Pub Date : 2024-02-01Epub Date: 2024-01-30DOI: 10.1161/CIRCGEN.123.004305
Chantal J M van Opbergen, Bitha Narayanan, Chester B Sacramento, Katie M Stiles, Vartika Mishra, Esther Frenk, David Ricks, Grace Chen, Mingliang Zhang, Paul Yarabe, Jonathan Schwartz, Mario Delmar, Chris D Herzog, Marina Cerrone
Background: Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human PKP2 gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival.
Methods: Experiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography.
Results: Consistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset.
Conclusions: These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.
{"title":"AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans.","authors":"Chantal J M van Opbergen, Bitha Narayanan, Chester B Sacramento, Katie M Stiles, Vartika Mishra, Esther Frenk, David Ricks, Grace Chen, Mingliang Zhang, Paul Yarabe, Jonathan Schwartz, Mario Delmar, Chris D Herzog, Marina Cerrone","doi":"10.1161/CIRCGEN.123.004305","DOIUrl":"10.1161/CIRCGEN.123.004305","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human <i>PKP2</i> gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival.</p><p><strong>Methods: </strong>Experiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography.</p><p><strong>Results: </strong>Consistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset.</p><p><strong>Conclusions: </strong>These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10923105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2024-01-23DOI: 10.1161/CIRCGEN.122.004224
Daniel B Rosoff, Andrew S Bell, Lucas A Mavromatis, Ali Hamandi, Lauren Park, Jeesun Jung, Josephin Wagner, Pal Pacher, David Ray, George Davey Smith, Falk W Lohoff
{"title":"Evaluating the Cardiovascular Impact of Genetically Proxied PCSK9 and HMGCR Inhibition in East Asian and European Populations: A Drug-Target Mendelian Randomization Study.","authors":"Daniel B Rosoff, Andrew S Bell, Lucas A Mavromatis, Ali Hamandi, Lauren Park, Jeesun Jung, Josephin Wagner, Pal Pacher, David Ray, George Davey Smith, Falk W Lohoff","doi":"10.1161/CIRCGEN.122.004224","DOIUrl":"10.1161/CIRCGEN.122.004224","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139519066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2023-12-07DOI: 10.1161/CIRCGEN.123.004285
Alexis Hermida, Flavie Ader, Gilles Millat, Guillaume Jedraszak, Phillipe Maury, Romain Cador, Pierre-Antoine Catalan, Gaël Clerici, Nicolas Combes, Pascal De Groote, Delphine Dupin-Deguine, Romain Eschalier, Laurence Faivre, Patricia Garcia, Benoit Guillon, Alexandre Janin, Beatrice Kugener, Marylin Lackmy, Mikael Laredo, Xavier Le Guillou, François Lesaffre, Hugues Lucron, Antoine Milhem, Gwenaël Nadeau, Karine Nguyen, Aurélien Palmyre, Elodie Perdreau, François Picard, Nicolas Rebotier, Pascale Richard, Caroline Rooryck, Julien Seitz, Alain Verloes, Agathe Vernier, Pierre Winum, Grace-A-Dieu Yabeta, Océane Bouchot, Philippe Chevalier, Philippe Charron, Estelle Gandjbakhch
Background: Few clinical data are available on NEXN mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants.
Methods: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected.
Results: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events.
Conclusions: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.
{"title":"NEXN Gene in Cardiomyopathies and Sudden Cardiac Deaths: Prevalence, Phenotypic Expression, and Prognosis.","authors":"Alexis Hermida, Flavie Ader, Gilles Millat, Guillaume Jedraszak, Phillipe Maury, Romain Cador, Pierre-Antoine Catalan, Gaël Clerici, Nicolas Combes, Pascal De Groote, Delphine Dupin-Deguine, Romain Eschalier, Laurence Faivre, Patricia Garcia, Benoit Guillon, Alexandre Janin, Beatrice Kugener, Marylin Lackmy, Mikael Laredo, Xavier Le Guillou, François Lesaffre, Hugues Lucron, Antoine Milhem, Gwenaël Nadeau, Karine Nguyen, Aurélien Palmyre, Elodie Perdreau, François Picard, Nicolas Rebotier, Pascale Richard, Caroline Rooryck, Julien Seitz, Alain Verloes, Agathe Vernier, Pierre Winum, Grace-A-Dieu Yabeta, Océane Bouchot, Philippe Chevalier, Philippe Charron, Estelle Gandjbakhch","doi":"10.1161/CIRCGEN.123.004285","DOIUrl":"10.1161/CIRCGEN.123.004285","url":null,"abstract":"<p><strong>Background: </strong>Few clinical data are available on <i>NEXN</i> mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in <i>NEXN</i> and to describe the phenotype and prognosis of patients carrying the variants.</p><p><strong>Methods: </strong>DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the <i>NEXN</i> gene were selected.</p><p><strong>Results: </strong>Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in <i>NEXN</i> only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events.</p><p><strong>Conclusions: </strong>Putative pathogenic <i>NEXN</i> variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double <i>NEXN</i> variants. We also detected <i>NEXN</i> variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138497962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2024-02-07DOI: 10.1161/CIRCGEN.123.004192
Ravi V Shah, Jiawei Zhong, Lucas Massier, Kahraman Tanriverdi, Shih-Jen Hwang, Jeffrey Haessler, Matthew Nayor, Shilin Zhao, Andrew S Perry, John T Wilkins, Aladdin H Shadyab, JoAnn E Manson, Lisa Martin, Daniel Levy, Charles Kooperberg, Jane E Freedman, Mikael Rydén, Venkatesh L Murthy
Background: The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults.
Methods: We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.6±4.9 kg/m2), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative).
Results: In 184 proteins in >2000 young adults in CARDIA, we identified 2 proteotypes of diabetes susceptibility-a proinflammatory fat proteotype (visceral fat, liver fat, inflammatory biomarkers) and a muscularity proteotype (muscle mass), linked to diabetes in CARDIA and WHI/FHS. These proteotypes specified broad mechanisms of early diabetes pathogenesis, including transorgan communication, hepatic and skeletal muscle stress responses, vascular inflammation and hemostasis, fibrosis, and renal injury. Using human adipose tissue single cell/nuclear RNA-seq, we demonstrate expression at transcriptional level for implicated proteins across adipocytes and nonadipocyte cell types (eg, fibroadipogenic precursors, immune and vascular cells). Using functional assays in human adipose tissue, we demonstrate the association of expression of genes encoding these implicated proteins with adipose tissue metabolism, inflammation, and insulin resistance.
Conclusions: A multifaceted discovery effort uniting proteomics, underlying clinical susceptibility phenotypes, and tissue expression patterns may uncover potentially novel functional biomarkers of early diabetes susceptibility in young adults for future mechanistic evaluation.
{"title":"Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.","authors":"Ravi V Shah, Jiawei Zhong, Lucas Massier, Kahraman Tanriverdi, Shih-Jen Hwang, Jeffrey Haessler, Matthew Nayor, Shilin Zhao, Andrew S Perry, John T Wilkins, Aladdin H Shadyab, JoAnn E Manson, Lisa Martin, Daniel Levy, Charles Kooperberg, Jane E Freedman, Mikael Rydén, Venkatesh L Murthy","doi":"10.1161/CIRCGEN.123.004192","DOIUrl":"10.1161/CIRCGEN.123.004192","url":null,"abstract":"<p><strong>Background: </strong>The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults.</p><p><strong>Methods: </strong>We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.6±4.9 kg/m<sup>2</sup>), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative).</p><p><strong>Results: </strong>In 184 proteins in >2000 young adults in CARDIA, we identified 2 proteotypes of diabetes susceptibility-a proinflammatory fat proteotype (visceral fat, liver fat, inflammatory biomarkers) and a muscularity proteotype (muscle mass), linked to diabetes in CARDIA and WHI/FHS. These proteotypes specified broad mechanisms of early diabetes pathogenesis, including transorgan communication, hepatic and skeletal muscle stress responses, vascular inflammation and hemostasis, fibrosis, and renal injury. Using human adipose tissue single cell/nuclear RNA-seq, we demonstrate expression at transcriptional level for implicated proteins across adipocytes and nonadipocyte cell types (eg, fibroadipogenic precursors, immune and vascular cells). Using functional assays in human adipose tissue, we demonstrate the association of expression of genes encoding these implicated proteins with adipose tissue metabolism, inflammation, and insulin resistance.</p><p><strong>Conclusions: </strong>A multifaceted discovery effort uniting proteomics, underlying clinical susceptibility phenotypes, and tissue expression patterns may uncover potentially novel functional biomarkers of early diabetes susceptibility in young adults for future mechanistic evaluation.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10940209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139696974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2024-01-30DOI: 10.1161/CIRCGEN.123.004355
Zachery R Gregorich, Yanghai Zhang, Timothy J Kamp, Henk L Granzier, Wei Guo
RBM20 (RNA-binding motif protein 20) is a vertebrate- and muscle-specific RNA-binding protein that belongs to the serine-arginine-rich family of splicing factors. The RBM20 gene was first identified as a dilated cardiomyopathy-linked gene over a decade ago. Early studies in Rbm20 knockout rodents implicated disrupted splicing of RBM20 target genes as a causative mechanism. Clinical studies show that pathogenic variants in RBM20 are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality. Subsequent studies employing pathogenic variant knock-in animal models revealed that variants in a specific portion of the arginine-serine-rich domain in RBM20 not only disrupt splicing but also hinder nucleocytoplasmic transport and lead to the formation of RBM20 biomolecular condensates in the sarcoplasm. Conversely, mice harboring a disease-associated variant in the RRM (RNA recognition motif) do not show evidence of adverse remodeling or exhibit sudden death despite disrupted splicing of RBM20 target genes. Thus, whether disrupted splicing, biomolecular condensates, or both contribute to dilated cardiomyopathy is under debate. Beyond this, additional questions remain, such as whether there is sexual dimorphism in the presentation of RBM20 cardiomyopathy. What are the clinical features of RBM20 cardiomyopathy and why do some individuals develop more severe disease than others? In this review, we summarize the reported observations and discuss potential mechanisms of RBM20 cardiomyopathy derived from studies employing in vivo animal models and in vitro human-induced pluripotent stem cell-derived cardiomyocytes. Potential therapeutic strategies to treat RBM20 cardiomyopathy are also discussed.
{"title":"Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems.","authors":"Zachery R Gregorich, Yanghai Zhang, Timothy J Kamp, Henk L Granzier, Wei Guo","doi":"10.1161/CIRCGEN.123.004355","DOIUrl":"10.1161/CIRCGEN.123.004355","url":null,"abstract":"<p><p>RBM20 (RNA-binding motif protein 20) is a vertebrate- and muscle-specific RNA-binding protein that belongs to the serine-arginine-rich family of splicing factors. The <i>RBM20</i> gene was first identified as a dilated cardiomyopathy-linked gene over a decade ago. Early studies in <i>Rbm20</i> knockout rodents implicated disrupted splicing of RBM20 target genes as a causative mechanism. Clinical studies show that pathogenic variants in <i>RBM20</i> are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality. Subsequent studies employing pathogenic variant knock-in animal models revealed that variants in a specific portion of the arginine-serine-rich domain in RBM20 not only disrupt splicing but also hinder nucleocytoplasmic transport and lead to the formation of RBM20 biomolecular condensates in the sarcoplasm. Conversely, mice harboring a disease-associated variant in the RRM (RNA recognition motif) do not show evidence of adverse remodeling or exhibit sudden death despite disrupted splicing of RBM20 target genes. Thus, whether disrupted splicing, biomolecular condensates, or both contribute to dilated cardiomyopathy is under debate. Beyond this, additional questions remain, such as whether there is sexual dimorphism in the presentation of RBM20 cardiomyopathy. What are the clinical features of RBM20 cardiomyopathy and why do some individuals develop more severe disease than others? In this review, we summarize the reported observations and discuss potential mechanisms of RBM20 cardiomyopathy derived from studies employing in vivo animal models and in vitro human-induced pluripotent stem cell-derived cardiomyocytes. Potential therapeutic strategies to treat RBM20 cardiomyopathy are also discussed.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10923161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2023-12-04DOI: 10.1161/CIRCGEN.123.004232
Chenxi Qin, Sara Hägg
{"title":"Associations Between Genetic Variation in the Targets of Low-Density Lipoprotein-Lowering Drugs and Rheumatoid Arthritis.","authors":"Chenxi Qin, Sara Hägg","doi":"10.1161/CIRCGEN.123.004232","DOIUrl":"10.1161/CIRCGEN.123.004232","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138476933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2024-01-23DOI: 10.1161/CIRCGEN.123.004163
Ayelet Shauer, Smadar Horowitz-Cederboim, Hagar Mor-Shaked, Ronen Durst, Donna R Zwas, Bernard Belhassen
{"title":"Calmodulinopathy Associated Long QT Syndrome, Hypertrophic Cardiomyopathy With Excessive Trabeculation in a 14-Year-Old Girl Presenting With Ventricular Fibrillation.","authors":"Ayelet Shauer, Smadar Horowitz-Cederboim, Hagar Mor-Shaked, Ronen Durst, Donna R Zwas, Bernard Belhassen","doi":"10.1161/CIRCGEN.123.004163","DOIUrl":"10.1161/CIRCGEN.123.004163","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139519059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2024-01-30DOI: 10.1161/CIRCGEN.123.004265
Aleksandra D Chybowska, Danni A Gadd, Yipeng Cheng, Elena Bernabeu, Archie Campbell, Rosie M Walker, Andrew M McIntosh, Nicola Wrobel, Lee Murphy, Paul Welsh, Naveed Sattar, Jackie F Price, Daniel L McCartney, Kathryn L Evans, Riccardo E Marioni
Background: Cardiovascular disease (CVD) is among the leading causes of death worldwide. The discovery of new omics biomarkers could help to improve risk stratification algorithms and expand our understanding of molecular pathways contributing to the disease. Here, ASSIGN-a cardiovascular risk prediction tool recommended for use in Scotland-was examined in tandem with epigenetic and proteomic features in risk prediction models in ≥12 657 participants from the Generation Scotland cohort.
Methods: Previously generated DNA methylation-derived epigenetic scores (EpiScores) for 109 protein levels were considered, in addition to both measured levels and an EpiScore for cTnI (cardiac troponin I). The associations between individual protein EpiScores and the CVD risk were examined using Cox regression (ncases≥1274; ncontrols≥11 383) and visualized in a tailored R application. Splitting the cohort into independent training (n=6880) and test (n=3659) subsets, a composite CVD EpiScore was then developed.
Results: Sixty-five protein EpiScores were associated with incident CVD independently of ASSIGN and the measured concentration of cTnI (P<0.05), over a follow-up of up to 16 years of electronic health record linkage. The most significant EpiScores were for proteins involved in metabolic, immune response, and tissue development/regeneration pathways. A composite CVD EpiScore (based on 45 protein EpiScores) was a significant predictor of CVD risk independent of ASSIGN and the concentration of cTnI (hazard ratio, 1.32; P=3.7×10-3; 0.3% increase in C-statistic).
Conclusions: EpiScores for circulating protein levels are associated with CVD risk independent of traditional risk factors and may increase our understanding of the etiology of the disease.
{"title":"Epigenetic Contributions to Clinical Risk Prediction of Cardiovascular Disease.","authors":"Aleksandra D Chybowska, Danni A Gadd, Yipeng Cheng, Elena Bernabeu, Archie Campbell, Rosie M Walker, Andrew M McIntosh, Nicola Wrobel, Lee Murphy, Paul Welsh, Naveed Sattar, Jackie F Price, Daniel L McCartney, Kathryn L Evans, Riccardo E Marioni","doi":"10.1161/CIRCGEN.123.004265","DOIUrl":"10.1161/CIRCGEN.123.004265","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular disease (CVD) is among the leading causes of death worldwide. The discovery of new omics biomarkers could help to improve risk stratification algorithms and expand our understanding of molecular pathways contributing to the disease. Here, ASSIGN-a cardiovascular risk prediction tool recommended for use in Scotland-was examined in tandem with epigenetic and proteomic features in risk prediction models in ≥12 657 participants from the Generation Scotland cohort.</p><p><strong>Methods: </strong>Previously generated DNA methylation-derived epigenetic scores (EpiScores) for 109 protein levels were considered, in addition to both measured levels and an EpiScore for cTnI (cardiac troponin I). The associations between individual protein EpiScores and the CVD risk were examined using Cox regression (n<sub>cases</sub>≥1274; n<sub>controls</sub>≥11 383) and visualized in a tailored R application. Splitting the cohort into independent training (n=6880) and test (n=3659) subsets, a composite CVD EpiScore was then developed.</p><p><strong>Results: </strong>Sixty-five protein EpiScores were associated with incident CVD independently of ASSIGN and the measured concentration of cTnI (<i>P</i><0.05), over a follow-up of up to 16 years of electronic health record linkage. The most significant EpiScores were for proteins involved in metabolic, immune response, and tissue development/regeneration pathways. A composite CVD EpiScore (based on 45 protein EpiScores) was a significant predictor of CVD risk independent of ASSIGN and the concentration of cTnI (hazard ratio, 1.32; <i>P</i>=3.7×10<sup>-3</sup>; 0.3% increase in C-statistic).</p><p><strong>Conclusions: </strong>EpiScores for circulating protein levels are associated with CVD risk independent of traditional risk factors and may increase our understanding of the etiology of the disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10876178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-10-11DOI: 10.1161/CIRCGEN.123.004184
Elizaveta Polyakova, Janine M van Gils, J Lauran Stöger, Philippine Kiès, Anastasia D Egorova, Tamara T Koopmann, Tessa van Dijk, Marco C DeRuiter, Daniela Q C M Barge-Schaapveld, Monique R M Jongbloed
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