Multi- Level and Integrated Analysis of Mechanisms Underlying Atrial Dysfunction

Overview

Integrated and cross-disciplinary analysis of human physiology and disease provides unbiased and deeply informative insights into human health and disease. In this study the investigators will recruit patients undergoing coronary artery bypass surgery to study the atrium of the heart or the aortic wall that when diseased can cause strokes. Hypothesis: Systems-level analysis of the left atrium and aorta cells that integrates imaging, histological, cellular and molecular data will identify new mechanism for cardiovascular form and function.

While there are many sub-aims to this study, the overarching goal is to define molecular mechanisms underlying atrial dysfunction. Here the investigator provide a power calculation based on detecting the genetic control points of gene expression (eQTLs) in the human atrial fibroblast. The investigator and many others have shown that tissue-specific eQTLs can be robustly identified at genome-wide significance in segregating populations of \~200. In this study the investigator propose eQTL association analysis in humans, which have previously been successfully performed in cohorts of less than 1000 subjects. The general applicability of this approach has been validated in multiple studies across multiple tissues in cohorts of between 200-1000 subjects.Based on published imaging genetic studies that have been successfully applied in small cohorts (\<500) and the success of echo-based, semi-quantitative studies of ventricular dimensions, the investigator are confident that our quantitative studies of 750 individuals are powered to detect genome wide significant loci for the traits under study. Despite intensive research there is a critical gap in our knowledge in the mechanisms underlying atrial fibrillation, which is a major cause of stroke and heart failure and increasingly common as it is a disease of the elderly. This project will address this important gap in our knowledge and provide new insights into disease pathogenesis with the goal of stratifying participants to prevent strokes and for treating the underlying substrate.

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Central Contacts