Exploring light chain cardiotoxicity in AL amyloidosis: Impact on hiPSC-derived Cardiomyocyte Activity

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.