Pub Date : 2025-11-12DOI: 10.1016/j.jacbts.2025.101411
Wahid Abu-Amer MD , Khaled Shorbaji MBBS , Rodrigo Meade BA , Sophia R. Pyeatte MD , Larisa Belaygorod MD , Mohamed S. Zaghloul MD , Shahab Hafezi MBBS , Louai Alrata MBBS , Amanda Penrose BA , Batool Arif MS , Stephen G. Wu PhD , Clay F. Semenkovich MD , Mohamed A. Zayed MD, PhD, MBA
There are currently no reliable serum biomarkers to aid in the diagnosis of peripheral artery disease (PAD). We hypothesized that circulating fatty acid synthase (cFAS) can be an independent diagnostic biomarker for PAD. Serum cFAS and demographics were compared for patients with and without PAD or chronic limb threatening ischemia (CLTI). Patients with PAD or CLTI had significantly higher serum cFAS content. We observed optimal cutoffs for cFAS in distinguishing between individuals with and without PAD or CLTI. Our study demonstrates that cFAS is an independent serum-based diagnostic biomarker for PAD, can distinguish between patients with PAD vs CLTI, and may predict disease severity.
{"title":"Serum cFAS Content Correlates With Incidence of Peripheral Arterial Disease","authors":"Wahid Abu-Amer MD , Khaled Shorbaji MBBS , Rodrigo Meade BA , Sophia R. Pyeatte MD , Larisa Belaygorod MD , Mohamed S. Zaghloul MD , Shahab Hafezi MBBS , Louai Alrata MBBS , Amanda Penrose BA , Batool Arif MS , Stephen G. Wu PhD , Clay F. Semenkovich MD , Mohamed A. Zayed MD, PhD, MBA","doi":"10.1016/j.jacbts.2025.101411","DOIUrl":"10.1016/j.jacbts.2025.101411","url":null,"abstract":"<div><div>There are currently no reliable serum biomarkers to aid in the diagnosis of peripheral artery disease (PAD). We hypothesized that circulating fatty acid synthase (cFAS) can be an independent diagnostic biomarker for PAD. Serum cFAS and demographics were compared for patients with and without PAD or chronic limb threatening ischemia (CLTI). Patients with PAD or CLTI had significantly higher serum cFAS content. We observed optimal cutoffs for cFAS in distinguishing between individuals with and without PAD or CLTI. Our study demonstrates that cFAS is an independent serum-based diagnostic biomarker for PAD, can distinguish between patients with PAD vs CLTI, and may predict disease severity.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 12","pages":"Article 101411"},"PeriodicalIF":8.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493113","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 : 2025-11-01DOI: 10.1016/j.jacbts.2025.101410
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.2025.101410","DOIUrl":"10.1016/j.jacbts.2025.101410","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 11","pages":"Article 101410"},"PeriodicalIF":8.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619978","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 : 2025-11-01DOI: 10.1016/j.jacbts.2025.101407
Douglas G. Tilley PhD , Jop H. van Berlo MD, PhD
{"title":"CD14 Blockade, A Next-Generation, Anti-Inflammatory Biological for Post-MI Remodeling","authors":"Douglas G. Tilley PhD , Jop H. van Berlo MD, PhD","doi":"10.1016/j.jacbts.2025.101407","DOIUrl":"10.1016/j.jacbts.2025.101407","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 11","pages":"Article 101407"},"PeriodicalIF":8.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619974","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 : 2025-11-01DOI: 10.1016/j.jacbts.2025.101364
Simon D. Brown PhD , Anna L. Malinowska PhD , Matthew Bennett PhD , Andrés F. Correa-Sánchez MSc , Laia Linda Horcasitas Valencia BSc (Hons) , Aimee P. Lucignoli MSc , Anna K. Barton MD , Laura Clark MD , Judith C. Sluimer PhD , Scott P. Webster PhD , Julie Rodor PhD , David E. Newby MD, PhD , Mark Cunningham BSc (Hons) , Andrew H. Baker PhD
Coronary artery bypass graft (CABG) surgery remains the gold standard of care to prevent myocardial ischemia in patients with advanced atherosclerosis; however, poor long-term graft patency remains a considerable and long-standing problem. Excessive vascular smooth muscle cell (SMC) proliferation in the grafted tissue is recognized as central to late CABG failure. We previously identified SMILR, a human-specific SMC-enriched long noncoding RNA that drives SMC proliferation, suggesting that targeting SMILR expression could be a novel way to prevent neointima formation, and thus CABG failure. Here, we sought to identify a lead siRNA for clinical development. We describe the design and synthesis of a library of 76 chemically enhanced SMILR-targeting siRNA. From this library, we identify a lead siRNA, BHF7, which demonstrates potent and reproducible silencing of SMILR expression, and which robustly blocks vascular smooth muscle cell proliferation, both in vitro and in the ex vivo human saphenous vein model. We further demonstrate using RNA-sequencing that BHF7 down-regulates the expression of genes associated with proliferation and does not induce the expression of interferon or apoptosis genes, suggesting it has a favorable safety profile, both on- and off-target. Finally, we performed TUNEL staining on BHF7-treated tissues and measured the levels of cleaved caspase-3 by enzyme-linked immunosorbent assay after BHF7 treatment. This demonstrated that BHF7 does not induce a cytotoxic response either in vitro or ex vivo. Collectively, these data represent a preclinical package into the function and specificity of BHF7 which warrants further investigation into the possibility of utilizing BHF7 as a novel, ex vivo RNA therapeutic for the prevention of CABG failure in humans.
{"title":"Small Interfering RNA Therapy Targeting the Long Noncoding RNA SMILR for Therapeutic Intervention in Coronary Artery Bypass Graft Failure","authors":"Simon D. Brown PhD , Anna L. Malinowska PhD , Matthew Bennett PhD , Andrés F. Correa-Sánchez MSc , Laia Linda Horcasitas Valencia BSc (Hons) , Aimee P. Lucignoli MSc , Anna K. Barton MD , Laura Clark MD , Judith C. Sluimer PhD , Scott P. Webster PhD , Julie Rodor PhD , David E. Newby MD, PhD , Mark Cunningham BSc (Hons) , Andrew H. Baker PhD","doi":"10.1016/j.jacbts.2025.101364","DOIUrl":"10.1016/j.jacbts.2025.101364","url":null,"abstract":"<div><div>Coronary artery bypass graft (CABG) surgery remains the gold standard of care to prevent myocardial ischemia in patients with advanced atherosclerosis; however, poor long-term graft patency remains a considerable and long-standing problem. Excessive vascular smooth muscle cell (SMC) proliferation in the grafted tissue is recognized as central to late CABG failure. We previously identified SMILR, a human-specific SMC-enriched long noncoding RNA that drives SMC proliferation, suggesting that targeting SMILR expression could be a novel way to prevent neointima formation, and thus CABG failure. Here, we sought to identify a lead siRNA for clinical development. We describe the design and synthesis of a library of 76 chemically enhanced SMILR-targeting siRNA. From this library, we identify a lead siRNA, BHF7, which demonstrates potent and reproducible silencing of <em>SMILR</em> expression, and which robustly blocks vascular smooth muscle cell proliferation, both in vitro and in the ex vivo human saphenous vein model. We further demonstrate using RNA-sequencing that BHF7 down-regulates the expression of genes associated with proliferation and does not induce the expression of interferon or apoptosis genes, suggesting it has a favorable safety profile, both on- and off-target. Finally, we performed TUNEL staining on BHF7-treated tissues and measured the levels of cleaved caspase-3 by enzyme-linked immunosorbent assay after BHF7 treatment. This demonstrated that BHF7 does not induce a cytotoxic response either in vitro or ex vivo. Collectively, these data represent a preclinical package into the function and specificity of BHF7 which warrants further investigation into the possibility of utilizing BHF7 as a novel, ex vivo RNA therapeutic for the prevention of CABG failure in humans.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 11","pages":"Article 101364"},"PeriodicalIF":8.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029808","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 : 2025-11-01DOI: 10.1016/j.jacbts.2025.101390
Tselmen Daria MD, PhD , Kruthika Iyer PhD , Hasan Alkhairo MS , Pik Fang Kho PhD , Ken Suzuki MD, PhD , Konstantinos Hatzikotoulas PhD , Lorraine Southam BSc , Henry J. Taylor BSc , Xianyong Yin MD , Ravi Mandla BA , Alicia Huerta-Chagoya PhD , William N. Rayner PhD , Michael G. Levin MD , Scott M. Damrauer MD , Philip S. Tsao PhD , James R. Priest MD , Derek Klarin MD , James Pirruccello MD , Justin B. Echouffo Tcheugui MD, PhD , Catherine Tcheandjieu DVM, PhD
We investigate the relationship between glycemic traits—specifically type 2 diabetes mellitus, fasting glucose, fasting insulin, glycated hemoglobin, and 2-hour post-load glucose—and thoracic aortic morphology and diseases. The results indicate an inverse association between elevated glycemic traits and aortic morphology, as well as a reduced risk of thoracic aortic aneurysm. Genetic predictors related to beta-cell proinsulin mechanisms in type 2 diabetes mellitus drive these associations. Key genes such as AGER, GLRX, TCF7L2, and GCK are implicated, highlighting their potential as therapeutic targets for the prevention and treatment of thoracic aortic aneurysm, given their role in glycemic control medication.
{"title":"Mendelian Randomization Suggests a Causal Link Between Glycemic Traits and Thoracic Aortic Structures and Diseases","authors":"Tselmen Daria MD, PhD , Kruthika Iyer PhD , Hasan Alkhairo MS , Pik Fang Kho PhD , Ken Suzuki MD, PhD , Konstantinos Hatzikotoulas PhD , Lorraine Southam BSc , Henry J. Taylor BSc , Xianyong Yin MD , Ravi Mandla BA , Alicia Huerta-Chagoya PhD , William N. Rayner PhD , Michael G. Levin MD , Scott M. Damrauer MD , Philip S. Tsao PhD , James R. Priest MD , Derek Klarin MD , James Pirruccello MD , Justin B. Echouffo Tcheugui MD, PhD , Catherine Tcheandjieu DVM, PhD","doi":"10.1016/j.jacbts.2025.101390","DOIUrl":"10.1016/j.jacbts.2025.101390","url":null,"abstract":"<div><div>We investigate the relationship between glycemic traits—specifically type 2 diabetes mellitus, fasting glucose, fasting insulin, glycated hemoglobin, and 2-hour post-load glucose—and thoracic aortic morphology and diseases. The results indicate an inverse association between elevated glycemic traits and aortic morphology, as well as a reduced risk of thoracic aortic aneurysm. Genetic predictors related to beta-cell proinsulin mechanisms in type 2 diabetes mellitus drive these associations. Key genes such as <em>AGER, GLRX, TCF7L2,</em> and <em>GCK</em> are implicated, highlighting their potential as therapeutic targets for the prevention and treatment of thoracic aortic aneurysm, given their role in glycemic control medication.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 11","pages":"Article 101390"},"PeriodicalIF":8.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421781","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 : 2025-11-01DOI: 10.1016/j.jacbts.2025.101393
Aascha A. D’Elia (nee Brown) PhD , Helen Kiriazis PhD , Jason Bloom MD , Jonathan Noonan PhD , Ian Hsu PhD , Gabriella E. Farrugia PhD , Haoyun Fang PhD , Stephanie Jansen BVetSc , Natalia Carvajal PhD , Crisdion Krstevski PhD , Waled A. Shihata PhD , Yow Keat Tham PhD , Angela Vais PhD , Camilla Cohen PhD , Adam C. Parslow PhD , Chad Johnson PhD , Anita C. Thomas PhD , Malathi S.I. Dona PhD , Kyah Grigolon BVetSc , Scott J.Y. Loh BSc (Hons) , Daniel G. Donner PhD
These preclinical trials provide the first evidence of cluster of differentiation 14 (CD14) blockade with a murine analogue of atibuclimab, a CD14-neutralizing antibody, preventing secondary immunological exacerbation of cardiac injury in a translational mouse model of reperfused ST-segment elevation myocardial infarction (STEMI), assessed using multiple clinical modalities. Multiomic studies suggest CD14 blockade downregulated macrophage-specific proinflammatory and tissue-wide remodeling processes without suppression of monocyte-macrophage infiltration or repair. These findings support a clinically practicable targeted immunomodulatory strategy of CD14 blockade initiated at reperfusion to prevent chronic immunological progression toward ischemic heart failure, and provide new insights into the pleiotropic roles of CD14 in inflammation and myocardial injury.
这些临床前试验提供了第一个证据，证明在再灌注st段抬高型心肌梗死（STEMI）的翻译小鼠模型中，用阿替克单抗（CD14中和抗体）的小鼠类似物阻断CD14簇（cluster of differentiation 14, CD14），可以预防心脏损伤的继发性免疫加重，使用多种临床模式进行评估。多组学研究表明，CD14阻断可下调巨噬细胞特异性促炎和组织重塑过程，而不抑制单核巨噬细胞浸润或修复。这些发现支持了临床上可行的CD14阻断在再灌注时启动的靶向免疫调节策略，以防止慢性免疫进展为缺血性心力衰竭，并为CD14在炎症和心肌损伤中的多效性作用提供了新的见解。
{"title":"CD14 Blockade Modulates Macrophage-Mediated Immunological Injury in a Translational Model of Reperfused ST-Segment Elevation Myocardial Infarction","authors":"Aascha A. D’Elia (nee Brown) PhD , Helen Kiriazis PhD , Jason Bloom MD , Jonathan Noonan PhD , Ian Hsu PhD , Gabriella E. Farrugia PhD , Haoyun Fang PhD , Stephanie Jansen BVetSc , Natalia Carvajal PhD , Crisdion Krstevski PhD , Waled A. Shihata PhD , Yow Keat Tham PhD , Angela Vais PhD , Camilla Cohen PhD , Adam C. Parslow PhD , Chad Johnson PhD , Anita C. Thomas PhD , Malathi S.I. Dona PhD , Kyah Grigolon BVetSc , Scott J.Y. Loh BSc (Hons) , Daniel G. Donner PhD","doi":"10.1016/j.jacbts.2025.101393","DOIUrl":"10.1016/j.jacbts.2025.101393","url":null,"abstract":"<div><div>These preclinical trials provide the first evidence of cluster of differentiation 14 (CD14) blockade with a murine analogue of atibuclimab, a CD14-neutralizing antibody, preventing secondary immunological exacerbation of cardiac injury in a translational mouse model of reperfused ST-segment elevation myocardial infarction (STEMI), assessed using multiple clinical modalities. Multiomic studies suggest CD14 blockade downregulated macrophage-specific proinflammatory and tissue-wide remodeling processes without suppression of monocyte-macrophage infiltration or repair. These findings support a clinically practicable targeted immunomodulatory strategy of CD14 blockade initiated at reperfusion to prevent chronic immunological progression toward ischemic heart failure, and provide new insights into the pleiotropic roles of CD14 in inflammation and myocardial injury.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 11","pages":"Article 101393"},"PeriodicalIF":8.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354853","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 : 2025-10-17DOI: 10.1016/j.jacbts.2025.101391
Hannah Kleppe BS , Anastasia Budan MS , Luke Zhang MS , Marie Majetic MS , Reva Shenwai MS , Alan R. Levinson BS , Olga Cisne-Thompson BS , Bernardo Zepeda MS , Charles E. MacKay PhD , Farshad Farshidfar MD, PhD , Jonathan H. Tsui PhD , Sylwia M. Figarska PhD , Timothy Hoey PhD , James R. Priest MD , Rebecca E. Slater PhD
The I-bar protein MTSS1 has been implicated in heart failure and contractility by multiple genome-wide association studies. Human genetic analyses suggested that a variant lowering cardiac MTSS1 expression was associated with significantly improved survival in individuals with TTN dilated cardiomyopathy (DCM). Experimental knockdown of MTSS1 via small interfering RNA (siRNA) in induced pluripotent stem cell–derived cardiomyocytes deficient in TTN, CSRP3, or RBM20 led to improved increased sarcomere number and enhanced contractility. Engineered heart tissue models confirmed increased twitch force following MTSS1 siRNA knockdown across these genetic forms of DCM. Unbiased mass-spectrometry suggests that MTSS1 was found to interact with MYO18A, a protein critical for sarcomere assembly, and siRNA knockdown of MTSS1 up-regulated MYH7 and other sarcomere-related genes. These findings may suggest that MTSS1 impacts contractility as a negative regulator of sarcomere formation or turnover, and that reduction of MTSS1 may be a therapeutic target in select forms of genetic DCM.
{"title":"Reduced Expression of MTSS1 Increases Sarcomere Number and Improves Contractility in Select Forms of Monogenic DCM","authors":"Hannah Kleppe BS , Anastasia Budan MS , Luke Zhang MS , Marie Majetic MS , Reva Shenwai MS , Alan R. Levinson BS , Olga Cisne-Thompson BS , Bernardo Zepeda MS , Charles E. MacKay PhD , Farshad Farshidfar MD, PhD , Jonathan H. Tsui PhD , Sylwia M. Figarska PhD , Timothy Hoey PhD , James R. Priest MD , Rebecca E. Slater PhD","doi":"10.1016/j.jacbts.2025.101391","DOIUrl":"10.1016/j.jacbts.2025.101391","url":null,"abstract":"<div><div>The I-bar protein MTSS1 has been implicated in heart failure and contractility by multiple genome-wide association studies. Human genetic analyses suggested that a variant lowering cardiac MTSS1 expression was associated with significantly improved survival in individuals with TTN dilated cardiomyopathy (DCM). Experimental knockdown of MTSS1 via small interfering RNA (siRNA) in induced pluripotent stem cell–derived cardiomyocytes deficient in TTN, CSRP3, or RBM20 led to improved increased sarcomere number and enhanced contractility. Engineered heart tissue models confirmed increased twitch force following MTSS1 siRNA knockdown across these genetic forms of DCM. Unbiased mass-spectrometry suggests that MTSS1 was found to interact with MYO18A, a protein critical for sarcomere assembly, and siRNA knockdown of MTSS1 up-regulated MYH7 and other sarcomere-related genes. These findings may suggest that MTSS1 impacts contractility as a negative regulator of sarcomere formation or turnover, and that reduction of MTSS1 may be a therapeutic target in select forms of genetic DCM.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 11","pages":"Article 101391"},"PeriodicalIF":8.4,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318359","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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