Distinguished iNANO Lecture by Professor Julia Gorelik, Imperial College London, National Heart & Lung Institute - Faculty of Medicine, UK

Prof. Julia Gorelik

Professor of Cellular Biophysics, Imperial College London
j.gorelik@imperial.ac.uk

This talk will focus on recent advances in understanding cell compartmentalised signalling in cardiomyocytes during heart failure. Heart failure (HF) is a major contributor to the global burden of cardiovascular disease and has a significant impact on healthcare systems worldwide. In HF, there is a progressive loss of transverse tubules (TTs), a network of deep membrane invaginations that are critical for excitation–contraction coupling. This structural remodelling is accompanied by molecular changes, including alterations in beta-adrenergic receptors (βARs), ion channels - particularly L-type calcium channels (LTCCs) - Ca²⁺-handling proteins, and proteins involved in cell–cell coupling. These changes exacerbate cardiomyocyte calcium-handling abnormalities and contribute to arrhythmogenic triggers such as early and delayed after-depolarisations (EADs and DADs). Many of these pathological alterations have only recently been revealed due to the emergence of nanoscale functional imaging techniques. Scanning ion conductance microscopy (SICM) provides high-resolution topographical imaging of the cell surface and can be combined with complementary methods to study living cardiomyocytes in real time. A scanning nanopipette can be used for precise, localised drug delivery to stimulate specific signalling nanodomains, and the same nanopipette can also be employed for patch-clamp recordings of ion currents. In addition, second messengers such as calcium and cAMP can be monitored using FRET microscopy in combination with SICM. Together, these techniques have enabled detailed investigation of TT remodelling and the functional communication between ion channels and receptors within signalling nanodomains.

In this talk, I will discuss recent findings on the loss of nanodomain functional integrity in heart failure. Furthermore, we have developed mechano-SICM, which allows measurement of mechanical properties such as Young’s modulus at the cellular level. We have demonstrated clear differences in stiffness between healthy cardiomyocytes and those from failing hearts. More recently, we established a methodology to measure the surface topography of isolated adult cardiomyocytes under diastolic stretch while simultaneously detecting subcellular β-adrenoceptor signalling. This approach provides new insights into cardiomyocyte function under mechanical load in both healthy and failing hearts.