Malformations of the Left Ventricle: What Comes First: Form or Function?

Abstract

Both left ventricular (LV) noncompaction of the myocardium (LVNC) and hypoplastic left heart (HLH) are thought to be congenital developmental defects of the LV musculature. Mutations in genes encoding sarcomere proteins have been identified in a significant proportion of LVNC patients,1,2 as well as in association with congenital heart defects (CHDs).3–5 The presence of sarcomere mutations suggest an underlying cohesiveness of cardiomyopathy and structural CHDs, supporting the essential role for normal sarcomere function during cardiac development. In this issue of Circulation Cardiovascular Genetics , 2 papers6,7 report on the results of whole exome sequencing and whole genome sequencing (WGS) in patients with LVNC and HLH, respectively. By next-generation sequencing of multiple affected and unaffected family members, they demonstrate (1) that heterozygous MHY7 mutations are common in LVNC and identify NNT , encoding a nuclear-encoded mitochondrial protein, as a novel LVNC gene (2) compound heterozygosity for recessive MYH6 mutations in patients with HLH and reduced right ventricular ejection fraction. Articles see p 544 and p 564 LVNC has been recognized as a distinct primary cardiomyopathy with a genetic pathogenesis by the American Heart Association and is still considered an unclassified cardiomyopathy according to the European Society of Cardiology. LVNC is characterized by a unique myocardial morphology: hypertrophic segments that consist of a thin compacted epicardial layer and a thick noncompacted endocardial layer which may be hypokinetic. The noncompacted layer contains numerous prominent trabeculations and deep intertrabecular recesses.8 During heart development, the myocardium is initially trabeculated during a period before coronary artery development. Between embryonic weeks 5 and 8, the trabeculae regress as the compact myocardium develops from base to apex. Therefore, LVNC is considered to be an abnormality reflecting arrested early cardiac morphogenesis.9 LVNC may be an isolated finding in …