Association of Genetic Polymorphisms With Atrial Fibrosis and Thrombogenic Substrate in Patients With Non-valvular Atrial Fibrillation

Study Overview
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Brief Summary
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Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia. Emerging data suggests that common genetic variants are associated with the development of AF. The main feature of the structural remodelling in AF is atrial fibrosis and is considered the substrate for AF perpetuation. Genome-wide association studies suggest that AF-susceptibility variants may modulate atrial fibrosis. However, the association between atrial fibrosis and genetic polymorphisms in humans has not yet been specifically investigated. In this study, we plan to investigate the relationship between genetic polymorphisms, atrial fibrosis and other components of thrombogenic substrate in patients with non-valvular AF. Primary objectives of this study are to assess associations between (i) polymorphic genetic variants and atrial fibrosis (detected by magnetic resonance imaging), (ii) polymorphic genetic variants and components of thrombogenic substrate (inflammation, endothelial function, prothrombotic state, atrial functions).

Detailed Description
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Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia. Emerging data suggests that common genetic variants are associated with the development of AF. The main feature of the structural remodelling in AF is atrial fibrosis and is considered the substrate for AF perpetuation. Genome-wide association studies suggest that AF-susceptibility variants may modulate atrial fibrosis. However, the association between atrial fibrosis and genetic polymorphisms in humans has not yet been specifically investigated. In this study, we plan to investigate the relationship between genetic polymorphisms, atrial fibrosis and other components of thrombogenic substrate in patients with non-valvular AF. Primary objectives of this study are to assess associations between (i) polymorphic genetic variants and atrial fibrosis (detected by magnetic resonance imaging), (ii) polymorphic genetic variants and components of thrombogenic substrate (inflammation, endothelial function, prothrombotic state, atrial functions). Patients are planned to be recruited from four major cardiology departments: Memorial Ankara Hospital, Ministry of Health Subspecialty Training Hospital of Turkey, Ufuk University and Gazi University hospitals. Key variables that will be recorded include the clinical, contrast-enhanced MRI, biomarkers, echocardiographic and assessment of endothelial function. All statistical analyses will be conducted using Stata version 11.0 (StataCorp, College Station, TX). Univariate and multivariate regression models will be used to determine the odds ratio of each variable to assess the association of the clinical and laboratory parameters, and genotype profiles with the presence of LA fibrosis. Furthermore, data mining methods like support vector machines and/or random forests are planned to be used for detecting the impact of each potential predictor on the risk of LA fibrosis. Additionally, to determine the effect of different alleles of the identified risk SNPs, 2-way and 3-way multi dimensionality reduction (MDR) analysis will be performed. Bioinformatics investigations to determine SNP-SNP, SNP-gene and SNP-Phenotype interactions will be performed by combined p-value and biological network analysis.

Official Title
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AssociatioN of Genetic Polymorphisms With ATrial fibrOsis and Thrombogenic Substrate in Patients With Non-vaLvular atrIAl Fibrillation

Conditions
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Atrial Fibrillation, Thrombosis, Stroke, Genetic Predisposition, Heart Diseases

Intervention / Treatment
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* Diagnostic Test: Biomarkers, Cardiac Magnetic Resonance Imaging, Echocardiography, Flow Mediated Dilatation, Genetic Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: >18 years Documented AF Paroxysmal and persistent AF Exclusion Criteria: Patients with infectious or non-infectious inflammatory disease Patients with structural heart disease Acute coronary syndrome Severe liver and kidney dysfunction Cancer Immune disorders Surgery and stroke within six months

Ages Eligible for Study
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Minimum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Diagnostic Test: Biomarkers, Cardiac Magnetic Resonance Imaging, Echocardiography, Flow Mediated Dilatation, Genetic Analysis|Key variables that will be recorded include the following: Clinical Age Gender BMI Diabetes Mellitus Hypertension Heart Failure Ischemic Stroke / TIA Thromboembolism Coronary Artery Disease Peripheral Arterial Disease Glomerular Filtration Rate Contrast-enhanced MRI o Presence and extent of atrial fibrosis Biomarkers IL-6 CRP D-dimer Fibrinogen Transthoracic Echocardiography LA Volume Index (LAVI) LA Strain, Global LA Strain rate, Positive peak, Global LA Strain rate, early negative peak, Global LA Strain rate, late negative peak, Global LA Emptying Fraction (LAEF) LVH LVEF Endothelial function o FMD|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Associations between polymorphic genetic variants and atrial fibrosis | (detected by MRI) | Through study completion, an average of 1 year | 
| Associations between polymorphic genetic variants and components of thrombogenic substrate | Thrombogenic substrate (inflammation, endothelial function, prothrombotic state, atrial functions) | Through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial Fibrillation, Atrial Fibrosis, Genome Wide Association Studies, Biomarkers, Echocardiography, Magnetic Resonance Imaging, Flow Mediated Dilatation, Thrombogenic Substrate