Clinical and morphological aspects of non-compaction cardiomyopathy

Left ventricular non-compact cardiomyopathy (LVNC) is known under several names, including spongy myocardium, fetal myocardium, non-compaction myocardium, hyper-tra-beculation syndrome, and left ventricular non-compaction, depending on clinical features observed in patients and dur-ing its clinical evolution to hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmic car-diomyopathy (ACM), terminal heart failure or to a form of reversible outcome with repair. These polymorphisms sug-gest different pathogenetic mechanisms and possibly differ-ent forms of the disease. Non-compact myocardium has been observed already at early ages of life, including during normal cardiac development, in neonatal, paediatric, and young patients, and then during adult or advanced ages (professional athletes, pregnancy, aging). Due to the absence of overt symptoms, non-compaction myocardium may be unexpectedly diagnosed after Cardiac Magnetic Resonance, ventriculography, or endomyocardial biopsies (EMB) performed for other purposes. In 40-50% of cases, the pathogenesis of LVNC has been associated with a num-ber of mutations of two classes of genes. One (transcription factors and related genes) is speculated to produce an arrest of the final stage of myocardial morphogenesis. A second set of mutated genes appears to be involved in the correct organization and composition of supramolecular aggregates that stabilize cardiomyocytes into the connective tissue scaf-fold (cytoskeletal intracellular elements and extracellular cell-to-scaffold junction proteins) [1]. In this study, an Italian family of 7 subjects, 4 aged 10 (II-1), 14 (II-2), 43 (I-4), and 46 years (I-5), presenting abnormal ECG changes, dyspnea and palpitation (II-2, I-4, and I-5), and recurrent cerebral ischemic attack (I-5), underwent 2-dimensional echo, car-diac magnetic resonance, Holter monitoring and, EMB. EMB were subjected to next-generation sequencing gene analysis and morphological evaluation [2]. Two-dimensional echo and cardiac magnetic resonance documented LV myocardial non-compaction in all. Coronary arteries were normal. LV angiography showed transmural crypts progressing to spongy myocardial transformation with LV dilatation and dys-function in the older subject. At histology and electron microscopy lateral detachment of cardiomyocytes was asso-ciated with cell shape alterations, subcellular changes, myofibrillar disarray, and degradation of intercalated discs causing also dysancorage of myofilaments from Z-discs and cell membrane. Next-generation sequencing showed in affected members an unreported p.(Ala21Val) mutation of ACTC1. We hypothesize that the novel p.(Ala21Val) muta-tion of ACTC1 may cause alterations of myofibrillar function, intercalated disc, and other cytosolic skeleton interaction, leading to familial paediatric spongy myocardium, hyper-trophic cardiomyopathy, and LV myocardial no compaction with transmural crypts with variable clinical features. However, this hypothesis may also explain why several types of LVNC occur, such as primary myocardial forms, a form associated with arrhythmias, and a form associated with congenital heart disease, including septal defects, right heart obstructive abnormalities and, hypoplastic left heart syndrome. While in late/reversible forms other mutations could be only a susceptibility condition in which triggering factors are still unknown.