameter, tricuspid regurgitation pressure gradient and TAPSE by M-mode echocardiography, respectively, although these images were not mandatory. In addition to the echocardiographic imaging, demographic and clinical data were collected. The study complied with the principles in the Declaration of Helsinki, and was approved by the regional ethics committee prior to initiation. All patients provided written informed consent before screening for the ECHOS trial was performed.

The ECHOS trial was a prospective, double-blind randomised, placebo-controlled multi-centre trial of a selective agonist of the pre-synaptic DA2 and {alpha}2 receptors. Patients were eligible for randomisation if, in addition to the criteria mentioned above, they had a left ventricular ejection fraction of 35% or less. However, since the study treatment had no effect on the primary end-point (overall mortality) in the randomised study [15]; no stratification based upon subsequent randomisation in the ECHOS main study was made in the present study. A total of 3078 Danish patients were screened for the ECHOS trial, and underwent a TTE to evaluate LV ejection fraction. Of these, 817 patients had imaging data available for the assessment of TAPSE by M-mode at the junction of the tricuspid valve and RV free wall in the apical 4 chamber view, see Fig. 1 [16]. RV end-diastolic diameter was measured in the parasternal long-axis view and the tricuspid regurgitation velocity was measured by continuous wave Doppler in the apical 4-chamber view, and used for calculation of Tricuspid regurgitation pressure gradient by the modified Bernoulli equation [17]. TTE was ECG-gated and recorded on videotape at the participating centres and shipped to the core lab for analysis. The videotapes were digitized (MPEGator, Darim Vision Corp., Pleasanton, CA, USA), all measurements were performed using electronic callipers on custom-made software following on-screen calibration, and were reported as the average of five measurements performed by two experienced readers, D.A. and J.K. The coefficient of variation between independent measurements of TAPSE was 10% (duplicate measurements, n=20). Left ventricular function was assessed by the Wall Motion Index (WMI), which has been shown to be closely correlated to LV ejection fraction [18].


Figure 01
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  		Fig. 1 Measurement of tricuspid annular plane systolic excursion (TAPSE) by M-mode echocardiography of the lateral tricuspid annulus. Left panel: Apical 4-chamber view with curser (dotted line) placed at the junction of the tricuspid annulus and right ventricular free wall. Right panel: M-mode echocardiography. TAPSE is measured as the maximal systolic excursion from the end-diastole after atrial contraction to end of systole, see vertical dashed line.

 
Baseline data recorded at screening included known cardiovascular risk factors associated with HF: demographic data, tobacco use, diabetes, paroxysmal or permanent atrial fibrillation, and co-existing cardiovascular disease including arterial hypertension, ischaemic heart disease and previous myocardial infarction (MI) and valvular heart disease (defined as moderate or severe aortic or mitral stenosis or insufficiency). The local investigator also recorded the presence of COPD and chronic reduced renal function. Smoking status was recorded as never/previous smoker vs. current smoker. Medication prescribed at discharge from hospital was also recorded. Survival status was obtained from the Danish Central Person Registry in May 2006, and was available for all patients included in the study.

2.1. Statistical analysis
Baseline data is presented as median and 25-75% percentiles for continuous data and number and percentage for categorical data. The baseline data was analyzed by quartiles of TAPSE, and differences were tested using the Kruskal-Wallis test for continuous data, and {chi}2 and Cochran-Armitage trend test for categorical data. Association between continuous variables was assessed with Spearman's non-parametric correlation. Reproducibility of TAPSE (inter-observer variability) was assessed by the coefficient of variation for repeated measures, in a random sample of 20 patients.

Kaplan Meier plots were used for presenting survival curves and the log rank test was used for initial comparison. For the univariate analysis a TAPSE cut-off of 14 mm was used, as previously established by Ghio et al. [4]. Multivariable comparisons were performed using a Cox proportional hazard model (backward elimination) after checking assumptions of proportionality, lack of interactions with TAPSE, and linearity of continuous variables. The linearity assumption required TAPSE to be log transformed. Right ventricular end-diastolic diameter and the maximal tricuspid regurgitation pressure gradient were not included in the Cox model due to the low number of measurements available. SAS software (Cary, NC) version 9.1 was used for all computations.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
TAPSE was available in 817(27%) of the 3078 patients screened. Baseline demographic data according to quartiles of TAPSE are shown in Table 1. There were no significant differences between patients based on the availability of TAPSE measurements with regards to age, sex, body mass index, presence of COPD or HF (data not shown); however, patients with TAPSE measurements had a lower LV ejection fraction 0.35(0.25-0.54) compared to patients without measurements of TAPSE, 0.41(0.28-0.60), p<0.0001. The population studied was predominantly Caucasian (98%). The maximal tricuspid regurgitation pressure gradient was not correlated to TAPSE, r=–0.07, not significant (NS), whereas a weak association between RV end-diastolic diameter and TAPSE was found, r=–0.13, p=0.04, however, measurements were only available in 268 and 254 patients, respectively. The medication received at discharge from the hospital for the 791 patients discharged alive is also shown in Table 1. Patients with permanent atrial fibrillation were more frequently prescribed digoxin than patients without atrial fibrillation, 42% vs. 13%, p<0.0001. The use of beta-blockers was less frequent in patients with COPD, 28% vs. 52%, p<0.0001.


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  		Table 1 Demographic data, medical history and echocardiographic measurements at screening in the 817 patients admitted for symptomatic heart failure and medication at discharge for the 791 patients who were discharged alive

 
3.1. Mortality
Median follow-up was 1487 days (4.1 years) and maximum follow-up was 2000 days (5.5 years). A total of 409(50%) patients died during follow-up. Patients with values of TAPSE of 14 mm or more had a higher survival rate compared patients with values of TAPSE below 14 mm (log rank test, p=0.01), see Fig. 2. At 1 year of follow-up, TAPSE provided improved discrimination of differences in survival, log rank p=0.0007. The presence of COPD was associated with an increased mortality both in the short-term (log rank test <0.0001) and at the end of follow-up (log rank test <0.0001). Known risk factors of HF, as listed in Table 1, were entered into the Cox proportional hazard model. The final model is shown in Table 2. Independent predictors of survival were logTAPSE with a HR=0.74 (0.60 to 0.91), i.e. a 26% risk reduction for every doubling of TAPSE, as well as presence of COPD, HR=2.39 (1.92 to 2.97). LV ejection fraction was not significantly associated with mortality, when logTAPSE and presence of HF were included in the model.


Figure 02
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  		Fig. 2 Survival plot (Kaplan Meier) for the 817 patients included in the study, stratified by TAPSE. A cut-off of 14 mm was applied. Differences in survival were tested at 365 days (1 year survival), marked with a vertical line, and at end of follow-up.

 


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  		Table 2 Results of the multivariate proportional hazard model of risk factors in 817 patients admitted for HF, including tricuspid annular plane excursion

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The present study is the first large-scale study to evaluate the long-term prognostic value of right ventricular function in an unselected population of patients hospitalised for new onset or worsening HF. Right ventricular function was estimated by TAPSE, and was found to be a significant predictor of survival. When adjusting for other known risk factors in HF as well as for the co-existence of COPD, TAPSE remained an independent predictor of survival, suggesting that a doubling of the value of TAPSE is associated with a 26% reduction in mortality, whereas left ventricular ejection fraction had no independent prognostic information when TAPSE was included in the model.

Previous studies, which have evaluated RV ejection fraction by angiography [19], radionuclide techniques including equilibrium angiography and first pass techniques [5], or thermo-dilution techniques during right heart catheterization [3]; have all identified RV ejection fraction as a predictor of exercise capacity, mortality or both in patients with HF. Echocardiographic measures of RV ejection fraction in relation to survival include fractional area change of the RV in patients with recent myocardial infarction and decreased LV ejection fraction [20], tricuspid annular systolic velocity [2], and TAPSE or other measures of tricuspid annular plane motion in patients with advanced systolic HF under evaluation for heart transplantation [4,9] or recent myocardial infarction, where a non-linear relation of TAPSE and mortality was seen, consistent with the findings in the present study [21]. Studies have suggested that RV function is independent of LV function, and that RV dysfunction following myocardial infarction may be more dependent upon the location and extent of infarction than on the extent of LV dysfunction [20,22]. This mainly relates to studies involving postmyocardial infarction cohorts limited to inferior infarctions with or without RV involvement, however, left ventricular dysfunction is known to be an important precursor for RV dysfunction [23].

The present study confirms the TAPSE cut-off of 14 mm, which was established in a population of patients with systolic heart failure using a combined end-point of death and cardiac transplantation, as a significant predictor of mortality in HF patients [4]. The present study shows that this cut-off is applicable not only in patients with reduced systolic left ventricular function, but in all heart failure patients regardless of left ventricular function or the presence of significant valve disease.

A recent study in HF patients found no difference in survival between patients with preserved and reduced left ventricular systolic function [1], thus new echocardiographic markers of adverse survival in HF are needed. The present study is the first large-scale study to establish the importance of a simple echocardiographic measure of RV ejection fraction (TAPSE) in a consecutive series of patients admitted for HF.

TAPSE as a measure of RV ejection fraction was first proposed by Kaul et al. in 1984, who demonstrated a close correlation to RV ejection fraction determined by radionuclide technique [8]. This has been confirmed in subsequent studies in patients with HF or ischaemic heart disease using thermo-dilution techniques or Magnetic Resonance Imaging [4,24,25]. TAPSE may be related to RVEF, because the RV free wall consists predominantly of longitudinal and oblique myocardial fibres [26] and because the RV sinus, defined as the space from the tricuspid valve to the proximal os infundibulum, is the major contributor to the combined RV stroke volume [27]. The feasibility of TAPSE measurement is likely to be higher than for parameters which are dependent on clear endocardial definition, which has been reported as a limiting factor in studies using fractional area change or 3-dimensional echocardiography [8,20]. Thus, although more dependent on geometrical assumptions than more complex techniques, TAPSE may be more appropriate for determination and quantification of RV ejection fraction in everyday clinical practice. The close correlation of TAPSE to RV ejection fraction measured by thermo-dilution or radionuclide techniques has been established in the lower range of RV ejection fraction [4,8,24],

Reasons for deterioration of RV function with left ventricular dysfunction, may include secondary pulmonary hypertension or generalized myocardial disease [10]. Small studies have shown that decreased RV ejection fraction is more predominant in HF due to idiopathic dilated cardiomyopathy than with ischaemic aetiology [28,29]. In the present study, there was no relation between TAPSE and maximal tricuspid regurgitation pressure gradient, and even though RV systolic pressure estimates were available in only 33% of the patients, this supports the theory that decreased RV ejection fraction is associated with myocardial involvement in HF.

The association between COPD and TAPSE was explored in an earlier study, which showed that TAPSE was decreased only in COPD patients with co-existing pulmonary hypertension [11]. The relationship between RV ejection fraction and COPD is complex, and RV contractility is well preserved in COPD [30], although measures of RV ejection fraction may be slightly reduced in patients with COPD, especially in end-stage pulmonary disease [12]. The present study suggests that RV ejection fraction is an independent predictor of death in patients with HF, regardless of co-existing COPD. Among other significant risk factors, BMI above 25 kg/m2 was associated with reduced mortality, consistent with a previous study [31].

The ECHOS study was initiated after the beneficial effects of beta-blockers in HF had been established, and thus the rate of beta-blocker use is higher than in earlier studies of HF patients. Furthermore, the use of beta-blockers is also likely to be an underestimate as new onset HF patients are usually prescribed ACE-inhibitors prior to commencing beta-blockers. The proportion of patients using ACE-inhibitors and angiotensin receptor II-blockers in our study is satisfactory, considering that about one third of the population screened had a LV ejection fraction above 45%. In the lowest quartile of TAPSE, digoxin was used more frequently, which was consistent with a more frequent occurrence of permanent atrial fibrillation in this group. To the best of our knowledge no studies have investigated the direct effect of atrial fibrillation on RV ejection fraction. By averaging measurements from five consecutive cardiac cycles in the present study, the preload and heart rate dependency of the RV ejection fraction estimates were minimized. However, atrial fibrillation was more frequent in the lower quartiles of TAPSE, although TAPSE was the more predictive parameter in the multivariate survival analyses.

4.1. Study limitations
The echocardiographic protocol for the ECHOS study was designed to confirm the presence of systolic left heart failure, and the measurement of right ventricular function by TAPSE was optional. No reimbursement was given for the time taken to perform the additional imaging needed for the evaluation of RV function by TAPSE, and therefore the generalization of the results may be limited despite that fact that no major bias was found when comparing the subgroup with measurements of TAPSE to the rest of the ECHOS study population. All patients screened were admitted for dyspnoea and were treated for heart failure with diuretics. No established criteria for HF diagnosis were used in the screening process, but since 70% of the population had previously been diagnosed with HF, more than 80% patients were found to have sub-normal LVEF on TTE, and more than 90% received diuretics at discharge, it is the opinion of the authors that the population studied are likely to have HF according to the ESC definition [32].

The presence of COPD was reported at the discretion of the local investigator, but objective measurements of lung function or chest X-ray were not available.


   5. Conclusion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
Decreased RV ejection fraction as estimated by TAPSE is independently associated with mortality in an unselected population of patients admitted for HF, even after adjusting for other known risk factors including LV ejection fraction or the presence of valvular disease. The co-existence of COPD was also associated with an adverse prognosis, independent of RV systolic function.

The evaluation of right ventricular function by the simple, non-invasive measurement of TAPSE by trans-thoracic echocardiography could be included as part of the routine work-up in patients hospitalised for HF, and the results can be interpreted without evaluation of pulmonary function.


   Acknowledgements
 
The ECHOS study was supported by un-restricted grants from Chiesi Pharmaceutical Company. The Danish Heart Foundation supported the research fellowship of Dr. Kjaergaard, grant no. 04-10-B109-A166-22192.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
{star} The work was performed at the Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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