Circulation: Genomic and Precision Medicine最新文献

{"title":"FGF12 Alleviates Cardiac Hypertrophy by Inhibiting Phosphorylation of CaM/CaMKII/CREB1 Axis.","authors":"Taojun Zhang, Kunlun Yin, Tianjiao Li, Shuiyun Wang, Zhou Zhou","doi":"10.1161/CIRCGEN.125.005362","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005362","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expression of the FGF12 (fibroblast growth factor 12), but its precise functional role remains unclear.</p><p><strong>Methods: </strong>To explore FGF12's function and interactions, we utilized clustered regularly interspaced short palindromic repeats-Cas9 technology in cardiomyocytes derived from human induced pluripotent stem cells-induced cardiomyocytes, as well as in other cell lines and mouse models (MYH7^R403Q/+, MYBPC3^{c790GtoA/c790GtoA}, and transverse aortic constriction models). We transfected HCM or mice model with FGF12-coding sequence and FGF12-ΔNLS plasmids or adeno-associated virus 9 vectors to reduce myocardial hypertrophy. As hypertrophy progressed, we used cleavage under targets and tagmentation) sequencing and AlphaFold3 on myocardial tissues from patients and induced pluripotent stem cells-induced cardiomyocytes. To predict mitochondrial function in cardiomyocytes, we measured mitochondrial Ca²⁺ concentrations and reactive oxygen species content.</p><p><strong>Results: </strong>First, we observed a decrease in FGF12 expression and a difference in its subcellular localization in patients with HCM compared with healthy volunteers. In hypertrophic mouse models, injecting adeno-associated virus 9 reduced myocardial hypertrophy. FGF12 binds to calmodulin and inhibits its phosphorylation. This interaction also suppresses the expression and phosphorylation of downstream proteins, including CaMKII, ERK1/2, CREB1, and MCU. The nuclear-localization FGF12 binds to the promoter region of CREB1. FGF12 inhibits the expression of the CREB1-MCU axis expression, leading to reductions in both mitochondrial Ca²⁺ concentration and mitochondrial reactive oxygen species.</p><p><strong>Conclusions: </strong>This study reveals a pathological mechanism associated with HCM linked to FGF12. FGF12, located outside the nucleus, suppresses the expression of metabolism-related genes by reducing the phosphorylation levels within the calmodulin-ERK1/2-CREB1-MCU axis. In contrast, the nuclear localization of FGF12 facilitates its binding to the promoter regions of CREB1, inhibiting CREB1 expression. This dual action maintains cardiomyocyte function and mitochondrial homeostasis. Our findings position FGF12 as a promising therapeutic target for HCM.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005362"},"PeriodicalIF":5.5,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670776","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}

{"title":"Yield of Postmortem Genetic Testing in Sudden Arrhythmic Death Syndrome: A Systematic Review and Meta-Analysis.","authors":"Emanuele Monda, Sabrina Montuoro, Lia Crotti, Cristina Basso, Martina Caiazza, Emanuele Bobbio, Camillo Autore, Elena Arbelo, Gaetano Diana, Perry Mark Elliott, Eloisa Arbustini, Giuseppe Limongelli","doi":"10.1161/CIRCGEN.125.005523","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005523","url":null,"abstract":"<p><strong>Background: </strong>Sudden arrhythmic death syndrome (SADS) refers to sudden cardiac death with structurally normal hearts at autopsy, most frequently attributed to inherited arrhythmia syndromes or concealed cardiomyopathies. Postmortem genetic testing may help identify underlying genetic causes. We aimed to investigate the yield of postmortem genetic testing in SADS cases by determining the prevalence of pathogenic or likely pathogenic variants in channelopathy- and cardiomyopathy-associated genes in autopsy-negative SADS victims.</p><p><strong>Methods: </strong>This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in PROSPERO (REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251067244). PubMed and Embase were searched on June 4, 2025, for observational studies including individuals aged 1 to 50 years with SADS and negative or nonspecific findings at autopsy. Eligible studies reported postmortem genetic testing for channelopathy and cardiomyopathy genes. Pathogenic or likely pathogenic variant classification followed American College of Medical Genetics and Genomics criteria and ClinGen gene-disease associations. Pooled prevalence was estimated using random-effects models.</p><p><strong>Results: </strong>A total of 45 studies involving 2498 SADS cases were included. Among 1697 SADS victims tested for both channelopathy and cardiomyopathy genes (33 studies), the pooled prevalence of pathogenic or likely pathogenic variants was 11.1% (95% CI, 4.1%-26.6%, <i>I</i>²=50.7%). Testing for cardiomyopathy genes (33 studies, 1697 cases) and for channelopathy genes (42 studies, 2354 cases) yielded a prevalence of 7.0% (95% CI, 1.9%-22.9%, <i>I</i>²=51.9%) and 6.3% (95% CI, 2.0%-18.4%, <i>I</i>²=49.8%), respectively. The most frequently involved genes encoded sarcomeric proteins and ion channels, with <i>TTN</i>, <i>MYBPC3</i>, <i>MYH7</i>, <i>KCNH2</i>, and <i>SCN5A</i> among the most commonly affected.</p><p><strong>Conclusions: </strong>Postmortem genetic testing identifies pathogenic or likely pathogenic variants in a significant subset of SADS cases, supporting its utility in postmortem evaluation.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005523"},"PeriodicalIF":5.5,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670809","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}

{"title":"Novel RYR2-A4510T Variant Presenting Both as Autosomal Dominant and Autosomal Recessive Catecholaminergic Polymorphic Ventricular Tachycardia.","authors":"Auke T Bergeman, Peter Lauffer, Johanna C Herkert, Frederik M A van den Heuvel, Sally-Ann B Clur, Alexa M C Vermeer, Alexander J A Groffen, Jan D H Jongbloed, Ingrid P C Krapels, Christian Schroer, Sabine C M Eijsbouts, Paul G A Volders, Vincent van der Pas, Shanshan Tian, Hai-Lei Zhu, Ruiwu Wang, John Paul Estillore, Arthur A M Wilde, Christian van der Werf, S R Wayne Chen, Saskia N van der Crabben","doi":"10.1161/CIRCGEN.125.005625","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005625","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005625"},"PeriodicalIF":5.5,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644189","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}

{"title":"Tumor Whole-Genome Sequencing for Prediction of Venous Thromboembolism in Patients With Metastasized Solid Cancer.","authors":"Frits I Mulder, Noori A M Guman, Job van Riet, Roos J van Geffen, Thijs F van Haaps, Vahram Hovsepjan, Hanneke W M van Laarhoven, Geert A Cirkel, Filip Y F L de Vos, Hans M Westgeest, Laurens V Beerepoot, Judith de Vos-Geelen, Mariette Labots, Paul Hamberg, Annelie J E Vulink, Maartje Los, Aeilko H Zwinderman, Debbie G J Robbrecht, Maja J A de Jonge, Harry R Büller, Pieter W Kamphuisen, Bart Ferwerda, Neeltje Steeghs, Nick van Es","doi":"10.1161/CIRCGEN.124.005182","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.005182","url":null,"abstract":"<p><strong>Background: </strong>International guidelines suggest prophylactic anticoagulation for patients with cancer at high risk of venous thromboembolism (VTE). Here, we evaluated whether tumor whole-genome sequencing data may improve the selection of high-risk patients.</p><p><strong>Methods: </strong>In a pan-cancer cohort of 3087 patients, associations of candidate clinical predictors, the germline extended 297-single nucleotide polymorphism polygenic risk score, tumor mutational characteristics, and somatic tumor mutations with VTE were estimated by calculating hazard ratios (HRs).</p><p><strong>Results: </strong>During 12-month follow-up, 237 (7.7%) developed VTE. The germline extended 297-single nucleotide polymorphism score was associated with VTE (HR per point increase, 2.11 [95% CI, 1.45-3.06]), as well as the total number of somatic structural variants (HR per 1000 increase, 1.21 [95% CI, 1.07-1.37]) and 129 somatic mutations (unadjusted <i>P</i><0.05), including <i>POLR2E</i> (HR, 3.34 [95% CI, 1.68-6.97]), <i>PALM</i> (HR, 3.73 [95% CI, 1.74-7.99]), <i>TBX22</i> (HR, 2.47 [95% CI, 1.40-4.35]), and <i>ELANE</i> (HR, 3.22 [95% CI, 1.51-6.87]). To further explore the potential of tumor whole-genome sequencing, prediction models were constructed including selected clinical predictors only (model 1), clinical predictors and germline variants (model 2), and the combination of clinical predictors, germline variants, and 14 top discriminating somatic mutations (model 3). The optimism corrected concordance index was 0.66 (95% CI, 0.62-0.69) for model 1, 0.67 (95% CI, 0.62-0.72) for model 2, and 0.77 (95% CI, 0.72-0.81) for model 3. This was significantly higher than that of the currently endorsed clinical Khorana VTE risk score (concordance index, 0.55 [95% CI, 0.51-0.59]; <i>P</i><0.005).</p><p><strong>Conclusions: </strong>These data indicate that tumor whole-genome sequencing may improve VTE prediction by clinical risk scores. Validation studies to confirm these findings are needed.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005182"},"PeriodicalIF":5.5,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644234","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}

{"title":"Development of an Integrated Monogenic and Polygenic Risk Assessment Tool for Coronary Artery Disease and Its Application in a Community-Based Health Care Biobank.","authors":"Jianfeng Xu, Zhuqing Shi, Sumeet A Khetarpal, Ashley J Mulford, Osama Siddiqui, Huy Tran, Jun Wei, Annabelle Ashworth, S Lilly Zheng, David Duggan, Brian T Helfand, Henry M Dunnenberger, Peter J Hulick, David J Davidson, Amit V Khera, Aniruddh P Patel, Alan R Sanders, Arman Qamar","doi":"10.1161/CIRCGEN.125.005494","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005494","url":null,"abstract":"<p><strong>Background: </strong>Current genetic testing for coronary artery disease (CAD) primarily targets monogenic variants in individuals with severe hypercholesterolemia. Whether supplementing monogenic testing with polygenic risk scores for CAD and Lp(a; lipoprotein[a]) levels [PRS_Lp(a)] improves identification of high-risk individuals in the general population remains understudied.</p><p><strong>Methods: </strong>A genetic probability for CAD (GenProb_CAD), incorporating monogenic pathogenic variants (PVs), polygenic risk scores for CAD, and PRS_Lp(a) was developed using Cox regression in 226 145 UK Biobank participants, validated in the remaining 226 145 UK Biobank participants, and applied to 20 477 participants of the Genomic Health Initiative, a community-based health care biobank. Predictive performance was evaluated and adjusted for clinical risk factors.</p><p><strong>Results: </strong>In the UK Biobank development cohort, PVs, polygenic risk scores for CAD and PRS_Lp(a) were each independently associated with CAD. In the UK Biobank validation cohort, GenProb_CAD outperformed PVs and the polygenic risk score in predicting CAD and reclassified risk among PV carriers. GenProb_CAD identified 16% of participants as high risk, 46-fold more than PV carriers (0.35%), with comparable observed CAD prevalence (15.60% versus 15.43%). Nearly 50% of CAD with high-risk GenProb_CAD were premature. GenProb_CAD also independently predicted incident CAD after adjusting for clinical risk factors. Importantly, high-risk individuals defined by GenProb_CAD showed consistently elevated CAD incidence across all low-density lipoprotein cholesterol strata. When UK Biobank-derived coefficients and cutoffs were applied in the Genomic Health Initiative, GenProb_CAD substantially outperformed the PV-only strategy, identifying 1966 high-risk participants (345 developed CAD), far exceeding the 20 PV carriers detected among those with low-density lipoprotein cholesterol ≥190 mg/dL (5 developed CAD). A universal genetic testing strategy using GenProb_CAD would hypothetically identify 20.75% of all incident CAD, 69-fold higher than current monogenic testing (0.3%). Results were generally consistent across ancestry populations, although the sample size of non-European participants was limited.</p><p><strong>Conclusions: </strong>GenProb_CAD, a novel integrated genetic risk tool combining monogenic PVs, polygenic risk scores for CAD, and PRS_Lp(a), improves identification of individuals at high genetic risk for CAD across diverse populations.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005494"},"PeriodicalIF":5.5,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644273","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}

{"title":"Rapid Genome Sequencing Shows Diagnostic Utility in Infants With Congenital Heart Defects.","authors":"Matthew D Durbin, Lindsey R Helvaty, Alyx Posorske, Samuel X Zhang, Manyan Huang, Ming Li, Daniel Abreu, Korre Fairman, Gabrielle C Geddes, Benjamin M Helm, Benjamin J Landis, Alexis McEntire, Dana K Mitchell, Stephanie M Ware","doi":"10.1161/CIRCGEN.125.005367","DOIUrl":"10.1161/CIRCGEN.125.005367","url":null,"abstract":"<p><strong>Background: </strong>Congenital heart disease (CHD) is the most common birth defect and a leading cause of infant mortality. CHD often has a genetic cause, and recent studies demonstrate the utility of genetic testing. In clinical practice, genetic testing continues to evolve, and the incorporation of rapid genome sequencing (rGS) in CHD is a recent development that requires evaluation. Although smaller studies demonstrate the value of rGS, they also highlight the burden of results interpretation.</p><p><strong>Methods: </strong>We analyzed genetic testing in CHD at 2 time points, in 2018 and from 2022 to 2023, across a change in clinical testing guidelines from chromosome microarray to rGS.</p><p><strong>Results: </strong>In an analysis of 421 hospitalized infants with CHD, genetic testing was performed in 77.7%, and the rate was consistent across time and in all patient subtypes analyzed. There was a significant shift in testing modalities, where in 2018, chromosome microarray was the most common test performed, with diagnostic results for CHD in 14.3%, whereas in 2022 to 2023, rGS was the most frequent test performed, with results diagnostic for CHD in 16.9%. In addition, rGS identified 44% more unique genetic diagnoses than chromosome microarray.</p><p><strong>Conclusions: </strong>This is the most extensive study to highlight the value of rGS in patients with CHD. These findings have important implications for CHD patient management.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005367"},"PeriodicalIF":5.5,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644227","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}

{"title":"Gamut of Patients Referred to Cardiology for Question of Clonal Hematopoiesis.","authors":"Ohad Oren, Peter Libby","doi":"10.1161/CIRCGEN.125.005544","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005544","url":null,"abstract":"<p><p>Clonal hematopoiesis encompasses diverse somatic mutations in hematopoietic cells, ranging from age-related expansions to mutations acquired after cytotoxic therapy, with implications for hematologic malignancy and cardiovascular disease. We characterize the spectrum of patients referred to cardiology for clonal hematopoiesis, including incidental detection during cytopenia or cancer predisposition workup, coexisting malignancy, and posttherapy surveillance. High-risk features, large clone size, multiple mutations, and specific driver genes interact with traditional cardiovascular risk factors to influence ischemic events. Contextualizing clonal hematopoiesis by detection setting, genotype, and clinical history informs individualized cardiovascular evaluation and risk mitigation, guiding mechanistically targeted preventive strategies and trial design.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005544"},"PeriodicalIF":5.5,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626606","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}

{"title":"Evaluation of Women With Peripartum or Dilated Cardiomyopathy and Their First-Degree Relatives: The DCM Precision Medicine Study.","authors":"Evan P Kransdorf, Rashmi Jain, Jonathan O Mead, Garrie Haas, Mark Hofmeyer, Gregory A Ewald, Jamie Diamond, Anjali Owens, Brian Lowes, Douglas Stoller, W H Wilson Tang, Mark H Drazner, Cindy M Martin, Palak Shah, Jose Tallaj, Stuart Katz, Javier Jimenez, Supriya Shore, Frank Smart, Jessica Wang, Stephen S Gottlieb, Daniel P Judge, Gordon S Huggins, Jason Cowan, Patricia Parker, Jinwen Cao, Natalie S Hurst, Elizabeth Jordan, Hanyu Ni, Daniel D Kinnamon, Ray E Hershberger","doi":"10.1161/CIRCGEN.125.005541","DOIUrl":"10.1161/CIRCGEN.125.005541","url":null,"abstract":"<p><strong>Background: </strong>Rare variant genetics have been associated with peripartum cardiomyopathy (PPCM), but the role of genetics remains unsettled. The study sought to compare dilated cardiomyopathy (DCM) genetic risk in first-degree relatives (FDRs) of female patients (probands) with DCM or PPCM to gain causal inference, and to assess DCM-relevant rare variant prevalence in DCM/PPCM probands and population controls.</p><p><strong>Methods: </strong>Clinical and genetic data were analyzed from the DCM Precision Medicine Study. Risk of DCM or partial DCM, where partial DCM was defined as left ventricular enlargement or a left ventricular ejection fraction of <50%, was estimated in 665 FDRs from 452 female probands, all of whom had been pregnant; 67 had PPCM and 385 had DCM; prevalence of pathogenic, likely pathogenic, or uncertain significance variants was estimated among probands.</p><p><strong>Results: </strong>The risk of DCM/partial DCM for FDRs of PPCM probands was similar to that for FDRs of DCM probands (hazard ratio, 0.77 [95% CI, 0.47-1.28]). Estimated DCM prevalence among the lowest-risk FDRs of non-Hispanic European ancestry probands with PPCM (7.0% [95% CI, 0%-14.1%] females, 9.0% [95% CI, 1.6%-16.3%] males) exceeded population estimates from a UK Biobank study (0.30% females, 0.63% males). Estimated prevalences of a pathogenic, likely pathogenic, or uncertain significance variant among African ancestry and European ancestry probands with PPCM were 55.4% (95% CI, 33.1%-77.7%) and 66.0% (95% CI, 38.6%-93.3%), respectively. The estimated prevalence of pathogenic/likely pathogenic variants among European ancestry PPCM probands (26.6% [95% CI, 12.6%-40.6%]) exceeded a population estimate from a UK Biobank study (0.6%).</p><p><strong>Conclusions: </strong>The risk of DCM/partial DCM among FDRs was similar regardless of whether their probands had PPCM or DCM. Also, DCM-relevant rare variant findings for females with PPCM or DCM were similar and greater than in population controls, suggesting a similar causal basis for PPCM and DCM. These findings underscore the need for genetic evaluations in all patients with PPCM.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005541"},"PeriodicalIF":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13020676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147510029","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}

{"title":"Newfoundland Mutation <i>TMEM43</i>-p.S358L Causes Impaired Cardiac Energy Metabolism and Mitochondrial Function Through Altered Protein Interaction.","authors":"Sandra Ratnavadivel, Kai Jürgens, Nora Klinke, Anna Gärtner, Joline Groß, Karin Klingel, Anders Malmendal, Stefan Walter, Hanne Boen, Emeline Van Craenenbroeck, René Schramm, Anna Kostareva, Jan Gummert, Astrid Kassner, Heiko Meyer, Achim Paululat, Hendrik Milting","doi":"10.1161/CIRCGEN.125.005171","DOIUrl":"10.1161/CIRCGEN.125.005171","url":null,"abstract":"<p><strong>Background: </strong>TMEM43 (transmembrane protein 43) is a ubiquitously expressed 4-transmembrane-protein localized in the endoplasmic reticulum and nuclear lamina. The missense mutation <i>TMEM43</i>-p.S358L causes fully penetrant ARVC5 (arrhythmogenic right ventricular cardiomyopathy type 5) especially in males. The TMEM43 function of the protein and the pathomechanisms of TMEM43-p.S358L remain poorly understood. We analyzed carrier-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), human myocardial tissue from TMEM43-wild-type, and TMEM43-p.S358L and identified differentially interacting proteins. Here we provide evidence for a novel pathomechanism contributing to the onset of ARVC5.</p><p><strong>Methods: </strong>Microsomes of human wild-type myocardium were separated by sucrose-gradient ultracentrifugation and characterized by mass-spectrometry to identify potential interacting proteins. Proteome and metabolome analyses of a <i>TMEM43</i>-p.S358L explanted human myocardium were performed. hiPSC-derived cardiomyocytes of <i>TMEM43</i>-p.S358L carrier and a corresponding isogenic control were generated. A 3'-end HA-Tag was introduced in <i>TMEM43</i> for pull-down experiments under optimized conditions. Lipidomics, proteomics, contractility, and ATP-content were measured in hiPSC-CMs.</p><p><strong>Results: </strong>Pull-down analyses of TMEM43-WT and mutant showed altered interacting proteins involved in metabolic pathways. Lipidomics revealed the accumulation of lipids and decreased lipid metabolism capacity in mutant hiPSC-CMs. The ATP to ADP ratio was lower in mutant hiPSC-CMs and could be associated with diminished contraction frequency. The human <i>TMEM43</i>-p.S358L myocardial proteome revealed altered protein-expression of metabolic pathways comparable to mutant hiPSC-CMs. Metabolic remodeling was also found in the mutant human myocardium. Ultracentrifugation fraction with the highest protein amount of TMEM43 and pull-down experiments of hiPSC-CMs revealed differentially interacting proteins of TMEM43-p.S358L from endoplasmic reticulum and mitochondrial membranes.</p><p><strong>Conclusions: </strong>We suggest differential interaction of mutant TMEM43 with proteins of mitochondria and endoplasmic reticulum influences endoplasmic reticulum-mitochondrial contact sites. <i>TMEM43</i>-p.S358L primarily contributes to changes in mitochondrial function affecting lipid homeostasis and energy supply.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005171"},"PeriodicalIF":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590336","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}

{"title":"Integrative Proteomic and Lipidomic Analysis of Patients With Acute Myocardial Infarction Treated With PCSK9 Antibodies and Statins.","authors":"Lukas E Schmidt, Sean A Burnap, Bhawana Singh, Kaloyan Takov, Sylvain Losdat, Lore Schrutka, Lukas Galli, Konstantinos Theofilatos, Georg W Otto, Christian Hengstenberg, Ioanna Tzoulaki, Irene M Lang, Konstantinos C Koskinas, Walter S Speidl, Lorenz Räber, Manuel Mayr","doi":"10.1161/CIRCGEN.125.005345","DOIUrl":"10.1161/CIRCGEN.125.005345","url":null,"abstract":"<p><strong>Background: </strong>PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition is a potent cholesterol-lowering strategy. This study examined the effects of PCSK9 monoclonal antibodies (mAbs) and high-intensity statins beyond low-density lipoprotein cholesterol reduction, which are not fully defined, particularly in patients with acute myocardial infarction (MI).</p><p><strong>Methods: </strong>Proteomic and lipidomic analyses were conducted on plasma from 265 patients with acute MI from the PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) randomized, placebo-controlled PCSK9 mAb trial and 34 patients without MI with hyperlipidemia from the Vienna Lipid Clinic registry, also receiving PCSK9 mAbs.</p><p><strong>Results: </strong>Discovery proteomics revealed changes in apolipoproteins and increased PCOLCE (procollagen C-endopeptidase enhancer 1) levels in both the PCSK9 mAb and placebo groups after MI. UK Biobank data confirmed PCOLCE and PCSK9 upregulation as associated with statin use. Hepatoma cell experiments demonstrated a dose-dependent PCOLCE induction on statin treatment. Compared with placebo (statins only), PCSK9 mAb therapy resulted in greater reductions in APOB (apolipoprotein B), APOE (apolipoprotein E), APOC2 (apolipoprotein C2), and APOC3 (apolipoprotein C3), as shown by targeted proteomics. Mediation analysis indicated that these changes were largely explained by low-density lipoprotein cholesterol lowering. Lipidomics identified more pronounced reductions in cholesteryl esters, ceramides, sphingomyelins, phosphatidylcholines, triglycerides, and diglycerides in PCSK9 mAb-treated patients with MI. Results were largely consistent in patients without MI. However, levels of LPA (apolipoprotein[a]), the characteristic protein component of lipoprotein(a), remained unchanged in PCSK9 mAb-treated patients with MI, since a rise of LPA was observed in the placebo group post-MI.</p><p><strong>Conclusions: </strong>Most apolipoprotein changes after PCSK9 mAb therapy following MI were mediated by low-density lipoprotein cholesterol lowering. Statin use is associated with increased circulating PCOLCE, with hepatoma cell experiments supporting a predominant hepatic origin. Combining PCSK9 mAbs with high-intensity statins mitigates post-MI increases in lipoprotein(a).</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005345"},"PeriodicalIF":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149312","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}