Long-term engraftment and maturation of autologous iPSC-derived cardiomyocytes in two rhesus macaques.

Cellular therapies with cardiomyocytes produced from induced pluripotent stem cells (iPSC-CMs) offer a potential route to cardiac regeneration as a treatment for chronic ischemic heart disease. Here, we report successful long-term engraftment and in vivo maturation of autologous iPSC-CMs in two rhesus macaques with small, subclinical chronic myocardial infarctions, all without immunosuppression. Longitudinal positron emission tomography imaging using the sodium/iodide symporter (NIS) reporter gene revealed stable grafts for over 6 and 12 months, with no teratoma formation. Histological analyses suggested capability of the transplanted iPSC-CMs to mature and integrate with endogenous myocardium, with no sign of immune cell infiltration or rejection. By contrast, allogeneic iPSC-CMs were rejected within 8 weeks of transplantation. This study provides the longest-term safety and maturation data to date in any large animal model, addresses concerns regarding neoantigen immunoreactivity of autologous iPSC therapies, and suggests that autologous iPSC-CMs would similarly engraft and mature in human hearts.

Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes.

Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore function. Recent large animal data, however, have revealed a significant risk of engraftment arrhythmia (EA). Although transient, the risk posed by EA presents a barrier to clinical translation. We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. This study uses a porcine model to provide proof-of-concept evidence that a combination of amiodarone and ivabradine can effectively suppress EA. None of the nine treated subjects experienced the primary endpoint of cardiac death, unstable EA, or heart failure compared with five out of eight (62.5%) in the control cohort (hazard ratio = 0.00; 95% confidence interval: 0-0.297; p = 0.002). Pharmacologic treatment of EA may be a viable strategy to improve safety and allow further clinical development of cardiac remuscularization therapy.

Quantitative Analyses of the Left Ventricle Volume and Cardiac Function in Normal and Infarcted Yucatan Minipigs.

(1) Background: The accuracy of the left ventricular volume (LVV) and contractility measurements with cardiac magnetic resonance imaging (CMRI) is decreased if the papillary muscles are abnormally enlarged, such as in hypertrophic cardiomyopathy in human patients or in pig models of human diseases. The purpose of this work was to establish the best method of LVV quantification with CMRI in pigs. (2) Methods: The LVV in 29 Yucatan minipig hearts was measured using two different techniques: the "standard method", which uses smooth contouring along the endocardial surface and adds the papillary volume to the ventricular cavity volume, and the "detailed method", which traces the papillary muscles and trabeculations and adds them to the ventricular mass. (3) Results: Papillary muscles add 21% to the LV mass in normal and infarcted hearts of Yucatan minipigs. The inclusion or exclusion of these from the CMRI analysis significantly affected the study results. In the normal pig hearts, the biggest differences were found in measurements of the LVV, ejection fraction (EF), LV mass and indices derived from the LV mass (p < 0.001). The EF measurement in the normal pig heart was 11% higher with the detailed method, and 19% higher in the infarcted pig hearts (p < 0.0001). The detailed method of endocardium tracing with CMRI closely represented the LV mass measured ex vivo. (4) Conclusions: The detailed method, which accounts for the large volume of the papillary muscles in the pig heart, provides better accuracy and interobserver consistency in the assessment of LV mass and ejection fraction, and might therefore be preferable for these analyses.

Pauci-immune glomerulonephritis in a captive chimpanzee (Pan troglodytes), and a review of spontaneous cases in animals.

BACKGROUND: Crescentic glomeruli are the hallmark finding in rapidly progressive glomerulonephritis (RPGN) and are characterized by disruption and proliferation of the glomerular capsule and an influx of cells into Bowman's space. Pauci-immune-type RPGN is identified by a lack of immunoglobulins and immune complexes in the glomerular basement membrane. METHODS: Complete necropsy and histology were performed on the affected chimpanzee. Electron microscopy was performed on kidney sections. A search of the literature was performed to identify spontaneous RPGN in animals. RESULTS: We report a case of crescentic glomerulonephritis of the pauci-immune-type in a hepatitis C virus-infected 28-year-old male chimpanzee (Pan troglodytes) who was humanely euthanized for a cardiac-related decline in health. CONCLUSION: To our knowledge, this is the first report describing pauci-immune crescentic glomerulonephritis in a non-human primate.