An investigation of the relationship between transcriptomic signals and functional phenotypes across atrial physiology and pharmacology

Thesis

Cardiovascular disease is the leading global cause of mortality and morbidity. Cardiac disease is a major contributor, including diseases of abnormal rhythm or rate. The most common dysrhythmia is atrial fibrillation (AF). Despite progress in our understanding of the cellular- and tissue-level remodelling that contributes to AF, and in our clinical treatments of AF, there remains a need for novel pharmacological therapies to treat and prevent AF. Here, I use single-cell and spatially-resolved transcriptomics alongside structural imaging and ex vivo Langendorff perfusion to reveal a novel catecholaminergic population of cardiomyocytes (CMs). I then go on to use hiPSC-CM differentiation and RNA sequencing to examine maturation-associated transcriptomic networks and calcium handling networks. Finally, I also further characterise novel atrial-like hiPSC-CMs’ pharmacology and their ability to model both inherited and acquired cardiac disease. My work provides multiple exciting avenues for further research to examine how transcriptomic signals in both mouse and hiPSC-CM models relate to both basic and translational atrial science.

Authors: Grassam-Rowe, A

• DOI: 10.5287/ora-2amqrjj10
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: atria; calcium handling; transcriptomics; iPSC-derived cardiomyocytes; 4-aminopyridine; iPSCs
• Subjects: Pharmacology, Experimental; Electrophysiology; Stem cells; Cardiology, Experimental