Abstract
Biomarkers of heart failure in adults have been extensively studied. However, biomarkers to monitor the progression of heart failure in children with univentricular physiology are less well understood. We proposed that as mediators of diverse pathophysiology, miRNAs contained within circulating microvesicles could serve as biomarkers for the presence and progression of heart failure in univentricular patients. To test this, we studied the association of heart failure with elevations in specific miRNAs isolated from circulating microvesicles in a cohort of children with univentricular heart disease and heart failure. We conducted a single site cross-sectional observational study of 71 children aged 1 month-7 years with univentricular heart disease and heart failure. We demonstrated that levels of miR129-5p isolated from plasma microvesicles were inversely related to the degree of clinical heart failure as assessed by Ross score. We then showed that miR129-5p levels are downregulated in HL1 cells and human embryonic stem cell-derived cardiomyocytes exposed to oxidative stress. We demonstrated that bone morphogenetic protein receptor 2, which has been implicated in the development of pulmonary vascular disease, is a target of miR129-5p, and conversely regulated in response to oxidative stress in cell culture. Levels of miR129-5p were inversely related to the degree of clinical heart failure in patients with univentricular heart disease. This study demonstrates that miR129-5p is a sensitive and specific biomarker for heart failure in univentricular heart disease independent of ventricular morphology or stage of palliation. Further study is warranted to understand the targets affected by miR129-5p with the development of heart failure in patients with univentricular physiology.
Highlights
Biomarkers of heart failure (HF) resulting from ischemic cardiomyopathy in adults have been extensively studied
This study demonstrated that microvesicles can be interrogated as a source of miRNAs released into the circulation with HF, that there is an inverse relationship between levels of miR129-5p in circulating microvesicles and the degree of HF in pediatric patients with univentricular heart disease, that miR129-5p is downregulated in cultured human cardiomyocytes and cardiomyocytes derived from human embryonic stem cell (hESC) exposed to oxidative stress, and that bone morphogenetic protein receptor 2 (BMPR2) expression is likely regulated by miR129-5p in the setting of cardiomyocyte stress
In previous studies of potential biomarkers for HF in this population, we found that both the morphology of the single ventricle and the stage of palliation affected the sensitivity of the biomarker for detecting HF
Summary
Biomarkers of heart failure (HF) resulting from ischemic cardiomyopathy in adults have been extensively studied. Biomarkers to monitor the progression of HF in infants and young children with univentricular physiology, are less well understood. This may be due to the etiology of HF in this population, myocardial dysfunction resulting from the altered hemodynamics of the pulmonary and systemic circulations [1] and pulmonary vascular disease [2]. MiRNAs are known to influence biological and metabolic processes that are dysregulated in various diseases [5]. The ability to evaluate circulating miRNA levels in patients is made difficult by their relatively low concentration in a large volume of circulating plasma
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