Evaluating and comparing the signalling and functional landscape of hiPSC-CMs derived from patients with dilated...

Non-ischaemic or dilated cardiomyopathy (DCM) is characterised 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 the discovery of new therapeutic agents. To address this, we use human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-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 hiPSC lines, then differentiated them into cardiomyocytes. Cellular signalling was assessed in each hiPSC-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 that can be used to uncover patient-specific molecular mechanisms and disease phenotypes as a pathway to potential development of personalised treatments for DCM.