NGS of microRNAs Involved in Cardioprotection Induced by Sevoflurane Compared to Propofol in Myocardial Revascularization Surgery: The ACDHUVV-16 Clinical Trial
Authors: Orriach Jose Luis Guerrero , Belmonte Juan Jose Escalona , Aliaga Marta Ramirez , Fernandez Alicia Ramirez , Capitan Maria Jose Rodriguez , Muñoz Guillermo Quesada , Ponferrada Aida Raigón , Torres Juan Alcaide , Santiago-Fernandez Concepcion , Gonzalez Emilio Matute , Navarro Manuel Rubio , Bautista Rocio , Maldonado Josefa Gómez , Garrido-Sanchez Lourdes , Mañas Jose Cruz 
Published: October 2020

Background:
Numerous studies have demonstrated that halogenated agents elicit myocardial
conditioning effects when administered perioperatively in cardiac surgery. Recent evidence has been published
on the benefits of maintaining exposure to halogenated agents during the early postoperative period.
The enzymatic mechanisms by which this beneficial effect is exerted were explained recently.

Objectives:
Our study was performed to investigate whether this phenomenon is mediated by either the
activation or suppression of miRNAs targeted by halogenated anesthetics.

Methods:
A double-blind, two-stage trial was conducted. The results of the first stage of the trial are presented
in this paper. The sample was composed of patients undergoing off-pump myocardial revascularization
surgery. Patients were randomized to receive either sevoflurane [S] or propofol [P] during the intraoperative
and early postoperative period (during the first six hours after the intervention). Hemodynamics
(heart rate, blood pressure, central venous pressure, cardiac index, systolic volume index, LVEF) and
myocardial enzymes (troponin I) were monitored at six hour intervals during the first 48 hours. In the first
stage of the trial, blood was drawn for gene sequencing from eight patients (four per group) at baseline
and at 24 h. In the second stage of the study, a qPCR analysis was performed of the miRNAs identified as
significant by gene sequencing. Levels of cardioprotective enzymes (serine/threonine protein kinase
(Akt), tumor necrosis factor alpha (TNFα), extracellular regulated protein kinase (ERK 1/2), and caspase
3) were measured to assess their role in myocardial conditioning pathways. The purpose was to identify
the miRNAs that play a major role in myocardial conditioning induced by halogenated agents. Concentrations
of cardioprotective enzymes were higher in patients who received sevoflurane than the patients who
were administered propofol.

Results:
NGS differences were observed between baseline and 24-h values in the two study groups. In
group P, miRNA 197-3p was overexpressed, whereas miRNAs 4443 and 1294, 708-3p were underexpressed.
In group S, miRNAs 615-3p, 4466, 29, 937-3p, 636, 197-3P, 184, 4685, 296-3p, 147b, 3199,
6815, 1294 and 3176 were underexpressed; whereas 708-3p was overexpressed. qPCR showed significant
variations in miRNAs 197-3p, 4443, 708-3p and 1294 in the P group, and in miRNAs 937-3p, 636, 197-
3p, 296-3p and 708-3p in the S group.

Download:
In the P Group, changes in the expression of some miRNAs were associated with lower concentrations of the enzymes involved in myocardial pre- and postconditioning. In contrast, in Group S, variations in miRNAs were associated with the activation of medi-ators of anesthetic-induced pre- and post-conditioning, a reduction in cell apoptosis, and a decrease in caspase and TnBF alpha concentra-tions. Changes in these miRNAs were associated with a better prognosis in patients with ischemic heart disease. The main limitation of this study will be overcome in the second stage of the trial, where the specific role of each miRNA will be determined.