Study of the Expression of Autophagy Markers in the Myocardium in Patients With Persistent or Permanent Atrial Fibrillation (MIPAR-02)

Atrial Fibrillation (AFib) is the most common cardiac arrhythmia, causing the loss of the normal and coordinated atrial contractility.

Several studies have demonstrated the existence of some atrial anatomical sites involved in the initiation and maintenance of this arrhythmia, first of all the posterior wall in the area around the outlet of the pulmonary veins. In fact, the existence of a complex of structural and functional modifications has been documented, collectively defined as "structural remodeling" which involve both the cardiomyocyte and the interstitium (the space between the cardiomyocytes) from a histopathological point of view; at the cardiomyocyte level, a loss of sarcomeres in the perinuclear site (myocytolysis), a reduction in the expression of "adult" cellular proteins (e.g. cardiotin and titin) with concomitant re-expression of "fetal" proteins (e.g. muscle actin smooth), as well as a modification of the mitochondrial structure. At the interstitial level, remodeling is characterized by the deposition of fibrous tissue in the interstitium between the muscle bundles and by a reduction in capillary density. Regarding the deposition of collagen fibers, some studies on an experimental model of AFib have shown that the latter is not reversible.

Autophagy is an intracellular process regulated by numerous biochemical signals; it is present at basal levels in most tissues and allows the physiological turnover of the various structural components of the cell, directing them to lysosomal degradation. It can also be stimulated by external signals in unfavorable environmental conditions, such as in the case of pathologies that determine a condition of tissue oxidative stress protracted over time. Experimentally, an excessive activation of the latter has been associated with the early stages of pathological cardiac remodeling in various animal models of cardiovascular diseases and some recent studies have hypothesized that altered levels of autophagy may contribute to the possible mechanisms involved in the generation and maintenance of the remodeling cardiomyocyte and interstitial structure in AFib. The levels of autophagic activity can be evaluated by studying specific markers - such as the Beclin-1 and LC3B proteins - constituents of the autophagic signaling cascade. In the case of LC3B, the "LC3BII/LC3BI" ratio (the processed form of autophagosomal vesicles and the unprocessed form constitutively present at the cytoplasmic level) was used as an autophagy biomarker. Furthermore, some microRNAs (miRNAs) capable of controlling the expression of proteins of the autophagic cascade have been described in the literature. This is the case of miRNA 30a and miRNA 204, respectively, which respectively inhibit the expression of Beclin-1 and of LC3B.

This study aims to investigate from a histo-morphological and molecular point of view the presence of alterations of autophagy mechanisms in patients with persistent or permanent AFib and which correlate these modifications with the degree of structural remodeling present at the level of the left atrial myocardium.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Other: Sampling

• Study Type: Observational
• Enrollment (Anticipated): 81

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • Recruiting
    • Irccs Ospedale San Raffaele
    • Contact: Davide Schiavi, BS; Phone Number: +390226435316; Email: schiavi.davide@hsr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Group 1 - Study

Description

Group 1 - Study Inclusion criteria

• Age between 18 and 85 years old
• Permanent or persistent AFib for which the patient undergoes ablation surgery surgery of atrial fibrillation with isolated radiofrequency or associated with possible correction of heart valve disease with or without coronary artery disease Exclusion criteria
• Age < 18 years
• Need for emergency cardiac surgery
• Presence of concomitant systemic inflammatory diseases

Group 2 - Control Inclusion criteria

• Age between 18 and 85 years old
• Sinus rhythm at the time of admission for surgery
• No AFib in history
• Hospitalized for correction of isolated mitral valve disease or associated with correction of other valve diseases Exclusion criteria
• Age < 18 years
• Need for surgical coronary revascularization
• Need for emergency cardiac surgery
• Presence of concomitant systemic inflammatory diseases

Group 3 - Autoptic control Inclusion criteria

• Age between 18 and 85 years old Exclusion criteria
• No signs of post-mortal tissue decomposition assessed by histological examination
• Documented history of arrhythmias, valvular dysfunction, atherosclerosis of the coronary arteries, previous myocardial infarctions, foci of myocardial fibrosis greater than 2 mm on histology, presence of inflammatory cells in the interstitium, sarcoidosis, amyloidosis, chronic inflammatory lung diseases and connective tissue diseases.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Study group; Patients with permanent or persistent AFib, undergoing surgical ablation, isolated or concomitant to valve surgery	Other: Sampling; Sample collection: a small fragment of atrial wall will be collected
Mitral surgery control group; Patients undergoing isolated or concomitant mitral valve surgery	Other: Sampling; Sample collection: a small fragment of atrial wall will be collected
Autoptic control group; Autopsy samples in subjects without arrhythmia	Other: Sampling; Sample collection: a small fragment of atrial wall will be collected

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Beclin-1 and LC3B levels in blood	Baseline

Collaborators and Investigators

• Sponsor: Ospedale San Raffaele

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2019
• Primary Completion (Anticipated): April 9, 2024
• Study Completion (Anticipated): June 9, 2024

Study Registration Dates

• First Submitted: March 13, 2023
• First Submitted That Met QC Criteria: April 28, 2023
• First Posted (Actual): May 9, 2023

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: April 28, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation
• Other Study ID Numbers: MIPAR-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No