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HomeCirculation ResearchVol. 129, No. 6In 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 published2 Sep 2021https://doi.org/10.1161/RES.0000000000000503Circulation Research. 2021;129:599is related toSARS-CoV-2 Initiates Programmed Cell Death in PlateletsThe Super-Relaxed State and Length Dependent Activation in Porcine MyocardiumCardiac Myoediting Attenuates Cardiac Abnormalities in Human and Mouse Models of Duchenne Muscular DystrophyCardiac Myoediting Attenuates Cardiac Abnormalities in Human and Mouse Models of Duchenne Muscular Dystrophy (p 602)Gene editing reduces heart cell abnormalities caused by dystrophin mutation, say Atmanli et al.Download figureDownload PowerPointDuchenne muscular dystrophy (DMD) affects 1 in 5,000 baby boys and is caused by mutations to the gene for dystrophin—an architectural protein essential for muscle cell integrity. Patients display profound muscle degeneration and weakness, with respiratory and heart muscle dysfunction being major causes of death. With recent improvements in respiratory medicine extending the lives of patients, Atmanli and colleagues focused on heart dysfunction—specifically, whether gene editing could mitigate it. The team created induced pluripotent stem cells (iPSCs) from a DMD patient and his healthy brother and showed that gene editing of the DMD cells enabled their development into normal-looking cardiomyoctes with normal contractile function and calcium handling—equivalent to the healthy control cells. The un-edited DMD cells, by contrast, did not develop normally. For greater clinical relevance, the team edited the DMD cells after cardiomyocyte differentiation, showing this reduced their propensity for arrhythmia compared with that of un-edited cells. Lastly, the team provided evidence to suggest gene editing may improve heart abnormalities in mice with the same mutation. Altogether, the results support the development of gene editing as a treatment for DMD, say the authors.The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium (p 617)Ma et al investigate the mechanics of myofilament length dependent activation.Download figureDownload PowerPointMyofilament length dependent activation (LDA) is the fundamental mechanism coupling the force of the heart’s contraction to its preceding diastolic volume. In other words, it ensures the more the heart fills, the stronger it contracts. While studies of rodent hearts have given insights into LDA mechanics, how it operates in a large mammalian heart is unknown. Using structural and biochemical analyses of pig myocardial fibers, Ma and colleagues show that, compared with small stretches of the fibers (equivalent to small diastolic volumes), long stretches induce greater ATP turnover and greater numbers of cross-bridges between myosin and actin filaments—the contractile machinery proteins. Myosin motors can be either engaged with actin, or in one of two unengaged states—disordered relaxed state, where they are ready to engage, or super relaxed state, where they are essentially switched off. The team showed that as muscle stretch increased, so the amount of super-relaxed myosin motors diminished—with more motors becoming engaged to enable a stronger contraction. Sure enough, when the fibers were treated with a myosin motor inhibitor, these stretch effects were impaired. In revealing the mechanisms of LDA, the work offers a basis for studying cardiomyopathies in which the system has gone awry.SARS-CoV-2 Initiates Programmed Cell Death in Platelets (p 631)In destroying SARS-CoV-2, platelets also destroy themselves, report Koupenova et al.Download figureDownload PowerPointSome patients with COVID-19, especially those with severe disease, exhibit abnormal blood clotting, which can lead to stroke, pulmonary clots or myocardial infarction. Because platelets—small cell-like structures abundant in the blood—play a major role in clotting, researchers have investigated platelet behavior in COVID-19, finding that they can become hyperactivated. What’s not clear, however, is whether the virus acts on platelets directly, or if they become activated due to the inflammatory environment. Koupenova and colleagues have now discovered that SARS-CoV-2 can enter platelets, but that it is quickly fragmented and digested therein to prevent viral replication. Indeed, while some platelets display ACE2 protein—the virus’s entry path—on their surfaces, ACE2 is not needed for entry as platelets more often engulf the viruses into large vacuoles where they are dispatched. This viral disposal comes at a price however. Platelets that gobble up the virus undergo budding and a loss of contents, ultimately succumbing to necroptosis or apoptosis, according to the analyses. And, it is this self-destruction that, if excessive, may contribute to the sort of dysregulated immunity and thrombosis seen in select patients, suggest the authors. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesSARS-CoV-2 Initiates Programmed Cell Death in PlateletsMilka Koupenova, et al. Circulation Research. 2021;129:631-646The Super-Relaxed State and Length Dependent Activation in Porcine MyocardiumWeikang Ma, et al. Circulation Research. 2021;129:617-630Cardiac Myoediting Attenuates Cardiac Abnormalities in Human and Mouse Models of Duchenne Muscular DystrophyAyhan Atmanli, et al. Circulation Research. 2021;129:602-616 September 3, 2021Vol 129, Issue 6 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000503 Originally publishedSeptember 2, 2021 PDF download Advertisement