Comparison of cardiovascular magnetic resonance characteristics and clinical consequences in children and adolescents with isolated left ventricular non-compaction with and without late gadolinium enhancement

We prospectively recruited a cohort of consecutive children with isolated LVNC who were referred to the Fuwai Hospital for CMR between June 2006 and December 2013. The diagnosis of LVNC was made on the basis of previously defined CMR and clinical criteria: [9] (a) appearance of 2 distinct myocardial layers; (b) prominent myocardial trabeculations and deep intertrabecular recesses communicating with the LV cavity; (c) end-diastolic ratio of non-compacted-to-compacted (NC:C) myocardium >2.3:1, and (d) absence of other known co-existing cardiac abnormalities. The study complied with the Declaration of Helsinki and was approved by the Fuwai Hospital ethics committee, and informed consent was obtained from the parents of each child with LVNC.

All CMR exams were performed using a 1.5-T scanner (Siemens Avanto). Retrospective electrocardiographic gated cine images were performed using true fast imaging with steady-state free precession sequence (image parameters: repetition time/echo time [TR/TE] = 40.0/1.1 ms; matrix = 256 × 192 mm; flip angle = 62°) in three long-axis (horizontal and vertical long-axis and LV outflow tract) and continuous short-axis views covering the entire LV from base to apex. Fifteen ± 5 min after the injection of 0.2 mmol/kg of gadolinium-DTPA (Magnevist; Schering, Berlin, Germany), the LGE images were obtained using an inversion recovery sequence (image parameters: TR/TE = 8.7/3.4 ms, matrix = 256 × 256 mm, flip angle = 15°) in three long-axis and standard short-axis views covering the whole LV.

All images were analyzed using a workstation with commercially available software (Siemens Argus). For children with multiple CMR studies, the initial baseline study was used for the primary analysis. Results for LV ejection fraction, ventricular volumes, and myocardial mass were derived from short-axis slices. As previously demonstrated, the papillary muscles were excluded from compacted myocardium because it is difficult to differentiate papillary muscles from dense trabeculations [20]. Left ventricular volumes and compacted mass were indexed to body surface area. The LV sphericity index was calculated as: end-diastolic volume (EDV)/([end-diastolic long-axis diameter³ × π]/6) [21]. The presence or absence of non-compaction and LGE was qualitatively assessed using the AHA 17 segment model [22]. For each segment with non-compaction, the end-diastole NC/C ratio was quantitatively calculated in the short-axis views, and the maximum ratio was then used for analysis. As previously demonstrated, the assessment of NC/C ratio of the apex (segment 17) was excluded [9]. LGE was deemed present only if myocardial enhancement was confirmed on both short-axis and matching long-axis areas using a signal intensity threshold of ≥ 6 standard deviations (SD) above a remote reference region (Fig. 1). The myocardial layer distributions of LGE were assessed using the following scale: 1 = subepicardial, 2 = mid-wall, 3 = subendocardial, and 4 = transmural (≥75 % LV wall thickness). The LGE score was finally summed. The evaluations of non-compaction and LGE were performed by 2 independent expert readers (ML and HC) who were blinded to the clinical data. Discordant findings were resolved by consensus.

All children were followed up via clinic visits or telephone interview after initial CMR examination. The endpoint of the study was cardiovascular death and heart transplantation. The duration of follow-up was determined from the first CMR evaluation date to the occurrence of an endpoint. Complete follow-up was available for all children.

Normality was tested using the Kolmogorov-Smirnov test. Continuous variables were expressed as mean ± SD and assessed using unpaired t tests or Wilcoxon’s rank-sum tests. Categorical variables were expressed as frequencies (percentages) and assessed using the χ ² or Fisher exact tests. Correlation analyses were performed using the Spearman’s rank correlation test. Survival curve was generated by the Kaplan-Meier method and compared by the log rank test. The statistical analysis was performed using SPSS for Windows 16.0 (Chicago, IL, USA). A two tailed p value of < 0.05 was considered statistically significant.

A cohort of 40 children was diagnosed with isolated LVNC. An additional 8 children with prominent trabeculations who met CMR diagnostic criteria were associated with either congenital heart diseases and thus excluded from the study, such as atrial septal defect (n = 4), Ebstein’s anomaly (n = 1), aorto-left ventricular tunnel (n = 1), membranous subaortic stenosis (n = 1), bicuspid aortic valve (n = 1). Twenty-nine children (72 %) were male and 11 (28 %) were female. The mean age at the time of initial CMR scan was 13.7 ± 3.3 years (range, 1.5-17 years). Three children (8 %) had a family history of LVNC. Twenty-one children (53 %) presented primarily with signs and symptoms of congestive heart failure. Seven children (18 %) presented with documented ventricular arrhythmias and 1 patient (3 %) presented with aborted sudden death. Five children (13 %) were referred for evaluation of unexplained syncope. Two children (5 %) presented with a primary complaint of chest pain. No children had signs of systemic emboli. Clinical and demographic characteristics of the study population are summarized in Table 1.

The detailed CMR characteristics of children with LVNC are listed in Table 2. The mean LV ejection fraction (EF) and EDV index were 38.1 ± 17.4 % and 131.0 ± 55.8 mL/m², respectively. No thrombus was detected in LV cavity on CMR. Non-compaction was present in 372 LV segments. The mean number of non-compacted segments per patient was 9.3 ± 2.5. The mean NC/C ratio was 3.64 ± 0.94.

A total of 10 (25 %) children with LVNC showed LV LGE. The LGE was observed in 46 segments, including 23 non-compacted segments and 23 normal segments. Of these, LGE was subendocardial in 11 segments, mid-wall in 18, subepicardial in 5, and transmural in 12. No association was found between myocardial layer distributions of LGE and LVEF (r = 0.49, p = 0.148). Compared LGE- children, LGE+ children had significantly lower LVEF (23.8 ± 10.7 % vs. 42.9 ± 16.7 %, p < 0.001) and greater LVEDV (169.2 ± 65.1 vs. 118.2 ± 48.9 mL/m², p = 0.010), LV end-systolic volume (131.3 ± 55.5 vs. 73.3 ± 46.7 mL/m², p = 0.002), and sphericity indices (0.75 ± 0.19 vs. 0.60 ± 0.20, p = 0.045). There were no differences in terms of number of non-compacted segments, NC/C ratio, and myocardial mass index between LGE+ and LGE- cohort. There was a similar distribution of non-compaction between LGE+ and LGE- children, which was more frequently observed on the apical segment than on the mid-cavity and basal segments (Fig. 2).

The average length of follow-up was 3.0 ± 2.2 years. During follow-up period, 6 children (15 %) died and 2 (5 %) underwent heart transplantation (Fig. 3), thereby resulting in a 20 % incidence of death and transplantation in the total cohort. There was no statistically significant difference in the length of follow-up between LGE+ and LGE- children (2.6 ± 2.3 versus 3.2 ± 2.3 years; p = 0.494). In LGE+ cohort, adverse events occurred in 6 children, including orthotropic heart transplantation in 2 children and death in 4 children. In LGE- cohort, adverse event was identified in 2 children. Kaplan-Meier analysis showed a significant difference in outcome between LGE+ and LGE- cohorts for cardiac death and heart transplantation (Fig. 4).

The present study has several limitations. First, the number of the cohort was still small owing to the relatively rare pediatric entity and a single-center nature. Second, there were potential selection and referral biases in our cohort, given most children clinically referred for CMR investigation had dramatic symptoms that may not be universally applicable to all populations. Third, LGE+ children had more adverse LV remodeling at baseline, which leads to indefinite relationship between the presence of LGE and adverse events. In order to conclusively ascertain incremental prognostic value of LGE in children with LVNC, larger studies with longer follow-up are required.