Published ahead of print on August 3, 2006, doi:10.1164/rccm.200604-547OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200604-547OC
Tricuspid Annular Displacement Predicts Survival in Pulmonary HypertensionDivisions of Cardiology and Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland Correspondence and requests for reprints should be addressed to Paul M. Hassoun, M.D., Division of Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Asthma & Allergy Center, 2B.34, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: phassoun{at}jhmi.edu
Rationale: Right ventricular (RV) function is an important determinant of prognosis in pulmonary hypertension. However, noninvasive assessment of the RV function is often limited by complex geometry and poor endocardial definition. Objectives: To test whether the degree of tricuspid annular displacement (tricuspid annular plane systolic excursion [TAPSE]) is a useful echo-derived measure of RV function with prognostic significance in pulmonary hypertension. Methods: We prospectively studied 63 consecutive patients with pulmonary hypertension who were referred for a clinically indicated right heart catheterization. Patients underwent right heart catheterization immediately followed by transthoracic echocardiogram and TAPSE measurement. Results: In the overall cohort, a TAPSE of less than 1.8 cm was associated with greater RV systolic dysfunction (cardiac index, 1.9 vs. 2.7 L/min/m2; RV % area change, 24 vs. 33%), right heart remodeling (right atrial area index, 17.0 vs. 12.1 cm2/m), and RV–left ventricular (LV) disproportion (RV/LV diastolic area, 1.7 vs. 1.2; all p < 0.001), versus a TAPSE of 1.8 cm or greater. In patients with pulmonary arterial hypertension (PAH; n = 47), survival estimates at 1 and 2 yr were 94 and 88%, respectively, in those with a TAPSE of 1.8 cm or greater versus 60 and 50%, respectively, in subjects with a TAPSE less than 1.8 cm. The unadjusted risk of death (hazard ratio) in patients with a TAPSE less than 1.8 versus 1.8 cm or greater was 5.7 (95% confidence interval, 1.3–24.9; p = 0.02) for the PAH cohort. For every 1-mm decrease in TAPSE, the unadjusted risk of death increased by 17% (hazard ratio, 1.17; 95% confidence interval, 1.05–1.30; p = 0.006), which persisted after adjusting for other echocardiographic and hemodynamic variables and baseline treatment status. Conclusions: TAPSE powerfully reflects RV function and prognosis in PAH.
Key Words: prognosis • pulmonary arterial hypertension • right ventricular function • tricuspid annular displacement, TAPSE Pulmonary arterial hypertension (PAH) is a clinical syndrome characterized by progressive increases in pulmonary vascular load, leading to marked increases in pulmonary artery pressure, exercise intolerance, and ultimately death (1). However, the natural history of PAH is heterogeneous, with more rapid clinical deterioration seen in patients with the greatest degree of right ventricular (RV) dysfunction (2, 3). This underscores the importance of RV function assessment in patients with PAH, and places a premium on a modality that is noninvasive and comprehensive, yet practical. However, complex RV chamber geometry and suboptimal RV endocardial definition have limited the application of noninvasive RV function assessment in clinical practice (4). Unlike the left ventricle, which shortens relatively symmetrically in the transverse and longitudinal planes, muscle fiber orientation of the right ventricle dictates that contraction occurs predominantly along the longitudinal plane (5). As a result, systolic displacement of the tricuspid annulus toward the RV apex (longitudinal plane), referred to as tricuspid annular plane systolic excursion (TAPSE), closely correlates with RV ejection fraction (6). Importantly, TAPSE does not require geometric assumptions or RV endocardial definition, and thus has been found to be highly reproducible and practical (6, 7). Subsequent studies have confirmed that TAPSE is an excellent measure of RV systolic function, and that a depressed TAPSE portends a poor prognosis in patients with dilated cardiomyopathy and after acute inferior wall myocardial infarction (7–9). However, the clinical and prognostic significance of TAPSE has not been tested in adult patients with PAH in whom the prevalence and prognostic importance of RV dysfunction would suggest that such an approach may be of great value. Thus, we conducted a prospective observational study to determine whether TAPSE represents a simple noninvasive measure of RV function and has prognostic value in patients with pulmonary hypertension, including PAH. Some of the results of the current study have been previously reported in abstract form (10).
This study was approved by the Johns Hopkins Institutional Review Board. Informed consent was obtained from all subjects prior to enrollment.
Patients
Hemodynamics
Echocardiography Additional hemodynamic and echocardiographic method details are reported in the online supplement.
Clinical Follow-up
Data Analysis A receiver operating characteristic (ROC) curve was used initially to test the ability of TAPSE to detect an RV stroke volume index (SVI) less than the median SVI value in the dataset (< 29 ml/m2). This value is an accepted lower limit of normal for SVI, corresponding to a cardiac index of 2.2 L/min, assuming a heart rate of 75 beats/min (11). The optimal cut point was based on the greatest proportion of correctly classified patients identified by ROC curve analysis (point highest and to the left on the ROC curve), and determined to be 1.8 cm. Thereafter, we compared hemodynamic and echocardiographic variables in patients with a TAPSE less than 1.8 cm or 1.8 cm or greater to examine the association between TAPSE and various aspects of RV function. Variables were grouped as measures of RV systolic function, right heart remodeling, and RV–left ventricular (LV) disproportion to illustrate differences in these three important aspects of RV function in patients with a TAPSE value less than 1.8 cm or 1.8 cm or greater.
Using this dichotomized TAPSE (</
Table 1 summarizes the clinical and hemodynamic characteristics of the overall study population. The majority of patients (47/63 patients; 75%) were in group 1 of the World Health Organization (WHO) classification of pulmonary hypertension, with the remaining patients having either pulmonary hypertension associated with respiratory disease and/or hypoxemia (WHO group 3, n = 13) or chronic thromboembolic pulmonary hypertension (WHO group 4, n = 3). At enrollment, 70% of the patients were WHO functional class III or IV. Approximately 50% of the patients were receiving therapy for pulmonary hypertension at the time of enrollment, with the remainder being newly diagnosed. During the study period, 95% of patients were receiving various medical therapies for pulmonary hypertension (Table 1).
The baseline hemodynamics of the study population were notable for a markedly reduced SVI, cardiac index, S  O2, and elevated right atrial pressure (RAP) as compared with normal reference values (11). Pulmonary vascular resistance (PVR) was also markedly elevated, whereas PCWP was normal, reflecting the precapillary etiology of pulmonary hypertension in our cohort.
Baseline echocardiographic values are listed in Table 2. Patients had TAPSE and RV fractional area change (RVFAC) values well below those previously reported in normal subjects (i.e., normal TAPSE
TAPSE and RV Function ROC curve analysis revealed that TAPSE was a highly sensitive and specific indicator of a depressed RV SVI (area under the ROC curve [AUC] 0.87, p < 0.0001; Figure 1). The optimal ROC-derived cutoff was 1.8 cm. Likewise, TAPSE also detected a depressed cardiac index (AUC, 0.76; p = 0.0006), also at a cutoff of 1.8 cm (Figure E1 of the online supplement). Figure 2 shows representative M-mode tracings and hemodynamics from two subjects: one with relatively preserved TAPSE (A) and the other with depressed TAPSE (B). The subjects had similar mPAP; however, the patient with a TAPSE of 1.5 cm had a much lower SVI and higher PVR than the subject with a TAPSE of 2.3 cm.
Figure 3 summarizes the striking differences in RV systolic function (A), right heart remodeling (B), and RV–LV disproportion (C) observed between patients with a TAPSE of 1.8 cm or greater and those with a TAPSE less than 1.8 cm. Patients with a TAPSE less than 1.8 cm also had significantly higher RAP (12 ± 5 mm Hg) than those with a TAPSE of 1.8 cm or greater (8 ± 5 mm Hg; p = 0.01).
Figure 4 highlights the differences in PVR and pulmonary arterial compliance (stroke volume to pulmonary artery pulse pressure ratio) between the TAPSE subgroups despite similar mPAP, implicating the significance of RV afterload on this measure of RV function. Similarly, we observed a linear inverse relationship between TAPSE and PVR (r = –0.52, p < 0.0001; y = –0.055x + 2.45).
Patients with a TAPSE less than 1.8 cm had significantly smaller left atrial (3.2 ± 0.6 vs. 3.6 ± 0.7 cm; p = 0.03) and LV diastolic dimensions (3.6 ± 0.7 vs. 4.5 ± 0.6 cm; p < 0.0001) than subjects with a TAPSE of 1.8 cm or greater. Furthermore, patients with a TAPSE less than 1.8 cm had comparatively worse LV diastolic function, because the maximal transmitral E-wave velocity (63 ± 33 vs. 80 ± 27 cm/s; p = 0.03) and E' septum (6.4 ± 2.0 vs. 8.1 ± 2.6 cm/s; p = 0.009) were significantly lower than in subjects with a TAPSE of 1.8 cm or greater. Interestingly, there was also a linear inverse correlation between the diastolic eccentricity index and E' septum (r = –0.45, p = 0.0004; y = –2.97x + 11.7), suggesting that LV relaxation was adversely affected by leftward interventricular septal displacement. Subjects with a TAPSE less than 1.8 cm also trended toward lower systolic blood pressure (115 ± 13 vs. 122 ± 16 mm Hg; p = 0.05), with higher heart rates (87 ± 17 vs. 78 ± 13 beats/min; p = 0.04) and systemic vascular resistance (1,980 ± 670 vs. 1,302 ± 373 dyne · s · cm–5; p < 0.0001) than those with a TAPSE of 1.8 cm or greater, indicating greater systemic hemodynamic compensation (and thus less hemodynamic reserve) in those with more depressed TAPSE.
Patients with a TAPSE less than 1.8 cm also had more tricuspid regurgitation (TR; grade 2.2 ± 0.9 vs. 1.4 ± 0.9; p = 0.002) than subjects with relative preservation of TAPSE. Likewise, patients with moderate or severe TR (grade
TAPSE and Patient Outcome
As illustrated, survival of the patients with a TAPSE less than 1.8 was significantly shorter than patients with a TAPSE of 1.8 cm or greater (log-rank test,
The unadjusted risk of death during the study period for patients in the overall cohort with a TAPSE less than 1.8 compared with those with a TAPSE of 1.8 cm or greater was 3.8 (95% CI, 1.6–9.3; p = 0.003). The risk of death was even greater for patients with PAH with a TAPSE less than 1.8 compared with those with a TAPSE of 1.8 or greater (unadjusted hazard ratio [HR], 5.7; 95% CI, 1.3–24.9; p = 0.02). When analyzed as a continuous variable in patients with PAH, for every 1-mm decrease in TAPSE, the unadjusted risk of death increased by 17% (HR, 1.17; 95% CI, 1.04–1.32; p = 0.006). Multivariable models using Cox proportional hazards were constructed that consisted of TAPSE as a continuous or dichotomous variable (</  1.8 cm), variables found to be significant in bivariable analyses (p < 0.20), and variables previously shown to have prognostic significance (Table 3). Although RAP was highly significant in bivariable analysis, and partially confounded the association between TAPSE and outcome on multivariable analyses, inclusion of RAP in the model did not add significantly to the predictive value of the overall model using global likelihood ratio testing, and thus was excluded.
The most parsimonious model included TAPSE as a continuous variable, pericardial effusion, and baseline WHO functional class, yielding an adjusted risk of death increase of 16% for every millimeter decrease in TAPSE (HR, 1.16; 95% CI, 1.03–1.28; p = 0.01). Moreover, when stratified for treatment status at baseline, the HR was unchanged, suggesting that TAPSE predicted outcome regardless of whether patients were being treated for pulmonary hypertension at the time of enrollment.
Reproducibility of TAPSE
In the present study, a TAPSE less than 1.8 cm identified the patients with pulmonary hypertension who had more advanced RV dysfunction, as compared with subjects with a TAPSE of 1.8 cm or greater. Patients with a TAPSE less than 1.8 cm had dramatically reduced survival over a median follow-up of 19 mo, a finding that was driven almost exclusively by the patients with a diagnosis of PAH. Patients with a TAPSE less than 1.5 cm had an especially poor outcome. The prognostic significance of TAPSE persisted after adjustment for several previously recognized echocardiographic and invasive predictors of outcome, as well as baseline treatment status. Thus, our results suggest that TAPSE is a robust measure of RV function and a powerful predictor of patient survival in pulmonary hypertension.
TAPSE and RV Function In the current study, TAPSE was shown to be a highly sensitive and specific predictor of a depressed RV SVI, which parallels a recent study showing that longitudinal RV displacement similarly predicted a reduced RV SVI in patients with PAH (18). These findings support studies showing that TAPSE closely correlates with RV ejection fraction, which is the proportion of stroke volume to end-diastolic volume (6). We also observed striking differences between a variety of other invasive hemodynamic and echocardiographic measures of RV systolic function in patients with a TAPSE less than 1.8 cm or in those with a TAPSE of 1.8 cm or greater. Moreover, subjects with a TAPSE less than 1.8 cm had comparatively greater degrees of right heart remodeling and RV–LV disproportion than subjects with a TAPSE of 1.8 cm or greater, with a low TAPSE capturing a patient phenotype with more globally decompensated RV function manifesting as a triad of poor RV systolic function, right heart remodeling, and RV–LV disproportion. These same patients also displayed relative underfilling of the LV, both in terms of smaller LV dimensions and greater LV diastolic impairment as compared with those with preserved TAPSE, likely reflecting the in-series and interdependent effects of the failing right ventricle on the LV filling (19). It is also worth noting that TAPSE was inversely associated with the degree of tricuspid regurgitation, which parallels the association between poor RV function and greater TR, and argues against the theoretic possibility that decreased RV afterload in the setting of significant TR would lead to increases in tricuspid annular motion. Taken together, these results suggest that systolic (base to apex) displacement of the tricuspid annulus is an accurate reflection of RV function in patients with pulmonary hypertension. Recognizing the strong association between measures of RV systolic function and afterload, it was logical that TAPSE correlated inversely with PVR, suggesting that TAPSE is afterload dependent. In keeping, recent data have shown a strong direct correlation (r = 0.75, p < 0.01) between an acute change in RV SVI and longitudinal RV shortening immediately after epoprostenol infusion (18). Likewise, we demonstrated that patients with a depressed TAPSE had significantly lower pulmonary artery compliance, which reflects afterload at the level of the proximal pulmonary arteries, and which has been shown to predict poor outcome in patients with PAH (20, 21). Future studies will be needed to determine if TAPSE can be followed serially to track RV responsiveness to chronic afterload-reducing therapies in PAH. In addition, it would be of interest to determine whether TAPSE is useful in detecting pulmonary hypertension, as others have shown that non-Doppler indices such as an increased ratio of RV diameter to tissue Doppler velocity of tricuspid annular motion are useful predictors of pulmonary hypertension (22).
TAPSE and Patient Outcome Importantly, the prognostic significance of TAPSE persisted across TAPSE tertiles, and when examined as a continuous variable, every 1-mm decrease in TAPSE conferred a 17% increase in risk of death in patients with PAH. This risk of death persisted after adjusting for echocardiographic and invasive hemodynamic variables previously established to be of prognostic importance in patients with PAH (2, 3). In light of these findings, future studies need to address the prognostic relevance of serial changes in TAPSE in the same patient, as well as determine if such changes can be used to alter treatment strategies. Likewise, it will be important to determine the precision with which changes in TAPSE can be identified, because very small changes in TAPSE may be difficult to appreciate given inherent limitations in echocardiographic resolution. Overall, our results align with prior investigations showing that worse RV function, reflected as a depressed TAPSE, is an adverse prognostic indicator in patients with dilated cardiomyopathy, and in subjects after acute inferior myocardial infarction (7–9). However, the current results represent the first demonstration of the prognostic significance of TAPSE in patients with pulmonary hypertension. In contrast to the above studies, which reported cutoffs ranging from 1.3 to 1.5 cm, our study showed that the optimal TAPSE cutoff for predicting outcome was 1.8 cm. Although the tertile in the current study with a TAPSE less than 1.5 cm clearly had the worst outcome, we also observed a relatively high mortality rate in patients with more intermediate depression of TAPSE (1.5–1.9 cm). However, prior reports focused on patients with severe LV systolic dysfunction. This is an important caveat, as LV systolic function plays an important role in determining RV systolic function (so-called systolic ventricular interdependence), which may dictate the level at which TAPSE (and other measures of RV function) reflects RV dysfunction and thus becomes prognostically important (23). Numerous studies have demonstrated the importance of RV function in predicting outcome in patients with PAH. However, most studies have relied on invasive hemodynamic indices of RV function; indirect measures of RV function, such as right atrial size, tricuspid regurgitation, and pericardial effusion; or more complex Doppler-derived methods, which, despite their validity, are not widely used in clinical practice (2, 3, 24–27). Thus, the finding from the current study that TAPSE imparts important prognostic information in patients with pulmonary hypertension is particularly relevant, because TAPSE is a direct measure of RV function that is easily obtained from a routine transthoracic echocardiographic examination, and does not require sophisticated post hoc analysis or expertise to measure. This combination of prognostic power and simplicity makes TAPSE especially applicable to clinical practice and facilitates its use equally in both community-based and tertiary care practice.
Reproducibility of TAPSE
Limitations Although the vast majority (75%) of patients in our cohort had PAH (WHO classification group 1), patients with other forms of pulmonary hypertension, such as pulmonary hypertension associated with respiratory disease or hypoxemia, were included. This simply reflected the makeup of the population referred to our pulmonary hypertension clinic. As such, our population may better represent the population referred for pulmonary hypertension evaluation in clinical practice. Within the PAH cohort, there was heterogeneity that could have affected the survival and hazard analyses. About half of the PAH cohort were patients with established PAH currently receiving therapy; the others were newly diagnosed with PAH and were not receiving therapy at the time of RHC and echocardiography. Thus, it is possible that survival analyses were skewed by lead-time bias, because patients with established disease may have been more likely to die in the follow-up period than newly diagnosed patients. However, when stratified by whether or not patients were receiving therapy for PAH at baseline evaluation, survival estimates did not vary. In addition, the risk of death adjusted for treatment status at baseline remained significantly greater in patients with a lower TAPSE (adjusted HR, 1.16; 95% CI, 1.04–1.29; p = 0.01). Moreover, the current study was not designed to examine the effects of therapy on TAPSE and how such effects relate to outcome, which, as discussed above, will be an important future application of TAPSE. Our results may have also been subject to referral bias, which may have enriched our population with a group of patients at higher risk for poor outcomes. This raises the question as to whether the prognostic importance of TAPSE would hold among a broader, and perhaps less ill, population. Conversely, it is encouraging that TAPSE did prognosticate in a population such as ours. Factors not included in these analyses (e.g., exercise capacity) or those factors that we have failed to identify may confound this relationship between TAPSE and mortality. Larger scale prospective studies will be needed to more directly address the prognostic ability of TAPSE within (e.g., idiopathic PAH vs. scleroderma-associated PAH) and across (e.g., idiopathic PAH vs. chronic thromboembolic pulmonary hypertension) the various categories of pulmonary hypertension, because the size of the current study population was not conducive to more definitive subgroup analyses. Finally, although the reproducibility of TAPSE was excellent, the experience and familiarity of the echocardiographic reviewers with the technique may have introduced bias.
Conclusions
The authors thank Ellen G. Reather for expert manuscript preparation.
Supported by the Johns Hopkins General Clinical Research Center. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200604-547OC on August 3, 2006 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form April 20, 2006; accepted in final form August 3, 2006
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ABSTRACT
METHODS
1). In addition, 83% of patients with a pericardial effusion greater than grade 1 had a TAPSE less than 1.8 cm (p = 0.001). 
2 =10.00, p = 0.001) in the overall cohort (
