Circulating MicroRNAs Identify Early Phenotypic Changes in Sarcomeric Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. Pathogenic germline variation in genes encoding the sarcomere is the predominant cause of disease. However diagnostic features, including unexplained left ventricular hypertrophy, typically do not develop until late adolescence or after. The early stages of disease pathogenesis and the mechanisms underlying the transition to a clinically overt phenotype are not well understood. In this study, we investigated if circulating microRNAs (miRNAs) could stratify disease stage in sarcomeric HCM. METHODS: We performed arrays for 381 miRNAs using serum from HCM sarcomere variant carriers with and without a diagnosis of HCM and healthy controls. To identify differentially expressed circulating miRNAs between groups, multiple approaches were used including random forest, Wilcoxon rank sum test, and logistic regression. The abundance of all miRNAs was normalized to miRNA-320. RESULTS: Of 57 sarcomere variant carriers, 25 had clinical HCM and 32 had subclinical HCM with normal left ventricular wall thickness (21 with early phenotypic manifestations and 11 with no discernible phenotypic manifestations). Circulating miRNA profile differentiated healthy controls from sarcomere variant carriers with subclinical and clinical disease. Additionally, circulating miRNAs differentiated clinical HCM from subclinical HCM without early phenotypic changes; and subclinical HCM with and without early phenotypic changes. Circulating miRNA profiles did not differentiate clinical HCM from subclinical HCM with early phenotypic changes, suggesting biologic similarity between these groups. CONCLUSIONS: Circulating miRNAs may augment the clinical stratification of HCM and improve understanding of the transition from health to disease in sarcomere gene variant carriers.

Cardiac Transcriptome Remodeling and Impaired Bioenergetics in Single-Ventricle Congenital Heart Disease.

The mechanisms responsible for heart failure in single-ventricle congenital heart disease are unknown. Using explanted heart tissue, we showed that failing single-ventricle hearts have dysregulated metabolic pathways, impaired mitochondrial function, decreased activity of carnitine palmitoyltransferase activity, and altered functioning of the tricarboxylic acid cycle. Interestingly, nonfailing single-ventricle hearts demonstrated an intermediate metabolic phenotype suggesting that they are vulnerable to development of heart failure in the future. Mitochondrial targeted therapies and treatments aimed at normalizing energy generation could represent a novel approach to the treatment or prevention of heart failure in this vulnerable group of patients.

Medical Therapies for Heart Failure in Hypoplastic Left Heart Syndrome.

Significant surgical and medical advances over the past several decades have resulted in a growing number of infants and children surviving with hypoplastic left heart syndrome (HLHS) and other congenital heart defects associated with a single systemic right ventricle (RV). However, cardiac dysfunction and ultimately heart failure (HF) remain the most common cause of death and indication for transplantation in this population. Moreover, while early recognition and treatment of single ventricle-related complications are essential to improving outcomes, there are no proven therapeutic strategies for single systemic RV HF in the pediatric population. Importantly, prototypical adult HF therapies have been relatively ineffective in mitigating the need for cardiac transplantation in HLHS, likely due to several unique attributes of the failing HLHS myocardium. Here, we discuss the most commonly used medical therapies for the treatment of HF symptoms in HLHS and other single systemic RV patients. Additionally, we provide an overview of potential novel therapies for systemic ventricular failure in the HLHS and related populations based on fundamental science, pre-clinical, clinical, and observational studies in the current literature.