Predicting Survival in Repaired Tetralogy of Fallot: A Lesion-Specific and Personalized Approach.

OBJECTIVES: This study sought to identify patients with repaired tetralogy of Fallot (rTOF) at high risk of death and malignant ventricular arrhythmia (VA). BACKGROUND: To date there is no robust risk stratification scheme to predict outcomes in adults with rTOF. METHODS: Consecutive patients were prospectively recruited for late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) to define right and left ventricular (RV, LV) fibrosis in addition to proven risk markers. RESULTS: The primary endpoint was all-cause mortality. Of the 550 patients (median age 32 years, 56% male), 27 died (mean follow-up 6.4 ± 5.8; total 3,512 years). Mortality was independently predicted by RVLGE extent, presence of LVLGE, RV ejection fraction ≤47%, LV ejection fraction ≤55%, B-type natriuretic peptide ≥127 ng/L, peak exercise oxygen uptake (V02) ≤17 mL/kg/min, prior sustained atrial arrhythmia, and age ≥50 years. The weighted scores for each of the preceding independent predictors differentiated a high-risk subgroup of patients with a 4.4%, annual risk of mortality (area under the curve [AUC]: 0.87; P < 0.001). The secondary endpoint (VA), a composite of life-threatening sustained ventricular tachycardia/resuscitated ventricular fibrillation/sudden cardiac death occurred in 29. Weighted scores that included several predictors of mortality and RV outflow tract akinetic length ≥55 mm and RV systolic pressure ≥47 mm Hg identified high-risk patients with a 3.7% annual risk of VA (AUC: 0.79; P < 0.001) RVLGE was heavily weighted in both risk scores caused by its strong relative prognostic value. CONCLUSIONS: We present a score integrating multiple appropriately weighted risk factors to identify the subgroup of patients with rTOF who are at high annual risk of death who may benefit from targeted therapy.

Comparison of 3 T and 1.5 T for T2* magnetic resonance of tissue iron.

BACKGROUND: T2* magnetic resonance of tissue iron concentration has improved the outcome of transfusion dependant anaemia patients. Clinical evaluation is performed at 1.5 T but scanners operating at 3 T are increasing in numbers. There is a paucity of data on the relative merits of iron quantification at 3 T vs 1.5 T. METHODS: A total of 104 transfusion dependent anaemia patients and 20 normal volunteers were prospectively recruited to undergo cardiac and liver T2* assessment at both 1.5 T and 3 T. Intra-observer, inter-observer and inter-study reproducibility analysis were performed on 20 randomly selected patients for cardiac and liver T2*. RESULTS: Association between heart and liver T2* at 1.5 T and 3 T was non-linear with good fit (R (2) = 0.954, p < 0.001 for heart white-blood (WB) imaging; R (2) = 0.931, p < 0.001 for heart black-blood (BB) imaging; R (2) = 0.993, p < 0.001 for liver imaging). R2* approximately doubled between 1.5 T and 3 T with linear fits for both heart and liver (94, 94 and 105 % respectively). Coefficients of variation for intra- and inter-observer reproducibility, as well as inter-study reproducibility trended to be less good at 3 T (3.5 to 6.5 %) than at 1.5 T (1.4 to 5.7 %) for both heart and liver T2*. Artefact scores for the heart were significantly worse with the 3 T BB sequence (median 4, IQR 2-5) compared with the 1.5 T BB sequence (4 [3-5], p = 0.007). CONCLUSION: Heart and liver T2* and R2* at 3 T show close association with 1.5 T values, but there were more artefacts at 3 T and trends to lower reproducibility causing difficulty in quantifying low T2* values with high tissue iron. Therefore T2* imaging at 1.5 T remains the gold standard for clinical practice. However, in centres where only 3 T is available, equivalent values at 1.5 T may be approximated by halving the 3 T tissue R2* with subsequent conversion to T2*.

Validation of T2* in-line analysis for tissue iron quantification at 1.5 T.

BACKGROUND: There is a need for improved worldwide access to tissue iron quantification using T2* cardiovascular magnetic resonance (CMR). One route to facilitate this would be simple in-line T2* analysis widely available on MR scanners. We therefore compared our clinically validated and established T2* method at Royal Brompton Hospital (RBH T2*) against a novel work-in-progress (WIP) sequence with in-line T2* measurement from Siemens (WIP T2*). METHODS: Healthy volunteers (n = 22) and patients with iron overload (n = 78) were recruited (53 males, median age 34 years). A 1.5 T study (Magnetom Avanto, Siemens) was performed on all subjects. The same mid-ventricular short axis cardiac slice and transaxial slice through the liver were used to acquire both RBH T2* images and WIP T2* maps for each participant. Cardiac white blood (WB) and black blood (BB) sequences were acquired. Intraobserver, interobserver and interstudy reproducibility were measured on the same data from a subset of 20 participants. RESULTS: Liver T2* values ranged from 0.8 to 35.7 ms (median 5.1 ms) and cardiac T2* values from 6.0 to 52.3 ms (median 31 ms). The coefficient of variance (CoV) values for direct comparison of T2* values by RBH and WIP were 6.1-7.8 % across techniques. Accurate delineation of the septum was difficult on some WIP T2* maps due to artefacts. The inability to manually correct for noise by truncation of erroneous later echo times led to some overestimation of T2* using WIP T2* compared with the RBH T2*. Reproducibility CoV results for RBH T2* ranged from 1.5 to 5.7 % which were better than the reproducibility of WIP T2* values of 4.1-16.6 %. CONCLUSIONS: Iron estimation using the T2* CMR sequence in combination with Siemens' in-line data processing is generally satisfactory and may help facilitate global access to tissue iron assessment. The current automated T2* map technique is less good for tissue iron assessment with noisy data at low T2* values.

Effect of deferiprone or deferoxamine on right ventricular function in thalassemia major patients with myocardial iron overload.

BACKGROUND: Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs. METHODS: In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment. RESULTS: From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p=0.008), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p=0.001). This was associated with a 27% increase in T2* (p<0.001) and 3.1% increase in LVEF (p<0.001). By contrast, deferoxamine showed no change in RVESV (38.1 to 39.1 mL, p=0.38), or RVEF (70.0 to 69.9%, p=0.93) whereas the T2* increased by 13% (p<0.001), but with no change in LVEF (0.32%; p=0.66). Analysis of between drugs treatment effects, showed significant improvements favouring deferiprone with a mean effect on RVESV of -1.82 mL (p=0.014) and 1.16% for RVEF (p=0.009). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p<0.001), with a significant difference in RVEF of 3.5% favouring deferiprone over deferoxamine (p=0.012). CONCLUSION: In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone.

International reproducibility of single breathhold T2* MR for cardiac and liver iron assessment among five thalassemia centers.

PURPOSE: To examine the reproducibility of the single breathhold T2* technique from different scanners, after installation of standard methodology in five international centers. MATERIALS AND METHODS: Up to 10 patients from each center were scanned twice locally for local interstudy reproducibility of heart and liver T2*, and then flown to a central MR facility to be rescanned on a reference scanner for intercenter reproducibility. Interobserver reproducibility for all scans was also assessed. RESULTS: Of the 49 patients scanned, the intercenter reproducibility for T2* was 5.9% for the heart and 5.8% for the liver. Local interstudy reproducibility for T2* was 7.4% for the heart and 4.6% for the liver. Interobserver reproducibility for T2* was 5.4% for the heart and 4.4% for the liver. CONCLUSION: These data indicate that T2* MR may be developed into a widespread test for tissue siderosis providing that well-defined and approved imaging and analysis techniques are used.

Right ventricular volumes and function in thalassemia major patients in the absence of myocardial iron overload.

AIM: We aimed to define reference ranges for right ventricular (RV) volumes, ejection fraction (EF) in thalassemia major patients (TM) without myocardial iron overload. METHODS AND RESULTS: RV volumes, EF and mass were measured in 80 TM patients who had no myocardial iron overload (myocardial T2* > 20 ms by cardiovascular magnetic resonance). All patients were receiving deferoxamine chelation and none had evidence of pulmonary hypertension or other cardiovascular comorbidity. Forty age and sex matched healthy non-anemic volunteers acted as controls. The mean RV EF was higher in TM patients than controls (males 66.2 +/- 4.1% vs 61.6 +/- 6%, p = 0.0009; females 66.3 +/- 5.1% vs 62.6 +/- 6.4%, p = 0.017), which yielded a raised lower threshold of normality for RV EF in TM patients (males 58.0% vs 50.0% and females 56.4% vs 50.1%). RV end-diastolic volume index was higher in male TM patients (mean 98.1 +/- 17.3 mL vs 88.4 +/- 11.2 mL/m2, p = 0.027), with a higher upper limit (132 vs 110 mL/m2) but this difference was of borderline significance for females (mean 86.5 +/- 13.6 mL vs 80.3 +/- 12.8 mL/m2, p = 0.09, with upper limit of 113 vs 105 mL/m2). The cardiac index was raised in TM patients (males 4.8 +/- 1.0 L/min vs 3.4 +/- 0.7 L/min, p < 0.0001; females 4.5 +/- 0.8 L/min vs 3.2 +/- 0.8 L/min, p < 0.0001). No differences in RV mass index were identified. CONCLUSION: The normal ranges for functional RV parameters in TM patients with no evidence of myocardial iron overload differ from healthy non-anemic controls. The new reference RV ranges are important for determining the functional effects of myocardial iron overload in TM patients.

Myocardial T2* measurements in iron-overloaded thalassemia: An in vivo study to investigate optimal methods of quantification.

Reproducible and accurate myocardial T2* measurements are required for the quantification of iron in heart tissue in transfused thalassemia. The aim of this study was to determine the best method to measure the myocardial T2* from multi-gradient-echo data acquired both with and without black-blood preparation. Sixteen thalassemia patients from six centers were scanned twice locally, within 1 week, using an optimized bright-blood T2* sequence and then subsequently scanned at the standardization center in London within 4 weeks, using a T2* sequence both with and without black-blood preparation. Different curve-fitting models (monoexponential, truncation, and offset) were applied to the data and the results were compared by means of reproducibility. T2* measurements obtained using the bright- and black-blood techniques. The black-blood data were well fitted by the monoexponential model, which suggests that a more accurate measure of T2* can be obtained by removing the main source of errors in the bright-blood data. For bright-blood data, the offset model appeared to underestimate T2* values substantially and was less reproducible. The truncation model gave rise to more reproducible T2* measurements, which were also closer to the values obtained from the black-blood data.

Direct comparison of myocardial perfusion cardiovascular magnetic resonance sequences with parallel acquisition.

PURPOSE: To directly compare the three main myocardial perfusion cardiovascular magnetic resonance (CMR) sequences incorporating parallel acquisition methods. MATERIALS AND METHODS: In 15 subjects (12 men, 57 +/- 15.7 years) referred for diagnostic coronary angiography, we acquired first-pass perfusion images (0.1 mmol/kg gadolinium-DTPA) at rest and during adenosine (140 microg/kg/min) on three separate occasions using three sequences incorporating parallel acquisition methods and approximately equivalent spatiotemporal resolution: hybrid echo planar imaging (hEPI), steady-state free precession (SSFP), and gradient echo imaging (GRE). We calculated the contrast-to-noise ratio (CNR) of each scan and blinded observers scored the presence and severity of artifacts (1, worst to 4, best), diagnostic confidence (0, low to 2, high), transmurality, area, and epicardial vessel territory of perfusion defects. RESULTS: CNR was greatest with SSFP and least with hEPI (13.15 vs 7.85 P < 0.001). The most artifacts were recorded with SSFP and least with hEPI (2.00 vs 3.03 P < 0.001). Observers were significantly more confident in reporting hEPI images (1.6 hEPI vs 0.9 SSFP, P < 0.001). Results for GRE were intermediate for all assessments. CONCLUSION: The hEPI sequence scored best for diagnostic performance despite the SSFP sequence having greater CNR. This trial favors hEPI for clinical myocardial perfusion CMR and suggests CNR should not be the sole criterion used to gauge the best candidate sequence.

Black-blood T2* technique for myocardial iron measurement in thalassemia.

PURPOSE: To compare the effectiveness and reproducibility of a new black-blood sequence vs. a conventional bright-blood gradient-echo T2* sequence for myocardial iron overload measurement in thalassemia. MATERIALS AND METHODS: Twenty thalassemia patients were studied. Black-blood sequence images were acquired in diastole after a double inversion recovery (DIR) preparation pulse. Bright-blood sequence images were acquired in both early systole and late diastole. The data were randomized and the T2* analysis was performed blindly by two independent observers. RESULTS: The T2* values from the black-blood sequence were comparable to those of the conventional bright-blood sequence (25.7 +/- 12.9 msec vs. 26.4 +/- 14.2 msec in early systole, P = 0.44; and 25.2 +/- 13.1 msec in late diastole, P = 0.41). The coefficient of variation (CV) for black-blood image T2* analysis was 4.1% compared with 8.9% (early systole P = 0.03) and 7.8% (late diastole P = 0.05) for bright-blood image analysis. CONCLUSION: The black-blood T2* technique yields high-contrast myocardial images, provides clearly depicted myocardial borders, and avoids blood signal contamination of the myocardium while yielding improvements in interobserver variability.

Cardiovascular magnetic resonance in arrhythmogenic right ventricular cardiomyopathy revisited: comparison with task force criteria and genotype.

OBJECTIVES: We sought to assess the utility of cardiovascular magnetic resonance (CMR) in the evaluation of arrhythmogenic right ventricular cardiomyopathy (ARVC) in relation to diagnostic criteria and genotype. BACKGROUND: Timely diagnosis of ARVC is difficult as clinical findings may be subtle and nonspecific in early disease. The role of CMR is controversial owing to the absence of a standardized protocol, insufficient experience with the modality, and inherent difficulties in imaging the right ventricle. METHODS: Comprehensive CMR examination was performed in 232 patients undergoing evaluation for suspected ARVC. CMR outcomes were compared with: 1) prospective clinical diagnosis using Task Force guidelines, with and without the proposed modifications for familial ARVC; and 2) gene-carrier status in 35 individuals from genotyped families. RESULTS: CMR studies were positive in all 64 patients who prospectively fulfilled Task Force criteria, resulting in 100% sensitivity. Specificity in relation to Task Force criteria was low (29%). Of the 119 apparent false positives detected by CMR, however, 63 fulfilled modified diagnostic criteria for familial ARVC and 7 were obligate gene carriers, suggesting that CMR frequently identifies individuals with early disease, in whom Task Force criteria are relatively insensitive. This was borne out by evaluation of genotyped individuals (26 gene-positive and 9 gene-negative), in whom CMR had a sensitivity of 96% and a specificity of 78%. CONCLUSIONS: CMR is a valuable component of the diagnostic workup for ARVC when performed with a dedicated protocol by specialists with experience in analysis of volumes, right ventricular wall motion, and delayed-enhancement imaging.

Effect of TGF-beta2 and anti-TGF-beta2 antibody in a new in vivo rodent model of posterior capsule opacification.

PURPOSE: This study evaluated the effect of transforming growth factor (TGF)-beta2 and anti-TGF-beta2 antibody in a rodent model of posterior capsule opacification (PCO). METHODS: An extracapsular lens extraction (ECLE) was performed in 72 Sprague-Dawley rats. At the end of the procedure, 10 microL TGF-beta2 (TGF-beta2-treated group), fetal calf serum (FCS)/phosphate-buffered saline (PBS; FCS/PBS-treated control group), a human monoclonal TGF-beta2 antibody (anti-TGF-beta2-treated group), or a null control IgG4 antibody (null antibody-treated control group) was injected into the capsule. Animals were killed 3 and 14 days postoperatively. Eyes were evaluated clinically prior to euthanatization, then enucleated and processed for light microscopy and immunohistochemistry afterward. PCO was evaluated clinically and histopathologically. Student's t-test and chi(2) were used to assess differences between groups. RESULTS: There were no statistically significant clinical or histopathological differences in degree of PCO between the TGF-beta2- and FCS/PBS-treated groups at 3 and 14 days after ECLE. Nor were there differences between the anti-TGF-beta2- and the null antibody-treated groups, with the exception of the histopathology score for capsule wrinkling 3 days after ECLE (P = 0.02). alpha-Smooth-muscle actin staining was observed in the lens capsular bag only in areas where there was close contact with the iris. CONCLUSIONS: No sustained effect of TGF-beta2 or anti-TGF-beta2 antibody on PCO was found in rodents at the dose and timing administered in this study. Iris cells may play a role in the process of epithelial mesenchymal transition linked to PCO.