[Off-pump Resection of Dopamine-secreting Cardiac Paraganglioma].

Dopamine-secreting paragangliomas is known to be rare. The average annual incidence rate was reported 0.8 per 100,000 person-years. Approximately 1 to 2% of paragangliomas occur in the chest. We describe a patient with a large dopamine-secreting cardiac paraganglioma, right adrenal tumor and carotid body tumor. A 26-year-old man with progressive exertional dyspnea was referred to our hospital for further management of multiple paragangliomas. Positron emission tomography (PET) and PET-computed tomography (CT) detected those three legions. The diameter of cardiac paraganglioma was over 45 mm and was biggest among three tumors. Firstly, therefore, we planned cardiac paraganglioma resection. Through left lateral thoracotomy in the 4th intercostal space via, cardiac paraganglioma was resected under cardiopulmonary bypass and beating heart. Postoperative course was uneventful. Tumor cells were positive for synaptophysin and chromogranin A. Free metanephrines in the serum and urinary fractionated metanephrines normalized after cardiac surgery while the other two tumors remained untreated.

Two-Step Operation for Aortoesophageal Fistula After Thoracic Endovascular Repair.

Aortoesophageal fistula (AEF) caused after thoracic endovascular aortic repair (TEVAR) is rare but a serious complication. We report a successful staged operation for AEF after TEVAR. A 70-year-old male underwent TEVAR for a ruptured aneurysm of the descending aorta and subsequently developed AEF three months later. First, the patient underwent the resection of the esophagus, which was the focus of the infection under the right thoracoscopic approach. Second, descending aorta replacement was performed using a left thoracotomy approach. The patient has been well for about two years since the second operation without recurring graft infection. Staged operation with a different approach to the infection zone is a useful method for AEF.

Impact of Recovery from Acute Kidney Injury After Aortic Arch Repair.

BACKGROUND: The impact of recovery from acute kidney injury (AKI) after open thoracic aortic surgery on follow-up outcomes is unclear. METHODS: This retrospective study included 214 patients who underwent aortic arch surgery requiring hypothermic circulatory arrest between 2007 and 2019. Patients who required preoperative renal replacement therapy and patients who died within 7 postoperative days were excluded. The incidence of recovery from AKI was examined. Renal outcomes were compared among patients with no AKI (Group N), recovery from AKI (Group R), and persistent AKI (Group P). RESULTS: Preoperative kidney function was similar among the 3 groups. Among the 115 patients who developed postoperative AKI, 80.9% recovered from AKI at discharge. The 5-year cumulative mortality rate was 18.0%, 24.5%, and 68.4% in Group N, R, and P, respectively (P < .001, Group R vs Group P). The 5-year cumulative incidence of renal replacement therapy dependency was 0.0%, 5.4%, and 22.7%, respectively (P = .04, Group N vs Group R; P = .01, Group R vs Group P). The medians (interquartile range) of estimated glomerular filtration rate (mL/min/1.73 m2) 2 years after surgery were 65.2 (50.4-80.2), 54.3 (41.4-65.9), and 56.9 (40.2-67.5), respectively (P = .03, Group N vs Group R). CONCLUSIONS: The majority of patients recovered from AKI after thoracic aortic repair by discharge. However, the prolonged impact of AKI recovery on kidney function was observed during the follow-up period. Diligent follow-up after discharge is warranted for early identification of patients at high risk of kidney disease progression.

Thrombocytopenia recovered by surgical resection of a myxoma.

Myxoma is the most common primary cardiac neoplasm, and causes a variety of symptoms, including hematological disorder. An 82-year-old man with anorexia was diagnosed with a gastrointestinal stromal tumor. Computed tomography and echocardiography showed a 2-cm tumor in the left atrium. The patient had a history of lung and skin sarcoidosis, and interstitial pneumonia. Laboratory examination showed thrombocytopenia with a platelet count of 23 × 103/µL and elevation of IgA and platelet-associated IgG (PAIgG). We suspected that the thrombocytopenia was caused by the left atrial tumor. He successfully underwent resection of the tumor with cardiopulmonary bypass. The platelet count increased to 166 × 103/µL after surgery. Pathological examination showed Alcian blue staining of the extracellular and intracellular matrix, suggesting a mucopolysaccharide matrix. Immunohistochemical examination of the tumor revealed expression of CD31, CD34, and calretinin, which was consistent with a myxoma. The PAIgG level decreased to the normal range at 36 days postoperatively. Thrombocytopenia is a relatively rare finding in patients with myxomas. However, in addition to mobility of the mass, thrombocytopenia should be kept in mind as an indication for surgery. .

Human iPS cell-derived cardiac tissue sheets for functional restoration of infarcted porcine hearts.

To realize human induced pluripotent stem cell (hiPSC)-based cardiac regenerative therapy, evidence of therapeutic advantages in human-sized diseased hearts are indispensable. In combination with an efficient and simultaneous differentiation of various cardiac lineages from hiPSCs and cell sheet technology, we aimed to generate clinical-sized large cardiac tissue sheets (L-CTSs) and to evaluate the therapeutic potential in porcine infarct heart. We simultaneously induced cardiomyocytes (CMs) and vascular cells [vascular endothelial cells (ECs) and vascular mural cells (MCs)] from hiPSCs. We generated L-CTSs using 10cm-sized temperature-responsive culture dishes. We induced myocardial infarction (MI) in micromini-pigs (15-25 kg) and transplanted the L-CTSs (Tx) 2 weeks after MI induction (4 sheets/recipient) under immunosuppression (Tx: n = 5, Sham: n = 5). Self-pulsating L-CTSs were approximately 3.5cm in diameter with 6.8×106±0.8 of cells containing cTnT+-CMs (45.6±13.2%), VE-cadherin+-ECs (5.3±4.4%) and PDGFRß+-MCs (14.4±20.7%), respectively (n = 5). In Tx group, echocardiogram indicated a significantly higher systolic function of the left ventricle (LV) compared to that in sham control (Sham vs Tx: fractional shortening: 24.2±8.6 vs 40.5±9.7%; p<0.05). Ejection fraction evaluated by left ventriculogram was significantly higher in Tx group (25.3±6.2% vs 39.8±4.2%; p<0.01). Speckle tracking echocardiogram showed a significant increase of circumference strain in infarct and border regions after transplantation. Fibrotic area was significantly lower in Tx group (23.8±4.5 vs 15.9±3.8%; P<0.001). Capillary density in the border region was significantly higher in Tx group (75.9±42.6/mm2 vs 137.4±44.8/mm2, p<0.001). These data indicate that the L-CTS transplantation attenuated LV remodeling. L-CTSs potentially restore cardiac dysfunction of human-sized infarct heart.

Correction: Efficient and robust differentiation of endothelial cells from human induced pluripotent stem cells via lineage control with VEGF and cyclic AMP.

[This corrects the article DOI: 10.1371/journal.pone.0173271.].

Efficient and robust differentiation of endothelial cells from human induced pluripotent stem cells via lineage control with VEGF and cyclic AMP.

Blood vessels are essential components for many tissues and organs. Thus, efficient induction of endothelial cells (ECs) from human pluripotent stem cells is a key method for generating higher tissue structures entirely from stem cells. We previously established an EC differentiation system with mouse pluripotent stem cells to show that vascular endothelial growth factor (VEGF) is essential to induce ECs and that cyclic adenosine monophosphate (cAMP) synergistically enhances VEGF effects. Here we report an efficient and robust EC differentiation method from human pluripotent stem cell lines based on a 2D monolayer, serum-free culture. We controlled the direction of differentiation from mesoderm to ECs using stage-specific stimulation with VEGF and cAMP combined with the elimination of non-responder cells at early EC stage. This "stimulation-elimination" method robustly achieved very high efficiency (>99%) and yield (>10 ECs from 1 hiPSC input) of EC differentiation, with no purification of ECs after differentiation. We believe this method will be a valuable technological basis broadly for regenerative medicine and 3D tissue engineering.

In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling.

The blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs) into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs) were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A) and efflux transporters (ABCA1, BCRP, PGP, MRP5), and strong barrier function based on tight junctions. Neuron-derived Dll1, which activates Notch signaling in ECs, was essential for the BEC specification. We performed in vitro BBB permeability tests and assessed ten clinical drugs by nanoLC-MS/MS, finding a good correlation with the BBB permeability reported in previous cases. This technology should be useful for research on human BBB physiology, pathology, and drug development.

Efficient long-term survival of cell grafts after myocardial infarction with thick viable cardiac tissue entirely from pluripotent stem cells.

Poor engraftment of cells after transplantation to the heart is a common and unresolved problem in the cardiac cell therapies. We previously generated cardiovascular cell sheets entirely from pluripotent stem cells with cardiomyocytes, endothelial cells and vascular mural cells. Though sheet transplantation showed a better engraftment and improved cardiac function after myocardial infarction, stacking limitation (up to 3 sheets) by hypoxia hampered larger structure formation and long-term survival of the grafts. Here we report an efficient method to overcome the stacking limitation. Insertion of gelatin hydrogel microspheres (GHMs) between each cardiovascular cell sheet broke the viable limitation via appropriate spacing and fluid impregnation with GHMs. Fifteen sheets with GHMs (15-GHM construct; >1 mm thickness) were stacked within several hours and viable after 1 week in vitro. Transplantation of 5-GHM constructs (≈2 × 10(6) of total cells) to a rat myocardial infarction model showed rapid and sustained functional improvements. The grafts were efficiently engrafted as multiple layered cardiovascular cells accompanied by functional capillary networks. Large engrafted cardiac tissues (0.8 mm thickness with 40 cell layers) successfully survived 3 months after TX. We developed an efficient method to generate thicker viable tissue structures and achieve long-term survival of the cell graft to the heart.

Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration.

To realize cardiac regeneration using human induced pluripotent stem cells (hiPSCs), strategies for cell preparation, tissue engineering and transplantation must be explored. Here we report a new protocol for the simultaneous induction of cardiomyocytes (CMs) and vascular cells [endothelial cells (ECs)/vascular mural cells (MCs)], and generate entirely hiPSC-engineered cardiovascular cell sheets, which showed advantageous therapeutic effects in infarcted hearts. The protocol adds to a previous differentiation protocol of CMs by using stage-specific supplementation of vascular endothelial cell growth factor for the additional induction of vascular cells. Using this cell sheet technology, we successfully generated physically integrated cardiac tissue sheets (hiPSC-CTSs). HiPSC-CTS transplantation to rat infarcted hearts significantly improved cardiac function. In addition to neovascularization, we confirmed that engrafted human cells mainly consisted of CMs in >40% of transplanted rats four weeks after transplantation. Thus, our HiPSC-CTSs show promise for cardiac regenerative therapy.

Gastroepiploic artery grafting does not improve the late outcome in patients with bilateral internal thoracic artery grafting.

BACKGROUND: Bilateral internal thoracic artery grafting in coronary artery bypass surgery has a better long-term outcome than single internal thoracic artery grafting. However, the efficacy of gastroepiploic artery (GEA) grafting in addition to bilateral internal thoracic artery grafting is still not well-established. METHODS: From 1989 to 1999, 311 patients underwent coronary artery bypass grafting using in situ bilateral internal thoracic arteries anastomosed to the left coronary arteries and either an in situ GEA or a saphenous vein graft (SVG) anastomosed to the right coronary artery. Ninety-nine patients using the in situ GEA (GEA group) were compared with 212 patients using the SVG (SVG group) anastomsed to the right coronary artery. Young patients and patients with hyperlipidemia were more prevalent in the GEA group. RESULTS: The seven-year survival rate in the GEA group and the SVG group were 94.7% and 87.2%, respectively (p = 0.068). In a multivariate analysis, the age, renal failure, and a low ejection fraction (<0.40) were all significant predictors of survival. The GEA was not a significant predictor. The seven-year freedom rates from cardiac events were similar in both groups (GEA group, 76.5%; SVG group, 78.6%; p = 0.455). The seven-year freedom rates from recurrent angina were also similar between the groups (GEA group, 85.3%; SVG group, 88.8%; p = 0.700). CONCLUSIONS: In comparison with SVG grafting, GEA grafting to the right coronary artery did not significantly improve the late outcomes in patients with bilateral internal thoracic artery grafting.