Long-Term Prognosis of Patients With Left Ventricular Noncompaction　― Comparison Between Infantile and Juvenile Types ―

Abstract

Background: The natural history of left ventricular noncompaction (LVNC) is largely unsolved, so the aim of the present study was to clarify the clinical features and long-term prognosis of children with LVNC until adulthood.

Methods and Results: We conducted a nationwide survey over 20 years and compared the clinical features, anatomical characteristics and long-term prognosis of 205 patients divided into 2 classifications: infantile type (diagnosed at <1 year of age: 108 cases) and juvenile type (diagnosed 1–15 years of age: 97 cases). Most patients diagnosed during infancy had heart failure (HF) at initial presentation (60.19%), while the majority of juvenile cases were asymptomatic (53.61%) but their event-free survival rate decreased gradually, because of later HF, thromboembolism and fatal arrhythmias. The initial LVEF was significantly lower in the infantile type and correlated with the thickness of the compacted layer in the LV posterior wall (LVPWC) and LV end-diastolic dimension (LVDD) Z-score, but not to the noncompacted to compacted layer (N/C) ratio. Survival analysis showed prognosis was similarly poor for both types after 2 decades. The significant risk factors for death, heart transplantation or implantable cardioverter-defibrillator insertion were congestive HF at diagnosis and lower LVPWC Z-score but not age of onset.

Conclusions: LVNC of both types showed poor long-term prognosis, therefore ongoing follow-up is recommended into adulthood. HF at diagnosis and LVPWC hypoplasia are major determinants of poor prognosis.

Left ventricular noncompaction (LVNC) was originally described as X-linked infantile cardiomyopathy with poor prognosis,¹ but has since been classified as a primary genetic cardiomyopathy by the American Heart Association.² LVNC is postulated to be caused by an arrest of the normal process of intrauterine endomyocardial morphogenesis. Noncompaction involves predominantly the distal (apical) portion of the LV chamber with deep intertrabecular recesses (sinusoids) in communication with the ventricular cavity.^2–4 An increasing number of reports describe prenatal diagnosis of LVNC using fetal echocardiography.⁵ These findings support the theory that arrested embryonic development underlies the pathogenesis of LVNC. However, juvenile or adult cases have increasingly been reported, and might have a longer clinical course with gradually depressed LV function than patients identified when infants.^6–11

In this report, we identified and analyzed the largest series of patients with LVNC via a nationwide survey, and compared the clinical features and long-term prognosis over 20 years between infantile and juvenile cases of LVNC.

Methods

We conducted follow-up nationwide surveys to elucidate the clinical features and prognosis of LVNC in Japanese children who had been identified in a primary nationwide survey in 1996.⁶ A questionnaire designed specifically for this follow-up study was sent in 2000 (1st follow-up survey), 2005 (2nd follow-up survey) and 2014 (3rd follow-up survey) to 61 hospitals in Japan that house a division of pediatric cardiology. A total of 205 patients were included in this study, comprising patients with LVNC identified through the 1st survey and additional patients diagnosed between 2000 and 2014. The questionnaires were similar to the primary survey and included questions concerning clinical presentation and symptoms; details of clinical course; personal and family histories; arrhythmia; thromboembolism; developmental delay and facial dysmorphism; findings of scalar ECG; 2D Doppler, and color Doppler echocardiography.⁶ The diagnosis of heart failure (HF) was based on clinical symptoms of feeding difficulty, tachypnea, and cyanosis; and decreased LV ejection fraction (LVEF) on echocardiography and cardiomegaly on chest X-ray. Cardiomegaly was defined as a cardiothoracic ratio (CTR) ≥0.55 (≥0.60 for patients <1 year old) on chest X-ray, or LV end-diastolic dimension (LVDD) ≥120% of normal on echocardiography.

Echocardiography video tapes were reviewed and interpreted by 2 independent pediatric cardiologists (SWO and CW) to confirm the diagnosis of LVNC and measure the wall thicknesses of the LV. We excluded 41 patients with congenital heart anomalies, leaving data from a total of 205 patients, including 5 patients with Barth syndrome, to be evaluated. None of them had neuromuscular disorders or other systemic syndromes. The clinical features and anatomical characteristics of the infantile cases of LVNC (age at presentation <1 year: 108 cases, infantile type) were compared with juvenile cases (age at presentation 1–15 years: 97 cases, juvenile type). Echocardiographic data included LVDD; LVEF; and the distribution and depth of prominent trabeculations in the LV. LVEF was calculated by the Pombo single-plane method. LVDD as defined by the actual tissue-blood interface, was measured at the level of the LV minor axis, approximately at the mitral valve leaflet tips on 2D images, with the tip of noncompacted portion chosen according to the American Society of Echocardiography Committee recommendations.¹² To quantify the extent of the trabecular meshwork, the thickness of the LV wall and the noncompacted to compacted layer (N/C) ratio were measured according to methods previously reported, where N represents the depth of the trabecular recess and C represents compacted wall thickness.^8,9,11 A diagnosis of LVNC was based on (1) characteristic 2-layered appearance of the myocardium with an increased N/C ratio (N/C >2.0) and the disease process observed in ≥1 ventricular wall segments; and (2) multiple, deep intertrabecular recesses communicating with the ventricular cavity, as demonstrated by color Doppler imaging. N/C ratios were measured in 5 wall segments of the LV at end-diastole: 4 wall segments of the anterior, lateral, posterior walls, the interventricular septum at the level of the papillary muscles in the short-axis view, and 1 wall segment at the apex in the long-axis view. The final N/C ratio in each wall segment was the average of 3 measurements. We have developed an echocardiographic criteria-based “noncompaction score” to estimate the severity of noncompacted myocardium, in addition to the standard N/C ratio.^1,11,13–15 The noncompaction score represents an average of the points allocated for N/C ratios in 5 wall segments, where 2 points=N/C >2; 1 point, 0.4≤N/C≤2; 0 points, N/C <0.4. Chin et al showed that the thickness of the noncompacted layer becomes gradually more prominent from the mitral valve level to apex, and the N/C ratio at the mitral valve level is not significantly different from normal control measurements.¹ Therefore, we measured N/C ratios at the level of papillary muscles and at the apex. We calculated the N/C ratio and assessed and summarized noncompaction scores from 5 wall segments. The thickness of the compacted layer in the LV posterior wall (LVPWC) and the LVDD were expressed as Z-scores based on body surface area.^16–18 We evaluated the correlation between different echocardiographic parameters and LVEF. Patient confidentiality was assured through the use of coded patient identifiers. This was a partial retrospective study. At the 1st and 2nd surveys, patient data were corrected retrospectively. After these surveys, all patients were followed prospectively. The parents of every patient in the prospective study gave written informed consent for clinical data collection. The study was approved by the Research Ethics Committee of Toyama University Hospital.

Statistical Analysis

Statistical analysis was performed using the chi-squared test for comparison of clinical data. Data were calculated as mean±SD, and as medians for nonparametric data. The comparison of data between the 2 types of LVNC was performed using Student’s unpaired t test. Pearson correlation analysis was used to test the association between echocardiographic parameters and LVEF. A P-value <0.05 was considered statistically significant. Risk factors for death, heart transplantation (HT) and implantable cardioverter-defibrillator (ICD) implantation were assessed using Cox proportional hazards models. Each type was considered in the univariable analysis. All the patients’ data were first compared using separate univariable models, then in a multivariable model. Survival curves were plotted with Kaplan-Meier survival estimates. Endpoints were death, HT and ICD implantation.

Results

Clinical Features

The distribution of the age of diagnosis of patients showed that over half the patients (108) were diagnosed during their first year of life (Figure 1). The median age at the presentation was 2.7 months in the infantile type group and 7.3 years in the juvenile type group (Table 1). Demographic characteristics are summarized in Table 1. The male to female ratio was approximately 1 in both types. In the infantile type (108 cases), 42 patients (39%) presented in the neonatal period and 10 in the fetal period (9%). The duration of follow-up ranged from 1 day to 22 years for all patients (median 4.9 years). A total of 73 patients (36%) had a family history of LVNC. Although most patients in the infantile group had clinical signs or symptoms of HF at initial presentation (60%), most of the juvenile cases were asymptomatic and identified only when screened for cardiac abnormalities, such as ECG screening (56%). The number of patients with HF requiring hospitalization was significantly higher with the infantile type than with the juvenile type (72% vs. 30%, P<0.0001).

Figure 1.

Age distribution of all the patients with left ventricular noncompaction.

Table 1. Clinical Characteristics of Patients With the Infantile or Juvenile Type of Left Ventricular Noncompaction

	Infantile type (n=108)	Juvenile type (n=97)	P value
M:F	59:49	51:46
Age at diagnosis (median)	2.7 mo	7.3 yr
Mean duration of follow-up, yr (range)	3.5 (0–22)	5.9 (0–22)
Family history	37	36	0.77
Symptoms at diagnosis
Asymptomatic	21	52	<0.0001
CHF	65	22	<0.0001
Arrhythmia	9	11	0.4897
Cardiac function at diagnosis
LVEF (%)	43.38±2.17 (n=92)	57.06±1.96 (n=77)	<0.0001
LVEF <50%	61	27	<0.0001
HF requiring hospitalization	78	29	<0.0001
Systemic embolic events	5	5	–
Event (HT, death or ICD insertion)	20 (5, 14, 1 )	14 (4, 9, 1)	0.46

CHF, congestive heart failure; HT, heart transplantation; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; mo, months; yr, years.

Echocardiographic Findings

Reduced LVEF at initial presentation was significantly more common in the infantile type than in the juvenile type (Table 1); 56% of the patients with the infantile type had an LVEF <50%. The maximum N/C ratio was observed at the apex (N/C ratio ≥2.0 in all patients), followed by the posterior wall, lateral wall, interventricular septum, and anterior wall. The N/C ratios of the posterior wall and apex, and the mean N/C of the 5 segments were lower in the infantile type. There were no significant differences in noncompaction scores, LVPWC and LVDD Z-scores between the 2 types (Table 2).

Table 2. Echocardiographic Findings of Patients With the Infantile or Juvenile Type of Left Ventricular Noncompaction

	Infantile type (n=41)	Juvenile type (n=48)	P value
N/C ratio
Anterior wall	1.23±0.17	1.55±0.24	0.25
Septal wall	1.45±0.17	1.88±0.25	0.18
Lateral wall	2.18±0.19	2.62±0.24	0.16
Posterior wall	2.40±0.14	3.19±0.27	0.02
Apex	3.45±0.29	4.69±0.43	0.02
Mean 5 segments	2.30±0.15	2.67±0.13	0.04
Noncompaction score	7.47±0.22	7.95±0.20	0.11
LVPWC Z-score	−0.98±0.16	−1.23±0.12	0.24
LVDD Z-score	1.72±0.29	1.37±0.24	0.36

Values are mean±SD. N/C ratio, noncompacted to compacted layer ratio; LVDD, left ventricular end-diastolic dimension; LVPWC, thickness of compacted layer in left ventricular posterior wall.

LVPWC and LVDD Z-scores showed a moderate but significant correlation with LVEF (Table 3). In the group with LVPWC Z-scores <−1.5, LVEF were significantly lower than that in the group with LVPWC Z-scores >−1.5 (43.9±4.1% vs. 55.0±2.6%, P=0.02). There was not a significant correlation between the mean N/C ratio of 5 segments, noncompaction score, N/C ratio of posterior wall and LVEF.

Table 3. Correlation Between Echocardiographic Parameters and LVEF% in Patients With the Infantile or Juvenile Type of Left Ventricular Noncompaction

n=89	r	P value
Mean N/C ratio of 5 segments	0.08	0.49
Noncompaction score	0.10	0.39
N/C ratio of posterior wall	−0.02	0.86
LVPWC Z-score	0.38	0.0017
LVDD Z-score	−0.40	0.0001

Abbreviations as in Tables 1,2.

Electrocardiography

ECG abnormalities were significantly higher in the juvenile type. Of all the patients, 30% showed nonspecific ECG changes (Table S1). The incidence of Wolff-Parkinson-White (WPW) syndrome was high (7%) in both types, being complicated with supraventricular tachycardia (SVT) in 5 patients and indication for ablation in 1 patient. In contrast, the incidences of left bundle blanch block, ventricular tachycardia (VT) and atrial fibrillation (AF) were lower, being detected in 7 (3%), 11 (5%), and 4 (2%) patients, respectively. Among them, 1 patient died of VT. Complete atrioventricular block was identified in 8 patients (4%), and sick sinus syndrome in 5 (2%). Pacemaker implantation was performed in 3 patients. ICD implantation was performed in 2 patients.

Prognosis and Risk Factors

Among all patients, 34 (20 infantile vs. 14 juvenile) died, underwent HT or had ICD insertion (Table 1): there was not a significant difference between groups. Although survival analysis showed worse prognosis over the shorter term for the infantile type (Figure 2A), the survival rate was similarly poor for both types after 2 decades. However, congestive HF at diagnosis was a significant risk factor for survival free of death, HT or ICD insertion (Figure 2B).

Figure 2.

(A) Event-free survival to the combined endpoint of death, HT or ICD insertion of patients with infantile and juvenile types of left ventricular noncompaction. (B) Event-free survival to the combined endpoint of death, HT or ICD insertion of patients with and without congestive heart failure (CHF). Numbers of patients in both event-free groups are shown at each time point. HT, heart transplantation; ICD, implantable cardioverter-defibrillator.

In the infantile type, event-free rates were 80% at 5 years, 73% at 10 years, 64% at 15 years and 63% at 20 years after presentation (Figure 2A); 9 patients (64%) died of HF, 2 patients died of ventricular arrhythmia, 1 patient experienced sudden death after upper respiratory infection, 1 patient died of brain embolism and 1 patient died during the fetal period. In contrast, in the juvenile type group the event-free rate was 91% at 5 years, and decreased gradually to 81% at 15 years and 61%, ultimately similar to the infantile type group at 20 years (Figure 2A): 3 patients had sudden death resulting from arrhythmias, 2 patients died of lung embolisms and 3 patients died of HF. Thromboembolism was noted in 10 patients in both types; all of them had decreased cardiac function. Brain embolisms were reported in 4 patients, renal embolisms in 3 patients and pulmonary embolisms in 3 patients; 1 patient with a pulmonary embolism also had right ventricular noncompaction detected.

Risk factors for death, HT or ICD insertion for the 2 groups are shown in Table 4. Lower LVPWC Z-score was found to be the most significant risk factor for the infantile type whereas it was decreased LVEF for the juvenile type (Figure 3). A multivariable proportional hazards model for all the patients showed that congestive HF at diagnosis (Table 5A) was the independent risk factor for death, HT or ICD insertion, but not family history. The multivariable proportional hazards model including echocardiographic parameters showed that congestive HF at diagnosis and lower LVPWC Z-score (Table 5B) were independent risk factors for death, HT or ICD insertion in all LVNC patients.

Table 4. Risk Factors for Death, HT or ICD Insertion in in Patients With the Infantile or Juvenile Type of Left Ventricular Noncompaction

Variable	Infantile			Juvenile
	Subjects n	HR (95% CI)	P value	Subjects n	HR (95% CI)	P value
Sex (M vs. F)	108	0.84 (0.35–2.02)	0.70	97	2.73 (0.83–7.38)	0.10
Family history	108	1.63 (0.65–4.02)	0.31	97	1.31 (0.44–4.04)	0.62
LVEF <50%	108	3.53 (0.93–6.72)	0.07	97	9.93 (3.14–34.47)	0.0002
LVPW N/C ratio	41	2.00 (0.43–12.07)	0.90	48	3.54 (0.36–40.34)	0.26
Mean N/C ratio	41	1.12 (0.23–5.76)	0.89	48	2.77 (0.28–27.56)	0.38
LVPWC Z-score (≤−1.5)	41	4.34 (1.27–41.65)	0.03	48	16.26 (0.90–292.60)	0.06
LVDD Z-score	41	1.42 (0.32–6.25)	0.65	48	1.31 (0.21–8.48)	0.76

CI, confidence interval; HR, hazard ratio; HT, heart transplantation. Other abbreviations as in Tables 1,2.

Figure 3.

Event-free survival to the combined endpoint of death, HT or ICD insertion in (A) infantile LVNC patients according to LVPWC Z-score and (B) juvenile LVNC patients according to LVEF. Numbers of patients in both event-free groups are shown at each time point. HT, heart transplantation; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; LVNC, left ventricular noncompaction; LVPWC, thickness of compacted layer in left ventricular posterior wall.

Table 5. Risk Factors (A) and Risk Factors (Including Echocardiographic Parameters) (B) for Death, HT or ICD Insertion in Children With LVNC

Variable	Subjects n	Univariable survival analysis		Multivariable survival analysis
		HR (95% CI)	P value	HR (95% CI)	P value
A
Age at onset (infantile vs. juvenile)	205	2.14 (1.11–4.41)	0.02	1.76 (0.83–3.73)	0.13
Sex (M vs. F)	205	1.57 (0.79–3.09)	0.20	1.56 (0.78–3.12)	0.21
Family history	205	0.83 (0.41–1.67)	0.60	1.01 (0.51–2.02)	0.98
CHF at diagnosis	205	5.29 (2.63–13.38)	<0.0001	2.22 (1.53–4.67)	0.03
B
Age at onset (infantile vs. juvenile)	89	3.20 (0.78–9.54)	0.08	1.49 (0.23–9.50)	0.68
Sex (M vs. F)	89	1.01 (0.29–3.49)	0.71	1.19 (0.33–4.26)	0.79
Family history	89	3.12 (0.78–9.43)	0.11	1.29 (0.26–6.33)	0.76
CHF at diagnosis	89	4.40 (1.35– 18.30)	0.02	6.22 (1.08–35.82)	0.04
LVPW N/C ratio	89	1.85 (0.50–8.30)	0.33	0.93 (0.23–3.70)	0.915
Mean N/C ratio	89	1.43 (0.40–5.09)	0.60	1.88 (0.53–6.45)	0.33
LVPWC Z-score (≤−1.5)	89	4.86 (1.52– 26.98)	0.01	5.74 (1.50–21.98)	0.01
LVDD Z-score	89	1.09 (0.34–3.45)	0.89	3.22 (0.63–16.52)	0.16

LVNC, left ventricular noncompaction. Other abbreviations as in Tables 1,2.

Discussion

This is the largest series of nationwide surveys with the longest follow-up, over 20 years until adulthood, reported and the first to compare outcomes in infantile and juvenile patients with LVNC.

Clinical Presentation

The age distribution of the patients showed that most children were diagnosed before their first birthday, accounting for 53% of the patients surveyed, much higher than a recent study reported.¹⁹ However, 60% of the infantile type presented with congestive HF, which is similar to a previous report.²⁰ In contrast, juvenile cases were detected during the asymptomatic stage and might have a longer clinical course with gradually decreasing LV function. Juvenile asymptomatic cases would be predicted to develop symptoms as adults; the majority of adult LVNC cases presented at a mean age of 40 years, with signs of congestive HF.^8,11,20–22 Our study confirmed that the event-free survival rate was similar for both types after 2 decades (Figure 2A). However, patients with congestive HF at the time of diagnosis had a lower survival rate than those without (Figure 2B). Therefore, long-term follow-up of these patients is warranted, even into adulthood. In Japan, LVNC is often detected by school screening examinations, including ECG, during the asymptomatic stage, and for the second-line evaluation of these cases, echocardiography is a promising tool and careful evaluation, including of the apex, is necessary.^3,6 Early diagnosis and treatment, and emergency preparedness may improve the prognosis in this disorder. Family history was as common for these children as has been reported for adults,²² and is more frequent than reported for patients with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy.^23,24 Although family history was not a risk factor in the present study, as for DCM patients²⁴ clinical assessment of the family members of the probands is crucial.^25,26

Significance of Different Echocardiographic Parameters

Infantile-onset patients had a significantly lower LVEF at initial presentation. Recent studies have used different parameters to assess the number of segments involved and LVEF.^21,22 Therefore, we developed a “noncompaction score” to estimate the severity of the noncompacted myocardium.^1,13 However, there was no difference between the 2 types and it had no correlation with LVEF. Menon and colleagues noted that the noncompacted layer becomes more prominent with improvement of cardiac function and cardiomegaly during the clinical course of fetal-onset LVNC.²⁷ It is worth noting that 73% of infantile cases have cardiomegaly, and the N/C ratio might become lower in those cases with DCM hemodynamics, as a consequence of dilatation of the LV and thinning of the LV wall. In contrast to adult patients,²⁸ the N/C ratio of a mean of 5 segments had no correlation with LVEF. A higher N/C ratio in the juvenile type and adults²⁸ indicates that the N/C ratio may increase, along with remodeling of the myocardium with aging, but is not accompanied by decreased LVEF. Thus, although the N/C ratio is a useful criterion for diagnosis of LVNC, it may not be an assessment predictor of the severity of LVNC and cannot predict prognosis.

A thin compact layer had a correlation with poor LVEF. Ventricular noncompaction is characterized by a thin compact layer.¹ Mechanical dyssynchrony between the noncompacted and compacted myocardium and reduced LV compact thickness may contribute to LV dysfunction in LVNC.^28,29 The thickness of the compact myocardium was reduced in epicardium-deficient hearts.³⁰ Therefore, we used the LVPWC Z-score and showed its positive correlation with LVEF, which supports the conclusion of Chin et al that development of the subepicardial compact layer of the ventricle is important for maintaining cardiac function.¹ The LVDD Z-score had a significant negative correlation with cardiac function, as HF associated with DCM is common in LVNC,³¹ but univariable analysis showed it was not the risk factor for death or HT in our study.

Risk Factors, Prognosis and Treatment

In this study, risk factors for death, HT and ICD insertion for all the childhood LVNC patients were congestive HF at diagnosis and lower LVPWC Z-score, but not N/C ratio in contrast to a recent study.³² In addition, diagnosis during the first year of life (infantile type) was a risk factor in our univariable survival analysis, as reported previously in DCM pediatric patients.^24,33 In the infantile type, 64% of patients died of symptomatic HF, which the main reason for the high mortality. However, some infants revealed improved cardiac function later in spite of an initial presentation with congestive HF. Similar transient recovery of cardiac function, together with thickening of the noncompacted layer has been reported by Pignatelli et al.¹¹ In the juvenile type, 13% underwent HT, died or had ICD insertion during the follow-up period, and 39.1% required hospitalization. The main causes of death in the juvenile type were HF, ventricular arrhythmias, thromboembolic events and sudden cardiac death, similar to adults.⁸ Ventricular arrhythmias are an indicator of poor prognosis in both children and adults.^8,19

Our study showed that there was no significant difference between the 2 types of LVNC after 2 decades of follow-up, because late deaths occurred from fatal arrhythmias and thromboembolisms in the juvenile type, in addition to progressive congestive HF. Accordingly, control of congestive HF, arrhythmias, and thromboembolism are key issues for the treatment and follow-up of patients with LVNC. We found the incidence of systemic embolism was low in our series, probably because aspirin therapy was prescribed for the patients with reduced cardiac function.¹⁹ This may be related to the increased recognition and awareness of the disease currently and timely treatment when symptoms started. For asymptomatic patients with reduced cardiac function, medication with antiplatelet or anticoagulant drugs is recommended as well.³⁴ The patients with reduced cardiac function were treated with diuretics, positive inotropics, angiotensin-converting enzyme inhibitors, and vasodilators, similar to patients with DCM; anticoagulation was also used. In addition, for control of the congestive HF, β-blocker treatment has also been used in patients with LVNC,^35,36 which may improve the long-term prognosis.

Study Limitations

Further studies are needed to increase the number of patients with echocardiography data and compare their LVPWC Z-scores with those of controls to test and also compare with MRI. The novel parameters described would also need to be assessed.

In this study, we could not perform a genetic analysis for all the patients, so we could not analyze genetic abnormality as a risk factor. Although family history was not a risk factor in our study, genetic etiologies should be considered to compare phenotype and variations between the 2 types.³⁷

Conclusions

A nationwide survey over 20 years of patients with LVNC revealed poor prognosis for both the infantile and juvenile types after 2 decades; therefore, ongoing follow-up is recommended into adulthood. HF at diagnosis and hypoplasia of the compacted layer of the LV wall are the major determinants of poor prognosis.

Acknowledgments

The authors thank Dr. Hideki Origasa for assistance with the statistical analysis of this study, and Dr. Neil E Bowles for assistance with English editing of the manuscript.

This study was partially supported by a Japan Heart Foundation Research Grant on Dilated Cardiomyopathy awarded to F.I.

The authors are grateful to Professor Yuichi Adachi for steadfast counsel and guidance. All the LVNC study collaborators are listed in Supplementary File.

Disclosures

The authors report no relationships relevant to the content of this paper.

Supplementary Files

Supplementary File 1

Table S1. Observed arrhythmias in patients with the infantile or juvenile type of left ventricular noncompaction

LVNC Study Collaborators

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-16-1114

References

• 1.   Chin TK, Perloff JK, Williams RG, Jue K, Mohrmann R. Isolated noncompaction of left ventricular myocardium: A study of eight cases. Circulation 1990; 82: 507–513.
• 2.   Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. Contemporary definitions and classification of the cardiomyopathies: An American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006; 113: 1807–1816.
• 3.   Ichida F. Left ventricular noncompaction. Circ J 2009; 73: 19–26.
• 4.   Weiford BC, Subbarao VD, Mulhern KM. Noncompaction of the ventricular myocardium. Circulation 2004; 109: 2965–2971.
• 5.   Kitao K, Ohara N, Funakoshi T, Moriyama T, Maruo T, Yamane M, et al. Noncompaction of the left ventricular myocardium diagnosed in pregnant woman and neonate. J Perinat Med 2004; 32: 527–531.
• 6.   Ichida F, Hamamichi Y, Miyawaki T, Ono Y, Kamiya T, Akagi T, et al. Clinical features of isolated noncompaction of the ventricular myocardium: Long-term clinical course, hemodynamic properties, and genetic background. J Am Coll Cardiol 1999; 34: 233–240.
• 7.   Ritter M, Oechslin E, Sütsch G, Attenhofer C, Schneider J, Jenni R. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc 1997; 72: 26–31.
• 8.   Oechslin EN, Attenhofer Jost CH, Rojas JR, Rojas JR, Kaufmann PA, Jenni R. Long-term follow-up of 34 adults with isolated left ventricular noncompaction: A distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol 2000; 36: 493–500.
• 9.   Wald R, Veldtman G, Golding F, Kirsh J, McCrindle B, Benson L. Determinants of outcome in isolated ventricular noncompaction in childhood. Am J Cardiol 2004; 94: 1581–1584.
• 10.   Hussein A, Karimianpour A, Collier P, Krasuski RA. Isolated noncompaction of the left ventricle in adults. J Am Coll Cardiol 2015; 66: 578–585.
• 11.   Pignatelli RH, McMahon CJ, Dreyer WJ, Denfield SW, Price J, Belmont JW, et al. Clinical characterization of left ventricular noncompaction in children: A relatively common form of cardiomyopathy. Circulation 2003; 108: 2672–2678.
• 12.   Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: A report from the American Society of Echocardiography’s guidelines and standards committee and the chamber quantification writing group. J Am Soc Echocardiogr 2005; 18: 1440–1463.
• 13.   Jenni R, Oechslin E, Schenider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: A step towards classification as a distinct cardiomyopathy. Heart 2001; 86: 666–671.
• 14.   Stollberger C, Finsterer J, Blazek G. Left ventricular hypertrabeculation, noncompaction and association with additional cardiac abnormalities and neuromuscular disorders. Am J Cardiol 2002; 90: 899–902.
• 15.   Paterick TE, Umland MM, Jan MF, Ammar KA, Kramer C, Khandheria BK, et al. Left ventricular noncompaction: A 25-year odyssey. J Am Soc Echocardiogr 2012; 25: 363–375.
• 16.   Colan SD, Parness IA, Spevak PJ, Sanders SP. Developmental modulation of myocardial mechanics: Age- and growth-related alterations in afterload and contractility. J Am Coll Cardiol 1992; 19: 619–629.
• 17.   Sluysmans T, Colan SD. Theoretical and empirical derivation of cardiovascular allometric relationships in children. J Appl Physiol 2005; 99: 445–457.
• 18.   Kampmann C, Wiethoff CM, Wenzel A, Stolz G, Betancor M, Wippermann CF, et al. Normal values of M mode echocardiographic measurements of more than 2000 healthy infants and children in central Europe. Heart 2000; 83: 667–672.
• 19.   Brescia ST, Rossano JW, Pignatelli R, Jefferies JL, Price JF, Decker JA, et al. Mortality and sudden death in pediatric left ventricular noncompaction in a tertiary referral center. Circulation 2013; 127: 2202–2208.
• 20.   Lilje C, Rázek V, Joyce JJ, Rau T, Finckh BF, Weiss F, et al. Complications of non-compaction of the left ventricular myocardium in a paediatric population: A prospective study. Eur Heart J 2006; 27: 1855–1860.
• 21.   Stanton C, Bruce C, Connolly H, Brady P, Syed I, Hodge D, et al. Isolated left ventricular noncompaction syndrome. Am J Cardiol 2009; 104: 1135–1138.
• 22.   Aras D, Tufekcioglu O, Ergun K, Ozeke O, Yildiz A, Topaloglu S, et al. Clinical features of isolated ventricular noncompaction in adults long-term clinical course, echocardiographic properties, and predictors of left ventricular failure. J Card Fail 2006; 12: 726–733.
• 23.   Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M, Wilkinson LC, et al. National Australian Childhood Cardiomyopathy Study: The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 2003; 348: 1639–1646.
• 24.   Daubeney PE, Nugent AW, Chondros P, Carlin JB, Colan SD, Cheung M, et al. Clinical features and outcomes of childhood dilated cardiomyopathy: Results from a national population-based study. Circulation 2006; 114: 2671–2678.
• 25.   Murphy RT, Thaman R, Blanes JG, Ward D, Sevdalis E, Papra E, et al. Natural history and familial characteristics of isolated left ventricular non-compaction. Eur Heart J 2005; 26: 187–192.
• 26.   Lofiego C, Biagini E, Pasquale F, Ferlito M, Rocchi G, Perugini E, et al. Wide spectrum of presentation and variable outcomes of isolated left ventricular non-compaction. Heart 2007; 93: 65–71.
• 27.   Menon SC, O’Leary PW, Wright GB, Rios R, MacLellan-Tobert SG, Cabalka AK. Fetal and neonatal presentation of noncompacted ventricular myocardium: Expanding the clinical spectrum. J Am Soc Echocardiogr 2007; 20: 1344–1350.
• 28.   Oginosawa Y, Nogami A, Soejima K, Aonuma K, Kubota S, Sato T, et al. Effect of cardiac resynchronization therapy in isolated ventricular noncompaction in adults: Follow-up of four cases. J Cardiovasc Electrophysiol 2008; 19: 935–938.
• 29.   Gebhard C, Stähli BE, Greutmann M, Biaggi P, Jenni R, Tanner FC. Reduced left ventricular compacta thickness: A novel echocardiographic criterion for non-compaction cardiomyopathy. J Am Soc Echocardiogr 2012; 25: 1050–1057.
• 30.   Takahashi M, Yamagishi T, Narematsu M, Kamimura T, Kai M, Nakajima Y. Epicardium is required for sarcomeric maturation and cardiomyocyte growth in the ventricular compact layer mediated by transforming growth factor β and fibroblast growth factor before the onset of coronary circulation. Congenital Anomalies 2014; 54: 162–171.
• 31.   Jefferies JL, Wilkinson JD, Sleeper LA, Colan SD, Lu M, Pahl E, et al. Cardiomyopathy phenotypes and outcomes for children with left ventricular myocardial noncompaction: Results from the Pediatric Cardiomyopathy Registry. J Card Fail 2015; 21: 877–884.
• 32.   BharuchaT, Lee KJ, Daubeney PE, Nugent AW, Turner C, Sholler GF, et al. Sudden death in childhood cardiomyopathy: Results from a long-term national population-based study. J Am Coll Cardiol 2015; 65: 2302–2310.
• 33.   Alexander PM, Daubeney PE, Nugent AW, Lee KJ, Turner C, Colan SD, et al. Long-term outcomes of dilated cardiomyopathy diagnosed during childhood: Results from a national population-based study of childhood cardiomyopathy. Circulation 2013; 128: 2039–2046.
• 34.   Stöllberger C, Finsterer J. Left ventricular hypertrabeculation/noncompaction and stroke or embolism. Cardiology 2005; 103: 68–72.
• 35.   Toyono M, Kondo C, Nakajima Y, Nakazawa M, Momma K, Kusakabe K. Effects of carvedilol on left ventricular function, mass, and scintigraphic findings in isolated left ventricular non-compaction. Heart 2001; 86: E4.
• 36.   Li J, Franke J, Pribe-Wolferts R, Meder B, Ehlermann P, Mereles D, et al. Effects of β-blocker therapy on electrocardiographic and echocardiographic characteristics of left ventricular noncompaction. Clin Res Cardiol 2015; 104: 241–249.
• 37.   Kaneda T, Naruse C, Kawashima A, Fujino N, Oshima T, Namura M, et al. A novel beta-myosin heavy chain gene mutation, p. Met531Arg, identified in isolated left ventricular non-compaction in humans, results in left ventricular hypertrophy that progresses to dilation in a mouse model. Clin Sci (Lond) 2008; 114: 431–440.