Upregulation of the sodium potassium pump current supresses ectopic activity after stem cell delivery in the human-based heart after myocardial infarction

Abstract Background Cell therapy is being explored to restore the damaged and intrinsically irreparable human heart. Whilst preclinical studies showed improvements in cardiac function after injury, they also highlighted a critical pro-arrhythmic window when delivered cells produce ectopy-induced ventricular tachycardia. Recent experiments investigating the cells in vivo maturation suggested upregulation of the inward rectifier potassium current (IK1) and knock-out of the funny current (If) and sodium calcium exchanger (INaCa) to supress the arrhythmias[1]. Purpose Whilst promising, such modifications may impact the cells’ calcium dynamics and ultimately, their efficacy. The goal of this study is to identify novel ionic targets that improve therapy safety whilst maintaining efficacy by employing the unique predictive capabilities of modelling and simulation. Methods For this, we used our established modelling and simulation framework of cell therapy in the chronically infarcted human heart with Purkinje, validated against experimental and clinical data from the action potential to the ECG. We incorporated experimentally observed gene expression of in vivo cell maturation[1] into our framework to reproduce human pluripotent stem cell-induced cardiomyocyte (hPSC-CM) electrophysiology at day 0 and day 14 after injection. To consider variability amongst experimentally reported hPSC-CMs, we also created a fast-beating hPSC-CM model by upregulating the SERCA pump current, If and INaCa. Results Our results showed that while day 0 hPSC-CMs did not cause spontaneous activity, day 14 hPSC-CMs produced ectopic beats in the ventricles every 1.5s. The rapid beating hPSC-CM phenotype at day 14 elicited tachycardia through spontaneous beating and intermittent re-entrant wavefronts (see Figure 1). Next, we demonstrated 65% upregulation of the sodium-potassium pump current (INaK) together with a 50% increase in IK1 and knock-out of If as a novel pathway to quiescence. Importantly, our simulations highlighted that compared to INaCa knock-out, an increase in INaK allowed for physiological calcium transients. Conclusion To conclude, in this work we have utilised modelling and simulation of the injured human heart to 1) capture pre-clinically observed arrhythmias after cell therapy and 2) identify INaK upregulation as a novel target to mitigate safety concerns, whilst preserving efficacy.