Circulation最新文献

{"title":"Anticancer Drugs and Cancer-Associated Thrombosis","authors":"Hessam Kakavand,Maryam Aghakouchakzadeh,Parham Sadeghipour,Armin Pasukanovic,Jean M. Connors,Adam Cuker,Craig Beavers,Benjamin Van Tassell,Michelle Weisfelner Bloom,Behnood Bikdeli,Antonio Abbate,Nicola Potere,Jayant K. Raikhelkar,Azita H. Talasaz","doi":"10.1161/circulationaha.125.079141","DOIUrl":"https://doi.org/10.1161/circulationaha.125.079141","url":null,"abstract":"The rapid development of novel cancer therapies has considerably improved the care of cancer patients and cancer-related survival; however, these therapies are associated with a broad range of adverse events that have become a major burden in this population. Alongside other cancer-related factors, vascular toxicity from anticancer therapies contributes to an increased risk of venous thromboembolism. Among anticancer drugs, chemotherapeutic agents (eg, anthracyclines, platinum-based drugs, antimetabolites), hormonal therapies (eg, selective estrogen receptor modulators), agents used for multiple myeloma (including immunomodulatory drugs and proteasome inhibitors), asparaginase, as well as targeted inhibitors to immune checkpoints, vascular endothelial growth factor, epidermal growth factor receptor, tyrosine kinases, cyclin-dependent kinases, and poly(ADP-ribose) polymerase are primarily associated with increased risk of venous thromboembolism. Vascular adverse events associated with anticancer drugs are frequently underestimated, and significant gaps remain in the risk stratification, prevention, and management of thromboembolic events in patients receiving systemic anticancer therapies. This review examines the evidence linking anticancer drug exposure to the incidence of venous thromboembolism, summarizes the key underlying pathobiological mechanisms, and highlights current guideline recommendations for the prevention and treatment of cancer-associated thrombosis. Arterial thrombotic events are also discussed where clinically or mechanistically relevant. This review also offers advanced cardio-oncology perspectives on the identification, risk stratification, and therapeutic targeting of drug-induced vascular toxicity.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"150 1","pages":"1382-1403"},"PeriodicalIF":37.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088008","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":"Pathology of Genetic Variants in Spontaneous Coronary Artery Dissection.","authors":"Takamasa Tanaka, Rika Kawakami, Brady J Gaynor, Desiree Williams, Jacques Augenstreich, Atsushi Sakamoto, Hiroyuki Jinnouchi, Kenji Kawai, Takao Konishi, Tatsuya Shiraki, Teruo Sekimoto, Takafumi Nakayama, Kazuhiro Fujiyoshi, Tomoyo Hamana, Yusuke Adachi, Keisha Medina Diaz, Charles C Hong, Alyssa Grogan, Braxton D Mitchell, Renu Virmani, Aloke V Finn","doi":"10.1161/CIRCULATIONAHA.126.080495","DOIUrl":"10.1161/CIRCULATIONAHA.126.080495","url":null,"abstract":"<p><strong>Background: </strong>Spontaneous coronary artery dissection (SCAD) is characterized by a separation of the coronary artery wall, causing myocardial infarction and sudden death. This study is one of the first to clarify the impact of pathological genetic variants in candidate SCAD-related genes on the histopathological and morphological properties of human SCAD lesions.</p><p><strong>Methods: </strong>A total of 28 SCAD cases were selected from the CVPath Autopsy Registry. Histological differences in collagen and smooth muscle cells were compared among 3 groups: culprit SCAD (C-SCAD), defined as the coronary segment containing a dissection in cases with SCAD; nonculprit SCAD, defined as unaffected coronary segments (ie, healthy arteries) in cases with SCAD; and non-SCAD controls. Whole-exome sequencing was performed, and the identified variants were filtered to isolate pathogenic or likely pathogenic variants. Protein expression corresponding to the identified variants was assessed by immunostaining.</p><p><strong>Results: </strong>Collagen content was significantly reduced in C-SCAD lesions compared with controls, and immunohistochemical staining for smoothelin was reduced in the media of C-SCAD lesions compared with controls, whereas there were no significant differences between C-SCAD and nonculprit SCAD. Further, the nuclear height/width ratio of smooth muscle cells was increased, suggesting smooth muscle cell phenotypic modulation. In whole-exome sequencing analysis, pathogenic or likely pathogenic variants were detected in 25% of cases, which showed a higher frequency of multivessel dissection. In SCAD cases with pathogenic or likely pathogenic variants in <i>COL3A1</i> (collagen type III alpha 1), <i>FBN1</i> (fibrillin-1), or <i>FLNA</i> (filamin A), the expression of the corresponding protein was reduced in the media.</p><p><strong>Conclusions: </strong>Reduced medial collagen and smooth muscle cell phenotypic modulation may be possible predisposing conditions for SCAD, regardless of the presence of pathogenic or likely pathogenic variants. The presence of pathogenic variants in extracellular matrix-related genes may further compromise arterial wall medial integrity, contributing to more severe disease. These findings provide novel pathological and genetic insights into the pathogenesis of SCAD and may inform future diagnostic and therapeutic strategies.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1309-1321"},"PeriodicalIF":41.3,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863820","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":"Impact of Undertreated Antithrombotic Therapy on Adverse Patient Outcomes: A Scientific Statement From the American Heart Association","authors":"Kelly Rudd,Youssef Bessada,Geoffrey D. Barnes,Ulf G. Bronas,Ashley N. Budd,Taylor Goot,Natalie A. Montanez,Toby Trujillo,on behalf of the American Heart Association Council on Peripheral Vascular Disease; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Radiology and Intervention; Council o","doi":"10.1161/cir.0000000000001474","DOIUrl":"https://doi.org/10.1161/cir.0000000000001474","url":null,"abstract":"Antithrombotic therapy undertreatment includes omission, nonadherence, underdosing, and clinical circumstances that result in subtherapeutic antithrombotic levels. Antithrombotic undertreatment has profound implications for patient safety, public health, and healthcare costs. Due to deviation from evidence-based clinical practice, misperceptions of bleeding versus thrombotic risk, and inequities in healthcare access, many patients with atrial fibrillation, venous thromboembolism, or peripheral artery disease remain untreated or receive suboptimal anticoagulant dosing. Antithrombotic undertreatment has been shown to increase rates of ischemic stroke, systemic embolism, recurrent thrombosis, and mortality. Real-world data continue to highlight substantial gaps in care, which appear to be magnified in patients with inequity in social determinants of health. The emergence of antithrombotic stewardship, in concert with growing bodies of literature on antithrombotic agent underdosing, represents a transformative opportunity to address these gaps through structured, interprofessional, and evidence-based approaches. Through interdisciplinary collaboration, healthcare professionals are well positioned to enhance patient health and safety by recognizing and recommitting to reducing antithrombotic undertreatment.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"15 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087944","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":"Myeloid Cell Expansion Propels Right Ventricular Dysfunction in HFpEF Through Sterile Inflammation.","authors":"Lara Jaeschke, Ceren Koçana, Alexandra Maria Chitroceanu, Annika Winkler, Hannah Kleitke, Pauline Fahjen, Justus Kamp, David Faidel, Erik Asmus, Martin Meiser, Efstathios G Stamatiades, Karolin W Hublitz, Veronika Zach, Lucie Kretzler, Daniela Zurkan, Paul-Lennard Perret, Leonardo A von der Ohe, Kai Beckschulte, Szandor Simmons, Jonathan L Gillan, Kristina Franz, Lina Alasfar, Virginia S Hahn, Kavita Sharma, Edwardo Reynolds, Gabriele G Schiattarella, Sophie van Linthout, Burkert Pieske, Niklas Beyhoff, Christiane Ott, Niklas Hegemann, Philipp Mertins, Frank Edelmann, Wolfgang M Kuebler, Jana Grune","doi":"10.1161/CIRCULATIONAHA.125.078476","DOIUrl":"10.1161/CIRCULATIONAHA.125.078476","url":null,"abstract":"<p><strong>Background: </strong>The role of leukocytes in the pathogenesis of right ventricular (RV) dysfunction (RVD) associated with heart failure with preserved ejection fraction (HFpEF) remains poorly defined, partially due to the lack of suitable small animal models. Here, we followed a translational research approach by establishing a murine HFpEF model developing manifest RVD and analyzed human HFpEF cohorts to study the mechanistic link between leukocytes and RVD in HFpEF.</p><p><strong>Methods: </strong>Young (<20-week-old) and aged (>80-week-old) male and female C57BL/6J mice were divided into 4 experimental groups: chow, HFpEF (L-NAME [Nω-nitro-L-arginine methyl ester] plus a high-fat diet), chronic hypoxia (10% O₂), and HFpEF plus hypoxia (RV-HFpEF). Biventricular function and myeloid cell dynamics were assessed across groups. To test whether myeloid cells are causally involved in the development of RV remodeling in HFpEF, we treated RV-HFpEF mice with a colony-stimulating factor 1 receptor inhibitor to deplete myeloid cells.</p><p><strong>Results: </strong>RV-HFpEF resulted in left ventricular diastolic dysfunction, indicated by increased E/E' ratio, reduced global longitudinal peak strain, smaller end-diastolic diameters, and increased isovolumetric relaxation time compared with chow. RV-HFpEF animals developed RV hypertrophy and RVD, evident as increased Fulton index as well as elevated RV systolic pressure and reduced tricuspid annular plane systolic excursion, respectively. Total leukocyte, monocyte, and macrophage counts were elevated in RV tissue from RV-HFpEF mice compared with RV tissue from chow mice and left ventricular tissue from young and aged RV-HFpEF animals. These findings were confirmed by unbiased proteomic analyses of RV tissue from RV-HFpEF mice, demonstrating an increased abundance of proteins involved in activation of the innate immune system, macrophage chemotaxis, and leukocyte migration when compared with left ventricular tissue and the other experimental groups. Fate-mapping experiments revealed that recruited monocyte-derived macrophages became the main source of total cardiac macrophages in RV tissue from RV-HFpEF mice. Depletion of myeloid cells was associated with lower RVSP profiles in RV-HFpEF mice compared with controls. In RV biopsies from patients with HFpEF, we found increased expression of adhesion molecules, fibrotic markers, and inflammatory transcripts, as well as an association between RVD and CD68⁺ cells.</p><p><strong>Conclusions: </strong>We demonstrate that dysregulated myeloid cell dynamics are associated with, and directly contribute to, the pathogenesis of RVD associated with HFpEF in humans and mice.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1200-1220"},"PeriodicalIF":41.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7619445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788443","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":"Under Pressure: When Heart Failure Isn't Full.","authors":"Mabelissa Geagea, Elie Kozaily, Cole J Buchanan, Jane E Wilcox, Vishal N Rao, Brian A Houston, Ryan J Tedford","doi":"10.1161/CIRCULATIONAHA.126.082866","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.082866","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"154 13","pages":"1277-1285"},"PeriodicalIF":41.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073735","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":"Congress Paradox: Are We Learning or Performing?","authors":"Francesco Tona","doi":"10.1161/CIRCULATIONAHA.126.080575","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.080575","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"154 13","pages":"1168-1169"},"PeriodicalIF":41.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073697","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":"Epigenome-Wide Association Study of Abdominal Aortic Aneurysm Identifies Central Role for Inflammatory Pathways.","authors":"Shuai Yuan, Michael G Clark, Gabrielle Shakt, Michael G Levin, Katherine Hartmann, Renae Judy, Tia Dinatale, Amy Voorhees, Julie A Lynch, Saiju Pyarajan, Daniel Levy, Roby Joehanes, Kyong-Mi Chang, Jennifer A Brody, Joshua C Bis, Bruce M Psaty, Benjamin F Voight, Philip S Tsao, Gregory T Jones, Scott M Damrauer","doi":"10.1161/CIRCULATIONAHA.126.079863","DOIUrl":"10.1161/CIRCULATIONAHA.126.079863","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Epigenetic mechanisms underlying susceptibility to abdominal aortic aneurysm (AAA) remain poorly understood. Identifying causal DNA methylation markers for AAA can elucidate the regulatory processes that drive aneurysm formation and accelerate translational applications. We leveraged the Veterans Affairs (VA) Million Veteran Program to identify methylation biomarkers and delineate underlying pathways.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We first conducted an epigenome-wide association study of incident AAA (1324 cases and 42 065 noncases), performed stratified analyses by population group and smoking status, and conducted Mendelian randomization to facilitate causal inference of the CpG-AAA association. Chromatin state, island context, and transcription factor binding were implicated through functional annotation of identified CpGs. To identify genes impacted by change in methylation state, we aligned associations with transcriptional data obtained in blood, aorta, and liver. We performed expression quantitative trait methylation to capture CpG-gene-expression links across the genome. Network Mendelian randomization was used to test cardiometabolic and inflammatory mediation. Finally, we developed a methylation risk score for AAA using penalized regression and evaluated its performance against a clinical model in the Million Veteran Program and 2 external studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Epigenome-wide association study identified 1253 CpGs associated with incident AAA, and Mendelian randomization supported a putative causal role for 143 of these associations. Functional annotation pointed to predominantly distal, enhancer-centered regulation and enrichment of inflammatory transcription factor programs (eg, activator protein-1 and nuclear factor κB). This distal architecture was consistent with expression quantitative trait methylation results, which showed a larger number of trans associations. Among 143 CpGs associated with AAA in Mendelian randomization analyses, we identified 213 CpG-gene expression pairs with strong colocalization support, including &lt;i&gt;AGER, C2&lt;/i&gt;, and &lt;i&gt;DDR1&lt;/i&gt;. Multi-trait colocalization further prioritized 8 CpG-gene expression-AAA links with evidence of a shared genetic signal. Network Mendelian randomization identified 135 putative mediation pathways linking CpGs to AAA, including 58 via cardiometabolic traits and 77 via inflammation-related traits. Blood lipid traits mediated &gt;40% of the associations between AAA risk and CpGs near &lt;i&gt;LDLR&lt;/i&gt; (cg19305903) and &lt;i&gt;TRIB1&lt;/i&gt; (cg14128479). Among inflammation-related mediators, circulating DAG1, NEXN, MMP9, IL1RN, and MMP13 were prioritized as potential intermediates. Additionally, a CpG selection process was used to develop a methylation risk score for AAA, which strongly associated with disease in both the discovery cohort and 2 external validation cohorts, even after adjustment for a full suite of clinical covariates.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":41.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073663","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":"Mechanosensitive Endothelial METTL7A Regulates Internal m⁷G mRNA Methylation and Protects Against Atherosclerosis.","authors":"Tzu-Pin Shentu, Tong Wu, Zhengjie Zhou, Jin Li, Chih-Fan Yeh, Jiayu Zhu, Ru-Ting Huang, Bernadette A Miao, Brian Xi, Jason Lo, Lauryn Carver, Tzu-Han Lee, Lisheng Zhang, Devin Harrison, Chani J Hodonsky, Gaelle Auguste, Uma Thanigai Arasu, Minna U Kaikkonen, Aliya N Husain, Matthew V Tirrell, Clint L Miller, Bryan C Dickinson, Kai-Chien Yang, Yun Fang","doi":"10.1161/CIRCULATIONAHA.125.075682","DOIUrl":"10.1161/CIRCULATIONAHA.125.075682","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Internal N7-methylguanosine (m&lt;sup&gt;7&lt;/sup&gt;G) is a recently identified chemical modification of mammalian mRNA. Although the epitranscriptome plays a key role in regulating RNA metabolism and cellular function, the specific contribution of internal m&lt;sup&gt;7&lt;/sup&gt;G to cardiovascular disease remains unknown. Atherosclerosis preferentially develops at sites of disturbed blood flow, which promotes endothelial activation; however, whether internal m&lt;sup&gt;7&lt;/sup&gt;G regulates endothelial mechanotransduction and atherogenesis remains unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We integrated epitranscriptomic profiling, human tissues, genetically modified mice, and targeted nanomedicine approaches to investigate the role of METTL7A (methyltransferase-like protein 7A), a putative internal m&lt;sup&gt;7&lt;/sup&gt;G methyltransferase, in endothelial mechanobiology and atherosclerosis. Vascular endothelial cells were subjected to atheroprotective and atheroprone flow waveforms in vitro and in vivo. METTL7A function was assessed using RNA sequencing, liquid chromatography-tandem mass spectrometry, crosslinking immunoprecipitation sequencing, RNA stability assays, and a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated-inspired RNA targeting system. METTL7A expression was examined in human coronary arteries with and without atherosclerosis. Atherosclerosis studies were conducted using global and endothelial-specific &lt;i&gt;Mettl7a1&lt;/i&gt; knockout mice. Endothelial METTL7A expression was restored using polymer-based nanoparticles delivering cadherin 5 (CDH5) promoter-driven METTL7A plasmids or VCAM-1 (vascular cell adhesion molecule-1)-targeted lipid nanoparticles delivering N1-methylpseudouridine-modified METTL7A mRNA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Atheroprotective unidirectional flow significantly induced METTL7A expression, which promoted internal m&lt;sup&gt;7&lt;/sup&gt;G methylation of endothelial transcripts without affecting cap-associated m&lt;sup&gt;7&lt;/sup&gt;G. METTL7A preferentially bound AG-enriched motifs in protein-coding mRNAs and increased internal m&lt;sup&gt;7&lt;/sup&gt;G methylation and stability of &lt;i&gt;KLF4&lt;/i&gt; and &lt;i&gt;NFKBIA&lt;/i&gt; transcripts, thereby supporting vascular homeostasis. Endothelial METTL7A expression was significantly reduced by disturbed blood flow and in human atherosclerotic lesions. Global or endothelial-specific loss of &lt;i&gt;Mettl7a1&lt;/i&gt; exacerbated atherosclerosis in mice independent of serum lipid levels. Endothelial restoration of METTL7A through nanoparticle delivery of either a METTL7A plasmid or N1-methylpseudouridine-modified METTL7A mRNA markedly attenuated atherosclerotic lesion formation in &lt;i&gt;Mettl7a1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;/&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; and &lt;i&gt;ApoE&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;/&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt; mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;METTL7A is a mechanosensitive internal m&lt;sup&gt;7&lt;/sup&gt;G methyltransferase that maintains endothelial homeostasis by stabilizing the anti-inflammatory transc","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1221-1237"},"PeriodicalIF":41.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705654","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":"Inhibition of Programmed Cell Death-1 in Cytotoxic CD8⁺ T Cells Exacerbates Pressure Overload-Induced Cardiac Injury.","authors":"Ming-Ming Wu, Yu Sun, Yue Zhang, Yan-Chao Yang, Zhi-Xi He, Shuang Zhou, Xia Wang, Han Xiao, Miao Yu, Chang Miao, Bo-Wen Zhang, Xiao-Long Liu, Jie-Yu Chang, Di Zhu, Zi Hong, Mei Zhang, Hao-Tian Xu, Xin Bi, Song-Qi Han, Jian-Jun Mao, Jing Shi, Chen Liang, Qiu-Shi Wang, Qun Shao, Jun Zhang, Chang-Jiang Yu, Jian-Yu Liu, Xin-Hao Han, Tong Liu, Hai-Xia Liu, Lu-Yang Yu, Hai-Bo Jia, Yong Ji, Zhen-Wei Pan, Yue Li, Zhi-Ren Zhang","doi":"10.1161/CIRCULATIONAHA.125.074024","DOIUrl":"10.1161/CIRCULATIONAHA.125.074024","url":null,"abstract":"<p><strong>Background: </strong>The use of anti-programmed cell death-1 (PD-1) antibody increases heart failure (HF) risk in patients with cancer with preexisting cardiovascular conditions. However, the underlying mechanism remains incompletely understood.</p><p><strong>Methods: </strong>To evaluate the effects of anti-PD-1 antibody on transverse aortic constriction (TAC)-induced cardiac remodeling and HF, anti-PD-1 antibody-treated mice; T cell-, myeloid-, and CD8⁺ T cell-specific <i>Pdcd1</i> knockout; C-X-C motif chemokine receptor 3 (<i>Cxcr3</i>) knockout; and granzyme B (<i>Gzmb</i>) knockout mice combined with flow cytometry, Western blotting, immunofluorescence staining, pharmacological approaches, and bulk RNA-sequencing analyses were used.</p><p><strong>Results: </strong>Administration of anti-PD-1 antibody, T cell-, or CD8⁺ T cell-specific <i>Pdcd1</i> deletion, but not myeloid-specific <i>Pdcd1</i> knockout, aggravated TAC-induced cardiomyopathy and HF in mice. Mechanistically, PD-1 blockade or deletion increased myocardial infiltration of CXCR3⁺ CD8⁺ T cells, leading to granzyme B/perforin-mediated impairment of cardiomyocyte mitochondrial complex I to exacerbate TAC-induced cardiac injury and HF. TAC-enhanced chemotaxis, between cardiac fibroblast-derived CXCL9/CXCL10 and CXCR3⁺ CD8⁺ T cells, was a driving force for recruiting CXCR3⁺ CD8⁺ T cells under the conditions of PD-1 blockade or deletion. The worsened TAC-induced cardiomyopathy caused by anti-PD-1 antibody or T cell-specific <i>Pdcd1</i> deletion was rescued by genetic deletion or pharmacological blockade of granzyme B and CXCR3.</p><p><strong>Conclusions: </strong>Anti-PD-1 antibody enhances myocardial infiltration of CXCR3⁺ CD8⁺ T cells under TAC condition through CXCL9/CXCL10-mediated chemotaxis. The increased granzyme B and perforin likely derived from CD8⁺ T cells impair function of mitochondrial respiratory chain complexes to cause cardiomyocyte apoptosis, thereby exacerbating TAC-induced cardiomyopathy and HF. CXCL9/CXCL10-CXCR3⁺ CD8⁺ T cell axis may represent a promising target for combating anti-PD-1 antibody-associated cardiotoxicity.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1238-1257"},"PeriodicalIF":41.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863770","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":"Identification of Secreted Modular Calcium-Binding Protein 1 as a Novel Endogenous Protective Molecule Against Acute Myocardial Infarction-Induced Cardiac Rupture.","authors":"Wei Gong, Siyi Li, Zekun Zhang, Yan Yan, Hui Ai, Yu Li, Theodore A Christopher, Bernard Lopez, Xinliang Xin Ma, Shaoping Nie","doi":"10.1161/CIRCULATIONAHA.126.079324","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.079324","url":null,"abstract":"<p><strong>Background: </strong>Cardiac rupture is a catastrophic complication of acute myocardial infarction (AMI), with poorly understood molecular mechanisms and no available therapeutic interventions.</p><p><strong>Methods: </strong>Plasma samples were obtained from patients with AMI and animal models, while left ventricular tissue was collected from AMI mice. An unbiased proteomics analysis identified proteins significantly altered in patients with AMI with cardiac rupture. To explore causal relationships and underlying mechanisms, we used loss- and gain-of-function animal models.</p><p><strong>Results: </strong>Proteomics analysis revealed that 9 proteins were significantly upregulated and 24 proteins were significantly downregulated in patients with AMI with cardiac rupture compared with those without. Among these, SMOC-1 (secreted modular calcium-binding protein 1) was the most significantly upregulated protein. Validation in extended patient cohorts and animal models confirmed these findings. A time-course study revealed that SMOC-1 expression was transiently elevated, peaking 1 day after AMI and returning to baseline within a week. Immunological and cell-specific analyses identified cardiomyocytes as the predominant source of SMOC-1 in response to AMI. Surprisingly, cardiomyocyte-specific SMOC-1 knockout doubled the incidence of post-AMI cardiac rupture and reduced survival, while adeno-associated virus serotype 9-mediated SMOC-1 overexpression significantly decreased cardiac rupture rates. Mechanistic studies revealed that cardiomyocyte-derived SMOC-1 supports fibrosis by activating fibroblasts, enhancing collagen synthesis, and promoting collagen maturation, all of which are critical for the formation of reparative scars. SMOC-1 was shown to bind TGF-βR1 (transforming growth factor β receptor 1) in fibroblasts, recruiting EPRS (glutamyl-prolyl-tRNA synthetase) to form a signaling complex that activates the Smad pathway. Inhibiting EPRS abolished the profibrotic effects of SMOC-1.</p><p><strong>Conclusions: </strong>Our study provides the first evidence that the transient upregulation and secretion of cardiomyocyte-derived SMOC-1 constitute an intrinsic profibrotic and antirupture response to severe ischemic injury. However, this natural protective mechanism is insufficient to fully prevent cardiac rupture, highlighting the potential of enhancing the SMOC-1 pathway as a promising therapeutic strategy to mitigate cardiac rupture and reduce AMI-associated mortality.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":41.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073713","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}