Myocardial injury results in a loss of contractile tissue mass that, in the absence of efficient regeneration, is essentially irreversible. Transplantation of human pluripotent stem cell-derived cardiomyocytes has beneficial but variable effects. We created human engineered heart tissue (hEHT) strips from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and hiPSC-derived endothelial cells. The hEHTs were transplanted onto large defects (22% of the left ventricular wall, 35% decline in left ventricular function) of guinea pig hearts 7 days after cryoinjury, and the results were compared with those obtained with human endothelial cell patches (hEETs) or cell-free patches. Twenty-eight days after transplantation, the hearts repaired with hEHT strips exhibited, within the scar, human heart muscle grafts, which had remuscularized 12% of the infarct area. These grafts showed cardiomyocyte proliferation, vascularization, and evidence for electrical coupling to the intact heart tissue in a subset of engrafted hearts. hEHT strips improved left ventricular function by 31% compared to that before implantation, whereas the hEET or cell-free patches had no effect. Together, our study demonstrates that three-dimensional human heart muscle constructs can repair the injured heart.

V entricular electric propagation is governed by activation sequence, electric properties of the myocardial syncytium, and anatomy of the ventricular wall.1,2 Time course and rate of propagation of the action potential (AP) depends on ionic current flow across sarcolemmal membranes and the electric resistance and capacitance of nearby myocardium. 3 These factors are heterogeneous across the ventricular wall; because of polarized gap junction distribution, intercellular resistance depends on myocardial fiber orientation 4 ; electrotonic load at any given point in the myocardium depends on the activation sequence and distance from structural features, such as the epicardial surface. In addition, ion channel expression is heterogeneous in the apex-base 5 and endocardial-epicardial axes. 6 Therefore, the rate of depolarization of the AP reflects myocardial excitability. However, the influence of activation sequence on AP upstroke is still a matter of debate. 7,8 Although continuous cable theory predicts that a higher conduction velocity (CV) is associated with higher maximal upstroke velocity (dV/dt max ), 9 on the surface of isolated cardiac muscle preparations longitudinal propagation results in faster CV but lower dV/dt max relative to transverse propagation. 10 These observations were explained by (1) predominantly axial connexin distribution and (2) arrangement of capillary vessels parallel to the longitudinal axis of the cells.11 This has been challenged by computational modeling, which suggests that differences in upstroke characteristics are limited to myocardium close to the epicardial surface.7 Until now, this could not be verified experimentally because of the technical difficulty associated with accurate transmembrane © 2013 American Heart Association, Inc. Original Article Circ Arrhythm ElectrophysiolBackground-Electric excitability in the ventricular wall is influenced by cellular electrophysiology and passive electric properties of the myocardium. Action potential (AP) rise time, an indicator of myocardial excitability, is influenced by conduction pattern and distance from the epicardial surface. This study examined AP rise times and conduction velocity as the depolarizing wavefront approaches the epicardial surface. Methods and Results-Two-photon excitation of di-4-aminonaphthenyl-pyridinum-propylsulfonate was used to measure electric activity at discrete epicardial layers of isolated Langendorff-perfused rabbit hearts to a depth of 500 μm. Endoto-epicardial wavefronts were studied during right atrial or ventricular endocardial pacing. Similar measurements were made with epi-to-endocardial, transverse, and longitudinal pacing protocols. Results were compared with data from a bidomain model of 3-dimensional (3D) electric propagation within ventricular myocardium. During right atrial and endocardial pacing, AP rise time (10%-90% of upstroke) decreased by ≈50% between 500 and 50 μm from the epicardial surface, whereas conduction velocity increased and AP duration was only slightly shorter (≈4%). The...