{"title":"Elucidating the mechanisms of atrial fibrillation recurrence: opportunities and challenges for longitudinal digital twins.","authors":"Jordi Heijman","doi":"10.1093/cvr/cvag027","DOIUrl":"https://doi.org/10.1093/cvr/cvag027","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131242","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}
Qi Pan, Cheng Chen, Ce Zhang, Yao Jiang, Ziqin Zhou, Han Zhang, Thomas G Gillette, Joseph A Hill, Gabriele G Schiattarella, Guixin Wu, Yuejin Yang, Guihao Chen
Aims: Although growing evidence suggests that obesity/central adiposity predispose to development and exacerbation of heart failure with preserved ejection fraction (HFpEF), it remains to be clarified whether there is a causal relationship between adiposity and HFpEF pathogenesis.
Methods and results: HFpEF was induced in male, C57BL/6N mice using high-fat diet + Nω-nitro-l-arginine methyl ester. Resection or transplantation of visceral adipose tissue (VAT) blunted or exacerbated HFpEF phenotypes, respectively, the in mice. VAT from HFpEF mice displayed greater weight and secreted more small extracellular vesicles (sEVs) than those from chow-fed mice. Either systemic inhibition of sEV secretion or VAT-specific knockdown of Rab27b (an indispensable GTPase for sEV secretion) protected against HFpEF. Discovery-driven experiments identified miR-295-3p within sEVs as a possible mediator of the VAT-heart axis, which impaired cardiac autophagy by binding to Ulk1 mRNA. MiR-295-3p antagomir treatment mitigated HFpEF phenotypes. Additionally, neonatal mouse cardiomyocytes (NMCMs) manifested blunted autophagic flux after treatment with plasma sEVs from HFpEF mice. Notably, HFpEF patients displayed downregulated cardiac Ulk1 and autophagy compared with healthy individuals. Restoration of cardiac autophagy with rapamycin or ULK1 overexpression via AAV-9 attenuated the HFpEF phenotype in mice.
Conclusions: The present work unveils a mechanism whereby obesity promotes HFpEF progression, emphasizing the role of VAT-heart crosstalk. Specifically, VAT-derived sEVs, miR-295-3p, and the resultant disruption of cardiac autophagy contribute significantly to the pathogenesis of HFpEF.
目的：尽管越来越多的证据表明，肥胖/中心性肥胖易导致保留射血分数（HFpEF）心力衰竭的发展和加重，但肥胖与HFpEF发病机制之间是否存在因果关系仍有待明确。方法和结果：采用高脂饲料+ n ω-硝基精氨酸甲酯诱导雄性C57BL/6N小鼠HFpEF。在小鼠中，切除或移植内脏脂肪组织（VAT）分别使HFpEF表型变钝或加剧。HFpEF小鼠的VAT比普通小鼠重，分泌更多的小细胞外囊泡（sev）。无论是系统性抑制sEV分泌，还是vat特异性敲低Rab27b (sEV分泌中不可或缺的GTPase)，都可以预防HFpEF。发现驱动的实验发现，sev内的miR-295-3p可能是VAT-heart轴的介质，它通过与Ulk1 mRNA结合而损害心脏自噬。MiR-295-3p拮抗剂治疗可减轻HFpEF表型。此外，用HFpEF小鼠血浆sev处理后，新生小鼠心肌细胞（nmcm）表现出钝化的自噬通量。值得注意的是，与健康个体相比，HFpEF患者表现出下调的心脏Ulk1和自噬。通过AAV-9通过雷帕霉素或ULK1过表达恢复心脏自噬，可减弱小鼠HFpEF表型。结论：目前的研究揭示了肥胖促进HFpEF进展的机制，强调了VAT-heart串扰的作用。具体来说，vat衍生的sev、miR-295-3p以及由此导致的心脏自噬的破坏对HFpEF的发病机制有重要作用。
{"title":"Small extracellular vesicle-mediated adipocyte-cardiomyocyte crosstalk exacerbates heart failure with preserved ejection fraction.","authors":"Qi Pan, Cheng Chen, Ce Zhang, Yao Jiang, Ziqin Zhou, Han Zhang, Thomas G Gillette, Joseph A Hill, Gabriele G Schiattarella, Guixin Wu, Yuejin Yang, Guihao Chen","doi":"10.1093/cvr/cvag030","DOIUrl":"https://doi.org/10.1093/cvr/cvag030","url":null,"abstract":"<p><strong>Aims: </strong>Although growing evidence suggests that obesity/central adiposity predispose to development and exacerbation of heart failure with preserved ejection fraction (HFpEF), it remains to be clarified whether there is a causal relationship between adiposity and HFpEF pathogenesis.</p><p><strong>Methods and results: </strong>HFpEF was induced in male, C57BL/6N mice using high-fat diet + Nω-nitro-l-arginine methyl ester. Resection or transplantation of visceral adipose tissue (VAT) blunted or exacerbated HFpEF phenotypes, respectively, the in mice. VAT from HFpEF mice displayed greater weight and secreted more small extracellular vesicles (sEVs) than those from chow-fed mice. Either systemic inhibition of sEV secretion or VAT-specific knockdown of Rab27b (an indispensable GTPase for sEV secretion) protected against HFpEF. Discovery-driven experiments identified miR-295-3p within sEVs as a possible mediator of the VAT-heart axis, which impaired cardiac autophagy by binding to Ulk1 mRNA. MiR-295-3p antagomir treatment mitigated HFpEF phenotypes. Additionally, neonatal mouse cardiomyocytes (NMCMs) manifested blunted autophagic flux after treatment with plasma sEVs from HFpEF mice. Notably, HFpEF patients displayed downregulated cardiac Ulk1 and autophagy compared with healthy individuals. Restoration of cardiac autophagy with rapamycin or ULK1 overexpression via AAV-9 attenuated the HFpEF phenotype in mice.</p><p><strong>Conclusions: </strong>The present work unveils a mechanism whereby obesity promotes HFpEF progression, emphasizing the role of VAT-heart crosstalk. Specifically, VAT-derived sEVs, miR-295-3p, and the resultant disruption of cardiac autophagy contribute significantly to the pathogenesis of HFpEF.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123926","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":"Telomer length, integrity vs. telomerase-activity - who is to blame for heart failure?","authors":"Petra Kleinbongard, Andreas M Beyer","doi":"10.1093/cvr/cvag026","DOIUrl":"https://doi.org/10.1093/cvr/cvag026","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112209","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}
Philipp Hegner, Maria J Baier, Thomas Krammer, Simon Seitz, Anna-Katharina Käs, Tilman Zschiedrich, David Lukas, Vanessa Lutz, Matthias Wolf, Frederick Sinha, Simon Schopka, Christof Schmid, Kostiantyn Kozakov, Zdenek Provaznik, Lars S Maier, Julian Mustroph, Stefan Wagner
{"title":"Semaglutide improves contractile function in human atrial myocardium of patients with heart failure and preserved ejection fraction.","authors":"Philipp Hegner, Maria J Baier, Thomas Krammer, Simon Seitz, Anna-Katharina Käs, Tilman Zschiedrich, David Lukas, Vanessa Lutz, Matthias Wolf, Frederick Sinha, Simon Schopka, Christof Schmid, Kostiantyn Kozakov, Zdenek Provaznik, Lars S Maier, Julian Mustroph, Stefan Wagner","doi":"10.1093/cvr/cvag039","DOIUrl":"https://doi.org/10.1093/cvr/cvag039","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112219","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}
Konstantinos I Karampinos,Dimitrios Farmakis,Rijan Gurung,Roger S-Y Foo,Gerasimos S Filippatos,Dennis V Cokkinos
Ferroptosis is the form of regulated cell death driven by iron-induced lipid peroxidation, implicated in different cardiovascular diseases and especially heart failure. It is an abundant form of regulated cell death in the myocardium of many heart failure animal models, including the chronic ischemic, pressure overload, diabetic, septic, obesity-related and doxorubicin-induced cardiomyopathy models. Across these models, disordered iron handling, antioxidant failure, enzymatic phospholipid peroxidation, and mitochondrial stress converge on ferroptosis, leading to contractile dysfunction and adverse remodelling. Although definitive causality between ferroptosis and heart failure has not yet been established, emerging evidence suggests that ferroptosis contributes to heart failure progression, supported by multi-layer rescue with classic inhibitors (ferrostatin-1, liproxstatin-1, iron chelators) and by cardiometabolic drugs with clinical efficacy in heart failure (Sodium-Glucose Cotransporter 2 inhibitors, sacubitril/valsartan, finerenone, levosimendan, nicorandil) as well as polyphenols, which restore systolic and/or diastolic indices and reverse remodelling. Early human evidence aligns, showing that human failing myocardial and epicardial adipose tissue exhibit ferroptosis-specific transcriptional and lipidomic signatures, while circulating biomarkers and tissue profiles of patients receiving SGLT2 inhibitors indicate reduced ferroptosis activity. In this review, through critical synthesis of existing evidence, we analyse current literature, discuss translational barriers and propose a new conceptual mechanistic framework - "the ferroptosis nexus" - wherein iron mobilization, antioxidant collapse, lipid priming, and mitochondrial/calcium amplifiers form a self-reinforcing loop culminating in pump failure. Standardized ferroptosis signatures, single cell and spatial transcriptomics analysis, and mechanism-driven clinical trials are needed to identify responsive heart failure phenotypes and translate ferroptosis modulation into precision cardioprotection.
{"title":"Ferroptosis in heart failure: from molecular insights to therapeutic implications.","authors":"Konstantinos I Karampinos,Dimitrios Farmakis,Rijan Gurung,Roger S-Y Foo,Gerasimos S Filippatos,Dennis V Cokkinos","doi":"10.1093/cvr/cvag019","DOIUrl":"https://doi.org/10.1093/cvr/cvag019","url":null,"abstract":"Ferroptosis is the form of regulated cell death driven by iron-induced lipid peroxidation, implicated in different cardiovascular diseases and especially heart failure. It is an abundant form of regulated cell death in the myocardium of many heart failure animal models, including the chronic ischemic, pressure overload, diabetic, septic, obesity-related and doxorubicin-induced cardiomyopathy models. Across these models, disordered iron handling, antioxidant failure, enzymatic phospholipid peroxidation, and mitochondrial stress converge on ferroptosis, leading to contractile dysfunction and adverse remodelling. Although definitive causality between ferroptosis and heart failure has not yet been established, emerging evidence suggests that ferroptosis contributes to heart failure progression, supported by multi-layer rescue with classic inhibitors (ferrostatin-1, liproxstatin-1, iron chelators) and by cardiometabolic drugs with clinical efficacy in heart failure (Sodium-Glucose Cotransporter 2 inhibitors, sacubitril/valsartan, finerenone, levosimendan, nicorandil) as well as polyphenols, which restore systolic and/or diastolic indices and reverse remodelling. Early human evidence aligns, showing that human failing myocardial and epicardial adipose tissue exhibit ferroptosis-specific transcriptional and lipidomic signatures, while circulating biomarkers and tissue profiles of patients receiving SGLT2 inhibitors indicate reduced ferroptosis activity. In this review, through critical synthesis of existing evidence, we analyse current literature, discuss translational barriers and propose a new conceptual mechanistic framework - \"the ferroptosis nexus\" - wherein iron mobilization, antioxidant collapse, lipid priming, and mitochondrial/calcium amplifiers form a self-reinforcing loop culminating in pump failure. Standardized ferroptosis signatures, single cell and spatial transcriptomics analysis, and mechanism-driven clinical trials are needed to identify responsive heart failure phenotypes and translate ferroptosis modulation into precision cardioprotection.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"8 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089066","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}
AIMSCCAAT-enhancer-binding protein (C/EBP) β is a member of the basic leucine zipper transcription factor family that regulates cell differentiation, proliferation, cell death and survival, and inflammation. Although C/EBPβ plays both protective and detrimental roles in the heart at baseline and during stress, the cell type-specific functions of C/EBPβ in the heart are unknown. Here, we investigated the role of endogenous C/EBPβ in cardiomyocytes during pressure overload-induced heart failure.METHODS AND RESULTSWe found that C/EBPβ expression was reduced in wild-type (WT) mouse heart homogenates after 4 weeks of transverse aortic constriction (TAC). To elucidate the role of endogenous C/EBPβ during cardiac stress in vivo, we generated cardiomyocyte-specific Cebpb knockout (Cebpb-cKO) mice. Cebpb-cKO mice were born at a normal Mendelian ratio but displayed slightly decreased cardiac function under baseline conditions, starting at 3 months of age. Notably, in contrast to a previous report using systemic heterozygous Cebpb-knockout mice, which exhibited cardiac protection against TAC, Cebpb-cKO mice showed significantly exacerbated systolic dysfunction, cardiac hypertrophy, and fibrosis after 4 weeks of TAC. Cebpb-cKO mice also exhibited decreased expression of antioxidant genes, including Mnsod and Catalase, both at baseline and under TAC conditions. On the other hand, rescue of the C/EBPβ level in cardiomyocytes using AAV9-cTnT-Cebpb alleviated the left ventricular (LV) dysfunction in response to TAC.CONCLUSIONSOur findings suggest that C/EBPβ has a cell-type specific role in the heart and that endogenous C/EBPβ in cardiomyocytes plays a salutary role during pressure overload.
{"title":"Cardiomyocyte-specific deficiency of C/EBPβ aggravates pressure overload-induced heart failure.","authors":"Jihoon Nah,Eun-Ah Sung,Peiyong Zhai,Yasuhiro Maejima,Chengchen Hu,Jacqueline Ramos-Zepeda,Shohei Ikeda,Wataru Mizushima,Junichi Sadoshima","doi":"10.1093/cvr/cvag029","DOIUrl":"https://doi.org/10.1093/cvr/cvag029","url":null,"abstract":"AIMSCCAAT-enhancer-binding protein (C/EBP) β is a member of the basic leucine zipper transcription factor family that regulates cell differentiation, proliferation, cell death and survival, and inflammation. Although C/EBPβ plays both protective and detrimental roles in the heart at baseline and during stress, the cell type-specific functions of C/EBPβ in the heart are unknown. Here, we investigated the role of endogenous C/EBPβ in cardiomyocytes during pressure overload-induced heart failure.METHODS AND RESULTSWe found that C/EBPβ expression was reduced in wild-type (WT) mouse heart homogenates after 4 weeks of transverse aortic constriction (TAC). To elucidate the role of endogenous C/EBPβ during cardiac stress in vivo, we generated cardiomyocyte-specific Cebpb knockout (Cebpb-cKO) mice. Cebpb-cKO mice were born at a normal Mendelian ratio but displayed slightly decreased cardiac function under baseline conditions, starting at 3 months of age. Notably, in contrast to a previous report using systemic heterozygous Cebpb-knockout mice, which exhibited cardiac protection against TAC, Cebpb-cKO mice showed significantly exacerbated systolic dysfunction, cardiac hypertrophy, and fibrosis after 4 weeks of TAC. Cebpb-cKO mice also exhibited decreased expression of antioxidant genes, including Mnsod and Catalase, both at baseline and under TAC conditions. On the other hand, rescue of the C/EBPβ level in cardiomyocytes using AAV9-cTnT-Cebpb alleviated the left ventricular (LV) dysfunction in response to TAC.CONCLUSIONSOur findings suggest that C/EBPβ has a cell-type specific role in the heart and that endogenous C/EBPβ in cardiomyocytes plays a salutary role during pressure overload.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"43 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089069","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}
Kamila Krol,Piotr Szczepaniak,Tomasz P Mikolajczyk
{"title":"ChemR23 signalling as a potential therapeutic target in atherosclerosis and cardiovascular diseases.","authors":"Kamila Krol,Piotr Szczepaniak,Tomasz P Mikolajczyk","doi":"10.1093/cvr/cvag037","DOIUrl":"https://doi.org/10.1093/cvr/cvag037","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"37 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073045","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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