Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.02.021
María Valero-Muñoz PhD, Eng Leng Saw PhD, Hannah Cooper BA, David R. Pimentel MD, Flora Sam MD
Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction (HFpEF). Increased adiposity is implicated in its pathophysiology. We investigated changes in white adipose tissue (WAT) in obesity-associated HFpEF utilizing patient samples and a murine model of obesity-associated HFpEF. WAT analysis revealed "browning", characterized by smaller adipocytes and increased UCP1 expression, alongside fibrosis and reduced vascular markers during acute HF decompensation. During chronic, stable HFpEF, “browning” markers declined. There is a dynamic process in WAT, where acute HF exacerbations trigger transient “browning”, fibrosis, and vascular deterioration, which partially reverse but fibrosis persists. WAT dysfunction worsens during acute HF, highlighting a potential therapeutic target for obesity-related HFpEF.
{"title":"White Adipose Tissue in Obesity-Associated HFpEF","authors":"María Valero-Muñoz PhD, Eng Leng Saw PhD, Hannah Cooper BA, David R. Pimentel MD, Flora Sam MD","doi":"10.1016/j.jacbts.2025.02.021","DOIUrl":"10.1016/j.jacbts.2025.02.021","url":null,"abstract":"<div><div>Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction (HFpEF). Increased adiposity is implicated in its pathophysiology. We investigated changes in white adipose tissue (WAT) in obesity-associated HFpEF utilizing patient samples and a murine model of obesity-associated HFpEF. WAT analysis revealed \"browning\", characterized by smaller adipocytes and increased UCP1 expression, alongside fibrosis and reduced vascular markers during acute HF decompensation. During chronic, stable HFpEF, “browning” markers declined. There is a dynamic process in WAT, where acute HF exacerbations trigger transient “browning”, fibrosis, and vascular deterioration, which partially reverse but fibrosis persists. WAT dysfunction worsens during acute HF, highlighting a potential therapeutic target for obesity-related HFpEF.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101262"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019452","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}
Chronic low-grade inflammation and nitric oxide (NO) depletion are important contributors to heart failure with preserved ejection fraction (HFpEF) pathophysiology. Periodontitis (PD) is a common inflammatory disease implicated in dysregulation of NO hemostasis. Epidemiological studies have shown an association between PD and increased risk of cardiovascular disease, including heart failure. However, a causative relationship between the 2 diseases has not yet been proven. In this study, we sought to investigate the direct effect of PD induction on HFpEF progression in a mouse model. Induction of PD in HFpEF mice resulted in significant oral microbial dysbiosis, accelerated progression of diastolic dysfunction by echocardiography, and increased myocardial inflammation and fibrosis. These deleterious effects seen with PD were shown to be mediated by increased systemic blood pressure, increased systemic inflammation, and NO depletion. Our study provides evidence of potential mechanistic links between PD and HFpEF progression and suggests PD as a new therapeutic target for HFpEF.
{"title":"Periodontitis Accelerates Progression of Heart Failure With Preserved Ejection Fraction in Mice","authors":"Samar Daana MSc , Yair Rokach PhD , Suzan Abedat PhD , Dean Nachman MD , Hadeya Mohsen BSc , Sama Karram DMD, MSc , Yael Zandberg DMD , Rinat Tzach-Nachman DMD, PhD , Jonathan Cohen MD, PhD , Offer Amir MD , Yael Houri-Haddad DMD, PhD , Rabea Asleh MD, PhD, MHA","doi":"10.1016/j.jacbts.2025.03.002","DOIUrl":"10.1016/j.jacbts.2025.03.002","url":null,"abstract":"<div><div>Chronic low-grade inflammation and nitric oxide (NO) depletion are important contributors to heart failure with preserved ejection fraction (HFpEF) pathophysiology. Periodontitis (PD) is a common inflammatory disease implicated in dysregulation of NO hemostasis. Epidemiological studies have shown an association between PD and increased risk of cardiovascular disease, including heart failure. However, a causative relationship between the 2 diseases has not yet been proven. In this study, we sought to investigate the direct effect of PD induction on HFpEF progression in a mouse model. Induction of PD in HFpEF mice resulted in significant oral microbial dysbiosis, accelerated progression of diastolic dysfunction by echocardiography, and increased myocardial inflammation and fibrosis. These deleterious effects seen with PD were shown to be mediated by increased systemic blood pressure, increased systemic inflammation, and NO depletion. Our study provides evidence of potential mechanistic links between PD and HFpEF progression and suggests PD as a new therapeutic target for HFpEF.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101270"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274902","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.02.015
Ao Liu MD, PhD , Peiyuan Bai MD, PhD , Hongmin You MD , Zehao Zhuang MD , Fangyan Tian MD, PhD , Haobo Weng MD, PhD , Xuemei Wei MD , Lu Tang MD , Litao Wang MD, PhD , Chaobao Liu MD , Jinghong Zhang MD , Minmin Sun MD, PhD , Shuning Zhang MD, PhD , Xianhong Shu MD, PhD , Junbo Ge MD, PhD
Doxorubicin-induced cardiotoxicity (DIC) poses a significant challenge in cancer treatment. This study investigated the role of SLAMF7 in DIC, particularly in macrophage-mediated inflammation. Using SLAMF7 knockout mice, we found that SLAMF7 deficiency exacerbates DIC and amplifies inflammatory responses. Mechanistically, SLAMF7 interacts with TNF receptor-associated factor 6 to attenuate nuclear factor κB signaling, reducing oxidative stress and proinflammatory cytokines. Notably, administering recombinant SLAMF7 protein effectively mitigated DIC. These findings underscore the critical role of SLAMF7 in protecting against DIC, positioning it as a promising therapeutic target.
{"title":"SLAMF7 Restrains Pro-Inflammatory Macrophage Activation to Counteract Doxorubicin-Induced Cardiotoxicity","authors":"Ao Liu MD, PhD , Peiyuan Bai MD, PhD , Hongmin You MD , Zehao Zhuang MD , Fangyan Tian MD, PhD , Haobo Weng MD, PhD , Xuemei Wei MD , Lu Tang MD , Litao Wang MD, PhD , Chaobao Liu MD , Jinghong Zhang MD , Minmin Sun MD, PhD , Shuning Zhang MD, PhD , Xianhong Shu MD, PhD , Junbo Ge MD, PhD","doi":"10.1016/j.jacbts.2025.02.015","DOIUrl":"10.1016/j.jacbts.2025.02.015","url":null,"abstract":"<div><div>Doxorubicin-induced cardiotoxicity (DIC) poses a significant challenge in cancer treatment. This study investigated the role of SLAMF7 in DIC, particularly in macrophage-mediated inflammation. Using SLAMF7 knockout mice, we found that SLAMF7 deficiency exacerbates DIC and amplifies inflammatory responses. Mechanistically, SLAMF7 interacts with TNF receptor-associated factor 6 to attenuate nuclear factor κB signaling, reducing oxidative stress and proinflammatory cytokines. Notably, administering recombinant SLAMF7 protein effectively mitigated DIC. These findings underscore the critical role of SLAMF7 in protecting against DIC, positioning it as a promising therapeutic target.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101256"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078027","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.03.015
Xing Luo PhD , Ji Li PhD , Yuwu Chen MD , Xiuzhu Weng MD , Xiaoyi Bao PhD , Xiaoxuan Bai MD , Ying Lv PhD , Shan Zhang PhD , Xinxin Zhu MD , Biyi Xu MD , Chen Zhao MD , Ming Zeng MD , Tianyu Wu MD , Qianhui Sun MD , Shengfang Wang PhD , Minghao Liu MD , Thomas Johnson PhD , Stephen J. White PhD , Peter Libby MD , Sining Hu PhD , Haibo Jia PhD
Smoking is the only cardiovascular risk factor for plaque erosion. We found cigarette tar resulted in erosion-like lesion development in apolipoprotein E−/− mice, with mural thrombosis, discontinuous endothelium, platelet activation, smooth muscle cell proliferation, and hyaluronic acid accumulation in the aorta. Single-cell transcriptomics revealed that genes relating to pyroptosis, platelet activation, and leukocytes adhesion were significantly increased in an endothelial cell subset. Rescue assays indicated cigarette tar caused human coronary artery endothelial cell pyroptosis by enhanced calcium–calmodulin-dependent protein kinase II / dynamin-related protein 1–mediated mitochondrial fission and mitochondrial DNA release via activating Ca2+ signaling. Inhibition of endothelial cell pyroptosis may be a novel therapeutic strategy to reduce plaque erosion.
{"title":"Cigarette Tar Enhanced ECs Pyroptosis via CAMKII/Drp1/mtDNA","authors":"Xing Luo PhD , Ji Li PhD , Yuwu Chen MD , Xiuzhu Weng MD , Xiaoyi Bao PhD , Xiaoxuan Bai MD , Ying Lv PhD , Shan Zhang PhD , Xinxin Zhu MD , Biyi Xu MD , Chen Zhao MD , Ming Zeng MD , Tianyu Wu MD , Qianhui Sun MD , Shengfang Wang PhD , Minghao Liu MD , Thomas Johnson PhD , Stephen J. White PhD , Peter Libby MD , Sining Hu PhD , Haibo Jia PhD","doi":"10.1016/j.jacbts.2025.03.015","DOIUrl":"10.1016/j.jacbts.2025.03.015","url":null,"abstract":"<div><div>Smoking is the only cardiovascular risk factor for plaque erosion. We found cigarette tar resulted in erosion-like lesion development in apolipoprotein E<sup>−/−</sup> mice, with mural thrombosis, discontinuous endothelium, platelet activation, smooth muscle cell proliferation, and hyaluronic acid accumulation in the aorta. Single-cell transcriptomics revealed that genes relating to pyroptosis, platelet activation, and leukocytes adhesion were significantly increased in an endothelial cell subset. Rescue assays indicated cigarette tar caused human coronary artery endothelial cell pyroptosis by enhanced calcium–calmodulin-dependent protein kinase II / dynamin-related protein 1–mediated mitochondrial fission and mitochondrial DNA release via activating Ca<sup>2+</sup> signaling. Inhibition of endothelial cell pyroptosis may be a novel therapeutic strategy to reduce plaque erosion.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101283"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896128","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.03.013
Nipun Malhotra MSc , Omer Cavus MD , Michael J. Wallace BS , John T. Bobik BS , Kevin You , Sarah S. Takenaka BS , Danielle Abdallah BS , Eleanor J. Mohler , Steve Antwi-Boasiako BS , Nathaniel P. Murphy MD, PhD , Holly Sucharski-Argall PhD , Xianyao Xu MSc , Stephen P. Chelko PhD , Thomas J. Hund PhD , Jason D. Roberts MD, MAS , Peter J. Mohler PhD , Mona El Refaey PhD
Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease, and current pharmacological therapies are directed toward the management of electrical manifestations. To date, none address the underlying pathophysiology of this progressive condition. We evaluated the therapeutic efficacy of Tideglusib (TD) in Ank2 cardio-selective-knockout and homozygous desmoglein-2 mutant ACM mouse models. TD was able to prevent and reverse the reduced cardiac function in treated mice. Moreover, TD-treated adult mice displayed a reduction in ventricular arrhythmia following adrenergic stimulation. We provide compelling preclinical data for TD as a potential therapy for patients with ACM.
{"title":"Evaluation of Tideglusib as a Disease Modifying Therapy in Murine Models of Arrhythmogenic Cardiomyopathy","authors":"Nipun Malhotra MSc , Omer Cavus MD , Michael J. Wallace BS , John T. Bobik BS , Kevin You , Sarah S. Takenaka BS , Danielle Abdallah BS , Eleanor J. Mohler , Steve Antwi-Boasiako BS , Nathaniel P. Murphy MD, PhD , Holly Sucharski-Argall PhD , Xianyao Xu MSc , Stephen P. Chelko PhD , Thomas J. Hund PhD , Jason D. Roberts MD, MAS , Peter J. Mohler PhD , Mona El Refaey PhD","doi":"10.1016/j.jacbts.2025.03.013","DOIUrl":"10.1016/j.jacbts.2025.03.013","url":null,"abstract":"<div><div>Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease, and current pharmacological therapies are directed toward the management of electrical manifestations. To date, none address the underlying pathophysiology of this progressive condition. We evaluated the therapeutic efficacy of Tideglusib (TD) in Ank2 cardio-selective-knockout and homozygous desmoglein-2 mutant ACM mouse models. TD was able to prevent and reverse the reduced cardiac function in treated mice. Moreover, TD-treated adult mice displayed a reduction in ventricular arrhythmia following adrenergic stimulation. We provide compelling preclinical data for TD as a potential therapy for patients with ACM.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101281"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896068","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.04.017
Yi Ye PhD, Veli K. Topkara MD, MSc
{"title":"Exploring Mechanisms of Pulmonary Artery Banding in a Rat Model of Dilated Cardiomyopathy","authors":"Yi Ye PhD, Veli K. Topkara MD, MSc","doi":"10.1016/j.jacbts.2025.04.017","DOIUrl":"10.1016/j.jacbts.2025.04.017","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101303"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896123","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.101361
Alessio Alogna MD, PhD
{"title":"Closing the Loop on Right Ventricular Mechanics","authors":"Alessio Alogna MD, PhD","doi":"10.1016/j.jacbts.2025.101361","DOIUrl":"10.1016/j.jacbts.2025.101361","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101361"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896125","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.101321
Man Liu PhD, Hong Liu MD, PhD, Gyeoung-Jin Kang PhD, Lynn M. Hartweck PhD, Feng Feng BS, Eunji Kim PhD, Kurt W. Prins MD, PhD, Samuel C. Dudley Jr. MD, PhD
Hypomagnesemia (HypoMg) and subsequent oxidative stress cause diabetic cardiac diastolic dysfunction and heart failure with preserved ejection fraction. A Mg2+ transporter with channel and kinase function, transient receptor potential cation channel subfamily M 7 (TRPM7), is upregulated in HypoMg. Diabetes mellitus mice had HypoMg and elevated TRPM7 expression in the heart. TRPM7 kinase mediated mitochondrial dysfunction and cardiac diastolic dysfunction in HypoMg. TRPM7 kinase enhanced mitochondrial Fgr expression, with subsequent complex II dysfunction and mitochondrial reactive oxygen species overproduction. Inhibition of TRPM7 kinase represents a potential novel therapeutic strategy to treat diabetic heart failure with preserved ejection fraction.
{"title":"Cardiac TRPM7 Causes Diabetic Heart Failure With Preserved Ejection Fraction","authors":"Man Liu PhD, Hong Liu MD, PhD, Gyeoung-Jin Kang PhD, Lynn M. Hartweck PhD, Feng Feng BS, Eunji Kim PhD, Kurt W. Prins MD, PhD, Samuel C. Dudley Jr. MD, PhD","doi":"10.1016/j.jacbts.2025.101321","DOIUrl":"10.1016/j.jacbts.2025.101321","url":null,"abstract":"<div><div>Hypomagnesemia (HypoMg) and subsequent oxidative stress cause diabetic cardiac diastolic dysfunction and heart failure with preserved ejection fraction. A Mg<sup>2+</sup> transporter with channel and kinase function, transient receptor potential cation channel subfamily M 7 (TRPM7), is upregulated in HypoMg. Diabetes mellitus mice had HypoMg and elevated TRPM7 expression in the heart. TRPM7 kinase mediated mitochondrial dysfunction and cardiac diastolic dysfunction in HypoMg. TRPM7 kinase enhanced mitochondrial Fgr expression, with subsequent complex II dysfunction and mitochondrial reactive oxygen species overproduction. Inhibition of TRPM7 kinase represents a potential novel therapeutic strategy to treat diabetic heart failure with preserved ejection fraction.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101321"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896124","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.101360
Matthias Nahrendorf MD, PhD (Editor-in-Chief, JACC: Basic to Translational Science)
{"title":"Unleashing the Power of the Beehive to Begin a New Era for JACC: Basic to Translational Science","authors":"Matthias Nahrendorf MD, PhD (Editor-in-Chief, JACC: Basic to Translational Science)","doi":"10.1016/j.jacbts.2025.101360","DOIUrl":"10.1016/j.jacbts.2025.101360","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101360"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896131","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}
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