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.

There are growing numbers of infants and children living with single-ventricle congenital heart disease (SV). However, cardiac dysfunction and, ultimately, heart failure (HF) are common in the SV population and the ability to predict the progression to HF in SV patients has been limited, primarily due to an incomplete understanding of the disease pathogenesis. Here, we tested the hypothesis that non-invasive circulating metabolomic profiles can serve as novel biomarkers in the SV population. We performed systematic metabolomic and pathway analyses on a subset of pediatric SV non-failing (SVNF) and failing (SVHF) serum samples, compared with samples from biventricular non-failing (BVNF) controls. We determined that serum metabolite panels were sufficient to discriminate SVHF subjects from BVNF subjects, as well as SVHF subjects from SVNF subjects. Many of the identified significantly dysregulated metabolites were amino acids, energetic intermediates and nucleotides. Specifically, we identified pyruvate, palmitoylcarnitine, 2-oxoglutarate and GTP as promising circulating biomarkers that could be used for SV risk stratification, monitoring response to therapy and even as novel targets of therapeutic intervention in a population with few other options.

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.

Background: While operative and perioperative care continues to improve for single ventricle congenital heart disease (SV), long-term morbidities and mortality remain high. Importantly, phosphodiesterase-5 inhibitor therapies (PDE5i) are increasingly used, however, little is known regarding the direct myocardial effects of PDE5i therapy in the SV population. Objectives: Our group has previously demonstrated that the failing SV myocardium is characterized by increased PDE5 activity and impaired mitochondrial bioenergetics. Here we sought to determine whether serum circulating factors contribute to pathological metabolic remodeling in SV, and whether PDE5i therapy abrogates these changes. Methods: Using an established in vitro model whereby primary cardiomyocytes are treated with patient sera +/− PDE5i, we assessed the impact of circulating factors on cardiomyocyte metabolism. Mass spectrometry-based lipidomics and metabolomics were performed to identify phospholipid and metabolite changes. Mitochondrial bioenergetics were assessed using the Seahorse Bioanalyzer and a stable isotope based mitochondrial enzyme activity assay. Relative mitochondrial copy number was quantified using RT-qPCR. Results: Our data suggest that serum circulating factors contribute to fundamental changes in cardiomyocyte bioenergetics, including impaired mitochondrial function associated with decreased cardiolipin and other phospholipid species, increased reactive oxygen species (ROS) generation, and altered metabolite milieu. Treatment with PDE5i therapy was sufficient to abrogate a number of these metabolic changes, including a rescue of phosphatidylglycerol levels, a reduction in ROS, improved energy production, and normalization of several key metabolic intermediates. Conclusions: Together, these data suggest PDE5i therapy has direct cardiomyocyte effects and contributes to beneficial cardiomyocyte metabolic remodeling in SV failure.

Background: Although operative and perioperative care continues to improve for patients with single ventricle (SV) congenital heart disease, long‐term morbidities and mortality remain high. Importantly, phosphodiesterase‐5 inhibitor (PDE5i) therapies are increasingly used, but their direct myocardial effects in SV congenital heart disease remain poorly understood. We previously demonstrated that the failing SV myocardium is characterized by increased PDE5 (phosphodiesterase‐5) activity and impaired mitochondrial bioenergetics. Here we sought to determine whether systemic circulating factors contribute to pathological metabolic remodeling in SV congenital heart disease, and whether PDE5i therapy mitigates these changes. Methods: Using an established in vitro model whereby primary cardiomyocytes are treated with patient sera ± PDE5i, we assessed the impact of circulating factors on cardiomyocyte metabolism. Mass spectrometry‐based lipidomics and metabolomics assessed phospholipid and metabolite changes. Mitochondrial bioenergetics were evaluated using the Seahorse Bioanalyzer and a stable isotope‐based enzyme activity assay. Relative mitochondrial copy number was quantified using reverse transcriptase–quantitative polymerase chain reaction. Results: Our data suggest that circulating factors contribute to fundamental changes in cardiomyocyte bioenergetics, including impaired mitochondrial function associated with decreased cardiolipin and other phospholipid species, impaired carnitine palmitoyltransferase activity, increased reactive oxygen species generation, and altered metabolite milieu. PDE5i treatment partially reversed these abnormalities by restoring phosphatidylglycerol levels, reducing reactive oxygen species, increasing carnitine palmitoyltransferase activity, improving energy production, and normalizing several metabolic intermediates. Conclusions: Together, these data suggest circulating factors directly impair cardiomyocyte mitochondrial bioenergetics and may drive systemic metabolic dysfunction in SV congenital heart disease. PDE5i therapy partially attenuates these effects, supporting metabolic modulation as a potential therapeutic strategy for SV failure.