Study of the Expression of Autophagy Markers in the Myocardium in Patients With Persistent or Permanent Atrial Fibrillation

NCT05850039 | Unknown

• 1 other identifier: MIPAR-02
• Study Type: observational
• Target: 81
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Atrial Fibrillation

Outcome Measures

Primary Outcomes (1)

• Beclin-1 and LC3B levels in blood

  Baseline

Study Arms (3)

Study group

Patients with permanent or persistent AFib, undergoing surgical ablation, isolated or concomitant to valve surgery

Other: Sampling

Mitral surgery control group

Patients undergoing isolated or concomitant mitral valve surgery

Other: Sampling

Autoptic control group

Autopsy samples in subjects without arrhythmia

Other: Sampling

Interventions

Sampling OTHER

Sample collection: a small fragment of atrial wall will be collected

Autoptic control group; Mitral surgery control group; Study group

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Group 1 - Study

You may qualify if:

• Age between 18 and 85 years old

You may not qualify if:

• Age \< 18 years
• Need for emergency cardiac surgery
• Presence of concomitant systemic inflammatory diseases
• Age between 18 and 85 years old
• Sinus rhythm at the time of admission for surgery
• No AFib in history
• Age \< 18 years
• Need for surgical coronary revascularization
• Need for emergency cardiac surgery
• Presence of concomitant systemic inflammatory diseases
• 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.

Sponsors & Collaborators

• Ospedale San Raffaele: lead

Study Sites (1)

IRCCS Ospedale San Raffaele

Milan, 20132, Italy

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

fragments of posterior left atrial wall measuring between approximately 0.5 x 0.5 cm and approximately 1 x 1 cm and full thickness along the atriotomy incision line near the right pulmonary veins. The sample will be divided into 3 parts: one fixed in 10% buffered formalin for the morphological study by optical microscopy, one frozen in liquid nitrogen for molecular investigations and the last, with dimensions no larger than 1.5 x 1.5 mm and full thickness, fixed in Karnowsky liquid, for electron microscopy study

MeSH Terms

Conditions

Atrial Fibrillation

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Cardiac Surgery of Advanced and Research Therapies

Study Record Dates

• First Submitted: March 13, 2023
• First Posted: May 9, 2023
• Study Start: April 9, 2019
• Primary Completion: April 9, 2024
• Study Completion: June 9, 2024
• Last Updated: May 9, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)