Circulating miRNAs in Pediatric Pulmonary Hypertension Show Promise as Biomarkers of Vascular Function

Abstract

Background/Objectives The objective of this study was to evaluate the utility of circulating miRNAs as biomarkers of vascular function in pediatric pulmonary hypertension. Method Fourteen pediatric pulmonary arterial hypertension patients underwent simultaneous right heart catheterization (RHC) and blood biochemical analysis. Univariate and stepwise multivariate linear regression was used to identify and correlate measures of reactive and resistive afterload with circulating miRNA levels. Furthermore, circulating miRNA candidates that classified patients according to a 20% decrease in resistive afterload in response to oxygen (O2) or inhaled nitric oxide (iNO) were identified using receiver-operating curves. Results Thirty-two circulating miRNAs correlated with the pulmonary vascular resistance index (PVRi), pulmonary arterial distensibility, and PVRi decrease in response to O2 and/or iNO. Multivariate models, combining the predictive capability of multiple promising miRNA candidates, revealed a good correlation with resistive (r = 0.97, P2−tailed < 0.0001) and reactive (r = 0.86, P2−tailed < 0.005) afterloads. Bland-Altman plots showed that 95% of the differences between multivariate models and RHC would fall within 0.13 (mmHg−min/L)m2 and 0.0085/mmHg for resistive and reactive afterloads, respectively. Circulating miR-663 proved to be a good classifier for vascular responsiveness to acute O2 and iNO challenges. Conclusion This study suggests that circulating miRNAs may be biomarkers to phenotype vascular function in pediatric PAH.

Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia

“…with additional data points) for PH in BPD in a larger independent prospective BPD cohort is needed. Furthermore, in addition to SNPs and clinical data, miRNAs , metabolomics, and/or endothelial progenitor cells may also be useful contributors to a predictive model for PH in BPD patients .…”

The left ventricle undergoes biomechanical and gene expression changes in response to increased right ventricular pressure overload

“…However, the associations found in our data is purely observational and does not suggest any mechanistic link. We chose 4 miR candidates (miR‐93, miR‐130a, miR‐34a, let‐7b), based on their expected physiological relevance from literature and our unpublished preliminary circulating miRNA data in children with PH (Note: we have published circulating miR candidates associated with vascular dysfunction (Kheyfets et al, ), but have not published circulating miR candidates associated with ventricular dysfunction). Although, there are additional possible miRNA targets in the LV that have been revealed in Sugen + Hypoxia rat models (e.g.…”

“…Expression of selected miRNAs, which were chosen based on relevance in PH literature (Nishi et al, ; Reddy et al, ) and our previous studies on circulating miRNAs in children (V. O. Kheyfets et al, ), was measured using TaqMan probes and reverse transcriptase‐polymerase chain reaction (RT‐PCR). Below is a list of genes measured in LV tissue: (1) miR‐130; (2) miR‐93; (3) lethal‐7b (let‐7b); (4) miR‐34a; (5) α‐myosin heavy chain (MHC) mRNA; (6) β‐MHC mRNA; and (7) ATPase sarcoplasmic/endoplasmic reticulum Ca2 + transporting 2 (ATP2A2).…”

The Search for Disease-Modifying Therapies in Pulmonary Hypertension

“…Some are detectable as extracellular molecules in circulating plasma, making them potential biomarkers and therapeutic targets as well. 235,237,238 Although the study of miRNAs has offered a wealth of knowledge regarding the fundamental pathogenesis of PH, therapeutic strategies to modulate miRNAs have been more challenging. In general, 2 main techniques have been explored in more depth: administration of miRNA mimics (in the form of oligonucleotides or lentiviruses) or delivery of oligonucleotide inhibitors (ie, antagomirs).…”