Summary Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) show considerable promise for regenerating injured hearts, and we therefore tested their capacity to stably engraft in a translationally relevant preclinical model, the infarcted pig heart. Transplantation of immature hESC-CMs resulted in substantial myocardial implants within the infarct scar that matured over time, formed vascular networks with the host, and evoked minimal cellular rejection. While arrhythmias were rare in infarcted pigs receiving vehicle alone, hESC-CM recipients experienced frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. Electroanatomical mapping and pacing studies implicated focal mechanisms, rather than macro-reentry, for these graft-related tachyarrhythmias as evidenced by an abnormal centrifugal pattern with earliest electrical activation in histologically confirmed graft tissue. These findings demonstrate the suitability of the pig model for the preclinical development of a hESC-based cardiac therapy and provide new insights into the mechanistic basis of electrical instability following hESC-CM transplantation.

AimsImpaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized 13C magnetic resonance (MR), in which 13C-labelled metabolites are followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non-invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non-invasive hyperpolarized [13C]pyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease.Methods and resultsDilated cardiomyopathy (DCM) was induced in pigs (n = 5) by rapid pacing. Pigs were examined using MR at weekly time points: cine-MRI assessed cardiac structure and function; hyperpolarized [2-13C]pyruvate was administered intravenously, and 13C MRS monitored [13C]glutamate production; 31P MRS assessed cardiac energetics [phosphocreatine (PCr)/ATP]; and hyperpolarized [1-13C]pyruvate was administered for MRI of pyruvate dehydrogenase complex (PDC)-mediated pyruvate oxidation via [13C]bicarbonate production. Early in pacing, the cardiac index decreased by 25%, PCr/ATP decreased by 26%, and [13C]glutamate production decreased by 51%. After clinical features of DCM appeared, end-diastolic volume increased by 40% and [13C]bicarbonate production decreased by 67%. Pyruvate dehydrogenase kinase 4 protein increased by two-fold, and phosphorylated Akt decreased by half. Peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1 gene expression decreased by a half and a third, respectively.ConclusionDespite early changes associated with cardiac energetics and 13C incorporation into the Krebs cycle, pyruvate oxidation was maintained until DCM developed, when the heart's capacity to oxidize both pyruvate and fats was reduced. Hyperpolarized 13C MR may be important to characterize metabolic changes that occur during heart failure progression.

Pathophysiological responses after acute myocardial infarction include edema, hemorrhage, and microvascular obstruction along with cellular damage. The in vivo evolution of these processes simultaneously throughout infarct healing has not been well characterized. The purpose of our study was to quantitatively monitor the time course of these mechanisms by MRI in a porcine model of myocardial infarction. Ten pigs underwent MRI before coronary occlusion with subgroups studied at day 2 and weeks 1, 2, 4, and 6 post-infarction. Tissue characterization was performed using quantitative T2 and T2* maps to identify edema and hemorrhage, respectively. Contrast-enhanced MRI was used for infarct/ microvascular obstruction delineation. Inflammation was reflected by T2 fluctuations, however at day 2, edema and hemorrhage had counter-acting effects on T2. Hemorrhage (all forms) and mineralization (calcium) could be identified by T2* in the presence of edema. Simultaneous resolution of microvascular obstruction and T2* abnormality suggested that the two phenomenon were closely associated during the healing process. Our study demonstrates that quantitative T2 and T2* mapping techniques allow regional, longitudinal, and cross-subject comparisons and give insights into histological and tissue remodeling processes. Such in vivo characterization will be important in grading severity and evaluating treatment strategies for myocardial infarction, potentially improving clinical outcomes. Magn Reson Med 66:1129-1141, 2011. V C 2011 Wiley-Liss, Inc.