Pub Date : 2025-10-01DOI: 10.1016/j.jacbts.2025.04.006
Teagan S. Er MPath , Daniel Reinke PhD , Alice J. Francis PhD , Tanya M. Solomon BSc(Hons) , Helena M. Viola PhD , Henrietta Cserne Szappanos PhD , Caitlyn M. Richworth BSc(Hons) , Catherine Jenkins PhD , Juan E. Camacho Londoño PhD , Padmapriya Ponnuswamy PhD , Ciaran McFarlane PhD , Filip Van Petegem PhD , Livia C. Hool PhD
Mitochondrial dysfunction is considered to drive the development of hypertrophic cardiomyopathy (HCM). In search of a preventative HCM therapy, we explored the efficacy of amino acid peptide variants that could alter the L-type Ca2+ channel’s regulation of mitochondrial energetics. We confirmed that 3 of the 4 variant peptides bound with high affinity to the beta subunit. In vivo treatment of cTnI-G203S and αMHC403/+ mice with the peptide variants prevented the development of HCM and improved contractile function. Here, we describe a novel therapy that uniquely targets the L-type Ca2+ channel to modify mitochondrial function and prevent HCM.
{"title":"Novel Peptide Therapeutics Targeting the L-Type Calcium Channel Prevent Hypertrophic Cardiomyopathy by Decreasing Mitochondrial Energetics","authors":"Teagan S. Er MPath , Daniel Reinke PhD , Alice J. Francis PhD , Tanya M. Solomon BSc(Hons) , Helena M. Viola PhD , Henrietta Cserne Szappanos PhD , Caitlyn M. Richworth BSc(Hons) , Catherine Jenkins PhD , Juan E. Camacho Londoño PhD , Padmapriya Ponnuswamy PhD , Ciaran McFarlane PhD , Filip Van Petegem PhD , Livia C. Hool PhD","doi":"10.1016/j.jacbts.2025.04.006","DOIUrl":"10.1016/j.jacbts.2025.04.006","url":null,"abstract":"<div><div>Mitochondrial dysfunction is considered to drive the development of hypertrophic cardiomyopathy (HCM). In search of a preventative HCM therapy, we explored the efficacy of amino acid peptide variants that could alter the L-type Ca<sup>2+</sup> channel’s regulation of mitochondrial energetics. We confirmed that 3 of the 4 variant peptides bound with high affinity to the beta subunit. In vivo treatment of <em>cTnI-G203S</em> and <em>αMHC</em><sup><em>403/+</em></sup> mice with the peptide variants prevented the development of HCM and improved contractile function. Here, we describe a novel therapy that uniquely targets the L-type Ca<sup>2+</sup> channel to modify mitochondrial function and prevent HCM.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101292"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955045","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 : 2025-10-01DOI: 10.1016/j.jacbts.2025.04.009
Daniel Daou MD , Dan Tong MD, PhD , Gabriele G. Schiattarella MD, PhD , Thomas G. Gillette PhD , Joseph A. Hill MD, PhD
Cardiometabolic heart failure with preserved ejection fraction (HFpEF) has emerged as a distinct and dominant endotype of HFpEF. Driven by prevalent comorbidities, its incidence and prevalence are projected to continue to rise amid the current global pandemic of obesity and metabolic disease. Recognizing the characteristic clinical and molecular features of cardiometabolic HFpEF is paramount for developing an efficacious therapeutic arsenal and improving clinical outcomes, challenges in which success to date has been modest. Studying relevant and clinically informative animal models of cardiometabolic HFpEF can afford valuable insights into the molecular underpinnings of this syndrome, allowing the possibility of novel advances with clinical relevance. Here, we outline the clinical and molecular features that define cardiometabolic HFpEF as a distinct endotype. We also discuss the bona fide animal models of cardiometabolic HFpEF currently available, as well as methods for developing new models.
{"title":"What Is Cardiometabolic HFpEF and How Can We Study it Preclinically?","authors":"Daniel Daou MD , Dan Tong MD, PhD , Gabriele G. Schiattarella MD, PhD , Thomas G. Gillette PhD , Joseph A. Hill MD, PhD","doi":"10.1016/j.jacbts.2025.04.009","DOIUrl":"10.1016/j.jacbts.2025.04.009","url":null,"abstract":"<div><div>Cardiometabolic heart failure with preserved ejection fraction (HFpEF) has emerged as a distinct and dominant endotype of HFpEF. Driven by prevalent comorbidities, its incidence and prevalence are projected to continue to rise amid the current global pandemic of obesity and metabolic disease. Recognizing the characteristic clinical and molecular features of cardiometabolic HFpEF is paramount for developing an efficacious therapeutic arsenal and improving clinical outcomes, challenges in which success to date has been modest. Studying relevant and clinically informative animal models of cardiometabolic HFpEF can afford valuable insights into the molecular underpinnings of this syndrome, allowing the possibility of novel advances with clinical relevance. Here, we outline the clinical and molecular features that define cardiometabolic HFpEF as a distinct endotype. We also discuss the bona fide animal models of cardiometabolic HFpEF currently available, as well as methods for developing new models.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101295"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753426","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 : 2025-10-01DOI: 10.1016/j.jacbts.2025.04.012
Natalie Telis PhD , Hang Dai PhD , Ashley Waring MD , David Kann MD , Dana Wyman PhD , Simon White MSc , Basil Khuder MS , Francisco Tanudjaja BS , Alexandre Bolze PhD , Matthew E. Levy PhD , Cassie Hajek MD , Lisa M. McEwen PhD , Douglas Stoller MD , Christopher N. Chapman MD , C. Anwar A. Chahal MD, PhD , Daniel P. Judge MD , Douglas A. Olson MD , Joseph J. Grzymski PhD , Nicole L. Washington PhD , William Lee PhD , Kelly Schiabor Barrett PhD
Lipoprotein(a) (Lp[a]) is a genetic and often unmeasured contributor to atherosclerotic cardiovascular disease (ASCVD) risk. In this study, Lp(a) was estimated from exome data by quantifying Kringle IV subtype 2 repeats alongside a single-nucleotide variant–based genetic risk score. This method was applied to a diverse cohort (N = 76,147) from the Helix Research Network. The method better identified individuals with high Lp(a) levels, especially among individuals not genetically similar to Europeans. High genetic risk for high Lp(a) level was correlated with earlier and more frequent ASCVD diagnoses. Those with high genetic Lp(a) were more likely to have ASCVD without traditional risk factors present.
{"title":"Novel Method for Predicting Lp(a) From Genomic Testing Identifies ASCVD Risk Across a Diverse Cohort","authors":"Natalie Telis PhD , Hang Dai PhD , Ashley Waring MD , David Kann MD , Dana Wyman PhD , Simon White MSc , Basil Khuder MS , Francisco Tanudjaja BS , Alexandre Bolze PhD , Matthew E. Levy PhD , Cassie Hajek MD , Lisa M. McEwen PhD , Douglas Stoller MD , Christopher N. Chapman MD , C. Anwar A. Chahal MD, PhD , Daniel P. Judge MD , Douglas A. Olson MD , Joseph J. Grzymski PhD , Nicole L. Washington PhD , William Lee PhD , Kelly Schiabor Barrett PhD","doi":"10.1016/j.jacbts.2025.04.012","DOIUrl":"10.1016/j.jacbts.2025.04.012","url":null,"abstract":"<div><div>Lipoprotein(a) (Lp[a]) is a genetic and often unmeasured contributor to atherosclerotic cardiovascular disease (ASCVD) risk. In this study, Lp(a) was estimated from exome data by quantifying Kringle IV subtype 2 repeats alongside a single-nucleotide variant–based genetic risk score. This method was applied to a diverse cohort (N = 76,147) from the Helix Research Network. The method better identified individuals with high Lp(a) levels, especially among individuals not genetically similar to Europeans. High genetic risk for high Lp(a) level was correlated with earlier and more frequent ASCVD diagnoses. Those with high genetic Lp(a) were more likely to have ASCVD without traditional risk factors present.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101298"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753421","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 : 2025-10-01DOI: 10.1016/j.jacbts.2025.101316
Rongling Wang PhD , Gabriele G. Schiattarella MD, PhD
{"title":"Smells Like Therapy","authors":"Rongling Wang PhD , Gabriele G. Schiattarella MD, PhD","doi":"10.1016/j.jacbts.2025.101316","DOIUrl":"10.1016/j.jacbts.2025.101316","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101316"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794468","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 : 2025-10-01DOI: 10.1016/j.jacbts.2025.101315
Raul D. Santos MD, PhD, MSc
{"title":"Combining Genetic Tools to Determine Lipoprotein(a) Concentrations and Their Associated Cardiovascular Risks Across Different Ethnicities","authors":"Raul D. Santos MD, PhD, MSc","doi":"10.1016/j.jacbts.2025.101315","DOIUrl":"10.1016/j.jacbts.2025.101315","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101315"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753418","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 : 2025-09-16DOI: 10.1016/j.jacbts.2025.101378
Usman A. Tahir MD , Daniel Cruz MD , Dongxiao Shen MS , Gaurav Tiwari MS , Jing Liu PhD , Matthew Huber MD , Christopher Chan MS , Shuliang Deng MS , Mark D. Benson MD , Jeremy Robbins MD , Zsu Zsu Chen MD , Laurie Farrell BS , Lynette Ekunwe MS , Michael Hall MD , Bruce M. Psaty MD , James S. Floyd MD , Aarti Asnani MD , Filip K. Swirski PhD , James G. Wilson MD , Robert E. Gerszten MD
Proteomic profiling may provide insights into new biomarkers and pathways in coronary heart disease (CHD). We profiled ∼1,300 proteins in 1,967 Black individuals in the Jackson Heart Study and found Secreted and Transmembrane Protein 1 (SECTM1), a monocyte chemoattractant, to be our top novel finding associated with incident CHD. We validated our findings in the Cardiovascular Health Study. The top variant (rs116473040) associated with SECTM1 was associated with circulating monocyte percentage of white blood cells in a genomic database. In vivo studies demonstrated that recombinant SECTM1a increased the proportion of proatherogenic Ly6Chi monocytes, suggesting a pathway by which SECTM1 may contribute to CHD.
{"title":"SECTM1 Regulates Monocyte Levels and Is Associated With Incident Coronary Heart Disease","authors":"Usman A. Tahir MD , Daniel Cruz MD , Dongxiao Shen MS , Gaurav Tiwari MS , Jing Liu PhD , Matthew Huber MD , Christopher Chan MS , Shuliang Deng MS , Mark D. Benson MD , Jeremy Robbins MD , Zsu Zsu Chen MD , Laurie Farrell BS , Lynette Ekunwe MS , Michael Hall MD , Bruce M. Psaty MD , James S. Floyd MD , Aarti Asnani MD , Filip K. Swirski PhD , James G. Wilson MD , Robert E. Gerszten MD","doi":"10.1016/j.jacbts.2025.101378","DOIUrl":"10.1016/j.jacbts.2025.101378","url":null,"abstract":"<div><div>Proteomic profiling may provide insights into new biomarkers and pathways in coronary heart disease (CHD). We profiled ∼1,300 proteins in 1,967 Black individuals in the Jackson Heart Study and found Secreted and Transmembrane Protein 1 (SECTM1), a monocyte chemoattractant, to be our top novel finding associated with incident CHD. We validated our findings in the Cardiovascular Health Study. The top variant (rs116473040) associated with SECTM1 was associated with circulating monocyte percentage of white blood cells in a genomic database. In vivo studies demonstrated that recombinant SECTM1a increased the proportion of proatherogenic Ly6Chi monocytes, suggesting a pathway by which SECTM1 may contribute to CHD.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101378"},"PeriodicalIF":8.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080753","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 : 2025-09-16DOI: 10.1016/j.jacbts.2025.101324
Xiang Li PhD , Jian Wu PhD , Le Kang PhD , Xuan Li PhD , Weijiang Tan PhD , Shuang Zheng MS , Jianguo Jia BS , Shijun Wang PhD , Chunjie Yang BS , Xuecong Ren BS , Honghua Chen BS , Hui Gong PhD , Kuan Cheng PhD , Huan Sun MD, PhD , Fenghua Yang PhD , Yunzeng Zou MD, PhD
Although the prevalence of aortic regurgitation (AR), which causes eccentric remodeling and valvular heart disease (VHD), is increasing, suitable animal research models remain lacking. To address this issue, we established the first efficient, real-time visualized minimally invasive aortic regurgitation surgery mouse model by performing echocardiography-guided aortic valve tear using a modified insulin needle. The clinically relevant features of this AR model were verified by multimodal analysis, and feature genes closely associated with AR-induced VHD were obtained by time series analysis in conjunction with weighted gene co-expression network analysis. The results may provide comprehensive insights into the mechanistic study and potential therapeutic targets of AR-induced VHD.
{"title":"A Novel Model of Cardiac Remodeling by a Minimally Invasive Aortic Regurgitation Surgery in Mice","authors":"Xiang Li PhD , Jian Wu PhD , Le Kang PhD , Xuan Li PhD , Weijiang Tan PhD , Shuang Zheng MS , Jianguo Jia BS , Shijun Wang PhD , Chunjie Yang BS , Xuecong Ren BS , Honghua Chen BS , Hui Gong PhD , Kuan Cheng PhD , Huan Sun MD, PhD , Fenghua Yang PhD , Yunzeng Zou MD, PhD","doi":"10.1016/j.jacbts.2025.101324","DOIUrl":"10.1016/j.jacbts.2025.101324","url":null,"abstract":"<div><div>Although the prevalence of aortic regurgitation (AR), which causes eccentric remodeling and valvular heart disease (VHD), is increasing, suitable animal research models remain lacking. To address this issue, we established the first efficient, real-time visualized minimally invasive aortic regurgitation surgery mouse model by performing echocardiography-guided aortic valve tear using a modified insulin needle. The clinically relevant features of this AR model were verified by multimodal analysis, and feature genes closely associated with AR-induced VHD were obtained by time series analysis in conjunction with weighted gene co-expression network analysis. The results may provide comprehensive insights into the mechanistic study and potential therapeutic targets of AR-induced VHD.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101324"},"PeriodicalIF":8.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069509","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 : 2025-09-11DOI: 10.1016/j.jacbts.2025.101379
Adam R. Williams MD , Kevin M. Nash PhD, DABT , Robert D. Kirkton PhD , Garyn S. Levitan BS , Melissa A. Daubert MD , Susan A. Whitney MBA, BSRT(R)(N)(CT) , Kaleb M. Naegeli PhD , Abigail R. Benkert MD , Sharon L. McCartney MD , Heather L. Prichard PhD , Laura E. Niklason MD, PhD , Alan P. Kypson MD
Coronary artery bypass graft (CABG) uses the patient’s internal mammary artery and saphenous vein; however, unavailable or poor quality autologous vessels limit revascularization. This study addresses the critical need for alternative CABG conduits by evaluating a small diameter acellular tissue-engineered vessel ([sdATEV], 3.5 mm) in a primate model. Adult baboons (n = 5) underwent CABG to the right coronary artery (RCA) with an sdATEV. Patency, diameter, and cardiac function were longitudinally assessed by computed tomography angiography. All sdATEVs remained patent throughout the 6-month study. Computed tomography angiography demonstrated that the distal sdATEV diameter gradually remodeled to approximate the smaller baboon RCA. Histology and spatial transcriptomics revealed that sdATEVs recellularized with host endothelial and smooth muscle cells including a quiescent neomedia layer with gene expression patterns similar to the RCA, indicating that host cell ingrowth from the bypassed coronary artery regulates sdATEV diameter. These results suggest that the sdATEV is a durable alternative CABG conduit.
{"title":"Acellular Tissue Engineered Vessels as Coronary Artery Bypass Grafts","authors":"Adam R. Williams MD , Kevin M. Nash PhD, DABT , Robert D. Kirkton PhD , Garyn S. Levitan BS , Melissa A. Daubert MD , Susan A. Whitney MBA, BSRT(R)(N)(CT) , Kaleb M. Naegeli PhD , Abigail R. Benkert MD , Sharon L. McCartney MD , Heather L. Prichard PhD , Laura E. Niklason MD, PhD , Alan P. Kypson MD","doi":"10.1016/j.jacbts.2025.101379","DOIUrl":"10.1016/j.jacbts.2025.101379","url":null,"abstract":"<div><div>Coronary artery bypass graft (CABG) uses the patient’s internal mammary artery and saphenous vein; however, unavailable or poor quality autologous vessels limit revascularization. This study addresses the critical need for alternative CABG conduits by evaluating a small diameter acellular tissue-engineered vessel ([sdATEV], 3.5 mm) in a primate model. Adult baboons (n = 5) underwent CABG to the right coronary artery (RCA) with an sdATEV. Patency, diameter, and cardiac function were longitudinally assessed by computed tomography angiography. All sdATEVs remained patent throughout the 6-month study. Computed tomography angiography demonstrated that the distal sdATEV diameter gradually remodeled to approximate the smaller baboon RCA. Histology and spatial transcriptomics revealed that sdATEVs recellularized with host endothelial and smooth muscle cells including a quiescent neomedia layer with gene expression patterns similar to the RCA, indicating that host cell ingrowth from the bypassed coronary artery regulates sdATEV diameter. These results suggest that the sdATEV is a durable alternative CABG conduit.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 10","pages":"Article 101379"},"PeriodicalIF":8.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145047368","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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