Fig. 9.

Individuals with CD20 + B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms. In cellular studies, ACT-iPSC CM were persistently more susceptible to DOX toxicity including augmented, mitochondrial dysregulation, increased reactive oxygen species, increased apoptotic events, higher beating rate, and disorganized myofilament structure. ACT cells exhibited hyperactive CaMKIIδ and hyperphosphorylation of PLN-T17 and RYR2-S2814 but lowered SERCA2a expression. Ca²⁺ transient amplitude of ACT-iPSC CM was reduced compared to control cells, and diastolic sarcoplasmic reticulum Ca²⁺ leak was DOX-dependently increased. Prolonged action potentials in ACT CM suggest a cellular link to arrhythmogenic events and contractile dysfunction especially found in ACT engineered human myocardium. The CaMKII-inhibitor AIP rescues the DAD incidence in ACT-iPSC CM, confirming the contribution of the CaMKII to DOX-dependent altered electrophysiology, proarrhythmic triggers and ACT development. In contrast, control CM upregulated SERCA2a expression in a DOX-dependent manner, without altering CaMKIIδ activity. Therefore, control cancer survivors recover after DOX treatment without cardiac symptoms, whereas patients persue cardiac disease progression