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European Heart Journal Advance Access originally published online on March 6, 2007
European Heart Journal 2007 28(7):842-849; doi:10.1093/eurheartj/ehl534
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

A novel echocardiographic predictor of in-hospital mortality and mid-term haemodynamic improvement after pulmonary endarterectomy for chronic thrombo-embolic pulmonary hypertension

Maxim Hardziyenka1, Herre J. Reesink2, Berto J. Bouma3, H.A.C.M. Rianne de Bruin-Bon3, Maria E. Campian1, Michael W.T. Tanck4, Renée B.A. van den Brink3, Jaap J. Kloek5, Hanno L. Tan1,3,* and Paul Bresser2

1 Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
2 Department of Pulmonology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
3 Department of Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
4 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
5 Department of Cardiothoracic Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Received 19 July 2006; revised 23 November 2006; accepted 18 January 2007; online publish-ahead-of-print 6 March 2007.

* Corresponding author. Tel: +31 20 5663264; fax: +31 20 6975458. E-mail address: h.l.tan{at}amc.uva.nl

See page 785 for the editorial comment on this article (doi:10.1093/eurheartj/ehm040)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Supplementary material
 Acknowledgements
 References
 
Aims: To study whether pre-operative assessment, using echocardiography, of the timing of a particular feature in the pulmonary flow (pulmonary flow systolic notch) may predict in-hospital mortality and mid-term haemodynamic improvement after pulmonary endarterectomy (PEA) for chronic thrombo-embolic pulmonary hypertension (CTEPH).

Methods and results: Fifty-eight of 61 consecutive CTEPH patients (aged 53 ± 14 years; 36 women) who underwent PEA between June 2002 and June 2005 were studied. Clinical, haemodynamic, and echocardiographic variables were assessed pre-operatively and at 3 months post-PEA. Timing of the notch was expressed as notch ratio (NR). Pre-operatively, seven patients had no notch, 33 had NR < 1.0, and 18 had NR > 1.0. NR was associated with in-hospital mortality (P < 0.01). Moreover, multivariable analysis revealed that among pre-operative variables, NR was an independent predictor of residual-increased pulmonary artery systolic pressure (>40 mmHg) at 3 months post-PEA (P = 0.01). Receiver operator characteristic analysis established NR = 1.0 as optimal cutoff to distinguish patients at risk of such unfavourable outcomes, with NR > 1.0 conferring higher risk.

Conclusion: NR is related with in-hospital mortality and residual pulmonary hypertension after PEA. NR > 1.0 is associated with a higher risk of such unfavourable outcomes. NR may be considered a determinant of eligibility for PEA.

Key Words: Chronic thrombo-embolic pulmonary hypertension • Echocardiography • Pulmonary endarterectomy • Outcome


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Supplementary material
 Acknowledgements
 References
 
Chronic thrombo-embolic pulmonary hypertension (CTEPH) results from incomplete resolution of the vascular obstruction caused by pulmonary thrombo-emboli.1 Recent studies suggest that up to 4% of acute pulmonary embolism cases may progress to symptomatic CTEPH.2 If left untreated, the prognosis of CTEPH is poor and proportional to the degree of pulmonary hypertension.3 Pulmonary endarterectomy (PEA) is the therapy of choice for patients with surgically accessible CTEPH.1,4–6 However, in ~10% of patients, removal of proximally located thrombo-embolic material does not resolve pulmonary hypertension.7 These patients suffer from high morbidity and in-hospital mortality rates. Residual pulmonary hypertension may result from the development of secondary arteriopathy in the small pre-capillary pulmonary vessels, similar to idiopathic pulmonary arterial hypertension (IPAH),1,8,9 as shown in lung biopsy specimens of CTEPH patients.8

At present, only few parameters at pre-operative analysis may be of use to identify patients with unfavourable PEA outcome. Patients with high pulmonary vascular resistance (in the range of >1000 to 1100 dynes s cm–5)10,11 and/or pulmonary artery mean pressure (mPAP) >50 mmHg11 have a higher likelihood of operative mortality.7,10,11 Partitioning of pulmonary vascular resistance by a pulmonary artery occlusion technique may also predict post-operative mortality, but this method is invasive and requires specific technical skills and therefore has limited applicability.12 Importantly, predictors of haemodynamic outcome (mid-term or long-term) are lacking.13 Clearly, more clinically available predictors of peri-operative mortality and haemodynamic outcome of PEA are much needed.

A particular feature in the pulmonary systolic flow velocity profile, the so-called pulmonary flow systolic notch (mid-systolic deceleration in pulmonary flow, as assessed using Doppler echocardiography), may distinguish proximally located obstructions in the pulmonary arterial vasculature from distal obstructions.14 This notch occurs significantly later in systole in patients with IPAH than in those with proximal pulmonary embolism. Similarly, experimentally induced micro-embolization of distal pulmonary arteries in dogs resulted in a later notch than constriction of proximal pulmonary arteries.15 Since residual pulmonary hypertension is considered to result either from surgically inaccessible distal thrombi or from secondary small vessel arteriopathy, or both,7,11,16 we undertook the present study to test the hypothesis that a late notch, assessed pre-operatively by Doppler echocardiography, in patients with CTEPH is associated with in-hospital mortality and unfavourable mid-term haemodynamic PEA outcome.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Supplementary material
 Acknowledgements
 References
 
Patient inclusion
In this single-centre study, 61 consecutive CTEPH patients underwent PEA from June 2002 to July 2005. Assessments were undertaken pre-operatively to evaluate their eligibility for PEA, using generally recommended criteria,7,17,18 and 3 months after PEA to assess their functional status. All patients who were deemed eligible for PEA after pre-operative assessment were recruited for this study. After they gave written informed consent, they were included in this study. Three patients were excluded from further analysis because their pre-operative echocardiographic variables were not stored. Thus, 58 patients treated consecutively were included in this retrospective study. All investigations were approved by the local institutional review board.

Pre-operative assessments
Pre-operatively, all patients underwent transthoracic echocardiography, pulmonary angiography, determination of plasma levels of brain natriuretic peptide (BNP),19,20 and right heart catheterization. Using a Swan–Ganz catheter, we measured mPAP, pulmonary capillary wedge pressure (PCWP), cardiac output, and right atrial pressure (RAP), and calculated total pulmonary resistance (TPR) and cardiac index.21 Forty-five patients performed 6 min walk test (6-MWT) according to the guidelines of the American Thoracic Society.22 At the time of pre-operative assessments, five patients were receiving bosentan [four had a notch ratio (NR) < 1.0, one had NR > 1.0], two patients intravenous epoprostenol (one had NR < 1.0, the other NR > 1.0), and one patient sildenafil (NR < 1.0) (For a definition of NR, see the following paragraphs).

Echocardiographic examination
Echocardiographic images (M-mode, two-dimensional, and Doppler) were obtained with a 1.6–3.2 MHz transducer (System Seven, General Electric, USA), digitized, and analysed offline. From the apical four-chamber view, we recorded right ventricular end-diastolic diameter (RVEDD),23 tricuspid annular plane systolic excursion (TAPSE),24 and tricuspid regurgitation jet, and used the velocity of this jet to obtain pulmonary artery systolic pressure (sPAP) from the calculated right ventricle-to-right atrium systolic pressure gradient (Bernoulli equation)25,26; to obtain sPAP, RAP values were added to the calculated gradient, with RAP estimated using the collapsibility index of the inferior caval vein in each patient.27 The severity of tricuspid regurgitation was quantified according to recommendations of American Society of Echocardiography's Nomenclature and Standards Committee and The Task Force on Valvular Regurgitation.28 In Tables 1 and 5, we quantified the severity of tricuspid regurgitation as follows: 0, no; 1, mild; 2, moderate; 3, severe. From the parasternal short-axis view, we recorded pulmonary artery systolic flow by placing the pulsed Doppler sample volume in the middle of the right ventricular outflow tract just proximal to the pulmonic valve orifice. Care was taken to align the ultrasound beam to the flow and to obtain a good spectral envelope.29–31 Its waveform was analysed and the pulmonary flow systolic NR (see what follows) was averaged from two to four consecutive heart beats. For the pre-operative analysis, the last echocardiograms, obtained within a few weeks before PEA, were used.


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  		Table 1 Baseline patient characteristics

 

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  		Table 5 Pre-operative variables of patients with no, early, and late pulmonary flow systolic notch

 
Calculation of the pulmonary flow systolic NR
The pulmonary flow systolic NR was calculated as demonstrated in Figure 1. The time interval from the onset of pulmonary artery systolic flow to the maximal systolic flow deceleration (t1) was divided by the time interval from the maximal systolic flow deceleration to the end of pulmonary artery systolic flow (t2) (Figure 1A). Figure 1C shows a pulmonary flow envelope of a patient with NR < 1.0. Figure 1D shows NR > 1.0. The pulmonary flow envelope of a patient with no notch is shown in Figure 1B. To quantify interobserver variability, two observers measured the NRs of 15 patients, independently from each other. To assess intraobserver variability, the NRs of the patients were measured twice by the same observer with a 2 months' interval between measurements.


Figure 1
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  		Figure 1 (A) Schematic illustration of the method to calculate pulmonary flow systolic NR. The time interval from the onset of pulmonary artery systolic flow to the maximal systolic flow deceleration (t1) was divided by the time interval from the maximal systolic flow deceleration to the end of pulmonary artery systolic flow (t2). (B, top) Pulmonary flow without notch of a patient with exercise-induced pulmonary hypertension (parasternal short-axis view). (Bottom) Maximal tricuspid regurgitation flow (four-chamber view), used to calculate systolic pulmonary artery pressure. (C, top) Pulmonary flow systolic notch, NR < 1.0. (Bottom) Maximal tricuspid regurgitation flow. (D, top) Pulmonary flow systolic notch, NR > 1.0. (Bottom) Maximal tricuspid regurgitation flow. Note that timing of notch differs between panels C and D, despite similar amplitudes of tricuspid regurgitation flow. All demonstrated recordings of pulmonary flow (B–D) were performed at rest.

 
Surgical methods
All patients were operated on by one surgeon (J.J.K.) using a standardized technique with extracorporeal circulation and periods of circulatory arrest in deep hypothermia.32 Fourteen patients also underwent persistent foramen ovale closure.

Post-operative assessments
Three months after PEA, all patients underwent transthoracic echocardiography, using the pre-operative echocardiography protocols (sPAP could be determined only in the 48 patients in whom tricuspid regurgitation was present at that time).

Statistical analysis
Categorical variables are presented as number and percentages and were compared between groups, using a Fisher's exact test. Continuous variables were checked for normal distribution, using the Wilk–Shapiro test, and presented as mean ± SD in the case of a normal distribution and median and interquartile range (IQR) otherwise. Baseline values of survivors and non-survivors compared using a two-tailed unpaired Student's t-test or Mann–Whitney test were appropriate. Univariate logistic regression analysis was used to identify pre-operative variables associated with peri-operative mortality and the combined endpoint mortality or a post-operative sPAP > 40 mmHg. The linearity assumption for the continuous variables was tested using Harrell's (1991) SAS Macro %Psplinet (http://biostat.mc.vanderbilt.edu/twiki/pub/Main/SasMacros/survrisk.txt). The optimal cutoff was defined as the value with the maximal sum of sensitivity and specificity. The reported 95% confidence intervals (CI) for cutoff points, area under curves (AUCs), sensitivities, and specificities were obtained through bootstrapping.

Associations between pre-operative variables and post-operative sPAP were analysed using univariate ANOVA's. Subsequently, variables with a P-value < 0.05 were included into a multivariable model with a backward selection procedure. Parameters between patients with no notch, NR < 1.0, and NR > 1.0 pre-operatively and post-operatively were compared using ANOVA. Interobserver and intraobserver variabilities were described in two ways: (i) by correlation coefficients (r) assessed by linear regression analysis; (ii) by the mean and the range of absolute differences of the measured pairs. All analyses were performed using SAS (version 9, SAS Institute, Cary, NC, USA), and P-values < 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Supplementary material
 Acknowledgements
 References
 
Reproducibility of the calculation of NR
Interobserver and intraobserver correlations were good with r = 0.96 and r = 0.98, respectively. The mean intraobserver difference was 0.06 (range 0.01–0.13). The mean interobserver difference was 0.07 (range 0.01–0.18).

In-hospital mortality
Overall, six of the 61 operated patients died during surgery [persistent pulmonary hypertension (n = 1), intractable bleeding (n = 2)] or within days after surgery [persistent pulmonary hypertension resulting in right ventricular failure (n = 3)]. Thus, in-hospital mortality was 9.8%. The baseline characteristics of surviving and non-surviving patients included for further analysis are presented in Table 1. Echocardiographic and haemodynamic variables of all patients who were operated are also obtained (see Supplementary material online, Table S5).

Determinants of in-hospital mortality
Increased in-hospital mortality risk was associated with pre-operative high NYHA class, low 6-MWT, high plasma BNP, high mPAP, high TPR, high NR, and low TAPSE (Table 2). Extracorporeal circulation time was significantly longer in non-survivors (472 ± 146 min) than in survivors (321 ± 42 min, P < 0.001; all patients 334 ± 71 min), and this parameter was most strongly associated with in-hospital mortality (not shown). We did not use this variable for further analysis, because the aim of this study was to reveal variables that are useful at pre-operative workup to identify patients who have a relatively high mortality risk and those with a low risk, rather than variables that can only be found intraoperatively.


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  		Table 2 Pre-operative determinants of in-hospital mortality. Area under the ROC curve, optimal cutoff point, sensitivity (%), and specificity (%) at the optimal cutoff point with 95% CI

 
Determinants of mid-term haemodynamic improvement
No patient died after discharge from the hospital. As a measure of mid-term haemodynamic improvement, we analysed sPAP at 3 months after PEA. We found that, in univariate analysis, low mid-term sPAP was associated with pre-operative low NYHA class (II vs. III), mPAP, PCWP, sPAP, and NR (Table 3). In the subsequent multivariable analysis, only NR (ß ± SEM: 32.5 ± 10.53, P = 0.004) and sPAP (ß ± SEM: 0.33 ± 0.13, P = 0.019) remained as independent determinants of sPAP at mid-term follow-up, explaining 32.2% of the observed variance.


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  		Table 3 Pre-operative determinants of sPAP at 3 months after PEA. Mean (±SEM) per NYHA class or change per unit increase (ß ± SEM) in sPAP at 3 months and the percentage variation explained (R2) based on univariate ANOVA

 
Determination of NR with the strongest predictive power
After determining that NR was an important pre-operative determinant of both in-hospital death and haemodynamic improvement at 3 months post-PEA, with high NR being associated with a higher risk of death and residual pulmonary hypertension post-operatively, results from the receiver operator characteristic (ROC) analysis were used to establish the optimal NR cutoff value to distinguish patients at risk of such unfavourable outcomes Figure 2. In-hospital mortality was best predicted when NR = 1.0 was used as cutoff value (Table 2). Accordingly, all patients who died in-hospital had NR > 1.0. Residual pulmonary hypertension was defined by echocardiographically determined sPAP > 40 mmHg, in agreement with current guidelines.33 The AUC, sensitivity, and specificity for sPAP > 40 mmHg at 3 months post-PEA at both the optimal NR cutoff (NR > 1.1) and NR > 1 are shown in Table 4. When a combined endpoint of in-hospital mortality and sPAP > 40 mmHg at 3 months post-PEA was studied, NR = 1.0 was a near-optimal cutoff value to predict this combined endpoint. Although NR = 1.1 had a slightly higher AUC of the ROC curve for the combined endpoint of in-hospital mortality and sPAP > 40 mmHg at 3 months post-operatively (Table 4), we suggest to use NR = 1.0 for this combined endpoint for the sake of practicality.


Figure 2
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  		Figure 2 ROC curves used NR to predict peri-operative mortality (A), systolic pulmonary artery pressure >40 mmHg at 3 months follow-up after PEA (B), and combination of both endpoints (C).

 

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  		Table 4 AUC, sensitivity, and specificity with 95% CI at the optimal and suggested NR cutoff point

 
Pre-operative NR and mid-term haemodynamic improvement
To further illustrate the utility of NR = 1.0 as cutoff value to predict haemodynamic improvement, we compared sPAP at 3 months post-PEA between patients with NR < 1.0 and those with NR > 1.0. Although all pre-operative variables, except NR, were similar between both groups (Table 5), sPAP at 3 months post-PEA was significantly lower in patients with NR < 1.0 than in those with NR > 1.0 (Figure 3). Of note, the proportion of patients who still had a notch post-operatively was significantly lower among patients with pre-operative NR < 1.0 (four of 33) than among those with pre-operative NR > 1.0 (five of 12, P = 0.043). When a notch remained present post-operatively, there was no significant difference in NR between both groups (0.96 ± 0.18 vs. 1.12 ± 0.18, respectively).


Figure 3
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  		Figure 3 Pre-operative and post-operative (3 months after PEA) sPAP of surviving patients with no pulmonary flow systolic notch, NR < 1.0 and NR > 1.0; *P < 0.05 vs. no notch (pre-operative); {dagger}P < 0.05 post-operative vs. pre-operative within group; {ddagger}P < 0.05 vs. no notch or NR < 1.0 (post-operative).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Supplementary material
 Acknowledgements
 References
 
We identified a novel echocardiographic variable, the pulmonary flow systolic NR, to be associated with peri-operative mortality and haemodynamic improvement at mid-term follow-up in CTEPH patients who underwent PEA. The timing of such a notch within the cardiac cycle is an excellent predictor of peri-operative mortality and functional improvement after PEA, with lower mortality risk and better haemodynamic outcome in patients with NR < 1.0. Of note, this variable has a stronger and more consistent predictive power than more traditional variables, such as mPAP, sPAP, TPR, or indices of right ventricular function, e.g. TAPSE. Clearly, using this variable may be of great aid when pre-operative assessments must establish which CTEPH patients are eligible for PEA. For instance, patients with severe elevations of PAP are probably good candidates for PEA if their NR is low (<1.0), even if they are severely symptomatic, because their in-hospital mortality risk is low and their haemodynamic improvement is good. Conversely, given that patients with an NR > 1.0 have a relatively high in-hospital mortality risk and more limited haemodynamic improvement, alternative treatments may be considered for these patients (e.g. bosentan and/or epoprostenol). In this context, the fact that notch (and NR) analysis is easy and safe to perform, although also being non-invasive, is a great asset.

Proposed pathophysiological basis of pulmonary flow systolic notch and its timing
An echocardiographic hallmark of patients with pulmonary hypertension is systolic partial closure of the pulmonary valve, which is evident as a pulmonary flow systolic notch.14,34 The presence of such a notch has been demonstrated in patients with congenital heart disease, IPAH, chronic obstructive pulmonary disease, acute thrombo-embolic pulmonary hypertension,and CTEPH.14,34 Increased wave reflection is believed to be the main explanation of this notch,14,15,34 as wave reflection may contribute to transient systolic pulmonary flow deceleration in patients with pulmonary hypertension.35,36 Importantly, the timing of the notch may vary within the cardiac cycle.14,34 Clinical14 and experimental15 studies have provided evidence that an early notch signifies a proximal obstruction to pulmonary flow, whereas a late notch maps the obstruction site to a more distal position. Accordingly, a more proximal location of the functional reflection site was associated with a shorter time-to-peak of the reflected pressure wave.36 Still, various other factors may influence deceleration of pulmonary artery systolic flow. These include pulmonary artery pressure,15,34 stroke volume, and the diameter and viscoelastic properties of the pulmonary artery.15 The requirement that pulmonary artery pressure must be sufficiently elevated for a notch to occur may explain why we observed that patients with no notch (at rest) had only slightly elevated mPAP and sPAP at rest.

Notch timing and PEA outcome
This proposed pathophysiological basis of the notch is in accordance with the observation that patients with NR > 1.0 had an increased in-hospital mortality risk and a limited haemodynamic improvement after PEA. These unfavourable outcomes may be explained by distal obstruction to pulmonary flow caused by secondary arteriopathy. Clearly, this derangement cannot be alleviated by surgical intervention. In support of this proposal, four of the six deaths were due to persistent pulmonary hypertension resulting in right ventricular failure, despite successful surgical removal of thrombo-embolic material, whereas in the two remaining patients (who died intraoperatively from intractable bleeding), postmortem analysis revealed secondary arteriopathy in the small pre-capillary pulmonary vessels. Of note, although the timing of the notch is a pre-operative determinant of in-hospital mortality and mid-term haemodynamic improvement, it does not reflect the gross level of the obstruction of pulmonary artery vasculature (PAP, TPR), nor the contractility of the left ventricle (PCWP) or right ventricle (TAPSE, RVEDD, RAP), as these measures were similar between patients with NR < 1.0 and those with NR > 1.0. These findings further support the notion that notch timing has a distinct pathophysiological basis.

Study limitations
Although this study clearly identifies NR as a powerful independent determinant of PEA success, it was limited in number at 58 patients. In particular, the number of deaths, while being in accordance with the ~10% in-hospital mortality rates as reported by most other centres7,13,37–39 (with the exception of the San Diego group, which reported a 4% in-hospital mortality rate10), was small. Finally, seven patients with no notch underwent PEA because of disabling exercise limitation with thrombo-embolic occlusion (evidenced angiographically) and exercise-induced pulmonary hypertension (proved by right heart catheterization during exercise). However, we did not conduct echocardiographic examination during exercise in these patients.

We sought to identify pre-operative variables which are widely accepted in clinical practice. Therefore, we chose to use echocardiographically determined sPAP, rather than the tricuspid valve pressure gradient alone, because both variables yielded similar predictive power in our univariate models (not shown), but sPAP is a more widely reported variable. Although echocardiographic determination of sPAP has the potential weakness that it requires estimation of RAP using the collapsibility index of the inferior caval vein, this method has been validated.27


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Supplementary material
 Acknowledgements
 References
 
We identified a novel and easily applicable echocardiographic predictor of the risk and efficacy of PEA for CTEPH. A pre-operative late pulmonary flow systolic notch (NR > 1.0) is an independent predictor of in-hospital mortality and limited haemodynamic improvement at 3 months after PEA. Future studies must resolve how this novel predictor may be used to optimize patient selection for PEA and clinical management of CTEPH patients. Also, delineation of the pathophysiological basis of this notch may contribute to refining therapy strategies in other disorders associated with pulmonary hypertension.


   Supplementary material
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Supplementary material
Acknowledgements
 References
 
Supplementary material is available at European Heart Journal online.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Supplementary material
 Acknowledgements
References
 
H.L.T. was supported by the Royal Netherlands Academy of Arts and Sciences (KNAW), the Netherlands Heart Foundation (2002B191, 2005B180), and the Bekales Foundation.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Supplementary material
 Acknowledgements
 References
 

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