In This Issue

Abstract

HomeCirculation ResearchVol. 126, No. 8In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published9 Apr 2020https://doi.org/10.1161/RES.0000000000000339Circulation Research. 2020;126:943is related toNfatc1 Promotes Interstitial Cell Formation During Cardiac Valve Development in ZebrafishA Computational Pipeline to Predict Cardiotoxicityis related toCrystal Clots as Therapeutic Target in Cholesterol Crystal EmbolismCardiotoxicity From the Atom to the Cardiac Rhythm (p 947)Yang et al’s new computational method predicts proarrhythmic tendencies of drugs.Download figureDownload PowerPointCardiotoxicity is a common side effect of otherwise promising drugs that can lead to their removal from the market, or failure to get there. A chief cause of drug-induced arrhythmias is inhibition of the cardiac potassium channel hERG, which interacts with a variety of pharmacological agents. To determine a drug’s effect on hERG, researchers measure the heart’s QT interval—the time taken for ventricles to contract and relax—via electrocardiograms. However, while a number of drugs prolong QT intervals, they don’t all result in severe arrhythmias. Yang and colleagues have thus developed an approach to help differentiate damaging drugs from less risky ones. They show that computational modeling of drug interactions—using the atomic structures of hERG and the candidate drug—as well as the resulting cell and tissue effects can predict a drug’s proarrhythmic potential. The approach was tested with two drugs, doletilide and monofloxacin, both of which block hERG but which differ in arrhythmia risk. Comparing the results of the computer modeling with actual clinical data for the drugs showed tight agreement. This proof-of-principle study now lays the foundation for assessing more drugs and, ultimately, for applying the method as a screening aid during drug development.Nfatc1 in Zebrafish Cardiac Valve Development (p 968)Gunawan et al investigate the role of transcription factor Nfatc1 in heart valve development.Download figureDownload PowerPointBy ensuring the unidirectional flow of blood, the cardiac valves are critical to heart function. In humans, congenital valve defects have been associated with polymorphisms at the gene encoding transcription factor Nfatc1. Furthermore, mice lacking functional Nfatc1 die from cardiac valve defects during embryogenesis. The precise mechanisms by which Nfatc1 mediates valve development, however, are unknown. To investigate Nfatc1 activity, Gunawen and colleagues turned to zebrafish—because their transparent bodies facilitate heart imaging during development. By 96 hours postfertilization, fish that lacked functional Nfatc1 were noticeably different from wild-type controls, showing pericardial edema, retrograde blood flow, and significantly fewer valve interstitial cells (VICs)—fibroblast-like cells that secrete and maintain the extracellular matrix material of the valves. Indeed, fewer VICs was associated with reduced valve ECM. The team went on to show that Nfatc1 regulates the development and proliferation of VICs, in part by the activation of twist1b—a cell lineage determination factor. The work not only uncovers the role of Nfatc1 and twist1b in VIC production, but also highlights zebrafish as useful model organisms for further studies of this process.Crystal Clots in Cholesterol Embolism (p e37)Shi et al examine the formation, composition and dismantling of cholesterol clots.Download figureDownload PowerPointWhen an atherosclerotic plaque ruptures releasing crystals of cholesterol, it’s not the crystals themselves that are the major cause of vessel occlusion, but the cells and molecules that surround them, according to Shi and colleagues’ new findings. The team developed a mouse model of cholesterol crystal embolism (CCE) wherein they inject cholesterol crystals into the animal’s left kidney artery. The animals quickly develop an arterial blockage, infarct, and reduced kidney function—measured by glomerular filtration rate (GFR). The vessel occlusions consisted of typical thrombus components, including platelets, neutrophils, and fibrin, as well as extracellular DNA from dying neutrophils and endothelial cells, the team showed. Inhibition of platelet activation, or the use of anticoagulants prevented vascular obstruction, reduced infarct size and maintained GFR, even though the cholesterol crystals remained. As an alternative to anticoagulants, which cannot be used if patients need arterial surgery, the team examined DNase I treatment as a way to dismantle the clots showing it too decreased vessel occlusion. The work shows that clotting components are the critical factors leading to vessel blockage in CCE, and provides a model system in which to study CCE pathogenesis and treatments. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesNfatc1 Promotes Interstitial Cell Formation During Cardiac Valve Development in ZebrafishFelix Gunawan, et al. Circulation Research. 2020;126:968-984Crystal Clots as Therapeutic Target in Cholesterol Crystal EmbolismChongxu Shi, et al. Circulation Research. 2020;126:e37-e52A Computational Pipeline to Predict CardiotoxicityPei-Chi Yang, et al. Circulation Research. 2020;126:947-964 April 10, 2020Vol 126, Issue 8 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000339PMID: 32271676 Originally publishedApril 9, 2020 PDF download Advertisement