Abdel Daoud,Hannah Kalinoski,Monica Vladut Talor,Robin A Welsh,Wonyoung Jo,Camille M Jaime,Bianca Kolim,Neil Mahto,Martin Kveton,Ivana Weislová,Vojtěch Melenovský,Ondřej Fabián,Ashley L Kiemen,Daniela Čiháková
AIMSMyocarditis is an inflammation of the myocardium and is characterized by poor prognosis in symptomatic patients and significant correlation with dilated cardiomyopathy (DCM). We investigated spatial, morphological, immunological, and transcriptomic heterogeneity of myocarditis inflammatory foci in the 3D space.METHODS AND RESULTSUtilizing a novel large tissue histological reconstruction workflow, CODA (not an acronym), we generated whole-heart 3D reconstructions of acute mouse Coxsackievirus B3 (CVB3) myocarditis at the single-cell resolution. Furthermore, we integrated immunohistochemical staining and spatial RNA-sequencing into the CODA workflow. This approach allowed the simultaneous morphological, immunological and transcriptional 3D analysis of acute mouse CVB3 myocarditis. In addition, flow cytometry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses were used to validate our 3D findings. We show that acute mouse CVB3 myocarditis foci are multi-branched, elongated, and found mostly within myocardial regions of the left ventricular wall. We further show that significant T-cell- and macrophage-specific niches exist within the same focus. At the organ level, we show that T-cell-rich foci are more likely to be found anteriorly while macrophage-rich foci are more likely to be found posteriorly. We further demonstrate that T-cell hotspots are well-vascularized spatial niches. Moreover, using spatial transcriptomics and qRT-PCR, we show that T-cell-rich regions of anterior immune foci uniquely upregulate the expression of collagen I and T-cell-specific chemokines. Conversely, surrounding homogeneous foci regions upregulate the expression of broad-target chemokines and T-cell retentive molecules. We show the translatability of our work since 3D immunological heterogeneity mouse results were similar to human DCM explanted hearts with similar immune cell heterogeneity along the sagittal axis.CONCLUSIONOur multimodal findings highlight that acute mouse CVB3 myocarditis exhibits heterogeneous immune phenotype with distinct anterior T-cell hotspots that are well-vascularized and upregulate the expression of T-cell-specific chemokines and collagen I.
{"title":"Whole-heart 3D reconstruction of mouse CVB3 myocarditis reveals spatial and transcriptomic heterogeneity of immune foci.","authors":"Abdel Daoud,Hannah Kalinoski,Monica Vladut Talor,Robin A Welsh,Wonyoung Jo,Camille M Jaime,Bianca Kolim,Neil Mahto,Martin Kveton,Ivana Weislová,Vojtěch Melenovský,Ondřej Fabián,Ashley L Kiemen,Daniela Čiháková","doi":"10.1093/cvr/cvaf209","DOIUrl":"https://doi.org/10.1093/cvr/cvaf209","url":null,"abstract":"AIMSMyocarditis is an inflammation of the myocardium and is characterized by poor prognosis in symptomatic patients and significant correlation with dilated cardiomyopathy (DCM). We investigated spatial, morphological, immunological, and transcriptomic heterogeneity of myocarditis inflammatory foci in the 3D space.METHODS AND RESULTSUtilizing a novel large tissue histological reconstruction workflow, CODA (not an acronym), we generated whole-heart 3D reconstructions of acute mouse Coxsackievirus B3 (CVB3) myocarditis at the single-cell resolution. Furthermore, we integrated immunohistochemical staining and spatial RNA-sequencing into the CODA workflow. This approach allowed the simultaneous morphological, immunological and transcriptional 3D analysis of acute mouse CVB3 myocarditis. In addition, flow cytometry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses were used to validate our 3D findings. We show that acute mouse CVB3 myocarditis foci are multi-branched, elongated, and found mostly within myocardial regions of the left ventricular wall. We further show that significant T-cell- and macrophage-specific niches exist within the same focus. At the organ level, we show that T-cell-rich foci are more likely to be found anteriorly while macrophage-rich foci are more likely to be found posteriorly. We further demonstrate that T-cell hotspots are well-vascularized spatial niches. Moreover, using spatial transcriptomics and qRT-PCR, we show that T-cell-rich regions of anterior immune foci uniquely upregulate the expression of collagen I and T-cell-specific chemokines. Conversely, surrounding homogeneous foci regions upregulate the expression of broad-target chemokines and T-cell retentive molecules. We show the translatability of our work since 3D immunological heterogeneity mouse results were similar to human DCM explanted hearts with similar immune cell heterogeneity along the sagittal axis.CONCLUSIONOur multimodal findings highlight that acute mouse CVB3 myocarditis exhibits heterogeneous immune phenotype with distinct anterior T-cell hotspots that are well-vascularized and upregulate the expression of T-cell-specific chemokines and collagen I.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"27 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765482","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}
Julian Leberzammer, Wesley Tyler Abplanalp, Katharina Grikscheit, Emmanouil G Solomonidis, Simone-Franziska Glaser, Bianca Schuhmacher, Maximilian Merten, Gligorije Jeremijev, Annett Wilken-Schmitz, Lara Korth, David John, Stefan Günther, Carsten Kuenne, Mario Looso, Chanil Valasarajan, Vladimir Benes, Ferris Jung, Vivianne Niehaus, Gabriele Anton, Christoph Stellbrink, Christoph Römmele, Siri Göpel, Soni Savai Pullamsetti, Janne Vehreschild, Maria Vehreschild, Sandra Ciesek, David M Leistner, Andreas M Zeiher, Stefanie Dimmeler, Sebastian Cremer
Aims Patients with cardiovascular disease (CVD) have an increased risk of developing severe respiratory infections, including COVID-19. However, the underlying molecular mechanisms are not completely understood. It has been previously shown that cardiovascular disease predisposes to an altered responsiveness to subsequent inflammatory triggers by an imprinted epigenetic memory in innate immune cells. Therefore, we hypothesized that patients with preexisting atherosclerotic cardiovascular disease (ASCVD) and COVID-19 display a dysregulated inflammatory response compared to patients without ASCVD due to epigenetically altered immune cells leading to increased disease severity. Methods and results Single-cell RNA sequencing revealed a dysregulated myeloid immune response with hyperinflammatory and immunosuppressive features in patients with ASCVD and moderate COVID-19. Assay for Transposase-Accessible Chromatin sequencing and in-vitro experiments with isolated monocytes infected with SARS-CoV-2 showed epigenetic priming of monocytes from patients with ASCVD towards increased expression of inflammatory mediators and type I interferon signalling. In a German nationwide cohort (NAPKON), using multiplex cytokine assays, enzyme-linked immunosorbent assays, and bulk-RNA-sequencing, we confirmed that patients with ASCVD display an exaggerated inflammatory response during moderate COVID-19. Conclusions This study demonstrates that patients with ASCVD show a dysregulated myeloid immune response in moderate COVID-19 disease. Mechanistically, epigenetic imprinting sensitizes myeloid cells of patients with ASCVD to an exaggerated type I interferon-associated immune response. Translational Perspective This study evaluates the underlying molecular mechanisms of worse outcomes of patients with atherosclerotic cardiovascular disease during respiratory infections, specifically COVID-19. Patients with atherosclerotic cardiovascular disease present with a dysregulated hyperinflammatory, type I interferon-driven immune response already during moderate COVID-19. This not only explains a major risk factor for severe COVID-19 but might also enable targeted therapies for this specific risk group.
{"title":"Atherosclerosis licenses for an exceeding immune response in COVID-19 disease by interferon priming in circulating myeloid cells","authors":"Julian Leberzammer, Wesley Tyler Abplanalp, Katharina Grikscheit, Emmanouil G Solomonidis, Simone-Franziska Glaser, Bianca Schuhmacher, Maximilian Merten, Gligorije Jeremijev, Annett Wilken-Schmitz, Lara Korth, David John, Stefan Günther, Carsten Kuenne, Mario Looso, Chanil Valasarajan, Vladimir Benes, Ferris Jung, Vivianne Niehaus, Gabriele Anton, Christoph Stellbrink, Christoph Römmele, Siri Göpel, Soni Savai Pullamsetti, Janne Vehreschild, Maria Vehreschild, Sandra Ciesek, David M Leistner, Andreas M Zeiher, Stefanie Dimmeler, Sebastian Cremer","doi":"10.1093/cvr/cvaf268","DOIUrl":"https://doi.org/10.1093/cvr/cvaf268","url":null,"abstract":"Aims Patients with cardiovascular disease (CVD) have an increased risk of developing severe respiratory infections, including COVID-19. However, the underlying molecular mechanisms are not completely understood. It has been previously shown that cardiovascular disease predisposes to an altered responsiveness to subsequent inflammatory triggers by an imprinted epigenetic memory in innate immune cells. Therefore, we hypothesized that patients with preexisting atherosclerotic cardiovascular disease (ASCVD) and COVID-19 display a dysregulated inflammatory response compared to patients without ASCVD due to epigenetically altered immune cells leading to increased disease severity. Methods and results Single-cell RNA sequencing revealed a dysregulated myeloid immune response with hyperinflammatory and immunosuppressive features in patients with ASCVD and moderate COVID-19. Assay for Transposase-Accessible Chromatin sequencing and in-vitro experiments with isolated monocytes infected with SARS-CoV-2 showed epigenetic priming of monocytes from patients with ASCVD towards increased expression of inflammatory mediators and type I interferon signalling. In a German nationwide cohort (NAPKON), using multiplex cytokine assays, enzyme-linked immunosorbent assays, and bulk-RNA-sequencing, we confirmed that patients with ASCVD display an exaggerated inflammatory response during moderate COVID-19. Conclusions This study demonstrates that patients with ASCVD show a dysregulated myeloid immune response in moderate COVID-19 disease. Mechanistically, epigenetic imprinting sensitizes myeloid cells of patients with ASCVD to an exaggerated type I interferon-associated immune response. Translational Perspective This study evaluates the underlying molecular mechanisms of worse outcomes of patients with atherosclerotic cardiovascular disease during respiratory infections, specifically COVID-19. Patients with atherosclerotic cardiovascular disease present with a dysregulated hyperinflammatory, type I interferon-driven immune response already during moderate COVID-19. This not only explains a major risk factor for severe COVID-19 but might also enable targeted therapies for this specific risk group.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"170 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731056","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":"The SOUL trial: another important study for the reduction of CV risk in individuals with type 2 diabetes.","authors":"Nikolaus Marx","doi":"10.1093/cvr/cvaf216","DOIUrl":"https://doi.org/10.1093/cvr/cvaf216","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"110 1","pages":"2279-2280"},"PeriodicalIF":10.8,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710837","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":"Hypertensive remodelling: when bigger body means bigger problems.","authors":"Eric Lazartigues","doi":"10.1093/cvr/cvaf245","DOIUrl":"10.1093/cvr/cvaf245","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2281-2282"},"PeriodicalIF":13.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12687875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145539196","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}
Rachael E Redgrave, Laura K Booth, Gavin D Richardson
{"title":"From immunosenescence to diastolic dysfunction: tracing the senescence cascade in heart failure with preserved ejection fraction.","authors":"Rachael E Redgrave, Laura K Booth, Gavin D Richardson","doi":"10.1093/cvr/cvaf220","DOIUrl":"10.1093/cvr/cvaf220","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2288-2290"},"PeriodicalIF":13.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12687867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145480870","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}
Elsa D Silva, Inês Tomé, Francisco Vasques-Nóvoa, Glória Conceição, Andreia Silva, António S Barros, Pedro Mendes-Ferreira, Diana Santos-Ribeiro, Alexandre Gonçalves, António Angélico-Gonçalves, Rui Adão, Carolina Caetano, Daniel Sousa, Daniela Miranda-Silva, Rio P Juni, Tamara Tchkonia, James L Kirkland, Francisco Caramelo, Nádia Gonçalves, Vasco Sampaio-Pinto, João S Ribeiro, Reinier A Boon, Adelino Leite-Moreira, Patrícia Pitrez, Perpétua Pinto-do-Ó, Susana G Santos, Inês Falcão-Pires, Lino Ferreira, Diana S Nascimento
Aims: Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure with no effective treatment. While chronic systemic inflammation, triggered by comorbidities, is a critical factor of HFpEF pathophysiology and a relevant target for therapy, mechanisms underlying inflammation remain poorly understood. Here, we aim to understand the upstream mechanisms driving inflammation, including immune dysregulation and cellular senescence.
Methods and results: ZSF1-Obese rats, a cardiometabolic model of HFpEF, were used to investigate systemic and cardiac inflammation, and to characterise the senescent program in immune, circulating endothelial and cardiac cells, before disease onset and onward. Using patient samples, we further evaluated the association between cellular senescence and diagnostic and prognostic markers of HFpEF. Finally, we administered a senolytic - Navitoclax - at two time-points, before and after the appearance of HFpEF.
Conclusion: ZSF1-Obese rats had increased immune and endothelial senescent cells in their peripheral blood and myocardium, together with exacerbated systemic inflammation and endothelial damage, compared to control ZSF1-Lean rats. Moreover, increased circulating senescent leucocytes were associated with markers of disease severity in patients with HFpEF. Senescent cell clearance decreased circulating B-type natriuretic peptide levels and attenuated inflammation, vascular remodelling, and cardiac fibrosis. Additionally, it improved renal function and reduced pulmonary oedema. Our findings suggest that senotherapeutics may improve the treatment for HFpEF by attenuating systemic effects of the disease whilst reducing cardiac fibrosis and endothelial rarefaction.
{"title":"Pharmacological clearance of senescent cells reduces inflammation, endothelial damage and cardiac fibrosis in HFpEF.","authors":"Elsa D Silva, Inês Tomé, Francisco Vasques-Nóvoa, Glória Conceição, Andreia Silva, António S Barros, Pedro Mendes-Ferreira, Diana Santos-Ribeiro, Alexandre Gonçalves, António Angélico-Gonçalves, Rui Adão, Carolina Caetano, Daniel Sousa, Daniela Miranda-Silva, Rio P Juni, Tamara Tchkonia, James L Kirkland, Francisco Caramelo, Nádia Gonçalves, Vasco Sampaio-Pinto, João S Ribeiro, Reinier A Boon, Adelino Leite-Moreira, Patrícia Pitrez, Perpétua Pinto-do-Ó, Susana G Santos, Inês Falcão-Pires, Lino Ferreira, Diana S Nascimento","doi":"10.1093/cvr/cvaf208","DOIUrl":"10.1093/cvr/cvaf208","url":null,"abstract":"<p><strong>Aims: </strong>Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure with no effective treatment. While chronic systemic inflammation, triggered by comorbidities, is a critical factor of HFpEF pathophysiology and a relevant target for therapy, mechanisms underlying inflammation remain poorly understood. Here, we aim to understand the upstream mechanisms driving inflammation, including immune dysregulation and cellular senescence.</p><p><strong>Methods and results: </strong>ZSF1-Obese rats, a cardiometabolic model of HFpEF, were used to investigate systemic and cardiac inflammation, and to characterise the senescent program in immune, circulating endothelial and cardiac cells, before disease onset and onward. Using patient samples, we further evaluated the association between cellular senescence and diagnostic and prognostic markers of HFpEF. Finally, we administered a senolytic - Navitoclax - at two time-points, before and after the appearance of HFpEF.</p><p><strong>Conclusion: </strong>ZSF1-Obese rats had increased immune and endothelial senescent cells in their peripheral blood and myocardium, together with exacerbated systemic inflammation and endothelial damage, compared to control ZSF1-Lean rats. Moreover, increased circulating senescent leucocytes were associated with markers of disease severity in patients with HFpEF. Senescent cell clearance decreased circulating B-type natriuretic peptide levels and attenuated inflammation, vascular remodelling, and cardiac fibrosis. Additionally, it improved renal function and reduced pulmonary oedema. Our findings suggest that senotherapeutics may improve the treatment for HFpEF by attenuating systemic effects of the disease whilst reducing cardiac fibrosis and endothelial rarefaction.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2385-2403"},"PeriodicalIF":13.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12687878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653665","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}
Veronika Ramovs,H Sophia Chen,Athina Patra,Rayman Tjokrodirijo,Peter van Veelen,Aat A Mulder,Roman I Koning,Lauran Stöger,Catalina Hubner,Rodrigo Ibañez-Arenas,Bernardo Morales Catalan,Pilar Morandé,Rosario dell'Oro,Cristian Poblete,Andrés Schuster,María Joao Yubero,Francis Palisson,Cristina Has,Monique Jongbloed,Ignacia Fuentes,Christine L Mummery,Karine Raymond
AIMSA striking aspect of epidermolysis bullosa patients with a mutation in KLHL24 (KLHL24mut) is their life-threatening deterioration of heart function. KLHL24 is a component of the ubiquitin-proteasome system and acts as a substrate-specific adaptor protein for E3 ubiquitin ligase. KLHL24mut is thought to represent a gain-of-function mutation, with associated cardiac and skin pathologies arising from the excessive degradation of its target proteins. Although reduced desmin levels in cardiomyocytes (CMs) have already been documented, the potential involvement of additional mechanisms in KLHL24mut -driven heart pathology remains unexplored.METHODS AND RESULTSWe report on two patients with KLHL24mut who recently manifested heart failure. To gain insights into their physiopathology, we integrated clinical data with proteomic analyses of heart tissue as well as human induced pluripotent stem cell (hiPSC) models carrying KLHL24mut. Mass spectrometry analysis of CMs differentiated from patient-derived hiPSCs mirrored the proteomic profile of their corresponding left ventricle tissue samples. KLHL24mut resulted in a reduction of several intermediate filaments (IF), mitochondrial and muscle fibre proteins as well as the emergence of an early fibrotic signature. By utilising various hiPSC-derived cardiac models along with flow cytometry, immunofluorescence, and western blot analyses, we confirmed that the excessive proteasomal activity of endogenous KLHL24mut caused a decrease in levels of desmin, synemin and vimentin, IF proteins of CMs and cardiac fibroblasts. Moreover, KLHL24mut led to mitochondrial mislocalization and increased mitophagy, reduced PKA activity, and sarcomere shortening in CMs.CONCLUSIONThe deterioration of heart function in patients with KLHL24mut is driven by excessive proteasome-dependent degradation of multiple IF proteins across various cardiac cell types. Monotypic hiPSC-derived CMs and end-stage patient-derived cardiac explants from patients exhibit similar features, uncovering early pathological mechanisms and identifying a list of potential novel KLHL24mut target proteins. Finally, our findings validate that hiPSC-derived CMs represent a relevant model for future studies.
{"title":"KLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients.","authors":"Veronika Ramovs,H Sophia Chen,Athina Patra,Rayman Tjokrodirijo,Peter van Veelen,Aat A Mulder,Roman I Koning,Lauran Stöger,Catalina Hubner,Rodrigo Ibañez-Arenas,Bernardo Morales Catalan,Pilar Morandé,Rosario dell'Oro,Cristian Poblete,Andrés Schuster,María Joao Yubero,Francis Palisson,Cristina Has,Monique Jongbloed,Ignacia Fuentes,Christine L Mummery,Karine Raymond","doi":"10.1093/cvr/cvaf231","DOIUrl":"https://doi.org/10.1093/cvr/cvaf231","url":null,"abstract":"AIMSA striking aspect of epidermolysis bullosa patients with a mutation in KLHL24 (KLHL24mut) is their life-threatening deterioration of heart function. KLHL24 is a component of the ubiquitin-proteasome system and acts as a substrate-specific adaptor protein for E3 ubiquitin ligase. KLHL24mut is thought to represent a gain-of-function mutation, with associated cardiac and skin pathologies arising from the excessive degradation of its target proteins. Although reduced desmin levels in cardiomyocytes (CMs) have already been documented, the potential involvement of additional mechanisms in KLHL24mut -driven heart pathology remains unexplored.METHODS AND RESULTSWe report on two patients with KLHL24mut who recently manifested heart failure. To gain insights into their physiopathology, we integrated clinical data with proteomic analyses of heart tissue as well as human induced pluripotent stem cell (hiPSC) models carrying KLHL24mut. Mass spectrometry analysis of CMs differentiated from patient-derived hiPSCs mirrored the proteomic profile of their corresponding left ventricle tissue samples. KLHL24mut resulted in a reduction of several intermediate filaments (IF), mitochondrial and muscle fibre proteins as well as the emergence of an early fibrotic signature. By utilising various hiPSC-derived cardiac models along with flow cytometry, immunofluorescence, and western blot analyses, we confirmed that the excessive proteasomal activity of endogenous KLHL24mut caused a decrease in levels of desmin, synemin and vimentin, IF proteins of CMs and cardiac fibroblasts. Moreover, KLHL24mut led to mitochondrial mislocalization and increased mitophagy, reduced PKA activity, and sarcomere shortening in CMs.CONCLUSIONThe deterioration of heart function in patients with KLHL24mut is driven by excessive proteasome-dependent degradation of multiple IF proteins across various cardiac cell types. Monotypic hiPSC-derived CMs and end-stage patient-derived cardiac explants from patients exhibit similar features, uncovering early pathological mechanisms and identifying a list of potential novel KLHL24mut target proteins. Finally, our findings validate that hiPSC-derived CMs represent a relevant model for future studies.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"37 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680589","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}
Aims Pericardial drainage fluid (PCF) offers a non-invasive and direct window to detect surgery-induced microenvironmental changes implicated in postoperative atrial fibrillation (POAF) onset. We hypothesized that cardiac surgery elicits release of extracellular vesicles (EVs) in PCF, serving as a conduit transmitting proarrhythmic and profibrotic miRNAs and contributing to atrial remodeling and POAF. Methods and Results We investigated the role of PCF-EVs derived miRNAs in POAF in prospective, multicenter discovery and validation cohorts and spontaneous POAF (sPOAF) mouse model. PCF-EVs from POAF patients elicited marked atrial collagen deposition and a higher incidence of sPOAF in mice compared to non-POAF controls. Strikingly, EV blockage in sPOAF mouse model provided complete sPOAF protection (50% vs 0). A distinct profibrotic miRNA signature was identified in PCF-EVs from POAF patients. Among these, miR-4324, a previously unreported murine miRNA, emerged as a potent inducer of AF, triggered sPOAF in 83% of treated mice, and demonstrating excellent predictive accuracy (AUC=0.921) in a clinical validation cohort. Visualization of miR-4324 trajectory using miRNAscope demonstrated that miR-4324-containing EVs, originating from the surgically-damaged left ventricle, rapidly transported to thin-walled atria via PCF, where miR-4324 activated TGF-β1/Smad3 signaling by targeting SKP1. This facilitated collagen deposition and a proarrhythmic atrial substrate. In contrast, miR-4324 inhibition blocked these effects. Conclusion These findings uncover a previously unrecognized high-speed PCF-EVs pathway that propagates proarrhythmic miR-4324 signals from surgical sites to reshape the atrial microenvironment into a proarrhythmic milieu via SKP1-TGF-β1/Smad3 axis. PCF, typically discarded, could be repurposed for POAF prophylaxis.
{"title":"miR-4324-containing extracellular vesicles released in pericardial drainage fluid facilitate postoperative atrial fibrillation","authors":"Yisi Liu, Pan Shen, Gaofu Li, Taiwei Wang, Chaoyue Gao, Yue Sun, Yongqiang Zhou, Lin Luo, Jiamiao Li, Xinyu Wang, Jiangang Wang, Chen Bai, Shu Ding, Ying Wu, Yue Gao, Wei Zhou","doi":"10.1093/cvr/cvaf239","DOIUrl":"https://doi.org/10.1093/cvr/cvaf239","url":null,"abstract":"Aims Pericardial drainage fluid (PCF) offers a non-invasive and direct window to detect surgery-induced microenvironmental changes implicated in postoperative atrial fibrillation (POAF) onset. We hypothesized that cardiac surgery elicits release of extracellular vesicles (EVs) in PCF, serving as a conduit transmitting proarrhythmic and profibrotic miRNAs and contributing to atrial remodeling and POAF. Methods and Results We investigated the role of PCF-EVs derived miRNAs in POAF in prospective, multicenter discovery and validation cohorts and spontaneous POAF (sPOAF) mouse model. PCF-EVs from POAF patients elicited marked atrial collagen deposition and a higher incidence of sPOAF in mice compared to non-POAF controls. Strikingly, EV blockage in sPOAF mouse model provided complete sPOAF protection (50% vs 0). A distinct profibrotic miRNA signature was identified in PCF-EVs from POAF patients. Among these, miR-4324, a previously unreported murine miRNA, emerged as a potent inducer of AF, triggered sPOAF in 83% of treated mice, and demonstrating excellent predictive accuracy (AUC=0.921) in a clinical validation cohort. Visualization of miR-4324 trajectory using miRNAscope demonstrated that miR-4324-containing EVs, originating from the surgically-damaged left ventricle, rapidly transported to thin-walled atria via PCF, where miR-4324 activated TGF-β1/Smad3 signaling by targeting SKP1. This facilitated collagen deposition and a proarrhythmic atrial substrate. In contrast, miR-4324 inhibition blocked these effects. Conclusion These findings uncover a previously unrecognized high-speed PCF-EVs pathway that propagates proarrhythmic miR-4324 signals from surgical sites to reshape the atrial microenvironment into a proarrhythmic milieu via SKP1-TGF-β1/Smad3 axis. PCF, typically discarded, could be repurposed for POAF prophylaxis.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"1 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680153","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":"Graft versus atheroma in a battle of host dominion.","authors":"Anton Gisterå,Hannes Lindahl","doi":"10.1093/cvr/cvaf266","DOIUrl":"https://doi.org/10.1093/cvr/cvaf266","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"128 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664182","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}
Netra Nambiar Veetil,Tara Gransar,Shao-Fei Liu,Ahed Almalla,Marieluise Kirchner,Robyn Brackin-Helmers,Felix Hennig,Ruhi Yeter,Marie Weinhart,Philipp Mertins,Volkmar Falk,Robert Szulcek,Mariya M Kucherenko,Wolfgang M Kuebler,Christoph Knosalla
AIMSHyperplasia of pulmonary arterial smooth muscle cells (SMCs) contributes to the progression of pulmonary hypertension (PH), yet the underlying pathomechanism of this process in PH secondary to left heart disease (PH-LHD) is poorly understood. We aimed to investigate the role of the endothelial extracellular matrix (ECM), specifically the pulmonary arterial basement membrane (BM), in influencing SMC proliferation and phenotypic changes in PH-LHD.METHODS AND RESULTSSMC hyperplasia and endothelial ECM remodelling were characterized histologically on human pulmonary arterial samples, and by mass spectrometry, and atomic force microscopy on decellularized ECM (dECM) produced in vitro by endothelial cells isolated from pulmonary arteries (PA) of LHD patients without pulmonary hypertension (LHD w/o PH), PH-LHD patients, or healthy-heart controls. Proliferation and migration rates of SMC cultured on endothelial dECM were assessed by Ki67 immunostaining and by wound-healing assay, respectively. The role of mechanosensitive YAP1 in SMC hyperplasia was addressed in human cells and in an aortic-banding rat model of PH-LHD by analysing YAP1 activation and the effect of YAP1 inhibition. PA of LHD w/o PH and PH-LHD patients showed extensive remodelling of the BM. This was confirmed in vitro as altered composition and stiffening of dECM generated by respective patient endothelial cells. ECM remodelling was associated with SMC accumulation in the pulmonary arterial intima in patient samples and promoted SMC migration and proliferation in vitro. Conversely, dECM generated by healthy human endothelial cells reduced the hypermigration and hyperproliferation of SMC from LHD w/o PH and PH-LHD patients. Remodelling of the endothelial ECM in LHD w/o PH and PH-LHD patients also activated YAP1 in SMC, inhibition of which reduced SMC migration and proliferation in vitro. These findings were reproduced in vivo in a rat model of PH-LHD induced by aortic-banding.CONCLUSIONHere, we report endothelial ECM remodelling as a key mechanism driving SMC hyperplasia in PH-LHD. Notably, endothelial ECM remodelling is evident in both patients with LHD w/o PH and those with PH-LHD, raising the possibility that it may reflect an early event in LHD-induced pulmonary vascular remodelling. This ECM remodelling is associated with YAP1 in adjacent SMC, promoting their migration and proliferation and contributing to SMC hyperplasia. Consequently, targeting ECM remodelling and YAP1 activation may offer promising therapeutic strategies for preventing of PA remodelling in PH-LHD.
{"title":"Remodelling of the endothelial extracellular matrix promotes smooth muscle cell hyperplasia in pulmonary hypertension due to left heart disease.","authors":"Netra Nambiar Veetil,Tara Gransar,Shao-Fei Liu,Ahed Almalla,Marieluise Kirchner,Robyn Brackin-Helmers,Felix Hennig,Ruhi Yeter,Marie Weinhart,Philipp Mertins,Volkmar Falk,Robert Szulcek,Mariya M Kucherenko,Wolfgang M Kuebler,Christoph Knosalla","doi":"10.1093/cvr/cvaf238","DOIUrl":"https://doi.org/10.1093/cvr/cvaf238","url":null,"abstract":"AIMSHyperplasia of pulmonary arterial smooth muscle cells (SMCs) contributes to the progression of pulmonary hypertension (PH), yet the underlying pathomechanism of this process in PH secondary to left heart disease (PH-LHD) is poorly understood. We aimed to investigate the role of the endothelial extracellular matrix (ECM), specifically the pulmonary arterial basement membrane (BM), in influencing SMC proliferation and phenotypic changes in PH-LHD.METHODS AND RESULTSSMC hyperplasia and endothelial ECM remodelling were characterized histologically on human pulmonary arterial samples, and by mass spectrometry, and atomic force microscopy on decellularized ECM (dECM) produced in vitro by endothelial cells isolated from pulmonary arteries (PA) of LHD patients without pulmonary hypertension (LHD w/o PH), PH-LHD patients, or healthy-heart controls. Proliferation and migration rates of SMC cultured on endothelial dECM were assessed by Ki67 immunostaining and by wound-healing assay, respectively. The role of mechanosensitive YAP1 in SMC hyperplasia was addressed in human cells and in an aortic-banding rat model of PH-LHD by analysing YAP1 activation and the effect of YAP1 inhibition. PA of LHD w/o PH and PH-LHD patients showed extensive remodelling of the BM. This was confirmed in vitro as altered composition and stiffening of dECM generated by respective patient endothelial cells. ECM remodelling was associated with SMC accumulation in the pulmonary arterial intima in patient samples and promoted SMC migration and proliferation in vitro. Conversely, dECM generated by healthy human endothelial cells reduced the hypermigration and hyperproliferation of SMC from LHD w/o PH and PH-LHD patients. Remodelling of the endothelial ECM in LHD w/o PH and PH-LHD patients also activated YAP1 in SMC, inhibition of which reduced SMC migration and proliferation in vitro. These findings were reproduced in vivo in a rat model of PH-LHD induced by aortic-banding.CONCLUSIONHere, we report endothelial ECM remodelling as a key mechanism driving SMC hyperplasia in PH-LHD. Notably, endothelial ECM remodelling is evident in both patients with LHD w/o PH and those with PH-LHD, raising the possibility that it may reflect an early event in LHD-induced pulmonary vascular remodelling. This ECM remodelling is associated with YAP1 in adjacent SMC, promoting their migration and proliferation and contributing to SMC hyperplasia. Consequently, targeting ECM remodelling and YAP1 activation may offer promising therapeutic strategies for preventing of PA remodelling in PH-LHD.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"198200 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664089","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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