Novel 2D/3D Hybrid Organoid System for High-Throughput Drug Screening in iPSC Cardiomyocytes.

Human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) allow for high-throughput evaluation of cardiomyocyte (CM) physiology in health and disease. While multimodality testing provides a large breadth of information related to electrophysiology, contractility, and intracellular signaling in small populations of iPSC-CMs, current technologies for analyzing these parameters are expensive and resource-intensive. We sought to design a 2D/3D hybrid organoid system and harness optical imaging techniques to assess electromechanical properties, calcium dynamics, and signal propagation across CMs in a high-throughput manner. We validated our methods using a doxorubicin-based system, as the drug has well-characterized cardiotoxic, pro-arrhythmic effects. hiPSCs were differentiated into CMs, assembled into organoids, and thereafter treated with doxorubicin. The organoids were then replated to form a hybrid 2D/3D iPSC-CM construct where the 3D cardiac organoids acted as the source of electromechanical activity which propagated outwards into a 2D iPSC-CM sheet. The organoid recapitulated cardiac structure and connectivity, while 2D CMs facilitated analysis at an individual cellular level which recreated numerous doxorubicin-induced electrophysiologic and propagation abnormalities. Thus, we have developed a novel 2D/3D hybrid organoid model that employs an integrated optical analysis platform to provide a reliable high-throughput method for studying cardiotoxicity, providing valuable data on calcium, contractility, and signal propagation.

Anatomic Position and Durability of Polytetrafluoroethylene Conduit ≥18 mm: Single-Center Experience.

BACKGROUND: Conduit longevity after right ventricular outflow tract (RVOT) reconstruction is determined by the interaction of different factors. We evaluated the relationship between conduit anatomic position and long-term durability among ≥18 mm polytetrafluoroethylene (PTFE) conduits. METHODS: A single-institution RVOT reconstructions using a PTFE conduit ≥18 mm were identified. Catheter-based interventions or the need for conduit replacement were comparatively assessed between orthotopic vs heterotopic conduit position. Time to the first reintervention, censored by death, was compared between the groups. RESULTS: A total of 102 conduits were implanted in 99 patients, with a median age of 13.2 years (interquartile range [IQR] 8.9-17.8 years), median weight of 47 kg (IQR, 29-67 kg), and body surface area of 1.4 m2 (IQR, 1-1.7 m2). Overall, 50.9% (n = 52) of conduits were placed in an orthotopic position after the Ross procedure in congenital aortic valve abnormalities (80% [n = 36]). Tetrology of Fallot in 39% (n = 18), followed by truncus arteriosus with 33% (n = 15), were the most common in the heterotopic position. Trileaflet configuration was similar (67% vs 69%; P = .32) between the groups. Survival free from reintervention was 91% (95% CI, 79-97) and 88% (95% CI, 71-95) in the orthotopic and the heterotopic group, respectively, at 5 years, without differences in the Kaplan Meier curves (log-rank >.05). CONCLUSIONS: RVOT reconstruction with PTFE conduits ≥ 8 mm showed >90% conduit survival free from replacement in our cohort at 5 years. The anatomic position of the PTFE conduit does not seem to impact intermediate durability.

Impact of Transcatheter Aortic Valve Implantation on Severe Gastrointestinal Bleeding in Patients With Aortic Stenosis.

To investigate the effectiveness of transcatheter aortic valve implantation (TAVI) for resolving gastrointestinal bleeding (GIB) in patients with severe GIB and severe aortic stenosis. This was an observational study of consecutive TAVI procedures from 2011 to 2018, identified through a prospectively maintained institutional database. Patients with severe GIB defined as abnormal hemoglobin/hematocrit and overt bleeding or positive fecal occult blood test. Groups were compared for differences in baseline clinical and procedural characteristics and post-TAVI outcomes. A total of 1,192 patients who underwent TAVI were identified, of which 164 patients (13.8%) were found to have had severe GIB. Society of Thoracic Surgeons-Predicted Risk of Mortality scores were higher in the severe GIB group than in the non-GIB group (8.8 ± 5.3 vs 7.6 ± 4.5, p = 0.002). The 30-day mortality was similar across each group (p >0.05), with overall 30-day mortality being 3.2% (38 of 1,192) for the entire cohort. Of the 164 TAVIs with severe GIB, 130 (79.3%) had resolution of their GIB after their TAVI. Patients without resolution of their GIB had higher aortic valve mean pressure gradients after their TAVI (15.0 ± 5.3 vs 9.0 ± 4.3). In conclusion, TAVI was associated with substantial reductions in severe GIB. Despite higher baseline risk, patients with severe GIB achieved similar outcomes, including 30-day mortality, compared with patients without GIB. TAVI may be a safe and effective treatment for patients with severe aortic stenosis and severe GIB, whereas persistently high transvalvular pressure gradients after TAVI may be related to the likelihood of recurrent GIB.