Methods

Since 2005, adult patients with NCC and their family members have been prospectively followed up at our center, a tertiary referral center. Their data were collected and analyzed in accordance with the hospital institutional review board policies. We obtained detailed family histories from all 80 patients in the registry to construct pedigrees. The family history was considered abnormal, if it was positive for nonischemic heart failure, cardiomyopathies, documented supraventricular or ventricular arrhythmias, or pacemaker/implantable cardioverter-defibrillator placement. From 44 patients, we obtained informed consent to interview family members and completed the screening and counseling as described in the next paragraph ( Table 1 ). Subsequently, the 44 patients were referred to a clinical geneticist for genetic counseling, to initiate family studies, and to obtain additional informed consent for DNA analysis. The results have recently been published. All living first-degree relatives of these 44 patients were invited to undergo a cardiac examination after appropriate counseling. When possible, “cascade screening” for cardiomyopathies was pursued. From 231 first-degrees relatives, 136 (59%) accepted the invitation for cardiac screening (median 60%, interquartile range 20% to 83%).

The cardiac evaluation of the 156 relatives was done by 2 experienced clinicians (K.C., M.M.). The evaluation consisted of a review of the medical history, physical examination, electrocardiography, and 2-dimensional echocardiography. From the electrocardiogram-derived heart rate, the PQ, QRS, and QTc intervals were measured. The QTc interval was calculated after correction for the heart rate using Bazett’s formula. The electrocardiogram was considered abnormal if it showed pathologic Q waves (>40 ms or >25% R waves in ≥2 leads), left ventricular hypertrophy, complete bundle branch block, or nonspecific intraventricular conduction delay or (minor) repolarization abnormalities. The LV end-diastolic diameter, LV end-systolic diameter, and the presence or absence of significant valvular abnormalities were determined using 2-dimensional echocardiography. Measurements of the LV volumes and ejection fraction were not made because of the inherent problem of identifying the endocardial border in the presence of extensive trabeculation. Global LV function was estimated by visual assessment by 2 experienced observers and classified as 1, normal LV function; 2, mild LV dysfunction; 3, moderate LV dysfunction; and 4, severe LV dysfunction. Additionally, fractional shortening was measured: (LV end-diastolic diameter − LV end-systolic diameter)/LV end-diastolic diameter × 100%. The extent and severity of noncompaction was assessed by measuring the maximal noncompacted and compacted wall thickness with electronic calipers in the parasternal short-axis or apical 4-chamber view, in end-systole. A noncompacted wall thickness was diagnosed if prominent trabeculations were present with a noncompacted/compacted ratio >2 at the end-systole, regardless of LV function. In case of a diagnosis using magnetic resonance imaging (MRI), a noncompacted/compacted ratio of >2.3 at end-diastole was used. Because of poor echocardiographic image quality, especially at the level of the LV apical or midventricular walls, MRI (n = 10 [6%]) or contrast echocardiography (n = 6 [4%]) was performed for a firm diagnosis in 14 subjects (10%). All echocardiographic and MRI scans were reviewed by both clinicians, and the diagnosis was made by consensus. The cardiac assessment was extended with 24-hour electrocardiographic monitoring and an exercise test when NCC or other heart disease was suspected because of complaints or abnormal electrocardiographic, echocardiographic, or MRI findings. The diagnosis of NCC was established according to stringent echocardiographic criteria, as described by Jenni et al : (1) an excessively thickened LV myocardial wall with a 2-layered structure composed of a compacted epicardial layer and a noncompacted layer of prominent trabeculations on the endocardial side, (2) a noncompacted/compacted myocardial thickness ratio >2 measured at the moment of maximal thickness in end-systole on the parasternal short-axis view, (3) color Doppler evidence of deep intertrabecular recesses in communication with the LV cavity, and (4) the absence of coexisting cardiac anomalies. Dilated cardiomyopathy (DC) was diagnosed in the case of myocardial abnormalities that did not fulfill the diagnosis of NCC.

Continuous variables are summarized as the mean ± SD or median and interquartile range (25th, 75th percentile), as appropriate. Categorical variables are presented as frequencies and percentages. A comparison of continuous variables between groups was made using the unpaired Student t test. When comparing frequencies, the chi-square test or Fisher’s exact test was used, where applicable. All tests were 2-tailed, and p <0.05 was considered statistically significant.

Results

The baseline characteristics of the index patients, with or without family screening, were fully comparable ( Table 1 ). A total of 156 close relatives of 44 unrelated patients with NCC accepted our invitation for cardiac screening and counseling ( Figure 1 and Table 2 ). Cardiac screening revealed that familial disease was present in 49%. Sudden cardiac death at <60 years old was reported in 8 families (18%). In 1 sibling and 2 children, congenital heart disease had been diagnosed before the family screening, including a combination of pulmonary valve stenosis and atrial septal defect in 2 subjects.

Summary of evaluation of close relatives of patients with NCC.

NCC or DC was found in 41 relatives (26%) using transthoracic 2-dimensional echocardiography (n = 25), MRI (n = 10) or contrast echocardiography (n = 6; Figure 2 and Table 3 ). All the relatives diagnosed with DC had some form of prominent trabeculations (noncompacted/compacted ratio 1.0 to and 2.0), without fulfilling the diagnostic criteria for NCC (noncompacted/compacted ratio >2.0). Abnormal electrocardiographic findings were observed in 51 subjects (33%). Of the 41 subjects with NCC or DC, 16 (39%) had normal electrocardiographic findings. Of the subjects with NCC, 13 (32%) already had known cardiac symptoms and signs, but most (n = 28 [68%]) were asymptomatic. The 6 patients who presented with heart failure and/or a cerebrovascular accident had previously been regarded to have DC but at revision fulfilled the Jenni criteria for NCC. Most subjects with NCC had mild (n = 21 [51%]) or moderate to severe LV dysfunction (n = 8 [20%]).

Close view of 4-chamber echocardiographic and 3-chamber MRI view of 25-year-old asymptomatic son of a female patient who first presented in 2010 with paroxysmal atrial fibrillation and heart failure due to severe LV dysfunction at 58 years old. MRI revealed an ejection fraction of around 40%, and he was prophylactically treated with an angiotensin-converting enzyme inhibitor and a β blocker.

Table 3

Clinical, electrocardiographic, and echocardiographic characteristics of screened noncompaction cardiomyopathy (NCC) relatives

Variable	Affected (n = 41)	Not Affected (n = 115)	p Value
Mean age at diagnosis (years)	36 ± 19	43 ± 19	0.02
Men	23 (56%)	46 (40%)	0.10
Hypertension	2 (5%)	16 (14%)	Ns
Diabetes mellitus	2 (5%)	2 (2%)	Ns
Coronary artery disease	1 (2%)	1 (1%)	Ns
Congenital heart disease	2 (5%)	1 (1%)	Ns
Asymptomatic	28 (68%)	110 (96%)	<0.0001
Heart failure (New York Heart Association)	5 (12%)	0	0.009
I	2	0
II	3	0
Supraventricular arrhythmias	4 (10%)	3 (3%)	0.08
Cerebrovascular events	2 (5%)	0	0.08
Miscellaneous ⁎	3 (7%)	2 (2%)	0.06
Abnormal electrocardiogram	25 (61)	26 (23)	0.0001
Atrial fibrillation	2 (5%)	1 (1%)	Ns
First-degree atrioventricular block	1 (2%)	2 (2%)	Ns
Bundle branch block	1 (2%)	0	Ns
Left ventricular hypertrophy	4 (11%)	6 (5%)	Ns
Nonspecific intraventricular conduction abnormality	5 (14%)	7 (6%)	Ns
T-wave inversion (lateral/inferior)	2 (5%)	0	0.08
Minor repolarization abnormality	10 (24%)	11 (10%)	0.03
Left atrium (mm)	40 ± 8	39 ± 6	Ns
Intraventricular septum (mm)	9 ± 2	9 ± 2	Ns
Left ventricular end-diastolic diameter (mm)	56 ± 7	50 ± 5	<0.0001
Left ventricular end-systolic diameter (mm)	42 ± 8	31 ± 5	<0.0001
Fractional shortening (%)	26 ± 7	36 ± 7	0.001
Left ventricular dysfunction	29 (71%)	1 (1%)	<0.0001
Mild	21 (51%)	0
Moderate	4 (10%)	1 (1%)
Severe	4 (10%)	0
Noncompacted segments (%)	47 ± 14	0
Noncompacted/compacted ratio	2.6 ± 0.3
Valvular abnormalities	4 (10%)	3 (3%)	0.08

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