Circulation最新文献

{"title":"Lymphatic Endothelial Branched-Chain Amino Acid Catabolic Defects Undermine Cardiac Lymphatic Integrity and Drive HFpEF.","authors":"Xiong Guo, Chong Huang, Ling Zhang, Guangyu Hu, Yunhui Du, Xiyao Chen, Fangfang Sun, Tongzheng Li, Zhe Cui, Congye Li, Yongzhen Guo, Wenjun Yan, Yunlong Xia, Shan Wang, Hui Liu, Zhiyuan Liu, Zhen Lin, Xinyi Wang, Zhengyang Wang, Fuyang Zhang, Ling Tao","doi":"10.1161/CIRCULATIONAHA.124.071741","DOIUrl":"10.1161/CIRCULATIONAHA.124.071741","url":null,"abstract":"<p><strong>Background: </strong>Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored.</p><p><strong>Methods: </strong>We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms.</p><p><strong>Results: </strong>In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFC^C156S) that selectively activates vascular endothelial growth factor receptor 3 (VEGFR3) in LECs restored cardiac lymphatic integrity and substantially alleviated HFpEF. Through discovery-driven approaches, defective branched-chain amino acid (BCAA) catabolism was identified as a predominant metabolic signature in HFpEF cardiac LECs. Overexpression of branched-chain ketoacid dehydrogenase kinase (encoded by the <i>Bckdk</i> gene), which inactivates branched-chain ketoacid dehydrogenase (the rate-limiting enzyme in BCAA catabolism), resulted in spontaneous lymphangiogenic defects in LECs. In mice, inducible <i>Bckdk</i> gene deletion in LECs to enhance their BCAA catabolism preserved cardiac lymphatic integrity and protected against HFpEF. BCAA catabolic defects caused ligand-independent phosphorylation of VEGFR3 in the cytoplasm by Src kinase, leading to lysosomal degradation of VEGFR3 instead of its trafficking to the cell membrane. Reduced VEGFR3 availability on the cell surface impeded downstream Akt (protein kinase B) activation, hindered glucose uptake and utilization, and inhibited lymphangiogenesis in LECs with BCAA catabolic defects.</p><p><strong>Conclusions: </strong>Our study provides evidence that cardiac lymphatic disruption, driven by impaired BCAA catabolism in LECs, is a key factor contributing to HFpEF. These findings unravel the crucial role of BCAA catabolism in modulating lymphatic biology, and suggest that preserving cardiac lymphatic integrity may present a novel therapeutic strategy for HFpEF.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1651-1666"},"PeriodicalIF":35.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751367","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}

{"title":"FMO2 Prevents Pathological Cardiac Hypertrophy by Maintaining the ER-Mitochondria Association Through Interaction With IP3R2-Grp75-VDAC1.","authors":"Changchen Xiao, Chao Wang, Jingyi Wang, Xianpeng Wu, Changle Ke, Jinliang Nan, Hao Ding, Yinghui Xu, Yanna Shi, Jing Zhao, Cheng Ni, Qingnian Liu, Jiamin Li, Shuyuan Sheng, Hua Chen, Jiayue Cai, Tonghui Zhao, Jinghai Chen, Qiming Sun, Bin Zhou, Jian'an Wang, Wei Zhu, Xinyang Hu","doi":"10.1161/CIRCULATIONAHA.124.072661","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072661","url":null,"abstract":"<p><strong>Background: </strong>Cardiac hypertrophy, as an important pathological change, contributes to heart failure. Recent studies indicate that the mitochondria-associated endoplasmic reticulum membranes (MAMs) play key roles in this pathological process. However, the molecular mechanism remains unclear. This study aims to elucidate the effects and mechanisms of MAM-resident FMO2 (flavin-containing monooxygenase 2) in cardiac hypertrophy and heart failure.</p><p><strong>Methods: </strong>We performed bulk RNA-sequencing analysis using heart tissue from patients with cardiac hypertrophy and carried out MAM-targeted mass spectrometry analysis using heart tissue from a mouse model of pathological cardiac hypertrophy. In vitro cell culture using neonatal rat cardiomyocytes was used to study how MAMs formation affected cardiomyocyte functions. By generating different genetic mouse models combined with using adeno-associated virus 9 under the cardiac troponin T promoter techniques, we further investigated and confirmed the effects of MAM structure changes on cardiac hypertrophy.</p><p><strong>Results: </strong>We detected an unexpected component of MAMs structure, which was the FMO2, an endoplasmic reticulum-resident protein. FMO2 levels decreased during pathological cardiac hypertrophy. The deletion and overexpression of FMO2 can either worsen or prevent the pathological heart failure progression in vivo, respectively. Our data further demonstrated that FMO2 localizes to MAM structure, where it binds to inositol 1,4,5-trisphosphate type 2 receptor (IP3R2) as a component of the IP3R2-Grp75 (glucose-regulated protein 75)-VDAC1 (voltage-dependent anion channel protein 1) complex, maintaining endoplasmic reticulum-mitochondria contact and regulating mitochondrial Ca²⁺ signaling for bioenergetics. Last, we showed that a synthetic peptide-enhancing endoplasmic reticulum-mitochondria contact promoted Ca²⁺ transfer and prevented pathological cardiac hypertrophy.</p><p><strong>Conclusions: </strong>Our findings reveal a key role of FMO2 in myocardial hypertrophy and that FMO2 plays a pivotal role in maintaining MAM structure and function, which may represent a novel mechanism and therapeutic target for cardiac hypertrophy and heart failure.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 23","pages":"1667-1685"},"PeriodicalIF":35.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257484","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":"New Classification to Describe Clinical Presentation in Aortic Stenosis: Stable, Progressive, and Acute Valve Syndrome.","authors":"Philippe Généreux, Brian R Lindman, Philippe Pibarot","doi":"10.1161/CIRCULATIONAHA.125.074251","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.074251","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 23","pages":"1627-1629"},"PeriodicalIF":35.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257488","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":"Response by Campo and Pavasini to Letter Regarding Article, \"Complete Versus Culprit-Only Revascularization in Older Patients With ST-Segment-Elevation Myocardial Infarction: An Individual Patient Meta-Analysis\".","authors":"Gianluca Campo, Rita Pavasini","doi":"10.1161/CIRCULATIONAHA.125.074587","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.074587","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 23","pages":"e1049-e1050"},"PeriodicalIF":35.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257489","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":"Highlights From the <i>Circulation</i> Family of Journals.","authors":"","doi":"10.1161/CIRCULATIONAHA.125.075356","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.075356","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 23","pages":"1686-1691"},"PeriodicalIF":35.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257485","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":"A Nationwide Factorial Randomized Trial of Electronic Nudges to Patients with Chronic Kidney Disease and Their General Practices for Increasing Guideline-Directed Medical Therapy: The NUDGE-CKD Trial.","authors":"Kristoffer Grundtvig Skaarup, Niklas Dyrby Johansen, Lisbet Brandi, Morten Kofod Lindhardt, Jesper N Bech, My Svensson, Tilde Kristensen, Anne Daugaard Thuesen, Majbritt Grønborg Knudsen, Jan Dominik Kampman, Mads Hornnum, Birgitte Ørts, Daniel Modin, Mats C H Lassen, Kira Hyldekær Janstrup, Brian L Claggett, Muthiah Vaduganathan, Ankeet S Bhatt, Harriette G C Van Spall, Jens Ulrik Stæhr Jensen, Faiez Zannad, Scott D Solomon, Anne Møller, Rikke Borg, Henrik Birn, Ditte Hansen, Tor Biering-Sørensen","doi":"10.1161/CIRCULATIONAHA.125.075403","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.075403","url":null,"abstract":"<p><strong>Background: </strong>Many individuals with chronic kidney disease (CKD) face considerable but modifiable risk of cardiovascular and renal outcomes due to suboptimal implementation of guideline-directed medical therapy (GDMT). We investigated whether electronic letter-based nudges delivered to individuals with CKD and their general practices could increase GDMT uptake.</p><p><strong>Methods: </strong>This was a nationwide 2x2 factorial implementation trial, with randomization at the patient and general-practice level, and analyzed at the patient level. All Danish adults with a hospital-diagnosis of CKD and access to the official Danish electronic letter system were individually randomized in a 1:1 ratio to usual care (no letter) or to receive an electronic letter-based nudge on GDMT in CKD; general practices of individuals with CKD were independently randomized (1:1) to receive no letter or an electronic informational letter on GDMT. Intervention letters were delivered on August 19, 2024. Data were collected through the Danish administrative health registries. Primary endpoint was a filled prescription of a renin-angiotensin system inhibitor (RASi) or a sodium-glucose cotransporter-2 inhibitor (SGLT2i) within 6 months of intervention delivery.</p><p><strong>Results: </strong>A total of 22,617 patients with CKD were randomized to the patient-level intervention, with 11,223 allocated to receive the electronic nudge letter and 11,394 to usual care. Separately, 1,540 general practices caring for 28,069 patients with CKD were randomized to the provider-level intervention, with 774 practices (13,959 patients) allocated to the intervention and 766 practices (14,110 patients) to usual care. During follow-up, 7,303 (65.1%) allocated to the patient-directed nudge had filled a prescription of RASi or SGLT2i compared with 7,505 (65.9%) in usual care (difference, 0.79 percentage points; 95% confidence interval (CI), -2.03 to 0.45; P=0.21). Among patients of practices receiving the provider-directed letter, 8,921 (63.9%) filled a prescription for RASi or SGLT2i compared with 9,086 (64.4%) in the usual care group (difference, -0.49 percentage points; 95%CI, -1.64 to 0.66; P=0.41). No interaction was observed between the two interventions (p_interaction=0.85).</p><p><strong>Conclusions: </strong>In this nationwide pragmatic, 2x2 factorial implementation trial, electronic letter-based nudges on GDMT delivered to patients with CKD or their general practice did not increase the uptake of RASi or SGLT2i as compared with usual care.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246683","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":"High Dietary Phosphate Intake Induces Hypertension and Sympathetic Overactivation Through Central Fibroblast Growth Factor Receptor Signaling.","authors":"Han-Kyul Kim, Ayumi Fukazawa, Scott A Smith, Masaki Mizuno, Beverly A Rothermel, Teppei Fujikawa, Marco Galvan, Laurent Gautron, Johanne V Pastor, Isabelle Carroll, Orson W Moe, Wanpen Vongpatanasin","doi":"10.1161/CIRCULATIONAHA.124.071605","DOIUrl":"10.1161/CIRCULATIONAHA.124.071605","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have highlighted the deleterious role of high phosphate intake in hypertension by means of sympathetic overactivation, yet the underlying mechanisms remain unclear. Dietary phosphate loading triggers physiologic release of FGF23 (fibroblast growth factor-23) from the bone to maintain phosphate homeostasis. Both FGF23 and FGF receptors (FGFRs) are present in the central nervous system, but their role in neural control of blood pressure during phosphate loading is unknown. We investigated central FGF23/FGFR signaling in high-phosphate diet-induced sympathetic dysregulation of blood pressure in rats.</p><p><strong>Methods: </strong>FGF23 protein levels were measured by immunoprecipitation, immunoblotting, and immunohistochemistry. FGF23 translocation into the brain was determined by injecting infrared-labeled FGF23 intravenously into anesthetized Sprague-Dawley rats. Mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction were measured in decerebrate Sprague-Dawley rats treated with either a normal 0.6% phosphate diet (NP) or a high 1.2% phosphate diet (HP) for 12 weeks before and after intracerebroventricular (ICV) administration of FGFR signaling inhibitors.</p><p><strong>Results: </strong>Excess phosphate intake significantly increased FGF23 protein levels in the brainstem (HP versus NP, <i>P</i>=0.009) and cerebrospinal fluid (HP versus NP, <i>P</i><0.001). Peripheral injection of infrared-labeled FGF23 showed clear entry into the choroid plexus and medulla oblongata. ICV administration of PD173074, a pan-FGFR(1-4) inhibitor, significantly attenuated the heightened RSNA (Δ=84±53 versus 32±25% [<i>P</i><0.0001]) and MAP (Δ=35±14 versus 9±7 mm Hg [<i>P</i><0.0001]) responses to muscle contraction in HP animals, but did not affect the RSNA and MAP responses during stimulation in NP animals (ΔRSNA=40±29 versus 30±22% and ΔMAP=18±13 versus 13±9 mm Hg before versus after ICV injection). ICV injection of BLU9931, a relatively selective FGFR4 inhibitor, also decreased the responses in HP rats only (∆RSNA=112±70 versus 65±46% [<i>P</i>=0.006] and ∆MAP=41±14 versus 20±14 mm Hg [<i>P</i><0.0001] before versus after ICV injection). However, ICV administration of AZD4547, a FGFR1-3 inhibitor, and C-terminal FGF23 peptide, a competitive inhibitor of FGF23/FGFR/α-Klotho complex formation, did not alter the responses in either NP or HP animals.</p><p><strong>Conclusions: </strong>Our data reveal a novel pathophysiologic paradigm of high-phosphate diet-induced sympathoexcitation and hypertension by FGF23 crossing into the brain, possibly acting through FGFR4.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224551","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":"Aortic Aneurysm Risk and Somatic <i>JAK2</i>^<i>V617F</i>Variation: Insights From a Multicenter, Population-Based Cardiovascular Screening Study.","authors":"Lasse M Obel, Joachim S Skovbo, Axel C P Diederichsen, Mads Thomassen, Lasse Kjær, Morten K Larsen, Trine A Knudsen, Vibe Skov, Torben A Kruse, Mark Burton, Maja Dembic, Troels Wienecke, Maria Sabater-Lleal, Oke Gerke, Niels E Bruun, Christina Ellervik, Mette Brabrand, Flemming H Steffensen, Lars Frost, Jess Lambrechtsen, Martin Busk, Grazina Urbonaviciene, Kenneth Egstrup, Marek Karon, Søren Feddersen, Lars M Rasmussen, Hans C Hasselbalch, Jes S Lindholt","doi":"10.1161/CIRCULATIONAHA.125.074002","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.074002","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The somatic &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt; sequence variation, a key driver of myeloproliferative neoplasms, has been associated with increased risk of aortic aneurysms. This study aimed to explore associations between the &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt; variant allele frequency (VAF) and ascending, descending, and abdominal aortic aneurysms.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In the DANCAVAS I and II trials (Danish Cardiovascular Screening), 15 000 individuals underwent cardiovascular risk assessments including blood samples and noncontrast ECG-gated computed tomography scans. In this cross-sectional substudy, individuals with screening-detected aortic aneurysms (≥45 mm ascending, ≥35 mm descending, or ≥30 mm abdominal), random aneurysm-free male controls, and all women (only included during the DANCAVAS I pilot study) were tested for the &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt; sequence variation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A total of 8056 individuals (90.9% men, mean age 68±4 years) were tested for the &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt; sequence variation, which presented an overall prevalence of 7.1%. Ascending, descending, and abdominal aneurysm prevalences were 6.6%, 2.9%, and 6.8%, respectively. In &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt;-negative participants (n=7486), &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt;-positive participants with VAF &lt;1% (n=491), and &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt;-positive participants with VAF ≥1% (n=79), ascending aortic aneurysms were observed in 6.4%, 9.0%, and 16.5%, respectively (&lt;i&gt;P&lt;/i&gt;&lt;0.001). No significant differences were observed across sequence variation groups for descending and abdominal aneurysms. Among &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt;-positive individuals, the median VAF was higher in those with ascending aneurysm (9.5%; interquartile range, 3.0-40.0) than in controls (4.4%; interquartile range, 1.8-20.0; &lt;i&gt;P&lt;/i&gt;=0.021). Ascending aortic diameter correlated modestly with VAF (Spearman ρ=0.10; &lt;i&gt;P&lt;/i&gt;=0.026). No significant correlations were observed for descending or abdominal diameters. For ascending aneurysms, &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt; VAF &lt;1% and ≥1% presented adjusted odds ratios of 1.4 (95% CI, 1.01-2.0; &lt;i&gt;P&lt;/i&gt;=0.045) and 2.7 (95% CI, 1.5-5.1; &lt;i&gt;P&lt;/i&gt;=0.002), respectively, compared with &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt;-negative controls. For each doubling in VAF, the risk for ascending aneurysm increased by 11% (&lt;i&gt;P&lt;/i&gt;&lt;sub&gt;adjusted&lt;/sub&gt;=0.013). The &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt; sequence variation was not significantly associated with descending or abdominal aneurysms after adjusting for covariates and using these VAF thresholds.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;In a study population of primarily men 60 to 74 years of age, the somatic &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;V617F&lt;/i&gt;&lt;/sup&gt; sequence variation was strongly and independently associated with ascending aortic aneurysms, presenting a positive correlation between aneurysm size and &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;&lt;i&gt;","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215017","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":"Hierarchical Composite Outcomes and Win Ratio Methods in Cardiovascular Trials: A Review and Consequent Guidance.","authors":"John Gregson, Dylan Taylor, Ruth Owen, Tim Collier, David J Cohen, Stuart Pocock","doi":"10.1161/CIRCULATIONAHA.124.070251","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070251","url":null,"abstract":"<p><p>The win ratio is a method for analyzing a hierarchical composite outcome. It has been most widely used in randomized clinical trials (RCTs) in cardiovascular disease. We performed a review of cardiovascular RCTs using the win ratio published between January 2022 and July 2024. The aims were to summarize current use and to provide examples to illustrate effective use and communication. We identified 36 eligible RCTs, mainly in heart failure and ischemic heart disease. Intervention was pharmaceutical in 26, a procedure in 7, and treatment strategy in 3 trials. When outcomes were analyzed with both conventional composite end points or hierarchical analysis, the conclusions tended to be similar. The win ratio was often used to combine evidence from event outcomes and quantitative measures together in a hierarchical composite, as was done in 23 RCTs. It was also used to create a clinically more relevant measure in RCTs by recognizing the clinical priorities among event outcomes. Selected example RCTs illustrate how the clarity of win ratio findings can be improved by (1) complementing the win ratio (a relative measure) with the win difference, (2) identifying which components of a hierarchical composite drive the overall results, and (3) clearly prespecifying the outcomes and win ratio analysis to be used. We conclude with a set of recommendations for future use of hierarchical composite outcomes and the win ratio. When used wisely, the win ratio is a valuable tool in the analysis of RCTs.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 22","pages":"1606-1619"},"PeriodicalIF":35.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207832","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":"Biomarkers to Guide the Timing of Aortic Valve Replacement in Asymptomatic Aortic Stenosis: Where Do We Stand After Early TAVR?","authors":"Jarett D Berry, James A de Lemos","doi":"10.1161/CIRCULATIONAHA.125.075062","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.075062","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 22","pages":"1565-1567"},"PeriodicalIF":35.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207831","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}