Project 459029

Atrial fibrillation is the most common heart rhythm disorder in the world and is linked to an increased risk of life-threatening diseases like stroke and heart failure. When atrial fibrillation occurs, the upper chambers of the heart, the atria, contract too quickly and out of rhythm, preventing the heart from pumping blood effectively. While multiple risk factors of atrial fibrillation have been identified (e.g. high blood pressure or a prior heart attack) some individuals without any risk factors still develop atrial fibrillation. In these cases, genetics is likely playing a large role in their disease. Genetic mutations in the gene that encodes titin protein were recently identified as a potential cause of atrial fibrillation. It is unclear how titin mutations lead to atrial fibrillation, and efforts to study titin in the atrial chambers of the heart have been hampered by a lack of suitable experimental models. Human heart samples are difficult to obtain and the heart cells of small animal models exhibit significantly different properties compared to human heart cells, making it difficult to relate findings from animal models to humans. Our lab has generated human induced pluripotent stem cells (iPSCs) from the blood cells of an atrial fibrillation patient who has a genetic mutation in titin. A key property of these iPSCs is that, under the right conditions, they can develop into any type of cell in the human body and these cells will have the same genetic makeup and similar characteristics as the patient's cells. In this study, I will generate atrial heart cells from patient iPSCs to study the rhythm perturbing effects of titin mutations. The results from this study will help us understand how titin mutations lead to atrial fibrillation and improve our knowledge of the underlying causes of atrial fibrillation. In the future, this patient-specific atrial heart cell model can be used to study mutations in other genes linked to atrial heart rhythm disorders.