Differential miRNAs in acute spontaneous coronary artery dissection: Pathophysiological insights from a potential biomarker
Marta Lozano-Prieto,
David Adlam,
Marcos García-Guimaraes,
Ancor Sanz-García,
Paula Vera-Tomé,
Fernando Rivero,
Javier Cuesta,
Teresa Bastante,
Anna A. Baranowska-Clarke,
Alicia Vara,
Enrique Martin-Gayo,
Miguel Vicente-Manzanares,
Pilar Martín,
Nilesh J Samani,
Francisco Sánchez-Madrid,
Fernando Alfonso,
Hortensia de la Fuente
Affiliations
Marta Lozano-Prieto
Department of Immunology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain
David Adlam
Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
Marcos García-Guimaraes
Department of Cardiology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain; Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
Ancor Sanz-García
Data Analysis Unit, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain
Paula Vera-Tomé
Department of Immunology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain
Fernando Rivero
Department of Cardiology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain
Javier Cuesta
Department of Cardiology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain
Teresa Bastante
Department of Cardiology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain
Anna A. Baranowska-Clarke
Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
Alicia Vara
Department of Immunology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain
Enrique Martin-Gayo
Department of Immunology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain; Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
Miguel Vicente-Manzanares
Instituto de Biología Molecular y Celular del Cáncer USAL-CSIC, 37007, Salamanca, Spain
Pilar Martín
Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares,; CIBER de Enfermedades Cardiovasculares, Spain
Nilesh J Samani
Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
Francisco Sánchez-Madrid
Department of Immunology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain; Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares,; CIBER de Enfermedades Cardiovasculares, Spain
Fernando Alfonso
Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK; CIBER de Enfermedades Cardiovasculares, Spain
Hortensia de la Fuente
Department of Immunology, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain; CIBER de Enfermedades Cardiovasculares, Spain; Corresponding author.
Background: Spontaneous Coronary Artery Dissection (SCAD) is an important cause of acute coronary syndromes, particularly in young to middle-aged women. Differentiating acute SCAD from coronary atherothrombosis remains a major clinical challenge. Methods: A case-control study was used to explore the usefulness of circulating miRNAs to discriminate both clinical entities. The profile of miRNAs was evaluated using an unbiased human RT-PCR platform and confirmed using individual primers. miRNAs were evaluated in plasma samples from acute SCAD and atherothrombotic acute myocardial infarction (AT-AMI) from two independent cohorts; discovery cohort (SCAD n = 15, AT-AMI n = 15), and validation cohort (SCAD n = 11, AT-AMI n = 41) with 9 healthy control subjects. Plasma levels of IL-8, TGFB1, TGBR1, Endothelin-1 and MMP2 were analysed by ELISA assays. Findings: From 15 differentially expressed miRNAs detected in cohort 1, we confirmed in cohort 2 the differential expression of 4 miRNAs: miR-let-7f-5p, miR-146a-5p, miR-151a-3p and miR-223-5p, whose expression was higher in SCAD compared to AT-AMI. The combined expression of these 4 miRNAs showed the best predictive value to distinguish between both entities (AUC: 0.879, 95% CI 0.72–1.0) compared to individual miRNAs. Functional profiling of target genes identified an association with blood vessel biology, TGF-beta pathway and cytoskeletal traction force. ELISA assays showed high plasma levels of IL-8, TGFB1, TGFBR1, Endothelin-1 and MMP2 in SCAD patients compared to AT-AMI. Interpretation: We present a novel signature of plasma miRNAs in patients with SCAD. miR-let-7f-5p, miR-146a-5p, miR-151a-3p and miR-223-5p discriminate SCAD from AT-AMI patients and also shed light on the pathological mechanisms underlying this condition. Funding: Spanish Ministry of Economy and Competitiveness (MINECO): Plan Nacional de Salud SAF2017-82886-R, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV). Fundación BBVA a equipos de Investigación Científica 2018 and from Caixa Banking Foundation under the project code HR17-00016 to F.S.M. Instituto de Salud Carlos III (AES 2019): PI19/00565 to F.R, PI19/00545 to P.M. CAM (S2017/BMD-3671-INFLAMUNE-CM) from Comunidad de Madrid to FSM and PM. The UK SCAD study was supported by BeatSCAD, the British Heart Foundation (BHF) PG/13/96/30608 the NIHR rare disease translational collaboration and the Leicester NIHR Biomedical Research Centre.
