Background
Speckle-tracking echocardiographic (STE) measures of right ventricular (RV) function appear to improve after transcatheter pulmonary valve implantation (TPVI). Measures of exercise function, such as ventilatory efficiency (the minute ventilation [V E ]/carbon dioxide production [V co 2 ] slope), have been shown to be prognostic of mortality in patients who may require TPVI. The aim of this study was to evaluate the correlation between STE measures of RV function and changes in V E /V co 2 after TPVI.
Methods
Speckle-tracking echocardiography and cardiopulmonary exercise testing were performed at baseline and 6 months after TPVI in 24 patients from four centers. Conventional echocardiographic measures of RV function were also assessed. Echocardiographic and exercise stress test results were interpreted by single blinded observers at separate core laboratories.
Results
All patients demonstrated relief of pulmonary regurgitation and stenosis after TPVI. Improvements in RV longitudinal strain (−16.9 ± 3.5% vs −19.7 ± 4.3%, P < .01) and strain rate (−0.9 ± 0.4 vs. −1.2 ± 0.4 s −1 , P < .01) were noted. The V E /V co 2 slope improved (32.4 ± 5.7 vs 31.5 ± 8.8, P = .03). No other significant echocardiographic or exercise changes were found. On multivariate regression, the change in V E /V co 2 was independently associated with change in RV longitudinal early diastolic strain rate ( P < .001) and tricuspid A velocity ( P < .001). Preintervention RV longitudinal strain was found to be a predictor of change in V E /V co 2 after TPVI ( r = −0.60, P < .001).
Conclusions
STE measures of RV function appear to hold the potential for use as predictors of improved outcomes in patients requiring TPVI. Future studies should directly assess the prognostic significance of STE measures of RV function in this population.
Highlights
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Improvements were seen in RV STE measures of deformation and V E /V co 2 6 months after TPVI in patients with conduits that were purely regurgitant or displayed mixed disease.
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Changes in STE measures of RV diastolic function were correlated with changes seen in V E /V co 2 after TPVI.
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Patients with decreased preintervention RV longitudinal strain were more likely to display improved V E /V co 2 after TPVI than those without.
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STE measures of RV function appear to hold the potential use as predictors of improved outcomes in patients requiring TPVI.
Patients with congenital heart disease requiring right ventricular (RV)–to–pulmonary artery (PA) conduits frequently develop free pulmonary regurgitation, severely dilated right ventricles, and decreased ventricular function over time. Measures of ventilatory efficiency derived from exercise testing, such as the minute ventilation [V E ]/carbon dioxide production [V co 2 ] slope, have been shown to be prognostic of mortality in these patients and are improved after pulmonary valve replacement secondary to improvement in effective stroke volume.
The relationship between echocardiographic measures of ventricular function and these exercise derived surrogates of outcome are unknown. These patients show little improvement in ventricular function when assessed using traditional echocardiographic markers. Speckle-tracking echocardiographic (STE) measures of ventricular function have been shown to be more sensitive than conventional measures in many disease processes, including in those patients undergoing transcatheter pulmonary valve implantation (TPVI). However, the relationship between STE measures of RV function before and after TPVI and exercise measures is unknown in this population. The objective of this study was to determine the usefulness of assessing RV STE measures of function by assessing their relationships with changes in cardiopulmonary exercise function both before and after TPVI. We hypothesized that RV STE measures of cardiac function would correlate with changes seen in exercise function after TPVI.
Methods
This was a retrospective, secondary analysis of data collected during the Congenital Multicenter Trial of Pulmonic Valve Regurgitation Studying the SAPIEN Interventional Transcatheter Heart Valve (COMPASSION) trial. COMPASSION is a prospective, nonrandomized, multicenter study whose aim is to assess the safety and efficacy of the SAPIEN transcatheter heart valve (Edwards Lifesciences, Irvine, California) for the treatment of dysfunctional RV-PA conduits. Early phase 1 results have shown good feasibility, effectiveness, and safety. Patients included in COMPASSION were enrolled prospectively from four participating centers. Inclusion criteria were (1) weight ≥ 35 kg; (2) in situ conduit diameter of 16 to 24 mm; (3) moderate or severe pulmonary regurgitation, defined as grade 3+ pulmonary regurgitation on echocardiography and/or RV-PA conduit obstruction with a mean gradient of >35 mm Hg; and (4) peak oxygen uptake (V o 2 ) or V E /V co 2 < 70% of the predicted value. Informed consent was obtained from all potential subjects and/or their legal guardians. The institutional review board at each participating institution approved the trial.
Procedure
The protocol for valve implantation has been reported previously and is summarized here for convenience. Procedures were performed under general anesthesia with biplane fluoroscopic guidance. The minimum diameter of the conduit was assessed by angiography. Risk for coronary compression was assessed with aortic root angiography or selective coronary angiography with simultaneous inflation of a noncompliant balloon in the conduit. Prestenting of the conduit with a bare-metal stent was performed. A 23- or 26-mm SAPIEN transcatheter heart valve was then implanted over a stiff guidewire and expanded via balloon inflation.
Echocardiographic Protocol
Analysis of echocardiograms submitted to the COMPASSION core laboratory was performed. Echocardiograms were acquired by experienced sonographers at each center following a protocol that included a complete set of standardized views to evaluate ventricular function. The image acquisition protocol was developed by the echocardiography core laboratory. On-site or Web-based training to the local SAPIEN TPVI sites was provided. Echocardiograms used for this analysis were obtained at baseline before TPVI, before discharge after TPVI, at 30-day follow-up, and at 6-month follow-up. All studies were performed under baseline physiologic conditions, not under the influence of anesthesia. Measures were recorded at end-expiration with quiet respiration. Pre-TPVI echocardiograms were obtained ≤1 week before TPVI. Echocardiograms were in Digital Imaging and Communications in Medicine format. All measurements were made offline by a single reviewer and averaged over three beats. Pulmonary regurgitation was graded from 0 to 4 on the basis of the jet width/annulus ratio and flow reversal in the branch pulmonary arteries as follows: 0 = no regurgitation, 1 = jet width/annulus ratio < 0.25, 2 = jet width/annulus ratio between 0.25 and 0.5, 3 = jet width/annulus ratio between 0.5 and 0.7, and 4 = jet width/annulus > 0.7 with flow reversal in the branch pulmonary arteries. Tricuspid valve regurgitant orifice area was calculated from the apical four-chamber and parasternal short-axis windows.
Two-Dimensional, Spectral, and Tissue Doppler Measures of Myocardial Function
From a standard apical four-chamber window, RV fractional area change was defined as [(end-diastolic area − end-systolic area)/end-diastolic area] × 100. Tricuspid annular plane systolic excursion was obtained, and indexed tricuspid annular plane systolic excursion was calculated as [(RV end-diastolic length − RV end-systolic length)/RV end-diastolic length]. Pulsed Doppler tissue imaging S′ velocities at the tricuspid valve annulus and interventricular septum were obtained from the apical four-chamber view.
To evaluate diastolic function, Doppler velocities of transtricuspid flow (E and A) were obtained from an apical four-chamber window. Tissue Doppler velocities of the tricuspid annulus and interventricular septum (E′ and A′) were obtained. Derived ratios (E/A and E/E′) were calculated.
STE Measures of Myocardial Function
Speckle-tracking was performed as a secondary analysis of echocardiograms submitted to the COMPASSION echocardiography core laboratory. A single, blinded observer performed offline analysis of Digital Imaging and Communications in Medicine images using vendor-independent software (2D Cardiac Performance Analysis version 3.0; TomTec Imaging Systems GmbH, Munich, Germany). Myocardial motion was tracked through the cardiac cycle, calculating myocardial deformation from echogenic speckles in the B-mode image. The endocardium and epicardium were manually traced in the right ventricle from the lateral tricuspid annulus to the septal component of the tricuspid annulus ( Figure 1 ). The septum was included because of its importance to global RV function. End-systole was defined as end-ejection of the pulmonic valve for the right ventricle and of the aortic valve for the left ventricle using spectral Doppler. Speckle-tracking measures of deformation from the apical four-chamber view included peak longitudinal strain, strain rate, and early diastolic strain rate. Left ventricular (LV) measures of deformation from the apical four-chamber view were also assessed. Global deformation measurements were calculated as averages of six segments. Tracking was visually assessed, and deformation curves were not accepted if greater than one segment demonstrated inadequate tracking. It should be noted that longitudinal strain is by convention expressed using negative numbers. When describing relative differences, the absolute value of the strain amplitude (ignoring the minus sign) is referenced. For example, a strain value of −23% represents better function than a strain value of −13%.
Exercise Protocol
All patients underwent a symptom-limited cardiopulmonary exercise test with progressive protocols using either a bicycle ergometer or a treadmill, depending on the equipment available at the individual centers. Patients had a rest period to capture baseline, then a warmup period without load, followed by an increase of load depending on the expected individual physical capacity as estimated by the investigator. The end of the exercise test was marked by symptom limitation and was followed by a recovery period. All exercise tests were analyzed by a blinded observer at a separate COMPASSION cardiopulmonary testing core laboratory.
The exercise test used breath-by-breath gas exchange analysis using a metabolic cart. The primary exercise measure of interest was ventilatory efficiency, as analyzed by the V E /V co 2 slope. Peak V o 2 was defined as the highest mean uptake during exercise. Anaerobic threshold (AT) was determined by use of the modified V-slope method. Peak oxygen pulse was defined as peak V o 2 divided by peak heart rate.
Statistical Analysis
Paired t tests were used to assess for changes in exercise test variables between baseline and 6 months. For echocardiograms, to determine the trend from time 0 to time 3, repeated-measures analysis of variance with Greenhouse-Geisser correction was conducted on all individuals with measurements for each of the four time points. Post hoc comparisons using the Bonferroni correction were then performed for those variables that showed statistical significance on repeated-measure analysis of variance. Missing data were not imputed, because numbers were sufficient to conduct appropriate analyses. Pearson correlation and multiple variable stepwise linear regression were used to assess for linear relationships between echocardiographic variables and exercise function. Independent variables assessed with stepwise regression techniques included baseline and percentage change in RV size (end-diastolic and end-systolic area), conduit peak and mean gradients, and all measures of RV and LV systolic function as described above. Age and sex were also included in the analysis. Results of multivariate analysis are reported as partial correlations; its purpose is to quantify the association between two variables while eliminating the variance from other variables in the model. A receiver operating characteristic curve was developed to assess the sensitivity and specificity of optimal cutoff values for the preoperative echocardiographic variable that best predicted an improvement in exercise function. Intraobserver and interobserver variability was assessed by absolute percentage error of the mean (the difference between the two measurements was divided by the mean of those two measurements) and by intraclass correlation coefficient using a random-effects model measuring absolute agreement. An intraclass correlation coefficient ≥ 0.75 was deemed to indicate acceptable intra- or interobserver variability. P values < .05 were considered to indicate statistical significance. Statistics were analyzed using SPSS version 22 (IBM, Armonk, NY).
Results
The first 33 patients from four centers who underwent successful SAPIEN TPVI in the COMPASSION trial were eligible. A total of 132 echocardiographic studies were performed. Of these, 17 were excluded for inability to perform speckle-tracking echocardiography because of inadequate RV free wall and/or apical segment capture in the echocardiographic window or for inadequate apical four-chamber windows. These 17 echocardiograms came from a total of nine patients. Therefore, 24 patients had echocardiograms suitable for speckle-tracking analysis (two or fewer segments were excluded from the RV analysis) at each of the four time points so that a comprehensive analysis of changes in ventricular function after TPVI could be performed. Demographic data from these patients are presented in Table 1 . After TPVI, no patient had greater than mild stenosis or regurgitation.
| Variable | Value |
|---|---|
| Age (y) | 32.3 ± 17.0 |
| Weight (kg) | 73.5 ± 24.1 |
| Men/women | 17/7 |
| Diagnosis | |
| Tetralogy of Fallot | 12 |
| Ross procedure | 7 |
| Other | 5 |
| Conduit dysfunction | |
| Regurgitation only | 7 |
| Mixed | 17 |
| Pulmonary stenosis grade | |
| None (<16 mm Hg) | 4 |
| Mild (16–30 mm Hg) | 3 |
| Moderate (31–45 mm Hg) | 8 |
| Severe (>45 mm Hg) | 9 |
| Pulmonary regurgitation grade | |
| None | 0 |
| Trivial | 0 |
| Mild | 1 |
| Moderate | 1 |
| Severe | 22 |
Changes after TPVI
Peak and mean gradients through the conduit, pulmonary regurgitation grade, RV end-diastolic and end-systolic areas, and tricuspid regurgitation velocity decreased between baseline and 6 months ( Table 2 ). No significant changes were detected in the conventional measures of RV systolic or diastolic function at 6-month follow-up, with the exception of an increase in tricuspid inflow Doppler A velocity ( Table 3 ). Statistically significant improvements in RV longitudinal strain and strain rate were noted, while changes in RV early diastolic strain rate trended toward significance ( Table 4 ). The V E /V co 2 slope and oxygen pulse improved between baseline and 6 months; in contrast, there were no statistically significant changes in peak V o 2 , V o 2 at AT, or respiratory exchange ratio at AT ( Table 5 ).
| Measure | Baseline (time 0) | Discharge (time 1) | 30-d follow-up (time 2) | 6-mo follow-up (time 3) | ANOVA ( P value) | Multiple comparison ( P < .05) |
|---|---|---|---|---|---|---|
| Conduit stenosis peak gradient (mm Hg) | 42.4 ± 5.5 | 22.1 ± 2.1 | 22.3 ± 3.1 | 20.7 ± 2.6 | <.01 | Time 0 vs 1, 2, 3 |
| Conduit stenosis mean gradient (mm Hg) | 24.1 ± 3.2 | 13.2 ± 1.3 | 13.1 ± 1.8 | 12.3 ± 1.7 | <.01 | Time 0 vs 1, 2, 3 |
| RV end-diastolic area (cm 2 ) | 41.4 ± 1.9 | 42.3 ± 2.3 | 37.6 ± 2.0 | 37.1 ± 1.6 | <.01 | Time 0 vs 2, 3 Time 1 vs 2, 3 |
| RV end-systolic area (cm 2 ) | 29.3 ± 1.3 | 29.7 ± 2.0 | 26.1 ± 1.6 | 25.4 ± 1.0 | <.01 | Time 0 vs 3 Time 1 vs 2, 3 |
| TR peak gradient (mm Hg) | 56.2 ± 5.1 | 47.1 ± 3.2 | 40.2 ± 2.6 | 40.9 ± 2.6 | <.01 | Time 0 vs 2, 3 Time 1 vs 2 |
| Indexed TR jet area (cm 2 /m 2 ) | 0.18 ± 0.20 | 0.11 ± 0.12 | 0.11 ± 0.17 | 0.10 ± 0.09 | <.01 | Time 0 vs 1, 2, 3 |
| Tricuspid valve annulus Z score | 1.36 ± 0.94 | 1.41 ± 0.99 | 1.49 ± 1.00 | 1.64 ± 0.80 | .89 | None |
| Measure | Baseline (time 0) | Discharge (time 1) | 30-d follow-up (time 2) | 6-mo Follow-up (time 3) | ANOVA ( P value) | Multiple comparison ( P < .05) |
|---|---|---|---|---|---|---|
| RV FAC (%) | 29.0 ± 1.9 | 30.1 ± 1.7 | 29.2 ± 2.0 | 31.4 ± 1.1 | .72 | NA |
| Indexed TAPSE (%) | 0.14 ± 0.01 | 0.15 ± 0.01 | 0.15 ± 0.01 | 0.16 ± 0.01 | .48 | NA |
| DTI: tricuspid S (cm/sec) | 7.7 ± 0.5 | 9.1 ± 0.4 | 8.0 ± 0.4 | 8.2 ± 0.4 | <.01 | Time 0 vs 1 Time 1 vs 2 |
| RV Doppler E (cm/sec) | 72.6 ± 5.5 | 77.9 ± 5.1 | 76.6 ± 5.7 | 70.3 ± 3.7 | .31 | NA |
| RV Doppler A (cm/sec) | 44.9 ± 4.0 | 59.1 ± 5.5 | 51.1 ± 4.4 | 49.2 ± 4.9 | .02 | NA |
| RV Doppler E/A ratio | 1.8 ± 0.2 | 1.5 ± 0.2 | 1.6 ± 0.2 | 1.7 ± 0.2 | .37 | NA |
| DTI: tricuspid e′ (cm/sec) | 7.9 ± 2.1 | 8.9 ± 2.1 | 7.8 ± 1.7 | 7.9 ± 1.7 | <.01 | Time 0 vs 1 Time 1 vs 2 |
| DTI: tricuspid E/e′ ratio | 7.4 ± 0.9 | 8.4 ± 0.7 | 9.3 ± 1.2 | 8.3 ± 0.8 | .29 | NA |
| Measure | Baseline (time 0) | Discharge (time 1) | 30-d follow-up (time 2) | 6-mo follow-up (time 3) | ANOVA ( P value) | Multiple comparison ( P < .05) |
|---|---|---|---|---|---|---|
| Global RV LS (%) | −16.9 ± 0.7 | −17.3 ± 1.0 | −17.8 ± 0.6 | −19.6 ± 0.9 | <.01 | Time 0 vs 3 |
| Global RV LSR (sec −1 ) | −0.87 ± 0.09 | −1.03 ± 0.07 | −1.03 ± 0.05 | −1.16 ± 0.08 | .01 | Time 0 vs 3 |
| Global RV LEDSR (sec −1 ) | 1.11 ± 0.10 | 1.16 ± 0.11 | 1.12 ± 0.09 | 1.31 ± 0.10 | .15 | NA |
| RV free wall LS (%) | −17.0 ± 3.7 | −17.2 ± 6.1 | −19.1 ± 4.8 | −21.9 ± 6.2 | <.01 | Time 0 vs 3 Time 1 vs 3 |
| RV free wall LSR (sec −1 ) | −0.98 ± 0.33 | −1.04 ± 0.39 | −1.11 ± 0.30 | −1.31 ± 0.68 | .04 | Time 0 vs 3 |
| RV free wall LEDSR (sec −1 ) | 1.10 ± 0.48 | 1.16 ± 0.56 | 1.27 ± 0.61 | 1.43 ± 0.64 | .11 | NA |
| Septal LS (%) | −16.0 ± 3.9 | −16.5 ± 4.5 | −15.9 ± 2.9 | −17.8 ± 5.4 | .30 | NA |
| Septal LSR (sec −1 ) | −0.91 ± 0.24 | −1.01 ± 0.35 | −0.93 ± 0.27 | −1.05 ± 0.42 | .22 | NA |
| Septal LEDSR (sec −1 ) | 1.10 ± 0.46 | 1.08 ± 0.49 | 0.97 ± 0.34 | 1.17 ± 0.46 | .29 | NA |
| Global LV LS (%) | −16.2 ± 0.8 | −18.5 ± 0.8 | −18.0 ± 1.1 | −18.2 ± 0.9 | .01 | Time 0 vs 3 |
| Global LV LSR (sec −1 ) | −1.13 ± 0.09 | −1.18 ± 0.07 | −1.11 ± 0.08 | −1.06 ± 0.15 | .69 | NA |
| Global LV LEDSR (sec −1 ) | 1.28 ± 0.08 | 1.34 ± 0.11 | 1.30 ± 0.10 | 1.32 ± 0.09 | .90 | NA |
| Measure | Baseline | 6 months | P value |
|---|---|---|---|
| Peak V o 2 (mL/kg/min) | 24.1 ± 10.3 | 25.5 ± 8.2 | .18 |
| V o 2 at AT (mL/kg/min) | 14.1 ± 5.2 | 15.0 ± 5.1 | .53 |
| RER at AT | 0.89 ± 0.09 | 0.91 ± 0.10 | .94 |
| V E /V co 2 at AT | 32.4 ± 5.7 | 29.5 ± 8.8 | .02 |
| Oxygen pulse (mL/beat) | 10.9 ± 3.4 | 12.1 ± 3.8 | .01 |
Changes in Echocardiographic Measures versus Changes in Exercise Measures
Changes in conventional echocardiographic measures of RV function were not correlated with changes in measures of exercise function. Furthermore, changes in echocardiographic measures of RV size, conduit stenosis, conduit insufficiency, and tricuspid regurgitant jet gradient were not correlated with changes in measures of exercise function. The change in V E /V co 2 was correlated with the change in RV longitudinal strain ( r = 0.54, P = .02) ( Figure 2 ) and early diastolic strain rate ( r = −0.59, P = .01) ( Figure 3 ). No other correlations were found between changes in STE measures of function and exercise measures of function. No correlations were found between changes in LV measures of deformation and changes in exercise function variables. On multiple variable regression, only percentage change in RV early diastolic strain rate and tricuspid valve inflow Doppler A velocity demonstrated a statistically significant relationship with percentage change in V E /V co 2 ( Table 6 ). No variables demonstrated collinearity (variance inflation factors for all variables < 5).
| Model | Variable | B | SE | β | t | Partial R | P | F | R | R 2 |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | .03 | 6.35 | −0.57 | 0.33 | ||||||
| Constant | 7.33 | 2.44 | 3.00 | .01 | ||||||
| Percentage change RV EDSR | −0.13 | 0.05 | −0.57 | −2.52 | 0.57 | .03 | ||||
| 2 | <.01 | 10.63 | −0.80 | 0.64 | ||||||
| Constant | 8.70 | 1.91 | 4.55 | <.01 | ||||||
| Percentage change RV EDSR | −0.14 | 0.04 | −0.61 | −3.53 | 0.71 | <.01 | ||||
| Percentage change TV A velocity | 0.12 | 0.04 | 0.56 | 3.22 | 0.68 | <.01 |
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