Prolonged action potentials in HCM-derived iPSC - biology or artefact?

With great interest we read the article by Han et al. ‘Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells’ recently published in ‘Cardiovascular Research’.1 Life-threatening ventricular arrhythmias in hypertrophic cardiomyopathy (HCM) remain a challenge not only for clinical management of individual patients, but also from the viewpoint of cellular cardiac electrophysiology. It remains an enigma how mutations of sarcomeric proteins can increase the propensity for arrhythmias. A recent concept suggests that the often increased Ca2+-binding affinity of mutated sarcomeres in HCM increases Ca2+ buffering and, by diastolic release of Ca2+, the propensity for arrhythmias.2 The advantage of patient-specific induced pluripotent stem cells (iPSC) should be that effects of patient-relevant mutations can be studied in the correct genetic and cellular background. With the rich toolbox of experimental electrophysiology at hand, iPSC-derived cardiac myocytes can be evaluated without restriction in time and numbers. The critical and unanswered question is whether (immature) iPSC-derived cardiac myocytes really reflect the phenotype of the patient or predict it. Data answering this question are lacking also in the recent study. Han et al. report six-fold higher sodium current density and almost two times higher APD90 in HCM-derived iPSC cardiac myocytes compared with those from healthy controls. Both numbers appear somewhat surprising. There are few data recording Na currents in human ventricular myocytes. Data indicate that different disease processes (congenital heart disease vs. cardiomyopathy, terminal heart failure vs. non-failing) do not affect sodium currents.3 However, it should be noted that this work not specifically addressed HCM. Nevertheless, calculations with a well-established computer model for human ventricular AP4 predict a six-fold higher peak sodium current to cause three-fold higher maximum upstroke velocity, but unchanged APD90 (own unpublished data). Unfortunately, data on upstroke velocity are lacking in the current paper by Han et al.1 Transient outward potassium currents depicted in Figure 5J likely indicate peak currents of Ito (no methodological details are given) and show a 25% increase in HCM-derived iPSC cardiac myocytes. Recent work in dog ventricular myocardium suggests that 90% block of Ito can evoke marked APD prolongation when other potassium channels are blocked.5 Therefore, we would rather expect shortened rather than prolonged APD because of increased Ito. However, the computer model mentioned above suggest that such small increase in Ito should not affect APD90. Only the slight increase in l-type Ca2+-current density by ∼50% would substantially prolong APD90 (+9% in our computer simulation). Thus, the measurements of ion currents and APD90 do not correspond to each other when applying an established computer model, indicating Increases in APD90 at a magnitude described herein are expected to correlate with markedly prolonged QT-interval in the ECG of the respective patient. No such information is provided in the paper by Han et al. With regard to clinical implications of this study, it is important to note that marked QT prolongation is not a regular phenotype in patients with HCM. In the largest study into this question, QTc was only mildly associated with the extent of hypertrophy.6 In summary, the available clinical data argue against an LQT mechanism of HCM-related arrhythmias, and we believe that it is premature to conclude from the iPSC data obtained from just one patient that the conduction delay and repolarization abnormalities in HCM result from changes of ionic currents and action potential duration. either that repolarization in HCM-derived iPSC cardiac myocytes has little resemblance with that of mature undiseased ventricular myocytes (as reflected by experimental obtained from dog or computer models), or that this particular patient shows more, not yet identified abnormalities in the delicate balance between depolarizing and repolarizing forces. Conflict of interest: none declared.