CirculationPub Date : 2025-03-25Epub Date: 2025-03-24DOI: 10.1161/CIRCULATIONAHA.124.071784
Shouxin Wei, Sijia Yu
{"title":"Letter by Wei and Yu Regarding Article, \"Intracranial Atherosclerotic Disease and Incident Dementia: The ARIC Study (Atherosclerosis Risk in Communities)\".","authors":"Shouxin Wei, Sijia Yu","doi":"10.1161/CIRCULATIONAHA.124.071784","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071784","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 12","pages":"e764"},"PeriodicalIF":35.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CirculationPub Date : 2025-03-25Epub Date: 2025-03-24DOI: 10.1161/CIRCULATIONAHA.124.072061
Lingyu Xu, Yanfei Wang, Yan Xu
{"title":"Letter by Xu et al Regarding Article, \"Intracranial Atherosclerotic Disease and Incident Dementia: The ARIC Study (Atherosclerosis Risk in Communities)\".","authors":"Lingyu Xu, Yanfei Wang, Yan Xu","doi":"10.1161/CIRCULATIONAHA.124.072061","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072061","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 12","pages":"e765"},"PeriodicalIF":35.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CirculationPub Date : 2025-03-25Epub Date: 2024-12-10DOI: 10.1161/CIRCULATIONAHA.124.071777
Seiko N Doi, Jawad H Butt, Jens Jakob Thune, Jens C Nielsen, Jens Haarbo, Niels E Bruun, Line L Olesen, Lars Videbæk, Finn Gustafsson, Hans Eiskjær, Christian Hassager, Jesper H Svendsen, Dan E Høfsten, Steen Pehrson, Lars Køber
{"title":"Left Ventricular Ejection Fraction and Implantable Cardioverter Defibrillator in Nonischemic Heart Failure With Reduced Ejection Fraction: Insights From DANISH.","authors":"Seiko N Doi, Jawad H Butt, Jens Jakob Thune, Jens C Nielsen, Jens Haarbo, Niels E Bruun, Line L Olesen, Lars Videbæk, Finn Gustafsson, Hans Eiskjær, Christian Hassager, Jesper H Svendsen, Dan E Høfsten, Steen Pehrson, Lars Køber","doi":"10.1161/CIRCULATIONAHA.124.071777","DOIUrl":"10.1161/CIRCULATIONAHA.124.071777","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"887-889"},"PeriodicalIF":35.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CirculationPub Date : 2025-03-25Epub Date: 2025-03-24DOI: 10.1161/CIRCULATIONAHA.125.073361
Di Zhao, Eliseo Guallar, Bruce A Wasserman
{"title":"Response by Zhao et al to Letters Regarding Article, \"Intracranial Atherosclerotic Disease and Incident Dementia: The ARIC Study (Atherosclerosis Risk in Communities)\".","authors":"Di Zhao, Eliseo Guallar, Bruce A Wasserman","doi":"10.1161/CIRCULATIONAHA.125.073361","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.073361","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 12","pages":"e766"},"PeriodicalIF":35.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CirculationPub Date : 2025-03-25DOI: 10.1161/CIRCULATIONAHA.124.072194
Oveena Fonseka, Rida Raja, Claire Ross, Sanskruti R Gare, Jiayan Zhang, Susanne S Hille, Katharine King, Andrea Ruiz-Velasco, Namrita Kaur, Xinyi Chen, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Zhiyong Zou, Xiangjun Zhao, Cristian Sotomayor-Flores, Derk Frank, Eileithyia Swanton, Martin R Pool, Sara Missaglia, Daniela Tavian, Gabriele G Schiattarella, Tao Wang, Luigi Venetucci, Christian Pinali, Martin K Rutter, Bernard D Keavney, Elizabeth J Cartwright, Tamer M A Mohamed, Oliver J Müller, Wei Liu
{"title":"XBP1s-EDEM2 Prevents the Onset and Development of HFpEF by Ameliorating Cardiac Lipotoxicity.","authors":"Oveena Fonseka, Rida Raja, Claire Ross, Sanskruti R Gare, Jiayan Zhang, Susanne S Hille, Katharine King, Andrea Ruiz-Velasco, Namrita Kaur, Xinyi Chen, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Zhiyong Zou, Xiangjun Zhao, Cristian Sotomayor-Flores, Derk Frank, Eileithyia Swanton, Martin R Pool, Sara Missaglia, Daniela Tavian, Gabriele G Schiattarella, Tao Wang, Luigi Venetucci, Christian Pinali, Martin K Rutter, Bernard D Keavney, Elizabeth J Cartwright, Tamer M A Mohamed, Oliver J Müller, Wei Liu","doi":"10.1161/CIRCULATIONAHA.124.072194","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072194","url":null,"abstract":"<p><strong>Background: </strong>Morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) is increased in metabolic disorders. However, options for preventing and treating these prevalent outcomes are limited. Intramyocardial lipotoxicity contributes to cardiac dysfunction. Here, we investigate the mechanisms underlying endoplasmic reticulum degradation enhancing EDEM2 (endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2) regulation of cardiac lipid homeostasis and assess strategies that inhibit the incidence and progression of HFpEF.</p><p><strong>Methods: </strong>Metabolic stress was induced in C57BL/6 male mice using a high-fat diet and Nω-nitro-l-arginine methyl ester. The recombinant adeno-associated virus 9 delivery system was used for loss- and gain-of-function studies. Palmitic acid and oleic acid stimulation of rat cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes imitated a condition of high lipids in vitro. Molecular mechanisms were investigated via RNA sequencing, mass spectrometry proteomics, lipidomic analyses, transmission electron microscopy, histology, and luciferase reporter assays.</p><p><strong>Results: </strong>In the human heart, we first detected lipid overload accompanied by a reduction of XBP1 (X-box binding protein 1) under metabolic stress. Thereafter, a decrease in EDEM2 was confirmed in human and mouse HFpEF hearts. Given that the spliced form of XBP1 (XBP1s) is a transcription factor, EDEM2 was identified as its new target in cardiomyocytes. EDEM2 knockdown mice manifested lipid droplet accumulation and higher levels of triglycerides and diglycerides in the myocardium, aggravating oxidative stress, hypertrophy, and the onset and progression of HFpEF under metabolic stress. XBP1s ablation mice displayed a similar myocardial lipid disturbance and cardiac phenotypes, which were reversed by EDEM2 overexpression. Mechanistically, the findings obtained from rat cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes demonstrated that, in the presence of EDEM2, SEC23A mediated intracellular translocation of ATGL (adipose triglyceride lipase) under fatty acid stimulation, inhibiting ATGL degradation and excessive intracellular lipid droplets. Furthermore, the functional studies supported that EDEM2 prevention of lipid overload occurred in an ATGL-dependent manner. Therapeutically, cardiac XBP1s or EDEM2 restoration mitigated lipid deposition and preserved lipid profiles in the myocardium, thus preventing the development of HFpEF.</p><p><strong>Conclusions: </strong>We demonstrate a cardioprotective mechanism regulating myocardial lipid homeostasis. The findings provide a promising therapeutic target to prevent and treat HfpEF, a condition with limited treatment options.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CirculationPub Date : 2025-03-25Epub Date: 2024-12-10DOI: 10.1161/CIRCULATIONAHA.124.070563
Bo Sun, Mingke Ni, Yanhui Li, Zhenpeng Song, Hui Wang, Hai-Lei Zhu, Jinhong Wei, Darrell Belke, Shitian Cai, Wenting Guo, Jinjing Yao, Shanshan Tian, John Paul Estillore, Ruiwu Wang, Mads Toft Søndergaard, Malene Brohus, Palle Duun Rohde, Yongxin Mu, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, Michael Toft Overgaard, Glenn I Fishman, Ju Chen, Shubhayan Sanatani, Arthur A M Wilde, Michael Fill, Josefina Ramos-Franco, Mette Nyegaard, S R Wayne Chen
{"title":"Inositol 1,4,5-Trisphosphate Receptor 1 Gain-of-Function Increases the Risk for Cardiac Arrhythmias in Mice and Humans.","authors":"Bo Sun, Mingke Ni, Yanhui Li, Zhenpeng Song, Hui Wang, Hai-Lei Zhu, Jinhong Wei, Darrell Belke, Shitian Cai, Wenting Guo, Jinjing Yao, Shanshan Tian, John Paul Estillore, Ruiwu Wang, Mads Toft Søndergaard, Malene Brohus, Palle Duun Rohde, Yongxin Mu, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, Michael Toft Overgaard, Glenn I Fishman, Ju Chen, Shubhayan Sanatani, Arthur A M Wilde, Michael Fill, Josefina Ramos-Franco, Mette Nyegaard, S R Wayne Chen","doi":"10.1161/CIRCULATIONAHA.124.070563","DOIUrl":"10.1161/CIRCULATIONAHA.124.070563","url":null,"abstract":"<p><strong>Background: </strong>Ca<sup>2+</sup> mishandling in cardiac Purkinje cells is a well-known cause of cardiac arrhythmias. The Purkinje cell resident inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is believed to play an important role in Ca<sup>2+</sup> handling, and ITPR1 gain-of-function (GOF) has been implicated in cardiac arrhythmias. However, nearly all known disease-associated ITPR1 variants are loss-of-function and are primarily linked to neurological disorders. Whether ITPR1 GOF has pathological consequences, such as cardiac arrhythmias, is unclear. This study aimed to identify human ITPR1 GOF variants and determine the impact of ITPR1 GOF on Ca<sup>2+</sup> handling and arrhythmia susceptibility.</p><p><strong>Methods: </strong>There are a large number of rare ITPR1 missense variants reported in open data repositories. Based on their locations in the ITPR1 channel structure, we selected and characterized 33 human ITPR1 missense variants from open databases and identified 21 human ITPR1 GOF variants. We generated a mouse model carrying a human ITPR1 GOF variant, ITPR1-W1457G (W1447G in mice).</p><p><strong>Results: </strong>We showed that the ITPR1-W1447G<sup>+/-</sup> and recently reported ITPR1-D2594K<sup>+/-</sup> GOF mutant mice were susceptible to stress-induced ventricular arrhythmias. Confocal Ca<sup>2+</sup> and voltage imaging in situ in heart slices and Ca<sup>2+</sup> imaging and patch-clamp recordings of isolated Purkinje cells showed that ITPR1-W1447G<sup>+/-</sup> and ITPR1-D2594K<sup>+/-</sup> variants increased the occurrence of stress-induced spontaneous Ca<sup>2+</sup> release, delayed afterdepolarization, and triggered activity in Purkinje cells. To assess the potential role of ITPR1 variants in arrhythmia susceptibility in humans, we looked up a gene-based association study in the UK Biobank data set and identified 7 rare ITPR1 missense variants showing potential association with cardiac arrhythmias. Remarkably, in vitro functional characterization revealed that all these 7 ITPR1 variants resulted in GOF.</p><p><strong>Conclusions: </strong>Our studies in mice and humans reveal that enhanced function of <i>ITPR1</i>, a well-known movement disorder gene, increases the risk for cardiac arrhythmias.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"847-862"},"PeriodicalIF":35.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CirculationPub Date : 2025-03-25Epub Date: 2025-03-24DOI: 10.1161/CIRCULATIONAHA.125.072978
Ryan R Davies, Maryjane Farr
{"title":"Differences in Pediatric and Adult Heart Allocation Policies and Some of the Reasons Why.","authors":"Ryan R Davies, Maryjane Farr","doi":"10.1161/CIRCULATIONAHA.125.072978","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.072978","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 12","pages":"825-827"},"PeriodicalIF":35.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CirculationPub Date : 2025-03-25Epub Date: 2025-03-24DOI: 10.1161/CIRCULATIONAHA.124.070862
Karin A Ziegler, Manuel Zeitler, Sandro Meunier, Inga Sinicina, Tim P Hasenbein, Daniel Andergassen, Anton Bomhard, Reginald V C T van der Kwast, Stefan Engelhardt
{"title":"Ganglionic Inflammation in a Patient With Takotsubo Syndrome.","authors":"Karin A Ziegler, Manuel Zeitler, Sandro Meunier, Inga Sinicina, Tim P Hasenbein, Daniel Andergassen, Anton Bomhard, Reginald V C T van der Kwast, Stefan Engelhardt","doi":"10.1161/CIRCULATIONAHA.124.070862","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070862","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 12","pages":"890-892"},"PeriodicalIF":35.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}