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HomeCirculation ResearchVol. 126, No. 2In 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 published16 Jan 2020https://doi.org/10.1161/RES.0000000000000321Circulation Research. 2020;126:159is related toMonogenic and Polygenic Contributions to Atrial Fibrillation RiskMetabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesisis related toActivated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1TGFβ Signaling and Defective Thrombus Resolution (p 162)Aberrant TGFβ1 signaling is a likely driver of chronic thromboembolic pulmonary hypertension, say Bochenek et al.Download figureDownload PowerPointChronic thromboembolic pulmonary hypertension (CTEPH) is a rare, life-threatening form of pulmonary hypertension characterized by persistent blood clots in the lung arteries that ultimately result in the formation of fibrotic lesions containing irregular vasculature. The mechanisms underlying CTEPH are largely unknown, but because the cytokine TGFβ1 regulates fibrosis and angiogenesis, and because mutations affecting TGFβ1 signaling have been implicated in another form of pulmonary hypertension, Bochenek and colleagues hypothesized this factor’s involvement. Sure enough, they found that, in CTEPH patient tissue, components of the TGFβ1 pathway were upregulated, including TGFβ1 itself and endothelin-1—a vasoconstrictor and promoter of fibrosis. The team also showed that mice engineered to lack TGFβ1 in platelet cells had faster resolution of experimental thrombosis than did control animals. Furthermore, inhibition of endothelin-1 activity prevented human and mouse endothelial cells converting to a fibrotic phenotype. The results suggest the TGFβ1-to-endothelin-1 pathway plays a pathological role in CTEPH and lends supporting evidence that the clinical use of endothelin-1 receptor blockers—prescribed to some patients with CTEPH—is a worthwhile therapy.ACC2 Deletion Prevents Aspartate Synthesis(p 182)Boosting fatty acid oxidation prevents aspartate synthesis and cardiac hypertrophy, report Ritterhoff et al.Download figureDownload PowerPointCardiac hypertrophy, in which the heart and its component cells become enlarged, can be a normal physiological process to cope with increased demand—for example, in pregnancy or elite athletes—but can also be pathological—caused by high blood pressure and other cardiovascular conditions. Pathological hypertrophy is associated with a metabolic switch in the heart from primarily fatty acid-based to glucose-based. And, boosting fatty acid oxidation (FAO) can protect against hypertrophy in cultured cardiomyocytes and animals. The mechanism underlying this protection is unknown, however. Now, Ritterhoff and colleagues show that in addition to increased glucose consumption, hypertrophic rat cardiomyocytes ramp up their levels of aspartate—a molecule involved in cell growth via synthesis of nucleic acids, RNAs, and proteins. And, boosting FAO (by genetic manipulation) prevents both the aspartate rise and hypertrophy in the cells as well as in live mice. Adding aspartate to such FAO-boosted cells could reinstate the hypertrophic phenotype. The discovery of this relationship between glucose metabolism, aspartate, and FAO may inform the design of new therapies aimed at manipulating heart cell metabolism to manage hypertrophy, say the authors.Genetic Basis of Atrial Fibrillation (p 200)Choi et al examine poly-and mono-genetic predisposition to atrial fibrillation.Download figureDownload PowerPointAffecting ≈30 million individuals worldwide, atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of heart failure, stroke, dementia, and death. While the condition can be idiopathic, there is also evidence of inheritance. Indeed, a quarter of patients have a parent, sibling, or child with the condition. Genome-wide association studies have identified numerous common genetic variants linked to AF, and the more of these variants a person carries, the greater the risk—referred to as their polygenic risk score (PRS). Studies of families with AF have also revealed rarer monogenic variants, such as loss-of-function (LOF) mutations in the sarcomeric gene titin (TTN). Now, Choi and colleagues look at these common polygenic and rare monogenic variants together to examine their relative contributions. Studying the genomes of 1546 AF patients and more than 41 000 controls, the team discovered a significant association between AF and rare LOF variants at TTN. Indeed, 14% of individuals with such variants had AF. However, the team also showed that while TTN variants were highly penetrant, PRS scores accounted for considerably more of the variance in AF susceptibility. Thus, the study indicates that, generally speaking, a person’s PRS is a better indicator of overall AF risk. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesMonogenic and Polygenic Contributions to Atrial Fibrillation RiskSeung Hoan Choi, et al. Circulation Research. 2020;126:200-209Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate BiosynthesisJulia Ritterhoff, et al. Circulation Research. 2020;126:182-196Activated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1Magdalena L. Bochenek, et al. Circulation Research. 2020;126:162-181 January 17, 2020Vol 126, Issue 2 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000321 Originally publishedJanuary 16, 2020 PDF download Advertisement