Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy, few immunological studies have been carried out with iPSCs. Here we describe an allogeneic transplantation model established using the cynomolgus monkey (Macaca fascicularis), the MHC structure of which is identical to that of humans. Fibroblast-derived iPSCs were generated from a MHC haplotype (HT4) homozygous animal and subsequently differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intra-myocardial injection of iPSC-CMs. The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection in monkeys treated with clinically relevant doses of methylprednisolone and tacrolimus, and showed electrical coupling with host cardiomyocytes as assessed by use of the fluorescent calcium indicator G-CaMP7.09. Additionally, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks after transplantation; however, the incidence of ventricular tachycardia was transiently, but significantly, increased when compared to vehicle-treated controls. Collectively, our data demonstrate that allogeneic iPSC-CM transplantation is sufficient to regenerate the infarcted non-human primate heart; however, further research to control post-transplant arrhythmias is necessary.

OBJECTIVES We aimed to identify predictors of postoperative permanent neurological deficits (PNDs) and evaluate the early management of cerebral perfusion in patients undergoing surgical repair of acute type A aortic dissection with cerebral malperfusion. METHODS Between October 2009 and September 2018, a total of 197 patients with acute type A aortic dissection underwent aortic replacement. Of these, 42 (21.3%) patients had an imaging cerebral malperfusion (ICM). ICM was assessed preoperatively, which also revealed whether dissected supra-aortic branch vessels were occluded or narrowed by a thrombosed false lumen. After September 2017, early reperfusion and extra-anatomic revascularization were performed in cases with ICM. RESULTS Hospital mortality rates for cases with ICM were 4.8% (2/42). Before September 2017, PND were observed in 6 patients (54.5%) with preoperative neurological symptoms (n = 11), and 7 patients (33.3%) without neurological symptoms (n = 21) in patients with ICM. Occlusion or severe stenosis of supra-aortic branch vessels (odds ratio, 7.66; P < 0.001), regardless of preoperative clinical neurological symptoms, was a risk factor for PND. After September 2017, 7 of 10 patients with ICM underwent early reperfusion and extra-anatomic revascularization. PND did not occur in any of these 7 patients. CONCLUSIONS Occlusion or severe stenosis of supra-aortic branch vessels is a predictor of PND risk in patients undergoing surgery for acute type A aortic dissection. Early reperfusion and extra-anatomic revascularization may reduce the risk of neurological complications in patients with ICM, with or without neurological symptoms.

Pluripotent stem cell-derived cardiomyocytes show great promise in regenerating the heart after myocardial infarction; however, several uncertainties exist that must be addressed before clinical trials. One practical issue is graft survival following transplantation. Although a pro-survival cocktail with Matrigel has been shown to enhance graft survival, the use of Matrigel may not be clinically feasible. The purpose of this study was to test whether a hyaluronan-based hydrogel, HyStem, could be a substitute for Matrigel. Human induced pluripotent stem cell-derived cardiomyocytes diluted with HyStem alone, HyStem plus pro-survival factors, or a pro-survival cocktail with Matrigel (PSC/MG), were transplanted into a rat model of acute myocardial infarction. Histological analysis at 4 weeks post transplantation revealed that, among the three groups, recipients of PSC/MG showed the largest graft size. Additionally, the grafted cardiomyocytes in the recipients of PSC/MG had a more matured phenotype compared to those in the other two groups. These findings suggest that further studies will be required to enhance not only graft size, but also the maturation of grafted cardiomyocytes.

Accumulating evidence suggests that human pluripotent stem cell-derived cardiomyocytes can affect "heart regeneration", replacing injured cardiac scar tissue with concomitant electrical integration. However, electrically coupled graft cardiomyocytes were found to innately induce transient post-transplant ventricular tachycardia in recent large animal model transplantation studies. We hypothesised that these phenomena were derived from alterations in the grafted cardiomyocyte characteristics. In vitro experiments showed that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) contain nodal-like cardiomyocytes that spontaneously contract faster than working-type cardiomyocytes. When transplanted into athymic rat hearts, proliferative capacity was lower for nodal-like than working-type cardiomyocytes with grafted cardiomyocytes eventually comprising only relatively matured ventricular cardiomyocytes. RNA-sequencing of engrafted hESC-CMs confirmed the increased expression of matured ventricular cardiomyocyte-related genes, and simultaneous decreased expression of nodal cardiomyocyte-related genes. Temporal engraftment of electrical excitable nodal-like cardiomyocytes may thus explain the transient incidence of post-transplant ventricular tachycardia, although further large animal model studies will be required to control posttransplant arrhythmia. Pluripotent stem cells are attractive cell sources for regenerative medicine to treat refractory diseases including heart failure. As adult cardiomyocytes have extremely limited capacity to proliferate 1 , necrotic cardiomyocytes resulting from cardiac injury, such as myocardial infarction, will no longer spontaneously regenerate and are replaced with non-contractile scar tissue, eventually leading to heart failure. To regenerate the heart, transplantation studies of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) were performed initially in small animal models, in which human embryonic stem cell-derived cardiomyocytes (hESC-CMs) engrafted and survived in the injured heart 2 , restored contractile function 3,4 , and electrically integrated with host cardiomyocytes 5,6. In these and other small animal studies 7 , ventricular arrhythmia caused by the transplantation of hPSC-CMs was not detected, likely owing to the much faster heart rate of the host species than that of graft cardiomyocytes.

PDT is effective not only in improving the cytological and histological measures when treating CIN but also for eradicating cervical HPV.

Frailty, as defined using a seven-component frailty index, can serve as an independent predictor of the risk of late mortality for patients undergoing surgery for acute type A aortic dissection. Such frailty markers, all of which are easily assessed preoperatively, may provide valuable information for patient counseling and risk stratification before aortic surgery.

Pluripotent stem cells (PSCs) have gained interest for cell-based regenerative therapies because of their capacity to differentiate into most somatic cell types, including cardiomyocytes. Remarkable progress in the generation of PSC-derived cardiomyocytes has been made in this decade, and recent preclinical transplantation studies using various animal models have provided proof-of-principle for their use in heart regeneration. However, several obstacles preclude their effective and safe clinical application for cardiac repair, including the need for approaches that prevent tumorigenesis, arrhythmogenesis, and immune rejection. In this review, we focus on recent progress in the field of PSC-based cardiac regenerative therapy, including the remaining hurdles and potential approaches to circumventing them.

Major lung resection for lung cancer in patients with coronary artery disease is feasible. Our study suggests that discontinuation of antiplatelet therapy may not increase postoperative complications in patients with coronary artery disease.