Prevalence of Left Ventricular Noncompaction in Newborns
Left ventricular noncompaction (LVNC) is characterized by excessive trabeculations of the LV and may be associated with reduced systolic function or severe adverse outcomes. Several aspects remain to be elucidated; there is controversy to whether LVNC cardiomyopathy is a distinct cardiomyopathy caused by failure of the spongy fetal myocardium to condense during fetal development or acquired later in life as a morphological trait associated with other types of cardiomyopathy; the prevalence in unselected populations is unknown and the distinction between normal variation and pathology remains to be defined. In this study, we aimed to determine the prevalence of LVNC and the association to LV systolic function in a large, population-based cohort of neonates. In addition, we assessed the normal ratio of noncompact to compact (NC:C) myocardium in 150 healthy neonates.
Echocardiographic data were prospectively collected in the population study Copenhagen Baby Heart Study. The ratio of NC:C was measured in 12 ventricular segments. LVNC was defined as NC:C ≥2 in at least one segment. Neonates with LVNC were matched 1:10 to controls on sex, gestational age, and weight and age at the examination day.
In total, 25 590 neonates (52% males, median age 11 [interquartile range, 7–15] days) underwent echocardiography. Among 21 133 with satisfactory visualization of ventricular segments, we identified a prevalence of LVNC of 0.076% (95% CI, 0.047–0.123). LV ejection fraction was lower in neonates with LVNC compared with matched controls (median 49.5 versus 59.0%; P<0.0001). In neonates with otherwise healthy hearts, the median NC:C ratio ranged from 0.0 to 0.7 and the 99th percentiles from 1.0 to 1.9 for each of the 12 segments.
The prevalence of LVNC based on neonatal echocardiography was 0.076%. LVNC was associated with lower LV systolic function. The findings in normal newborns support the cutoff NC:C ≥2 as an appropriate diagnostic criterion.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02753348.
With this study, we can present novel aspects of left ventricular noncompaction, which have not been fully elucidated previously. The prevalence of left ventricular noncompaction in a large cohort of unselected neonates was 0.076%, and even when present in asymptomatic neonates, excessive trabeculation was associated to impaired left ventricular systolic function. To clarify the clinical implications of left ventricular noncompaction in the future, distinction between normal variants and pathology is essential. Follow-up of individuals with extensive trabeculations will clarify the prospective importance of left ventricular noncompaction on echocardiography in the context of normal systolic function. Until further data are available follow-up should be considered. Also, assessment of first-degree relatives of individuals with extensive trabeculation in this population study will demonstrate if there is a familial pattern of left ventricular noncompaction in the context of asymptomatic neonates detected by systematic echocardiography.
See Editorial by Towbin & Johnson
Left ventricular noncompaction (LVNC) is characterized by a thin, compact outer layer and a thick noncompact inner layer with prominent trabeculations and deep intertrabecular recesses in the ventricular myocardium.1,2 The extensive trabeculations seen together with LV dilatation and systolic dysfunction in LVNC cardiomyopathy are associated to heart failure, arrythmias, thromboembolism, and sudden cardiac death. LVNC is also seen in individuals with normal ventricular function.3,4 LVNC cardiomyopathy is frequently familial with a reported prevalence of 30% in first-degree relatives.5 Phenotypic plasticity may occur and isolated dilated or hypertrophic cardiomyopathy can be seen in family members harboring the same genetic variant.1,6 Several aspects of LVNC remain to be fully elucidated. First, there is controversy to whether LVNC cardiomyopathy is a distinct cardiomyopathy that occurs as a consequence of failure of the spongy fetal myocardium to condense to a compact, outer layer and a noncompact inner layer during fetal development, or whether LVNC is acquired later in life as a morphological trait associated with other types of cardiomyopathy1 or even as a part of a physiological adaption.7 Second, it is not evident how to distinguish between normal variants of pronouncedly trabeculated myocardium and pathology. A ratio between noncompact and compact (NC:C) myocardium ≥2 has been suggested as a diagnostic criterion.8,9 Several diagnostic imaging criteria for isolated LVNC have been proposed but none are considered gold standard.3,8,10–15 Finally, the prevalence of LVNC by echocardiography in an unselected population is uncertain. LVNC cardiomyopathy is seen in 0.001% to 0.3% of adults referred for echocardiography10,14 and in 3.7% of adults with a reduced ejection fraction.12
With this study, we aimed to examine the prevalence of LVNC in a large cohort of unselected neonates based on the previously suggested diagnostic criterion of a ratio of NC:C myocardium ≥2, to assess the relation of noncompaction of the myocardium with LV systolic dysfunction, and to determine the normal ratio of NC:C myocardium in healthy neonates.
Data Availability Statement
Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to the CBHS (Copenhagen Baby Heart Study; contact information available on babyheart.dk).
Study Population and Design
The CBHS is a population-based cohort study of neonates focusing on cardiac structure and function. Detailed descriptions of the study have been published previously.16–18 Data were registered prospectively from children born between April 2016 and October 2018 in Copenhagen, Denmark. Parents were consecutively approached with information about the CBHS at the routine second trimester ultrasound scan. Verbal and written information were given to the parents and consent was obtained from the parents before inclusion. Included neonates underwent transthoracic echocardiography, ECG, and pulse oximetry within 30 days of life, and data regarding pregnancy, delivery, and parents’ health, lifestyle, and socioeconomic status were collected through questionnaire and medical records. Additional follow-up in medical records for later diagnosis of noncardiac disease in cases fulfilling criteria for LVNC was performed in May 2021.
Cases fulfilling the criteria for LVNC were matched to controls in a 1:10 ratio on sex, gestational age at birth (±7 days), and age and weight at the examination day (±3 days and ±200 g). Controls could not have complex structural heart disease, ventricular septal defect, or bicuspid aortic valve. In addition to the matched controls, a randomly selected sample from the CBHS consisting of 150 healthy neonates with normal echocardiography was used for the assessment of the normal ratio of NC:C myocardium.
The CBHS was approved by the Regional Ethics Committee of the Capital City Region of Denmark (H-16001518), and the Danish Data Protection Agency (I-Suite no.: 04546, ID-no. HGH-2016-53). Clinical trial registered for CBHS.
The echocardiographic protocol in CBHS included standard subxiphoid, apical, parasternal, and suprasternal views obtained in accordance with guidelines.16,19 Images were acquired using Vivid E9 ultrasound machines (General Electric, Horten, Norway) and cardiac probes 12S-D and 6S-D. The images were stored digitally and analyzed offline using EchoPac software version 113 (General Electric, Horten, Norway).
A group of 5 reviewers performed the primary evaluation of all 25 590 echocardiograms for the presence of noncompaction in the apical long-axis views (4-chamber, 5-chamber, and sinus coronarius views, the latter which is a modified 4-chamber view with posteriorly tilting of the probe), parasternal long-axis view, and parasternal short axis view (SAX) at the level of the papillary muscles in the end diastole (Figure 1). Based on a visual evaluation by the one of 5 primary reviewers from all the above projections, noncompaction was suspected (possible versus not possible) in the presence of pronounced trabeculation, or visual impression of a ratio of NC:C myocardium >1. The delineation between myocardium and blood had to be acceptable and with all segments within the sector in at least 2 out of 3 apical views for the echocardiogram to be included. Color flow Doppler was not used in the delineation between myocardium and blood since it was not a part of the standard echocardiographic protocol of CBHS. After analysis of 150 exams we decided not to include a ratio of NC:C myocardium >1 in the anterior segment of the SAX view (Figure 2) as a sign of possible noncompaction. In the initial observations (the assessment of normal ratio in 150 random children), we observed that 75% of the neonates had a NC:C ratio >1 in the anterior segment, so it was decided to apply a more conservative criteria for this segment when filtering individuals for the secondary review. Instead, trabeculation in the anterior segment of the SAX view was included as a sign of possible noncompaction by the primary reviewer when the NC:C ratio was ≥2.
Echocardiograms with possible noncompaction underwent a second expert review by one reviewer with quantification of the NC:C ratio perpendicular to the LV cavity in 6 segments in the apical 4-chamber view and 6 segments in the SAX view (level of the papillary muscles) in end diastole (Figure 2). For the main analysis, we defined the presence of noncompaction as a NC:C ratio ≥2 in end diastole in at least one segment as suggested by Paterick et al.8 In addition, in a supplementary analysis, the prevalence of LVNC was determined based on our own normal data defined as NC:C >99th percentile for that particular segment (Tables S1 and S2). LV dimensions and systolic function were assessed in all neonates in left parasternal long-axis views, and the reviewers of these parameters were blinded to the assessment of noncompaction. Systolic function was assessed as LV ejection fraction from 4-chamber view (LVEF) and medial and lateral systolic mitral annulus velocity. The apical 2-chamber view was not included in the original echocardiographic protocol in CBHS because biplane estimations of the LVEF could not be performed.
Normal Ratio of NC:C Myocardium
To determine the normal ratio of NC:C myocardium, the ratio was measured in 150 randomly selected neonates from the CBHS population by an experienced reviewer. Inclusion required that both the apical 4-chamber view and SAX view were available and that measurements could be obtained in at least 3 out of 6 segments in both apical 4-chamber view and SAX view. Measurement of the normal ratio of NC:C myocardium was performed in end diastole in 6 segments in SAX view (level of the papillary muscles) and 6 segments in the apical 4-chamber view (Figure 2). For each segment, it was first noted whether 2 distinct layers (noncompact and compact) could be distinguished. If 2 distinct layers could be distinguished, the ratio of NC:C myocardium was measured perpendicular to the LV cavity in 12 segments in the apical 4-chamber and SAX views.
Prevalence of LVNC is presented with 95% CI. In this study, all continuous variables are presented as medians and either interquartile ranges or full ranges due to consistency in the article. Comparisons between neonates with LVNC and matched controls were performed with the Mann-Whitney U test (Wilcoxon rank-sum) for continuous variables, and χ2 or Fisher exact test for categorical variables. Two-sided P values were used for all statistical analyses with significance defined as <0.05. Prevalence of LVNC in the supplementary analysis was defined as NC:C >99th percentile for the particular segment to assess if the cutoff value of NC:C ≥2 in any segment is an appropriate diagnostic criterion. Statistical analyses and graphical illustrations were performed in R version 3.5.2.
Prevalence of LVNC Based on Previously Suggested Criteria
In total, 25 590 neonates (52% males, median age 11 days [interquartile range, 7–15]) underwent echocardiography in the CBHS. Maternal median age at delivery was 31.7 years of age (range 15–54) and 92% were White participants. For the assessment of LVNC, 4457 echocardiograms were excluded due to suboptimal visualization of all ventricular segments (Figure 1). In total, 253 596 segments were evaluated. Trabeculations with a ratio of NC:C myocardium ≥2 in at least one segment was identified in 16 out of 21 133 neonates, corresponding to a prevalence of noncompaction of 0.076% (95% CI, 0.047–0.123).
Demographic and Other Echocardiographic Characteristics of Neonates With LVNC
Demographic, maternal, and echocardiographic characteristics of the 16 neonates with LVNC and matched controls are shown in Tables 1 and 2. Two neonates with LVNC were born prematurely in gestational weeks 30+6 and 36+4, respectively. Except for one neonate with suspected infantile autism, no extracardiac conditions or syndromes have yet (May 2021) been diagnosed in the neonates with LVNC. None of the parents to neonates with LVNC reported consanguinity or a family history of cardiomyopathy, congenital heart diseases, or sudden cardiac death. LVNC was observed in 0.07% of White participants (13/19 282 [95% CI, 0.04%–0.12%]), 0.39% of Black particpants (1/255 [95% CI, 0.07%–2.19%]), and 0.49% of other or unknown ethnicities (2/406 [95% CI, 0.14%–1.78%]). LVNC was not found in any neonates of Asian ethnicity (0/1190).
|Parameters*||Cases with noncompaction (n=16)||Matched controls (n=159)†||P value|
|Age, y||30.5 (25.5–36.5)||32.0 (29.0–35.0)||0.54|
|Prepregnancy BMI, kg/m2||25.3 (23.0–29.0)||22.4 (20.7–24.5)||0.03|
|Nullipara, n (%)||12 (75.0)||82 (51.6)||0.11|
|Multiple pregnancy, n (%)||2 (12.5)||5 (3.1)||0.13|
|Ethnicity, n (%)||0.38|
|White||13 (81.3)||136 (85.5)|
|Black||1 (6.3)||1 (0.6)|
|Asian||0 (0.0)||3 (1.9)|
|Other/unknown||2 (12.5)||19 (12.0)|
|Birth data of the neonates|
|Gestational age, wk||39.9 (38.3–40.3)||39.7 (38.7–40.7)||NA|
|Height, cm||52.5 (50.5–53.5)||52.0 (51.0–54.0)||0.82|
|Weight, g||3618 (3388–3857)||3616 (3257–3890)||1.0|
|Data from the examination day|
|Age, d||12.5 (7.5–14.3)||11.0 (6.5–14.0)||NA|
|Height, cm||53.0 (51.0–55.1)||52.0 (49.0–54.0)||NA|
|Weight, g||3850 (3250–4025)||3800 (3300–4000)||NA|
|Parameters*||Cases with noncompaction (n=16)||Matched controls (n=159)||P value|
|LVEF, %||49.5 (43.8 to 54.0)||59.0 (57.0 to 61.0)||<0.0001|
|LV EDV, mL||6.0 (5.0 to 6.3)||6.0 (5.0 to 7.0)||0.40|
|LV ESV, mL||3.0 (2.0 to 4.0)||2.0 (2.0 to 3.0)||0.046|
|FS, %||29.1 (28.4 to 30.7)||32.0 (29.5 to 34.9)||0.01|
|LVIDd, mm||20.7 (19.2 to 22.9)||20.4 (18.9 to 21.4)||0.22|
|LVIDs, mm||14.3 (13.4 to 16.4)||13.6 (12.6 to 14.7)||0.047|
|IVSd, mm||2.4 (2.3 to 2.7)||2.5 (2.2 to 2.8)||0.77|
|LA diameter, mm||11.0 (10.2 to 12.1)||12.0 (10.2 to 13.0)||0.31|
|LVPWd, mm||2.1 (1.8 to 2.2)||2.0 (1.8 to 2.3)||0.85|
|TAPSE, mm||10.0 (9.6 to 11.0)||9.9 (8.9 to 11.1)||0.35|
|Med. S’, cm/s||2.9 (2.8 to 3.5)||3.5 (3.0 to 4.1)||0.15|
|Med. E’, cm/s||−3.6 (−3.9 to −2.7)||−4.2 (−5.1 to −3.3)||0.053|
|Lat. S’, cm/s||2.7 (2.5 to 3.1)||3.0 (2.6 to 3.6)||0.09|
|Lat. E’, cm/s||−3.1 (−3.7 to −2.2)||−3.9 (−5.0 to −3.0)||0.04|
When compared with matched controls, the systolic function, measured as LVEF, was significantly lower in neonates with LVNC (median LVEF 49.5% [range 43.8%–54.0%] versus 59.0% [range 57.0%–61.0%]; P<0.0001; Table 2). Thirteen out of 16 neonates with LVNC had a LVEF below 55%. The LV end-diastolic volumes did not differ significantly between cases and controls (end-diastolic volume 6.0 [range 4.0–11.0] versus 6.0 [range 2.0–9.0] mL; P=0.40) while the LV end-systolic volumes were significantly larger in children with LVNC (end-systolic volume 3.0 [range 2.0–8.0] versus 2.0 [range 1.0–4.0] mL; P=0.046; Table 2, Figure 3). No significant differences were found for other measures of left or right ventricular dimensions or function.
The majority (9 out of 16) of the neonates with LVNC had a ratio of NC:C myocardium ≥2 in only one of the 12 segments, 4 had in 2 of the 12 segments, 2 had in 3 of the 12 segments, and one had in 4 of the 12 segments. Noncompaction was found most frequent (12 out of 27 segments) in the 2 apical segments of the 4-chamber view. None was found in the basal segments or in the inferior septal segment of SAX (Figure 2). The mean ratio of NC:C for all 12 segments in children fulfilling the diagnostic criteria for noncompaction was 1.9 (SD 0.4).
Normal Ratio of NC:C Myocardium
The normal ratio of NC:C was assessed in a sample of 150 healthy, randomly selected neonates from CBHS (46% females, median age 11 days [range 0–26]). This sample was separate to the matched controls. Additional characteristics of these neonates are presented in Table S3. Image quality was optimal for assessment in 1153 (77%) segments, and 2 distinct layers of NC:C myocardium could be clearly distinguished in 610 (53%) segments in 147 (98%) of the 150 neonates. In the remaining 3 neonates, no visible noncompact layer was found. The most frequent localizations of a noncompact layer were the apical segments of the 4-chamber view and the anterior and anterolateral segments of the SAX view. The distribution of NC:C ratios of all 610 segments are shown in Figure 4. The median ratios of NC:C myocardium for 12 segments in neonates with normal hearts ranged from 0.0 to 0.7 with corresponding 99th percentiles of 1.0 to 1.9. Median NC:C ratio, 99th percentile, and percentage of examinations with a clear noncompact layer for each of the individual 12 segments can be found in Figure S1. Further results from an additional assessment of the prevalence of LVNC based on 99th percentile can be found in the Supplemental Results.
To date, characterization of several aspects of LVNC remain incomplete. We sought to provide additional insights by systematic echocardiography assessing an unselected cohort of >25 000 neonates included in the population study CBHS. The study revealed 3 major findings: (1) Based on previously suggested diagnostic criteria for LVNC, NC:C myocardium ratio ≥2, the prevalence of LVNC was 0.076% neonates. (2) Compared with matched controls, neonates with LVNC had significantly reduced systolic function of the LV and (3) the median ratios of NC:C myocardium for 12 segments in a cohort of neonates with normal hearts ranged from 0.0 to 0.7 with a corresponding 99th percentiles of 1.0 to 1.9.
Prevalence and Localizations of LVNC
When applying previously suggested echocardiographic diagnostic criteria of NC:C ratio ≥2, we found the prevalence of LVNC in neonates to be 0.076%. Comparison with previous studies is challenged by the divergent study populations. While the present study was performed with prospectively collected data from a population study of newborns, previous studies have primarily been retrospective assessment of adults referred for echocardiography (range of mean age 33–69 years, n=7–201).3,11–14 However, both prevalences found in this study are within the range of 0.001% to 0.3% reported in previous echocardiographic studies. In striking contrast, Zemrak et al15 reported that as many as 26% of adults included in the MESA (Multi-Ethnic Study of Atherosclerosis) population study (n=2742) fulfilled criteria for LVNC using CMR imaging.15 Although the high prevalence was determined in a population study, there are at least 2 important differences from CBHS. First, the mean age of the included subjects was 69 years as opposed to neonates in our study. Due to the higher mean age in the MESA study, an impact of lifestyle factors on the general health of the population is expected and embodied by, among others, the prevalence of hypertension of 56% and diabetes of 17%. Second, measurements of NC:C ratio were performed on CMR images using an NC:C ratio ≥2.3 as the diagnostic criteria of LVNC as suggested for this modality. Despite these 2 important aspects causing difficulties in direct comparing of the 2 populations, the difference in prevalence of the same condition in these large prospective studies of unselected individuals is striking. It emphasizes the lack of diagnostic golden standards as well as the importance of which imaging modality is used for the assessment of noncompaction.7,20 The concurrence of the prevalence found in our study of unselected neonates with those found for older populations for echocardiography,3,10–14 potentially support the understanding of noncompaction primarily being an inborn condition proposedly due to an arrest of the normal embryological development of the myocardium.1 However, the much greater prevalence in the older MESA population potentially also supports that a distinct type of noncompaction may develop later in life. Future follow-up studies of the CBHS cohort have the potential to elucidate this conundrum.
If interested in further discussion of a prevalence based on the 99th percentile from our own normal material, please continue to the Supplemental Discussion and Conclusion.
Segmental Distribution of a Ratio of NC:C Myocardium ≥2
Segments with a ratio of NC:C myocardium ≥2 in the 16 neonates with LVNC were distributed primarily in the apical and in the mid septal and mid lateral segments, which is consistent with the distribution pattern seen in previous studies of LVNC despite differences in the study populations.3,5,11,21 However, the mean ratio of NC:C myocardium in the 16 neonates with LVNC was 1.9, which is lower than the mean of 3.4 previously reported in adults with LVNC.5,11 The difference is not unexpected since our population consisted of newborns from a population study as opposed to older individuals with a diagnosis of LVNC.
Associated LV Dysfunction and Clinical Significance
LVNC is seen both in the context of reduced LV function as a distinct form of cardiomyopathy as well as in individuals with normal systolic function. In the study by Bhatia et al5 of adults with LVNC (n=241), the average ejection fraction was 37%. Also, previous studies of children with LVNC report more severely impaired systolic function than the discrete, but significant, difference from controls found in the present study.21,22 However, our data still add to the available body of evidence of an association between LVNC and ventricular dysfunction. A pivotal difference from our study is that the vast majority of the children in previous studies were older and examined after clinical presentation.21,22 In contrast to the impact of noncompaction in children, the quarter of the sample that fulfilled LVNC criteria in the MESA population study did not have systolic dysfunction either at the time of examination or at 10 years follow-up.15
As a consequence of the occurrence of arrythmias or abnormal cardiac dimensions, children diagnosed with LVNC cardiomyopathy have been demonstrated to have a high mortality rate, and outcome is associated with cardiac dysfunction.4 In adults from the general population, increased LV trabeculation, irrespective of systolic function, is associated with major adverse cardiovascular events, including death and heart failure.23 The clinical significance of noncompaction in presumably healthy newborns has, however, not yet been studied. The study design of the CBHS, with baseline echocardiography shortly after birth combined with the possibility of life-long follow-up of both cases and controls, provides a unique opportunity to describe disease development, progressive impairment of systolic function and prognostic significance of LVNC. As mentioned previously, the study also presents us with a unique opportunity to clarify to what extent noncompaction is a congenital trait as opposed to a morphological trait associated to other types of cardiomyopathy presenting later in life.
The standard protocol used in the CBHS did not include all views and modalities suggested in previous diagnostic criteria, because apical 2-chamber and visualization of perfusion in intertrabecular recesses by Color Doppler could not be applied in this study.16 During primary screening of neonates with NC:C >1, the method might have been prone to manual errors and interobserver variability since it was performed by a team of 5 reviewers.
We acknowledge that biplane or even 3-dimensional assessment of systolic function would have provided a more accurate estimation of the systolic function of the LV. We also acknowledge that although CBHS was a population-based study, not all children born in the uptake area in the study period were included. In total 27 595 infants, representing 55.0% of children born at the participating hospitals in the recruitment period, contributed data at baseline. Our results may thus be subject to selection bias. Congenital cardiac abnormalities including cardiomyopathy may have come to medical attention prenatally or shortly after birth and thus might have escaped inclusion in the study, although the CBHS made effort to also include children with an established diagnosis or suspicion of disease. In addition, the CBHS cohort was predominantly white and it is unclear whether results can be generalized to other ethnicities.
Systematic echocardiography of a >25 000 unselected neonates demonstrated a prevalence of LVNC of 0.076% using a previously suggested criteria and showed that LVNC was associated with lower LV systolic function. In healthy newborns, the 99th percentile of the ratio of noncompact to compact myocardium ranged from 1.0 to 1.9 depending on myocardial segment, supporting a ratio ≥2, as suggested previously, to be a truly abnormal finding. Longitudinal evaluation of the cohort is expected to provide further insight into the prognostic significance of LVNC at long-term and to determine to what extent noncompaction is a congenital trait as opposed to a morphological trait associated to other types of cardiomyopathy presenting later in life.
Sources of Funding
The Copenhagen Baby Heart Study was supported by the Danish Heart Association, Copenhagen, Denmark; the Danish Children’s Heart Foundation, Copenhagen, Denmark; the Toyota Foundation, Copenhagen, Denmark; the Herlev-Gentofte Hospital Research Foundation, Copenhagen, Denmark; and Candy’s Foundation, Vaduz, Lichtenstein. The funders had no part in the design of the study; in the collection, analysis, or interpretation of data or publication.
Copenhagen Baby Heart Study
left ventricular ejection fraction
Multi-Ethnic Study of Atherosclerosis
parasternal short axis view
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