Pub Date : 2025-09-01DOI: 10.1016/j.jacbts.2025.03.014
Daniel Diaz-Gil MD , Gregor Gierlinger MD , Natalia Silva-Gomez Cand Med , Lavinia Rech MD, PhD , Jesus Ortiz-Urbina MD , Kerstin Saraci Cand Med , Sophia Koutsogiannaki PhD , Cordula M. Wolf MD , Rainer G. Kozlik-Feldmann MD , Rudolf Mair MD , Juan M. Melero-Martin PhD , Sitaram M. Emani MD , Guillermo García-Cardeña PhD , Pedro J. del Nido MD , Ingeborg Friehs MD
Endocardial fibroelastosis is a condition caused by the fibrogenic activation of endothelial cells via endothelial-to-mesenchymal transition of the endocardium, which is regulated by the transforming growth factor-β pathway. Atorvastatin, a statin, can protect the vascular endothelium by up-regulating KLF2 and inhibiting the transforming growth factor-β pathway. This study aimed to investigate the effects of atorvastatin on the fibrogenic activation of endothelial cells in the endocardium. The study found that atorvastatin treatment reduced fibrogenic activation of endocardial endothelial cells and increased KLF2 expression in both in vitro and in vivo models of endocardial fibroelastosis–related left ventricular restriction.
{"title":"Preclinical Assessment of Atorvastatin for Treatment of Endocardial Fibroelastosis","authors":"Daniel Diaz-Gil MD , Gregor Gierlinger MD , Natalia Silva-Gomez Cand Med , Lavinia Rech MD, PhD , Jesus Ortiz-Urbina MD , Kerstin Saraci Cand Med , Sophia Koutsogiannaki PhD , Cordula M. Wolf MD , Rainer G. Kozlik-Feldmann MD , Rudolf Mair MD , Juan M. Melero-Martin PhD , Sitaram M. Emani MD , Guillermo García-Cardeña PhD , Pedro J. del Nido MD , Ingeborg Friehs MD","doi":"10.1016/j.jacbts.2025.03.014","DOIUrl":"10.1016/j.jacbts.2025.03.014","url":null,"abstract":"<div><div>Endocardial fibroelastosis is a condition caused by the fibrogenic activation of endothelial cells via endothelial-to-mesenchymal transition of the endocardium, which is regulated by the transforming growth factor-β pathway. Atorvastatin, a statin, can protect the vascular endothelium by up-regulating KLF2 and inhibiting the transforming growth factor-β pathway. This study aimed to investigate the effects of atorvastatin on the fibrogenic activation of endothelial cells in the endocardium. The study found that atorvastatin treatment reduced fibrogenic activation of endocardial endothelial cells and increased KLF2 expression in both in vitro and in vivo models of endocardial fibroelastosis–related left ventricular restriction.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101282"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753422","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 : 2025-09-01DOI: 10.1016/j.jacbts.2025.101376
Michael D. Shapiro DO, MCR
{"title":"T Cells, Triglycerides, and the Immune Roots of Residual Cardiovascular Risk","authors":"Michael D. Shapiro DO, MCR","doi":"10.1016/j.jacbts.2025.101376","DOIUrl":"10.1016/j.jacbts.2025.101376","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101376"},"PeriodicalIF":8.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117572","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 : 2025-08-21DOI: 10.1016/j.jacbts.2025.101359
Nathalie A. Reilly PhD , Janneke W.C.M. Mulder MD , Koen F. Dekkers PhD , Thomas B. Kuipers BSc , Leonie C. van Vark-van der Zee BSc , Monique T. Mulder PhD , Jeanine E. Roeters van Lennep MD, PhD , J. Wouter Jukema MD, PhD , Bastiaan T. Heijmans PhD
Triglycerides and T cells play a key role in atherosclerosis, the leading cause of cardiovascular disease (CVD). Moderately elevated triglycerides have emerged as a causal risk factor, and T cells are a prominent component of atherosclerotic plaques. This cross-sectional study examined transcriptomic differences in T cells among patients with varying triglyceride levels via RNA sequencing. We analyzed CD4+ and CD8+ T cells from 49 participants, including those with primary (genetic) and secondary moderate hypertriglyceridemia, severe hypertriglyceridemia, and hypotriglyceridemia. Patients with primary moderate hypertriglyceridemia exhibited a proinflammatory transcriptomic profile, including increased interleukin-6 receptor (IL6R) expression, which is implicated in CVD risk. Similar patterns appeared in CD8+ T cells and, to a lesser extent, in secondary moderate hypertriglyceridemia patients. Conversely, transcriptomic differences were reversed in hypotriglyceridemia and absent in severe hypertriglyceridemia patients. These findings suggest that elevated triglycerides may contribute to CVD by promoting a proinflammatory transcriptomic profile in T cells.
{"title":"Triglycerides and T Cells in Cardiovascular Risk","authors":"Nathalie A. Reilly PhD , Janneke W.C.M. Mulder MD , Koen F. Dekkers PhD , Thomas B. Kuipers BSc , Leonie C. van Vark-van der Zee BSc , Monique T. Mulder PhD , Jeanine E. Roeters van Lennep MD, PhD , J. Wouter Jukema MD, PhD , Bastiaan T. Heijmans PhD","doi":"10.1016/j.jacbts.2025.101359","DOIUrl":"10.1016/j.jacbts.2025.101359","url":null,"abstract":"<div><div>Triglycerides and T cells play a key role in atherosclerosis, the leading cause of cardiovascular disease (CVD). Moderately elevated triglycerides have emerged as a causal risk factor, and T cells are a prominent component of atherosclerotic plaques. This cross-sectional study examined transcriptomic differences in T cells among patients with varying triglyceride levels via RNA sequencing. We analyzed CD4<sup>+</sup> and CD8<sup>+</sup> T cells from 49 participants, including those with primary (genetic) and secondary moderate hypertriglyceridemia, severe hypertriglyceridemia, and hypotriglyceridemia. Patients with primary moderate hypertriglyceridemia exhibited a proinflammatory transcriptomic profile, including increased interleukin-6 receptor (<em>IL6R</em>) expression, which is implicated in CVD risk. Similar patterns appeared in CD8<sup>+</sup> T cells and, to a lesser extent, in secondary moderate hypertriglyceridemia patients. Conversely, transcriptomic differences were reversed in hypotriglyceridemia and absent in severe hypertriglyceridemia patients. These findings suggest that elevated triglycerides may contribute to CVD by promoting a proinflammatory transcriptomic profile in T cells.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101359"},"PeriodicalIF":8.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144886152","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 : 2025-08-21DOI: 10.1016/j.jacbts.2025.101345
Alex M. Parker MBiomedSc , Jarmon G. Lees PhD , Andrew J. Murray PhD , Anida Velagic PhD , Shiang Y. Lim MPharm, PhD , Miles J. De Blasio PhD , Rebecca H. Ritchie PhD
A substantial component of the increasing global burden of cardiovascular disease is attributed to heart failure (HF), affecting over 64 million adults worldwide. Maladaptive mitochondrial respiratory alterations and oxidative stress are major contributors to HF development and progression, with subsequent downstream myocardial energetic impairment as a strong predictor of mortality. Current conventional therapeutic approaches, including renin-angiotensin-aldosterone system inhibition and β-adrenergic blockade, target neurohormonal aspects of HF and are effective in slowing disease progression. However, although these therapies may be associated with some improvement in myocardial energetics, they do not specifically address alterations in myocardial mitochondrial respiration or redox homeostasis. Targeting mitochondria has hence become a promising approach for more effective and tailored therapies. This review summarizes metabolic derangements that drive HF progression, with a specific focus on mitochondria. Importantly, here we address the essential knowledge gaps in the field, highlighting key translational strategies used to date, and the challenges associated with therapeutically targeting mitochondrial pathways, alongside recent developments seeking to deploy novel mitochondrial-targeted therapeutic approaches to treat HF.
{"title":"Precision Medicine","authors":"Alex M. Parker MBiomedSc , Jarmon G. Lees PhD , Andrew J. Murray PhD , Anida Velagic PhD , Shiang Y. Lim MPharm, PhD , Miles J. De Blasio PhD , Rebecca H. Ritchie PhD","doi":"10.1016/j.jacbts.2025.101345","DOIUrl":"10.1016/j.jacbts.2025.101345","url":null,"abstract":"<div><div>A substantial component of the increasing global burden of cardiovascular disease is attributed to heart failure (HF), affecting over 64 million adults worldwide. Maladaptive mitochondrial respiratory alterations and oxidative stress are major contributors to HF development and progression, with subsequent downstream myocardial energetic impairment as a strong predictor of mortality. Current conventional therapeutic approaches, including renin-angiotensin-aldosterone system inhibition and β-adrenergic blockade, target neurohormonal aspects of HF and are effective in slowing disease progression. However, although these therapies may be associated with some improvement in myocardial energetics, they do not specifically address alterations in myocardial mitochondrial respiration or redox homeostasis. Targeting mitochondria has hence become a promising approach for more effective and tailored therapies. This review summarizes metabolic derangements that drive HF progression, with a specific focus on mitochondria. Importantly, here we address the essential knowledge gaps in the field, highlighting key translational strategies used to date, and the challenges associated with therapeutically targeting mitochondrial pathways, alongside recent developments seeking to deploy novel mitochondrial-targeted therapeutic approaches to treat HF.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101345"},"PeriodicalIF":8.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144880129","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 : 2025-08-20DOI: 10.1016/j.jacbts.2025.101371
Senthil Selvaraj MD, MS, MA , G. Michael Felker MD, MHS
{"title":"Therapeutic Implications of ErbB Pathway Modification in Heart Failure with Reduced Ejection Fraction","authors":"Senthil Selvaraj MD, MS, MA , G. Michael Felker MD, MHS","doi":"10.1016/j.jacbts.2025.101371","DOIUrl":"10.1016/j.jacbts.2025.101371","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101371"},"PeriodicalIF":8.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879347","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 : 2025-08-20DOI: 10.1016/j.jacbts.2025.101327
Avinash B. Khandagale PhD , Padraic Corcoran PhD , Yuzhen Dan PhD , Anders Isaksson PhD , Stefan James MD, PhD , Agneta Siegbahn MD, PhD , Christina Christersson MD, PhD
Extracellular vesicles (EVs) and microRNAs (miRs) have been found to be differently expressed in patients with aortic valve stenosis (AS). Here, we profiled the expression of miRs associated with circulating EVs from severe AS patients and found several altered miRs compared with healthy counterparts. EVs from AS patients induced calcification through expression of the pro-osteogenic genes osteocalcin and osteopontin with corresponding proteins. The expression levels of miR-455-3p and miR-103a-3p were found correlated to the calcification of VICs. Alteration in these miR abrogated osteogenic differentiation of VICs. Additionally, BMP4 and transcriptional factor RUNX2 were found affected by these miRs.
{"title":"Plasma-Derived Extracellular Vesicle-Propagated microRNA From Aortic Stenosis Patients Render Pro-Calcifying Effects on Valve Interstitial Cells","authors":"Avinash B. Khandagale PhD , Padraic Corcoran PhD , Yuzhen Dan PhD , Anders Isaksson PhD , Stefan James MD, PhD , Agneta Siegbahn MD, PhD , Christina Christersson MD, PhD","doi":"10.1016/j.jacbts.2025.101327","DOIUrl":"10.1016/j.jacbts.2025.101327","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) and microRNAs (miRs) have been found to be differently expressed in patients with aortic valve stenosis (AS). Here, we profiled the expression of miRs associated with circulating EVs from severe AS patients and found several altered miRs compared with healthy counterparts. EVs from AS patients induced calcification through expression of the pro-osteogenic genes osteocalcin and osteopontin with corresponding proteins. The expression levels of miR-455-3p and miR-103a-3p were found correlated to the calcification of VICs. Alteration in these miR abrogated osteogenic differentiation of VICs. Additionally, BMP4 and transcriptional factor RUNX2 were found affected by these miRs.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101327"},"PeriodicalIF":8.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863905","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 : 2025-08-15DOI: 10.1016/j.jacbts.2025.101356
Evgeni Efimenko PhD , Hairu Zhao MS , Keith Moskowitz PhD , Conrad Smith MD , Robert Pyo MD , Thomas G. Diacovo MD
This preclinical evaluation of a prohemostatic agent involved patients who received aspirin and clopidogrel before coronary artery stenting, the use of a humanized animal model to assess the hemostatic properties of patient platelets, as well as microfluidic assays to measure platelet reactivity. We demonstrate that our investigational product can bypass the effects of dual antiplatelet therapy (DAPT) by generating thrombin at sites of vascular injury, thereby restoring the hemostatic properties of patient platelets. Importantly, its effects could be reversed upon administration of a thrombin inhibitor. Thus, this product offers a titratable and reversible strategy for the management of defective hemostasis associated with DAPT.
{"title":"Preclinical Efficacy of a Hemostatic Agent in Overcoming Dual Antiplatelet Therapy","authors":"Evgeni Efimenko PhD , Hairu Zhao MS , Keith Moskowitz PhD , Conrad Smith MD , Robert Pyo MD , Thomas G. Diacovo MD","doi":"10.1016/j.jacbts.2025.101356","DOIUrl":"10.1016/j.jacbts.2025.101356","url":null,"abstract":"<div><div>This preclinical evaluation of a prohemostatic agent involved patients who received aspirin and clopidogrel before coronary artery stenting, the use of a humanized animal model to assess the hemostatic properties of patient platelets, as well as microfluidic assays to measure platelet reactivity. We demonstrate that our investigational product can bypass the effects of dual antiplatelet therapy (DAPT) by generating thrombin at sites of vascular injury, thereby restoring the hemostatic properties of patient platelets. Importantly, its effects could be reversed upon administration of a thrombin inhibitor. Thus, this product offers a titratable and reversible strategy for the management of defective hemostasis associated with DAPT.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101356"},"PeriodicalIF":8.4,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851915","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 : 2025-08-15DOI: 10.1016/j.jacbts.2025.101334
Andrew A. Gibb PhD , Kyle LaPenna MD, PhD , Ryan B. Gaspar BS , Nadina R. Latchman BS , Yinfei Tan PhD , Carmen Choya-Foces PhD , Jake E. Doiron PhD , Zhen Li PhD , Huijing Xia PhD , Michael P. Lazaropoulos PhD , Mariell Conwell BS , Thomas E. Sharp III PhD , Traci T. Goodchild PhD , David J. Lefer PhD , John W. Elrod PhD
Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of HF cases. The ZSF1-obese rat model recapitulates clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and diastolic dysfunction. We utilized a systems-biology approach to define the metabolic and transcriptional signatures to gain mechanistic insight into pathways contributing to HFpEF development. Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14 weeks of age for extensive physiological phenotyping and left ventricle (LV) tissue harvesting for unbiased-metabolomics, RNA-sequencing, and mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes driving HFpEF pathology, versus hypertension + metabolic syndrome. Comparison of ZSF1-lean vs WKY (ie, hypertension-exclusive effects) revealed metabolic remodeling suggesting increased aerobic glycolysis, decreased β-oxidation, and dysregulated purine and pyrimidine metabolism with few transcriptional changes. ZSF1-obese rats displayed worsened metabolic remodeling and robust transcriptional remodeling highlighted by upregulation of inflammatory genes and downregulation of the mitochondrial structure/function and metabolic processes. Integrated network analysis of metabolomic and RNAseq datasets revealed downregulation of most catabolic energy producing pathways, manifesting in a marked decrease in the energetic state (ie, reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure analysis revealed decreased mitochondrial area, size, and cristae density, as well as increased lipid droplet content in HFpEF hearts. Impaired mitochondrial function was demonstrated by decreased substrate-mediated respiration and dysregulated calcium handling. Collectively, the integrated omics approach applied here provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial energy metabolism as a potential interventional target.
{"title":"Integrated Systems Biology Identifies Disruptions in Mitochondrial Function and Metabolism as Key Contributors to HFpEF","authors":"Andrew A. Gibb PhD , Kyle LaPenna MD, PhD , Ryan B. Gaspar BS , Nadina R. Latchman BS , Yinfei Tan PhD , Carmen Choya-Foces PhD , Jake E. Doiron PhD , Zhen Li PhD , Huijing Xia PhD , Michael P. Lazaropoulos PhD , Mariell Conwell BS , Thomas E. Sharp III PhD , Traci T. Goodchild PhD , David J. Lefer PhD , John W. Elrod PhD","doi":"10.1016/j.jacbts.2025.101334","DOIUrl":"10.1016/j.jacbts.2025.101334","url":null,"abstract":"<div><div>Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of HF cases. The ZSF1-obese rat model recapitulates clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and diastolic dysfunction. We utilized a systems-biology approach to define the metabolic and transcriptional signatures to gain mechanistic insight into pathways contributing to HFpEF development. Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14 weeks of age for extensive physiological phenotyping and left ventricle (LV) tissue harvesting for unbiased-metabolomics, RNA-sequencing, and mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes driving HFpEF pathology, versus hypertension + metabolic syndrome. Comparison of ZSF1-lean vs WKY (ie, hypertension-exclusive effects) revealed metabolic remodeling suggesting increased aerobic glycolysis, decreased β-oxidation, and dysregulated purine and pyrimidine metabolism with few transcriptional changes. ZSF1-obese rats displayed worsened metabolic remodeling and robust transcriptional remodeling highlighted by upregulation of inflammatory genes and downregulation of the mitochondrial structure/function and metabolic processes. Integrated network analysis of metabolomic and RNAseq datasets revealed downregulation of most catabolic energy producing pathways, manifesting in a marked decrease in the energetic state (ie, reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure analysis revealed decreased mitochondrial area, size, and cristae density, as well as increased lipid droplet content in HFpEF hearts. Impaired mitochondrial function was demonstrated by decreased substrate-mediated respiration and dysregulated calcium handling. Collectively, the integrated omics approach applied here provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial energy metabolism as a potential interventional target.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101334"},"PeriodicalIF":8.4,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851797","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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