Circulation: Genomic and Precision Medicine最新文献

{"title":"Evaluating the Cardiometabolic Efficacy and Safety of Lipoprotein Lipase Pathway Targets in Combination With Approved Lipid-Lowering Targets: A Drug Target Mendelian Randomization Study.","authors":"Eloi Gagnon, Dipender Gill, Dominique Chabot, Héléne T Cronjé, Shuai Yuan, Stephen Brennan, Sébastien Thériault, Stephen Burgess, Benoit J Arsenault, Marie-Joe Dib","doi":"10.1161/CIRCGEN.124.004933","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004933","url":null,"abstract":"<p><strong>Background: </strong>Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy-both alone and in combination with existing lipid-lowering therapies-modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects.</p><p><strong>Methods: </strong>We selected triglyceride-lowering genetic variants located in the genes encoding ANGPTL3 (angiopoietin-like 3), ANGPTL4 (angiopoietin-like 4), APOC3 (apolipoprotein C3), and LPL and conducted drug target Mendelian randomization on primary outcomes including coronary artery disease and type 2 diabetes, and secondary outcomes, including apolipoprotein B, waist-to-hip ratio, body mass index, and 233 metabolic biomarkers. We conducted interaction Mendelian randomization analyses in 488 139 UK Biobank participants to test the effect of combination therapy targeting the LPL and LDLR (low-density lipoprotein receptor) pathways. Finally, we investigated potential secondary indications and adverse effects by leveraging genetic association data on 1204 disease end points.</p><p><strong>Results: </strong>Genetically predicted triglyceride lowering through the perturbation of LPL pathway activation targets ANGPTL4, APOC3, and LPL was associated with a lower risk of coronary artery disease and type 2 diabetes and lower apolipoprotein B. Genetically predicted triglyceride lowering through ANGPTL4 was associated with a lower waist-to-hip ratio, suggestive of a favorable body fat distribution. There was no evidence of a multiplicative interaction between genetically proxied perturbation of ANGPTL4, APOC3, and LPL and that of HMGCR (HMG-CoA reductase) and PCSK9 (proprotein convertase subtilisin/kexin type 9) on coronary artery disease and type 2 diabetes, consistent with additive effects. Finally, associations of genetically predicted LPL pathway targeting were supportive of the broad safety of these targets.</p><p><strong>Conclusions: </strong>Our findings provide genetic evidence supporting the efficacy and safety of LPL pathway activation therapies for the prevention of coronary artery disease and type 2 diabetes, alone or in combination with statins or PCSK9 inhibitors.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004933"},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572370","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":"Artificial Intelligence to Enhance Precision Medicine in Cardio-Oncology: A Scientific Statement From the American Heart Association.","authors":"Rohan Khera, Aarti H Asnani, Jacob Krive, Daniel Addison, Han Zhu, Alexi Vasbinder, Matthew R Fleming, Rima Arnaout, Pedram Razavi, Tochukwu M Okwuosa","doi":"10.1161/HCG.0000000000000097","DOIUrl":"10.1161/HCG.0000000000000097","url":null,"abstract":"<p><p>Artificial intelligence is poised to transform cardio-oncology by enabling personalized care for patients with cancer, who are at a heightened risk of cardiovascular disease due to both the disease and its treatments. The rising prevalence of cancer and the availability of multiple new therapeutic options has resulted in improved survival among patients with cancer and has expanded the scope of cardio-oncology to not only short-term but also long-term cardiovascular risks resulting from both cancer and its treatments. However, there is considerable heterogeneity in cardiovascular risk, driven by the nature of the malignancy as well as each individual's unique characteristics. The use of novel therapies, such as targeted therapies and immune checkpoint inhibitors, across multiple cancer groups has also broadened the populations among which cardiotoxicity has become an important consideration of therapy. Therefore, the ability to understand and personalize cardiovascular risk management in patients with cancer is a key target for artificial intelligence, which can deduce and respond to complex patterns within the data. These advances necessitate an overview of established biomarkers of risk, spanning advanced imaging, diagnostic testing, and multi-omics, the evidence supporting their use, and the proven and proposed role of artificial intelligence in refining this risk to attain greater precision in risk prediction and management in cardio-oncologic care.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e000097"},"PeriodicalIF":6.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482257","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":"Analysis of <i>TTN</i> Truncating Variants in >74 000 Cases Reveals New Clinically Relevant Gene Regions.","authors":"Matteo Vatta, Ellen Regalado, Michael Parfenov, Dan Swartzlander, Andrea Nagl, Meghan Mannello, Rachel Lewis, Daniel Clemens, John Garcia, Rachel E Ellsworth, Ana Morales, Yi-Lee Ting, Swaroop Aradhya","doi":"10.1161/CIRCGEN.124.004982","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004982","url":null,"abstract":"<p><strong>Background: </strong>Truncating variants (TTNtvs) in the titin (<i>TTN</i>) gene have been associated with cardiomyopathies or arrhythmias (C/A) and autosomal recessive neuromuscular diseases (NM). However, the clinical significance of TTNtvs across the entire coding sequence of <i>TTN</i> has not been comprehensively assessed. The purpose of this study was to examine the burden of TTNtvs in C/A and NM cases compared with controls in the genome aggregation database.</p><p><strong>Methods: </strong>This was a retrospective study of probands who underwent multigene testing (49 740 C/A panel, 24 514 NM panel) that included <i>TTN</i> from November 2017 to October 2021. Burden testing was performed using controls in the genome aggregation database v3.1.2 database, and the analysis was stratified by exon/band location and exon usage in cardiac or skeletal muscle. Frequency and odds ratio of TTNtv alleles in C/A or NM cases and genome aggregation database controls were measured.</p><p><strong>Results: </strong>There were 2446 (4.9%) C/A and 482 (2.0%) NM cases with 2446 and 528 TTNtv alleles, respectively. TTNtvs in all bands were significantly enriched in both C/A and NM cases compared with controls. A significant enrichment of TTNtvs in C/A was observed for exon 358 of the M-band (odds ratio, 2.55 [95% CI, 1.85-3.54]) but not the other M-band exons.</p><p><strong>Conclusions: </strong>In the largest single-site cohort of C/A and NM cases with TTNtvs, an enrichment of TTNtvs across <i>TTN</i> was observed. These findings expand the clinically relevant regions of <i>TTN</i>.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004982"},"PeriodicalIF":6.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448159","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":"Natural History, Phenotype Spectrum, and Clinical Outcomes of Desmin (<i>DES</i>)-Associated Cardiomyopathy.","authors":"Babken Asatryan, Marina Rieder, Brittney Murray, Steven A Muller, Crystal Tichnell, Alessio Gasperetti, Richard T Carrick, Emily Joseph, Doris G Leung, Anneline S J M Te Riele, Stefan L Zimmerman, Hugh Calkins, Cynthia A James, Andreas S Barth","doi":"10.1161/CIRCGEN.124.004878","DOIUrl":"10.1161/CIRCGEN.124.004878","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic/likely pathogenic (LP) desmin (<i>DES</i>) variants cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACEs), including cardiac conduction disease, sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, left ventricular assist device/cardiac transplant, HF-related death) in patients with pathogenic/LP <i>DES</i> variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization. We aimed to describe the natural history, phenotype spectrum, familial penetrance and outcomes in patients with pathogenic/LP <i>DES</i> variants through a systematic review and individual patient data meta-analysis using published reports.</p><p><strong>Methods: </strong>We searched Medline (PubMed) and Embase for studies that evaluated cardiac phenotypes in patients with pathogenic/LP <i>DES</i> variants. Cardiomyopathy diagnosis or occurrence of MACE was considered evidence of cardiac involvement/penetrance. Lifetime event-free survival from cardiac conduction disease, sustained VA, HF events, and composite MACE was assessed.</p><p><strong>Results: </strong>Of the 4212 screened publications, 71 met the inclusion criteria. A total of 230 patients were included (52.6% male, 52.2% probands, median age: 31 years [22.0-42.8] at first evaluation, median follow-up: 3 years [0-11.0]). Overall, 124 (53.9%) patients were diagnosed with cardiomyopathy, predominantly dilated cardiomyopathy (14.8%), followed by restrictive cardiomyopathy (13.5%), whereas other forms were less common: arrhythmogenic cardiomyopathy (7.0%), hypertrophic cardiomyopathy (6.1%), arrhythmogenic right ventricular cardiomyopathy (5.2%), and other forms (7.4%). Overall, 132 (57.4%) patients developed MACE, with 96 (41.7%) having cardiac conduction disease, 36 (15.7%) sustained VA, and 43 (18.7%) HF events. Familial penetrance of cardiac disease was 63.6% among relatives with pathogenic/LP <i>DES</i> variants. Male sex was associated with an increased risk of sustained VA (hazard ratio, 2.28; <i>P</i>=0.02) and HF events (hazard ratio, 2.45; <i>P</i>=0.008).</p><p><strong>Conclusions: </strong><i>DES</i> cardiomyopathy exhibits heterogeneous phenotypes and a distinct natural history, characterized by high familial penetrance and a substantial MACE burden. Male patients face a higher risk of sustained VA events.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004878"},"PeriodicalIF":6.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448161","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":"Prognostic Implications Between hsCRP and <i>CYP2C19</i> Genotype in Patients From East Asia: Insights From the PTRG-DES Consortium.","authors":"Se Hun Kang, Jae Youn Moon, Seung-Yul Lee, Sang-Hoon Kim, Jeehoon Kang, Hyo-Soo Kim, Hyung Joon Joo, Do-Sun Lim, Sang Yup Lee, Young-Hoon Jeong, Jung-Won Suh, Byeong-Keuk Kim, Kiyuk Chang, Yongwhi Park, Young Bin Song, Sung Gyun Ahn, Jung Rae Cho, Ae-Young Her, Eun-Seok Shin, Moo Hyun Kim","doi":"10.1161/CIRCGEN.124.004998","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004998","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004998"},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406099","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":"Use of Advanced Echocardiographic Modalities to Discriminate Preclinical Hypertrophic Cardiomyopathy Mutation Carriers From Non-Carriers.","authors":"Ada K C Lo, Thomas Mew, Christina Mew, Kristyan Guppy-Coles, Arun Dahiya, Arnold Ng, Julie McGaughran, Louise McCormack, Sandhir Prasad, John J Atherton","doi":"10.1161/CIRCGEN.124.004806","DOIUrl":"10.1161/CIRCGEN.124.004806","url":null,"abstract":"<p><strong>Background: </strong>It remains challenging to determine which hypertrophic cardiomyopathy (HCM) family members will subsequently develop HCM. Standard 2-dimensional and conventional Doppler echocardiography have been unable to reliably distinguish HCM genotype-positive and phenotype-negative (G+P-) from genotype-negative and phenotype-negative (G-P-) family members. We aimed to determine if advanced echocardiographic modalities can discriminate HCM G+P- from G-P- individuals.</p><p><strong>Methods: </strong>Comprehensive echocardiography including speckle tracking evaluation of myocardial deformation and color M-mode were performed in 199 participants aged ≥16 years who had undergone genetic testing from families with a known HCM pathogenic variant: 58 G+P-, 39 G-P-, and 102 overt patients with HCM (genotype-positive and phenotype-positive). The primary analysis compared these measures in all G+P- and G-P- individuals. A secondary analysis was undertaken in younger subjects (age ≤40 years).</p><p><strong>Results: </strong>Comparing G+P- and G-P- individuals, there were no significant differences in left ventricular ejection fraction, cavity size, wall thickness and outflow tract gradient, and tissue Doppler-derived myocardial velocities; however, septal/posterior wall thickness ratio was higher (1.06±0.09 versus 1.02±0.04, <i>P</i>=0.007). G+P- individuals had significantly lower color M-mode flow propagation velocity (color M-mode velocity propagation, 42.6 cm/s [interquartile range, 34.5-48.5 cm/s] versus 51.0 cm/s [interquartile range, 45.2-61.0 cm/s]; <i>P</i><0.001) and higher global longitudinal strain (<i>P</i>=0.021), circumferential strain (<i>P</i>=0.003), and peak apical rotation (<i>P</i>=0.005). Multivariable logistic regression identified 2 independent predictors (color M-mode velocity propagation and peak apical rotation). A derived regression equation allowed reasonable discrimination of G+P- individuals with a sensitivity of 82.6% and specificity of 72.2% (<i>P</i><0.0001) at the optimal cutoff. Similar findings were demonstrated when the analysis was restricted to younger subjects, although in addition to color M-mode velocity propagation and apical rotation, left ventricular ejection fraction was also independently predictive.</p><p><strong>Conclusions: </strong>In HCM family members, color M-mode velocity propagation and apical rotation provide good sensitivity and specificity for identifying mutation carriers and may represent early disease markers before the onset of hypertrophy. Longitudinal studies involving larger cohorts are required to validate these findings.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004806"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398321","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":"Dynamic Importance of Genomic and Clinical Risk for Coronary Artery Disease Over the Life Course.","authors":"Sarah M Urbut, So Mi Jemma Cho, Kaavya Paruchuri, Buu Truong, Sara Haidermota, Gina M Peloso, Whitney E Hornsby, Anthony Philippakis, Akl C Fahed, Pradeep Natarajan","doi":"10.1161/CIRCGEN.124.004681","DOIUrl":"10.1161/CIRCGEN.124.004681","url":null,"abstract":"<p><strong>Background: </strong>Earlier identification of high coronary artery disease (CAD) risk individuals may enable more effective prevention strategies. However, existing 10-year risk frameworks are ineffective at earlier identification. We sought to understand how the variable importance of genomic and clinical factors across life stages may significantly improve lifelong CAD event prediction.</p><p><strong>Methods: </strong>A longitudinal study was performed using data from 2 cohort studies: the FOS (Framingham Offspring Study) with 3588 participants aged 19 to 57 years and the UKB (UK Biobank) with 327 837 participants aged 40 years to 70 years. A total of 134 765 and 3 831 734 person-time years were observed in FOS and UKB, respectively. Hazard ratios for CAD were calculated for polygenic risk score (PRS) and clinical risk factors at each age of enrollment. The relative importance of PRS and pooled cohort equations in predicting CAD events was also evaluated by age groups.</p><p><strong>Results: </strong>The importance of CAD PRS diminished over the life course, with a hazard ratio of 3.58 (95% CI, 1.39-9.19) at the age of 19 years in FOS and a hazard ratio of 1.51 (95% CI, 1.48-1.54) by the age of 70 years in UKB. Clinical risk factors exhibited similar age-dependent trends. PRS significantly outperformed pooled cohort equations in identifying subsequent CAD events in the 40- to 45-year age group, with 3.2-fold more appropriately identified events. Overall, adding PRS improved the area under the receiving operating curve of the pooled cohort equations by an average of +5.1% (95% CI, 4.9%-5.2%) across all age groups; among individuals <55 years, PRS augmented the area under the receiver operater curve (ROC) of the pooled cohort equations by 6.5% (95% CI, 5.5%-7.5%; <i>P</i><0.001).</p><p><strong>Conclusions: </strong>Genomic and clinical risk factors for CAD display time-varying importance across the lifespan. The study underscores the added value of CAD PRS, particularly among individuals younger than 55 years, for enhancing early risk prediction and prevention strategies. All results are available at https://surbut.github.io/dynamicHRpaper/index.html.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004681"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028075","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":"Evaluation of a Machine Learning-Guided Strategy for Elevated Lipoprotein(a) Screening in Health Systems.","authors":"Arya Aminorroaya, Lovedeep S Dhingra, Evangelos K Oikonomou, Rohan Khera","doi":"10.1161/CIRCGEN.124.004632","DOIUrl":"10.1161/CIRCGEN.124.004632","url":null,"abstract":"<p><strong>Background: </strong>While universal screening for Lipoprotein(a) [Lp(a)] is increasingly recommended, <0.5% of patients undergo Lp(a) testing. Here, we assessed the feasibility of deploying Algorithmic Risk Inspection for Screening Elevated Lp(a) (ARISE), a validated machine learning tool, to health system electronic health records to increase the yield of Lp(a) testing.</p><p><strong>Methods: </strong>We randomly sampled 100 000 patients from the Yale-New Haven Health System to evaluate the feasibility of ARISE deployment. We also evaluated Lp(a)-tested populations in the Yale-New Haven Health System (n=7981) and the Vanderbilt University Medical Center (n=10 635) to assess the association of ARISE score with elevated Lp(a). To compare the representativeness of the Lp(a)-tested population, we included 456 815 participants from the UK Biobank and 23 280 from 3 US-based cohorts of Atherosclerosis Risk in Communities, Coronary Artery Risk Development in Young Adults, and Multi-Ethnic Study of Atherosclerosis.</p><p><strong>Results: </strong>Among 100 000 randomly selected Yale-New Haven Health System patients, 413 (0.4%) had undergone Lp(a) measurement. ARISE score could be computed for 31 586 patients based on existing data, identifying 2376 (7.5%) patients with a high probability of elevated Lp(a). A positive ARISE score was associated with significantly higher odds of elevated Lp(a) in the Yale-New Haven Health System (odds ratio, 1.87 [95% CI, 1.65-2.12]) and the Vanderbilt University Medical Center (odds ratio, 1.41 [95% CI, 1.24-1.60]). The Lp(a)-tested population significantly differed from other study cohorts in terms of ARISE features.</p><p><strong>Conclusions: </strong>We demonstrate the feasibility of deployment of ARISE in US health systems to define the risk of elevated Lp(a), enabling a high-yield testing strategy. We also confirm the markedly low adoption of Lp(a) testing, which is also being restricted to a highly selected population.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004632"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022412","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":"Lipoprotein(a) Atherosclerotic Cardiovascular Disease Risk Score Development and Prediction in Primary Prevention From Real-World Data.","authors":"Wenjun Fan, Chuyue Wu, Nathan D Wong","doi":"10.1161/CIRCGEN.124.004631","DOIUrl":"10.1161/CIRCGEN.124.004631","url":null,"abstract":"<p><strong>Background: </strong>Lipoprotein(a) [Lp(a)] is a predictor of atherosclerotic cardiovascular disease (ASCVD); however, there are few algorithms incorporating Lp(a), especially from real-world settings. We developed an electronic health record (EHR)-based risk prediction algorithm including Lp(a).</p><p><strong>Methods: </strong>Utilizing a large EHR database, we categorized Lp(a) cut points at 25, 50, and 75 mg/dL and constructed 10-year ASCVD risk prediction models incorporating Lp(a), with external validation in a pooled cohort of 4 US prospective studies. Net reclassification improvement was determined among borderline-intermediate risk patients.</p><p><strong>Results: </strong>We included 5902 patients aged ≥18 years (mean age 48.7±16.7 years, 51.2% women, and 7.7% Black). Our EHR model included Lp(a), age, sex, Black race/ethnicity, systolic blood pressure, total and high-density lipoprotein cholesterol, diabetes, smoking, and hypertension medication. Over a mean follow-up of 6.8 years, ASCVD event rates (per 1000 person-years) ranged from 8.7 to 16.7 across Lp(a) groups. A 25 mg/dL increment in Lp(a) was associated with an adjusted hazard ratio of 1.23 (95% CI, 1.10-1.37) for composite ASCVD. Those with Lp(a) ≥75 mg/dL had an 88% higher risk of ASCVD (hazard ratio, 1.88 [95% CI, 1.30-2.70]) and more than double the risk of incident stroke (hazard ratio, 2.55 [95% CI, 1.54-4.23]). C-statistics for our EHR and EHR+Lp(a) models in our EHR training data set were 0.7475 and 0.7556, respectively, with external validation in our pooled cohort (n=21 864) of 0.7350 and 0.7368, respectively. Among those at borderline/intermediate risk, the net reclassification improvement was 21.3%.</p><p><strong>Conclusions: </strong>We show the feasibility of developing an improved ASCVD risk prediction model incorporating Lp(a) based on a real-world adult clinic population. The inclusion of Lp(a) in ASCVD prediction models can reclassify risk in patients who may benefit from more intensified ASCVD prevention efforts.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004631"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028076","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":"Family Screening in Patients With Dilated and Arrhythmogenic Cardiomyopathy: The Road Toward Gene-Specific Recommendations.","authors":"Sophie L V M Stroeks, Steven Muller, Nina J Beelen, Max F G H M Venner, Annette F Baas, Vanessa P M van Empel, Ingrid P C Krapels, Mark R Hazebroek, Anneline S J M Te Riele, Job A J Verdonschot","doi":"10.1161/CIRCGEN.124.004778","DOIUrl":"10.1161/CIRCGEN.124.004778","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004778"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001120","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}