Patient-derived IPSC as a tool to unravel molecular determinants of familial atrial fibrillation

Atrial fibrillation (AF) is the most frequently diagnosed cardiac arrhythmia and is associated with an increased risk of stroke. Although AF can be easily diagnosed with an electrocardiogram, the underlying biological mechanism remains poorly understood. The major drawback in studying the molecular mechanism at the basis of familial AF has been the paucity of diseased myocardium and the unavailability of control healthy myocardium. The possibility to generate human induced pluripotent stem cells (hIPSCs) and differentiate them into cardiomyocytes, has opened the possibility to compare the functional properties of cardiac cells derived from patients affected by AF and from healthy individuals. We generated patient-derived iPS clones from one of three siblings with a history of persistent AF and from unaffected controls. These iPSC were differentiated toward CMs that were studied by patch clamp experiments. Electrophysiological analysis indicated that spontaneously beating AF-derived cardiomyocytes have a mean firing rate significantly higher than that of control-derived cardiomyocytes while other parameters such as the maximum diastolic potential and action potential duration did not differ. Since cardiac rate is controlled by the pacemaker If current we have recorded If and found that, in diseased cells, this current activated at more positive voltages than in control cells, a difference compatible with the faster rate. Preliminary data obtained using ion channel blockers showed also that AF-derived cells are less sensitive to 50 mM Ni2+, a blocker of the calcium current ICaT, than control cells, suggesting a minor contribution of this current to the action potential. In conclusion, our data show that iPSC represent a good in vitro cellular model to unravel functional alterations caused by unknown genetic mutations at the basis of complex cardiac diseases such as AF.