Circulating microRNAs May Serve as Biomarkers for Hypertensive Emergency End-Organ Injuries and Address Underlying Pathways in an Animal Model

Abstract

There is an incomplete understanding of the underlying pathophysiology in hypertensive emergencies, where severely elevated blood pressure causes acute end-organ injuries, as opposed to the long-term manifestations of chronic hypertension. Furthermore, current biomarkers are unable to detect early end-organ injuries like hypertensive encephalopathy and renal thrombotic microangiopathy. We hypothesized that circulating microRNAs (c-miRs) could identify acute and chronic complications of severe hypertension, and that combinations of c-miRs could elucidate important pathways involved. We studied the diagnostic accuracy of 145 c-miRs in Dahl salt-sensitive rats fed either a low-salt (N = 20: 0.3% NaCl) or a high-salt (N = 60: 8% NaCl) diet. Subclinical hypertensive encephalopathy and thrombotic microangiopathy were diagnosed by histopathology. In addition, heart failure with preserved ejection fraction was evaluated with echocardiography and N-terminal pro-brain natriuretic peptide; and endothelial dysfunction was studied using acetylcholine-induced aorta ring relaxation. Systolic blood pressure increased severely in animals on a high-salt diet (high-salt 205 ± 20 mm Hg vs. low-salt 152 ± 18 mm Hg, p < 0.001). Partial least squares discriminant analysis revealed 68 c-miRs discriminating between animals with and without hypertensive emergency complications. Twenty-nine c-miRs were strongly associated with hypertensive encephalopathy, 24 c-miRs with thrombotic microangiopathy, 30 c-miRs with heart failure with preserved ejection fraction, and 28 c-miRs with endothelial dysfunction. Hypertensive encephalopathy, thrombotic microangiopathy and heart failure with preserved ejection fraction were associated with deviations in many of the same c-miRs, whereas endothelial dysfunction was associated with a different set of c-miRs. Several of these c-miRs demonstrated fair to good diagnostic accuracy for a composite outcome of hypertensive encephalopathy, thrombotic microangiopathy and heart failure with preserved ejection fraction in receiver-operating-curve analyses (area-under-curve 0.75–0.88). Target prediction revealed an enrichment of genes related to several pathways relevant for cardiovascular disease (e.g., mucin type O-glycan biosynthesis, MAPK, Wnt, Hippo, and TGF-beta signaling). C-miRs could potentially serve as biomarkers of severe hypertensive end-organ injuries and elucidate important pathways involved.

Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure model

“…The variable onset of TMA in this study likely associates with expression variation of Vegfa , model-dependent factors, and reflects the variable clinical onset ( 50 ). These findings support a recent study that emphasizes the regulatory role of miRNAs in different disease mechanisms of TMA ( 51 ).…”

“…These observations strongly correspond with our histological findings in HF mice that died prematurely, and underpin the threefold higher predisposition for TMA development. The variable onset of TMA in this study likely associates with expression variation of Vegfa, model-dependent factors, and reflects the variable clinical onset (50). These findings support a recent study that emphasizes the regulatory role of miRNAs in different disease mechanisms of TMA (51).…”

Diagnostic performance of microRNAs in the detection of heart failure with reduced or preserved ejection fraction: a systematic review and meta‐analysis

“…64 In this regard, our results confirmed higher pooled diagnostic performance of miRNA-based biomarkers for the detection of HFpEF. The miRNA detection in different biofluids has been explored as novel diagnostic and prognostic biomarkers for cardiovascular diseases, 10,72 but might also serve as a potential mediator of cell-to-cell communication, due to its paracrine properties. 73 A better understanding of the pathophysiological processes associated with the miRNA panels identified for both HFrEF and HFpEF conditions is fundamental to improve the current diagnostic approaches, and might help to develop novel therapeutic strategies or guide current treatments.…”