Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including MYH7, MYBPC3, ACTC1, TPM1, MYL2, MYL3, TNNI3, and TNNT23. Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding RNAs (lncRNAs) are a large class of transcripts ≥200 nucleotides in length that do not encode proteins. Compared to coding mRNAs, most lncRNAs are not as well-annotated and their functions are greatly unexplored. Nevertheless, increasing evidence shows that lncRNAs are involved in a variety of biological processes and diseases including HCM. Accumulating evidence has indicated that lncRNAs are dysregulated in HCM, and closely related to sarcomere construction, calcium channeling and homeostasis of mitochondria. In this review, we have summarized the known regulatory and functional roles of lncRNAs in HCM.

Impact of Genetic Testing for Cardiomyopathy on Emotional Well-Being and Family Dynamics: A Study of Parents and Adolescents

Background: Genetic testing is indicated for children with a personal or family history of hereditary cardiomyopathy to determine appropriate management and inform risk stratification for family members. The implications of a positive genetic result for children can potentially impact emotional well-being. Given the nuances of cardiomyopathy genetic testing for minors, this study aimed to understand how parents involve their children in the testing process and investigate the impact of genetic results on family dynamics. Methods: A survey was distributed to participants recruited from the Children’s Cardiomyopathy Foundation and 7 North American sites in the Pediatric Cardiomyopathy Registry. The survey explored adolescent and parent participants’ emotions upon receiving their/their child’s genetic results, parent-child result communication and its impact on family functionality, using the McMaster Family Assessment Device. Results: One hundred sixty-two parents of minors and 48 adolescents who were offered genetic testing for a personal or family history of cardiomyopathy completed the survey. Parents whose child had cardiomyopathy were more likely to disclose positive diagnostic genetic results to their child ( P =0.014). Parents with unaffected children and positive predictive testing results were more likely to experience negative emotions about the result ( P ≤0.001) but also had better family functioning scores than those with negative predictive results ( P =0.019). Most adolescents preferred results communicated directly to the child, but parents were divided about whether their child’s result should first be released to them or their child. Conclusions: These findings have important considerations for how providers structure genetic services for adolescents and facilitate discussion between parents and their children about results.

Genetic Diagnosis in Sudden Cardiac Death: The Crucial Role of Multidisciplinary Care

Sudden death, especially at a young age, may be caused by an underlying genetic cause. Hereditary conditions with an increased risk of sudden death at a young age include cardiomyopathies, arrhythmia syndromes, and hereditary thoracic aortic aneurysms and dissections. The identification of a genetic cause allows for genetic testing and cardiological surveillance in at-risk relatives. Three sudden death cases from our hospital illustrate the value of autopsy, genetic, and cardiological screening in relatives following a sudden death. On autopsy, histology consistent with hereditary cardiomyopathy is a reason for the referral of relatives. In addition, in the absence of an identifiable cause of death by autopsy in young sudden death patients, arrhythmia syndrome should be considered as a potential genetic cause.

Myocardial Fibrosis in the Pathogenesis, Diagnosis, and Treatment of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a type of hereditary cardiomyopathy caused by gene mutation. Its histologicalfeatures include cardiomyocyte hypertrophy and disarray as well as myocardial fibrosis. Gene mutation, abnormal signal transduction, and abnormal energy metabolism are considered the main mechanisms of myocardial fibrosis.There is a strong correlation between myocardial fibrosis and the occurrence, development, and prognosis of HCM.We review the application of myocardial fibrosis in the diagnosis and treatment of HCM, focusing on research progressand the application of magnetic resonance imaging on the basis of the characteristics of fibrosis in the diagnosis andprognosis of HCM.

Increase of NADPH oxidase 3 in heart failure of hereditary cardiomyopathy

During the development of heart failure in humans and animal models, an increase in reactive oxygen species (ROS) levels was observed. However, there is no information whether this increase of ROS is associated with an increase in the density of specific isoforms of NADPH oxidases (NOXs) 1–5. The objective of this study was to verify whether the densities of NOXs 1–5 change during the development of heart failure. Using the well-known model of cardiomyopathic hamsters, the UM-X 7.1 line, a model that strongly resembles the pathology observed in humans from a morphological and functional point of view, our studies showed that, as in humans, NOXs 1–5 are present in both normal and UM-X7.1 hamster hearts. Even though the densities of NOXs 2 and 5 were unchanged, the levels of both NOXs 1 and 4 significantly decreased in UM-X7.1 hamster hearts during heart failure. These changes were accompanied with a significant increase in NOX3 level. These results suggest that, during heart failure, NOX3 plays a vital role in compensating the decrease of NOXs 1 and 4. This increase in NOX3 may also be responsible, at least in part, for the reported increase in ROS levels in heart failure.

Exome sequencing identified mutations in CASK and MYBPC3 as the cause of a complex dilated cardiomyopathy phenotype

SummaryWhole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the initial tool to study patients with clinically recognized disorders when more than one gene is responsible for the phenotype or in complex phenotypes, when variants in more than one gene can be the cause for the disease. Here we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations, and a second variant, in MYBPC3, that is associated with hereditary cardiomyopathy. We conclude that although the potential for co-occurrence of rare diseases is higher when analyzing undefined phenotypes in consanguineous families, it should also be given consideration in the genetic evaluation of complex phenotypes in non-consanguineous families.

Na+–H+ exchanger inhibitor prevents early death in hereditary cardiomyopathy

Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular Na+ and Ca2+ overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented Na+ and Ca2+ overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent Na+ and Ca2+ overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy.