Serotype-dependent bioenergetic and electrophysiological remodelling in iPSC-derived cardiomyocytes from rheumatoid arthritis patients
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Patients 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.
Methods
Human 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-α, IL-1β, IL-6) and anti-rheumatic drugs (adalimumab, tofacitinib) were assessed using Seahorse assays, patch-clamp electrophysiology, multi-electrode array recordings and RT-qPCR.
Results
snRA cardiomyocytes exhibited impaired TNF-α-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-α depolarised the maximum diastolic potential in both RA serotypes. At the multicellular level, cytokine effects were serotype-specific: IL-1β selectively prolonged QT interval in spRA monolayers (p < 0.001), whereas IL-6 prolonged QT in snRA (p < 0.05). Both RA serotypes showed impaired TNF-α-driven induction of KCNJ3 and KCNA5 . Adalimumab selectively induced ATP5B in spRA but failed to engage either pathway in snRA, while tofacitinib selectively induced KCNJ3 in healthy but not RA cardiomyocytes.
Conclusions
These findings define distinct, serotype-specific pathways of cardiac remodelling in RA that converge on a shared proarrhythmic phenotype, provide a cellular framework for cardiovascular risk in RA and identify candidate mechanisms relevant to therapy-associated cardiovascular safety.
