Right ventricular function during exercise in children after heart transplantation

Right ventricular function during exercise in children after heart transplantation Abstract Aims Right ventricular (RV) dysfunction is a common problem after heart transplant (HTx). In this study, we used semi-supine bicycle ergometry (SSBE) stress echocardiography to evaluate RV systolic and diastolic reserve in paediatric HTx recipients. Methods and results Thirty-nine pediatric HTx recipients and 23 controls underwent stepwise SSBE stress echocardiography. Colour tissue doppler imaging (TDI) peak systolic (s’) and peak diastolic (e’) velocities, myocardial acceleration during isovolumic contraction (IVA), and RV free wall longitudinal strain were measured at incremental heart rates (HR). The relationship with increasing HR was evaluated for each parameter by plotting values at each stage of exercise versus HR using linear and non-linear regression models. At rest, HTx recipients had higher HR with lower TDI velocities (s’: 5.4 ± 1.7 vs. 10.4 ± 1.8 cm/s, P < 0.001; e’: 6.4 ± 2.2 vs.12 ± 2.4 cm/s, P < 0.001) and RV IVA values (IVA: 1.2 ± 0.4 vs. 1.6 ± 0.8 m/s2, P = 0.04), while RV free wall longitudinal strain was similar between groups. At peak exercise, HR was higher in controls and all measurements of RV function were significantly lower in HTx recipients, except for RV free wall longitudinal strain. When assessing the increase in each parameter vs. HR, the slopes were not significantly different between patients and controls except for IVA, which was lower in HTx recipients. Conclusion In pediatric HTx recipients RV systolic and diastolic functional response to exercise is preserved with a normal increase in TDI velocities and strain values with increasing HR. The blunted IVA response possibly indicates a mildly decreased RV contractile response but it requires further investigation. Heart transplantation, Children, Exercise, Stress imaging, RV function Introduction Right ventricular (RV) dysfunction is a common problem after heart transplant (HTx) with multiple factors involved. Early RV dysfunction is mainly related to donor brain death, graft ischaemia, and increased pulmonary vascular resistance in the recipient.1–9 The development of late RV dysfunction is associated with acute and chronic rejection, development of tricuspid regurgitation (TR) and myocardial fibrosis due to repeated myocardial biopsies.10–15 Different studies documented biventricular systolic and diastolic dysfunction early after pediatric HTx.16–18 While left ventricle (LV) functional parameters at rest and during exercise normalize over time, RV functional parameters often remain reduced 1-year after transplantation.19 The RV functional response to exercise has not been well described in pediatric HTx recipients, despite this may help to better understand the functional implications of the RV function abnormalities observed at rest. Semi-supine bicycle ergometry (SSBE) stress echocardiography combined with colour tissue doppler imaging (TDI) and two-dimensional speckle tracking echocardiography (2D STE) allow the evaluation of myocardial function during exercise. The semi-supine position facilitates the acquisition of images at different exercise stages which can be used for studying the dynamic myocardial response.20,21 Our group has previously applied this methodology for studying LV myocardial response to exercise in pediatric patients after HTx demonstrating a preserved LV dynamic response.22 We hypothesized that RV dynamic myocardial response to exercise may be abnormal in pediatric HTx patients given the abnormal RV resting parameters. The aim of the present study was to investigate RV systolic and diastolic myocardial reserve during SSBE stress echocardiography in a cohort of pediatric HTx recipients and to compare the myocardial response of pediatric HTx recipients to normal controls. Patients and methods This study is a secondary analysis of prospectively collected datasets and was approved by the institutional Research Ethics Board. The study population consisted of children transplanted between 1994 and 2009 and followed at our institution.23 In 2013, our clinical echocardiography stress protocol for HTx recipients was modified by including the acquisition of a 4-chamber view and a high-frame rate narrow-sector colour TDI view focused on the RV. For this reason, only exercise stress echocardiogram performed between 2013 and 2015 were included in this study. Controls were selected from a larger cohort of healthy volunteers previously recruited at our institution.23 Prior to SSBE stress echocardiography, HTx recipients underwent a baseline echocardiogram according to the routine clinical hospital protocol, following the American Society of Echocardiography Pediatric Guidelines.24 SSBE stress echocardiography protocol All stress exams followed a standardized Bruce exercise protocol, using 3-min stages with a target speed of 60 rev/min. Twenty-Watt increments every 3 min were used for individuals up to 14 years of age, and 25-Watt increments above this age. A semi supine bicycle (Lode B.V., Groningen, The Netherlands) was used for all echocardiographic stress studies. The target heart rates (HR) was 85% of the maximal HR calculated as 220-age. A cardiologist supervised all tests and early termination was determined based on patient fatigue, the occurrence of predefined adverse events (arrhythmia, ischaemia, chest pain, clinical signs of circulatory compromise, progressive fall in systolic blood pressure >10%, severe hypertension) or decline in image quality related to moving or breathing at the more intense phases of exercise. Patients were monitored with a continuous 12-lead ECG and sphygmomanometry blood pressure measurements were obtained during the last 30 s of each stage (Dinamap ®, USA). Image acquisition Images were obtained using a Vivid E-9 ultrasound system (GE Healthcare, USA) during the last 2 min of each stage using the Smart Stress application®. The stress protocol included acquisition of colour TDI velocities and storage of raw DICOM grey-scale images that can be analysed using 2D STE. Echocardiographic images acquired at each stage and during recovery included: a parasternal long axis view, a parasternal short axis view at the papillary muscle level and two apical 4 chambers view optimized for off-line 2D STE analysis each focused on the LV and RV (frame rate >60 frames/s), spectral pulsed wave Doppler of mitral inflow, high-frame rate narrow-sector colour TDI of the LV lateral wall and the interventricular septum and of the RV free wall, apical 3 and 2 chambers. Image analysis Images were digitally stored for offline analysis, using the Echopac system (version 110.1.3, GE Healthcare, USA). To avoid translational movements of the region of interest during the cardiac cycle, manual tracking was performed. Velocity measurements were recorded as the average value from three consecutive cardiac cycles. Fusion of e’ and a’ wave was seen during exercise in all subjects and the fused wave was measured as e’. Isovolumic contraction (IVA) was calculated as the difference between baseline and peak velocity divided by the time interval (m/s2). Right ventricular free wall longitudinal strain was calculated at the basal, mid and apical segments and the resulting mean strain value was derived by averaging the three segmental values. Reproducibility Fifteen randomly selected studies were analysed by two independent observers for inter-observer variability of colour TDI and longitudinal strain. The same studies were used for assessment of intra-observer variability of the same measurements, with the observer blinded to the initial results and a time interval of at least 2 weeks between the two analyses. Statistics Data are presented as mean with standard deviations, median with range, and frequencies as appropriate. Comparisons between the two groups were performed using Student's t-tests assuming unequal variance between samples and Fisher's exact test. Linear and non-linear regression models adjusted for repeated measures through an autoregressive covariance structure was used to compare average values and the slope of change over increasing HR between HTx and controls. Intra-class correlation coefficients (ICC) were calculated to assess inter- and intra-observer variability. All statistical analyses were performed using SAS Statistical Software v9.4 (The SAS Institute, Cary, NC). Results Study population Thirty-nine pediatric HTx recipients (16 males), who underwent a SSBE stress echocardiography between 2013 and 2015, were included in the study. Fourteen patients were excluded for suboptimal quality of the RV images during stress. The remaining 25 constituted the cohort for this study and their demographic data are summarized in Table 1. Twenty-three healthy subjects with similar age and gender were selected as controls from the large healthy volunteer’s database. No significant differences in height and weight were found between the Htx recipients and controls. For the HTx group, median age at transplantation was 3.7 years (2 days to 15 years), with a median time since transplant of 9 years (2–17 years). Nine patients had no episode of rejection at the time of the study. From the remaining 14 patients, 12 had one episode of rejection very early post-transplant (median time of rejection episode from transplant was 2 days), and 2 patients had 2 episodes. All rejections were classified as low grade. The last cardiopulmonary test performed before SSBE stress echocardiograph demonstrated that the patients had an average percent-predicted peak VO2 of 91%. Table 1 Demographics   HTx (n = 25)  Controls (n = 23)  P-value  Age at the study (years)  14 ± 2.1  14 ± 2.1  0.9  Males (%)  16 (64%)  14 (60%)    Height (cm)  159 ± 13.1  160 ± 13.3  0.80  Weight (kg)  51.5 ± 14  52 ± 13.7  0.80  BSA (m2)  1.51 ± 0.2  1.5 ± 0.2  0.80    HTx (n = 25)  Controls (n = 23)  P-value  Age at the study (years)  14 ± 2.1  14 ± 2.1  0.9  Males (%)  16 (64%)  14 (60%)    Height (cm)  159 ± 13.1  160 ± 13.3  0.80  Weight (kg)  51.5 ± 14  52 ± 13.7  0.80  BSA (m2)  1.51 ± 0.2  1.5 ± 0.2  0.80  BSA, body surface area. Table 1 Demographics   HTx (n = 25)  Controls (n = 23)  P-value  Age at the study (years)  14 ± 2.1  14 ± 2.1  0.9  Males (%)  16 (64%)  14 (60%)    Height (cm)  159 ± 13.1  160 ± 13.3  0.80  Weight (kg)  51.5 ± 14  52 ± 13.7  0.80  BSA (m2)  1.51 ± 0.2  1.5 ± 0.2  0.80    HTx (n = 25)  Controls (n = 23)  P-value  Age at the study (years)  14 ± 2.1  14 ± 2.1  0.9  Males (%)  16 (64%)  14 (60%)    Height (cm)  159 ± 13.1  160 ± 13.3  0.80  Weight (kg)  51.5 ± 14  52 ± 13.7  0.80  BSA (m2)  1.51 ± 0.2  1.5 ± 0.2  0.80  BSA, body surface area. Haemodynamic responses to exercise At rest, HR (mean ± SD) (HTx 88 ± 12 vs. controls 70 ± 12 bpm P < 0.001), systolic blood pressure (HTx 114 ± 13 vs. controls 107 ± 14 mmHg, P = 0.08) and diastolic blood pressure (HTx 70 ±8 vs controls 64 ± 9 mmHg, P = 0.01) were higher in HTx recipients. At peak exercise, the highest HR achieved was lower in the HTx group compared with controls (HTx 142 ± 20 vs. controls 153 ± 11 bpm, P = 0.02), while systolic blood pressure (HTx 150 ± 25 vs. controls 154 ± 22 mmHg, P = 0.5) and diastolic blood pressure (HTx 73 ± 14 vs. controls 74 ± 15 mmHg, P = 0.8) were not different between the two groups (Tables 2 and 3). No adverse medical events were observed during stress echocardiography. As expected, with the increasing HR there was a progressive decline of image quality for myocardial assessment, and therefore all tests were terminated before the target HR was achieved and the tests were classified as sub-maximal. Table 2 Haemodynamic and echocardiography parameters at rest Resting values  HTx (n = 25)  Controls (n = 23)  P-value  Exercise time (minutes)  12 ± 2.6  13 ± 3.4  0.06  Heart rate (bpm)  88 ± 12  70 ± 12  <0.001  Systolic BP (mmHg)  114 ± 13  107 ± 14  0.08  Diastolic BP (mmHg)  70 ± 8  64 ± 9  0.01  FAC (%)  36 ± 9  38 ± 9  0.5  TAPSE (mm)  10.3 ± 2.5  19.2 ± 3.0  <0.001  RV free wall e’ (cm/s)  6.4 ± 2.2  12 ± 2.4  <0.001  RV free wall s’ (cm/s)  5.4 ± 1.7  10.4 ± 1.8  <0.001  RV free wall IVA (m/s2)  1.2 ± 0.4  1.6 ± 0.8  0.04  RV longitudinal strain (%)  27 ± 3.0 (n = 18)  26 ± 4.0 (n = 23)  0.9  Resting values  HTx (n = 25)  Controls (n = 23)  P-value  Exercise time (minutes)  12 ± 2.6  13 ± 3.4  0.06  Heart rate (bpm)  88 ± 12  70 ± 12  <0.001  Systolic BP (mmHg)  114 ± 13  107 ± 14  0.08  Diastolic BP (mmHg)  70 ± 8  64 ± 9  0.01  FAC (%)  36 ± 9  38 ± 9  0.5  TAPSE (mm)  10.3 ± 2.5  19.2 ± 3.0  <0.001  RV free wall e’ (cm/s)  6.4 ± 2.2  12 ± 2.4  <0.001  RV free wall s’ (cm/s)  5.4 ± 1.7  10.4 ± 1.8  <0.001  RV free wall IVA (m/s2)  1.2 ± 0.4  1.6 ± 0.8  0.04  RV longitudinal strain (%)  27 ± 3.0 (n = 18)  26 ± 4.0 (n = 23)  0.9  BP, blood pressure; FAC, fractional area change; TAPSE, tricuspid annular plane systolic excursion. Table 2 Haemodynamic and echocardiography parameters at rest Resting values  HTx (n = 25)  Controls (n = 23)  P-value  Exercise time (minutes)  12 ± 2.6  13 ± 3.4  0.06  Heart rate (bpm)  88 ± 12  70 ± 12  <0.001  Systolic BP (mmHg)  114 ± 13  107 ± 14  0.08  Diastolic BP (mmHg)  70 ± 8  64 ± 9  0.01  FAC (%)  36 ± 9  38 ± 9  0.5  TAPSE (mm)  10.3 ± 2.5  19.2 ± 3.0  <0.001  RV free wall e’ (cm/s)  6.4 ± 2.2  12 ± 2.4  <0.001  RV free wall s’ (cm/s)  5.4 ± 1.7  10.4 ± 1.8  <0.001  RV free wall IVA (m/s2)  1.2 ± 0.4  1.6 ± 0.8  0.04  RV longitudinal strain (%)  27 ± 3.0 (n = 18)  26 ± 4.0 (n = 23)  0.9  Resting values  HTx (n = 25)  Controls (n = 23)  P-value  Exercise time (minutes)  12 ± 2.6  13 ± 3.4  0.06  Heart rate (bpm)  88 ± 12  70 ± 12  <0.001  Systolic BP (mmHg)  114 ± 13  107 ± 14  0.08  Diastolic BP (mmHg)  70 ± 8  64 ± 9  0.01  FAC (%)  36 ± 9  38 ± 9  0.5  TAPSE (mm)  10.3 ± 2.5  19.2 ± 3.0  <0.001  RV free wall e’ (cm/s)  6.4 ± 2.2  12 ± 2.4  <0.001  RV free wall s’ (cm/s)  5.4 ± 1.7  10.4 ± 1.8  <0.001  RV free wall IVA (m/s2)  1.2 ± 0.4  1.6 ± 0.8  0.04  RV longitudinal strain (%)  27 ± 3.0 (n = 18)  26 ± 4.0 (n = 23)  0.9  BP, blood pressure; FAC, fractional area change; TAPSE, tricuspid annular plane systolic excursion. Table 3 Haemodynamic and echocardiography parameters at the highest HR achieved Peak values  HTx (n = 25)  Controls (n = 23)  P-value  Workload (watts)  91  104  0.1  Heart rate (bpm)  142 ± 20  153 ± 11  0.02  Systolic BP (mmHg)  150 ± 25  154 ± 22  0.5  Diastolic BP (mmHg)  73 ± 14  74 ± 15  0.8  RV free wall e’ (cm/s)  13.3 ± 3.4  22.3 ± 3.3  <0.001  RV free wall s’ (cm/s)  11.7 ± 9.3  16.2 ± 2.4  <0.001  RV free wall IVA (m/s2)  3.4 ± 1.4 (n = 18)  6.7 ± 1.4 (n = 20)  <0.001  RV Longitudinal Strain (%)  30 ± 3.5 (n = 18)  31 ± 4.6 (n = 22)  0.5  Peak values  HTx (n = 25)  Controls (n = 23)  P-value  Workload (watts)  91  104  0.1  Heart rate (bpm)  142 ± 20  153 ± 11  0.02  Systolic BP (mmHg)  150 ± 25  154 ± 22  0.5  Diastolic BP (mmHg)  73 ± 14  74 ± 15  0.8  RV free wall e’ (cm/s)  13.3 ± 3.4  22.3 ± 3.3  <0.001  RV free wall s’ (cm/s)  11.7 ± 9.3  16.2 ± 2.4  <0.001  RV free wall IVA (m/s2)  3.4 ± 1.4 (n = 18)  6.7 ± 1.4 (n = 20)  <0.001  RV Longitudinal Strain (%)  30 ± 3.5 (n = 18)  31 ± 4.6 (n = 22)  0.5  BP, blood pressure. Table 3 Haemodynamic and echocardiography parameters at the highest HR achieved Peak values  HTx (n = 25)  Controls (n = 23)  P-value  Workload (watts)  91  104  0.1  Heart rate (bpm)  142 ± 20  153 ± 11  0.02  Systolic BP (mmHg)  150 ± 25  154 ± 22  0.5  Diastolic BP (mmHg)  73 ± 14  74 ± 15  0.8  RV free wall e’ (cm/s)  13.3 ± 3.4  22.3 ± 3.3  <0.001  RV free wall s’ (cm/s)  11.7 ± 9.3  16.2 ± 2.4  <0.001  RV free wall IVA (m/s2)  3.4 ± 1.4 (n = 18)  6.7 ± 1.4 (n = 20)  <0.001  RV Longitudinal Strain (%)  30 ± 3.5 (n = 18)  31 ± 4.6 (n = 22)  0.5  Peak values  HTx (n = 25)  Controls (n = 23)  P-value  Workload (watts)  91  104  0.1  Heart rate (bpm)  142 ± 20  153 ± 11  0.02  Systolic BP (mmHg)  150 ± 25  154 ± 22  0.5  Diastolic BP (mmHg)  73 ± 14  74 ± 15  0.8  RV free wall e’ (cm/s)  13.3 ± 3.4  22.3 ± 3.3  <0.001  RV free wall s’ (cm/s)  11.7 ± 9.3  16.2 ± 2.4  <0.001  RV free wall IVA (m/s2)  3.4 ± 1.4 (n = 18)  6.7 ± 1.4 (n = 20)  <0.001  RV Longitudinal Strain (%)  30 ± 3.5 (n = 18)  31 ± 4.6 (n = 22)  0.5  BP, blood pressure. Right ventricular myocardial function at rest At rest all subjects had normal baseline LV systolic function as confirmed by an average ejection fraction (EF) of 60% and fractional shortening of 38%. Right ventricular fractional area change (FAC) was also within normal range in both groups. No significant TR was present at rest in the HTx recipients. Resting RV echocardiographic parameters of HTx recipients and controls are shown in Table 2. Systolic and diastolic TDI velocities were significantly lower in HTx recipients (s’: 5.4 ± 1.7 vs. 10.4 ± 1.8 cm/s, P < 0.001; e’: 6.4 ± 2.2 vs. 12 ± 2.4 cm/s, P < 0.001). Right ventricular IVA values were also lower in the HTx group compared to controls (1.2 ± 0.4 vs. 1.6 ± 0.8 m/s2, P = 0.04), while average RV free wall longitudinal systolic strain was the only systolic parameter similar between the two groups (27% ±3 vs. 26% ±4, P = 0.90). Right ventricular function during exercise At the maximal HR achieved during exercise, all measurements of RV systolic and diastolic function were significantly lower in HTx recipients, except for RV free wall longitudinal strain (Table 3). When each echocardiographic parameter was assessed in relation to the increase in HR, we noted preserved RV systolic and diastolic dynamic response in the HTx group, as shown by the similar increase in s’ and e’ vs. HR slopes between the two groups (Figure 1). The slope of increase in RV free wall longitudinal strain vs. HR was also similar between the two groups (Figure 2). In contrast, RV IVA response was reduced in HTx recipients as seen by a lower increase of the IVA slope versus HR compared to controls (Figure 3). Figure 1 View largeDownload slide Colour TDI velocities of the RV free wall demonstrate that systolic and diastolic reserve is preserved during exercise in HTx paediatric recipients. All linear regression models adjusted for repeated measures through an autoregressive covariance structure. No difference in slopes was found for RV free wall s’ and s’ (P = 0.54) and e’ (P = 0.23). Figure 1 View largeDownload slide Colour TDI velocities of the RV free wall demonstrate that systolic and diastolic reserve is preserved during exercise in HTx paediatric recipients. All linear regression models adjusted for repeated measures through an autoregressive covariance structure. No difference in slopes was found for RV free wall s’ and s’ (P = 0.54) and e’ (P = 0.23). Figure 2 View largeDownload slide Right ventricular free wall longitudinal myocardial deformation is preserved in paediatric HTx recipients compared to controls during exercise when corrected for HR. All linear regression models adjusted for repeated measures through an autoregressive covariance structure. Difference in slopes was not significantly different for RV free wall longitudinal strain (P = 0.42). Figure 2 View largeDownload slide Right ventricular free wall longitudinal myocardial deformation is preserved in paediatric HTx recipients compared to controls during exercise when corrected for HR. All linear regression models adjusted for repeated measures through an autoregressive covariance structure. Difference in slopes was not significantly different for RV free wall longitudinal strain (P = 0.42). Figure 3 View largeDownload slide Contractile responses to exercise expressed by the force-frequency relationship in paediatric HTx recipients and controls. Non-linear regression models adjusted for repeated measures through an autoregressive covariance structure. Heart rate modelled after exponential mathematical transformation. Difference in slope is statistically significant (P = 0.001). Figure 3 View largeDownload slide Contractile responses to exercise expressed by the force-frequency relationship in paediatric HTx recipients and controls. Non-linear regression models adjusted for repeated measures through an autoregressive covariance structure. Heart rate modelled after exponential mathematical transformation. Difference in slope is statistically significant (P = 0.001). Feasibility In total, 39 patients were included but 14 patients were excluded because of insufficient image quality during exercise, resulting in an overall feasibility of 64%. We further analysed the feasibility of TDI and strain measurements in the selected 25 patients at rest, at the maximal HR achieved during exercise and at the different stages of incremental HR. At rest, systolic and diastolic TDI velocities could be measured in all twenty-five HTx recipients. Baseline RV free wall longitudinal strain could be measured in 72% (Table 2). At the maximal HR achieved, s’ and e’ velocities were measurable in all subjects, while IVA and RV free wall strain could be measured in 72% (Table 3). For the analysis of dynamic response to exercise at incremental HR, we excluded subjects in whom images were suboptimal for offline analysis in more than two stages of exercise. Based on these criteria the feasibility for TDI measurements was excellent (s’ and e’ in 100%, IVA in 92%) but RV strain feasibility declined to 60% (Figure 4). Figure 4 View largeDownload slide Feasibility of Colour TDI and two-dimensional speckle tracking echocardiography during exercise. Figure 4 View largeDownload slide Feasibility of Colour TDI and two-dimensional speckle tracking echocardiography during exercise. Inter-observer and intra-observer variability Table 4 summarizes the results for intra and inter-observer variability. Overall we found good intra and inter-observer ICC for TDI and strain measurements. Table 4 Intraclass correlation coefficient for intra- and interobserver reliability   Intraobserver  Interobserver  TDI (cm/sec)  0.95 (95% CI: 0.86–0.98)  0.90 (95% CI: 0.84–0.94)  IVA (m/s2)  0.86 (95% CI: 0.80–0.90)  0.93 (95% CI: 0.88–0.95)  RV longitudinal strain (%)  0.86 (95% CI: 0.43–0.96)  0.76 (95% CI: 0.45–0.94)    Intraobserver  Interobserver  TDI (cm/sec)  0.95 (95% CI: 0.86–0.98)  0.90 (95% CI: 0.84–0.94)  IVA (m/s2)  0.86 (95% CI: 0.80–0.90)  0.93 (95% CI: 0.88–0.95)  RV longitudinal strain (%)  0.86 (95% CI: 0.43–0.96)  0.76 (95% CI: 0.45–0.94)  Table 4 Intraclass correlation coefficient for intra- and interobserver reliability   Intraobserver  Interobserver  TDI (cm/sec)  0.95 (95% CI: 0.86–0.98)  0.90 (95% CI: 0.84–0.94)  IVA (m/s2)  0.86 (95% CI: 0.80–0.90)  0.93 (95% CI: 0.88–0.95)  RV longitudinal strain (%)  0.86 (95% CI: 0.43–0.96)  0.76 (95% CI: 0.45–0.94)    Intraobserver  Interobserver  TDI (cm/sec)  0.95 (95% CI: 0.86–0.98)  0.90 (95% CI: 0.84–0.94)  IVA (m/s2)  0.86 (95% CI: 0.80–0.90)  0.93 (95% CI: 0.88–0.95)  RV longitudinal strain (%)  0.86 (95% CI: 0.43–0.96)  0.76 (95% CI: 0.45–0.94)  Discussion The study investigated RV systolic and diastolic functional response to exercise after pediatric HTx using echocardiographic assessment of myocardial velocities and myocardial deformation. Our findings suggest that while systolic and diastolic TDI velocities are lower at baseline and at the maximal HR achieved during exercise, pediatric HTx recipients have a preserved RV systolic and diastolic myocardial response to exercise, as shown by the similar increase of TDI velocities and RV strain vs. HR slopes. The decreased response of IVA possibly indicates a reduced force-frequency response, which could reflect an underlying decreased contractility. Our data provide novel insights into RV myocardial function and RV functional reserve in pediatric HTx recipients. Using a similar approach we previously demonstrated a normal LV systolic and diastolic myocardial dynamic response to exercise in paediatric HTx recipients.22 Studying RV myocardial reserve was a logical next step since RV dysfunction has been identified as a clinical concern after HTx. In both studies, we chose imaging techniques such as TDI and strain imaging that directly assess myocardial function and don’t measure dimensional changes such as EF or FAC. Tissue doppler imaging velocities are representative of ventricular function but they are influenced by loading conditions and by overall cardiac translation. IVA measures the acceleration of myocardium during the isovolumetric phase of the cardiac cycle. During this short time a small motion in the myocardium is recorded related to fibre-force development, and this motion is related to a change in ventricular shape. IVA measures the speed of this shape change, it is influenced by contractile function, HR and preload but it is afterload independent.25 IVA vs. HR response represents the force-frequency relationship, a fundamental property of the myocardium of increasing contractility at higher HR.26 Strain method measures myocardial deformation is not influenced by cardiac translational but it is affected by changes in loading conditions. Each of these methods provides complementary information on cardiac function, therefore, we combined them for studying RV myocardial response to exercise in pediatric HTx recipients. Resting right ventricular function after transplantation The reduced resting RV TDI data are in accordance with previous studies showing lower resting RV TDI velocities in pediatric HTx recipients compared to normal controls. Lunze et al.19 demonstrated that, whereas LV TDI velocities normalize after HTx, RV s’ values remain reduced even 1-year after surgery. Pauliks et al.17 studied 30 children without history of rejection and found lower RV systolic and diastolic TDI velocities about 3 years after HTx. Fyfe et al.16 studied RV function in 35 children after Htx and demonstrated a reduction in tricuspid s’ and e’ velocities. Interestingly, when they compared children below and above 5 years after HTx, lower RV TDI velocities were observed in the group >5 years after surgery suggesting a progressive decrease in RV velocities over time. Patients with more severe TR also had lower TDI velocities. In our study, none of our patients had more than mild TR so this could be excluded as a factor contributing to reduced s’ velocities. Mahle et al.27 serially assess RV systolic function with TDI in 13 paediatric HTx recipients for 6 months after surgery, showing that tricuspid s’ improved significantly from 10 days to 6 months post HTx but was still significantly reduced compared to normal values after 6 months. These data suggest a persistent decrease in RV longitudinal function in children after HTx and they have been interpreted as a marker of persistent global RV dysfunction in these patients. However, as longitudinal velocities are influenced by cardiac translation or passive motion of the heart, these data need to be interpreted with caution as opening the pericardium may influence cardiac motion and could partially explain the lower RV TDI velocities observed after surgery. Due to its anterior position in the chest, RV may be more sensitive to pericardial removal and adhesions to the chest wall developed after surgery may influence the overall RV motion related to cardiac translation. It is worth noting that in our transplant group, we measured normal resting FAC, indicating normal global RV function. Interestingly, resting longitudinal RV strain was within normal range, suggesting normal longitudinal shortening in the RV free wall. Normal resting longitudinal RV strain values were also reported in adults HTx patients 2 years after surgery.28 The discrepancy between TDI systolic velocities and FAC and strain imaging suggest that decrease in resting TDI values do not accurately reflect global RV function. Decreased RV TDI velocities have been observed after any type of open heart surgery suggesting that lower RV s’ represents a non-specific finding and should probably not be interpreted as a reliable parameter for global RV function in post-operative patients.29–31 In our study, IVA values are lower in the HTx group compared to controls, despite patients having higher HR. This finding might indicate some reduction in contractile function as IVA was proven as a relative load-independent parameter for contractility.26,32 IVA change with HR has been used to assess myocardial contractile response to exercise in different populations of patients with congenital heart disease and higher HR has been associated with higher IVA.33–36 However, one of the problems with IVA is that to some degree it is preload-dependent and can be theoretically influenced by cardiac geometry. Since during isovolumic contraction the development of fibre tension is associated with change in ventricular shape, the speed of shape change can be influenced by resting shape and geometry. Thus the lower resting IVA could be a reflection of the decreased TDI velocities in general or be a reflection of decreased RV contractility in the transplanted heart. It is evident how a correct interpretation of the differences in baseline echocardiographic parameters of RV function becomes difficult in a clinical setting. Right ventricular function during exercise Studying the RV response to exercise is relevant and important as physiologically, the loading imposed on the RV during exercise is greater than that imposed on LV due to the limited reserve of the pulmonary circulation compared to the systemic circulation.37 The systemic circulation has far greater vasodilatory reserve and this determines a higher work demand on the RV compared to the LV at the same exercise intensity. Thus, evaluation of RV response during exercise is even more important after HTx, considering the changes in vascular resistance already present at rest in some patients. Few data are available on RV stress response after transplantation and this is due to several factors. Obtaining consistent adequate RV images during exercise with increasing HR and breathing represents the main challenge. To overcome this limitation, we included an RV-centric view in our exercise protocol to assess RV longitudinal function and we used a semi-supine ergometer. Nonetheless, we had to exclude 14 patients because of poor image quality, and we observed a different degree of feasibility for TDI and strain measurements. While TDI has higher feasibility and excellent reproducibility, strain imaging seems to better reflect longitudinal function as less influenced by cardiac translation. Two-dimensional speckle tracking echocardiography (2D STE) strain analysis during exercise has been used by other groups in adult endurance athletes and adult patients with arrhythmogenic RV dysplasia38–40 with similar feasibility. Apart from the challenges associated with image acquisition, we also observed that the maximal HR achieved during exercise in the paediatric HTx recipients was lower than in controls, an expected finding considering the decreased chronotropic response after transplantation. This difference in maximal HR achieved during exercise made it very difficult to compare peak exercise data between patients and controls. For this reason, we studied the dynamic myocardial response by investigating the relationship of each of the measured myocardial parameters with increase in HR. We found no significant differences between the slopes of increase in TDI velocities and RV strain vs. HR between HTx recipients and controls. This normal increase of TDI velocities with increasing HR suggests that, despite having lower baseline values, RV myocardial TDI velocities increase normally during exercise. Additionally, strain values, which were normal at baseline, increased normally during exercise. These are reassuring findings suggesting that RV functional reserve is overall preserved in pediatric HTx recipients. The only significant difference observed in RV dynamic response was a mildly blunted IVA response to exercise in patients compared to controls, which may indicate a reduced contractile RV reserve. Given the normal s’ and strain response, we question whether the decreased IVA response really reflects a real decrease in contractility. It is possible that the altered RV geometry related to the lack of pericardial constraint could have contributed to this finding. We also looked at RV diastolic response by studying TDI e’ velocity. We noticed lower e’ values at baseline and at the maximal HR achieved during exercise but again the slope of increase of e’ vs. HR was similar between the two groups, suggesting a normal diastolic response in patients. Overall, our findings on preserved myocardial RV response to exercise combined with our previous findings on normal LV response to exercise, might explain the preserved exercise capacity observed in pediatric HTx patients.41 In the contest of a clinical evaluation, TDI dynamic response currently is probably the most feasible and reproducible technique but hopefully novel developments in strain analysis will allow better strain quantification during exercise in the future. Study limitation The relatively small number of patients in this study was related to several factors, but mostly influenced by the physical requirements for the use of the bicycle ergometer (height 140 cm). Also, all tests were classified as submaximal, and this is due multiple factors. The supine ergometer makes more difficult to perform a maximal test compare to upright ergometers,42,43 and the increase in HR and respiratory rates with exercise affects the quality of image acquisition at higher exercise intensity. Additionally, we could not assess RV pressures during exercise. Abnormal increase in pulmonary vascular resistance during exercise has been observed in patients with congenital heart defects,44 but in our patient group the TR jets at rest were too small to reliably assess RV systolic pressure during exercise. Further study looking in pulmonary haemodynamics and relationship to RV functional response is required. Conclusion Paediatric HTx patients have preserved RV systolic and diastolic reserve during exercise. The IVA versus HR response suggest a possible mild decrease in RV contractile reserve but further studies are required to demonstrate the clinical significance of this finding. Our study show that it is important to look at the RV response to exercise because decreased resting RV functional parameters could be a normal finding in pediatric HTx recipients. Conflict of interest: None declared. References 1 Hoskote A, Carter C, Rees P, Elliott M, Burch M, Brown K. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Right ventricular function during exercise in children after heart transplantation

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
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2047-2404
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10.1093/ehjci/jex137
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Abstract

Abstract Aims Right ventricular (RV) dysfunction is a common problem after heart transplant (HTx). In this study, we used semi-supine bicycle ergometry (SSBE) stress echocardiography to evaluate RV systolic and diastolic reserve in paediatric HTx recipients. Methods and results Thirty-nine pediatric HTx recipients and 23 controls underwent stepwise SSBE stress echocardiography. Colour tissue doppler imaging (TDI) peak systolic (s’) and peak diastolic (e’) velocities, myocardial acceleration during isovolumic contraction (IVA), and RV free wall longitudinal strain were measured at incremental heart rates (HR). The relationship with increasing HR was evaluated for each parameter by plotting values at each stage of exercise versus HR using linear and non-linear regression models. At rest, HTx recipients had higher HR with lower TDI velocities (s’: 5.4 ± 1.7 vs. 10.4 ± 1.8 cm/s, P < 0.001; e’: 6.4 ± 2.2 vs.12 ± 2.4 cm/s, P < 0.001) and RV IVA values (IVA: 1.2 ± 0.4 vs. 1.6 ± 0.8 m/s2, P = 0.04), while RV free wall longitudinal strain was similar between groups. At peak exercise, HR was higher in controls and all measurements of RV function were significantly lower in HTx recipients, except for RV free wall longitudinal strain. When assessing the increase in each parameter vs. HR, the slopes were not significantly different between patients and controls except for IVA, which was lower in HTx recipients. Conclusion In pediatric HTx recipients RV systolic and diastolic functional response to exercise is preserved with a normal increase in TDI velocities and strain values with increasing HR. The blunted IVA response possibly indicates a mildly decreased RV contractile response but it requires further investigation. Heart transplantation, Children, Exercise, Stress imaging, RV function Introduction Right ventricular (RV) dysfunction is a common problem after heart transplant (HTx) with multiple factors involved. Early RV dysfunction is mainly related to donor brain death, graft ischaemia, and increased pulmonary vascular resistance in the recipient.1–9 The development of late RV dysfunction is associated with acute and chronic rejection, development of tricuspid regurgitation (TR) and myocardial fibrosis due to repeated myocardial biopsies.10–15 Different studies documented biventricular systolic and diastolic dysfunction early after pediatric HTx.16–18 While left ventricle (LV) functional parameters at rest and during exercise normalize over time, RV functional parameters often remain reduced 1-year after transplantation.19 The RV functional response to exercise has not been well described in pediatric HTx recipients, despite this may help to better understand the functional implications of the RV function abnormalities observed at rest. Semi-supine bicycle ergometry (SSBE) stress echocardiography combined with colour tissue doppler imaging (TDI) and two-dimensional speckle tracking echocardiography (2D STE) allow the evaluation of myocardial function during exercise. The semi-supine position facilitates the acquisition of images at different exercise stages which can be used for studying the dynamic myocardial response.20,21 Our group has previously applied this methodology for studying LV myocardial response to exercise in pediatric patients after HTx demonstrating a preserved LV dynamic response.22 We hypothesized that RV dynamic myocardial response to exercise may be abnormal in pediatric HTx patients given the abnormal RV resting parameters. The aim of the present study was to investigate RV systolic and diastolic myocardial reserve during SSBE stress echocardiography in a cohort of pediatric HTx recipients and to compare the myocardial response of pediatric HTx recipients to normal controls. Patients and methods This study is a secondary analysis of prospectively collected datasets and was approved by the institutional Research Ethics Board. The study population consisted of children transplanted between 1994 and 2009 and followed at our institution.23 In 2013, our clinical echocardiography stress protocol for HTx recipients was modified by including the acquisition of a 4-chamber view and a high-frame rate narrow-sector colour TDI view focused on the RV. For this reason, only exercise stress echocardiogram performed between 2013 and 2015 were included in this study. Controls were selected from a larger cohort of healthy volunteers previously recruited at our institution.23 Prior to SSBE stress echocardiography, HTx recipients underwent a baseline echocardiogram according to the routine clinical hospital protocol, following the American Society of Echocardiography Pediatric Guidelines.24 SSBE stress echocardiography protocol All stress exams followed a standardized Bruce exercise protocol, using 3-min stages with a target speed of 60 rev/min. Twenty-Watt increments every 3 min were used for individuals up to 14 years of age, and 25-Watt increments above this age. A semi supine bicycle (Lode B.V., Groningen, The Netherlands) was used for all echocardiographic stress studies. The target heart rates (HR) was 85% of the maximal HR calculated as 220-age. A cardiologist supervised all tests and early termination was determined based on patient fatigue, the occurrence of predefined adverse events (arrhythmia, ischaemia, chest pain, clinical signs of circulatory compromise, progressive fall in systolic blood pressure >10%, severe hypertension) or decline in image quality related to moving or breathing at the more intense phases of exercise. Patients were monitored with a continuous 12-lead ECG and sphygmomanometry blood pressure measurements were obtained during the last 30 s of each stage (Dinamap ®, USA). Image acquisition Images were obtained using a Vivid E-9 ultrasound system (GE Healthcare, USA) during the last 2 min of each stage using the Smart Stress application®. The stress protocol included acquisition of colour TDI velocities and storage of raw DICOM grey-scale images that can be analysed using 2D STE. Echocardiographic images acquired at each stage and during recovery included: a parasternal long axis view, a parasternal short axis view at the papillary muscle level and two apical 4 chambers view optimized for off-line 2D STE analysis each focused on the LV and RV (frame rate >60 frames/s), spectral pulsed wave Doppler of mitral inflow, high-frame rate narrow-sector colour TDI of the LV lateral wall and the interventricular septum and of the RV free wall, apical 3 and 2 chambers. Image analysis Images were digitally stored for offline analysis, using the Echopac system (version 110.1.3, GE Healthcare, USA). To avoid translational movements of the region of interest during the cardiac cycle, manual tracking was performed. Velocity measurements were recorded as the average value from three consecutive cardiac cycles. Fusion of e’ and a’ wave was seen during exercise in all subjects and the fused wave was measured as e’. Isovolumic contraction (IVA) was calculated as the difference between baseline and peak velocity divided by the time interval (m/s2). Right ventricular free wall longitudinal strain was calculated at the basal, mid and apical segments and the resulting mean strain value was derived by averaging the three segmental values. Reproducibility Fifteen randomly selected studies were analysed by two independent observers for inter-observer variability of colour TDI and longitudinal strain. The same studies were used for assessment of intra-observer variability of the same measurements, with the observer blinded to the initial results and a time interval of at least 2 weeks between the two analyses. Statistics Data are presented as mean with standard deviations, median with range, and frequencies as appropriate. Comparisons between the two groups were performed using Student's t-tests assuming unequal variance between samples and Fisher's exact test. Linear and non-linear regression models adjusted for repeated measures through an autoregressive covariance structure was used to compare average values and the slope of change over increasing HR between HTx and controls. Intra-class correlation coefficients (ICC) were calculated to assess inter- and intra-observer variability. All statistical analyses were performed using SAS Statistical Software v9.4 (The SAS Institute, Cary, NC). Results Study population Thirty-nine pediatric HTx recipients (16 males), who underwent a SSBE stress echocardiography between 2013 and 2015, were included in the study. Fourteen patients were excluded for suboptimal quality of the RV images during stress. The remaining 25 constituted the cohort for this study and their demographic data are summarized in Table 1. Twenty-three healthy subjects with similar age and gender were selected as controls from the large healthy volunteer’s database. No significant differences in height and weight were found between the Htx recipients and controls. For the HTx group, median age at transplantation was 3.7 years (2 days to 15 years), with a median time since transplant of 9 years (2–17 years). Nine patients had no episode of rejection at the time of the study. From the remaining 14 patients, 12 had one episode of rejection very early post-transplant (median time of rejection episode from transplant was 2 days), and 2 patients had 2 episodes. All rejections were classified as low grade. The last cardiopulmonary test performed before SSBE stress echocardiograph demonstrated that the patients had an average percent-predicted peak VO2 of 91%. Table 1 Demographics   HTx (n = 25)  Controls (n = 23)  P-value  Age at the study (years)  14 ± 2.1  14 ± 2.1  0.9  Males (%)  16 (64%)  14 (60%)    Height (cm)  159 ± 13.1  160 ± 13.3  0.80  Weight (kg)  51.5 ± 14  52 ± 13.7  0.80  BSA (m2)  1.51 ± 0.2  1.5 ± 0.2  0.80    HTx (n = 25)  Controls (n = 23)  P-value  Age at the study (years)  14 ± 2.1  14 ± 2.1  0.9  Males (%)  16 (64%)  14 (60%)    Height (cm)  159 ± 13.1  160 ± 13.3  0.80  Weight (kg)  51.5 ± 14  52 ± 13.7  0.80  BSA (m2)  1.51 ± 0.2  1.5 ± 0.2  0.80  BSA, body surface area. Table 1 Demographics   HTx (n = 25)  Controls (n = 23)  P-value  Age at the study (years)  14 ± 2.1  14 ± 2.1  0.9  Males (%)  16 (64%)  14 (60%)    Height (cm)  159 ± 13.1  160 ± 13.3  0.80  Weight (kg)  51.5 ± 14  52 ± 13.7  0.80  BSA (m2)  1.51 ± 0.2  1.5 ± 0.2  0.80    HTx (n = 25)  Controls (n = 23)  P-value  Age at the study (years)  14 ± 2.1  14 ± 2.1  0.9  Males (%)  16 (64%)  14 (60%)    Height (cm)  159 ± 13.1  160 ± 13.3  0.80  Weight (kg)  51.5 ± 14  52 ± 13.7  0.80  BSA (m2)  1.51 ± 0.2  1.5 ± 0.2  0.80  BSA, body surface area. Haemodynamic responses to exercise At rest, HR (mean ± SD) (HTx 88 ± 12 vs. controls 70 ± 12 bpm P < 0.001), systolic blood pressure (HTx 114 ± 13 vs. controls 107 ± 14 mmHg, P = 0.08) and diastolic blood pressure (HTx 70 ±8 vs controls 64 ± 9 mmHg, P = 0.01) were higher in HTx recipients. At peak exercise, the highest HR achieved was lower in the HTx group compared with controls (HTx 142 ± 20 vs. controls 153 ± 11 bpm, P = 0.02), while systolic blood pressure (HTx 150 ± 25 vs. controls 154 ± 22 mmHg, P = 0.5) and diastolic blood pressure (HTx 73 ± 14 vs. controls 74 ± 15 mmHg, P = 0.8) were not different between the two groups (Tables 2 and 3). No adverse medical events were observed during stress echocardiography. As expected, with the increasing HR there was a progressive decline of image quality for myocardial assessment, and therefore all tests were terminated before the target HR was achieved and the tests were classified as sub-maximal. Table 2 Haemodynamic and echocardiography parameters at rest Resting values  HTx (n = 25)  Controls (n = 23)  P-value  Exercise time (minutes)  12 ± 2.6  13 ± 3.4  0.06  Heart rate (bpm)  88 ± 12  70 ± 12  <0.001  Systolic BP (mmHg)  114 ± 13  107 ± 14  0.08  Diastolic BP (mmHg)  70 ± 8  64 ± 9  0.01  FAC (%)  36 ± 9  38 ± 9  0.5  TAPSE (mm)  10.3 ± 2.5  19.2 ± 3.0  <0.001  RV free wall e’ (cm/s)  6.4 ± 2.2  12 ± 2.4  <0.001  RV free wall s’ (cm/s)  5.4 ± 1.7  10.4 ± 1.8  <0.001  RV free wall IVA (m/s2)  1.2 ± 0.4  1.6 ± 0.8  0.04  RV longitudinal strain (%)  27 ± 3.0 (n = 18)  26 ± 4.0 (n = 23)  0.9  Resting values  HTx (n = 25)  Controls (n = 23)  P-value  Exercise time (minutes)  12 ± 2.6  13 ± 3.4  0.06  Heart rate (bpm)  88 ± 12  70 ± 12  <0.001  Systolic BP (mmHg)  114 ± 13  107 ± 14  0.08  Diastolic BP (mmHg)  70 ± 8  64 ± 9  0.01  FAC (%)  36 ± 9  38 ± 9  0.5  TAPSE (mm)  10.3 ± 2.5  19.2 ± 3.0  <0.001  RV free wall e’ (cm/s)  6.4 ± 2.2  12 ± 2.4  <0.001  RV free wall s’ (cm/s)  5.4 ± 1.7  10.4 ± 1.8  <0.001  RV free wall IVA (m/s2)  1.2 ± 0.4  1.6 ± 0.8  0.04  RV longitudinal strain (%)  27 ± 3.0 (n = 18)  26 ± 4.0 (n = 23)  0.9  BP, blood pressure; FAC, fractional area change; TAPSE, tricuspid annular plane systolic excursion. Table 2 Haemodynamic and echocardiography parameters at rest Resting values  HTx (n = 25)  Controls (n = 23)  P-value  Exercise time (minutes)  12 ± 2.6  13 ± 3.4  0.06  Heart rate (bpm)  88 ± 12  70 ± 12  <0.001  Systolic BP (mmHg)  114 ± 13  107 ± 14  0.08  Diastolic BP (mmHg)  70 ± 8  64 ± 9  0.01  FAC (%)  36 ± 9  38 ± 9  0.5  TAPSE (mm)  10.3 ± 2.5  19.2 ± 3.0  <0.001  RV free wall e’ (cm/s)  6.4 ± 2.2  12 ± 2.4  <0.001  RV free wall s’ (cm/s)  5.4 ± 1.7  10.4 ± 1.8  <0.001  RV free wall IVA (m/s2)  1.2 ± 0.4  1.6 ± 0.8  0.04  RV longitudinal strain (%)  27 ± 3.0 (n = 18)  26 ± 4.0 (n = 23)  0.9  Resting values  HTx (n = 25)  Controls (n = 23)  P-value  Exercise time (minutes)  12 ± 2.6  13 ± 3.4  0.06  Heart rate (bpm)  88 ± 12  70 ± 12  <0.001  Systolic BP (mmHg)  114 ± 13  107 ± 14  0.08  Diastolic BP (mmHg)  70 ± 8  64 ± 9  0.01  FAC (%)  36 ± 9  38 ± 9  0.5  TAPSE (mm)  10.3 ± 2.5  19.2 ± 3.0  <0.001  RV free wall e’ (cm/s)  6.4 ± 2.2  12 ± 2.4  <0.001  RV free wall s’ (cm/s)  5.4 ± 1.7  10.4 ± 1.8  <0.001  RV free wall IVA (m/s2)  1.2 ± 0.4  1.6 ± 0.8  0.04  RV longitudinal strain (%)  27 ± 3.0 (n = 18)  26 ± 4.0 (n = 23)  0.9  BP, blood pressure; FAC, fractional area change; TAPSE, tricuspid annular plane systolic excursion. Table 3 Haemodynamic and echocardiography parameters at the highest HR achieved Peak values  HTx (n = 25)  Controls (n = 23)  P-value  Workload (watts)  91  104  0.1  Heart rate (bpm)  142 ± 20  153 ± 11  0.02  Systolic BP (mmHg)  150 ± 25  154 ± 22  0.5  Diastolic BP (mmHg)  73 ± 14  74 ± 15  0.8  RV free wall e’ (cm/s)  13.3 ± 3.4  22.3 ± 3.3  <0.001  RV free wall s’ (cm/s)  11.7 ± 9.3  16.2 ± 2.4  <0.001  RV free wall IVA (m/s2)  3.4 ± 1.4 (n = 18)  6.7 ± 1.4 (n = 20)  <0.001  RV Longitudinal Strain (%)  30 ± 3.5 (n = 18)  31 ± 4.6 (n = 22)  0.5  Peak values  HTx (n = 25)  Controls (n = 23)  P-value  Workload (watts)  91  104  0.1  Heart rate (bpm)  142 ± 20  153 ± 11  0.02  Systolic BP (mmHg)  150 ± 25  154 ± 22  0.5  Diastolic BP (mmHg)  73 ± 14  74 ± 15  0.8  RV free wall e’ (cm/s)  13.3 ± 3.4  22.3 ± 3.3  <0.001  RV free wall s’ (cm/s)  11.7 ± 9.3  16.2 ± 2.4  <0.001  RV free wall IVA (m/s2)  3.4 ± 1.4 (n = 18)  6.7 ± 1.4 (n = 20)  <0.001  RV Longitudinal Strain (%)  30 ± 3.5 (n = 18)  31 ± 4.6 (n = 22)  0.5  BP, blood pressure. Table 3 Haemodynamic and echocardiography parameters at the highest HR achieved Peak values  HTx (n = 25)  Controls (n = 23)  P-value  Workload (watts)  91  104  0.1  Heart rate (bpm)  142 ± 20  153 ± 11  0.02  Systolic BP (mmHg)  150 ± 25  154 ± 22  0.5  Diastolic BP (mmHg)  73 ± 14  74 ± 15  0.8  RV free wall e’ (cm/s)  13.3 ± 3.4  22.3 ± 3.3  <0.001  RV free wall s’ (cm/s)  11.7 ± 9.3  16.2 ± 2.4  <0.001  RV free wall IVA (m/s2)  3.4 ± 1.4 (n = 18)  6.7 ± 1.4 (n = 20)  <0.001  RV Longitudinal Strain (%)  30 ± 3.5 (n = 18)  31 ± 4.6 (n = 22)  0.5  Peak values  HTx (n = 25)  Controls (n = 23)  P-value  Workload (watts)  91  104  0.1  Heart rate (bpm)  142 ± 20  153 ± 11  0.02  Systolic BP (mmHg)  150 ± 25  154 ± 22  0.5  Diastolic BP (mmHg)  73 ± 14  74 ± 15  0.8  RV free wall e’ (cm/s)  13.3 ± 3.4  22.3 ± 3.3  <0.001  RV free wall s’ (cm/s)  11.7 ± 9.3  16.2 ± 2.4  <0.001  RV free wall IVA (m/s2)  3.4 ± 1.4 (n = 18)  6.7 ± 1.4 (n = 20)  <0.001  RV Longitudinal Strain (%)  30 ± 3.5 (n = 18)  31 ± 4.6 (n = 22)  0.5  BP, blood pressure. Right ventricular myocardial function at rest At rest all subjects had normal baseline LV systolic function as confirmed by an average ejection fraction (EF) of 60% and fractional shortening of 38%. Right ventricular fractional area change (FAC) was also within normal range in both groups. No significant TR was present at rest in the HTx recipients. Resting RV echocardiographic parameters of HTx recipients and controls are shown in Table 2. Systolic and diastolic TDI velocities were significantly lower in HTx recipients (s’: 5.4 ± 1.7 vs. 10.4 ± 1.8 cm/s, P < 0.001; e’: 6.4 ± 2.2 vs. 12 ± 2.4 cm/s, P < 0.001). Right ventricular IVA values were also lower in the HTx group compared to controls (1.2 ± 0.4 vs. 1.6 ± 0.8 m/s2, P = 0.04), while average RV free wall longitudinal systolic strain was the only systolic parameter similar between the two groups (27% ±3 vs. 26% ±4, P = 0.90). Right ventricular function during exercise At the maximal HR achieved during exercise, all measurements of RV systolic and diastolic function were significantly lower in HTx recipients, except for RV free wall longitudinal strain (Table 3). When each echocardiographic parameter was assessed in relation to the increase in HR, we noted preserved RV systolic and diastolic dynamic response in the HTx group, as shown by the similar increase in s’ and e’ vs. HR slopes between the two groups (Figure 1). The slope of increase in RV free wall longitudinal strain vs. HR was also similar between the two groups (Figure 2). In contrast, RV IVA response was reduced in HTx recipients as seen by a lower increase of the IVA slope versus HR compared to controls (Figure 3). Figure 1 View largeDownload slide Colour TDI velocities of the RV free wall demonstrate that systolic and diastolic reserve is preserved during exercise in HTx paediatric recipients. All linear regression models adjusted for repeated measures through an autoregressive covariance structure. No difference in slopes was found for RV free wall s’ and s’ (P = 0.54) and e’ (P = 0.23). Figure 1 View largeDownload slide Colour TDI velocities of the RV free wall demonstrate that systolic and diastolic reserve is preserved during exercise in HTx paediatric recipients. All linear regression models adjusted for repeated measures through an autoregressive covariance structure. No difference in slopes was found for RV free wall s’ and s’ (P = 0.54) and e’ (P = 0.23). Figure 2 View largeDownload slide Right ventricular free wall longitudinal myocardial deformation is preserved in paediatric HTx recipients compared to controls during exercise when corrected for HR. All linear regression models adjusted for repeated measures through an autoregressive covariance structure. Difference in slopes was not significantly different for RV free wall longitudinal strain (P = 0.42). Figure 2 View largeDownload slide Right ventricular free wall longitudinal myocardial deformation is preserved in paediatric HTx recipients compared to controls during exercise when corrected for HR. All linear regression models adjusted for repeated measures through an autoregressive covariance structure. Difference in slopes was not significantly different for RV free wall longitudinal strain (P = 0.42). Figure 3 View largeDownload slide Contractile responses to exercise expressed by the force-frequency relationship in paediatric HTx recipients and controls. Non-linear regression models adjusted for repeated measures through an autoregressive covariance structure. Heart rate modelled after exponential mathematical transformation. Difference in slope is statistically significant (P = 0.001). Figure 3 View largeDownload slide Contractile responses to exercise expressed by the force-frequency relationship in paediatric HTx recipients and controls. Non-linear regression models adjusted for repeated measures through an autoregressive covariance structure. Heart rate modelled after exponential mathematical transformation. Difference in slope is statistically significant (P = 0.001). Feasibility In total, 39 patients were included but 14 patients were excluded because of insufficient image quality during exercise, resulting in an overall feasibility of 64%. We further analysed the feasibility of TDI and strain measurements in the selected 25 patients at rest, at the maximal HR achieved during exercise and at the different stages of incremental HR. At rest, systolic and diastolic TDI velocities could be measured in all twenty-five HTx recipients. Baseline RV free wall longitudinal strain could be measured in 72% (Table 2). At the maximal HR achieved, s’ and e’ velocities were measurable in all subjects, while IVA and RV free wall strain could be measured in 72% (Table 3). For the analysis of dynamic response to exercise at incremental HR, we excluded subjects in whom images were suboptimal for offline analysis in more than two stages of exercise. Based on these criteria the feasibility for TDI measurements was excellent (s’ and e’ in 100%, IVA in 92%) but RV strain feasibility declined to 60% (Figure 4). Figure 4 View largeDownload slide Feasibility of Colour TDI and two-dimensional speckle tracking echocardiography during exercise. Figure 4 View largeDownload slide Feasibility of Colour TDI and two-dimensional speckle tracking echocardiography during exercise. Inter-observer and intra-observer variability Table 4 summarizes the results for intra and inter-observer variability. Overall we found good intra and inter-observer ICC for TDI and strain measurements. Table 4 Intraclass correlation coefficient for intra- and interobserver reliability   Intraobserver  Interobserver  TDI (cm/sec)  0.95 (95% CI: 0.86–0.98)  0.90 (95% CI: 0.84–0.94)  IVA (m/s2)  0.86 (95% CI: 0.80–0.90)  0.93 (95% CI: 0.88–0.95)  RV longitudinal strain (%)  0.86 (95% CI: 0.43–0.96)  0.76 (95% CI: 0.45–0.94)    Intraobserver  Interobserver  TDI (cm/sec)  0.95 (95% CI: 0.86–0.98)  0.90 (95% CI: 0.84–0.94)  IVA (m/s2)  0.86 (95% CI: 0.80–0.90)  0.93 (95% CI: 0.88–0.95)  RV longitudinal strain (%)  0.86 (95% CI: 0.43–0.96)  0.76 (95% CI: 0.45–0.94)  Table 4 Intraclass correlation coefficient for intra- and interobserver reliability   Intraobserver  Interobserver  TDI (cm/sec)  0.95 (95% CI: 0.86–0.98)  0.90 (95% CI: 0.84–0.94)  IVA (m/s2)  0.86 (95% CI: 0.80–0.90)  0.93 (95% CI: 0.88–0.95)  RV longitudinal strain (%)  0.86 (95% CI: 0.43–0.96)  0.76 (95% CI: 0.45–0.94)    Intraobserver  Interobserver  TDI (cm/sec)  0.95 (95% CI: 0.86–0.98)  0.90 (95% CI: 0.84–0.94)  IVA (m/s2)  0.86 (95% CI: 0.80–0.90)  0.93 (95% CI: 0.88–0.95)  RV longitudinal strain (%)  0.86 (95% CI: 0.43–0.96)  0.76 (95% CI: 0.45–0.94)  Discussion The study investigated RV systolic and diastolic functional response to exercise after pediatric HTx using echocardiographic assessment of myocardial velocities and myocardial deformation. Our findings suggest that while systolic and diastolic TDI velocities are lower at baseline and at the maximal HR achieved during exercise, pediatric HTx recipients have a preserved RV systolic and diastolic myocardial response to exercise, as shown by the similar increase of TDI velocities and RV strain vs. HR slopes. The decreased response of IVA possibly indicates a reduced force-frequency response, which could reflect an underlying decreased contractility. Our data provide novel insights into RV myocardial function and RV functional reserve in pediatric HTx recipients. Using a similar approach we previously demonstrated a normal LV systolic and diastolic myocardial dynamic response to exercise in paediatric HTx recipients.22 Studying RV myocardial reserve was a logical next step since RV dysfunction has been identified as a clinical concern after HTx. In both studies, we chose imaging techniques such as TDI and strain imaging that directly assess myocardial function and don’t measure dimensional changes such as EF or FAC. Tissue doppler imaging velocities are representative of ventricular function but they are influenced by loading conditions and by overall cardiac translation. IVA measures the acceleration of myocardium during the isovolumetric phase of the cardiac cycle. During this short time a small motion in the myocardium is recorded related to fibre-force development, and this motion is related to a change in ventricular shape. IVA measures the speed of this shape change, it is influenced by contractile function, HR and preload but it is afterload independent.25 IVA vs. HR response represents the force-frequency relationship, a fundamental property of the myocardium of increasing contractility at higher HR.26 Strain method measures myocardial deformation is not influenced by cardiac translational but it is affected by changes in loading conditions. Each of these methods provides complementary information on cardiac function, therefore, we combined them for studying RV myocardial response to exercise in pediatric HTx recipients. Resting right ventricular function after transplantation The reduced resting RV TDI data are in accordance with previous studies showing lower resting RV TDI velocities in pediatric HTx recipients compared to normal controls. Lunze et al.19 demonstrated that, whereas LV TDI velocities normalize after HTx, RV s’ values remain reduced even 1-year after surgery. Pauliks et al.17 studied 30 children without history of rejection and found lower RV systolic and diastolic TDI velocities about 3 years after HTx. Fyfe et al.16 studied RV function in 35 children after Htx and demonstrated a reduction in tricuspid s’ and e’ velocities. Interestingly, when they compared children below and above 5 years after HTx, lower RV TDI velocities were observed in the group >5 years after surgery suggesting a progressive decrease in RV velocities over time. Patients with more severe TR also had lower TDI velocities. In our study, none of our patients had more than mild TR so this could be excluded as a factor contributing to reduced s’ velocities. Mahle et al.27 serially assess RV systolic function with TDI in 13 paediatric HTx recipients for 6 months after surgery, showing that tricuspid s’ improved significantly from 10 days to 6 months post HTx but was still significantly reduced compared to normal values after 6 months. These data suggest a persistent decrease in RV longitudinal function in children after HTx and they have been interpreted as a marker of persistent global RV dysfunction in these patients. However, as longitudinal velocities are influenced by cardiac translation or passive motion of the heart, these data need to be interpreted with caution as opening the pericardium may influence cardiac motion and could partially explain the lower RV TDI velocities observed after surgery. Due to its anterior position in the chest, RV may be more sensitive to pericardial removal and adhesions to the chest wall developed after surgery may influence the overall RV motion related to cardiac translation. It is worth noting that in our transplant group, we measured normal resting FAC, indicating normal global RV function. Interestingly, resting longitudinal RV strain was within normal range, suggesting normal longitudinal shortening in the RV free wall. Normal resting longitudinal RV strain values were also reported in adults HTx patients 2 years after surgery.28 The discrepancy between TDI systolic velocities and FAC and strain imaging suggest that decrease in resting TDI values do not accurately reflect global RV function. Decreased RV TDI velocities have been observed after any type of open heart surgery suggesting that lower RV s’ represents a non-specific finding and should probably not be interpreted as a reliable parameter for global RV function in post-operative patients.29–31 In our study, IVA values are lower in the HTx group compared to controls, despite patients having higher HR. This finding might indicate some reduction in contractile function as IVA was proven as a relative load-independent parameter for contractility.26,32 IVA change with HR has been used to assess myocardial contractile response to exercise in different populations of patients with congenital heart disease and higher HR has been associated with higher IVA.33–36 However, one of the problems with IVA is that to some degree it is preload-dependent and can be theoretically influenced by cardiac geometry. Since during isovolumic contraction the development of fibre tension is associated with change in ventricular shape, the speed of shape change can be influenced by resting shape and geometry. Thus the lower resting IVA could be a reflection of the decreased TDI velocities in general or be a reflection of decreased RV contractility in the transplanted heart. It is evident how a correct interpretation of the differences in baseline echocardiographic parameters of RV function becomes difficult in a clinical setting. Right ventricular function during exercise Studying the RV response to exercise is relevant and important as physiologically, the loading imposed on the RV during exercise is greater than that imposed on LV due to the limited reserve of the pulmonary circulation compared to the systemic circulation.37 The systemic circulation has far greater vasodilatory reserve and this determines a higher work demand on the RV compared to the LV at the same exercise intensity. Thus, evaluation of RV response during exercise is even more important after HTx, considering the changes in vascular resistance already present at rest in some patients. Few data are available on RV stress response after transplantation and this is due to several factors. Obtaining consistent adequate RV images during exercise with increasing HR and breathing represents the main challenge. To overcome this limitation, we included an RV-centric view in our exercise protocol to assess RV longitudinal function and we used a semi-supine ergometer. Nonetheless, we had to exclude 14 patients because of poor image quality, and we observed a different degree of feasibility for TDI and strain measurements. While TDI has higher feasibility and excellent reproducibility, strain imaging seems to better reflect longitudinal function as less influenced by cardiac translation. Two-dimensional speckle tracking echocardiography (2D STE) strain analysis during exercise has been used by other groups in adult endurance athletes and adult patients with arrhythmogenic RV dysplasia38–40 with similar feasibility. Apart from the challenges associated with image acquisition, we also observed that the maximal HR achieved during exercise in the paediatric HTx recipients was lower than in controls, an expected finding considering the decreased chronotropic response after transplantation. This difference in maximal HR achieved during exercise made it very difficult to compare peak exercise data between patients and controls. For this reason, we studied the dynamic myocardial response by investigating the relationship of each of the measured myocardial parameters with increase in HR. We found no significant differences between the slopes of increase in TDI velocities and RV strain vs. HR between HTx recipients and controls. This normal increase of TDI velocities with increasing HR suggests that, despite having lower baseline values, RV myocardial TDI velocities increase normally during exercise. Additionally, strain values, which were normal at baseline, increased normally during exercise. These are reassuring findings suggesting that RV functional reserve is overall preserved in pediatric HTx recipients. The only significant difference observed in RV dynamic response was a mildly blunted IVA response to exercise in patients compared to controls, which may indicate a reduced contractile RV reserve. Given the normal s’ and strain response, we question whether the decreased IVA response really reflects a real decrease in contractility. It is possible that the altered RV geometry related to the lack of pericardial constraint could have contributed to this finding. We also looked at RV diastolic response by studying TDI e’ velocity. We noticed lower e’ values at baseline and at the maximal HR achieved during exercise but again the slope of increase of e’ vs. HR was similar between the two groups, suggesting a normal diastolic response in patients. Overall, our findings on preserved myocardial RV response to exercise combined with our previous findings on normal LV response to exercise, might explain the preserved exercise capacity observed in pediatric HTx patients.41 In the contest of a clinical evaluation, TDI dynamic response currently is probably the most feasible and reproducible technique but hopefully novel developments in strain analysis will allow better strain quantification during exercise in the future. Study limitation The relatively small number of patients in this study was related to several factors, but mostly influenced by the physical requirements for the use of the bicycle ergometer (height 140 cm). Also, all tests were classified as submaximal, and this is due multiple factors. The supine ergometer makes more difficult to perform a maximal test compare to upright ergometers,42,43 and the increase in HR and respiratory rates with exercise affects the quality of image acquisition at higher exercise intensity. Additionally, we could not assess RV pressures during exercise. Abnormal increase in pulmonary vascular resistance during exercise has been observed in patients with congenital heart defects,44 but in our patient group the TR jets at rest were too small to reliably assess RV systolic pressure during exercise. Further study looking in pulmonary haemodynamics and relationship to RV functional response is required. Conclusion Paediatric HTx patients have preserved RV systolic and diastolic reserve during exercise. The IVA versus HR response suggest a possible mild decrease in RV contractile reserve but further studies are required to demonstrate the clinical significance of this finding. Our study show that it is important to look at the RV response to exercise because decreased resting RV functional parameters could be a normal finding in pediatric HTx recipients. Conflict of interest: None declared. References 1 Hoskote A, Carter C, Rees P, Elliott M, Burch M, Brown K. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Jun 23, 2017

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