Speckle-Tracking Echocardiographic Measures of Right Ventricular Function Correlate With Improvement in Exercise Function After Percutaneous Pulmonary Valve Implantation Shahryar M. Chowdhury, MD, MSCR, Ziyad M. Hijazi, MD, MPH, MSCAI, John T. Fahey, MD, John F. Rhodes, MD, Saibal Kar, MD, Raj Makkar, MD, Michael Mullen, MD, Qi-Ling Cao, MD, and Girish S. Shirali, MBBS, FACC, FASE, Charleston, South Carolina; Doha, Qatar; New Haven, Connecticut; Miami, Florida; Los Angeles, California; London, United Kingdom; Chicago, Illinois; and Kansas City, Missouri

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 [VE]/carbon dioxide production [VCO2] 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 VE/VCO2 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 6 3.5% vs
19.7 6 4.3%, P < .01) and strain rate (
0.9 6 0.4 vs.
1.2 6 0.4 s
1, P < .01) were noted. The VE/VCO2 slope improved (32.4 6 5.7 vs 31.5 6 8.8, P = .03). No other significant echocardiographic or exercise changes were found. On multivariate regression, the change in VE/VCO2 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 VE/VCO2 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. (J Am Soc Echocardiogr 2015;28:1036-44.) Keywords: Speckle-tracking echocardiography, Transcatheter pulmonary valve implantation, Congenital heart disease

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.1 Measures of ventilatory efficiency derived from exercise testing, such as the minute ventilation [VE]/carbon dioxide production [VCO2] slope, have been shown to be prognostic of mortality in these patients and are improved after pul-

monary valve replacement secondary to improvement in effective stroke volume.2-7 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.8 Speckle-tracking echocardiographic (STE) measures of ventricular function have been

From the Department of Pediatrics, Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina (S.M.C.); the Department of Pediatrics, Sidra Medical and Research Center, Doha, Qatar (Z.M.H.); the Department of Pediatrics, Yale-New Haven Hospital, New Haven, Connecticut (J.T.F.); the Department of Pediatrics, Miami Children’s Hospital, Miami, Florida (J.F.R.); the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.K.); the Department of Medicine, The Heart Hospital, London, United Kingdom (M.M.); Rush Center for Congenital & Structural Heart Disease, Rush University Medical Center, Chicago, Illinois (Q.-L.C.); and The Ward Family Heart Center, Children’s Mercy Hospital, Kansas City, Missouri (G.S.S.).

This study was funded by Edwards Lifesciences, LLC (Irvine, CA). Drs Hijazi and Shirali received grant funding through Edwards Lifesciences. Dr Chowdhury received funding from National Heart, Lung, and Blood Institute grant 5 T32 HL07710-19.

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Reprint requests: Shahryar M. Chowdhury, MD, MSCR, Medical University of South Carolina, Department of Pediatrics, Division of Cardiology, 165 Ashley Avenue, MSC 915, Charleston, SC 29425 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.05.010

Journal of the American Society of Echocardiography Volume 28 Number 9

Abbreviations

AT = Anaerobic threshold COMPASSION = Congenital Multicenter Trial of Pulmonic Valve Regurgitation Studying the SAPIEN Interventional Transcatheter Heart Valve

LV = Left ventricular MRI = Magnetic resonance imaging

PA = Pulmonary artery RV = Right ventricular STE = Speckle-tracking echocardiographic TPVI = Transcatheter pulmonary valve implantation Vco2 = Carbon dioxide production

VE = Minute ventilation

shown to be more sensitive than conventional measures in many disease processes, including in those patients undergoing transcatheter pulmonary valve implantation (TPVI).9-12 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

Vo2 = Oxygen uptake

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.13 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 (VO2) or VE /VCO2 < 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.13 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

Chowdhury et al 1037

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.14,15 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)/enddiastolic 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)/RVend-diastolic length]. Pulsed Doppler tissue imaging S0 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 (E0 and A0 ) were obtained. Derived ratios (E/A and E/E0 ) 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.16 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 fourchamber 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

1038 Chowdhury et al

Journal of the American Society of Echocardiography September 2015

Figure 1 Speckle-tracking echocardiography of the right ventricle. Two-dimensional speckle-tracking echocardiogram of RV longitudinal strain in a patient with tetralogy of Fallot with mixed conduit stenosis and insufficiency. Endocardial and epicardial traces are shown.

Table 1 Patient demographics Variable

Value

Age (y)

32.3 6 17.0

Weight (kg)

73.5 6 24.1

Men/women

17/7

Diagnosis Tetralogy of Fallot

12

Ross procedure

7

Other

5

Conduit dysfunction Regurgitation only Mixed

7 17

Pulmonary stenosis grade None (45 mm Hg)

9

Pulmonary regurgitation grade None

0

Trivial

0

Mild

1

Moderate

1

Severe

22

Data are expressed as mean 6 SD or as numbers. Pulmonary stenosis was graded on the basis of net peak gradient. Pulmonary regurgitation was graded on the basis of jet width/annulus ratio and flow reversal in the branch pulmonary arteries as follows: none = no regurgitation, trivial = jet width/annulus ratio < 0.25, mild = jet width/annulus ratio between 0.25 and 0.5, moderate = jet width/annulus ratio between 0.5 and 0.7, severe = jet width/annulus > 0.7 with flow reversal in the branch pulmonary arteries.

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 VE /VCO2 slope. Peak VO2 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 VO2 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

Chowdhury et al 1039

Journal of the American Society of Echocardiography Volume 28 Number 9

Table 2 Pulmonary and tricuspid valve function and RV size after TPVI Baseline (time 0)

Measure

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 6 5.5

22.1 6 2.1

22.3 6 3.1

20.7 6 2.6