Circulation research最新文献

{"title":"AMPK Attenuation of β-Adrenergic Receptor-Induced Cardiac Injury via Phosphorylation of β-Arrestin-1-ser330.","authors":"Mingming Zhao, Ning Cao, Huijun Gu, Jiachao Xu, Wenli Xu, Di Zhang, Tong-You Wade Wei, Kang Wang, Ruiping Guo, Hongtu Cui, Xiaofeng Wang, Xin Guo, Zhiyuan Li, Kangmin He, Zijian Li, Youyi Zhang, John Y-J Shyy, Erdan Dong, Han Xiao","doi":"10.1161/CIRCRESAHA.124.324762","DOIUrl":"10.1161/CIRCRESAHA.124.324762","url":null,"abstract":"<p><strong>Background: </strong>β-adrenergic receptor (β-AR) overactivation is a major pathological cue associated with cardiac injury and diseases. AMPK (AMP-activated protein kinase), a conserved energy sensor, regulates energy metabolism and is cardioprotective. However, whether AMPK exerts cardioprotective effects via regulating the signaling pathway downstream of β-AR remains unclear.</p><p><strong>Methods: </strong>Using immunoprecipitation, mass spectrometry, site-specific mutation, in vitro kinase assay, and in vivo animal studies, we determined whether AMPK phosphorylates β-arrestin-1 at serine (Ser) 330. Wild-type mice and mice with site-specific mutagenesis (S330A knock-in [KI]/S330D KI) were subcutaneously injected with the β-AR agonist isoproterenol (5 mg/kg) to evaluate the causality between β-adrenergic insult and β-arrestin-1 Ser330 phosphorylation. Cardiac transcriptomics was used to identify changes in gene expression from β-arrestin-1-S330A/S330D mutation and β-adrenergic insult.</p><p><strong>Results: </strong>Metformin could decrease cAMP/PKA (protein kinase A) signaling induced by isoproterenol. AMPK bound to β-arrestin-1 and phosphorylated Ser330 with the highest phosphorylated mass spectrometry score. AMPK activation promoted β-arrestin-1 Ser330 phosphorylation in vitro and in vivo. Neonatal mouse cardiomyocytes overexpressing β-arrestin-1-S330D (active form) inhibited the β-AR/cAMP/PKA axis by increasing PDE (phosphodiesterase) 4 expression and activity. Cardiac transcriptomics revealed that the differentially expressed genes between isoproterenol-treated S330A KI and S330D KI mice were mainly involved in immune processes and inflammatory response. β-arrestin-1 Ser330 phosphorylation inhibited isoproterenol-induced reactive oxygen species production and NLRP3 (NOD-like receptor protein 3) inflammasome activation in neonatal mouse cardiomyocytes. In S330D KI mice, the β-AR-activated cAMP/PKA pathways were attenuated, leading to repressed inflammasome activation, reduced expression of proinflammatory cytokines, and mitigated macrophage infiltration. Compared with S330A KI mice, S330D KI mice showed diminished cardiac fibrosis and improved cardiac function upon isoproterenol exposure. However, the cardiac protection exerted by AMPK was abolished in S330A KI mice.</p><p><strong>Conclusions: </strong>AMPK phosphorylation of β-arrestin-1 Ser330 potentiated PDE4 expression and activity, thereby inhibiting β-AR/cAMP/PKA activation. Subsequently, β-arrestin-1 Ser330 phosphorylation blocks β-AR-induced cardiac inflammasome activation and remodeling.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"651-667"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855001","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":"Intramyocardial Sprouting Tip Cells Specify Coronary Arterialization.","authors":"Elena Cano, Jennifer Schwarzkopf, Masatoshi Kanda, Eric L Lindberg, Irene Hollfinger, Cristina Pogontke, Caroline Braeuning, Cornelius Fischer, Norbert Hübner, Holger Gerhardt","doi":"10.1161/CIRCRESAHA.124.324868","DOIUrl":"10.1161/CIRCRESAHA.124.324868","url":null,"abstract":"<p><strong>Background: </strong>The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart.</p><p><strong>Methods: </strong>Single-cell transcriptomics and histological validation were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. Genetic lineage tracing and high-resolution 3-dimensional imaging were used to characterize the origin and mechanisms of coronary angiogenic sprouting, as well as to fate-map selective endothelial lineages. Integration of single-cell transcriptomic data from ischemic adult mouse hearts and human embryonic data served to assess the conservation of transcriptional states across development, disease, and species.</p><p><strong>Results: </strong>We discover that coronary arteries originate from cells that have previously transitioned through a specific tip cell phenotype. We identify nonoverlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways. <i>Esm1</i>-lineage tracing confirmed that intramyocardial tip cells selectively contribute to coronary arteries and endocardial tunnels, but not veins. Notably, prearterial cells are detected from development stages to adulthood, increasingly in response to ischemic injury, and in human embryos, suggesting that tip cell-to-artery specification is a conserved mechanism.</p><p><strong>Conclusions: </strong>A tip cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life and is reactivated upon ischemic injury. Differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"671-684"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874330","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":"Monocyte Single-Cell Multimodal Profiling in Cardiovascular Disease Risk States.","authors":"Alexander C Bashore, Chenyi Xue, Eunyoung Kim, Hanying Yan, Lucie Y Zhu, Huize Pan, Michael Kissner, Leila S Ross, Hanrui Zhang, Mingyao Li, Muredach P Reilly","doi":"10.1161/CIRCRESAHA.124.324457","DOIUrl":"10.1161/CIRCRESAHA.124.324457","url":null,"abstract":"<p><strong>Background: </strong>Monocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. They have been identified historically by the cell surface expression of CD14 and CD16. However, recent single-cell studies have revealed that they are much more heterogeneous than previously realized.</p><p><strong>Methods: </strong>We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing to describe the comprehensive transcriptional and phenotypic landscape of 437 126 monocytes.</p><p><strong>Results: </strong>This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCII^hi (major histocompatibility complex class II), monocyte-platelet aggregates, as well as nonclassical, and several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII⁺CD275⁺ MHCII^hi, CD42b⁺ monocyte-platelet aggregates, CD16⁺CD99^- nonclassical monocytes, and CD99⁺ classical monocytes. Each subpopulation exhibited unique characteristics, developmental trajectories, transcriptional regulation, and tissue distribution. In addition, alterations associated with cardiovascular disease risk factors, including race, smoking, and hyperlipidemia were identified. Moreover, the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol.</p><p><strong>Conclusions: </strong>This integrative and cross-species comparative analysis provides a new perspective on the comparison of alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in cardiovascular disease and the potential for monocyte subpopulation targeted therapies.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"685-700"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11430373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892994","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":"Prostacyclin Synthase Deficiency Leads to Exacerbation or Occurrence of Endothelium-Dependent Contraction and Causes Cardiovascular Disorders Mainly via the Non-TxA₂ Prostanoids/TP Axis.","authors":"Jiahui Ge, Yingbi Zhou, Hui Li, Ruhui Zeng, Kaiqi Xie, Jing Leng, Xijian Chen, Gang Yu, Xinya Shi, Yineng Xu, Dong He, Pi Guo, Yongyin Zhou, Hongjun Luo, Wenhong Luo, Bin Liu","doi":"10.1161/CIRCRESAHA.124.324924","DOIUrl":"10.1161/CIRCRESAHA.124.324924","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Prostaglandin I&lt;sub&gt;2&lt;/sub&gt; synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I&lt;sub&gt;2&lt;/sub&gt; production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I&lt;sub&gt;2&lt;/sub&gt; synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Experiments were performed with wild-type, &lt;i&gt;Pgis&lt;/i&gt; knockout (&lt;i&gt;Pgis&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt;) and &lt;i&gt;Pgis&lt;/i&gt;/thromboxane-prostanoid receptor gene (&lt;i&gt;Tp&lt;/i&gt;) double knockout (&lt;i&gt;Pgis&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Tp&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt;) mice and &lt;i&gt;Pgis&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; mice transplanted with unfractionated wild-type or &lt;i&gt;Cox-1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;PGF&lt;sub&gt;2α&lt;/sub&gt;, PGE&lt;sub&gt;2&lt;/sub&gt;, and a trace amount of PGD&lt;sub&gt;2&lt;/sub&gt;, but not thromboxane A&lt;sub&gt;2&lt;/sub&gt; (TxA&lt;sub&gt;2&lt;/sub&gt;), were produced in response to acetylcholine in &lt;i&gt;Pgis&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in &lt;i&gt;Pgis&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; aortas. &lt;i&gt;Pgis&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA&lt;sub&gt;2&lt;/sub&gt; receptor) not only restrained EDC and the downregulation of NO signaling in &lt;i&gt;Pgis&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; mice but also ameliorated the cardiovascular abnormalities. Stimulation of &lt;i&gt;Pgis&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; vessels with acetylcholine in the presence of platelets led to increased TxA&lt;sub&gt;2&lt;/sub&gt; generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in &lt;i&gt;Pgis&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;/&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; mice though it largely suppressed the increase of plasma TxB&lt;sub&gt;2&lt;/sub&gt; (TxA&lt;sub&gt;2&lt;/sub&gt; metabolite) level.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our study demonstrates that the non-TxA&lt;sub&gt;2&lt;/sub&gt; prostanoids/T","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e133-e149"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855002","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 New Piece to the AMPK Puzzle in Heart Repair: Phosphorylation of β-Arrestin-1.","authors":"Julio Silva-Neto, Walter J Koch","doi":"10.1161/CIRCRESAHA.124.325195","DOIUrl":"10.1161/CIRCRESAHA.124.325195","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 6","pages":"668-670"},"PeriodicalIF":19.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11407748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104846","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":"Single-Cell Sleuthing: Cracking the Monocyte Code for Cardiovascular Clues.","authors":"Catherine C Hedrick","doi":"10.1161/CIRCRESAHA.124.325134","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325134","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 6","pages":"701-703"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104848","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000690","DOIUrl":"https://doi.org/10.1161/RES.0000000000000690","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 6","pages":"636-638"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104847","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":"Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.","authors":"Khaled Z Abd-Elmoniem, Jehad H Edwan, Katrina B Dietsche, Alfredo Villalobos-Perez, Nour Shams, Jatin Matta, Leilah Baumgarten, Waleed N Qaddumi, Sydney A Dixon, Aruba Chowdhury, Michael Stagliano, Lilian Mabundo, Annemarie Wentzel, Colleen Hadigan, Ahmed M Gharib, Stephanie T Chung","doi":"10.1161/CIRCRESAHA.124.324272","DOIUrl":"10.1161/CIRCRESAHA.124.324272","url":null,"abstract":"<p><strong>Background: </strong>Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.</p><p><strong>Methods: </strong>Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate.</p><p><strong>Results: </strong>Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; <i>P</i>=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; <i>P</i><0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; <i>P</i>=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells.</p><p><strong>Conclusions: </strong>Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"639-650"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787368","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":"Biomimetic Nanodisks Are Effective Against Tubulointerstitial Fibrosis via Targeting Interstitial Microenvironment.","authors":"Chuchu Zhou, Rou Tang, Huajin Tan, Yige Yang, Peipei Meng, He Li, Kaichao Song, Xiaochuan Tan, Xiuping Guo, Ling Ren, Shuwang He, Ya Meng, Yumei Hao, Mingbao Lin, Yujia Zhang, Hongdong Huang, Lulu Wang, Wensheng Zheng","doi":"10.1161/CIRCRESAHA.124.324322","DOIUrl":"10.1161/CIRCRESAHA.124.324322","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e150-e153"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874329","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":"Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial.","authors":"Andreia Morais, Takahiko Imai, Xuyan Jin, Joseph J Locascio, Ligia Boisserand, Alison L Herman, Anjali Chauhan, Jessica Lamb, Karisma Nagarkatti, Marcio A Diniz, Mariia Kumskova, Nirav Dhanesha, Pradip K Kamat, Mohammad Badruzzaman Khan, Krishnan M Dhandapani, Rakesh B Patel, Brijesh Sutariya, Yanrong Shi, Klaus van Leyen, W Taylor Kimberly, David C Hess, Jaroslaw Aronowski, Enrique C Leira, Raymond C Koehler, Anil K Chauhan, Lauren H Sansing, Patrick D Lyden, Cenk Ayata","doi":"10.1161/CIRCRESAHA.123.324139","DOIUrl":"10.1161/CIRCRESAHA.123.324139","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivaria","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"575-592"},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11428171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733667","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}