We read with interest the article by Rodríguez-Serrano et al1 about familial left ventricular hypertrabeculation/noncompaction (LVHT) associated with a novel alpha-cardiac actin gene (ACTC1)-mutation in 4 family members (II:4, III:4, III:6, IV:1), of whom 3 (II:4, III:4, III:6) presented with noncompaction and 1 with hypertrabeculation of the explanted heart. We have the following comments and concerns.
We do not agree with the statement that the described ACTC1-mutation “caused” LVHT.1 LVHT is associated with mutations in a large number of different genes but no proof has ever been provided for any of these associations that a particular mutation is truly causative of this myocardial abnormality. Reservations against a causal relation comes from the following arguments: first, in most cases of hereditary disease in which LVHT has been described, only a limited number of mutation carriers also had LVHT.2 Second, LVHT may be a dynamic abnormality that may not be present at birth in single patients (acquired LVHT)3 and may more rarely even disappear during life.4 Third, most of the few patients with acquired LVHT did not carry a mutated gene and did not have LVHT on previous echocardiographic or other cardiac imaging studies.5 Fourth, according to the authors themselves, the pathogenicity of the detected ACTC1 variant was neither confirmed nor excluded by in silico analysis.1 Fifth, the mutated genes so far associated with LVHT are responsible for a variety of hereditary disorders, ranging from cardiac to neuromuscular disease, including hereditary neuropathies and cobalamin-C deficiency.4 Sixth, LVHT frequently occurs in patients with chromosomal defects (eg, p1.36 syndrome).2 Given these arguments, we consider LVHT to be a secondary myocardial abnormality in compensation for other cardiac disease, possibly induced by upregulation of regulatory genes.
Concerning the index patient, some confusion derives from the description of the explanted heart as having shown LVHT but this is not mentioned in the pedigree. Instead, the authors describe the patient as having “left ventricular hypertrabeculation”. What is the difference between noncompaction and left ventricular hypertrabeculation? In our understanding, noncompaction and hypertrabeculation are 2 different terms for the same entity.6 The term hypertrabeculation, however, appears to be the more favorable one since it is descriptive and does not imply a causal relation.
Since there is no general agreement on the definition of LVHT, it would be interesting to know if LVHT in the 4 individuals presented would meet Chin's or Stöllberger's diagnostic criteria.
The echocardiographic image of patient IV:1 is not convincing. Why was LVHT absent on echocardiography? Were the cine loops of this investigation revised? Was LVHT truly absent? If truly absent, what was the reason for the discrepancy with the histologic finding in the explanted heart? Since it is mentioned that this patient had undergone heart transplantation, a picture of the explanted heart would be helpful.
Although involvement of the skeletal muscle in ACTC1-mutations has not been reported, it is advisable to investigate all individuals with LVHT neurologically. This is because neuromuscular disorders are the diseases most frequently associated with LVHT7and because of the uncertainty whether the ACTC1 alteration is a polymorphism or a pathogenic mutation. It would also be worthwhile to conduct a neurological examination in family members who did not show LVHT. Were creatine-kinase serum levels normal in all investigated patients?
Overall, this interesting report could benefit from clarification of some inconsistencies. It is also important to discuss the absence of LVHT on echocardiography in patient IV:1. The more details that are provided about patients or families with LVHT, the more likely the cryptogenic pathogenesis of this still enigmatic myocardial abnormality will be clarified.
