Pub Date : 2026-01-01DOI: 10.1016/j.jacbts.2025.101466
Kevin Hill MD, MS
{"title":"Striking the Balance: From Dysregulated Inflammation to Immunoparalysis","authors":"Kevin Hill MD, MS","doi":"10.1016/j.jacbts.2025.101466","DOIUrl":"10.1016/j.jacbts.2025.101466","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"11 1","pages":"Article 101466"},"PeriodicalIF":8.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146052025","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 : 2026-01-01DOI: 10.1016/j.jacbts.2025.101467
Matthias Nahrendorf MD (Editor-in-Chief: JACC: Basic to Translational Science)
{"title":"Recognizing Early Career Translational Investigators","authors":"Matthias Nahrendorf MD (Editor-in-Chief: JACC: Basic to Translational Science)","doi":"10.1016/j.jacbts.2025.101467","DOIUrl":"10.1016/j.jacbts.2025.101467","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"11 1","pages":"Article 101467"},"PeriodicalIF":8.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146051860","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 : 2026-01-01DOI: 10.1016/j.jacbts.2025.101456
Nikolaos G. Frangogiannis MD
From early experimental physiology to modern mouse genetics, animal models have been central to the advancement of biomedical knowledge, enabling mechanistic insights into human disease and driving the development of transformative therapies. Animal model investigations have generated most of the key concepts in modern medicine and established therapeutic breakthroughs, including insulin replacement, renin–angiotensin system inhibition, lipid-lowering strategies, and cancer immunotherapy. Recent enthusiasm for new approach methodologies, such as organoids, microphysiological devices, and computational platforms, has prompted speculation that animal experimentation may be rendered obsolete. However, new approach methodologies remain reductionist and are incapable of reproducing the architectural, cellular, and integrative complexity of living organisms. Although animal studies face challenges related to research rigor, publication bias favoring low-probability findings, and disease heterogeneity, these limitations reflect problems rooted in current research practices rather than fundamental intrinsic flaws of the models. Animal experimentation therefore remains indispensable and irreplaceable for mechanistic discovery and therapeutic innovation.
{"title":"Animal Models in Biomedical Research","authors":"Nikolaos G. Frangogiannis MD","doi":"10.1016/j.jacbts.2025.101456","DOIUrl":"10.1016/j.jacbts.2025.101456","url":null,"abstract":"<div><div>From early experimental physiology to modern mouse genetics, animal models have been central to the advancement of biomedical knowledge, enabling mechanistic insights into human disease and driving the development of transformative therapies. Animal model investigations have generated most of the key concepts in modern medicine and established therapeutic breakthroughs, including insulin replacement, renin–angiotensin system inhibition, lipid-lowering strategies, and cancer immunotherapy. Recent enthusiasm for new approach methodologies, such as organoids, microphysiological devices, and computational platforms, has prompted speculation that animal experimentation may be rendered obsolete. However, new approach methodologies remain reductionist and are incapable of reproducing the architectural, cellular, and integrative complexity of living organisms. Although animal studies face challenges related to research rigor, publication bias favoring low-probability findings, and disease heterogeneity, these limitations reflect problems rooted in current research practices rather than fundamental intrinsic flaws of the models. Animal experimentation therefore remains indispensable and irreplaceable for mechanistic discovery and therapeutic innovation.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"11 1","pages":"Article 101456"},"PeriodicalIF":8.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146051404","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 : 2026-01-01DOI: 10.1016/j.jacbts.2025.101450
Alexis Chenouard MD, PhD , Mélanie Petrier MSc , Constance Bridonneau MD , Estelle André MD , Marion Davieau MSc , Cynthia Fourgeux PhD , Christopher Mancuso PhD , Jesse Davidson MD, MPH , Alexis Broquet PhD , Nicolas Joram MD, PhD , Pierre Bourgoin MD, PhD , Victor Gourain Dr.rer.nat , Jérémie Poschmann PhD , Cédric Jacqueline PhD , Antoine Roquilly MD, PhD
Cardiopulmonary bypass (CPB) induces a complex immune response which can lead to complications after pediatric cardiac surgery. We hypothesized that analyzing the whole blood transcriptomic response after cardiac surgery with or without CPB in children would provide new insights into the pathophysiological mechanisms of CPB-related postoperative complications. In this study focusing on infants ≤3 months of age requiring CPB who are more likely to develop postoperative complications, we defined an immune transcriptomic signature related to CPB. Among the genes included in the CPB signature, we identified only 18 genes that were differentially expressed after surgery in patients with a complicated outcome. In contrast, more than 2,000 genes were differentially expressed before and after the surgery in the uncomplicated group. We demonstrated the predictive potential of the preoperative plasma TNFSF12 abundance to identify patients at risk of CPB-induced complications, which was confirmed in an external cohort.
{"title":"Immune Unresponsiveness to Cardiopulmonary Bypass Is Associated With Unfavorable Outcome in Infants Requiring Cardiac Surgery","authors":"Alexis Chenouard MD, PhD , Mélanie Petrier MSc , Constance Bridonneau MD , Estelle André MD , Marion Davieau MSc , Cynthia Fourgeux PhD , Christopher Mancuso PhD , Jesse Davidson MD, MPH , Alexis Broquet PhD , Nicolas Joram MD, PhD , Pierre Bourgoin MD, PhD , Victor Gourain Dr.rer.nat , Jérémie Poschmann PhD , Cédric Jacqueline PhD , Antoine Roquilly MD, PhD","doi":"10.1016/j.jacbts.2025.101450","DOIUrl":"10.1016/j.jacbts.2025.101450","url":null,"abstract":"<div><div>Cardiopulmonary bypass (CPB) induces a complex immune response which can lead to complications after pediatric cardiac surgery. We hypothesized that analyzing the whole blood transcriptomic response after cardiac surgery with or without CPB in children would provide new insights into the pathophysiological mechanisms of CPB-related postoperative complications. In this study focusing on infants ≤3 months of age requiring CPB who are more likely to develop postoperative complications, we defined an immune transcriptomic signature related to CPB. Among the genes included in the CPB signature, we identified only 18 genes that were differentially expressed after surgery in patients with a complicated outcome. In contrast, more than 2,000 genes were differentially expressed before and after the surgery in the uncomplicated group. We demonstrated the predictive potential of the preoperative plasma TNFSF12 abundance to identify patients at risk of CPB-induced complications, which was confirmed in an external cohort.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"11 1","pages":"Article 101450"},"PeriodicalIF":8.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146051462","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 : 2025-12-19DOI: 10.1016/j.jacbts.2025.101449
Saffie Mohran PhD , Kristina B. Kooiker PhD , Ateeqa Naim BS , Matvey Pilagov BS , Anthony Asencio BS , Kyrah L. Turner BS , Weikang Ma PhD , Galina Flint MD. , Siyao Jiang BS , Jing Zhao BS , Timothy S. McMillen PhD , Christian Mandrycky PhD , Max Mahoney-Schaefer BS , Thomas C. Irving PhD , Bertrand C.W. Tanner PhD , Neil M. Kad PhD , Michael Regnier PhD , Farid Moussavi-Harami MD
We investigated the effects of aficamten on cardiac muscle structure, biochemical activity, and contractile function. Aficamten does not structurally sequester myosin heads along the thick filament. It inhibits ATPase activity by decreasing myosin ATPase cycling kinetics, with the emergence of a super slow biochemical nucleotide turnover. This results in decreased force and calcium sensitivity without altering cross-bridge cycling. Our myofibril mechanical assay showed inhibition of force with accelerated relaxation. In engineered heart tissues, while mavacamten and aficamten inhibit cardiac twitch forces, mavacamten reduces the activation kinetics while both accelerate relaxation.
{"title":"Myosin Modulator Aficamten Inhibits Force by Altering Myosin’s Biochemical Activity Without Changing Thick Filament Structure","authors":"Saffie Mohran PhD , Kristina B. Kooiker PhD , Ateeqa Naim BS , Matvey Pilagov BS , Anthony Asencio BS , Kyrah L. Turner BS , Weikang Ma PhD , Galina Flint MD. , Siyao Jiang BS , Jing Zhao BS , Timothy S. McMillen PhD , Christian Mandrycky PhD , Max Mahoney-Schaefer BS , Thomas C. Irving PhD , Bertrand C.W. Tanner PhD , Neil M. Kad PhD , Michael Regnier PhD , Farid Moussavi-Harami MD","doi":"10.1016/j.jacbts.2025.101449","DOIUrl":"10.1016/j.jacbts.2025.101449","url":null,"abstract":"<div><div>We investigated the effects of aficamten on cardiac muscle structure, biochemical activity, and contractile function. Aficamten does not structurally sequester myosin heads along the thick filament. It inhibits ATPase activity by decreasing myosin ATPase cycling kinetics, with the emergence of a super slow biochemical nucleotide turnover. This results in decreased force and calcium sensitivity without altering cross-bridge cycling. Our myofibril mechanical assay showed inhibition of force with accelerated relaxation. In engineered heart tissues, while mavacamten and aficamten inhibit cardiac twitch forces, mavacamten reduces the activation kinetics while both accelerate relaxation.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"11 1","pages":"Article 101449"},"PeriodicalIF":8.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789023","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 : 2025-12-19DOI: 10.1016/j.jacbts.2025.101435
Rana Hamouche MD , Sean M. Tatum PhD , Elizabeth Dranow PhD , J. Alan Maschek PhD , Christos P. Kyriakopoulos MD , Thirupura S. Shankar PhD , Joseph R. Visker PhD , Jing Ling AS , Konstantinos Sideris MD , Craig H. Selzman MD , Abdallah G. Kfoury MD , Josef Stehlik MD, MPH , Rami Alharethi MD , James C. Fang MD , TingTing Hong MD, PhD , Sutip Navankasattusas PhD , Matthew T. Rondina MD , William L. Holland PhD , Scott A. Summers PhD , Stavros G. Drakos MD, PhD , Eleni Tseliou MD, PhD
Myocardial recovery after left ventricular assist device (LVAD) support is a critical phenomenon that allows advanced heart failure patients to retain their native heart. We quantified targeted sphingolipids in serum and cardiac tissue of patients who exhibited recovery post-LVAD. Our analysis revealed sustained elevated circulating ceramides levels in nonresponders post-LVAD, whereas responders showed reduced sphingosine-1-phosphate (S1P) levels. In contrast, cardiac tissue from nonresponders displayed increased S1P levels. We suggest that diminished ceramide and S1P may contribute to an increased likelihood of recovery after LVAD support. Collectively, our findings implicate the sphingolipid metabolic pathway as a potential therapeutic target to promote myocardial recovery after mechanical support.
{"title":"The Role of Sphingolipids in Myocardial Recovery Mediated by Mechanical Unloading and Circulatory Support","authors":"Rana Hamouche MD , Sean M. Tatum PhD , Elizabeth Dranow PhD , J. Alan Maschek PhD , Christos P. Kyriakopoulos MD , Thirupura S. Shankar PhD , Joseph R. Visker PhD , Jing Ling AS , Konstantinos Sideris MD , Craig H. Selzman MD , Abdallah G. Kfoury MD , Josef Stehlik MD, MPH , Rami Alharethi MD , James C. Fang MD , TingTing Hong MD, PhD , Sutip Navankasattusas PhD , Matthew T. Rondina MD , William L. Holland PhD , Scott A. Summers PhD , Stavros G. Drakos MD, PhD , Eleni Tseliou MD, PhD","doi":"10.1016/j.jacbts.2025.101435","DOIUrl":"10.1016/j.jacbts.2025.101435","url":null,"abstract":"<div><div>Myocardial recovery after left ventricular assist device (LVAD) support is a critical phenomenon that allows advanced heart failure patients to retain their native heart. We quantified targeted sphingolipids in serum and cardiac tissue of patients who exhibited recovery post-LVAD. Our analysis revealed sustained elevated circulating ceramides levels in nonresponders post-LVAD, whereas responders showed reduced sphingosine-1-phosphate (S1P) levels. In contrast, cardiac tissue from nonresponders displayed increased S1P levels. We suggest that diminished ceramide and S1P may contribute to an increased likelihood of recovery after LVAD support. Collectively, our findings implicate the sphingolipid metabolic pathway as a potential therapeutic target to promote myocardial recovery after mechanical support.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"11 1","pages":"Article 101435"},"PeriodicalIF":8.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788487","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 : 2025-12-15DOI: 10.1016/j.jacbts.2025.101433
Libo Wang PhD , Xulei Duan MS , Huibing Liu PhD , Fei Lin PhD , Chaoyuan Zhou MD , Katrin Schröder PhD , Ajay M. Shah MD , Guoan Zhao MD, PhD , Min Zhang MD, PhD
Previous studies have shown that Nox4 activates eIF2α/ATF4 signaling during the integrated stress response (ISR) and protects heart injury. However, their roles in calcific aortic valve disease (CAVD) remain unclear. Here, we show that both ATF4 and Nox4 are up-regulated in porcine aortic valve interstitial cells (AVIC) and in human aortic valves with CAVD. Nox4 knockdown promotes while Nox4 overexpression suppresses CAVD by modulating ISR. Importantly, ISR activators Guanabenz and Sephin1 effectively attenuate AVIC osteoblastic-like differentiation and mitigate CAVD in rabbits and mice, respectively. These findings highlight that pharmacological enhancement of the ISR is a promising therapeutic strategy for CAVD.
{"title":"Pharmacological Enhancement of Integrated Stress Response Confers Protection in Calcific Aortic Valve Disease","authors":"Libo Wang PhD , Xulei Duan MS , Huibing Liu PhD , Fei Lin PhD , Chaoyuan Zhou MD , Katrin Schröder PhD , Ajay M. Shah MD , Guoan Zhao MD, PhD , Min Zhang MD, PhD","doi":"10.1016/j.jacbts.2025.101433","DOIUrl":"10.1016/j.jacbts.2025.101433","url":null,"abstract":"<div><div>Previous studies have shown that Nox4 activates eIF2α/ATF4 signaling during the integrated stress response (ISR) and protects heart injury. However, their roles in calcific aortic valve disease (CAVD) remain unclear. Here, we show that both ATF4 and Nox4 are up-regulated in porcine aortic valve interstitial cells (AVIC) and in human aortic valves with CAVD. Nox4 knockdown promotes while Nox4 overexpression suppresses CAVD by modulating ISR. Importantly, ISR activators Guanabenz and Sephin1 effectively attenuate AVIC osteoblastic-like differentiation and mitigate CAVD in rabbits and mice, respectively. These findings highlight that pharmacological enhancement of the ISR is a promising therapeutic strategy for CAVD.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"11 1","pages":"Article 101433"},"PeriodicalIF":8.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768124","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 : 2025-12-11DOI: 10.1016/j.jacbts.2025.101434
Bob S.L. Lee PhD , Joshua K. Dunn BSc , Cassandra Liang BSc , Grace Chensee BSc , Renhua Song PhD , Cassandra Malecki PhD , Elizabeth N. Robertson MD, PhD , Gavin J. Sutton PhD , Christopher P. Stanley PhD , Brett D. Hambly MD, PhD , Xiangjian Zheng PhD , Paul G. Bannon MD, PhD , Wai Ho Tang PhD , Justin J.-L. Wong PhD , Renjing Liu PhD
Vascular calcification arises from the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and is a hallmark of many cardiovascular pathologies. This study identifies Tet2, a DNA demethylase, as a critical epigenetic regulator that prevents this phenotypic switch. VSMC-specific loss of Tet2 promotes osteogenic differentiation, apoptosis, increased infiltration of Trem2hi macrophages and medial aortic calcification. High-dose ascorbate used to enhance Tet2 activity significantly reduced calcification and preserved aortic structure in mice. These findings support Tet2 reactivation as a potential therapeutic strategy to prevent or reverse vascular calcification in cardiovascular disease.
{"title":"Epigenetic Reprogramming via TET2 Prevents Medial Calcification and Restores Vascular Smooth Muscle Cell Identity","authors":"Bob S.L. Lee PhD , Joshua K. Dunn BSc , Cassandra Liang BSc , Grace Chensee BSc , Renhua Song PhD , Cassandra Malecki PhD , Elizabeth N. Robertson MD, PhD , Gavin J. Sutton PhD , Christopher P. Stanley PhD , Brett D. Hambly MD, PhD , Xiangjian Zheng PhD , Paul G. Bannon MD, PhD , Wai Ho Tang PhD , Justin J.-L. Wong PhD , Renjing Liu PhD","doi":"10.1016/j.jacbts.2025.101434","DOIUrl":"10.1016/j.jacbts.2025.101434","url":null,"abstract":"<div><div>Vascular calcification arises from the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and is a hallmark of many cardiovascular pathologies. This study identifies Tet2, a DNA demethylase, as a critical epigenetic regulator that prevents this phenotypic switch. VSMC-specific loss of Tet2 promotes osteogenic differentiation, apoptosis, increased infiltration of Trem2<sup>hi</sup> macrophages and medial aortic calcification. High-dose ascorbate used to enhance Tet2 activity significantly reduced calcification and preserved aortic structure in mice. These findings support Tet2 reactivation as a potential therapeutic strategy to prevent or reverse vascular calcification in cardiovascular disease.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"11 1","pages":"Article 101434"},"PeriodicalIF":8.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718952","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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