Pub Date : 2025-12-01DOI: 10.1016/j.jacbts.2025.101428
J. Alex Aycinena MS , Anley E. Tefera PhD , Isaac Perea-Gil PhD , Duncan Holbrook-Smith PhD , Kevin Williams PhD , Reva Shenwai MS , Farshad Farshidfar PhD , Brendan Ryback PhD , Katelyn Foppe MS , Iris Wu BS , Aliya Zeng BS , Melissa Van Pell BS , Emma Xu PhD , Joseph Woods BS , Samantha Jones MBA , Yolanda Hatter BS , Cristina Dee-Hoskins BS , Jessie Madariaga BS , Kevin Robinson BS , Amara Greer-Short PhD , Zhihong Jane Yang PhD
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Alterations in the desmosome gene plakophilin-2 (PKP2) lead to compromised contractility and electrical instability of cardiomyocytes. In this study, we utilized ARVC mouse and human induced pluripotent stem cell-derived cardiomyocyte models to confirm impaired energy metabolism that concorded with the human data. Our results supported an intrinsic cellular link between PKP2 and energy metabolism. TN-401–mediated PKP2 expression improved mitochondrial and glycolytic energetics and rescued cardiomyocyte functions that are dictated by mechanical and structural integrity of desmosome. Therefore, maintaining energy metabolism of cardiomyocytes is an integral part of PKP2 and desmosome functions, adding a new layer of understanding to ARVC disease mechanism.
{"title":"Maintenance of Energy Metabolism Is an Integral Part of Plakophilin-2 and Desmosome Functions","authors":"J. Alex Aycinena MS , Anley E. Tefera PhD , Isaac Perea-Gil PhD , Duncan Holbrook-Smith PhD , Kevin Williams PhD , Reva Shenwai MS , Farshad Farshidfar PhD , Brendan Ryback PhD , Katelyn Foppe MS , Iris Wu BS , Aliya Zeng BS , Melissa Van Pell BS , Emma Xu PhD , Joseph Woods BS , Samantha Jones MBA , Yolanda Hatter BS , Cristina Dee-Hoskins BS , Jessie Madariaga BS , Kevin Robinson BS , Amara Greer-Short PhD , Zhihong Jane Yang PhD","doi":"10.1016/j.jacbts.2025.101428","DOIUrl":"10.1016/j.jacbts.2025.101428","url":null,"abstract":"<div><div>Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Alterations in the desmosome gene plakophilin-2 (PKP2) lead to compromised contractility and electrical instability of cardiomyocytes. In this study, we utilized ARVC mouse and human induced pluripotent stem cell-derived cardiomyocyte models to confirm impaired energy metabolism that concorded with the human data. Our results supported an intrinsic cellular link between PKP2 and energy metabolism. TN-401–mediated PKP2 expression improved mitochondrial and glycolytic energetics and rescued cardiomyocyte functions that are dictated by mechanical and structural integrity of desmosome. Therefore, maintaining energy metabolism of cardiomyocytes is an integral part of PKP2 and desmosome functions, adding a new layer of understanding to ARVC disease mechanism.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 12","pages":"Article 101428"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810201","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 : 2025-12-01DOI: 10.1016/j.jacbts.2025.101431
Frank M. Davis MD
{"title":"Improving Detection of Peripheral Arterial Disease","authors":"Frank M. Davis MD","doi":"10.1016/j.jacbts.2025.101431","DOIUrl":"10.1016/j.jacbts.2025.101431","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 12","pages":"Article 101431"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810146","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 : 2025-11-17DOI: 10.1016/j.jacbts.2025.101409
Maximilian Y. Emmert MD, PhD , Johannes Holzmeister MD , Ole Blank MSc , Heike Meyborg MSc , Anne Jomard PhD , Giulia Mearini PhD , Maria Vono PhD , Miriam Weisskopf DVM, PhD , Marco Michalski PhD , Chandan Kadur Nagaraju PhD , Mark Dehdashtian BSc , Dominic Hollamby MA , Chris Rusconi PhD , Steven Zelenkofske MD , Volkmar Falk MD , Eduard Ayuso DVM, PhD , Josef El Andari PhD , Nikola Cesarovic DVM, PhD
Safe and efficient in vivo delivery of advanced therapies (ATs) remains a major challenge hindering their path to clinical adoption. We present a novel, fully percutaneous, catheter-based locoregional perfusion (LRP) system for targeted delivery of ATs, minimizing systemic exposure. Using principles from extracorporeal membrane oxygenation and cardiovascular perfusion, we developed and validated the LRP concept in porcine models, focusing on the kidney as a clinically relevant target. Custom catheter prototypes enabled safe, isolated perfusion of the kidney. Using adeno-associated viruses (AAVs) as model cargos, LRP achieved up to 69,000-fold higher vector retention within the LRP circulation than systemic circulation, and significantly reduced delivery to off-target organs such as the liver and spleen. AAV5 showed the highest transduction efficiency, with up to 75-fold greater gene expression. These findings demonstrate the feasibility, safety, and precision of LRP for organ-specific AT delivery while preventing plausible off-target toxicity. It may therefore represent a unique platform for next-generation delivery of AT and potentially beyond, including other therapeutic agents such as pharmaco- or chemotherapy to the target-organ.
{"title":"Next-Generation Percutaneous Catheter–Based Closed-Loop Perfusion Concept Enables High-Precision Organ Delivery of Advanced Therapies","authors":"Maximilian Y. Emmert MD, PhD , Johannes Holzmeister MD , Ole Blank MSc , Heike Meyborg MSc , Anne Jomard PhD , Giulia Mearini PhD , Maria Vono PhD , Miriam Weisskopf DVM, PhD , Marco Michalski PhD , Chandan Kadur Nagaraju PhD , Mark Dehdashtian BSc , Dominic Hollamby MA , Chris Rusconi PhD , Steven Zelenkofske MD , Volkmar Falk MD , Eduard Ayuso DVM, PhD , Josef El Andari PhD , Nikola Cesarovic DVM, PhD","doi":"10.1016/j.jacbts.2025.101409","DOIUrl":"10.1016/j.jacbts.2025.101409","url":null,"abstract":"<div><div>Safe and efficient in vivo delivery of advanced therapies (ATs) remains a major challenge hindering their path to clinical adoption. We present a novel, fully percutaneous, catheter-based locoregional perfusion (LRP) system for targeted delivery of ATs, minimizing systemic exposure. Using principles from extracorporeal membrane oxygenation and cardiovascular perfusion, we developed and validated the LRP concept in porcine models, focusing on the kidney as a clinically relevant target. Custom catheter prototypes enabled safe, isolated perfusion of the kidney. Using adeno-associated viruses (AAVs) as model cargos, LRP achieved up to 69,000-fold higher vector retention within the LRP circulation than systemic circulation, and significantly reduced delivery to off-target organs such as the liver and spleen. AAV5 showed the highest transduction efficiency, with up to 75-fold greater gene expression. These findings demonstrate the feasibility, safety, and precision of LRP for organ-specific AT delivery while preventing plausible off-target toxicity. It may therefore represent a unique platform for next-generation delivery of AT and potentially beyond, including other therapeutic agents such as pharmaco- or chemotherapy to the target-organ.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 12","pages":"Article 101409"},"PeriodicalIF":8.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145549536","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 : 2025-11-15DOI: 10.1016/j.jacbts.2025.101395
Matthew A. Muller MS , Elliot Luttrell-Williams MS , Hannah Bash BS , Macintosh G. Cornwell PhD , H. Michael Belmont MD , Peter Izmirly MD , Haley Rosmann BS , Michael S. Garshick MD , Tessa J. Barrett PhD , Stuart Katz MD , Kelly V. Ruggles PhD , Jill P. Buyon MD , Jeffrey S. Berger MD, MS
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with an increased risk of vascular dysfunction and cardiovascular disease. We validate our previously developed Systemic Lupus Erythematosus Activity Platelet-Gene Expression Signature (SLAP-GES) score and investigate its relationship with platelet activity and vascular health. SLAP-GES was associated with the SLE Disease Activity Index (Padj < 0.001) and consistent over time (r = 0.76; P = 9 × 10−5). Moreover, SLAP-GES was associated increased platelet aggregation in response to submaximal epinephrine (P = 0.084), leukocyte platelet aggregates (P = 0.014), and neutrophil platelet aggregates (P = 0.043). SLAP-GES was also associated with impaired glycocalyx (P = 0.011) and brachial artery flow-mediated dilation (P = 0.045). Altogether, SLAP-GES is associated with SLE disease activity, platelet activity, and impaired vascular health.
{"title":"Platelet Gene Expression in Systemic Lupus Erythematosus and Cardiovascular Health","authors":"Matthew A. Muller MS , Elliot Luttrell-Williams MS , Hannah Bash BS , Macintosh G. Cornwell PhD , H. Michael Belmont MD , Peter Izmirly MD , Haley Rosmann BS , Michael S. Garshick MD , Tessa J. Barrett PhD , Stuart Katz MD , Kelly V. Ruggles PhD , Jill P. Buyon MD , Jeffrey S. Berger MD, MS","doi":"10.1016/j.jacbts.2025.101395","DOIUrl":"10.1016/j.jacbts.2025.101395","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is a complex autoimmune disease with an increased risk of vascular dysfunction and cardiovascular disease. We validate our previously developed Systemic Lupus Erythematosus Activity Platelet-Gene Expression Signature (SLAP-GES) score and investigate its relationship with platelet activity and vascular health. SLAP-GES was associated with the SLE Disease Activity Index (<em>Padj</em> < 0.001) and consistent over time (r = 0.76; <em>P =</em> 9 × 10<sup>−5</sup>). Moreover, SLAP-GES was associated increased platelet aggregation in response to submaximal epinephrine <em>(P =</em> 0.084), leukocyte platelet aggregates <em>(P =</em> 0.014), and neutrophil platelet aggregates <em>(P =</em> 0.043). SLAP-GES was also associated with impaired glycocalyx <em>(P =</em> 0.011) and brachial artery flow-mediated dilation <em>(P =</em> 0.045). Altogether, SLAP-GES is associated with SLE disease activity, platelet activity, and impaired vascular health.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 12","pages":"Article 101395"},"PeriodicalIF":8.4,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519324","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 : 2025-11-12DOI: 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}
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