Which Examination Is Most Useful in Assessing the Phenotype of Left Ventricular Noncompaction Cardiomyopathy in Children – Echocardiography, Cardiovascular Magnetic Resonance, or Both?

is in assessing the phenotype of left ventricular noncompaction cardiomyopathy in children – echocardiography, Abstract Background: Left ventricular noncompaction (LVNC) is a distinct cardiomyopathy characterized by the presence of a two-layer myocardium with prominent trabeculation and deep intertrabecular recesses. The diagnosis of LVNC can be challenging because the diagnostic criteria are not uniform. The aim of our study was to evaluate echocardiographic and CMR findings in a group of children with isolated LVNC. Methods : From February 2008 to July 2021, pediatric patients under 18 years of age at the time of diagnosis with echocardiographic evidence of isolated LVNC were prospectively enrolled. The patients underwent echocardiography and contrast-enhanced cardiovascular magnetic resonance (CMR) with late gadolinium enhancement to assess myocardial noncompaction, ventricular size, and function. Results: A total of 34 patients with a median age of 11.9 years were recruited. Patients were followed prospectively for a median of 5.1 years. Of the 31 patients who met Jenni’s criteria in echocardiography, CMR was performed in 27 (79%). Further comprehensive analysis was performed in the group of 25 patients who met the echocardiographic and CMR criteria for LVNC. In echocardiography, the median NC/C ratio in systole was 2.60 and in diastole 3.40. In 25 out of 27 children (93%), LVNC was confirmed by CMR according to Petersen’s criteria, with a median NC/C ratio of 3.27. Conclusions: Echocardiography a good method for monitoring LV systolic function, but CMR is for the precise assessment of LV remodeling and RV size and function as well as for the detection of myocardial fibrosis.


INTRODUCTION
Left ventricular noncompaction (LVNC) is described as a distinct cardiomyopathy characterized by a two-layer myocardium with prominent trabeculation, deep intertrabecular recesses, and a thin compacted myocardial layer. LVNC was classified as a primary cardiomyopathy by the American Heart Association in 2006 [1], but remains unclassified by the European Society of Cardiology [2]. It typically involves the left ventricle, although involvement of the right ventricle (RV) has been reported [3]. LVNC can occur as an isolated or non-isolated phenotype. Non-isolated LVNC may be accompanied by congenital heart diseases or features of other cardiomyopathy or neuromuscular diseases. LVNC is a genetically determined myocardial disease, the third most common cardiomyopathy in the pediatric population (after dilated and hypertrophic cardiomyopathy). Molecular studies have confirmed the genetic etiology in approximately 40% of LVNC patients [4,5]. The clinical presentation is very heterogeneous, ranging from no symptoms to major events such as heart failure, arrhythmias, thromboembolism, and sudden cardiac death [6,7,8].
The diagnosis of LVNC can be challenging due to the non-uniform diagnostic criteria.
Echocardiography is the initial and basic tool for diagnosing this cardiomyopathy according to the morphological criteria [9,10]. So far, no separate morphological criteria for LVNC in children have been proposed. The most commonly used echocardiographic criteria are those provided by Jenni et al. [11].
In recent years, cardiovascular magnetic resonance (CMR) imaging has increasingly been used in the assessment of cardiomyopathies. It is currently considered the non-invasive gold standard for the evaluation of biventricular volumes, myocardial mass, regional and global systolic function, and tissue characteristics [12]. CMR may provide clinically relevant information and it allows for LVNC diagnosis, though the proposed diagnostic criteria vary.
Because these criteria are based on small samples of patients and various assumptions and because there is no accepted standard for children, their reliability remains undetermined for the pediatric population [13]. For CMR, Petersen's criteria are most frequently used in clinical practice [14]. The emergence of CMR has enabled high-resolution imaging of cardiac structures, which provides detailed functional and morphologic information and allows for the presence and extent of fibrosis to be assessed [15]. Literature reports indicate that CMR is superior to echocardiography in assessing the extent of myocardial noncompaction, especially in areas which are not accessible by echocardiography, such as the left ventricular apex and the lateral wall [16].
The aim of our study was to evaluate echocardiographic and CMR findings in a group of children with isolated LVNC.

Study patients
From February 2008 to July 2021, pediatric patients with echocardiographic features of LVNC who were hospitalized in the Department of Cardiology of the Children's Memorial Health Institute were prospectively enrolled. The criteria for inclusion in the study were an age of less than 18 years at the time of diagnosis and echocardiographic evidence of isolated LVNC, defined as 1) the presence of a two-layer structure with a compacted and noncompacted endocardial layer of trabecular meshwork with deep endomyocardial spaces, 2) a maximal end-systolic ratio between the noncompacted and compacted (NC/C) layers of 2.0 or greater, and 3) color Doppler evidence of deep perfused intertrabecular recesses. The Institutional Ethics Committee approved this study. Informed consent was obtained from all individual participants included in the study.

Data collection
Patients' demographics, family history of cardiomyopathies and sudden cardiac death (SCD), and results from echocardiography, 12-lead resting ECG, 24-hour Holter ECG, and CMR were collected. NYHA/Ross functional class and clinical symptoms -such as chest pain, palpitations, syncope, pre-syncope, and thromboembolic events -were evaluated in all children.

Echocardiographic imaging and analysis
Echocardiographic imaging was performed using a Philips Epiq7 (Philips Medical Systems, Bothell, WA). Two-dimensional, Doppler, and M-mode echocardiography were performed at rest using standard methods. Echocardiographic images, including parasternal long-and short-axis and apical two-, three-, and four-chamber views were obtained and reviewed by cardiologists certified in echocardiography.
Echocardiographic measurements were reviewed based on Jenni's criteria [11]: a ratio of LV NC to C myocardial layer of 2.0 or greater, measured in the parasternal short-axis view in end-systolic phase below the papillary muscle. The NC/C ratio was additionally calculated in the parasternal short-axis projection in end-diastolic phase. Color Doppler imaging was performed in all children with visualization of the recess filling between the trabeculae with blood flowing in from the left ventricle (LV). LV dimension and systolic function were evaluated in detail. Echocardiographic measurements included LV end-diastolic (LVED) and end-systolic (LVES) volume [17] and area [18] in the apical four-chamber view, as well as LV diastolic (LVDd) and systolic (LVSd) diameters in the parasternal long-axis projection [19]. These parameters were evaluated for each patient and indexed to the patient's BSA according to Du Bois' formula. Moreover, z-scores were calculated using the formula for zscores reported in the literature [20]. LV systolic function was assessed by calculating the shortening fraction (SF), ejection fraction (LVEF) -according to Simpson's method -the value of mitral annulus peak systolic excursion (MAPSE) in mm, and z-score [21]. LA dimension (LAd) was measured at end-systole as the anteroposterior linear diameter from the parasternal long-axis view and was indexed to the patient's BSA. The z-score for LAd was calculated with the formula for z-scores [17]. LA enlargement was defined as a z-score greater than 2. It should be pointed out that the echocardiographic study also assessed the RV dimension and systolic function. RV diastolic diameter (RVDd) was evaluated in the parasternal long-axis view (mm, z-score) [17]. RV systolic function was assessed by calculating tricuspid annular plane systolic excursion values in mm and the z-score [22] and by measuring the fractional area change as a percentage of the difference between the RV end-diastolic and end-systolic areas evaluated in the apical four-chamber view. The studies were visually assessed for the presence of myocardial LGE, which had to be present in two different spatial orientations. Additionally, the extent of LGE was quantitatively assessed using a dedicated module within CVI42, where pathological enhancement was defined as a myocardium with a signal intensity more than 6 SD above the mean in a remote reference region of effectively nulled myocardium.

Statistical analysis
The distribution of all continuous variables was assessed using the Shapiro-Wilk test.
Normally distributed variables are presented as mean ± SD, whereas non-normally distributed parameters are given as median (interquartile range). Echocardiographic diagnostic performance was assessed in relation to CMR using standard accuracy criteria for binary diagnostic tests (i.e., sensitivity, specificity, and accuracy) with Clopper-Pearson confidence intervals and positive and negative predictive values with confidence intervals calculated according to Mercado et al. [24]. Pearson's correlation coefficient and the Bland-Altman plot were used to compare LV EDV between the imaging methods. Participants with myocardial LGE detected in CMR were compared with the children without myocardial LGE using an unpaired t-test or Mann-Whitney test, depending on the normality of the distribution.
Categorical variables between groups were compared using the chi-squared test. P-values less than 0.05 were considered statistically significant. Statistical analysis was carried out using MedCalc Statistical Software 20.014 (MedCalc Software Ltd, Belgium).

Clinical characteristics
A total of 34 patients with an echocardiographic diagnosis of LVNC were recruited between February 2008 and July 2021. The median age was 11.9 years (6.6-14.7) and 50% were male.
The patients were followed prospectively for a median of 5.1 years (2.2-12.2).
In the study group, 3% of patients were under 1 year of age; 32% were between 1 and 10 years of age; and 65% were over 10 years of age. Family history revealed cardiomyopathy in first-degree relatives in 11 children (32%) (LVNC in 20% of patients; both LVNC and DCM in 6%; LVNC and HCM in 3%; and HCM in 3%). Sudden cardiac deaths occurred in the families of 3 children (9%). The NYHA/Ross functional class in the majority of patients (74%) was evaluated as grade II; 3% had grade IV, while 24% had grade I. In 24-hour ECG Holter monitoring, the most prominent features were premature ventricular and atrial contractions, found in 26% and 15% of patients, respectively. Other findings were observed, including sinus bradycardia in 21% of children, paroxysmal third-degree atrioventricular block in 12%, ventricular tachycardia in 9%, and Wolff-Parkinson-White syndrome in 6% of patients.

Echocardiographic results
In 31 of the 34 patients (91%), the median NC/C ratio was 2.60 (IQR, 2.22,3.40). In the remaining 3 patients (9%) referred from a regional center with a diagnosis of LVNC, the echocardiography performed in our cardiology center did not confirm the diagnosis, as the NC/C ratios ranged from 1.46 to 1.9. These patients were excluded from further analysis and were not referred for CMR examination.
CMR was performed in 27 of the 31 children (79%) who met Jenni's criteria in echocardiography. In 4 (13%) patients, CMR was not performed due to their severe clinical condition and the implantation of an LV assist device for mechanical circulatory support (n = 1), an implanted pacemaker (n = 2), and hemodynamic instability and low body weight (n = 1). Among the 27 children who underwent CMR, the diagnosis of LVNC was confirmed in 25 (93%) according to Petersen's criteria. In 2 patients (7%), the CMR investigations did not confirm echocardiographic diagnosis of LVNC, as the NC/C ratio was less than 2.3.
A comprehensive and detailed analysis was performed on a group of 25 patients who met the echocardiographic and CMR criteria for LVNC diagnosis. The baseline characteristics of the study group are presented in Table 1.

Comparison of echocardiographic and CMR results
In the CMR investigations, LV NC/C ratio significantly correlated with echocardiographic NC/C ratio measured in systole (r=0.41; p=0.044) , but not in diastole (Table 3).
However, the LVEF values measured using the two imaging methods were not significantly correlated (r=0.36; p=0.08). The mean difference between the echocardiographic and CMR results was −2.4%±7.8% and the lower and upper limits of agreement (LoA) were −18.1% and 13.3%.

DISCUSSION
The main findings of this prospective observational study on LVNC in children are as follows: 1. Echocardiography is a precise method for diagnosing LVNC and it can accurately identify LV function impairment. Among the cardiac imaging techniques used in patients with LVNC, echocardiography and CMR are the primary diagnostic methods. The advantages of echocardiography over CMR are that it is more available, the costs of examination are lower, and there is no need for anesthesia in younger children. Consequently, echocardiography is the first choice in the diagnosis of LVNC [25]. Echocardiography, however, has its limitations. First of all, there is a wide range of echocardiographic diagnostic criteria in the literature, based on studies with small samples using different research methodologies [9,17]. The cardiac cycle (end-systole or end-diastole) in which the measurements of the noncompacted and compacted layers are made is also important, as the thickness of the myocardium is maximal in systole and minimal in diastole, which directly affects the NC/C ratio. The next point of discussion is the echocardiographic projection in which the measurements for the NC/C ratio should be made.
Most of the published diagnostic criteria suggest that these measurements should be performed in the LV parasternal short-axis view; however, the apical four-and two-chamber views are most commonly used in everyday clinical practice. Finally, there is no uniform consensus on the threshold value of NC/C ratio to use as a diagnostic criterion for LVNC [17]. The most frequently used criteria are those presented by Jenni et al., which are dedicated to adult patients; the suggested NC/C ratio is 2:1 or higher [11]. These echocardiographic criteria were used in our study, as in other published studies on children with LVNC [26], although some authors have proposed an NC/C ratio of greater than 1.4 as diagnostic criterion for LVNC in the pediatric population [27]. Improvements in cardiac imaging modalities, such as echocardiography and CMR imaging, have increased the identification of LVNC [28]. CMR is superior to echocardiography methodologies with regard to the number of segments that can be analyzed and the evaluation of the extent of two-layered myocardia. Moreover, CMR imaging has the potential to detect segmental non-compaction in any area of the LV wall and can provide supplemental morphological information beyond that obtained from conventional echocardiography [29].
Only a few previous studies have compared NC/C ratios assessed by CMR versus echocardiography [29,30]. The advantage of our study is that for the first time it compares data obtained with CMR and standard echocardiography in a larger group of pediatric patients. The results of our study demonstrate that in as many as 93% of children with LVNC features on echocardiography, CMR confirmed the diagnosis of the disease, which indicates that echocardiography is a precise diagnostic method for LVNC assessment in children.
Some authors have emphasized the role of better visualization of the noncompacted layer of the myocardium and trabeculae in end-diastole in echocardiography [31], while others have shown that end-systolic measurements of LVNC in CMR have stronger associations with cardiac events [32]. In our pediatric study, echocardiography images obtained at end-systole and end-diastole were compared with those obtained by CMR at end-diastole to assess NC/C ratio. Only systolic -not diastolic -NC/C ratios measured in echocardiography significantly correlated with NC/C ratio measurements in CMR, which is different from the results of a study on adult patients that reported good agreement between echocardiography at enddiastole and CMR measurements [29]. The results of our study suggest a strong advantage of evaluating the noncompacted myocardium during systole in echocardiographic studies.
Other authors [33,34] have assessed the correlation between NC/C ratio and LVEF. The results of these studies revealed that patients with increasing severity of noncompaction in echocardiography had significantly lower LVEF and LVEF correlated with parameters of specific diagnostic criteria for LVNC in CMR, such as an NC/C ratio greater than 2.3 and a more than 20% proportion of the noncompacted myocardium being LV mass. We did not find such a correlation in our study group. Nevertheless, 24% of the participants with LVNC confirmed by CMR presented with LV systolic function impairment, which is an important finding, as decreased LVEF is a significant risk factor [35]. Moreover, we observed a high accuracy of echocardiography in diagnosing LV systolic function impairment when referenced to the CMR, indicating its utility in patient follow-up. LV enlargement was observed in CMR in 5 of the 25 participants with LVNC (20%), indicating a significant incidence of LV remodeling in children with LVNC. Admittedly, echocardiography had moderate sensitivity for diagnosing LV enlargement (80%), though its specificity and overall accuracy in this aspect was relatively low.
Contrast-enhanced CMR with LGE imaging may detect myocardial fibrosis [36]. It is relatively frequently observed in patients with LVNC, though its presence or absence is not a reliable diagnostic marker of the disease [37]. In a study by Grothoff et al. [38], none of the LVNC patients demonstrated LGE, while other authors have described the presence of LGE in isolated LVNC, which is associated with a poorer LV systolic function [39,40]. In our study, we found LGE in pediatric patients with isolated LVNC and confirmed a relationship between LGE and features of LV remodeling. As in the case of other authors [41], in our study group the presence of LGE was associated with higher values of LVEDV. In contrast, LVEF did not differ between LVNC patients with LGE and other children with LVNC, similar to a study by Andreini et al. [31]. As the presence of LGE in adult LVNC patients was shown to be a significant risk factor [35] of cardiovascular events, our findings of significant incidence of myocardial fibrosis in children with LVNC and associated LV remodeling indicate the clinical importance of CMR imaging in routine evaluation of those patients [31],Error! Bookmark not defined. as in children with hypertrophic cardiomyopathy [42].
The results of studies published in the literature [27] indicate a significant share of RV systolic dysfunction in patients with isolated LVNC. There are reports [43] that have emphasized the relationship between RV systolic dysfunction and significantly lower LVEF and relevant LV enlargement. According to the authors [27], patients with impaired RV systolic function have a greater LV volume, lower LV systolic function, and more pronounced myocardial fibrosis, which may indicate that RV dysfunction is a marker of a more advanced stage of LVNC. The results of our study showed a significant correlation between left and right ventricular function, but we did not prove a relationship between RVEF and the size of the right and left ventricles. The significant incidence of RV enlargement and RV systolic function impairment observed in children with LVNC further highlights the clinical significance of CMR imaging in this population, since the possibilities of echocardiography RV evaluation are limited.
Based on our experience, we can summarize that echocardiography should be used as the first diagnostic test in LVNC, while CMR is strongly recommended as a complementary examination to accurately assess the extent of myocardial noncompaction and to reliably analyze the size and systolic function of the ventricles.
The results of studies on LVNC in children published so far require further research due to the many unanswered questions regarding diagnostic methods, diagnosis, and clinical management. 3. Echocardiography is a good method for monitoring LV systolic function, but CMR is indicated for precisely assessing the left ventricle and its enlargement. 4. CMR significantly exceeds echocardiography in the assessment of the right ventricle in children with LVNC and should be included in the basic diagnostics of these patients. 5. CMR imaging allows for the detection of areas of LGE, which are indicative of myocardial fibrosis.

6.
LGE incidence is relatively high in pediatric patients with LVNC and is associated with LV remodeling. As it is also a risk factor of future cardiovascular events, contrast-enhanced CMR should be a part of a standard diagnostic work-up of pediatric patients with LVNC.  Data Availability Statement: The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.