Letter regarding the article by Xue et al, "Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes".

“Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes” To the Editor: The article by Xue et al1 on human embryonic stem cellderived pacemakers illustrates that embryonic stem cells differentiated into spontaneously beating cardiocytes may function as biological pacemakers and mentions a potential limitation: The intrinsic pacemaker rate was slower than desirable. They suggest that incorporating HCN pacemaker channel genes might achieve more desirable rates, an idea consistent with our published results using HCN2 in geneand adult human mesenchymal stem cell (hMSC)-based therapies.2–4 However, certain of the comments by Xue et al misinterpret our own work on HCN-loaded hMSCs. They state that “. . .these modified, undifferentiated, human mesenchymal stem cells are incapable of pacing quiescent cells because the former are neither electrically active nor genuine cardiac cells” (p 19). This statement suggests a misunderstanding of the rationale and underlying biophysics of the hMSC experiments. In fact, generation of pacemaker activity does not require delivery of an “excitable differentiated cardiac cell,” but only that the delivered cell (1) carry sufficient pacemaker current and (2) make gap junctions; thus, the hMSC-myocyte pair should behave as a pacemaker unit entirely equivalent to a single heart cell with substantial if. We clearly demonstrated both functions for our genetically engineered hMSCs.4,5 We further take issue with the statement by Xue et al that biological pacemakers must pace quiescent cells. Extrapolating this to human disease implies that biological pacemakers should initiate activity in non-beating hearts. Yet, this is not what an electronic or a biological pacemaker is expected to do clinically. Rather, both types of pacemaker should initiate activity in hearts beating perilously slowly, putting patients at risk of devastating arrhythmia, syncope, or death. Therefore, although our HCNload hMSC biological pacemaker can pace quiescent cells, there is much to be said conceptually for a biological pacemaker that increases dangerously slow heart rates. Xue et al also criticize our earliest in situ gene therapy publication.2 They imply a deficiency in this study derived from our use of vagal suppression to eliminate sinoatrial pacemaker function. Given that in the absence of atrioventricular block a physiologically adequate rate generated by gene therapy might be overdriven by the sinoatrial node, the requirement for vagal suppression is not relevant to examination of therapeutic potential. Moreover, in subsequent studies, we showed that during vagal stimulation, an HCN2-based biological pacemaker inserted locally into a bundle branch is functional,3 and that in chronic atrioventricular block and bundle branch insertion of HCN2, physiologically relevant rates are achieved.6 In closing, we welcome criticism and discourse but believe it essential that this be based on an accurate interpretation of the subject matter under discussion.