Evaluating and comparing the signalling and functional landscape of iPSC- CMs derived from patients with dilated cardiomyopathy

Non-ischemic or dilated cardiomyopathy (DCM) is characterized by abnormal enlargement of the left ventricle, compromising the ability of the heart to pump blood to the body. All patients with DCM are offered the same treatment regimen regardless of individual differences, with highly variable results on disease progression. Some patients fully recover cardiac function, while others continue to deteriorate, requiring heart replacement therapy or palliation. Incomplete molecular knowledge of dilated cardiomyopathy pathophysiology poses challenges for discovery of new therapeutic agents. To address this, we use induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess individual molecular signalling and functional signatures in patients with DCM. Using blood samples from two healthy controls and two patients with DCM, we generated and validated iPSC lines, then differentiated them into cardiomyocytes. Cellular signalling was assessed in each iPSC-CM line after treatment with several disease-relevant G protein-coupled receptor (GPCR)-targeting ligands, measured using nuclear and cytosolic PKA and ERK biosensors at single cell resolution. Differences in functional properties such as calcium handling, contractility, and electrophysiology revealed additional features altered in patients with DCM. We have now established a pipeline to uncover patient-specific molecular mechanisms and disease phenotypes as a pathway to the development of personalized treatment for DCM. One Sentence Summary : Building a pipeline for bench-to-bedside study of DCM