Gene Expression Profiles in Patients With Permanent Atrial Fibrillation (AF) Versus Sinus Rhythm (SR)

Comparative Gene Expression Profiles in Patients With Permanent Atrial Fibrillation and Normal Sinus Rhythm

The aim of this project is to determine the morphological criteria of apoptosis in atrial tissues of patients with AF versus SR at transcriptome and genomic size.

Mitral valve regurgitation (MR) is the second most common valvular heart disease encountered in adults. Furthermore, atrial fibrillation (AF) is the most common cardiac arrhythmia seen in clinical practice. Overall, 70% of the patients with severe MR are associated with AF independent from etiopathogenesis of MR. AF is clinically divided into three subgroups; 1) paroxysmal AF, occurs as episodes and ends spontaneously, 2) persistent AF, episodes terminate only with medical or electrical cardioversion, and 3) permanent AF, current medical treatments and electrical cardioversion does not restore a normal sinus rhythm. Despite intensive electrophysiological studies, the molecular mechanisms and pathways of AF are still not fully elucidated.

Apoptosis which has distinctive morphological and biochemical characteristics is genetically regulated, active programmed cell death process. It is known that cardiac morphogenesis restore from apoptosis. In addition, apoptosis has an important role in several cardiovascular system pathologies. It has been shown that atrial apoptosis causes numerous arrhythmias including AF. Likewise, in the pilot study which has been performed by our study group, AF is associated with apoptosis by immunohistochemical and DNA fragmentation analysis methods.

The aim of this project is to determine the morphological criteria of apoptosis in atrial tissues of patients with AF by using electron microscopy and immunohistochemistry. Moreover, we will investigate the transcriptional profile of AF associated genes by oligonucleotide microarray method. The gene expression profiles of patients with AF and degenerative MR will be compared with the atrial tissue samples from the patients with degenerative MR who preserve normal sinus rhythm which will serve as controls. In summary the apoptotic pathways would be analyzed at transcriptomic and genomic level. Besides, the pathways that may interfere AF pathophysiology would also be evaluated. The expression profiles of the genes primarily verified by quantitative real time RT-PCR will be further confirmed by translation of end-result proteins determined with Western blot technique. Thus, brand-new clues about physiology of fibrillating atrial cells would be achieved.

Keywords: Atrial fibrillation, apoptosis, oligonucleotide microarray

Inclusion Criteria:

• Patients with permanent atrial fibrillation or sinus rhythm and degenerative mitral valve regurgitation who require cardiac surgery
• Pulmonary hypertension (systolic PA > 45 mmHg)
• Left ventricular ejection fraction > 30%

Exclusion Criteria:

• Paroxysmal AF or atrial flutter
• Second or third degree heart block
• Permanent pacemaker
• Wolff-Parkinson-White syndrome
• Brugada syndrome
• Ischemic or rheumatic mitral valve disease
• Dilated cardiomyopathy
• LVEF < 30%
• Infective endocarditis, myocarditis
• Trauma
• Active HBV, HCV, HIV infection
• Chronic renal failure
• Autoimmune diseases
• Vasculitis
• Known genetic disorders