CirculationPub Date : 2025-05-27DOI: 10.1161/CIRCULATIONAHA.124.072636
YanLing He, Xueping Wu, Andre Serra-Roma, Maggie Markiewicz, Emma Healy, Jing-He Yan, Kenneth Kulmatycki, Tong Zhang, John L Diener, Arvind G Kinhikar, Denise P Yates, David Nguyen, Markus Hinder, Cesare Russo, Christopher J O'Donnell
{"title":"Blood Pressure Lowering Effects of a Novel Long-Acting NPR1 Agonist, XXB750, in Healthy Participants: A Randomized, First-in-Human Clinical Study.","authors":"YanLing He, Xueping Wu, Andre Serra-Roma, Maggie Markiewicz, Emma Healy, Jing-He Yan, Kenneth Kulmatycki, Tong Zhang, John L Diener, Arvind G Kinhikar, Denise P Yates, David Nguyen, Markus Hinder, Cesare Russo, Christopher J O'Donnell","doi":"10.1161/CIRCULATIONAHA.124.072636","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072636","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 21","pages":"1544-1546"},"PeriodicalIF":35.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157163","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}
{"title":"Atrial Translocation of <i>Porphyromonas gingivalis</i> Exacerbates Atrial Fibrosis and Atrial Fibrillation.","authors":"Shunsuke Miyauchi, Miki Kawada-Matsuo, Hisako Furusho, Hiromi Nishi, Ayako Nakajima, Pham Trong Phat, Fumie Shiba, Masae Kitagawa, Kazuhisa Ouhara, Noboru Oda, Takehito Tokuyama, Yousaku Okubo, Sho Okamura, Taiichi Takasaki, Shinya Takahashi, Toru Hiyama, Hiroyuki Kawaguchi, Hitoshi Komatsuzawa, Mutsumi Miyauchi, Yukiko Nakano","doi":"10.1161/CIRCULATIONAHA.124.071310","DOIUrl":"10.1161/CIRCULATIONAHA.124.071310","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have indicated an association between periodontitis and atrial fibrillation (AF), although the underlying mechanisms remain unclear. <i>Porphyromonas gingivalis (P ginigivalis</i>) is a causative agent of periodontal disease and is highly pathogenic. This study focused on <i>P</i> <i>gingivalis</i> and aimed to investigate the relationship among periodontitis, atrial translocation of <i>P</i> <i>gingivalis</i>, and atrial fibrosis and AF.</p><p><strong>Methods: </strong>An experiment was conducted using <i>P</i> <i>gingivalis</i>-infected C57BL/6J mice, in which <i>P</i> <i>gingivalis</i> was inoculated into the pulp of the molars. Immunohistochemistry was used to visualize the localization of <i>P</i> <i>gingivalis</i>, and loop-mediated isothermal amplification was employed to detect <i>P</i> <i>gingivalis</i> DNA in the left atrium. AF inducibility was examined by intracardiac stimulation. Moreover, left atrial appendage specimens were obtained from 68 patients with AF. A periodontal examination was conducted before the surgery, and the periodontal epithelial surface area and periodontal inflamed surface area, which are quantitative indices used to determine the clinical severity of periodontitis, were measured. The bacterial number of <i>P</i> <i>gingivalis</i> in human atrial tissue was analyzed via quantitative polymerase chain reaction. Atrial fibrosis was assessed using Azan-Mallory staining.</p><p><strong>Results: </strong>The translocation path of <i>P</i> <i>gingivalis</i> from the dental granuloma to the left atrium via the circulatory system was demonstrated by immunohistochemistry and loop-mediated isothermal amplification in <i>P</i> <i>gingivalis</i>-infected mice, which showed a higher degree of atrial fibrosis (21.9% versus 16.3%; <i>P</i>=0.0003) and a higher AF inducibility (30.0% versus 5.0%; <i>P</i>=0.04) than the control mice. Upregulation of galectin-3 and transforming growth factor-beta 1 in the left atrium was observed in <i>P</i> <i>gingivalis</i>-infected mice. Moreover, immunohistochemistry revealed that <i>P</i> <i>gingivalis</i> was also present in human atrial tissue. The number of <i>P</i> <i>gingivalis</i> in the human atrial tissue was positively correlated with periodontal epithelial surface area (ρ=0.35; <i>P</i>=0.004), periodontal inflamed surface area (ρ=0.52, <i>P</i><0.0001), and the degree of atrial fibrosis (ρ=0.38; <i>P</i>=0.002).</p><p><strong>Conclusions: </strong><i>P</i> <i>gingivalis</i> translocation to the left atrium correlates with the clinical severity of periodontitis, which may exacerbate atrial fibrosis and AF. Atrial translocation of <i>P</i> <i>gingivalis</i> is a potential pathway explaining the causal relationship between periodontitis and AF.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1527-1540"},"PeriodicalIF":35.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647520","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 : 2025-05-27DOI: 10.1161/CIRCULATIONAHA.125.074568
Giovanni Vitale, Paolo Ortolani, Carmine Pizzi
{"title":"Electrical Alternance in a Patient With Type 1 Myotonic Dystrophy: What Diagnosis?","authors":"Giovanni Vitale, Paolo Ortolani, Carmine Pizzi","doi":"10.1161/CIRCULATIONAHA.125.074568","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.074568","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 21","pages":"1541-1543"},"PeriodicalIF":35.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157165","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 : 2025-05-27DOI: 10.1161/CIRCULATIONAHA.125.074928
Dharam J Kumbhani, Ambarish Pandey
{"title":"From Passive to Proactive: A Call to Action on Valve Disease Screening.","authors":"Dharam J Kumbhani, Ambarish Pandey","doi":"10.1161/CIRCULATIONAHA.125.074928","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.074928","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 21","pages":"1508-1511"},"PeriodicalIF":35.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157221","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}
{"title":"Disruption of cTnT-Mediated Sarcomere-Mitochondrial Communication Results in Dilated Cardiomyopathy.","authors":"Lingqun Ye,Junwei Liu,Wei Lei,Baoqiang Ni,Xinglong Han,Yan Zhang,Yong Wang,Kaili Hao,Yuanhui Peng,Hongchun Wu,Miao Yu,Huadong Li,Zhen-Ao Zhao,Zhenya Shen,Jianyi Zhang,Shijun Hu","doi":"10.1161/circulationaha.125.071523","DOIUrl":"https://doi.org/10.1161/circulationaha.125.071523","url":null,"abstract":"BACKGROUNDDilated cardiomyopathy (DCM) is substantially influenced by genetic factors. Sarcomere function is intricately associated with other organelles, particularly the reciprocal regulation between sarcomeres and mitochondria. Mitochondrial stress dysregulation is linked to DCM progression, yet mechanisms remain unclear. In this study, we investigated the effects of cTnT (cardiac troponin T) dysregulation on sarcomere-mitochondrial communication in DCM.METHODSInduced pluripotent stem cells (iPSCs) derived from a DCM family cohort were used in this study, and CRISPR-Cas9 genome editing was used to rectify the TNNT2 (c.A553G) sequence variation in iPSCs. A knock-in mouse model harboring the (p.K192E) sequence variation, equivalent to the human cTnT (p.K185E) sequence variation, was subsequently established. The pathological phenotypes were analyzed in iPSC-derived cardiomyocytes, iPSC-derived cardiac organoids, and mice. RNA sequencing, metabolite profiling, and coimmunoprecipitation mass spectrometry were used to elucidate the molecular mechanisms.RESULTSThrough whole exome sequencing, we identified a novel pathogenic variant in cTnT (p.K185E) as the causal sequence variation in a familial DCM cohort. In iPSC-derived cardiomyocytes from patients with DCM, we observed sarcomere disarray and mitochondrial fragmentation accompanied by severe mitochondrial dysfunction. The diminished interaction between cTnT (p.K185E) and 14-3-3 proteins resulted in the dissociation of 14-3-3 proteins from sarcomeric structures. The free 14-3-3 proteins aberrantly engaged in the RAS/RAF1 signaling axis, driving aberrant p44/42 kinase activation that culminated in the phosphorylation of mitochondrial fission regulators DRP1 (dynamin-related protein 1) and MFF (mitochondrial fission factor). These observations were replicated in iPSC-derived cardiac organoids. The knock-in mice bearing the orthologous cTnT sequence variation faithfully recapitulated the hallmark features of human DCM, including cardiac dysfunction, ventricular dilatation, sarcomeric disarray, and mitochondrial fragmentation. Mdivi-1, a mitochondrial fission inhibitor, alleviated DCM phenotypes in vivo.CONCLUSIONSOur findings delineate a novel pathogenic mechanism underlying DCM, demonstrating that cTnT (p.K185E) sequence variation disrupts sarcomere-mitochondrial communication by weakening the interaction between cTnT and 14-3-3 proteins, thereby accelerating mitochondrial fragmentation through excessive activation of the 14-3-3 protein-mediated RAS/RAF1-p44/42-DRP1/MFF signaling axis. Therefore, therapeutic targeting of 14-3-3 proteins and p44/42 kinase activity may represent a promising strategy for DCM and other cardiac diseases associated with aberrant mitochondrial dynamics.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"4 21 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146161","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 : 2025-05-27Epub Date: 2025-03-12DOI: 10.1161/CIRCULATIONAHA.124.072336
YangYang Guan, Xiaomin Liu, Zetian Yang, Xinyu Zhu, Min Liu, Mingkun Du, Xiaowei Pan, Yan Wang
{"title":"PCSK9 Promotes LDLR Degradation by Preventing SNX17-Mediated LDLR Recycling.","authors":"YangYang Guan, Xiaomin Liu, Zetian Yang, Xinyu Zhu, Min Liu, Mingkun Du, Xiaowei Pan, Yan Wang","doi":"10.1161/CIRCULATIONAHA.124.072336","DOIUrl":"10.1161/CIRCULATIONAHA.124.072336","url":null,"abstract":"<p><strong>Background: </strong>Low-density lipoprotein (LDL) is internalized into cells mainly through LDLR (LDL receptor)-mediated endocytosis. In an acidic endosome, LDLR is released from LDL and recycles back to the cell surface, whereas LDL is left in the endosome and degraded in the lysosome. Circulating PCSK9 (proprotein convertase subtilisin/kexin 9) binds with LDLR and is internalized into the endosome, similar to LDL. In an acidic endosome, LDLR fails to disassociate from PCSK9, and both proteins are degraded in the lysosome. PCSK9 inhibitors are widely used for treating hypercholesterolemia. However, how PCSK9 diverts LDLR to the lysosome for degradation remains elusive. Some patients are resistant to PCSK9 inhibitors, for unknown reasons.</p><p><strong>Methods: </strong>Both in vitro and in vivo approaches were used to investigate the molecular and cellular mechanisms of PCSK9-mediated LDLR degradation. LDLR containing <i>FH</i> sequence variations was expressed in <i>Ldlr</i> knockout mice and knockout HuH7 cells to evaluate their response to PCSK9 and PCSK9 inhibitors.</p><p><strong>Results: </strong>Acidic pH induces a conformational change in LDLR extracellular domain and promotes its interaction with SNX17 (sorting nexin 17) through the intracellular domain. Knocking down <i>SNX17</i> abolishes LDLR recycling and causes accelerated degradation in the lysosome. PCSK9 prevents the acidic pH-induced conformational change in LDLR and blocks its interaction with SNX17. Knocking down <i>SNX17</i> abolishes PCSK9-mediated LDLR degradation. Any <i>FH</i> sequence variations that disrupt LDLR recycling are unresponsive to PCSK9 or PCSK9 inhibitors, even though they can internalize LDL.</p><p><strong>Conclusions: </strong>PCSK9 promotes LDLR degradation by preventing SNX17-mediated LDLR recycling. Patients with sequence variations in <i>FH</i> leading to defects in LDLR recycling are resistant to PCSK9 inhibitors. Genetic diagnosis and alternative drugs independent of LDLR will be needed for treatment of these patients.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1512-1526"},"PeriodicalIF":35.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604095","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 : 2025-05-27Epub Date: 2025-03-30DOI: 10.1161/CIRCULATIONAHA.125.074470
Varsha Keelara Tanguturi, Roukoz Abou-Karam, Fangzhou Cheng, Rong Duan, Ignacio Inglessis-Azuaje, Nathaniel B Langer, Evin N Yucel, Jonathan J Passeri, Judy W Hung, Sammy Elmariah
{"title":"Electronic Provider Notification to Facilitate the Recognition and Management of Severe Aortic Stenosis: A Randomized Clinical Trial.","authors":"Varsha Keelara Tanguturi, Roukoz Abou-Karam, Fangzhou Cheng, Rong Duan, Ignacio Inglessis-Azuaje, Nathaniel B Langer, Evin N Yucel, Jonathan J Passeri, Judy W Hung, Sammy Elmariah","doi":"10.1161/CIRCULATIONAHA.125.074470","DOIUrl":"10.1161/CIRCULATIONAHA.125.074470","url":null,"abstract":"<p><strong>Background: </strong>Symptomatic severe aortic stenosis (AS) remains undertreated with high resultant mortality despite increased growth and availability of aortic valve replacement (AVR) since the advent of transcatheter therapies. We evaluate the impact of electronic provider notifications (EPNs) on rates of AVR at 1 year.</p><p><strong>Methods: </strong>In a pragmatic cluster randomized clinical trial conducted within a multicenter academic health system from March 2022 through November 2023, 285 providers who had ordered a transthoracic echocardiogram (TTE) with findings potentially indicative of severe AS with an aortic valve area ≤1.0 cm<sup>2</sup> were enrolled. Providers were randomly assigned to receive EPNs for each of their patients with severe AS on TTE or to usual care. Notifications highlighted the detection of severe AS and included patient-specific clinical guideline recommendations for its management. The primary end point was the proportion of patients with severe AS receiving AVR within 1 year of the index TTE.</p><p><strong>Results: </strong>A total of 144 providers were randomized to intervention and 141 to control, resulting in 496 and 443 patients assigned to each group, respectively. The patient cohort had mean age of 77±11 years, was 47% female, and had a mean aortic valve area of 0.8±0.1 cm<sup>2</sup>. Rates of AVR within 1 year were 48.2% with EPNs versus 37.2% with usual care (odds ratio [OR], 1.62 [95% CI, 1.13-2.32]; <i>P</i>=0.009]) and 60.7% and 46.5%, respectively, among symptomatic patients (OR, 1.77 [95% CI, 1.17-2.65]; <i>P</i>=0.006). Notification treatment effect was highest with EPNs for patients >80 years of age (OR, 2.00 [95% CI, 1.17-3.41]; <i>P</i>=0.01), for women (OR, 2.78, [95% CI, 1.69-4.57]; <i>P</i><0.001), and when the index TTE was performed within the inpatient setting (OR, 2.49 [95% CI, 1.44-4.31]; <i>P</i><0.001). Within 1 year, the restricted mean survival time was longer with EPNs in all (12 days; <i>P</i>=0.04) and symptomatic patients (23 days; <i>P</i>=0.01).</p><p><strong>Conclusions: </strong>In this first study of EPNs for valvular heart disease, EPNs increased rates of AVR for severe AS, lessened sex and age disparities in AVR use, and improved survival time. EPNs may be a simple, scalable intervention to raise awareness of critical TTE findings and improve the quality of care for patients with severe AS.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT05230225.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1498-1507"},"PeriodicalIF":35.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751366","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 : 2025-05-27DOI: 10.1161/CIRCULATIONAHA.124.072925
Tianxiang Luo, Tiefu Zhao, Hanying Ma
{"title":"Letter by Luo et al Regarding Article, \"Half-Life and Clearance of Cardiac Troponin I and Troponin T in Humans\".","authors":"Tianxiang Luo, Tiefu Zhao, Hanying Ma","doi":"10.1161/CIRCULATIONAHA.124.072925","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072925","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 21","pages":"e1027"},"PeriodicalIF":35.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157222","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 : 2025-05-27DOI: 10.1161/CIRCULATIONAHA.125.073964
Jonas Henrik Kristensen, Rasmus Bo Hasselbalch, Nina Strandkjær, Peter Hasse Møller-Sørensen, Pia Rørbæk Kamstrup, Morten Dahl, Mustafa Vakur Bor, Ruth Frikke-Schmidt, Niklas Rye Jørgensen, Line Rode, Lene Holmvang, Jesper Kjærgaard, Lia Evi Bang, Julie Forman, Kim Dalhoff, Allan S Jaffe, Kristian Thygesen, Henning Bundgaard, Kasper Karmark Iversen
{"title":"Response by Kristensen et al to Letter Regarding Article, \"Half-Life and Clearance of Cardiac Troponin I and Troponin T in Humans\".","authors":"Jonas Henrik Kristensen, Rasmus Bo Hasselbalch, Nina Strandkjær, Peter Hasse Møller-Sørensen, Pia Rørbæk Kamstrup, Morten Dahl, Mustafa Vakur Bor, Ruth Frikke-Schmidt, Niklas Rye Jørgensen, Line Rode, Lene Holmvang, Jesper Kjærgaard, Lia Evi Bang, Julie Forman, Kim Dalhoff, Allan S Jaffe, Kristian Thygesen, Henning Bundgaard, Kasper Karmark Iversen","doi":"10.1161/CIRCULATIONAHA.125.073964","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.073964","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 21","pages":"e1028-e1029"},"PeriodicalIF":35.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157225","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}