Induced Pluripotent Stem Cell–Derived Cardiomyocytes Provide In Vivo Biological Pacemaker Function

Abstract

Background—Although multiple approaches have been used to create biological pacemakers in animal models, induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) have not been investigated for this purpose. We now report pacemaker function of iPSC-CMs in a canine model.Methods and Results—Embryoid bodies were derived from human keratinocytes, their action potential characteristics determined, and their gene expression profiles and markers of differentiation identified. Atrioventricular blocked dogs were immunosuppressed, instrumented with VVI pacemakers, and injected subepicardially into the anterobasal left ventricle with 40 to 75 rhythmically contracting embryoid bodies (totaling 1.3–2×106 cells). ECG and 24-hour Holter monitoring were performed biweekly. After 4 to 13 weeks, epinephrine (1 μg kg−1 min−1) was infused, and the heart removed for histological or electrophysiological study. iPSC-CMs largely lost the markers of pluripotency, became positive for cardiac-specific markers. and manifested If-dependent automaticity. Epicardial pacing of the injection site identified matching beats arising from that site by week 1 after implantation. By week 4, 20% of beats were electronically paced, 60% to 80% of beats were matching, and mean and maximal biological pacemaker rates were 45 and 75 beats per minute. Maximum night and day rates of matching beats were 53±6.9 and 69±10.4 beats per minute, respectively, at 4 weeks. Epinephrine increased rate of matching beats from 35±4.3 to 65±4.0 beats per minute. Incubation of embryoid bodies with the vital dye, Dil, revealed the persistence of injected cells at the site of administration.Conclusions—iPSC-CMs can integrate into host myocardium and create a biological pacemaker. Although this is a promising development, rate and rhythm of the iPSC-CMs pacemakers remain to be optimized.

Next-generation pacemakers: from small devices to biological pacemakers

“…Although attractive, iPSC-derived biological pacemakers face substantial hurdles for clinical translation: current iPSC technologies produce a mixed population of cells with various phenotypes. This issue not only affects the function of iPSC-derived biological pacemakers (as previously reported 92 ), but is also a safety concern given the potential of immature cells to migrate or to differentiate into different cell types (such as teratomas). Moreover, generating iPSCs requires weeks to months; any given patient would have to defer implantation until their autologous cardiomyocytes became available, which limits the potential patient candidates to those not requiring urgent chronotropic support.…”

“…In another study from an independent group, iPSC-derived cardiomyocytes were delivered into dog hearts by open thoracotomy 92 . Biological pacemaker activity was seen in only 50% of the animals, with beating rates of 40–50 bpm (REF.…”

Year in Review in Cardiac Electrophysiology

“…1 Although only 40% to 80% of the beats matched the site of cell injection, this is first study to test a human induced pluripotent stem cell-based biological pacemaker in a large animal model of heart block and represents an important step forward in biological pacing.…”

Cardiac Conduction System in Congenitally Corrected Transposition of the Great Arteries and Its Clinical Relevance

“…Furthermore, the insights gained will likely also advance our understanding of the arrhythmogenicity of the failing right ventricle and risk stratification/prediction against sudden cardiac death. Finally it has become impossible to imagine a future of pacing without leadless systems and more importantly without biological therapies43, 44 that can restore automaticity or conduction so that current transvenous and epicardial systems become obsolete. This latter innovation is especially attractive for those patients with ccTGA, as they frequently require pacing at a much younger age than the conventional patient with AV block22 and therefore have many more years exposed to the risks of intravascular leads and generator replacement surgeries.…”