Preoperative myocardial expression of E3 ubiquitin ligases in aortic stenosis patients undergoing valve replacement and their association to postoperative hypertrophy

Data de publicação: 18/09/2020 Data Ahead of Print: 18/09/2020

Autores da FMUP

• Francisca Almeida Saraiva

  Autor

• Joaquim Adelino Correia Ferreira Leite Moreira

  Autor

• Inês Maria Falcão Sousa Pires Marques

  Autor

Participantes de fora da FMUP

• Trindade, F
• Keane, S
• Vitorino, R.
• Tajsharghi, H

Unidades de investigação

• Cirurgia e Fisiologia

• RISE-Health

  

  Investigador

  Fernando Carlos De Landér Schmitt

Abstract

Currently, aortic valve replacement is the only treatment capable of relieving left ventricle pressure overload in patients with severe aortic stenosis. It aims to improve cardiac function and revert hypertrophy, by triggering myocardial reverse remodeling. Despite immediately relieving afterload, reverse remodeling turns out to be extremely variable. Among other factors, the extent of reverse remodeling may depend on how well ubiquitin-proteasome system tackle hypertrophy. Therefore, we assessed tagged ubiquitin and ubiquitin ligases in the left ventricle collected from patients undergoing valve replacement and tested their association to the degree of reverse remodeling. Patients were classified according to the regression of left ventricle mass (Delta LVM) and assigned to complete (Delta LVM >= 15%) or incomplete (Delta LVM <= 5%) reverse remodeling groups. No direct inter-group differences were observed. Nevertheless, correlation analysis supports a fundamental role of the ubiquitin-proteasome system during reverse remodeling. Indeed, total protein ubiquitination was associated to hypertrophic indexes such as interventricular septal thickness (r = 0.55,p= 0.03) and posterior wall thickness (r = 0.65,p= 0.009). No significant correlations were observed for Muscle Ring Finger 3. Surprisingly, though, higher levels of atrogin-1 were associated to postoperative interventricular septal thickness (r = 0.71,p= 0.005). In turn, Muscle Ring Finger 1 correlated negatively with this postoperative hypertrophy marker (r = -0.68,p= 0.005), suggesting a cardioprotective role during reverse remodeling. No significant correlations were found with left ventricle mass regression, although a trend for a negative association between the ligase Murine Double Minute 2 and mass regression (r = -0.44,p= 0.10) was found. Animal studies will be necessary to understand whether this ligase is protective or detrimental. Herein, we show, for the first time, an association between the preoperative myocardial levels of ubiquitin ligases and postoperative hypertrophy, highlighting the therapeutic potential of targeting ubiquitin ligases in incomplete reverse remodeling.

Keywords

• Aged; Aortic Valve; Aortic Valve Stenosis; Female; Heart Valve Prosthesis Implantation; Humans; Hypertrophy, Left Ventricular; Male; Myocardium; Postoperative Period; Preoperative Period; Ubiquitin-Protein Ligases; Ventricular Remodeling; atrogin 1; Muscle Ring Finger 3 protein; proteasome; protein MDM2; RING finger protein; ubiquitin; ubiquitin protein ligase; ubiquitin protein ligase E3; unclassified drug; ubiquitin protein ligase; aged; aortic stenosis; aortic valve replacement; Article; cardiac muscle; clinical feature; controlled study; correlation analysis; disease association; disease marker; Doppler echocardiography; drug targeting; female; heart left ventricle hypertrophy; heart left ventricle mass; heart muscle biopsy; heart protection; heart ventricle remodeling; histopathology; human; human tissue; interventricular septal thickness; interventricular septum; major clinical study; male; posterior wall thickness; postoperative complication; preoperative evaluation; preoperativ