Advanced maturation of human cardiac tissue grown from pluripotent stem cells

Cardiac tissues generated from human induced pluripotent stem cells (iPSCs) can serve as platforms for patient-specific studies of physiology and disease1-6. However, the predictive power of these models is presently limited by the immature state of the cells1, 2, 5, 6. Here we show that this fundamental limitation can be overcome if cardiac tissues are formed from early-stage iPSC-derived cardiomyocytes soon after the initiation of spontaneous contractions and are subjected to physical conditioning with increasing intensity over time. After only four weeks of culture, for all iPSC lines studied, such tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiological sarcomere length (2.2 µm) and density of mitochondria (30%), the presence of transverse tubules, oxidative metabolism, a positive force-frequency relationship and functional calcium handling. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiological responses to isoproterenol and recapitulating pathological hypertrophy, supporting the utility of this tissue model for studies of cardiac development and disease.The authors acknowledge funding support from the National Institutes of Health of the USA (NIBIB and NCATS grant EB17103 (G.V.-N.); NIBIB, NCATS, NIAMS, NIDCR and NIEHS grant EB025765 (G.V.-N.); NHLBI grants HL076485 (G.V.-N.) and HL138486 (M.Y.); Columbia University MD/PhD program (S.P.M., T.C.); University of Minho MD/PhD program (D.T.); Japan Society for the Promotion of Science fellowship (K.M.); and Columbia University Stem Cell Initiative (D.S., L.S., M.Y.). We thank S. Duncan and B. Conklin for providing human iPSCs, M.B. Bouchard for assistance with image and video analysis, and L. Cohen-Gould for transmission electron microscopy services.info:eu-repo/semantics/publishedVersio

Automatic segmentation of the aortic root in CT angiography of candidate patients for transcatheter aortic valve implantation

Transcatheter aortic valve implantation is a minimal-invasive intervention for implanting prosthetic valves in patients with aortic stenosis. Accurate automated sizing for planning and patient selection is expected to reduce adverse effects such as paravalvular leakage and stroke. Segmentation of the aortic root in CTA is pivotal to enable automated sizing and planning. We present a fully automated segmentation algorithm to extract the aortic root from CTA volumes consisting of a number of steps: first, the volume of interest is automatically detected, and the centerline through the ascending aorta and aortic root centerline are determined. Subsequently, high intensities due to calcifications are masked. Next, the aortic root is represented in cylindrical coordinates. Finally, the aortic root is segmented using 3D normalized cuts. The method was validated against manual delineations by calculating Dice coefficients and average distance error in 20 patients. The method successfully segmented the aortic root in all 20 cases. The mean Dice coefficient was 0.95 ± 0.03, and the mean radial absolute error was 0.74 ± 0.39 mm, where the interobserver Dice coefficient was 0.95 ± 0.03 and the mean error was 0.68 ± 0.34¿mm. The proposed algorithm showed accurate results compared to manual segmentations