HomeCirculation ResearchVol. 131, 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 published29 Sep 2022https://doi.org/10.1161/RES.0000000000000573Circulation Research. 2022;131:651is related toExtracellular Vesicles Regulate Sympatho-Excitation by Nrf2 in Heart FailureImpaired Dynamic Sarcoplasmic Reticulum Ca Buffering in Autosomal Dominant CPVT2is related toTranscriptional and Immune Landscape of Cardiac SarcoidosisCardiac Sarcoidosis Immune Landscape (p 654)Download figureDownload PowerPointLiu et al examine the transcriptional and cellular composition of cardiac sarcoidosis.Sarcoidosis is a rare inflammatory disease in which granulomas—small, localized sites of inflammation—afflict various parts of the body, most commonly the lungs, skin and lymph nodes. While sarcoidosis can be managed, there is no cure for the condition and, if it manifests in the heart, it can be deadly. Because little is known about the specific pathology of cardiac sarcoidosis (CS), and because it can resemble other forms of heart inflammation, Liu and colleagues set out to map the specific transcriptional and cellular landscape of CS lesions. Using a combination of spatial transcriptomics, single-nucleus RNA sequencing and immunofluorescence, the team compared tissue samples from CS patients with those from patients with other types of myocarditis. CS granulomas had a particular cellular arrangement, the team found, with HLA-DR+ macrophages immediately adjacent to and surrounding multinucleated giant cells. The giant cells expressed transmembrane glycoprotein NMB—a novel marker of these cells—while activation of mTOR genes was a feature of the surrounding macrophages. These analyses were carried out on a small number of patient samples but, if further studies validate the findings, they could form the basis of future diagnostic tests for CS, say the team.Impaired Dynamic SR Ca Buffering Causes AD-CPVT2 (p 673)Download figureDownload PowerPointWleklinski et al reveal the molecular effects of a dominant CPVT-causing mutation.Exercise or emotional stress can prompt the release of catecholamine hormones, which induce a fast heart rate, increased blood pressure and other features of the fight-or-flight response. For people with catecholaminergic polymorphic ventricular tachycardia (CPVT), however, physical activity or stress can cause potentially lethal arrythmias. Mutation of calsequestrin-2 (CASQ2)—a sarcoplasmic reticulum (SR) calcium binding protein—is a major cause of CPVT and can be recessive or dominant in nature. For many recessive mutations, disease occurs due to loss of CASQ2 protein. Wleklenski and colleagues have investigated a dominant lysine-to-arginine mutation (K180R) and find, by contrast, protein levels remain normal. In mice carrying the mutation, not only was the level of CASQ2 comparable to that in control animals, but so too was the protein’s subcellular localization. The mutation instead interfered with CASQ2’s calcium binding, or buffering, capability within the SR. The result was that, upon catecholamine injection or exercise, the unbound calcium released prematurely from the SR triggering spontaneous cell contractions. In uncovering this novel molecular etiology of CPVT, the work provides a basis for studying the consequences of other dominant CASQ2 mutations, say the team.EV-Mediated Heart Brain Communication in CHF (p 687)Download figureDownload PowerPointTian et al discover signals from the failing heart to the brain that may further exacerbate cardiac dysfunction.After a myocardial infarction, increased oxidative stress in the heart can contribute to adverse cardiac remodeling and ultimately heart failure. Nrf2 is a master activator of antioxidant genes, suggesting a protective role, but studies in rats have shown its expression to be suppressed after MI—likely due to upregulation of Nrf2-targeting microRNAs. These miRNAs can also be packaged into vesicles and released from stressed heart cells, and now Tian and colleagues show that rats and humans with chronic heart failure (CHF) have an abundance of these miRNA-containing EVs in their blood. In the rats with CHF, these EVs were found to be taken up by neurons of the rostral ventrolateral medulla (RVLM) wherein the miRNAs suppressed Nrf2 expression. The RVLM is a brain region that controls the sympathetic nervous system and, in the presence of the EVs, it ramped up sympathetic excitation. Because such elevated sympathetic activity can induce the fight-or-flight response—including increased heart rate and blood pressure—this would likely worsen heart failure progression. The team found, however, that inhibiting the miRNAs in the EVs prevented Nrf2 suppression in the RVLM and sympathetic activation, suggesting the pathway could be targeted therapeutically. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesExtracellular Vesicles Regulate Sympatho-Excitation by Nrf2 in Heart FailureChanghai Tian, et al. Circulation Research. 2022;131:687-700Impaired Dynamic Sarcoplasmic Reticulum Ca Buffering in Autosomal Dominant CPVT2Matthew J. Wleklinski, et al. Circulation Research. 2022;131:673-686Transcriptional and Immune Landscape of Cardiac SarcoidosisJing Liu, et al. Circulation Research. 2022;131:654-669 September 30, 2022Vol 131, Issue 8 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000573 Originally publishedSeptember 29, 2022 PDF download Advertisement
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