Transplantation of hESC-CMs after extensive myocardial infarction in rats results in the formation of stable cardiomyocyte grafts, attenuation of the remodeling process, and functional benefit. These findings highlight the potential of hESCs for myocardial cell therapy strategies.

Human embryonic stem cells (hESC) are pluripotent lines that can differentiate in vitro into cell derivatives of all three germ layers, including cardiomyocytes. Successful application of these unique cells in the areas of cardiovascular research and regenerative medicine has been hampered by difficulties in identifying and selecting specific cardiac progenitor cells from the mixed population of differentiating cells. We report the generation of stable transgenic hESC lines, using lentiviral vectors, and single-cell clones that express a reporter gene (eGFP) under the transcriptional control of a cardiac-specific promoter (the human myosin light chain-2V promoter). Our results demonstrate the appearance of eGFP-expressing cells during the differentiation of the hESC as embryoid bodies (EBs) that can be identified and sorted using FACS (purity>95%, viability>85%). The eGFP-expressing cells were stained positively for cardiac-specific proteins (>93%), expressed cardiac-specific genes, displayed cardiac-specific action-potentials, and could form stable myocardial cell grafts following in vivo cell transplantation. The generation of these transgenic hESC lines may be used to identify and study early cardiac precursors for developmental studies, to robustly quantify the extent of cardiomyocyte differentiation, to label the cells for in vivo grafting, and to allow derivation of purified cell populations of cardiomyocytes for future myocardial cell therapy strategies.

Myocardial regeneration strategies have been hampered by the lack of sources for human cardiomyocytes (CMs) and by the significant donor cell loss following transplantation. We assessed the ability of a three-dimensional tissue-engineered human vascularized cardiac muscle to engraft in the in vivo rat heart and to promote functional vascularization. Human embryonic stem cell-derived CMs alone or with human endothelial cells (human umbilical vein endothelial cells) and embryonic fibroblasts (triculture constructs) were seeded onto biodegradable porous scaffolds. The resulting tissue constructs were transplanted to the in vivo rat heart and formed cardiac tissue grafts. Immunostaining studies for human-specific CD31 and alpha-smooth muscle actin demonstrated the formation of both donor (human) and host (rat)-derived vasculature within the engrafted triculture tissue constructs. Intraventricular injection of fluorescent microspheres or lectin resulted in their incorporation by human-derived vessels, confirming their functional integration with host coronary vasculature. Finally, the number of blood vessels was significantly greater in the triculture tissue constructs (60.3 +/- 8/mm(3), p < 0.05) when compared with scaffolds containing only CMs (39.0 +/- 14.4/mm(3)). In conclusion, a tissue-engineered human vascularized cardiac muscle can be established ex vivo and transplanted in vivo to form stable grafts. By utilizing a multicellular preparation we were able to increase biograft vascularization and to show that the preexisting human vessels can become functional and contribute to tissue perfusion.

AimsReactive pulmonary hypertension (PH) is a severe form of PH secondary to left-sided heart failure (HF). Given the structural and functional abnormalities in the pulmonary vasculature that occur in reactive PH, we hypothesized that pulmonary artery capacitance (PAC) may be profoundly affected, with implications for clinical outcome. Methods and resultsWe studied 393 HF patients of whom 124 (32%) were classified as having passive PH and 140 (36%) as having reactive PH, and 91 patients with pulmonary arterial hypertension (PAH). Mean PAC was highest in patients without PH (4.5 ± 2.1 mL/mmHg), followed by the passive PH group (2.8 ± 1.4 mL/mmHg) and was lowest in those with reactive PH (1.8 ± 0.7 mL/mmHg) (P = 0.0001). PAC and pulmonary vascular resistance (PVR) fitted well to a hyperbolic inverse relationship (PAC = 0.25/PVR, R 2 = 0.70), with reactive PH patients dispersed almost predominantly on the flat part of the curve where a reduction in PVR is associated with a small improvement in PAC. Elevated PCWP was associated with a significant lowering of PAC for any PVR (P = 0.036). During a median follow-up of 31 months, both reactive PH [hazard ratio (HR) 2.59, 95% confidence interval (CI) 1.14-4.46, P = 0.02] and reduced PAC (HR 0.72 per 1 mL/mmHg increase, 95% CI 0.59-0.88, P = 0.001) were independent predictors of mortality.

BackgroundAcute kidney injury (AKI) following primary percutaneous coronary intervention (pPCI) is frequently interpreted as contrast‐induced AKI but may result from other insults. We aimed to determine the causal association of contrast material exposure and the incidence of AKI following pPCI using a control group of propensity score–matched patients with ST‐segment–elevation myocardial infarction who were not exposed to contrast material.Methods and ResultsWe studied 2025 patients with ST‐segment–elevation myocardial infarction who underwent pPCI and 1025 patients receiving fibrinolysis or no reperfusion who were not exposed to contrast material during the first 72 hours of hospital stay (control group). AKI was defined as creatinine of ≥0.5 mg/dL or >25% rise within 72 hours. AKI rates were similar in the pPCI and control groups (10.3% versus 12.1%, respectively; P=0.38). Propensity score matching resulted in 931 matched pairs with PCI and no PCI, with balanced baseline covariates (standardized difference <0.1). Among propensity score–matched patients, AKI rates were not significantly different with and without PCI (8.6% versus 10.9%, P=0.12). In the pPCI cohort, independent predictors of AKI included age ≥70 years, insulin‐treated diabetes mellitus, diuretic therapy, anterior infarction, baseline estimated glomerular filtration rate, and variables related to the presence of pump failure (higher Killip class, intra‐aortic balloon pump use) and reduced left ventricular ejection fraction but not contrast material dose. A risk score based on the PCI cohort had similar discriminatory capacity for AKI in the control group (C statistic 0.81±0.02 and 0.78±0.02, respectively; P=0.26).ConclusionsThe development of AKI in patients with ST‐segment–elevation myocardial infarction undergoing pPCI is mainly related to older age, baseline estimated glomerular filtration rate, heart failure, and hemodynamic instability. Risk for AKI is similar among ST‐segment–elevation myocardial infarction patients with and without contrast material exposure.

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Human-induced pluripotent stem cells can be established from patients with advanced heart failure and coaxed to differentiate into cardiomyocytes, which can integrate with host cardiac tissue. This novel source for patient-specific heart cells may bring a unique value to the emerging field of cardiac regenerative medicine.