HomeCirculation ResearchVol. 127, No. 2In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published2 Jul 2020https://doi.org/10.1161/RES.0000000000000419Circulation Research. 2020;127:204is related toIn Situ Expansion, Differentiation, and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered OrganoidGlobal Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric Hypoxiais related toIdentification of Functional Variant Enhancers Associated With Atrial FibrillationIn Situ Differentiation to Produce Cardiac Tissues (p 207)Kupfer et al use 3D-printing to create beating human heart organoids.Download figureDownload PowerPointCultured human cardiac muscle is valuable for testing the efficacy and toxicity of drugs, studying diseases, assessing injury responses, and more. But growing such muscle in the lab is tricky. For one thing, adult cardiomyocytes don’t generally proliferate. For another, cells in a dish don’t recapitulate the forces and functions of a 3D heart. Generating cardiomyocytes from stem cells enables researchers to largely circumvent the issue of proliferation, so Kupfer and colleagues have focused their attention on the issue of 3D structure. They developed a photocrosslinkable bioink containing extracellular matrix proteins and pluripotent stem cells that can be printed within a supportive gel bath, and then stabilized with UV-induced crosslinking. After removal of the printed structure from the support gel, the stem cells proliferate to high density and are differentiated into cardiomyocytes. Using this approach, the team printed a chambered human heart organoid—approximately the size of a mouse heart—showing that it could propagate action potentials as well as beat and pump fluid. Furthermore, beat rate was pharmacologically modifiable. By showing the mechanical and electrical activities of this mini-heart, the work sets the stage for using such organoids in all manner of drug and disease studies.Functional Variant Elements in Atrial Fibrillation Models(p 229)van Ouwerkerk et al discover gene regulatory elements at atrial fibrillation associated loci.Download figureDownload PowerPointAtrial fibrillation (AF) is the most common form of arrhythmia and a major risk factor for heart failure, dementia, stroke, and sudden death. Genome-wide association studies have revealed more than 100 genetic loci linked to the condition, many of which are in intergenic or intronic regions and are enriched for transcription factor binding sites and epigenetic modifications suggesting potential gene regulatory roles. To test this idea, Ouwerkerk and colleagues used a method called self-transcribing active regulatory region sequencing (or STARR-Seq) to screen 12 of the strongest AF-linked regions of the genome—together containing more than 1600 AF-linked variants—for their gene regulatory activity in cultured rat atrial myocytes. From this screen, they found ≈400 regulatory elements, of which 24 exhibited variant-specific differences in regulatory activity. For one of these elements—upstream of the gene HCN4—deletion of the orthologous element in mice caused diminished transcriptional activity of the gene. Moreover, the mice had brachycardia and sinus node dysfunction. This proof-of-principle study confirms that such a regulatory element screen can provide insight into the consequences of variants associated with AF or, for that matter, other diseases.Vascular Function in Chronic Hypoxia(p e1)Tymko et al, examine how low oxygen at high altitudes affects vascular endothelium function.Download figureDownload PowerPointChronic hypoxia, whether due to disease or time spent at high altitude, is associated with increased sympathetic nerve activity and poor endothelial function—marked by reduced endothelial-dependent vasodilation. But whether the heightened nerve activity actually causes endothelial dysfunction was unclear. To investigate, Tymko and colleagues analyzed heart rate, nerve activity, and hemodynamics—including blood pressure, flow, and arterial diameter—in 9 people who normally live in lowlands after they spent 2-to-3 weeks at 4300 meters (14 000 feet) in the Andean highlands. The team found that, at high altitude, lowlanders had increased sympathetic nerve activity and reduced endothelial function—assessed by their vasodilatory responses to acetylcholine infusion. But also that administration of adrenergic blockers, which reduce sympathetic nerve activity, improved the subjects’ endothelial function. Similar results were seen in native Andean highlanders with excess red blood cell counts—a mark of endothelial dysfunction—compared with their healthy counterparts. The work provides the first direct link between sympathetic nerve activity and endothelial function as well as insights into the pathophysiological processes associated with low-oxygen conditions. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesIn Situ Expansion, Differentiation, and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered OrganoidMolly E. Kupfer, et al. Circulation Research. 2020;127:207-224Identification of Functional Variant Enhancers Associated With Atrial FibrillationAntoinette F. van Ouwerkerk, et al. Circulation Research. 2020;127:229-243Global Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric HypoxiaMichael M. Tymko, et al. Circulation Research. 2020;127:e1-e13 July 3, 2020Vol 127, Issue 2Article InformationMetrics Download: 200 © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000419 Originally publishedJuly 2, 2020 PDF download
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Jul 31, 2020
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