Key result
Z-disc affimers improve imaging resolution over conventional antibodies, revealing wider Z-discs and shorter sarcomeres in DCM.
Why the study?
Determining how dilated cardiomyopathy affects the structure and organization of human cardiomyocytes is important for understanding impaired heart contraction.
Do Affimers targeting Z-disc proteins improve imaging resolution of heart tissue compared to conventional antibodies in patients with dilated cardiomyopathy?
Do Affimers targeting Z-disc proteins improve imaging resolution of heart tissue compared to conventional antibodies in patients with dilated cardiomyopathy?
Affimers targeting Z-disc proteins provide superior imaging resolution compared to conventional antibodies, enabling detailed structural analysis of cardiomyocytes in failing hearts.
May improve preclinical sarcomere imaging in DCM models; leaves open human translation.
Dilated Cardiomyopathy is a common form of heart failure. Determining how this disease affects the structure and organization of cardiomyocytes in the human heart is important in understanding how the heart becomes less effective at contraction. Here we isolated and characterised Affimers (small non-antibody binding proteins) to Z-disc proteins ACTN2 (α-actinin-2), ZASP (also known as LIM domain binding protein 3 or LDB3) and the N-terminal region of the giant protein titin (TTN Z1-Z2). These proteins are known to localise in both the sarcomere Z-discs and the transitional junctions, found close to the intercalated discs that connect adjacent cardiomyocytes. We use cryosections of left ventricles from two patients diagnosed with end-stage Dilated Cardiomyopathy who underwent Orthotopic Heart Transplantation and were whole genome sequenced. We describe how Affimers substantially improve the resolution achieved by confocal and STED microscopy compared to conventional antibodies. We quantified the expression of ACTN2, ZASP and TTN proteins in two patients with dilated cardiomyopathy and compared them with a sex- and age-matched healthy donor. The small size of the Affimer reagents, combined with a small linkage error (the distance from the epitope to the dye label covalently bound to the Affimer) revealed new structural details in Z-discs and intercalated discs in the failing samples. Affimers are thus useful for analysis of changes to cardiomyocyte structure and organisation in diseased hearts.
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Parker et al. (2023) studied Dilated Cardiomyopathy (n=3). Affimers targeting ACTN2, ZASP, and TTN Z1-Z2 vs. Conventional antibodies was evaluated on Z-disc width and sarcomere length. Affimers targeting Z-disc proteins substantially improved imaging resolution compared to conventional antibodies, revealing significantly increased Z-disc width and decreased sarcomere length in dilated cardiomyopathy tissue.
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