Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot

Abstract

Introduction The adult congenital heart disease population with repaired tetralogy of Fallot (TOF) is subject to chronic volume and pressure loading leading to a 40% probability of right ventricular (RV) failure by the 3rd decade of life. We sought to identify a non-invasive signature of adverse RV remodeling using peripheral blood microRNA (miRNA) profiling to better understand the mechanisms of RV failure. Methods Demographic, clinical data, and blood samples were collected from adults with repaired TOF (N = 20). RNA was isolated from the buffy coat of peripheral blood and whole genome miRNA expression was profiled using Agilent’s global miRNA microarray platform. Fold change, pathway analysis, and unbiased hierarchical clustering of miRNA expression was performed and correlated to RV size and function assessed by echocardiography performed at or near the time of blood collection. Results MiRNA expression was profiled in the following groups: 1. normal RV size (N = 4), 2. mild/moderate RV enlargement (N = 11) and 3. severe RV enlargement (N = 5). 267 miRNAs were downregulated, and 66 were upregulated across the three groups (fold change >2.0, FDR corrected p<0.05) as RV enlargement increased and systolic function decreased. qPCR validation of a subset of these miRNAs identified increasing expression of miRNA 28-3p, 433-3p, and 371b-3p to be associated with increasing RV size and decreasing RV systolic function. Unbiased hierarchical clustering of all patients based on miRNA expression demonstrates three distinct patient clusters that largely coincide with progressive RV enlargement. Pathway analysis of dysregulated miRNAs demonstrates up and downregulation of cell cycle pathways, extracellular matrix proteins and fatty acid synthesis. HIF 1α signaling was downregulated while p53 signaling was predicted to be upregulated. Conclusion Adults with TOF have a distinct miRNA profile with progressive RV enlargement and dysfunction implicating cell cycle dysregulation and upregulation in extracellular matrix and fatty acid metabolism. These data suggest peripheral blood miRNA can provide insight into the mechanisms of RV failure and can potentially be used for monitoring disease progression and to develop RV specific therapeutics to prevent RV failure in TOF.

miRNA Dysregulation in Cardiovascular Diseases: Current Opinion and Future Perspectives

“…Moreover, they described that miR-29-5p was significantly higher in DCM compared with IHD. Weldy et al [ 45 ] reported that the high plasma levels of miR-28-3p, miR-433-3p, and miR-371b-3p are related to increased right ventricular size. Moscoso et al [ 75 ] described the prognostic value of miR-499a and miR-125b in response to cardiac resynchronization therapy: the patients who positively responded to therapy showed lower plasma levels of these miRNAs.…”

A Noninvasive Circulating Signature of Combined Right Ventricular Pressure and Volume Overload in Tetralogy of Fallot/Pulmonary Atresia/Major Aortopulmonary Collateral Arteries

“…7 Circulating miRNA is of particular interest as potential biomarkers of fibrosis and hypertrophy. 8–14 Circulating proteins of ventricular stretch, cardiac remodeling, oxidative stress, and inflammation are showing promise in guiding heart failure therapy in adult ischemic heart disease. 15 There are emerging data on circulating biomarkers to understand the mechanisms of heart failure in children with congenital heart disease including metabolic profiling to identify ventricular remodeling in aortic valve abnormalities, 16 defects in amino acid metabolism in Fontan circulation implicating altered energy metabolism 17 and altered extracellular matrix (ECM) proteins in interstage infants with single ventricle heart disease.…”

Transcriptome Analysis of Right Ventricular Outflow Tract Myocardium in Repaired TOF Patients with Pulmonary Regurgitation Revealed the Genetic Features of the Right Ventricle Dysfunction

“…From the genetic perspective, the etiology of TOF is multifactorial. Despite successful surgical repair, many patients have chronic volume loading caused by pulmonary regurgitation (PR) that leading to a 40% probability of right ventricular (RV) failure by the 3 rd decade of life [1,2] . In addition, some patients developed RV failure before 30 years of age.…”