The acquired and reversible forms of LVNC question the unique and a priori interpretation of the NC morphology as a genetic disease and cardiomyopathy.55,56,57,58,59,107,108 Acquired isolated LVNC has been reported in athletes47,99,100 and pregnant women,56 as well as in hematologic disorders,57,109 chronic renal failure,59 myopathies,58 and bicuspid aortic valve.60 These observations expand the spectrum of pathogenetic hypotheses from arrested embryogenesis maturation of LV trabeculae to acquired pathogenetic mechanisms, including hemodynamics, phenotype-driven trabecular gene expression, or epigenetic factors, as in CHD.110
The identification of LVNC in preparticipation screening studies had demonstrated that intense physical training may induce increased trabeculation that may fulfill current diagnostic criteria for the diagnosis of LVNC. In a large series including more than 1000 asymptomatic athletes, 18% had increased LV trabeculation and 76 (8%) fulfilled echocardiographic criteria for LVNC.55 The issue of athletes demonstrating LVNC is emerging from different sources111,112 and in real life (Fig. 60–8). Distinguishing between pathologic LVNC and physiologic hypertrabeculation is a diagnostic challenge, and detection is becoming increasingly common with enhanced echocardiography and magnetic resonance imaging modalities.111 The proportion of athletes who develop LVNC under intensive exercise is relevant (about 10%), but the proportion of those who do not develop LVNC under the same exercise levels is 90%. The impact of LVNC on otherwise normal hearts requires long-term follow-up studies to establish with certainty whether LVNC can be an early marker of myocardial disease or the phenotype of maladaptation of different individuals to strenuous physical effort. Therefore, “healthy” athletes diagnosed with LVNC should undergo deep phenotype examination, advanced imaging, and clinical monitoring as suggested by experts.107
The figure shows the pedigree of a small family in which the proband (III:2) is a 12-year-old healthy boy, who plays soccer. He has been incidentally diagnosed with left ventricular noncompaction (LVNC) after identification of nonspecific electrocardiogram abnormalities in preparticipation screening (diphasic T waves in V2-V3, D2, aVF). Left ventricular (LV) function and dimensions were within normal ranges (LV ejection fraction, 55%; LV end-diastolic diameter, 52 mm; according to Henry, 104.8; Z-score, 0.50). The echocardiographic evaluation of the brother (III:1; soccer player) showed prominent trabeculation confirmed by cardiac magnetic resonance (CMR), not fulfilling criteria for the diagnosis of LVNC. Both parents are not athletes and had normal echocardiographic evaluation. Extensive genetic testing analysis did not identify pathologic mutations. Both siblings are carriers of a genetic variant of unknown significance [p.(Lys393Asn)] in the KCNQ1 gene. The two echocardiographic panels show the trabecular pattern in the two siblings; the CMR panel shows prominent trabeculae in III:2. The variant is inherited from the healthy father.
A form of reversible LVNC has been described in pregnancy. In a prospective longitudinal echocardiographic study of 102 primigravida pregnant normotensive women (66 white women and 36 black women) without family history of cardiomyopathy or premature sudden cardiac death, 25% developed increased LV trabeculations during pregnancy. The finding was more common in black women than in white women. Furthermore, 10 women (9.8%) fulfilled the Jenni et al2 criteria, 19 (18.6%) fulfilled the Chin et al9criteria, and 8 (7.8%) fulfilled both criteria for LVNC. There was no significant association between increased LV trabeculations and age, body mass index, systolic blood pressure, LV cavity dimension, stroke volume, or LV mass. Ethnicity was the only independent predictor for the presence of increased (three or more) trabeculations during pregnancy, with black women being almost three times more likely to develop increased LV trabeculations than white women during pregnancy after adjustment for the aforementioned factors. After delivery, 18 women (69.2%) showed complete resolution of LV trabeculations over a mean duration of 8.1 ± 4.2 months, whereas 7 women (27%) continued to display LV trabeculations, without predilection for ethnicity.56 Further series are necessary to confirm this transient trabecular remodeling and the low risk.113 However, the study56 adds evidence to the possibility that LVNC can not only be acquired, but also transient and, therefore, does not necessarily represent a primary myocardial disorder.114
LVNC has been described in patients affected by different hematologic disorders such as hereditary spherocytosis,115 essential thrombocytopenia,116 and β-thalassemia57,117 with and without myocardial overload. In patients with β-thalassemia, isolated LVNC was identified in 13.3% of patients.57 The mechanisms by which chronic anemia, hemolysis, or ineffective erythropoiesis may influence the remodeling of the trabecular compartments are not known. In patients with myocardial iron overload and siderosis, a preferential distribution of intramyocyte iron in the compacted or NC layers has not been observed.118 Myocardial T2*-weighted CMR values should be able to provide more information about intramyocyte iron storage. However, cardiac abnormalities could be triggered by toxic iron species such as non–transferrin-bound iron.118 Whether LVNC represents a physiologic adaptation to the chronic nonprimary cardiac disorders or a disease-related pathologic effect is not clear.109
LVNC has been reported in two patients with chronic renal failure. In both cases, echocardiography demonstrated a dilated LV with thickened walls and a thin, compacted myocardium on the epicardial side and a thicker noncompacted endocardial layer. Ratio between the noncompacted myocardium and the compaction myocardial layer fulfilled diagnostic criteria in both cases. Clinically relevant is the fact that oral anticoagulation therapy was initiated in both patients after the diagnosis of LVNC. Family screening with echocardiography in first-degree relatives of one of the patients did not show additional affected members. Regular echocardiographic monitoring of patients with chronic renal failure is suggested to diagnose cardiovascular diseases including this rare association.59
A high prevalence of LVNC is reported in patients fulfilling the echocardiographic criteria for bicuspid aortic valve (BAV). Specifically, in one study, 12 (11.0%) of 109 patients with BAV fulfilled the criteria for LVNC, with nine of the 12 patients being men. Although the pathophysiologic basis of LVNC in patients with BAV is unclear, special attention should be given to the evaluation of LV trabecular anatomy.60
LV hypertrabeculation may occur in patients affected by different neuromuscular diseases such as dystrophinopathies, metabolic myopathies, myotonic dystrophy, Leber hereditary optic neuropathy, and Barth syndrome. Several pathogenetic hypotheses have been advocated to explain the occurrence of LV hypertrabeculation, including “an inborn error to hypertrophy, which either starts during embryogenesis, early childhood, or in adulthood."12 Alternative hypotheses include persisting sinusoids penetrating into the LV cavity or malfunctions of gap junctions.12
Considerations on Acquired Left Ventricular Noncompaction
All the above acquired conditions of LVNC demonstrate that a unique pathogenetic hypothesis of embryogenic defect is unlikely to explain acquired, late-onset, transient LVNC. Most studies on acquired LVNC are recent and constitute a stimulus to further explore this trait in cardiac and noncardiac diseases.