Serotype-dependent bioenergetic and electrophysiological remodelling in iPSC-derived cardiomyocytes from rheumatoid arthritis patients

Abstract

BackgroundPatients with rheumatoid arthritis (RA) exhibit increased cardiovascular morbidity and mortality that are not fully explained by traditional risk factors, with cardiovascular outcomes differing between seropositive (spRA) and seronegative (snRA) disease. The cellular mechanisms linking chronic inflammation to cardiac dysfunction remain poorly defined, and no patient-specific cardiomyocyte model has resolved cellular phenotypes by RA serotype. MethodsHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were generated from healthy donors and patients with spRA and snRA. Bioenergetic and electrophysiological responses to key RA proinflammatory cytokines (TNF-, IL-1{beta}, IL-6) and anti-rheumatic drugs (adalimumab, tofacitinib) were assessed using Seahorse assays, patch-clamp electrophysiology, multi-electrode array recordings and RT-qPCR. ResultssnRA cardiomyocytes exhibited impaired TNF--induced oxidative phosphorylation, accompanied by attenuated expression of ATP5B, LDHA and DLD. In contrast, spRA cardiomyocytes showed baseline electrophysiological alterations, including shortened APD90 and increased action-potential triangulation. TNF- depolarised the maximum diastolic potential in both RA serotypes. At the multicellular level, cytokine effects were serotype-specific: IL-1{beta} selectively prolonged QT interval in spRA monolayers (p View larger version (38K): org.highwire.dtl.DTLVardef@ceb808org.highwire.dtl.DTLVardef@1942a26org.highwire.dtl.DTLVardef@5b32eforg.highwire.dtl.DTLVardef@16cf774_HPS_FORMAT_FIGEXP M_FIG C_FIG