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Cardiovasc. Med."],"abstract":"<jats:p>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 (<jats:italic>N<\/jats:italic> = 20: 0.3% NaCl) or a high-salt (<jats:italic>N<\/jats:italic> = 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 \u00b1 20 mm Hg vs. low-salt 152 \u00b1 18 mm Hg, <jats:italic>p<\/jats:italic> &amp;lt; 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\u20130.88). 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.<\/jats:p>","DOI":"10.3389\/fcvm.2020.626699","type":"journal-article","created":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T18:05:06Z","timestamp":1613239506000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Circulating microRNAs May Serve as Biomarkers for Hypertensive Emergency End-Organ Injuries and Address Underlying Pathways in an Animal Model"],"prefix":"10.3389","volume":"7","author":[{"given":"Knut Asbj\u00f8rn Rise","family":"Langlo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo Jose Justo","family":"Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tina Syvertsen","family":"Overrein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Volker","family":"Adams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrik","family":"Wisl\u00f8ff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H\u00e5vard","family":"Dalen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natale","family":"Rolim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stein Ivar","family":"Hallan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"51","DOI":"10.3389\/fcvm.2016.00051","article-title":"Cardiovascular hypertensive crisis: recent evidence and review of the literature","volume":"3","author":"Varounis","year":"2016","journal-title":"Front Cardiovasc Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.22141\/2307-1257.7.1.2018.122220","article-title":"2017 ACC\/AHA\/AAPA\/ABC\/ACPM\/AGS\/APhA\/ASH\/ASPC\/NMA\/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines","author":"Whelton","year":"2018","journal-title":"J Am Soc Hypertens"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.1056\/NEJMcp1901117","article-title":"Acute severe hypertension","volume":"381","author":"Peixoto","year":"2019","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/s41440-020-00555-4","article-title":"Malignant hypertension and multiorgan damage: mechanisms to be elucidated and countermeasures","volume":"44","author":"Saito","year":"2021","journal-title":"Hypertens Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.clinimag.2017.08.008","article-title":"The imaging spectrum of posterior reversible encephalopathy syndrome: a pictorial review","volume":"47","author":"Brady","year":"2018","journal-title":"Clin Imaging"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1001\/archneur.1988.00520340032007","article-title":"Hypertensive encephalopathy. 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