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Etiology

Historically, it was thought that in the developing myocardium, the mesh of embryonic loose muscle fibers (present until coronary artery development) condensed to form a compact left ventricular myocardium, and an arrest in the embryogenic process caused the trabecular tissue to "non-compact" into the thinner myocardial layer. However, more recent data using pulse labeling and immunohistochemical staining suggest that the trabecular layers and compact layers of the myocardium develop independently of each other. Therefore, the terminology of "noncompaction" may actually be a misnomer, as the trabecular tissue does not normally compact.[3] In addition, more recent studies suggest that the pattern of increased trabeculations causing thickened endocardium may not necessarily be embryologic because this pattern is also found in healthy individuals, athletes, and pregnant adults. The morbidity in patients with increased trabecular tissue may be due to co-occurrence with other recognized myocardial disorders. At this time, it is unclear if this phenotype is related to hemodynamic stress (such as increased preload), a genetic predisposition, or, most likely, a combination of both.[1][3][4]

Some patients have sporadic LVNC with no family history or a proven genetic mutation. About 15% to 20% of cases are thought to be inherited and present earlier than those without a family history.[4] From 17% up to 50% of patients with LVNC have first-degree relatives with another cardiomyopathy, such as hypertrophic cardiomyopathy or dilated cardiomyopathy.[5] Currently, up to 40 different gene loci are associated with trabecular complexity.[3] Most of the known genetic mutations encode proteins linked to functions involving sarcomeres, mitochondria, arrhythmia, and congenital heart disease.[6][7]

The most commonly found mutations are in the β-Myosin heavy chain (MYH7), MYBPC3 (which encodes the cardiac isoform of myosin-binding protein C), and the titin (TTN) gene. The risk of lower systolic function is higher in patients carrying a genetic mutation, with the highest risk in those with TTN and in those who have more than one genetic mutation.[8] Other recognized genes associated with LVNC include cardiac troponin T (TNNT2), α-cardiac actin (ACTC), tafazzin, α-dystrobrevin, lamin A/C, ZASP/LDB3, dystrophin, HCN4, and MYH7. These genes encode the sarcomeric proteins associated with cardiac contractility.[9]

One associated syndrome is Barth syndrome, attributed to mutations in the tafazzin gene.[10] HCN4 mutations have been identified in patients with LVNC and bradycardia.[11] LVNC is also prevalent in up to 20% of patients with Duchenne muscular dystrophy and Becker muscular dystrophy, where its presence is highly associated with a rapid deterioration in LV function and higher mortality.[12] LVNC is also associated with other neuromuscular disorders, such as myotonic dystrophy and mitochondrial disorders. The causal relationship is yet to be identified but may be related to a fragile cytoskeleton.[3]