Key result
Cardiotoxic light chains reduce hiPSC-CM firing frequency and upstroke velocity, cutting peak sodium current ~40%.
Why the study?
Existing models lack human relevance for studying soluble light chain-induced toxicity in AL amyloidosis, where soluble cardiotoxic light chains contribute to cardiac dysfunction beyond fibril accumulation.
Do amyloidogenic cardiotoxic light chains alter electrophysiological properties in hiPSC-CMs compared to non-cardiotoxic light chains?
Do amyloidogenic cardiotoxic light chains alter electrophysiological properties in hiPSC-CMs compared to non-cardiotoxic light chains?
Cardiotoxic light chains from AL amyloidosis patients impair excitability and alter sodium and calcium currents in hiPSC-CMs, providing a human-relevant model for studying LC-induced cardiotoxicity.
Cardiotoxic LCs may disrupt cardiomyocyte electrophysiology in vitro; hypothesis-generating for AL amyloidosis mechanisms, no practice change yet.
Background: Immunoglobulin light chain (AL) amyloidosis is a protein misfolding disorder marked by systemic amyloid deposition from monoclonal light chains (LCs). Cardiac involvement determines prognosis, and soluble cardiotoxic LCs contribute to dysfunction beyond fibril accumulation. Existing models lack human relevance for studying soluble LC-induced toxicity. This study investigated the effects of cardiotoxic LCs in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods: Amyloidogenic cardiotoxic LCs (H3, H6) from AL patients and non-cardiotoxic LC (M10, M226) from multiple myeloma patients were tested in hiPSC-CMs at clinically relevant concentrations. Patch-clamp recordings assessed spontaneous action potentials frequency, upstroke velocity (dV/dt), action potential duration, and main transmembrane ionic currents. Results: H3 and H6 reduced spontaneous firing frequency and dV/dt, indicating impaired excitability; H6 also shortened action potential duration. H3 decreased peak sodium current by ~40% and altered L-type calcium current inactivation, without affecting IKr or IKs. M10 showed no electrophysiological effects, M226 affected the dV/dt, confirming the model’s ability sensitivity to distinguish toxic from nontoxic highlight LCs imapct. Conclusion: hiPSC-CMs provide a human-relevant platform to study LC-induced cardiotoxicity. Cardiotoxic LCs affecting sodium and calcium currents lead to altered excitability and action potentials. These findings reveal mechanisms underlying AL amyloidosis–related cardiac dysfunction and support this model for therapeutic testing against soluble LC toxicity.
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S et al. (2026) studied AL amyloidosis. Amyloidogenic cardiotoxic LCs (H3, H6) vs. Non-cardiotoxic LCs (M10, M226) was evaluated on Spontaneous action potentials frequency, upstroke velocity (dV/dt), action potential duration, and main transmembrane ionic currents. Cardiotoxic light chains (H3, H6) reduced spontaneous firing frequency and upstroke velocity in hiPSC-CMs, with H3 decreasing peak sodium current by ~40%.
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