The relationship between cardiovascular magnetic resonance imaging measurement of extracellular volume fraction and clinical outcomes in adults with repaired tetralogy of Fallot

The relationship between cardiovascular magnetic resonance imaging measurement of extracellular... Abstract Aims Our aims were to explore cardiac magnetic resonance quantification of myocardial extracellular volume (ECV) in adults with repaired tetralogy of Fallot (rTOF) when compared with healthy controls and to investigate the association between ECV and major adverse cardiovascular outcomes. Methods and results We prospectively recruited adults with rTOF (n = 44, 59% male, 32.9 ± 13.6 years) and evaluated right ventricular (RV) and left ventricular (LV) ECV by pre/post-gadolinium T1 measurements (modified Look–Locker inversion recovery technique) on a 1.5-T Siemens scanner compared with the healthy controls (n = 10, 50% male, 31.5 ± 4.4 years). The primary end point was a composite of death, out-of-hospital cardiac arrest, heart failure (HF) requiring admission for escalation of therapy, or haemodynamically significant ventricular tachycardia (VT) (lasting >30 s and/or resulting in invasive therapy). The association between ECV and adverse events was assessed using Cox proportional hazard models [median follow-up 236 days, interquartile range (IQR) 38–342]. RVECV was higher in patients compared with the controls (31.5 ± 5.4% vs. 26.3 ± 2.1%, P = 0.027). The following major adverse events occurred (n = 9, 21%): death (n = 1), out-of-hospital cardiac arrest (n = 1), HF (n = 1), and VT (n = 6). RVECV was higher among those with an adverse event compared to those without (35.0 ± 5.5% vs. 29.6 ± 4.5%, P = 0.014) and was associated with increased risk for adverse events [hazard ratio 1.13, 95% confidence interval (1.01–1.28); P = 0.037]. LVECV was not associated with adverse events (P = 0.667). Conclusion Increased RVECV is associated with adverse cardiovascular events in adults with rTOF. These results may lead to further studies exploring the potential role for RVECV in risk stratification and targeted therapeutic interventions in this population. cardiac MRI, T1 mapping, congenital heart disease, tetralogy of Fallot Introduction Cardiac magnetic resonance (CMR) imaging is routinely used in the evaluation of patients with repaired tetralogy of Fallot (rTOF).1 Segmental myocardial fibrosis is known to be present in rTOF based on histology and can be identified using CMR late gadolinium-enhanced (LGE) imaging.2,3 Myocardial fibrosis is associated with adverse cardiovascular outcomes and may be a substrate for arrhythmia including ventricular tachycardia (VT) in rTOF.4 However, LGE imaging may fail to characterize diffuse interstitial changes.5 CMR T1 mapping with calculation of the extracellular volume (ECV) fraction is an emerging technique that can be used for the evaluation of diffuse interstitial myocardial changes including fibrosis.6,7 The role of CMR for quantification of right ventricular (RV) extracellular volume (RVECV) measurements in relation to prediction of adverse outcomes in adults with rTOF has not been studied extensively. Although limited data are available on the predictive value of left ventricular (LV) ECV in those with rTOF, only two prior retrospective studies have investigated the differences in non-contrast and post-contrast T1 values of the RV in rTOF when compared with healthy controls.8–12 Furthermore, ECV assessment is particularly challenging in the thin-walled RV, given possible contamination by adjacent blood pool or epicardial fat. The aim of this study was to explore quantification of myocardial ECV in adults with rTOF when compared with healthy controls and to investigate the association between ECV and major adverse cardiovascular outcomes. Methods Study population From September 2014 to April 2017, patients with rTOF undergoing CMR were prospectively screened for study enrolment at the time of routine clinical evaluation at our institution. The study protocol was approved by the institutional research ethics board, and written informed consent was obtained from all subjects. Inclusion criteria for study subjects included age ≥18 years, history of rTOF, and clinically indicated referral for CMR with LGE. Subjects with contraindications to CMR with gadolinium were excluded. A reference healthy control cohort was identified, defined as volunteers without past medical history of cardiovascular disease based on history.13 CMR technique CMR studies were performed on a 1.5-T imager (Magnetom Avanto Fit; Siemens Healthcare, Erlangen, Germany). Retrospectively gated cine steady-state free precession (SSFP) images were obtained for assessment of ventricular volumes, mass, and systolic function by a stack of short-axis slices ensuring ventricular coverage (6–8 mm slice and 2 mm inter-slice gap). Among patients, ECG-gated, free-breathing cine phase-contrast flow measurements were obtained at the main pulmonary artery for assessment of pulmonary regurgitation (PR). Myocardial fibrosis was assessed using LGE imaging and modified Look–Locker inversion recovery (MOLLI) T1 mapping. Among patients, LGE imaging was performed approximately 10 min following administration of 10 mL gadobutrol (Gadovist; Bayer Healthcare, Berlin, Germany), employing a 2D inversion recovery gradient-recalled echo sequence (slice 6–8 mm and 2 mm inter-slice gap) with ventricular coverage in short-axis orientation. T1 mapping was performed pre-contrast and 12–15 min post-contrast in short-axis orientation at basal, mid, and apical slice locations (TI 120–4000 ms, flip angle 35°, field of view (FOV) 360 mm, matrix 256 × 192, and slice thickness 6 mm). Recommended MOLLI inversion groupings were used for optimized precision: pre-contrast (5(3)3) and post-contrast (4(1)3(1)2).14 The imaging technique used for healthy volunteers has been previously published.13 Haematocrit was determined from a venous blood sample following the CMR study. CMR analysis Evaluation of cardiac volumes, function, mass, and PR flow were performed using commercial software (QMASS MR, Medis Medical Imaging Systems, Leiden, The Netherlands). RV and LV endocardial and epicardial borders were contoured on SSFP images to assess for end-diastolic and end-systolic volumes, ejection fraction, and mass by a single experienced observer, blinded to patient outcomes, in a standardized fashion according to a previously published protocol.15 The presence of hinge-point and non-hinge-point ventricular LGE was qualitatively assessed by visual inspection of all available LGE images.2 We evaluated for RV LGE at the superior, anterior, and inferior RV walls and LV LGE with exclusion of regions expected to enhance (such as surgical material involved in patching of the RV outflow or ventricular septal defect closure). The interventricular septum was considered part of the LV. After inline, non-rigid motion correction of individual MOLLI images, an inline T1 map was generated using standard three-parameter fitting. Analysis was performed offline using commercial software (cvi42; Circle CVI, Calgary, Canada). All T1 maps were analysed by a single experienced observer (K.H., 5 years of cardiovascular imaging experience) blinded to clinical outcomes. Regions of interest (ROIs) were drawn manually in the LV blood pool with care taken to avoid the myocardium and papillary muscles. A single ROI was drawn in the thickest anterior or inferior RV segment at the basal or mid-ventricular level with a minimal ROI size of 0.15 cm2, avoiding regions with artefact or LGE and ensuring that neither blood pool nor epicardial fat was included within the contour (Figure 1).16 If an adequately sized ROI could not be drawn reliably within myocardium meeting these criteria, the T1 map was not included in the analysis. LV endocardial and epicardial borders were manually contoured on a single mid-ventricular slice avoiding regions with evidence of LGE. Myocardial RVECV and LVECV were calculated based on pre- and post-contrast T1 values and haematocrit, as proposed by Arheden et al.17 Elevated RVECV and LVECV were defined as 34% and 30%, respectively, based on prior published thresholds.7,16 Figure 1 View largeDownload slide Short-axis late gadolinium-enhanced image (a) and pre-contrast T1 map (b) in a 61-year-old male with repaired tetralogy of Fallot. On the T1 map, regions of interest were drawn in the right ventricular myocardium (blue ROI, white arrow), remote from areas of late gadolinium-enhanced in the right ventricular outflow tract (red arrow) and the inferior right ventricular insertion point (orange arrow). Contours were drawn along the left ventricular endocardial (red contour) and epicardial (green contour) surfaces with care taken to avoid areas of late gadolinium enhanced. Figure 1 View largeDownload slide Short-axis late gadolinium-enhanced image (a) and pre-contrast T1 map (b) in a 61-year-old male with repaired tetralogy of Fallot. On the T1 map, regions of interest were drawn in the right ventricular myocardium (blue ROI, white arrow), remote from areas of late gadolinium-enhanced in the right ventricular outflow tract (red arrow) and the inferior right ventricular insertion point (orange arrow). Contours were drawn along the left ventricular endocardial (red contour) and epicardial (green contour) surfaces with care taken to avoid areas of late gadolinium enhanced. To assess for inter-observer agreement of ECV values, 10 randomly selected pre- and post-contrast T1 maps were re-analysed by a second experienced imager (A.C., 15 years of cardiovascular imaging experience) who was blinded to patient identifying data and to the first set of measurements. To assess for intra-observer agreement of ECV measurements, 10 randomly selected pre- and post-contrast T1 maps were re-analysed by the first experienced imager after a minimum of 2 months interval, blinded to clinical outcomes and the first set of measurements. Clinical data Major adverse cardiovascular events were defined as a composite end point at the time of last follow-up including death, out-of-hospital cardiac arrest, heart failure (HF) requiring admission for escalation of therapy, and haemodynamically significant VT >30 s and/or requiring invasive therapy [ablation and/or automatic implantable cardiac defibrillator implantation (AICD)]. Patients without events were censored at the time of last clinical follow-up. Rhythm disturbances were identified by electrocardiogram (ECG), Holter monitoring, or other continuous rhythm recording. Only ECG, echocardiogram, and exercise tests closest to the time of CMR (within 6 months) were included. Patients underwent symptom-limited cardiopulmonary exercise testing as part of routine clinical care on a cycle ergometer (Elema, Solna, Sweden), with analysis of expiratory gases according to a previously published protocol.18 Statistical analysis Statistical analysis was performed using STATA v14.1 (StataCorp, College Station, TX, USA). All continuous data were first tested for normal distribution using the Shapiro–Wilk test. Continuous variables were described using mean and standard deviation or median and IQR, and categorical variables using numbers and percentage. Comparisons between patients and controls were made by t-test for continuous values with normal distribution and Mann–Whitney rank-sum test for continuous values with non-normal distribution. Categorical variables were compared using the χ2 or the Fisher’s exact test. Correlations between continuous variables were assessed with the Pearson’s or Spearman’s correlation coefficient. Inter-observer and intra-observer agreement was assessed via the intra-class correlation coefficient (ICC) with two-way random-effects model and coefficient of variance (COV). Cox proportional hazards analysis was used to obtain estimates of the hazard of the composite end point associated with CMR values. Adjustment for covariates in the model was limited by the number of adverse events observed. The proportionality of hazards over time was assessed by testing interactions between predictors and a continuous linear function of time. The linearity assumption was assessed for continuous variables with the addition of a quadratic term. Sensitivity analysis was performed, restricting the Cox proportional hazard analysis to patients without pulmonary valve replacement (PVR) at the time of enrolment. A two-tailed P-value <0.05 was considered statistically significant. Results Study population Forty-four patients (32.9 ± 13.6 years, 59% male) and 10 healthy controls (31.5 ± 4.4 years, 50% male) were studied. Baseline characteristics are summarized in Table 1. Patients did not differ significantly from healthy controls with respect to age, gender, body surface area, or haematocrit. Among patients, the median interval between TOF repair and CMR was 27 years (IQR 19–37 years). Median clinical follow-up duration was 236 days (IQR 38–342 days). Table 1 Baseline characteristics Characteristics Patients (n = 44) Healthy controls (n = 10) P-value Age at study entry (years) 32.9 ± 13.6 31.5 ± 4.4 0.749 Male 26 (59) 5 (50) 0.560 BSA (m2) 1.8 ± 0.2 1.9 ± 0.3 0.824 Haematocrit 0.419 ± 0.052 0.412 ± 0.030 0.671 TOF anatomy  TOF 42 (95)  TOF with absent pulmonary valve 2 (5) Age at TOF repair (months) 41 (IQR 18–87) Type of TOF repaira  Transannular patch 20 (57)  Valve sparing 11 (31)  RV–PA conduit 6 (16)  BT shunt preceding repair 14 (32) Pulmonary valve replacement 13 (30) Total number cardiac surgeries 2 (IQR 1-2) Echocardiography  RV pressure (mmHg) 36 ± 14  Peak RVOT–PA gradient (mmHg) 23 ± 17 ECG  QRS duration (ms) 152 ± 33 Exercise  Peak VO2 (cc/kg/min) 23.3 ± 4.9  Percent predicted peak VO2 (%) 68.1 ± 13.4  Percent predicted at AT (%) 43.8 ± 11.4  VE/VCO2 at AT 33.3 ± 4.7 Characteristics Patients (n = 44) Healthy controls (n = 10) P-value Age at study entry (years) 32.9 ± 13.6 31.5 ± 4.4 0.749 Male 26 (59) 5 (50) 0.560 BSA (m2) 1.8 ± 0.2 1.9 ± 0.3 0.824 Haematocrit 0.419 ± 0.052 0.412 ± 0.030 0.671 TOF anatomy  TOF 42 (95)  TOF with absent pulmonary valve 2 (5) Age at TOF repair (months) 41 (IQR 18–87) Type of TOF repaira  Transannular patch 20 (57)  Valve sparing 11 (31)  RV–PA conduit 6 (16)  BT shunt preceding repair 14 (32) Pulmonary valve replacement 13 (30) Total number cardiac surgeries 2 (IQR 1-2) Echocardiography  RV pressure (mmHg) 36 ± 14  Peak RVOT–PA gradient (mmHg) 23 ± 17 ECG  QRS duration (ms) 152 ± 33 Exercise  Peak VO2 (cc/kg/min) 23.3 ± 4.9  Percent predicted peak VO2 (%) 68.1 ± 13.4  Percent predicted at AT (%) 43.8 ± 11.4  VE/VCO2 at AT 33.3 ± 4.7 Data are represented as mean ± standard deviation, median and interquartile range, or n (%). a Unknown surgical history in nine subjects. AT, anaerobic threshold; BSA, body surface area; BT shunt, Blalock–Taussig shunt; ECG, electrocardiogram; PA, pulmonary artery; RV, right ventricle; RVOT, right ventricular outflow tract; TOF, tetralogy of Fallot. Table 1 Baseline characteristics Characteristics Patients (n = 44) Healthy controls (n = 10) P-value Age at study entry (years) 32.9 ± 13.6 31.5 ± 4.4 0.749 Male 26 (59) 5 (50) 0.560 BSA (m2) 1.8 ± 0.2 1.9 ± 0.3 0.824 Haematocrit 0.419 ± 0.052 0.412 ± 0.030 0.671 TOF anatomy  TOF 42 (95)  TOF with absent pulmonary valve 2 (5) Age at TOF repair (months) 41 (IQR 18–87) Type of TOF repaira  Transannular patch 20 (57)  Valve sparing 11 (31)  RV–PA conduit 6 (16)  BT shunt preceding repair 14 (32) Pulmonary valve replacement 13 (30) Total number cardiac surgeries 2 (IQR 1-2) Echocardiography  RV pressure (mmHg) 36 ± 14  Peak RVOT–PA gradient (mmHg) 23 ± 17 ECG  QRS duration (ms) 152 ± 33 Exercise  Peak VO2 (cc/kg/min) 23.3 ± 4.9  Percent predicted peak VO2 (%) 68.1 ± 13.4  Percent predicted at AT (%) 43.8 ± 11.4  VE/VCO2 at AT 33.3 ± 4.7 Characteristics Patients (n = 44) Healthy controls (n = 10) P-value Age at study entry (years) 32.9 ± 13.6 31.5 ± 4.4 0.749 Male 26 (59) 5 (50) 0.560 BSA (m2) 1.8 ± 0.2 1.9 ± 0.3 0.824 Haematocrit 0.419 ± 0.052 0.412 ± 0.030 0.671 TOF anatomy  TOF 42 (95)  TOF with absent pulmonary valve 2 (5) Age at TOF repair (months) 41 (IQR 18–87) Type of TOF repaira  Transannular patch 20 (57)  Valve sparing 11 (31)  RV–PA conduit 6 (16)  BT shunt preceding repair 14 (32) Pulmonary valve replacement 13 (30) Total number cardiac surgeries 2 (IQR 1-2) Echocardiography  RV pressure (mmHg) 36 ± 14  Peak RVOT–PA gradient (mmHg) 23 ± 17 ECG  QRS duration (ms) 152 ± 33 Exercise  Peak VO2 (cc/kg/min) 23.3 ± 4.9  Percent predicted peak VO2 (%) 68.1 ± 13.4  Percent predicted at AT (%) 43.8 ± 11.4  VE/VCO2 at AT 33.3 ± 4.7 Data are represented as mean ± standard deviation, median and interquartile range, or n (%). a Unknown surgical history in nine subjects. AT, anaerobic threshold; BSA, body surface area; BT shunt, Blalock–Taussig shunt; ECG, electrocardiogram; PA, pulmonary artery; RV, right ventricle; RVOT, right ventricular outflow tract; TOF, tetralogy of Fallot. CMR findings Baseline CMR findings are shown in Table 2. RV LGE was present in 19 patients. Non-hinge-point LV LGE was present in nine patients, while hinge-point LGE was present in 27 patients. Inability to draw a reliable myocardial ROI precluded ECV assessment in eight patients and five controls. Table 2 Cardiac MRI findings Measurement Patients (n = 44) Healthy controls (n = 10) P-value RVEDV (mL) 263.7 ± 93.9 194.4 ± 56.6 0.037 Indexed RVEDV (mL/m2) 142.7 ± 45.8 102.9 ± 15.8 0.004 RVESV (mL) 150.9 ± 72.6 91.2 ± 31.7 0.003 Indexed RVESV (mL/m2) 81.1 ± 35.0 48.2 ± 10.9 0.001 RVEF (%) 44.2 ± 8.2 53.5 ± 4.4 0.001 RV mass (g) 56.0 ± 17.3 40.6 ± 9.0 0.006 Indexed RV mass (g/m2) 30.4 ± 8.4 21.8 ± 2.5 0.001 RV mass to volume ratio 0.22 ± 0.03 0.21 ± 0.02 0.361 LVEDV (mL) 157.6 ± 42.8 189.0 ± 56.5 0.119 Indexed LVEDV (mL/m2) 85.0 ± 17.5 99.8 ± 15.3 0.021 LVESV (mL) 72.3 ± 25.0 76.4 ± 27.3 0.806 Indexed LVESV (mL/m2) 38.9 ± 10.8 40.1 ±  8.7 0.490 LVEF (%) 54.3 ± 5.7 60.1 ± 3.1 0.002 LV mass (g) 97.4 ± 30.0 81.9 ±  32.1 0.151 Indexed LV mass (g/m2) 52.1 ± 11.2 42.6  ± 10.4 0.018 LV mass to volume ratio 0.62 ± 0.11 0.42 ± 0.07 <0.001 Right atrial area (cm2) 21.6 ± 6.9 23.0 ± 5.1 0.360 Left atrial area (cm2) 16.9 ± 4.4 23.6 ± 4.4 0.001 Pulmonary regurgitation (mL) 33.5 ± 36.7 Pulmonary regurgitation (%) 25.7 ± 23.6 RV LGE 19 (48.7%) 0 (0%) 0.004 RV T1 pre-contrast (ms) 1062.3 ± 66.9 954.2 ± 177.7 0.011 RVECV* (%) 31.5 ± 5.4 26.3 ± 2.1 0.027 Increased RVECV (>34%) 9 (29.0%) 0 (0%) 0.004 LV LGE (non hinge-point) 9 (23.0%) 0 (0%) 0.098 LV T1 pre-contrast (ms) 1009.7 ± 42.2 980.3 ± 51.4 0.139 LVECVa (%) 25.4 ± 5.9 24.9 ± 4.0 0.941 Increased LVECV (>30%) 6 (15.4%) 0 (0%) 0.186 Measurement Patients (n = 44) Healthy controls (n = 10) P-value RVEDV (mL) 263.7 ± 93.9 194.4 ± 56.6 0.037 Indexed RVEDV (mL/m2) 142.7 ± 45.8 102.9 ± 15.8 0.004 RVESV (mL) 150.9 ± 72.6 91.2 ± 31.7 0.003 Indexed RVESV (mL/m2) 81.1 ± 35.0 48.2 ± 10.9 0.001 RVEF (%) 44.2 ± 8.2 53.5 ± 4.4 0.001 RV mass (g) 56.0 ± 17.3 40.6 ± 9.0 0.006 Indexed RV mass (g/m2) 30.4 ± 8.4 21.8 ± 2.5 0.001 RV mass to volume ratio 0.22 ± 0.03 0.21 ± 0.02 0.361 LVEDV (mL) 157.6 ± 42.8 189.0 ± 56.5 0.119 Indexed LVEDV (mL/m2) 85.0 ± 17.5 99.8 ± 15.3 0.021 LVESV (mL) 72.3 ± 25.0 76.4 ± 27.3 0.806 Indexed LVESV (mL/m2) 38.9 ± 10.8 40.1 ±  8.7 0.490 LVEF (%) 54.3 ± 5.7 60.1 ± 3.1 0.002 LV mass (g) 97.4 ± 30.0 81.9 ±  32.1 0.151 Indexed LV mass (g/m2) 52.1 ± 11.2 42.6  ± 10.4 0.018 LV mass to volume ratio 0.62 ± 0.11 0.42 ± 0.07 <0.001 Right atrial area (cm2) 21.6 ± 6.9 23.0 ± 5.1 0.360 Left atrial area (cm2) 16.9 ± 4.4 23.6 ± 4.4 0.001 Pulmonary regurgitation (mL) 33.5 ± 36.7 Pulmonary regurgitation (%) 25.7 ± 23.6 RV LGE 19 (48.7%) 0 (0%) 0.004 RV T1 pre-contrast (ms) 1062.3 ± 66.9 954.2 ± 177.7 0.011 RVECV* (%) 31.5 ± 5.4 26.3 ± 2.1 0.027 Increased RVECV (>34%) 9 (29.0%) 0 (0%) 0.004 LV LGE (non hinge-point) 9 (23.0%) 0 (0%) 0.098 LV T1 pre-contrast (ms) 1009.7 ± 42.2 980.3 ± 51.4 0.139 LVECVa (%) 25.4 ± 5.9 24.9 ± 4.0 0.941 Increased LVECV (>30%) 6 (15.4%) 0 (0%) 0.186 Data are represented as mean  ±  standard deviation or n (%). a Haematocrit was unavailable in five patients. ECV, extracellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LGE, late gadolinium enhancement; LV, left ventricle; RV, right ventricle. Bold values are significant (P-value <0.05). Table 2 Cardiac MRI findings Measurement Patients (n = 44) Healthy controls (n = 10) P-value RVEDV (mL) 263.7 ± 93.9 194.4 ± 56.6 0.037 Indexed RVEDV (mL/m2) 142.7 ± 45.8 102.9 ± 15.8 0.004 RVESV (mL) 150.9 ± 72.6 91.2 ± 31.7 0.003 Indexed RVESV (mL/m2) 81.1 ± 35.0 48.2 ± 10.9 0.001 RVEF (%) 44.2 ± 8.2 53.5 ± 4.4 0.001 RV mass (g) 56.0 ± 17.3 40.6 ± 9.0 0.006 Indexed RV mass (g/m2) 30.4 ± 8.4 21.8 ± 2.5 0.001 RV mass to volume ratio 0.22 ± 0.03 0.21 ± 0.02 0.361 LVEDV (mL) 157.6 ± 42.8 189.0 ± 56.5 0.119 Indexed LVEDV (mL/m2) 85.0 ± 17.5 99.8 ± 15.3 0.021 LVESV (mL) 72.3 ± 25.0 76.4 ± 27.3 0.806 Indexed LVESV (mL/m2) 38.9 ± 10.8 40.1 ±  8.7 0.490 LVEF (%) 54.3 ± 5.7 60.1 ± 3.1 0.002 LV mass (g) 97.4 ± 30.0 81.9 ±  32.1 0.151 Indexed LV mass (g/m2) 52.1 ± 11.2 42.6  ± 10.4 0.018 LV mass to volume ratio 0.62 ± 0.11 0.42 ± 0.07 <0.001 Right atrial area (cm2) 21.6 ± 6.9 23.0 ± 5.1 0.360 Left atrial area (cm2) 16.9 ± 4.4 23.6 ± 4.4 0.001 Pulmonary regurgitation (mL) 33.5 ± 36.7 Pulmonary regurgitation (%) 25.7 ± 23.6 RV LGE 19 (48.7%) 0 (0%) 0.004 RV T1 pre-contrast (ms) 1062.3 ± 66.9 954.2 ± 177.7 0.011 RVECV* (%) 31.5 ± 5.4 26.3 ± 2.1 0.027 Increased RVECV (>34%) 9 (29.0%) 0 (0%) 0.004 LV LGE (non hinge-point) 9 (23.0%) 0 (0%) 0.098 LV T1 pre-contrast (ms) 1009.7 ± 42.2 980.3 ± 51.4 0.139 LVECVa (%) 25.4 ± 5.9 24.9 ± 4.0 0.941 Increased LVECV (>30%) 6 (15.4%) 0 (0%) 0.186 Measurement Patients (n = 44) Healthy controls (n = 10) P-value RVEDV (mL) 263.7 ± 93.9 194.4 ± 56.6 0.037 Indexed RVEDV (mL/m2) 142.7 ± 45.8 102.9 ± 15.8 0.004 RVESV (mL) 150.9 ± 72.6 91.2 ± 31.7 0.003 Indexed RVESV (mL/m2) 81.1 ± 35.0 48.2 ± 10.9 0.001 RVEF (%) 44.2 ± 8.2 53.5 ± 4.4 0.001 RV mass (g) 56.0 ± 17.3 40.6 ± 9.0 0.006 Indexed RV mass (g/m2) 30.4 ± 8.4 21.8 ± 2.5 0.001 RV mass to volume ratio 0.22 ± 0.03 0.21 ± 0.02 0.361 LVEDV (mL) 157.6 ± 42.8 189.0 ± 56.5 0.119 Indexed LVEDV (mL/m2) 85.0 ± 17.5 99.8 ± 15.3 0.021 LVESV (mL) 72.3 ± 25.0 76.4 ± 27.3 0.806 Indexed LVESV (mL/m2) 38.9 ± 10.8 40.1 ±  8.7 0.490 LVEF (%) 54.3 ± 5.7 60.1 ± 3.1 0.002 LV mass (g) 97.4 ± 30.0 81.9 ±  32.1 0.151 Indexed LV mass (g/m2) 52.1 ± 11.2 42.6  ± 10.4 0.018 LV mass to volume ratio 0.62 ± 0.11 0.42 ± 0.07 <0.001 Right atrial area (cm2) 21.6 ± 6.9 23.0 ± 5.1 0.360 Left atrial area (cm2) 16.9 ± 4.4 23.6 ± 4.4 0.001 Pulmonary regurgitation (mL) 33.5 ± 36.7 Pulmonary regurgitation (%) 25.7 ± 23.6 RV LGE 19 (48.7%) 0 (0%) 0.004 RV T1 pre-contrast (ms) 1062.3 ± 66.9 954.2 ± 177.7 0.011 RVECV* (%) 31.5 ± 5.4 26.3 ± 2.1 0.027 Increased RVECV (>34%) 9 (29.0%) 0 (0%) 0.004 LV LGE (non hinge-point) 9 (23.0%) 0 (0%) 0.098 LV T1 pre-contrast (ms) 1009.7 ± 42.2 980.3 ± 51.4 0.139 LVECVa (%) 25.4 ± 5.9 24.9 ± 4.0 0.941 Increased LVECV (>30%) 6 (15.4%) 0 (0%) 0.186 Data are represented as mean  ±  standard deviation or n (%). a Haematocrit was unavailable in five patients. ECV, extracellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LGE, late gadolinium enhancement; LV, left ventricle; RV, right ventricle. Bold values are significant (P-value <0.05). Mean pre-contrast RV T1 and RVECV values were significantly higher in patients compared with the controls (1062.3 ± 66.9 ms vs. 954.2 ± 177.7 ms, P = 0.011 and 31.5 ± 5.4% vs. 26.3 ± 2.1%, P = 0.027, respectively), although pre-contrast LV T1 and LVECV values did not differ significantly (P = 0.139 and P = 0.941, respectively). RVECV was significantly higher than LVECV (P < 0.001). Six (15%) patients had increased LVECV and 9 (29%) patients had elevated RVECV. Correlations between RVECV and LVECV, respectively, with clinical parameters and CMR measurements are shown in Table 3. Among patients with rTOF, RVECV was found to have a positive correlation of moderate strength with RVEDV (absolute and indexed), with RVESV (absolute and indexed) and with indexed RV mass, respectively. RVECV has a negative correlation of moderate strength with RVEF. Clinical parameters did not correlate significantly with either RVECV or LVECV. Table 3 RVECV and LVECV correlations Characteristics RVECV LVECV r-value P-value r-value P-value Age at study entry (years) 0.139 0.418 −0.229 0.114 Age at TOF repair (years) −0.010 0.957 −0.067 0.686 Echocardiography  RV pressure (mmHg) −0.233 0.252 −0.051 0.782  Peak RVOT–PA gradient (mmHg) −0.252 0.172 0.053 0.749 ECG  QRS duration (ms) 0.254 0.168 −0.285 0.079 Exercise  Peak VO2 (cc/kg/min) 0.399 0.066 −0.158 0.413  Percent predicted peak VO2 (%) 0.290 0.191 −0.211 0.272  Percent predicted at AT (%) −0.006 0.979 −0.202 0.312  VE/VCO2 at AT −0.099 0.686 0.102 0.629 CMR  RVEDV (mL) 0.364 0.029 −0.096 0.514  Indexed RVEDV (mL/m2) 0.360 0.031 −0.028 0.847  RVESV (mL) 0.435 0.008 −0.045 0.762  Indexed RVESV (mL/m2) 0.427 0.010 −0.018 0.923  RVEF (%) −0.386 0.020 0.081 0.582  RV mass (g) 0.367 0.028 −0.026 0.857  Indexed RV mass (g/m2) 0.369 0.027 0.061 0.680  RV mass-to-volume ratio −0.014 0.935 0.163 0.262  LVEDV (mL) 0.125 0.394 −0.125 0.394  Indexed LVEDV (mL/m2) 0.103 0.548 −0.019 0.898  LVESV (mL) 0.192 0.261 −0.054 0.711  Indexed LVESV (mL/m2) 0.214 0.210 0.035 0.813  LVEF (%) −0.213 0.212 −0.023 0.875  LV mass (g) 0.136 0.428 −0.158 0.278  Indexed LV mass (g/m2) 0.200 0.244 −0.097 0.506  LV mass to volume ratio 0.115 0.505 −0.154 0.292  Right atrial area (cm2) −0.003 0.986 −0.022 0.883  Left atrial area (cm2) 0.027 0.6875 0.086 0.556  Pulmonary regurgitation (mL) −0.026 0.893 −0.062 0.713  Pulmonary regurgitation (%) −0.094 0.647 0.022 0.895 Characteristics RVECV LVECV r-value P-value r-value P-value Age at study entry (years) 0.139 0.418 −0.229 0.114 Age at TOF repair (years) −0.010 0.957 −0.067 0.686 Echocardiography  RV pressure (mmHg) −0.233 0.252 −0.051 0.782  Peak RVOT–PA gradient (mmHg) −0.252 0.172 0.053 0.749 ECG  QRS duration (ms) 0.254 0.168 −0.285 0.079 Exercise  Peak VO2 (cc/kg/min) 0.399 0.066 −0.158 0.413  Percent predicted peak VO2 (%) 0.290 0.191 −0.211 0.272  Percent predicted at AT (%) −0.006 0.979 −0.202 0.312  VE/VCO2 at AT −0.099 0.686 0.102 0.629 CMR  RVEDV (mL) 0.364 0.029 −0.096 0.514  Indexed RVEDV (mL/m2) 0.360 0.031 −0.028 0.847  RVESV (mL) 0.435 0.008 −0.045 0.762  Indexed RVESV (mL/m2) 0.427 0.010 −0.018 0.923  RVEF (%) −0.386 0.020 0.081 0.582  RV mass (g) 0.367 0.028 −0.026 0.857  Indexed RV mass (g/m2) 0.369 0.027 0.061 0.680  RV mass-to-volume ratio −0.014 0.935 0.163 0.262  LVEDV (mL) 0.125 0.394 −0.125 0.394  Indexed LVEDV (mL/m2) 0.103 0.548 −0.019 0.898  LVESV (mL) 0.192 0.261 −0.054 0.711  Indexed LVESV (mL/m2) 0.214 0.210 0.035 0.813  LVEF (%) −0.213 0.212 −0.023 0.875  LV mass (g) 0.136 0.428 −0.158 0.278  Indexed LV mass (g/m2) 0.200 0.244 −0.097 0.506  LV mass to volume ratio 0.115 0.505 −0.154 0.292  Right atrial area (cm2) −0.003 0.986 −0.022 0.883  Left atrial area (cm2) 0.027 0.6875 0.086 0.556  Pulmonary regurgitation (mL) −0.026 0.893 −0.062 0.713  Pulmonary regurgitation (%) −0.094 0.647 0.022 0.895 AT, anaerobic threshold; ECG, electrocardiogram; ECV, extra-cellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LGE, late gadolinium enhancement; LV, left ventricle; PA, pulmonary artery; RV, right ventricle; RVOT, right ventricular outflow tract. Table 3 RVECV and LVECV correlations Characteristics RVECV LVECV r-value P-value r-value P-value Age at study entry (years) 0.139 0.418 −0.229 0.114 Age at TOF repair (years) −0.010 0.957 −0.067 0.686 Echocardiography  RV pressure (mmHg) −0.233 0.252 −0.051 0.782  Peak RVOT–PA gradient (mmHg) −0.252 0.172 0.053 0.749 ECG  QRS duration (ms) 0.254 0.168 −0.285 0.079 Exercise  Peak VO2 (cc/kg/min) 0.399 0.066 −0.158 0.413  Percent predicted peak VO2 (%) 0.290 0.191 −0.211 0.272  Percent predicted at AT (%) −0.006 0.979 −0.202 0.312  VE/VCO2 at AT −0.099 0.686 0.102 0.629 CMR  RVEDV (mL) 0.364 0.029 −0.096 0.514  Indexed RVEDV (mL/m2) 0.360 0.031 −0.028 0.847  RVESV (mL) 0.435 0.008 −0.045 0.762  Indexed RVESV (mL/m2) 0.427 0.010 −0.018 0.923  RVEF (%) −0.386 0.020 0.081 0.582  RV mass (g) 0.367 0.028 −0.026 0.857  Indexed RV mass (g/m2) 0.369 0.027 0.061 0.680  RV mass-to-volume ratio −0.014 0.935 0.163 0.262  LVEDV (mL) 0.125 0.394 −0.125 0.394  Indexed LVEDV (mL/m2) 0.103 0.548 −0.019 0.898  LVESV (mL) 0.192 0.261 −0.054 0.711  Indexed LVESV (mL/m2) 0.214 0.210 0.035 0.813  LVEF (%) −0.213 0.212 −0.023 0.875  LV mass (g) 0.136 0.428 −0.158 0.278  Indexed LV mass (g/m2) 0.200 0.244 −0.097 0.506  LV mass to volume ratio 0.115 0.505 −0.154 0.292  Right atrial area (cm2) −0.003 0.986 −0.022 0.883  Left atrial area (cm2) 0.027 0.6875 0.086 0.556  Pulmonary regurgitation (mL) −0.026 0.893 −0.062 0.713  Pulmonary regurgitation (%) −0.094 0.647 0.022 0.895 Characteristics RVECV LVECV r-value P-value r-value P-value Age at study entry (years) 0.139 0.418 −0.229 0.114 Age at TOF repair (years) −0.010 0.957 −0.067 0.686 Echocardiography  RV pressure (mmHg) −0.233 0.252 −0.051 0.782  Peak RVOT–PA gradient (mmHg) −0.252 0.172 0.053 0.749 ECG  QRS duration (ms) 0.254 0.168 −0.285 0.079 Exercise  Peak VO2 (cc/kg/min) 0.399 0.066 −0.158 0.413  Percent predicted peak VO2 (%) 0.290 0.191 −0.211 0.272  Percent predicted at AT (%) −0.006 0.979 −0.202 0.312  VE/VCO2 at AT −0.099 0.686 0.102 0.629 CMR  RVEDV (mL) 0.364 0.029 −0.096 0.514  Indexed RVEDV (mL/m2) 0.360 0.031 −0.028 0.847  RVESV (mL) 0.435 0.008 −0.045 0.762  Indexed RVESV (mL/m2) 0.427 0.010 −0.018 0.923  RVEF (%) −0.386 0.020 0.081 0.582  RV mass (g) 0.367 0.028 −0.026 0.857  Indexed RV mass (g/m2) 0.369 0.027 0.061 0.680  RV mass-to-volume ratio −0.014 0.935 0.163 0.262  LVEDV (mL) 0.125 0.394 −0.125 0.394  Indexed LVEDV (mL/m2) 0.103 0.548 −0.019 0.898  LVESV (mL) 0.192 0.261 −0.054 0.711  Indexed LVESV (mL/m2) 0.214 0.210 0.035 0.813  LVEF (%) −0.213 0.212 −0.023 0.875  LV mass (g) 0.136 0.428 −0.158 0.278  Indexed LV mass (g/m2) 0.200 0.244 −0.097 0.506  LV mass to volume ratio 0.115 0.505 −0.154 0.292  Right atrial area (cm2) −0.003 0.986 −0.022 0.883  Left atrial area (cm2) 0.027 0.6875 0.086 0.556  Pulmonary regurgitation (mL) −0.026 0.893 −0.062 0.713  Pulmonary regurgitation (%) −0.094 0.647 0.022 0.895 AT, anaerobic threshold; ECG, electrocardiogram; ECV, extra-cellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LGE, late gadolinium enhancement; LV, left ventricle; PA, pulmonary artery; RV, right ventricle; RVOT, right ventricular outflow tract. Adverse outcomes A major adverse cardiovascular event occurred in nine (21%) patients: death (n = 1), out-of-hospital cardiac arrest (n = 1), HF (n = 1), and VT (n = 6). Death occurred in one patient unexpectedly <30 days following PVR. The patient with the out-of-hospital cardiac arrest ultimately went on to PVR and device implantation. The patient admitted for escalation of HF therapy subsequently received a device with resynchronization and defibrillation capacities. Documented VT occurred in six patients (sustained VT >30 s in five patients; one patient had recurrent, haemodynamically destabilizing non-sustained VT resulting in AICD implantation); five of these patients went on to AICD implantation and one was found to be non-inducible following preoperative mapping and intraoperative ablation. In patients with a major adverse cardiac event, RVECV was significantly elevated when compared with those without an adverse event (35.0 ± 5.5% vs. 29.6 ± 4.5%, P = 0.014). On univariable analysis to evaluate the relationship between CMR measurements and clinical outcomes (Table 4), RVECV was associated with increased risk for the composite end point [hazard ratio (HR) 1.13, 95% confidence interval (CI) (1.01–1.28), P = 0.037]. After the analysis was restricted to patients without PVR at study entry, the association remained statistically significant between RVECV and adverse outcomes [seven events, HR 1.17, 95% CI (1.01–1.36), P = 0.038]. Indexed measures of RV volumes, indexed RV mass, and RVEF were also associated with the composite end point, whereas LVECV, indexed LV volumes, and LV systolic function were not (Table 4). Table 4 Univariable model examining the association between CMR measurements and major adverse cardiovascular outcomesa Finding HR 95% CI P-value Indexed RVEDV (mL/m2) 1.02 1.01–1.03 0.002 Indexed RVESV (mL/m2) 1.02 1.01–1.04 0.001 RVEF (%) 0.90 0.84–0.96 0.002 Indexed RV mass (g/m2) 1.15 1.06–1.24 0.001 RV mass-to-volume ratio (%) 0.95 0.78–1.15 0.604 Indexed LVEDV (mL/m2) 1.01 0.97–1.04 0.738 Indexed LVESV (mL/m2) 1.02 0.97–1.08 0.459 LVEF (%) 0.94 0.84–1.05 0.258 Indexed LV mass (g/m2) 1.05 1.01–1.10 0.008 Right atrial area (cm2) 1.05 0.97–1.14 0.235 Left atrial area (cm2) 1.11 1.02–1.55 0.092 Pulmonary regurgitation (mL) 1.01 0.99–1.03 0.114 Pulmonary regurgitation (%) 1.02 0.99–1.05 0.286 RV LGE 7.36 0.90–60.2 0.063 RV T1 pre-contrast (ms) 1.01 1.00–1.02 0.079 RVECV (%) 1.13 1.01–1.28 0.037 Elevated RVECV (>34%) 2.19 0.58–8.18 0.245 LV LGE (non-hinge point) 4.63 1.03–20.72 0.045 LV T1 pre-contrast (ms) 1.00 0.99–1.02 0.891 LVECV (%) 0.97 0.84–1.11 0.667 Elevated LVECV (>30%) 0.39 0.04–3.68 0.413 Finding HR 95% CI P-value Indexed RVEDV (mL/m2) 1.02 1.01–1.03 0.002 Indexed RVESV (mL/m2) 1.02 1.01–1.04 0.001 RVEF (%) 0.90 0.84–0.96 0.002 Indexed RV mass (g/m2) 1.15 1.06–1.24 0.001 RV mass-to-volume ratio (%) 0.95 0.78–1.15 0.604 Indexed LVEDV (mL/m2) 1.01 0.97–1.04 0.738 Indexed LVESV (mL/m2) 1.02 0.97–1.08 0.459 LVEF (%) 0.94 0.84–1.05 0.258 Indexed LV mass (g/m2) 1.05 1.01–1.10 0.008 Right atrial area (cm2) 1.05 0.97–1.14 0.235 Left atrial area (cm2) 1.11 1.02–1.55 0.092 Pulmonary regurgitation (mL) 1.01 0.99–1.03 0.114 Pulmonary regurgitation (%) 1.02 0.99–1.05 0.286 RV LGE 7.36 0.90–60.2 0.063 RV T1 pre-contrast (ms) 1.01 1.00–1.02 0.079 RVECV (%) 1.13 1.01–1.28 0.037 Elevated RVECV (>34%) 2.19 0.58–8.18 0.245 LV LGE (non-hinge point) 4.63 1.03–20.72 0.045 LV T1 pre-contrast (ms) 1.00 0.99–1.02 0.891 LVECV (%) 0.97 0.84–1.11 0.667 Elevated LVECV (>30%) 0.39 0.04–3.68 0.413 a Composite of death, out-of-hospital cardiac arrest, heart failure requiring admission for escalation of therapy, or haemodynamic destabilizing ventricular tachycardia (lasting >30 s and/or requiring invasive therapy) by the time of last follow-up. CI, confidence interval; ECV, extracellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LV, left ventricle; RV, right ventricle; HR, hazard ratio; RVOT, right ventricular outflow tract. Table 4 Univariable model examining the association between CMR measurements and major adverse cardiovascular outcomesa Finding HR 95% CI P-value Indexed RVEDV (mL/m2) 1.02 1.01–1.03 0.002 Indexed RVESV (mL/m2) 1.02 1.01–1.04 0.001 RVEF (%) 0.90 0.84–0.96 0.002 Indexed RV mass (g/m2) 1.15 1.06–1.24 0.001 RV mass-to-volume ratio (%) 0.95 0.78–1.15 0.604 Indexed LVEDV (mL/m2) 1.01 0.97–1.04 0.738 Indexed LVESV (mL/m2) 1.02 0.97–1.08 0.459 LVEF (%) 0.94 0.84–1.05 0.258 Indexed LV mass (g/m2) 1.05 1.01–1.10 0.008 Right atrial area (cm2) 1.05 0.97–1.14 0.235 Left atrial area (cm2) 1.11 1.02–1.55 0.092 Pulmonary regurgitation (mL) 1.01 0.99–1.03 0.114 Pulmonary regurgitation (%) 1.02 0.99–1.05 0.286 RV LGE 7.36 0.90–60.2 0.063 RV T1 pre-contrast (ms) 1.01 1.00–1.02 0.079 RVECV (%) 1.13 1.01–1.28 0.037 Elevated RVECV (>34%) 2.19 0.58–8.18 0.245 LV LGE (non-hinge point) 4.63 1.03–20.72 0.045 LV T1 pre-contrast (ms) 1.00 0.99–1.02 0.891 LVECV (%) 0.97 0.84–1.11 0.667 Elevated LVECV (>30%) 0.39 0.04–3.68 0.413 Finding HR 95% CI P-value Indexed RVEDV (mL/m2) 1.02 1.01–1.03 0.002 Indexed RVESV (mL/m2) 1.02 1.01–1.04 0.001 RVEF (%) 0.90 0.84–0.96 0.002 Indexed RV mass (g/m2) 1.15 1.06–1.24 0.001 RV mass-to-volume ratio (%) 0.95 0.78–1.15 0.604 Indexed LVEDV (mL/m2) 1.01 0.97–1.04 0.738 Indexed LVESV (mL/m2) 1.02 0.97–1.08 0.459 LVEF (%) 0.94 0.84–1.05 0.258 Indexed LV mass (g/m2) 1.05 1.01–1.10 0.008 Right atrial area (cm2) 1.05 0.97–1.14 0.235 Left atrial area (cm2) 1.11 1.02–1.55 0.092 Pulmonary regurgitation (mL) 1.01 0.99–1.03 0.114 Pulmonary regurgitation (%) 1.02 0.99–1.05 0.286 RV LGE 7.36 0.90–60.2 0.063 RV T1 pre-contrast (ms) 1.01 1.00–1.02 0.079 RVECV (%) 1.13 1.01–1.28 0.037 Elevated RVECV (>34%) 2.19 0.58–8.18 0.245 LV LGE (non-hinge point) 4.63 1.03–20.72 0.045 LV T1 pre-contrast (ms) 1.00 0.99–1.02 0.891 LVECV (%) 0.97 0.84–1.11 0.667 Elevated LVECV (>30%) 0.39 0.04–3.68 0.413 a Composite of death, out-of-hospital cardiac arrest, heart failure requiring admission for escalation of therapy, or haemodynamic destabilizing ventricular tachycardia (lasting >30 s and/or requiring invasive therapy) by the time of last follow-up. CI, confidence interval; ECV, extracellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LV, left ventricle; RV, right ventricle; HR, hazard ratio; RVOT, right ventricular outflow tract. Inter- and intra-observer agreement Inter-observer agreement was good for RVECV [ICC 0.834, 95% CI (0.086–0.963); COV 9.4%, 95% CI (7.6–10.9%)] and LVECV [ICC 0.938, 95% CI (0.729–0.985); COV 4.8%, 95% CI (4.4–5.2%)]. Intra-observer agreement was good for RVECV [ICC 0.864, 95% CI (0.485–0.966); COV 8.4%, 95% CI (6.7–9.9%)] and LVECV [ICC 0.949, 95% CI (0.780–0.988); COV 3.8%, 95% CI (3.5–4.2%)]. Discussion This prospective study is the first to demonstrate that increased RVECV is associated with major adverse cardiovascular events in adults with rTOF. When considering a surrogate marker of diffuse fibrosis, RVECV was elevated in 29% of this study population, suggesting that remodelling at the tissue level may be associated with adverse clinical outcomes. We found that the hazard of major adverse cardiovascular events increased by 13% for every 1% absolute increase in RVECV. Only three prior studies have reported RV T1 and ECV values in rTOF, all in a retrospective fashion (see Supplementary data online, Table S1). Kozak et al.10 reported that post-contrast RV and LV T1 values were lower in children with rTOF compared with the healthy controls. Post-contrast T1 values were shorter in the RV compared with the LV, suggesting a higher RV fibrotic burden. Unlike our study, they were not able to calculate ECV values due to absent pre-contrast T1 measurements and haematocrit values, and they did not explore associations with clinical outcomes. Chen et al.18 measured RVECV retrospectively in a cohort of children and young adults with rTOF. RVECV was significantly higher in patients compared with the controls, but RVECV was not associated with arrhythmia.18 In this study, RVECV values were slightly higher in TOF patients (34.2 ± 5.6%) and healthy controls (28.4 ± 6.3%) compared with our results (31.5 ± 5.4% and 26.3 ± 2.1%, respectively), which may be due to differences in technique.19 We employed a strict minimum ROI size for RV T1 mapping analysis, resulting in exclusion of some cases but in doing so minimizing the potential for erroneously high ECV if adjacent structures were inadvertently included in the RV myocardial ROI. The same authors reported that increased LVECV in rTOF was associated with arrhythmia.18 The definition of arrhythmia in this study was more encompassing than ours, including a variety of atrial arrhythmias, ventricular ectopy, and non-sustained arrhythmia (atrial or ventricular), which did not necessarily result in escalation of therapy. In contrast, our definition of arrhythmia was restricted to haemodynamically significant VT resulting in invasive therapies, including AICD implantation, and/or surgical ablation. Yim et al.8 reported that non-contrast RV T1 values are elevated in children with rTOF and were associated with longer cross-clamp times at surgery. However, they evaluated neither RVECV nor the relationship to major adverse events. Additional reports examined LVECV values in patients with rTOF9,11,18 with conflicting results, possibly related to differences in ages of the populations studied. While Riesenkampff et al.11 reported no significant difference in LV non-contrast T1 and LVECV values between children with rTOF and healthy controls, Broberg et al.9 reported that LVECV was higher in older adults with rTOF compared with the controls. In the latter study, those with increased LVECV were more likely to develop adverse events (specifically new atrial arrhythmias and cardiovascular death). The relatively young age of our adult population, the length of follow-up, a more restrictive definition of adverse outcomes, and differences in imaging technique may explain, at least in part, the lack of association between LVECV and the composite outcome in our study. Notably, previous publications have not demonstrated the association between RVECV and development of major adverse cardiovascular events in adults with rTOF, which is a strength of this study. We demonstrate that RVECV may be a predictor of major adverse events, despite our modest sample size. The principal novel findings to emerge from our study include the following: RVECV increases the hazard of major adverse cardiovascular events in adults with rTOF. RVECV correlates positively with both RVEDV (absolute and indexed) and RV mass (indexed). In line with previous studies, we found an association between RV volumes, mass, and systolic function with major adverse outcomes in the rTOF population.20,21 Increasingly, research efforts are focusing on what causes or mediates late onset of complications in adults with rTOF. Adverse events, including VT, HF, and sudden death, are seen with increasing frequency with advancing age, despite successful repair in early childhood.22 Identification of non-invasive imaging markers of poor outcome are highly desirable, and standard CMR measurements of ventricular size, function, and mass have been linked to clinical compromise in a growing body of publications.20,21 CMR-derived ECV has been shown to correlate with histological myocardial fibrosis in other conditions and has been associated with adverse events including death and HF in non-congenital populations.23,24 RV non-contrast T1 and ECV values are elevated in patients without congenital heart disease (CHD) in the setting of RV dysfunction and pulmonary hypertension25–28 and correlate with pulmonary haemodynamics, RV arterial coupling, and RV function.29 In our study, RVECV values are higher compared with LVECV values, which may be explained by higher collagen content and fibrosis of the RV.26,30 This finding is concordant with the results of prior studies.10,18 Increased RVECV has been proposed to reflect cardiomyocyte atrophy/death with expansion of the extracellular extravascular space and is expected to be a diffuse process.18 In comparison with the LV, the thin-walled RV presents unique imaging challenges. Although our methodology for RV assessment focused on sampling myocardial regions of greatest hypertrophy for assessment of diffuse fibrosis, more extensive study of the RV may yield higher fidelity results. Several techniques have been proposed to improve T1 quantification of the RV, including imaging in systole rather than diastole, and newer higher spatial resolution sequences.10,26,27,31 The results of a recent study indicate that RV T1 maps could be evaluated successfully in approximately half of the healthy controls and a larger proportion of patients with CHD, similar to our findings.16 They report that RVECV can be assessed with T1 mapping, provided that the image quality allows for sufficient distinction between blood and myocardium and RV wall thickness is >one pixel and conclude that under these conditions RVECV measurements can be integrated into clinical practice in CHD.16 In our analysis, a minimum RV myocardial ROI size of 0.15 cm2 was required (>one pixel) for inclusion, and T1 maps with insufficient distinction between blood and myocardium were not analysed (18% of rTOF and 50% of controls), in keeping with these recommendations. Furthermore, it is important to remember that generation of T1 maps requires exact co-registration of individual pixels and inconsistency in this process may further introduce error. Myocardial fibrosis in patients with TOF can be attributed to a variety of factors prior to repair (such as duration of cyanosis and exposure to pressure overload), during repair (including myocardial protection strategies and intraoperative technique), and following repair (specifically advancing age and adaptation of the ventricle to chronic volume/pressure overload). Our data demonstrate a relationship between various CMR measures, including RVECV, increased RV volume, and increased RV mass, with outcomes, underscoring a multifactorial process that likely contributes to major adverse clinical events. These observations lend support to the postulate that chronic haemodynamic sequelae following initial repair can trigger development of RV fibrosis, which may potentially mediate development of late electrical and/or mechanical complications in adults with rTOF. The results of this study have several potential clinical implications with respect to prognosis and management. Myocardial fibrosis could be a potential target for pharmacological intervention with antifibrotic agents. Non-invasive imaging with CMR with detection of myocardial fibrosis could allow for more refined timing of interventions such as PVR. A better understanding of how ECV may improve the discrimination of traditional risk factors, such as QRS duration on ECG, RV size, and ejection fraction is highly desirable, although beyond the scope of our study. Limitations This study is primarily limited by the relatively small number of subjects and modest total number of adverse events. A multivariable model could not be developed with the number of patient outcomes observed, and therefore, the value of RVECV over other clinical and imaging parameters could not be determined. The cohort of patients studied does not reflect the entire spectrum of adult patients with rTOF, as patients unsuitable for CMR assessment with gadolinium were excluded. There is a potential referral bias as clinicians may refer sicker patients for CMR, although this is mitigated by the fact that CMR is used for routine clinical surveillance (typically every 2–3 years) in this population,15,32,33 and the fact that patients with AICD/pacemakers were excluded. Although care was taken to draw ROIs in the RV myocardium only, partial volume averaging and contamination of T1 values from the inadvertent inclusion of blood pool or epicardial fat are potential pitfalls, which could result in artificially high ECV values, despite the relatively stringent methodology for contour definition employed. Conclusion Increased RVECV is associated with major adverse cardiovascular events in adults with rTOF. If myocardial fibrosis plays a role in mediating adverse outcomes, this could be a potential target for future pharmacological therapies and may allow for more refined timing of intervention. The results of this study may lead to future larger studies exploring the potential role for RVECV in risk stratification within the adult population with rTOF. Supplementary material Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Conflict of interest: none declared. Funding Radiological Society of North America Research Scholar Grant (RSCH1608 to K.H.); Canadian Institutes of Health Research Operating Grant (MOP 119353 to R.W.); and Canadian Institutes of Health Research New Investigator Award (FRN 147814 to D.T.). References 1 Kilner PJ , Geva T , Kaemmerer H , Trindade PT , Schwitter J , Webb GD. Recommendations for cardiovascular magnetic resonance in adults with congenital heart disease from the respective working groups of the European Society of Cardiology . Eur Heart J 2010 ; 31 : 794 – 805 . Google Scholar CrossRef Search ADS PubMed 2 Babu-Narayan SV , Kilner PJ , Li W , Moon JC , Goktekin O , Davlouros PA et al. Ventricular fibrosis suggested by cardiovascular magnetic resonance in adults with repaired tetralogy of Fallot and its relationship to adverse markers of clinical outcome . Circulation 2006 ; 113 : 405 – 13 . Google Scholar CrossRef Search ADS PubMed 3 Wald RM , Haber I , Wald R , Valente AM , Powell AJ , Geva T. Effects of regional dysfunction and late gadolinium enhancement on global right ventricular function and exercise capacity in patients with repaired tetralogy of Fallot . Circulation 2009 ; 119 : 1370 – 7 . Google Scholar CrossRef Search ADS PubMed 4 Chaudhry A , Biederman RW , Candia R , Reddy S , Williams RW , Yamrozik J et al. Ventricular tachycardia and right ventricular fibrosis after tetralogy of fallot surgical repair . Circulation 2013 ; 128 : 185 – 7 . Google Scholar CrossRef Search ADS PubMed 5 Ide S , Riesenkampff E , Chiasson DA , Dipchand AI , Kantor PF , Chaturvedi RR et al. Histological validation of cardiovascular magnetic resonance T1 mapping markers of myocardial fibrosis in paediatric heart transplant recipients . J Cardiovasc Magn Reson 2017 ; 19 : 10. Google Scholar CrossRef Search ADS PubMed 6 Iles L , Pfluger H , Phrommintikul A , Cherayath J , Aksit P , Gupta SN et al. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping . J Am Coll Cardiol 2008 ; 52 : 1574 – 80 . Google Scholar CrossRef Search ADS PubMed 7 Kellman P , Wilson JR , Xue H , Bandettini WP , Shanbhag SM , Druey KM et al. Extracellular volume fraction mapping in the myocardium, part 2: initial clinical experience . J Cardiovasc Magn Reson 2012 ; 14 : 64. Google Scholar CrossRef Search ADS PubMed 8 Yim D , Riesenkampff E , Caro-Dominguez P , Yoo S-J , Seed M , Grosse-Wortmann L. Assessment of diffuse ventricular myocardial fibrosis using native T1 in children with repaired tetralogy of Fallot . Circ Cardiovasc Imaging 2017 ; 10 : e005695. Google Scholar CrossRef Search ADS PubMed 9 Broberg CS , Huang J , Hogberg I , McLarry J , Woods P , Burchill LJ et al. Diffuse LV myocardial fibrosis and its clinical associations in adults with repaired tetralogy of Fallot . JACC Cardiovasc Imaging 2016 ; 9 : 86 – 7 . Google Scholar CrossRef Search ADS PubMed 10 Kozak MF , Redington A , Yoo S-J , Seed M , Greiser A , Grosse-Wortmann L. Diffuse myocardial fibrosis following tetralogy of Fallot repair: a T1 mapping cardiac magnetic resonance study . Pediatr Radiol 2014 ; 44 : 403 – 9 . Google Scholar CrossRef Search ADS PubMed 11 Riesenkampff E , Luining W , Seed M , Chungsomprasong P , Manlhiot C , Elders B et al. Increased left ventricular myocardial extracellular volume is associated with longer cardiopulmonary bypass times, biventricular enlargement and reduced exercise tolerance in children after repair of Tetralogy of Fallot . J Cardiovasc Magn Reson 2017 ; 18 : 75. Google Scholar CrossRef Search ADS 12 Geva T. Diffuse myocardial fibrosis in repaired tetralogy of Fallot . Circ Cardiovasc Imaging 2017 ; 10 : e006184. Google Scholar CrossRef Search ADS PubMed 13 Hanneman K , Nguyen ET , Thavendiranathan P , Ward R , Greiser A , Jolly M-P et al. Quantification of myocardial extracellular volume fraction with cardiac MR imaging in thalassemia major . Radiology 2016 ; 279 : 720 – 30 . Google Scholar CrossRef Search ADS PubMed 14 Kellman P , Arai AE , Xue H. T1 and extracellular volume mapping in the heart: estimation of error maps and the influence of noise on precision . J Cardiovasc Magn Reson 2013 ; 15 : 56. Google Scholar CrossRef Search ADS PubMed 15 Wald RM , Altaha MA , Alvarez N , Caldarone CA , Cavallé-Garrido T , Dallaire F et al. Rationale and design of the canadian outcomes registry late after tetralogy of fallot repair: the CORRELATE study . Can J Cardiol 2014 ; 30 : 1436 – 43 . Google Scholar CrossRef Search ADS PubMed 16 Al-Wakeel N , Nordmeyer S , Yilmaz S , Rastin S , Münch FH , Berger F et al. The right ventricle in congenital heart disease—cardiac T1 mapping for measurements of diffuse myocardial fibrosis . J Cardiovasc Magn Reson 2016 ; 18 : O25. Google Scholar CrossRef Search ADS 17 Arheden H , Saeed M , Higgins CB , Gao D-W , Bremerich J , Wyttenbach R et al. Measurement of the distribution volume of gadopentetate dimeglumine at echo-planar MR imaging to quantify myocardial infarction: comparison with 99mTc-DTPA autoradiography in rats . Radiology 1999 ; 211 : 698 – 708 . Google Scholar CrossRef Search ADS PubMed 18 Chen C-A , Dusenbery SM , Valente AM , Powell AJ , Geva T. Myocardial ECV fraction assessed by CMR is associated with type of hemodynamic load and arrhythmia in repaired tetralogy of Fallot . JACC Cardiovasc Imaging 2016 ; 9 : 1 – 10 . Google Scholar CrossRef Search ADS PubMed 19 Nacif MS , Turkbey EB , Gai N , Nazarian S , van der Geest RJ , Noureldin RA et al. Myocardial T1 mapping with MRI: comparison of Look-Locker and MOLLI sequences . J Magn Reson Imaging 2011 ; 34 : 1367 – 73 . Google Scholar CrossRef Search ADS PubMed 20 Bokma JP , de Wilde KC , Vliegen HW , van Dijk AP , van Melle JP , Meijboom FJ et al. Value of cardiovascular magnetic resonance imaging in noninvasive risk stratification in tetralogy of Fallot . JAMA Cardiol 2017 ; 2 : 678 . Google Scholar CrossRef Search ADS PubMed 21 Valente AM , Gauvreau K , Assenza GE , Babu-Narayan SV , Schreier J , Gatzoulis MA et al. Contemporary predictors of death and sustained ventricular tachycardia in patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort . Heart 2014 ; 100 : 247 – 53 . Google Scholar CrossRef Search ADS PubMed 22 Nollert G , Fischlein T , Bouterwek S , Böhmer C , Klinner W , Reichart B. Long-term survival in patients with repair of tetralogy of Fallot: 36-year follow-up of 490 survivors of the first year after surgical repair . J Am Coll Cardiol 1997 ; 30 : 1374 – 83 . Google Scholar CrossRef Search ADS PubMed 23 Wong TC , Piehler K , Meier CG , Testa SM , Klock AM , Aneizi AA et al. Association between extracellular matrix expansion quantified by cardiovascular magnetic resonance and short-term mortality . Circulation 2012 ; 126 : 1206 – 16 . Google Scholar CrossRef Search ADS PubMed 24 Puntmann VO , Carr-White G , Jabbour A , Yu C-Y , Gebker R , Kelle S et al. T1-mapping and outcome in nonischemic cardiomyopathy: all-cause mortality and heart failure . JACC Cardiovasc Imaging 2016 ; 9 : 40 – 50 . Google Scholar CrossRef Search ADS PubMed 25 Spruijt OA , Vissers L , Bogaard H-J , Hofman MBM , Vonk-Noordegraaf A , Marcus JT. Increased native T1-values at the interventricular insertion regions in precapillary pulmonary hypertension . Int J Cardiovasc Imaging 2016 ; 32 : 451 – 9 . Google Scholar CrossRef Search ADS PubMed 26 Mehta BB , Auger DA , Gonzalez JA , Workman V , Chen X , Chow K et al. Detection of elevated right ventricular extracellular volume in pulmonary hypertension using Accelerated and Navigator-Gated Look-Locker Imaging for Cardiac T1 Estimation (ANGIE) cardiovascular magnetic resonance . J Cardiovasc Magn Reson 2015 ; 17 : 1 – 11 . Google Scholar CrossRef Search ADS PubMed 27 Bilchick KC , Mehta BB , Workman V , Auger D , Chen X , Kennedy J et al. Abstract 14921: right ventricular extracellular volume fraction by magnetic resonance T1 mapping in pulmonary hypertension and heart failure . Circulation 2015 ; 132 : A14921 . 28 Jellis CL , Yingchoncharoen T , Gai N , Popovic Z , Flamm S , Kwon D. Assessment of right ventricular structure and function: novel CMR T1 mapping and strain techniques . J Am Coll Cardiol 2014 ; 63 : A1198. Google Scholar CrossRef Search ADS 29 García-Álvarez A , García-Lunar I , Pereda D , Fernandez-Jimenez R , Sánchez-González J , Mirelis JG et al. Association of myocardial T1-mapping CMR with hemodynamics and RV performance in pulmonary hypertension . JACC Cardiovasc Imaging 2015 ; 8 : 76 – 82 . Google Scholar CrossRef Search ADS PubMed 30 Kawel-Boehm N , Dellas Buser T , Greiser A , Bieri O , Bremerich J , Santini F. In-vivo assessment of normal T1 values of the right-ventricular myocardium by cardiac MRI . Int J Cardiovasc Imaging 2014 ; 30 : 323 – 8 . Google Scholar CrossRef Search ADS PubMed 31 Kawel N , Nacif M , Zavodni A , Jones J , Liu S , Sibley CT et al. T1 mapping of the myocardium: intra-individual assessment of the effect of field strength, cardiac cycle and variation by myocardial region . J Cardiovasc Magn Reson 2012 ; 14 : 27. Google Scholar CrossRef Search ADS PubMed 32 Wald RM , Valente AM , Gauvreau K , Babu-Narayan SV , Assenza GE , Schreier J et al. Cardiac magnetic resonance markers of progressive RV dilation and dysfunction after tetralogy of Fallot repair . Heart 2015 ; 101 : 1724 – 30 . Google Scholar CrossRef Search ADS PubMed 33 Valente AM , Cook S , Festa P , Ko HH , Krishnamurthy R , Taylor AM et al. Multimodality imaging guidelines for patients with repaired tetralogy of Fallot: a report from the AmericanSsociety of Echocardiography: developed in collaboration with the Society for Cardiovascular Magnetic Resonance and the Society for Pediatric Radiology . J Am Soc Echocardiogr 2014 ; 27 : 111 – 41 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. 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

The relationship between cardiovascular magnetic resonance imaging measurement of extracellular volume fraction and clinical outcomes in adults with repaired tetralogy of Fallot

Loading next page...
 
/lp/ou_press/the-relationship-between-cardiovascular-magnetic-resonance-imaging-sJLJxEHDKb
Publisher
Oxford University Press
Copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
ISSN
2047-2404
D.O.I.
10.1093/ehjci/jex248
Publisher site
See Article on Publisher Site

Abstract

Abstract Aims Our aims were to explore cardiac magnetic resonance quantification of myocardial extracellular volume (ECV) in adults with repaired tetralogy of Fallot (rTOF) when compared with healthy controls and to investigate the association between ECV and major adverse cardiovascular outcomes. Methods and results We prospectively recruited adults with rTOF (n = 44, 59% male, 32.9 ± 13.6 years) and evaluated right ventricular (RV) and left ventricular (LV) ECV by pre/post-gadolinium T1 measurements (modified Look–Locker inversion recovery technique) on a 1.5-T Siemens scanner compared with the healthy controls (n = 10, 50% male, 31.5 ± 4.4 years). The primary end point was a composite of death, out-of-hospital cardiac arrest, heart failure (HF) requiring admission for escalation of therapy, or haemodynamically significant ventricular tachycardia (VT) (lasting >30 s and/or resulting in invasive therapy). The association between ECV and adverse events was assessed using Cox proportional hazard models [median follow-up 236 days, interquartile range (IQR) 38–342]. RVECV was higher in patients compared with the controls (31.5 ± 5.4% vs. 26.3 ± 2.1%, P = 0.027). The following major adverse events occurred (n = 9, 21%): death (n = 1), out-of-hospital cardiac arrest (n = 1), HF (n = 1), and VT (n = 6). RVECV was higher among those with an adverse event compared to those without (35.0 ± 5.5% vs. 29.6 ± 4.5%, P = 0.014) and was associated with increased risk for adverse events [hazard ratio 1.13, 95% confidence interval (1.01–1.28); P = 0.037]. LVECV was not associated with adverse events (P = 0.667). Conclusion Increased RVECV is associated with adverse cardiovascular events in adults with rTOF. These results may lead to further studies exploring the potential role for RVECV in risk stratification and targeted therapeutic interventions in this population. cardiac MRI, T1 mapping, congenital heart disease, tetralogy of Fallot Introduction Cardiac magnetic resonance (CMR) imaging is routinely used in the evaluation of patients with repaired tetralogy of Fallot (rTOF).1 Segmental myocardial fibrosis is known to be present in rTOF based on histology and can be identified using CMR late gadolinium-enhanced (LGE) imaging.2,3 Myocardial fibrosis is associated with adverse cardiovascular outcomes and may be a substrate for arrhythmia including ventricular tachycardia (VT) in rTOF.4 However, LGE imaging may fail to characterize diffuse interstitial changes.5 CMR T1 mapping with calculation of the extracellular volume (ECV) fraction is an emerging technique that can be used for the evaluation of diffuse interstitial myocardial changes including fibrosis.6,7 The role of CMR for quantification of right ventricular (RV) extracellular volume (RVECV) measurements in relation to prediction of adverse outcomes in adults with rTOF has not been studied extensively. Although limited data are available on the predictive value of left ventricular (LV) ECV in those with rTOF, only two prior retrospective studies have investigated the differences in non-contrast and post-contrast T1 values of the RV in rTOF when compared with healthy controls.8–12 Furthermore, ECV assessment is particularly challenging in the thin-walled RV, given possible contamination by adjacent blood pool or epicardial fat. The aim of this study was to explore quantification of myocardial ECV in adults with rTOF when compared with healthy controls and to investigate the association between ECV and major adverse cardiovascular outcomes. Methods Study population From September 2014 to April 2017, patients with rTOF undergoing CMR were prospectively screened for study enrolment at the time of routine clinical evaluation at our institution. The study protocol was approved by the institutional research ethics board, and written informed consent was obtained from all subjects. Inclusion criteria for study subjects included age ≥18 years, history of rTOF, and clinically indicated referral for CMR with LGE. Subjects with contraindications to CMR with gadolinium were excluded. A reference healthy control cohort was identified, defined as volunteers without past medical history of cardiovascular disease based on history.13 CMR technique CMR studies were performed on a 1.5-T imager (Magnetom Avanto Fit; Siemens Healthcare, Erlangen, Germany). Retrospectively gated cine steady-state free precession (SSFP) images were obtained for assessment of ventricular volumes, mass, and systolic function by a stack of short-axis slices ensuring ventricular coverage (6–8 mm slice and 2 mm inter-slice gap). Among patients, ECG-gated, free-breathing cine phase-contrast flow measurements were obtained at the main pulmonary artery for assessment of pulmonary regurgitation (PR). Myocardial fibrosis was assessed using LGE imaging and modified Look–Locker inversion recovery (MOLLI) T1 mapping. Among patients, LGE imaging was performed approximately 10 min following administration of 10 mL gadobutrol (Gadovist; Bayer Healthcare, Berlin, Germany), employing a 2D inversion recovery gradient-recalled echo sequence (slice 6–8 mm and 2 mm inter-slice gap) with ventricular coverage in short-axis orientation. T1 mapping was performed pre-contrast and 12–15 min post-contrast in short-axis orientation at basal, mid, and apical slice locations (TI 120–4000 ms, flip angle 35°, field of view (FOV) 360 mm, matrix 256 × 192, and slice thickness 6 mm). Recommended MOLLI inversion groupings were used for optimized precision: pre-contrast (5(3)3) and post-contrast (4(1)3(1)2).14 The imaging technique used for healthy volunteers has been previously published.13 Haematocrit was determined from a venous blood sample following the CMR study. CMR analysis Evaluation of cardiac volumes, function, mass, and PR flow were performed using commercial software (QMASS MR, Medis Medical Imaging Systems, Leiden, The Netherlands). RV and LV endocardial and epicardial borders were contoured on SSFP images to assess for end-diastolic and end-systolic volumes, ejection fraction, and mass by a single experienced observer, blinded to patient outcomes, in a standardized fashion according to a previously published protocol.15 The presence of hinge-point and non-hinge-point ventricular LGE was qualitatively assessed by visual inspection of all available LGE images.2 We evaluated for RV LGE at the superior, anterior, and inferior RV walls and LV LGE with exclusion of regions expected to enhance (such as surgical material involved in patching of the RV outflow or ventricular septal defect closure). The interventricular septum was considered part of the LV. After inline, non-rigid motion correction of individual MOLLI images, an inline T1 map was generated using standard three-parameter fitting. Analysis was performed offline using commercial software (cvi42; Circle CVI, Calgary, Canada). All T1 maps were analysed by a single experienced observer (K.H., 5 years of cardiovascular imaging experience) blinded to clinical outcomes. Regions of interest (ROIs) were drawn manually in the LV blood pool with care taken to avoid the myocardium and papillary muscles. A single ROI was drawn in the thickest anterior or inferior RV segment at the basal or mid-ventricular level with a minimal ROI size of 0.15 cm2, avoiding regions with artefact or LGE and ensuring that neither blood pool nor epicardial fat was included within the contour (Figure 1).16 If an adequately sized ROI could not be drawn reliably within myocardium meeting these criteria, the T1 map was not included in the analysis. LV endocardial and epicardial borders were manually contoured on a single mid-ventricular slice avoiding regions with evidence of LGE. Myocardial RVECV and LVECV were calculated based on pre- and post-contrast T1 values and haematocrit, as proposed by Arheden et al.17 Elevated RVECV and LVECV were defined as 34% and 30%, respectively, based on prior published thresholds.7,16 Figure 1 View largeDownload slide Short-axis late gadolinium-enhanced image (a) and pre-contrast T1 map (b) in a 61-year-old male with repaired tetralogy of Fallot. On the T1 map, regions of interest were drawn in the right ventricular myocardium (blue ROI, white arrow), remote from areas of late gadolinium-enhanced in the right ventricular outflow tract (red arrow) and the inferior right ventricular insertion point (orange arrow). Contours were drawn along the left ventricular endocardial (red contour) and epicardial (green contour) surfaces with care taken to avoid areas of late gadolinium enhanced. Figure 1 View largeDownload slide Short-axis late gadolinium-enhanced image (a) and pre-contrast T1 map (b) in a 61-year-old male with repaired tetralogy of Fallot. On the T1 map, regions of interest were drawn in the right ventricular myocardium (blue ROI, white arrow), remote from areas of late gadolinium-enhanced in the right ventricular outflow tract (red arrow) and the inferior right ventricular insertion point (orange arrow). Contours were drawn along the left ventricular endocardial (red contour) and epicardial (green contour) surfaces with care taken to avoid areas of late gadolinium enhanced. To assess for inter-observer agreement of ECV values, 10 randomly selected pre- and post-contrast T1 maps were re-analysed by a second experienced imager (A.C., 15 years of cardiovascular imaging experience) who was blinded to patient identifying data and to the first set of measurements. To assess for intra-observer agreement of ECV measurements, 10 randomly selected pre- and post-contrast T1 maps were re-analysed by the first experienced imager after a minimum of 2 months interval, blinded to clinical outcomes and the first set of measurements. Clinical data Major adverse cardiovascular events were defined as a composite end point at the time of last follow-up including death, out-of-hospital cardiac arrest, heart failure (HF) requiring admission for escalation of therapy, and haemodynamically significant VT >30 s and/or requiring invasive therapy [ablation and/or automatic implantable cardiac defibrillator implantation (AICD)]. Patients without events were censored at the time of last clinical follow-up. Rhythm disturbances were identified by electrocardiogram (ECG), Holter monitoring, or other continuous rhythm recording. Only ECG, echocardiogram, and exercise tests closest to the time of CMR (within 6 months) were included. Patients underwent symptom-limited cardiopulmonary exercise testing as part of routine clinical care on a cycle ergometer (Elema, Solna, Sweden), with analysis of expiratory gases according to a previously published protocol.18 Statistical analysis Statistical analysis was performed using STATA v14.1 (StataCorp, College Station, TX, USA). All continuous data were first tested for normal distribution using the Shapiro–Wilk test. Continuous variables were described using mean and standard deviation or median and IQR, and categorical variables using numbers and percentage. Comparisons between patients and controls were made by t-test for continuous values with normal distribution and Mann–Whitney rank-sum test for continuous values with non-normal distribution. Categorical variables were compared using the χ2 or the Fisher’s exact test. Correlations between continuous variables were assessed with the Pearson’s or Spearman’s correlation coefficient. Inter-observer and intra-observer agreement was assessed via the intra-class correlation coefficient (ICC) with two-way random-effects model and coefficient of variance (COV). Cox proportional hazards analysis was used to obtain estimates of the hazard of the composite end point associated with CMR values. Adjustment for covariates in the model was limited by the number of adverse events observed. The proportionality of hazards over time was assessed by testing interactions between predictors and a continuous linear function of time. The linearity assumption was assessed for continuous variables with the addition of a quadratic term. Sensitivity analysis was performed, restricting the Cox proportional hazard analysis to patients without pulmonary valve replacement (PVR) at the time of enrolment. A two-tailed P-value <0.05 was considered statistically significant. Results Study population Forty-four patients (32.9 ± 13.6 years, 59% male) and 10 healthy controls (31.5 ± 4.4 years, 50% male) were studied. Baseline characteristics are summarized in Table 1. Patients did not differ significantly from healthy controls with respect to age, gender, body surface area, or haematocrit. Among patients, the median interval between TOF repair and CMR was 27 years (IQR 19–37 years). Median clinical follow-up duration was 236 days (IQR 38–342 days). Table 1 Baseline characteristics Characteristics Patients (n = 44) Healthy controls (n = 10) P-value Age at study entry (years) 32.9 ± 13.6 31.5 ± 4.4 0.749 Male 26 (59) 5 (50) 0.560 BSA (m2) 1.8 ± 0.2 1.9 ± 0.3 0.824 Haematocrit 0.419 ± 0.052 0.412 ± 0.030 0.671 TOF anatomy  TOF 42 (95)  TOF with absent pulmonary valve 2 (5) Age at TOF repair (months) 41 (IQR 18–87) Type of TOF repaira  Transannular patch 20 (57)  Valve sparing 11 (31)  RV–PA conduit 6 (16)  BT shunt preceding repair 14 (32) Pulmonary valve replacement 13 (30) Total number cardiac surgeries 2 (IQR 1-2) Echocardiography  RV pressure (mmHg) 36 ± 14  Peak RVOT–PA gradient (mmHg) 23 ± 17 ECG  QRS duration (ms) 152 ± 33 Exercise  Peak VO2 (cc/kg/min) 23.3 ± 4.9  Percent predicted peak VO2 (%) 68.1 ± 13.4  Percent predicted at AT (%) 43.8 ± 11.4  VE/VCO2 at AT 33.3 ± 4.7 Characteristics Patients (n = 44) Healthy controls (n = 10) P-value Age at study entry (years) 32.9 ± 13.6 31.5 ± 4.4 0.749 Male 26 (59) 5 (50) 0.560 BSA (m2) 1.8 ± 0.2 1.9 ± 0.3 0.824 Haematocrit 0.419 ± 0.052 0.412 ± 0.030 0.671 TOF anatomy  TOF 42 (95)  TOF with absent pulmonary valve 2 (5) Age at TOF repair (months) 41 (IQR 18–87) Type of TOF repaira  Transannular patch 20 (57)  Valve sparing 11 (31)  RV–PA conduit 6 (16)  BT shunt preceding repair 14 (32) Pulmonary valve replacement 13 (30) Total number cardiac surgeries 2 (IQR 1-2) Echocardiography  RV pressure (mmHg) 36 ± 14  Peak RVOT–PA gradient (mmHg) 23 ± 17 ECG  QRS duration (ms) 152 ± 33 Exercise  Peak VO2 (cc/kg/min) 23.3 ± 4.9  Percent predicted peak VO2 (%) 68.1 ± 13.4  Percent predicted at AT (%) 43.8 ± 11.4  VE/VCO2 at AT 33.3 ± 4.7 Data are represented as mean ± standard deviation, median and interquartile range, or n (%). a Unknown surgical history in nine subjects. AT, anaerobic threshold; BSA, body surface area; BT shunt, Blalock–Taussig shunt; ECG, electrocardiogram; PA, pulmonary artery; RV, right ventricle; RVOT, right ventricular outflow tract; TOF, tetralogy of Fallot. Table 1 Baseline characteristics Characteristics Patients (n = 44) Healthy controls (n = 10) P-value Age at study entry (years) 32.9 ± 13.6 31.5 ± 4.4 0.749 Male 26 (59) 5 (50) 0.560 BSA (m2) 1.8 ± 0.2 1.9 ± 0.3 0.824 Haematocrit 0.419 ± 0.052 0.412 ± 0.030 0.671 TOF anatomy  TOF 42 (95)  TOF with absent pulmonary valve 2 (5) Age at TOF repair (months) 41 (IQR 18–87) Type of TOF repaira  Transannular patch 20 (57)  Valve sparing 11 (31)  RV–PA conduit 6 (16)  BT shunt preceding repair 14 (32) Pulmonary valve replacement 13 (30) Total number cardiac surgeries 2 (IQR 1-2) Echocardiography  RV pressure (mmHg) 36 ± 14  Peak RVOT–PA gradient (mmHg) 23 ± 17 ECG  QRS duration (ms) 152 ± 33 Exercise  Peak VO2 (cc/kg/min) 23.3 ± 4.9  Percent predicted peak VO2 (%) 68.1 ± 13.4  Percent predicted at AT (%) 43.8 ± 11.4  VE/VCO2 at AT 33.3 ± 4.7 Characteristics Patients (n = 44) Healthy controls (n = 10) P-value Age at study entry (years) 32.9 ± 13.6 31.5 ± 4.4 0.749 Male 26 (59) 5 (50) 0.560 BSA (m2) 1.8 ± 0.2 1.9 ± 0.3 0.824 Haematocrit 0.419 ± 0.052 0.412 ± 0.030 0.671 TOF anatomy  TOF 42 (95)  TOF with absent pulmonary valve 2 (5) Age at TOF repair (months) 41 (IQR 18–87) Type of TOF repaira  Transannular patch 20 (57)  Valve sparing 11 (31)  RV–PA conduit 6 (16)  BT shunt preceding repair 14 (32) Pulmonary valve replacement 13 (30) Total number cardiac surgeries 2 (IQR 1-2) Echocardiography  RV pressure (mmHg) 36 ± 14  Peak RVOT–PA gradient (mmHg) 23 ± 17 ECG  QRS duration (ms) 152 ± 33 Exercise  Peak VO2 (cc/kg/min) 23.3 ± 4.9  Percent predicted peak VO2 (%) 68.1 ± 13.4  Percent predicted at AT (%) 43.8 ± 11.4  VE/VCO2 at AT 33.3 ± 4.7 Data are represented as mean ± standard deviation, median and interquartile range, or n (%). a Unknown surgical history in nine subjects. AT, anaerobic threshold; BSA, body surface area; BT shunt, Blalock–Taussig shunt; ECG, electrocardiogram; PA, pulmonary artery; RV, right ventricle; RVOT, right ventricular outflow tract; TOF, tetralogy of Fallot. CMR findings Baseline CMR findings are shown in Table 2. RV LGE was present in 19 patients. Non-hinge-point LV LGE was present in nine patients, while hinge-point LGE was present in 27 patients. Inability to draw a reliable myocardial ROI precluded ECV assessment in eight patients and five controls. Table 2 Cardiac MRI findings Measurement Patients (n = 44) Healthy controls (n = 10) P-value RVEDV (mL) 263.7 ± 93.9 194.4 ± 56.6 0.037 Indexed RVEDV (mL/m2) 142.7 ± 45.8 102.9 ± 15.8 0.004 RVESV (mL) 150.9 ± 72.6 91.2 ± 31.7 0.003 Indexed RVESV (mL/m2) 81.1 ± 35.0 48.2 ± 10.9 0.001 RVEF (%) 44.2 ± 8.2 53.5 ± 4.4 0.001 RV mass (g) 56.0 ± 17.3 40.6 ± 9.0 0.006 Indexed RV mass (g/m2) 30.4 ± 8.4 21.8 ± 2.5 0.001 RV mass to volume ratio 0.22 ± 0.03 0.21 ± 0.02 0.361 LVEDV (mL) 157.6 ± 42.8 189.0 ± 56.5 0.119 Indexed LVEDV (mL/m2) 85.0 ± 17.5 99.8 ± 15.3 0.021 LVESV (mL) 72.3 ± 25.0 76.4 ± 27.3 0.806 Indexed LVESV (mL/m2) 38.9 ± 10.8 40.1 ±  8.7 0.490 LVEF (%) 54.3 ± 5.7 60.1 ± 3.1 0.002 LV mass (g) 97.4 ± 30.0 81.9 ±  32.1 0.151 Indexed LV mass (g/m2) 52.1 ± 11.2 42.6  ± 10.4 0.018 LV mass to volume ratio 0.62 ± 0.11 0.42 ± 0.07 <0.001 Right atrial area (cm2) 21.6 ± 6.9 23.0 ± 5.1 0.360 Left atrial area (cm2) 16.9 ± 4.4 23.6 ± 4.4 0.001 Pulmonary regurgitation (mL) 33.5 ± 36.7 Pulmonary regurgitation (%) 25.7 ± 23.6 RV LGE 19 (48.7%) 0 (0%) 0.004 RV T1 pre-contrast (ms) 1062.3 ± 66.9 954.2 ± 177.7 0.011 RVECV* (%) 31.5 ± 5.4 26.3 ± 2.1 0.027 Increased RVECV (>34%) 9 (29.0%) 0 (0%) 0.004 LV LGE (non hinge-point) 9 (23.0%) 0 (0%) 0.098 LV T1 pre-contrast (ms) 1009.7 ± 42.2 980.3 ± 51.4 0.139 LVECVa (%) 25.4 ± 5.9 24.9 ± 4.0 0.941 Increased LVECV (>30%) 6 (15.4%) 0 (0%) 0.186 Measurement Patients (n = 44) Healthy controls (n = 10) P-value RVEDV (mL) 263.7 ± 93.9 194.4 ± 56.6 0.037 Indexed RVEDV (mL/m2) 142.7 ± 45.8 102.9 ± 15.8 0.004 RVESV (mL) 150.9 ± 72.6 91.2 ± 31.7 0.003 Indexed RVESV (mL/m2) 81.1 ± 35.0 48.2 ± 10.9 0.001 RVEF (%) 44.2 ± 8.2 53.5 ± 4.4 0.001 RV mass (g) 56.0 ± 17.3 40.6 ± 9.0 0.006 Indexed RV mass (g/m2) 30.4 ± 8.4 21.8 ± 2.5 0.001 RV mass to volume ratio 0.22 ± 0.03 0.21 ± 0.02 0.361 LVEDV (mL) 157.6 ± 42.8 189.0 ± 56.5 0.119 Indexed LVEDV (mL/m2) 85.0 ± 17.5 99.8 ± 15.3 0.021 LVESV (mL) 72.3 ± 25.0 76.4 ± 27.3 0.806 Indexed LVESV (mL/m2) 38.9 ± 10.8 40.1 ±  8.7 0.490 LVEF (%) 54.3 ± 5.7 60.1 ± 3.1 0.002 LV mass (g) 97.4 ± 30.0 81.9 ±  32.1 0.151 Indexed LV mass (g/m2) 52.1 ± 11.2 42.6  ± 10.4 0.018 LV mass to volume ratio 0.62 ± 0.11 0.42 ± 0.07 <0.001 Right atrial area (cm2) 21.6 ± 6.9 23.0 ± 5.1 0.360 Left atrial area (cm2) 16.9 ± 4.4 23.6 ± 4.4 0.001 Pulmonary regurgitation (mL) 33.5 ± 36.7 Pulmonary regurgitation (%) 25.7 ± 23.6 RV LGE 19 (48.7%) 0 (0%) 0.004 RV T1 pre-contrast (ms) 1062.3 ± 66.9 954.2 ± 177.7 0.011 RVECV* (%) 31.5 ± 5.4 26.3 ± 2.1 0.027 Increased RVECV (>34%) 9 (29.0%) 0 (0%) 0.004 LV LGE (non hinge-point) 9 (23.0%) 0 (0%) 0.098 LV T1 pre-contrast (ms) 1009.7 ± 42.2 980.3 ± 51.4 0.139 LVECVa (%) 25.4 ± 5.9 24.9 ± 4.0 0.941 Increased LVECV (>30%) 6 (15.4%) 0 (0%) 0.186 Data are represented as mean  ±  standard deviation or n (%). a Haematocrit was unavailable in five patients. ECV, extracellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LGE, late gadolinium enhancement; LV, left ventricle; RV, right ventricle. Bold values are significant (P-value <0.05). Table 2 Cardiac MRI findings Measurement Patients (n = 44) Healthy controls (n = 10) P-value RVEDV (mL) 263.7 ± 93.9 194.4 ± 56.6 0.037 Indexed RVEDV (mL/m2) 142.7 ± 45.8 102.9 ± 15.8 0.004 RVESV (mL) 150.9 ± 72.6 91.2 ± 31.7 0.003 Indexed RVESV (mL/m2) 81.1 ± 35.0 48.2 ± 10.9 0.001 RVEF (%) 44.2 ± 8.2 53.5 ± 4.4 0.001 RV mass (g) 56.0 ± 17.3 40.6 ± 9.0 0.006 Indexed RV mass (g/m2) 30.4 ± 8.4 21.8 ± 2.5 0.001 RV mass to volume ratio 0.22 ± 0.03 0.21 ± 0.02 0.361 LVEDV (mL) 157.6 ± 42.8 189.0 ± 56.5 0.119 Indexed LVEDV (mL/m2) 85.0 ± 17.5 99.8 ± 15.3 0.021 LVESV (mL) 72.3 ± 25.0 76.4 ± 27.3 0.806 Indexed LVESV (mL/m2) 38.9 ± 10.8 40.1 ±  8.7 0.490 LVEF (%) 54.3 ± 5.7 60.1 ± 3.1 0.002 LV mass (g) 97.4 ± 30.0 81.9 ±  32.1 0.151 Indexed LV mass (g/m2) 52.1 ± 11.2 42.6  ± 10.4 0.018 LV mass to volume ratio 0.62 ± 0.11 0.42 ± 0.07 <0.001 Right atrial area (cm2) 21.6 ± 6.9 23.0 ± 5.1 0.360 Left atrial area (cm2) 16.9 ± 4.4 23.6 ± 4.4 0.001 Pulmonary regurgitation (mL) 33.5 ± 36.7 Pulmonary regurgitation (%) 25.7 ± 23.6 RV LGE 19 (48.7%) 0 (0%) 0.004 RV T1 pre-contrast (ms) 1062.3 ± 66.9 954.2 ± 177.7 0.011 RVECV* (%) 31.5 ± 5.4 26.3 ± 2.1 0.027 Increased RVECV (>34%) 9 (29.0%) 0 (0%) 0.004 LV LGE (non hinge-point) 9 (23.0%) 0 (0%) 0.098 LV T1 pre-contrast (ms) 1009.7 ± 42.2 980.3 ± 51.4 0.139 LVECVa (%) 25.4 ± 5.9 24.9 ± 4.0 0.941 Increased LVECV (>30%) 6 (15.4%) 0 (0%) 0.186 Measurement Patients (n = 44) Healthy controls (n = 10) P-value RVEDV (mL) 263.7 ± 93.9 194.4 ± 56.6 0.037 Indexed RVEDV (mL/m2) 142.7 ± 45.8 102.9 ± 15.8 0.004 RVESV (mL) 150.9 ± 72.6 91.2 ± 31.7 0.003 Indexed RVESV (mL/m2) 81.1 ± 35.0 48.2 ± 10.9 0.001 RVEF (%) 44.2 ± 8.2 53.5 ± 4.4 0.001 RV mass (g) 56.0 ± 17.3 40.6 ± 9.0 0.006 Indexed RV mass (g/m2) 30.4 ± 8.4 21.8 ± 2.5 0.001 RV mass to volume ratio 0.22 ± 0.03 0.21 ± 0.02 0.361 LVEDV (mL) 157.6 ± 42.8 189.0 ± 56.5 0.119 Indexed LVEDV (mL/m2) 85.0 ± 17.5 99.8 ± 15.3 0.021 LVESV (mL) 72.3 ± 25.0 76.4 ± 27.3 0.806 Indexed LVESV (mL/m2) 38.9 ± 10.8 40.1 ±  8.7 0.490 LVEF (%) 54.3 ± 5.7 60.1 ± 3.1 0.002 LV mass (g) 97.4 ± 30.0 81.9 ±  32.1 0.151 Indexed LV mass (g/m2) 52.1 ± 11.2 42.6  ± 10.4 0.018 LV mass to volume ratio 0.62 ± 0.11 0.42 ± 0.07 <0.001 Right atrial area (cm2) 21.6 ± 6.9 23.0 ± 5.1 0.360 Left atrial area (cm2) 16.9 ± 4.4 23.6 ± 4.4 0.001 Pulmonary regurgitation (mL) 33.5 ± 36.7 Pulmonary regurgitation (%) 25.7 ± 23.6 RV LGE 19 (48.7%) 0 (0%) 0.004 RV T1 pre-contrast (ms) 1062.3 ± 66.9 954.2 ± 177.7 0.011 RVECV* (%) 31.5 ± 5.4 26.3 ± 2.1 0.027 Increased RVECV (>34%) 9 (29.0%) 0 (0%) 0.004 LV LGE (non hinge-point) 9 (23.0%) 0 (0%) 0.098 LV T1 pre-contrast (ms) 1009.7 ± 42.2 980.3 ± 51.4 0.139 LVECVa (%) 25.4 ± 5.9 24.9 ± 4.0 0.941 Increased LVECV (>30%) 6 (15.4%) 0 (0%) 0.186 Data are represented as mean  ±  standard deviation or n (%). a Haematocrit was unavailable in five patients. ECV, extracellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LGE, late gadolinium enhancement; LV, left ventricle; RV, right ventricle. Bold values are significant (P-value <0.05). Mean pre-contrast RV T1 and RVECV values were significantly higher in patients compared with the controls (1062.3 ± 66.9 ms vs. 954.2 ± 177.7 ms, P = 0.011 and 31.5 ± 5.4% vs. 26.3 ± 2.1%, P = 0.027, respectively), although pre-contrast LV T1 and LVECV values did not differ significantly (P = 0.139 and P = 0.941, respectively). RVECV was significantly higher than LVECV (P < 0.001). Six (15%) patients had increased LVECV and 9 (29%) patients had elevated RVECV. Correlations between RVECV and LVECV, respectively, with clinical parameters and CMR measurements are shown in Table 3. Among patients with rTOF, RVECV was found to have a positive correlation of moderate strength with RVEDV (absolute and indexed), with RVESV (absolute and indexed) and with indexed RV mass, respectively. RVECV has a negative correlation of moderate strength with RVEF. Clinical parameters did not correlate significantly with either RVECV or LVECV. Table 3 RVECV and LVECV correlations Characteristics RVECV LVECV r-value P-value r-value P-value Age at study entry (years) 0.139 0.418 −0.229 0.114 Age at TOF repair (years) −0.010 0.957 −0.067 0.686 Echocardiography  RV pressure (mmHg) −0.233 0.252 −0.051 0.782  Peak RVOT–PA gradient (mmHg) −0.252 0.172 0.053 0.749 ECG  QRS duration (ms) 0.254 0.168 −0.285 0.079 Exercise  Peak VO2 (cc/kg/min) 0.399 0.066 −0.158 0.413  Percent predicted peak VO2 (%) 0.290 0.191 −0.211 0.272  Percent predicted at AT (%) −0.006 0.979 −0.202 0.312  VE/VCO2 at AT −0.099 0.686 0.102 0.629 CMR  RVEDV (mL) 0.364 0.029 −0.096 0.514  Indexed RVEDV (mL/m2) 0.360 0.031 −0.028 0.847  RVESV (mL) 0.435 0.008 −0.045 0.762  Indexed RVESV (mL/m2) 0.427 0.010 −0.018 0.923  RVEF (%) −0.386 0.020 0.081 0.582  RV mass (g) 0.367 0.028 −0.026 0.857  Indexed RV mass (g/m2) 0.369 0.027 0.061 0.680  RV mass-to-volume ratio −0.014 0.935 0.163 0.262  LVEDV (mL) 0.125 0.394 −0.125 0.394  Indexed LVEDV (mL/m2) 0.103 0.548 −0.019 0.898  LVESV (mL) 0.192 0.261 −0.054 0.711  Indexed LVESV (mL/m2) 0.214 0.210 0.035 0.813  LVEF (%) −0.213 0.212 −0.023 0.875  LV mass (g) 0.136 0.428 −0.158 0.278  Indexed LV mass (g/m2) 0.200 0.244 −0.097 0.506  LV mass to volume ratio 0.115 0.505 −0.154 0.292  Right atrial area (cm2) −0.003 0.986 −0.022 0.883  Left atrial area (cm2) 0.027 0.6875 0.086 0.556  Pulmonary regurgitation (mL) −0.026 0.893 −0.062 0.713  Pulmonary regurgitation (%) −0.094 0.647 0.022 0.895 Characteristics RVECV LVECV r-value P-value r-value P-value Age at study entry (years) 0.139 0.418 −0.229 0.114 Age at TOF repair (years) −0.010 0.957 −0.067 0.686 Echocardiography  RV pressure (mmHg) −0.233 0.252 −0.051 0.782  Peak RVOT–PA gradient (mmHg) −0.252 0.172 0.053 0.749 ECG  QRS duration (ms) 0.254 0.168 −0.285 0.079 Exercise  Peak VO2 (cc/kg/min) 0.399 0.066 −0.158 0.413  Percent predicted peak VO2 (%) 0.290 0.191 −0.211 0.272  Percent predicted at AT (%) −0.006 0.979 −0.202 0.312  VE/VCO2 at AT −0.099 0.686 0.102 0.629 CMR  RVEDV (mL) 0.364 0.029 −0.096 0.514  Indexed RVEDV (mL/m2) 0.360 0.031 −0.028 0.847  RVESV (mL) 0.435 0.008 −0.045 0.762  Indexed RVESV (mL/m2) 0.427 0.010 −0.018 0.923  RVEF (%) −0.386 0.020 0.081 0.582  RV mass (g) 0.367 0.028 −0.026 0.857  Indexed RV mass (g/m2) 0.369 0.027 0.061 0.680  RV mass-to-volume ratio −0.014 0.935 0.163 0.262  LVEDV (mL) 0.125 0.394 −0.125 0.394  Indexed LVEDV (mL/m2) 0.103 0.548 −0.019 0.898  LVESV (mL) 0.192 0.261 −0.054 0.711  Indexed LVESV (mL/m2) 0.214 0.210 0.035 0.813  LVEF (%) −0.213 0.212 −0.023 0.875  LV mass (g) 0.136 0.428 −0.158 0.278  Indexed LV mass (g/m2) 0.200 0.244 −0.097 0.506  LV mass to volume ratio 0.115 0.505 −0.154 0.292  Right atrial area (cm2) −0.003 0.986 −0.022 0.883  Left atrial area (cm2) 0.027 0.6875 0.086 0.556  Pulmonary regurgitation (mL) −0.026 0.893 −0.062 0.713  Pulmonary regurgitation (%) −0.094 0.647 0.022 0.895 AT, anaerobic threshold; ECG, electrocardiogram; ECV, extra-cellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LGE, late gadolinium enhancement; LV, left ventricle; PA, pulmonary artery; RV, right ventricle; RVOT, right ventricular outflow tract. Table 3 RVECV and LVECV correlations Characteristics RVECV LVECV r-value P-value r-value P-value Age at study entry (years) 0.139 0.418 −0.229 0.114 Age at TOF repair (years) −0.010 0.957 −0.067 0.686 Echocardiography  RV pressure (mmHg) −0.233 0.252 −0.051 0.782  Peak RVOT–PA gradient (mmHg) −0.252 0.172 0.053 0.749 ECG  QRS duration (ms) 0.254 0.168 −0.285 0.079 Exercise  Peak VO2 (cc/kg/min) 0.399 0.066 −0.158 0.413  Percent predicted peak VO2 (%) 0.290 0.191 −0.211 0.272  Percent predicted at AT (%) −0.006 0.979 −0.202 0.312  VE/VCO2 at AT −0.099 0.686 0.102 0.629 CMR  RVEDV (mL) 0.364 0.029 −0.096 0.514  Indexed RVEDV (mL/m2) 0.360 0.031 −0.028 0.847  RVESV (mL) 0.435 0.008 −0.045 0.762  Indexed RVESV (mL/m2) 0.427 0.010 −0.018 0.923  RVEF (%) −0.386 0.020 0.081 0.582  RV mass (g) 0.367 0.028 −0.026 0.857  Indexed RV mass (g/m2) 0.369 0.027 0.061 0.680  RV mass-to-volume ratio −0.014 0.935 0.163 0.262  LVEDV (mL) 0.125 0.394 −0.125 0.394  Indexed LVEDV (mL/m2) 0.103 0.548 −0.019 0.898  LVESV (mL) 0.192 0.261 −0.054 0.711  Indexed LVESV (mL/m2) 0.214 0.210 0.035 0.813  LVEF (%) −0.213 0.212 −0.023 0.875  LV mass (g) 0.136 0.428 −0.158 0.278  Indexed LV mass (g/m2) 0.200 0.244 −0.097 0.506  LV mass to volume ratio 0.115 0.505 −0.154 0.292  Right atrial area (cm2) −0.003 0.986 −0.022 0.883  Left atrial area (cm2) 0.027 0.6875 0.086 0.556  Pulmonary regurgitation (mL) −0.026 0.893 −0.062 0.713  Pulmonary regurgitation (%) −0.094 0.647 0.022 0.895 Characteristics RVECV LVECV r-value P-value r-value P-value Age at study entry (years) 0.139 0.418 −0.229 0.114 Age at TOF repair (years) −0.010 0.957 −0.067 0.686 Echocardiography  RV pressure (mmHg) −0.233 0.252 −0.051 0.782  Peak RVOT–PA gradient (mmHg) −0.252 0.172 0.053 0.749 ECG  QRS duration (ms) 0.254 0.168 −0.285 0.079 Exercise  Peak VO2 (cc/kg/min) 0.399 0.066 −0.158 0.413  Percent predicted peak VO2 (%) 0.290 0.191 −0.211 0.272  Percent predicted at AT (%) −0.006 0.979 −0.202 0.312  VE/VCO2 at AT −0.099 0.686 0.102 0.629 CMR  RVEDV (mL) 0.364 0.029 −0.096 0.514  Indexed RVEDV (mL/m2) 0.360 0.031 −0.028 0.847  RVESV (mL) 0.435 0.008 −0.045 0.762  Indexed RVESV (mL/m2) 0.427 0.010 −0.018 0.923  RVEF (%) −0.386 0.020 0.081 0.582  RV mass (g) 0.367 0.028 −0.026 0.857  Indexed RV mass (g/m2) 0.369 0.027 0.061 0.680  RV mass-to-volume ratio −0.014 0.935 0.163 0.262  LVEDV (mL) 0.125 0.394 −0.125 0.394  Indexed LVEDV (mL/m2) 0.103 0.548 −0.019 0.898  LVESV (mL) 0.192 0.261 −0.054 0.711  Indexed LVESV (mL/m2) 0.214 0.210 0.035 0.813  LVEF (%) −0.213 0.212 −0.023 0.875  LV mass (g) 0.136 0.428 −0.158 0.278  Indexed LV mass (g/m2) 0.200 0.244 −0.097 0.506  LV mass to volume ratio 0.115 0.505 −0.154 0.292  Right atrial area (cm2) −0.003 0.986 −0.022 0.883  Left atrial area (cm2) 0.027 0.6875 0.086 0.556  Pulmonary regurgitation (mL) −0.026 0.893 −0.062 0.713  Pulmonary regurgitation (%) −0.094 0.647 0.022 0.895 AT, anaerobic threshold; ECG, electrocardiogram; ECV, extra-cellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LGE, late gadolinium enhancement; LV, left ventricle; PA, pulmonary artery; RV, right ventricle; RVOT, right ventricular outflow tract. Adverse outcomes A major adverse cardiovascular event occurred in nine (21%) patients: death (n = 1), out-of-hospital cardiac arrest (n = 1), HF (n = 1), and VT (n = 6). Death occurred in one patient unexpectedly <30 days following PVR. The patient with the out-of-hospital cardiac arrest ultimately went on to PVR and device implantation. The patient admitted for escalation of HF therapy subsequently received a device with resynchronization and defibrillation capacities. Documented VT occurred in six patients (sustained VT >30 s in five patients; one patient had recurrent, haemodynamically destabilizing non-sustained VT resulting in AICD implantation); five of these patients went on to AICD implantation and one was found to be non-inducible following preoperative mapping and intraoperative ablation. In patients with a major adverse cardiac event, RVECV was significantly elevated when compared with those without an adverse event (35.0 ± 5.5% vs. 29.6 ± 4.5%, P = 0.014). On univariable analysis to evaluate the relationship between CMR measurements and clinical outcomes (Table 4), RVECV was associated with increased risk for the composite end point [hazard ratio (HR) 1.13, 95% confidence interval (CI) (1.01–1.28), P = 0.037]. After the analysis was restricted to patients without PVR at study entry, the association remained statistically significant between RVECV and adverse outcomes [seven events, HR 1.17, 95% CI (1.01–1.36), P = 0.038]. Indexed measures of RV volumes, indexed RV mass, and RVEF were also associated with the composite end point, whereas LVECV, indexed LV volumes, and LV systolic function were not (Table 4). Table 4 Univariable model examining the association between CMR measurements and major adverse cardiovascular outcomesa Finding HR 95% CI P-value Indexed RVEDV (mL/m2) 1.02 1.01–1.03 0.002 Indexed RVESV (mL/m2) 1.02 1.01–1.04 0.001 RVEF (%) 0.90 0.84–0.96 0.002 Indexed RV mass (g/m2) 1.15 1.06–1.24 0.001 RV mass-to-volume ratio (%) 0.95 0.78–1.15 0.604 Indexed LVEDV (mL/m2) 1.01 0.97–1.04 0.738 Indexed LVESV (mL/m2) 1.02 0.97–1.08 0.459 LVEF (%) 0.94 0.84–1.05 0.258 Indexed LV mass (g/m2) 1.05 1.01–1.10 0.008 Right atrial area (cm2) 1.05 0.97–1.14 0.235 Left atrial area (cm2) 1.11 1.02–1.55 0.092 Pulmonary regurgitation (mL) 1.01 0.99–1.03 0.114 Pulmonary regurgitation (%) 1.02 0.99–1.05 0.286 RV LGE 7.36 0.90–60.2 0.063 RV T1 pre-contrast (ms) 1.01 1.00–1.02 0.079 RVECV (%) 1.13 1.01–1.28 0.037 Elevated RVECV (>34%) 2.19 0.58–8.18 0.245 LV LGE (non-hinge point) 4.63 1.03–20.72 0.045 LV T1 pre-contrast (ms) 1.00 0.99–1.02 0.891 LVECV (%) 0.97 0.84–1.11 0.667 Elevated LVECV (>30%) 0.39 0.04–3.68 0.413 Finding HR 95% CI P-value Indexed RVEDV (mL/m2) 1.02 1.01–1.03 0.002 Indexed RVESV (mL/m2) 1.02 1.01–1.04 0.001 RVEF (%) 0.90 0.84–0.96 0.002 Indexed RV mass (g/m2) 1.15 1.06–1.24 0.001 RV mass-to-volume ratio (%) 0.95 0.78–1.15 0.604 Indexed LVEDV (mL/m2) 1.01 0.97–1.04 0.738 Indexed LVESV (mL/m2) 1.02 0.97–1.08 0.459 LVEF (%) 0.94 0.84–1.05 0.258 Indexed LV mass (g/m2) 1.05 1.01–1.10 0.008 Right atrial area (cm2) 1.05 0.97–1.14 0.235 Left atrial area (cm2) 1.11 1.02–1.55 0.092 Pulmonary regurgitation (mL) 1.01 0.99–1.03 0.114 Pulmonary regurgitation (%) 1.02 0.99–1.05 0.286 RV LGE 7.36 0.90–60.2 0.063 RV T1 pre-contrast (ms) 1.01 1.00–1.02 0.079 RVECV (%) 1.13 1.01–1.28 0.037 Elevated RVECV (>34%) 2.19 0.58–8.18 0.245 LV LGE (non-hinge point) 4.63 1.03–20.72 0.045 LV T1 pre-contrast (ms) 1.00 0.99–1.02 0.891 LVECV (%) 0.97 0.84–1.11 0.667 Elevated LVECV (>30%) 0.39 0.04–3.68 0.413 a Composite of death, out-of-hospital cardiac arrest, heart failure requiring admission for escalation of therapy, or haemodynamic destabilizing ventricular tachycardia (lasting >30 s and/or requiring invasive therapy) by the time of last follow-up. CI, confidence interval; ECV, extracellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LV, left ventricle; RV, right ventricle; HR, hazard ratio; RVOT, right ventricular outflow tract. Table 4 Univariable model examining the association between CMR measurements and major adverse cardiovascular outcomesa Finding HR 95% CI P-value Indexed RVEDV (mL/m2) 1.02 1.01–1.03 0.002 Indexed RVESV (mL/m2) 1.02 1.01–1.04 0.001 RVEF (%) 0.90 0.84–0.96 0.002 Indexed RV mass (g/m2) 1.15 1.06–1.24 0.001 RV mass-to-volume ratio (%) 0.95 0.78–1.15 0.604 Indexed LVEDV (mL/m2) 1.01 0.97–1.04 0.738 Indexed LVESV (mL/m2) 1.02 0.97–1.08 0.459 LVEF (%) 0.94 0.84–1.05 0.258 Indexed LV mass (g/m2) 1.05 1.01–1.10 0.008 Right atrial area (cm2) 1.05 0.97–1.14 0.235 Left atrial area (cm2) 1.11 1.02–1.55 0.092 Pulmonary regurgitation (mL) 1.01 0.99–1.03 0.114 Pulmonary regurgitation (%) 1.02 0.99–1.05 0.286 RV LGE 7.36 0.90–60.2 0.063 RV T1 pre-contrast (ms) 1.01 1.00–1.02 0.079 RVECV (%) 1.13 1.01–1.28 0.037 Elevated RVECV (>34%) 2.19 0.58–8.18 0.245 LV LGE (non-hinge point) 4.63 1.03–20.72 0.045 LV T1 pre-contrast (ms) 1.00 0.99–1.02 0.891 LVECV (%) 0.97 0.84–1.11 0.667 Elevated LVECV (>30%) 0.39 0.04–3.68 0.413 Finding HR 95% CI P-value Indexed RVEDV (mL/m2) 1.02 1.01–1.03 0.002 Indexed RVESV (mL/m2) 1.02 1.01–1.04 0.001 RVEF (%) 0.90 0.84–0.96 0.002 Indexed RV mass (g/m2) 1.15 1.06–1.24 0.001 RV mass-to-volume ratio (%) 0.95 0.78–1.15 0.604 Indexed LVEDV (mL/m2) 1.01 0.97–1.04 0.738 Indexed LVESV (mL/m2) 1.02 0.97–1.08 0.459 LVEF (%) 0.94 0.84–1.05 0.258 Indexed LV mass (g/m2) 1.05 1.01–1.10 0.008 Right atrial area (cm2) 1.05 0.97–1.14 0.235 Left atrial area (cm2) 1.11 1.02–1.55 0.092 Pulmonary regurgitation (mL) 1.01 0.99–1.03 0.114 Pulmonary regurgitation (%) 1.02 0.99–1.05 0.286 RV LGE 7.36 0.90–60.2 0.063 RV T1 pre-contrast (ms) 1.01 1.00–1.02 0.079 RVECV (%) 1.13 1.01–1.28 0.037 Elevated RVECV (>34%) 2.19 0.58–8.18 0.245 LV LGE (non-hinge point) 4.63 1.03–20.72 0.045 LV T1 pre-contrast (ms) 1.00 0.99–1.02 0.891 LVECV (%) 0.97 0.84–1.11 0.667 Elevated LVECV (>30%) 0.39 0.04–3.68 0.413 a Composite of death, out-of-hospital cardiac arrest, heart failure requiring admission for escalation of therapy, or haemodynamic destabilizing ventricular tachycardia (lasting >30 s and/or requiring invasive therapy) by the time of last follow-up. CI, confidence interval; ECV, extracellular volume fraction; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LV, left ventricle; RV, right ventricle; HR, hazard ratio; RVOT, right ventricular outflow tract. Inter- and intra-observer agreement Inter-observer agreement was good for RVECV [ICC 0.834, 95% CI (0.086–0.963); COV 9.4%, 95% CI (7.6–10.9%)] and LVECV [ICC 0.938, 95% CI (0.729–0.985); COV 4.8%, 95% CI (4.4–5.2%)]. Intra-observer agreement was good for RVECV [ICC 0.864, 95% CI (0.485–0.966); COV 8.4%, 95% CI (6.7–9.9%)] and LVECV [ICC 0.949, 95% CI (0.780–0.988); COV 3.8%, 95% CI (3.5–4.2%)]. Discussion This prospective study is the first to demonstrate that increased RVECV is associated with major adverse cardiovascular events in adults with rTOF. When considering a surrogate marker of diffuse fibrosis, RVECV was elevated in 29% of this study population, suggesting that remodelling at the tissue level may be associated with adverse clinical outcomes. We found that the hazard of major adverse cardiovascular events increased by 13% for every 1% absolute increase in RVECV. Only three prior studies have reported RV T1 and ECV values in rTOF, all in a retrospective fashion (see Supplementary data online, Table S1). Kozak et al.10 reported that post-contrast RV and LV T1 values were lower in children with rTOF compared with the healthy controls. Post-contrast T1 values were shorter in the RV compared with the LV, suggesting a higher RV fibrotic burden. Unlike our study, they were not able to calculate ECV values due to absent pre-contrast T1 measurements and haematocrit values, and they did not explore associations with clinical outcomes. Chen et al.18 measured RVECV retrospectively in a cohort of children and young adults with rTOF. RVECV was significantly higher in patients compared with the controls, but RVECV was not associated with arrhythmia.18 In this study, RVECV values were slightly higher in TOF patients (34.2 ± 5.6%) and healthy controls (28.4 ± 6.3%) compared with our results (31.5 ± 5.4% and 26.3 ± 2.1%, respectively), which may be due to differences in technique.19 We employed a strict minimum ROI size for RV T1 mapping analysis, resulting in exclusion of some cases but in doing so minimizing the potential for erroneously high ECV if adjacent structures were inadvertently included in the RV myocardial ROI. The same authors reported that increased LVECV in rTOF was associated with arrhythmia.18 The definition of arrhythmia in this study was more encompassing than ours, including a variety of atrial arrhythmias, ventricular ectopy, and non-sustained arrhythmia (atrial or ventricular), which did not necessarily result in escalation of therapy. In contrast, our definition of arrhythmia was restricted to haemodynamically significant VT resulting in invasive therapies, including AICD implantation, and/or surgical ablation. Yim et al.8 reported that non-contrast RV T1 values are elevated in children with rTOF and were associated with longer cross-clamp times at surgery. However, they evaluated neither RVECV nor the relationship to major adverse events. Additional reports examined LVECV values in patients with rTOF9,11,18 with conflicting results, possibly related to differences in ages of the populations studied. While Riesenkampff et al.11 reported no significant difference in LV non-contrast T1 and LVECV values between children with rTOF and healthy controls, Broberg et al.9 reported that LVECV was higher in older adults with rTOF compared with the controls. In the latter study, those with increased LVECV were more likely to develop adverse events (specifically new atrial arrhythmias and cardiovascular death). The relatively young age of our adult population, the length of follow-up, a more restrictive definition of adverse outcomes, and differences in imaging technique may explain, at least in part, the lack of association between LVECV and the composite outcome in our study. Notably, previous publications have not demonstrated the association between RVECV and development of major adverse cardiovascular events in adults with rTOF, which is a strength of this study. We demonstrate that RVECV may be a predictor of major adverse events, despite our modest sample size. The principal novel findings to emerge from our study include the following: RVECV increases the hazard of major adverse cardiovascular events in adults with rTOF. RVECV correlates positively with both RVEDV (absolute and indexed) and RV mass (indexed). In line with previous studies, we found an association between RV volumes, mass, and systolic function with major adverse outcomes in the rTOF population.20,21 Increasingly, research efforts are focusing on what causes or mediates late onset of complications in adults with rTOF. Adverse events, including VT, HF, and sudden death, are seen with increasing frequency with advancing age, despite successful repair in early childhood.22 Identification of non-invasive imaging markers of poor outcome are highly desirable, and standard CMR measurements of ventricular size, function, and mass have been linked to clinical compromise in a growing body of publications.20,21 CMR-derived ECV has been shown to correlate with histological myocardial fibrosis in other conditions and has been associated with adverse events including death and HF in non-congenital populations.23,24 RV non-contrast T1 and ECV values are elevated in patients without congenital heart disease (CHD) in the setting of RV dysfunction and pulmonary hypertension25–28 and correlate with pulmonary haemodynamics, RV arterial coupling, and RV function.29 In our study, RVECV values are higher compared with LVECV values, which may be explained by higher collagen content and fibrosis of the RV.26,30 This finding is concordant with the results of prior studies.10,18 Increased RVECV has been proposed to reflect cardiomyocyte atrophy/death with expansion of the extracellular extravascular space and is expected to be a diffuse process.18 In comparison with the LV, the thin-walled RV presents unique imaging challenges. Although our methodology for RV assessment focused on sampling myocardial regions of greatest hypertrophy for assessment of diffuse fibrosis, more extensive study of the RV may yield higher fidelity results. Several techniques have been proposed to improve T1 quantification of the RV, including imaging in systole rather than diastole, and newer higher spatial resolution sequences.10,26,27,31 The results of a recent study indicate that RV T1 maps could be evaluated successfully in approximately half of the healthy controls and a larger proportion of patients with CHD, similar to our findings.16 They report that RVECV can be assessed with T1 mapping, provided that the image quality allows for sufficient distinction between blood and myocardium and RV wall thickness is >one pixel and conclude that under these conditions RVECV measurements can be integrated into clinical practice in CHD.16 In our analysis, a minimum RV myocardial ROI size of 0.15 cm2 was required (>one pixel) for inclusion, and T1 maps with insufficient distinction between blood and myocardium were not analysed (18% of rTOF and 50% of controls), in keeping with these recommendations. Furthermore, it is important to remember that generation of T1 maps requires exact co-registration of individual pixels and inconsistency in this process may further introduce error. Myocardial fibrosis in patients with TOF can be attributed to a variety of factors prior to repair (such as duration of cyanosis and exposure to pressure overload), during repair (including myocardial protection strategies and intraoperative technique), and following repair (specifically advancing age and adaptation of the ventricle to chronic volume/pressure overload). Our data demonstrate a relationship between various CMR measures, including RVECV, increased RV volume, and increased RV mass, with outcomes, underscoring a multifactorial process that likely contributes to major adverse clinical events. These observations lend support to the postulate that chronic haemodynamic sequelae following initial repair can trigger development of RV fibrosis, which may potentially mediate development of late electrical and/or mechanical complications in adults with rTOF. The results of this study have several potential clinical implications with respect to prognosis and management. Myocardial fibrosis could be a potential target for pharmacological intervention with antifibrotic agents. Non-invasive imaging with CMR with detection of myocardial fibrosis could allow for more refined timing of interventions such as PVR. A better understanding of how ECV may improve the discrimination of traditional risk factors, such as QRS duration on ECG, RV size, and ejection fraction is highly desirable, although beyond the scope of our study. Limitations This study is primarily limited by the relatively small number of subjects and modest total number of adverse events. A multivariable model could not be developed with the number of patient outcomes observed, and therefore, the value of RVECV over other clinical and imaging parameters could not be determined. The cohort of patients studied does not reflect the entire spectrum of adult patients with rTOF, as patients unsuitable for CMR assessment with gadolinium were excluded. There is a potential referral bias as clinicians may refer sicker patients for CMR, although this is mitigated by the fact that CMR is used for routine clinical surveillance (typically every 2–3 years) in this population,15,32,33 and the fact that patients with AICD/pacemakers were excluded. Although care was taken to draw ROIs in the RV myocardium only, partial volume averaging and contamination of T1 values from the inadvertent inclusion of blood pool or epicardial fat are potential pitfalls, which could result in artificially high ECV values, despite the relatively stringent methodology for contour definition employed. Conclusion Increased RVECV is associated with major adverse cardiovascular events in adults with rTOF. If myocardial fibrosis plays a role in mediating adverse outcomes, this could be a potential target for future pharmacological therapies and may allow for more refined timing of intervention. The results of this study may lead to future larger studies exploring the potential role for RVECV in risk stratification within the adult population with rTOF. Supplementary material Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Conflict of interest: none declared. Funding Radiological Society of North America Research Scholar Grant (RSCH1608 to K.H.); Canadian Institutes of Health Research Operating Grant (MOP 119353 to R.W.); and Canadian Institutes of Health Research New Investigator Award (FRN 147814 to D.T.). References 1 Kilner PJ , Geva T , Kaemmerer H , Trindade PT , Schwitter J , Webb GD. Recommendations for cardiovascular magnetic resonance in adults with congenital heart disease from the respective working groups of the European Society of Cardiology . Eur Heart J 2010 ; 31 : 794 – 805 . Google Scholar CrossRef Search ADS PubMed 2 Babu-Narayan SV , Kilner PJ , Li W , Moon JC , Goktekin O , Davlouros PA et al. Ventricular fibrosis suggested by cardiovascular magnetic resonance in adults with repaired tetralogy of Fallot and its relationship to adverse markers of clinical outcome . Circulation 2006 ; 113 : 405 – 13 . Google Scholar CrossRef Search ADS PubMed 3 Wald RM , Haber I , Wald R , Valente AM , Powell AJ , Geva T. Effects of regional dysfunction and late gadolinium enhancement on global right ventricular function and exercise capacity in patients with repaired tetralogy of Fallot . Circulation 2009 ; 119 : 1370 – 7 . Google Scholar CrossRef Search ADS PubMed 4 Chaudhry A , Biederman RW , Candia R , Reddy S , Williams RW , Yamrozik J et al. Ventricular tachycardia and right ventricular fibrosis after tetralogy of fallot surgical repair . Circulation 2013 ; 128 : 185 – 7 . Google Scholar CrossRef Search ADS PubMed 5 Ide S , Riesenkampff E , Chiasson DA , Dipchand AI , Kantor PF , Chaturvedi RR et al. Histological validation of cardiovascular magnetic resonance T1 mapping markers of myocardial fibrosis in paediatric heart transplant recipients . J Cardiovasc Magn Reson 2017 ; 19 : 10. Google Scholar CrossRef Search ADS PubMed 6 Iles L , Pfluger H , Phrommintikul A , Cherayath J , Aksit P , Gupta SN et al. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping . J Am Coll Cardiol 2008 ; 52 : 1574 – 80 . Google Scholar CrossRef Search ADS PubMed 7 Kellman P , Wilson JR , Xue H , Bandettini WP , Shanbhag SM , Druey KM et al. Extracellular volume fraction mapping in the myocardium, part 2: initial clinical experience . J Cardiovasc Magn Reson 2012 ; 14 : 64. Google Scholar CrossRef Search ADS PubMed 8 Yim D , Riesenkampff E , Caro-Dominguez P , Yoo S-J , Seed M , Grosse-Wortmann L. Assessment of diffuse ventricular myocardial fibrosis using native T1 in children with repaired tetralogy of Fallot . Circ Cardiovasc Imaging 2017 ; 10 : e005695. Google Scholar CrossRef Search ADS PubMed 9 Broberg CS , Huang J , Hogberg I , McLarry J , Woods P , Burchill LJ et al. Diffuse LV myocardial fibrosis and its clinical associations in adults with repaired tetralogy of Fallot . JACC Cardiovasc Imaging 2016 ; 9 : 86 – 7 . Google Scholar CrossRef Search ADS PubMed 10 Kozak MF , Redington A , Yoo S-J , Seed M , Greiser A , Grosse-Wortmann L. Diffuse myocardial fibrosis following tetralogy of Fallot repair: a T1 mapping cardiac magnetic resonance study . Pediatr Radiol 2014 ; 44 : 403 – 9 . Google Scholar CrossRef Search ADS PubMed 11 Riesenkampff E , Luining W , Seed M , Chungsomprasong P , Manlhiot C , Elders B et al. Increased left ventricular myocardial extracellular volume is associated with longer cardiopulmonary bypass times, biventricular enlargement and reduced exercise tolerance in children after repair of Tetralogy of Fallot . J Cardiovasc Magn Reson 2017 ; 18 : 75. Google Scholar CrossRef Search ADS 12 Geva T. Diffuse myocardial fibrosis in repaired tetralogy of Fallot . Circ Cardiovasc Imaging 2017 ; 10 : e006184. Google Scholar CrossRef Search ADS PubMed 13 Hanneman K , Nguyen ET , Thavendiranathan P , Ward R , Greiser A , Jolly M-P et al. Quantification of myocardial extracellular volume fraction with cardiac MR imaging in thalassemia major . Radiology 2016 ; 279 : 720 – 30 . Google Scholar CrossRef Search ADS PubMed 14 Kellman P , Arai AE , Xue H. T1 and extracellular volume mapping in the heart: estimation of error maps and the influence of noise on precision . J Cardiovasc Magn Reson 2013 ; 15 : 56. Google Scholar CrossRef Search ADS PubMed 15 Wald RM , Altaha MA , Alvarez N , Caldarone CA , Cavallé-Garrido T , Dallaire F et al. Rationale and design of the canadian outcomes registry late after tetralogy of fallot repair: the CORRELATE study . Can J Cardiol 2014 ; 30 : 1436 – 43 . Google Scholar CrossRef Search ADS PubMed 16 Al-Wakeel N , Nordmeyer S , Yilmaz S , Rastin S , Münch FH , Berger F et al. The right ventricle in congenital heart disease—cardiac T1 mapping for measurements of diffuse myocardial fibrosis . J Cardiovasc Magn Reson 2016 ; 18 : O25. Google Scholar CrossRef Search ADS 17 Arheden H , Saeed M , Higgins CB , Gao D-W , Bremerich J , Wyttenbach R et al. Measurement of the distribution volume of gadopentetate dimeglumine at echo-planar MR imaging to quantify myocardial infarction: comparison with 99mTc-DTPA autoradiography in rats . Radiology 1999 ; 211 : 698 – 708 . Google Scholar CrossRef Search ADS PubMed 18 Chen C-A , Dusenbery SM , Valente AM , Powell AJ , Geva T. Myocardial ECV fraction assessed by CMR is associated with type of hemodynamic load and arrhythmia in repaired tetralogy of Fallot . JACC Cardiovasc Imaging 2016 ; 9 : 1 – 10 . Google Scholar CrossRef Search ADS PubMed 19 Nacif MS , Turkbey EB , Gai N , Nazarian S , van der Geest RJ , Noureldin RA et al. Myocardial T1 mapping with MRI: comparison of Look-Locker and MOLLI sequences . J Magn Reson Imaging 2011 ; 34 : 1367 – 73 . Google Scholar CrossRef Search ADS PubMed 20 Bokma JP , de Wilde KC , Vliegen HW , van Dijk AP , van Melle JP , Meijboom FJ et al. Value of cardiovascular magnetic resonance imaging in noninvasive risk stratification in tetralogy of Fallot . JAMA Cardiol 2017 ; 2 : 678 . Google Scholar CrossRef Search ADS PubMed 21 Valente AM , Gauvreau K , Assenza GE , Babu-Narayan SV , Schreier J , Gatzoulis MA et al. Contemporary predictors of death and sustained ventricular tachycardia in patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort . Heart 2014 ; 100 : 247 – 53 . Google Scholar CrossRef Search ADS PubMed 22 Nollert G , Fischlein T , Bouterwek S , Böhmer C , Klinner W , Reichart B. Long-term survival in patients with repair of tetralogy of Fallot: 36-year follow-up of 490 survivors of the first year after surgical repair . J Am Coll Cardiol 1997 ; 30 : 1374 – 83 . Google Scholar CrossRef Search ADS PubMed 23 Wong TC , Piehler K , Meier CG , Testa SM , Klock AM , Aneizi AA et al. Association between extracellular matrix expansion quantified by cardiovascular magnetic resonance and short-term mortality . Circulation 2012 ; 126 : 1206 – 16 . Google Scholar CrossRef Search ADS PubMed 24 Puntmann VO , Carr-White G , Jabbour A , Yu C-Y , Gebker R , Kelle S et al. T1-mapping and outcome in nonischemic cardiomyopathy: all-cause mortality and heart failure . JACC Cardiovasc Imaging 2016 ; 9 : 40 – 50 . Google Scholar CrossRef Search ADS PubMed 25 Spruijt OA , Vissers L , Bogaard H-J , Hofman MBM , Vonk-Noordegraaf A , Marcus JT. Increased native T1-values at the interventricular insertion regions in precapillary pulmonary hypertension . Int J Cardiovasc Imaging 2016 ; 32 : 451 – 9 . Google Scholar CrossRef Search ADS PubMed 26 Mehta BB , Auger DA , Gonzalez JA , Workman V , Chen X , Chow K et al. Detection of elevated right ventricular extracellular volume in pulmonary hypertension using Accelerated and Navigator-Gated Look-Locker Imaging for Cardiac T1 Estimation (ANGIE) cardiovascular magnetic resonance . J Cardiovasc Magn Reson 2015 ; 17 : 1 – 11 . Google Scholar CrossRef Search ADS PubMed 27 Bilchick KC , Mehta BB , Workman V , Auger D , Chen X , Kennedy J et al. Abstract 14921: right ventricular extracellular volume fraction by magnetic resonance T1 mapping in pulmonary hypertension and heart failure . Circulation 2015 ; 132 : A14921 . 28 Jellis CL , Yingchoncharoen T , Gai N , Popovic Z , Flamm S , Kwon D. Assessment of right ventricular structure and function: novel CMR T1 mapping and strain techniques . J Am Coll Cardiol 2014 ; 63 : A1198. Google Scholar CrossRef Search ADS 29 García-Álvarez A , García-Lunar I , Pereda D , Fernandez-Jimenez R , Sánchez-González J , Mirelis JG et al. Association of myocardial T1-mapping CMR with hemodynamics and RV performance in pulmonary hypertension . JACC Cardiovasc Imaging 2015 ; 8 : 76 – 82 . Google Scholar CrossRef Search ADS PubMed 30 Kawel-Boehm N , Dellas Buser T , Greiser A , Bieri O , Bremerich J , Santini F. In-vivo assessment of normal T1 values of the right-ventricular myocardium by cardiac MRI . Int J Cardiovasc Imaging 2014 ; 30 : 323 – 8 . Google Scholar CrossRef Search ADS PubMed 31 Kawel N , Nacif M , Zavodni A , Jones J , Liu S , Sibley CT et al. T1 mapping of the myocardium: intra-individual assessment of the effect of field strength, cardiac cycle and variation by myocardial region . J Cardiovasc Magn Reson 2012 ; 14 : 27. Google Scholar CrossRef Search ADS PubMed 32 Wald RM , Valente AM , Gauvreau K , Babu-Narayan SV , Assenza GE , Schreier J et al. Cardiac magnetic resonance markers of progressive RV dilation and dysfunction after tetralogy of Fallot repair . Heart 2015 ; 101 : 1724 – 30 . Google Scholar CrossRef Search ADS PubMed 33 Valente AM , Cook S , Festa P , Ko HH , Krishnamurthy R , Taylor AM et al. Multimodality imaging guidelines for patients with repaired tetralogy of Fallot: a report from the AmericanSsociety of Echocardiography: developed in collaboration with the Society for Cardiovascular Magnetic Resonance and the Society for Pediatric Radiology . J Am Soc Echocardiogr 2014 ; 27 : 111 – 41 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. 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)

Journal

European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Oct 17, 2017

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off