Background: Pericoronary epicardial adipose tissue (EAT) is a unique visceral fat depot that surrounds the adventitia of the coronary arteries without any anatomic barrier. Clinical studies have demonstrated the association between EAT volume and increased risks for coronary artery disease (CAD). However, the cellular and molecular mechanisms underlying the association remain elusive.
Methods: We performed single-nucleus RNA sequencing on pericoronary EAT samples collected from 3 groups of subjects: patients undergoing coronary bypass surgery for severe CAD (n=8), patients with CAD with concomitant type 2 diabetes (n=8), and patients with valvular diseases but without concomitant CAD and type 2 diabetes as the control group (n=8). Comparative analyses were performed among groups, including cellular compositional analysis, cell type-resolved transcriptomic changes, gene coexpression network analysis, and intercellular communication analysis. Immunofluorescence staining was performed to confirm the presence of CAD-associated subclusters.
Results: Unsupervised clustering of 73 386 nuclei identified 15 clusters, encompassing all known cell types in the adipose tissue. Distinct subpopulations were identified within primary cell types, including adipocytes, adipose stem and progenitor cells, and macrophages. CD83high macrophages and FOSBhigh adipocytes were significantly expanded in CAD. In comparison to normal controls, both disease groups exhibited dysregulated pathways and altered secretome in the primary cell types. Nevertheless, minimal differences were noted between the disease groups in terms of cellular composition and transcriptome. In addition, our data highlight a potential interplay between dysregulated circadian clock and altered physiological functions in adipocytes of pericoronary EAT. ANXA1 (annexin A1) and SEMA3B (semaphorin 3B) were identified as important adipokines potentially involved in functional changes of pericoronary EAT and CAD pathogenesis.
Conclusions: We built a complete single-nucleus transcriptomic atlas of human pericoronary EAT in normal and diseased conditions of CAD. Our study lays the foundation for developing novel therapeutic strategies for treating CAD by targeting and modifying pericoronary EAT functions.
{"title":"Single-Nucleus Transcriptomic Atlas of Human Pericoronary Epicardial Adipose Tissue in Normal and Pathological Conditions.","authors":"Xuanyu Liu, Meng Yuan, Danni Zhao, Qingyi Zeng, Wenke Li, Tianjiao Li, Qi Li, Yue Zhuo, Mingyao Luo, Pengfei Chen, Liqing Wang, Wei Feng, Zhou Zhou","doi":"10.1161/ATVBAHA.124.320923","DOIUrl":"10.1161/ATVBAHA.124.320923","url":null,"abstract":"<p><strong>Background: </strong>Pericoronary epicardial adipose tissue (EAT) is a unique visceral fat depot that surrounds the adventitia of the coronary arteries without any anatomic barrier. Clinical studies have demonstrated the association between EAT volume and increased risks for coronary artery disease (CAD). However, the cellular and molecular mechanisms underlying the association remain elusive.</p><p><strong>Methods: </strong>We performed single-nucleus RNA sequencing on pericoronary EAT samples collected from 3 groups of subjects: patients undergoing coronary bypass surgery for severe CAD (n=8), patients with CAD with concomitant type 2 diabetes (n=8), and patients with valvular diseases but without concomitant CAD and type 2 diabetes as the control group (n=8). Comparative analyses were performed among groups, including cellular compositional analysis, cell type-resolved transcriptomic changes, gene coexpression network analysis, and intercellular communication analysis. Immunofluorescence staining was performed to confirm the presence of CAD-associated subclusters.</p><p><strong>Results: </strong>Unsupervised clustering of 73 386 nuclei identified 15 clusters, encompassing all known cell types in the adipose tissue. Distinct subpopulations were identified within primary cell types, including adipocytes, adipose stem and progenitor cells, and macrophages. <i>CD83</i><sup>high</sup> macrophages and <i>FOSB</i><sup>high</sup> adipocytes were significantly expanded in CAD. In comparison to normal controls, both disease groups exhibited dysregulated pathways and altered secretome in the primary cell types. Nevertheless, minimal differences were noted between the disease groups in terms of cellular composition and transcriptome. In addition, our data highlight a potential interplay between dysregulated circadian clock and altered physiological functions in adipocytes of pericoronary EAT. ANXA1 (annexin A1) and SEMA3B (semaphorin 3B) were identified as important adipokines potentially involved in functional changes of pericoronary EAT and CAD pathogenesis.</p><p><strong>Conclusions: </strong>We built a complete single-nucleus transcriptomic atlas of human pericoronary EAT in normal and diseased conditions of CAD. Our study lays the foundation for developing novel therapeutic strategies for treating CAD by targeting and modifying pericoronary EAT functions.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141173652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-26DOI: 10.1161/ATVBAHA.124.321178
James H Morrissey
{"title":"HRG to the Rescue.","authors":"James H Morrissey","doi":"10.1161/ATVBAHA.124.321178","DOIUrl":"10.1161/ATVBAHA.124.321178","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11210687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: While it has been hypothesized that high plaque stress and strain may be related to plaque rupture, its direct verification using in vivo coronary plaque rupture data and full 3-dimensional fluid-structure interaction models is lacking in the current literature due to difficulty in obtaining in vivo plaque rupture imaging data from patients with acute coronary syndrome. This case-control study aims to use high-resolution optical coherence tomography-verified in vivo plaque rupture data and 3-dimensional fluid-structure interaction models to seek direct evidence for the high plaque stress/strain hypothesis.
Methods: In vivo coronary plaque optical coherence tomography data (5 ruptured plaques, 5 no-rupture plaques) were acquired from patients using a protocol approved by the local institutional review board with informed consent obtained. The ruptured caps were reconstructed to their prerupture morphology using neighboring plaque cap and vessel geometries. Optical coherence tomography-based 3-dimensional fluid-structure interaction models were constructed to obtain plaque stress, strain, and flow shear stress data for comparative analysis. The rank-sum test in the nonparametric test was used for statistical analysis.
Results: Our results showed that the average maximum cap stress and strain values of ruptured plaques were 142% (457.70 versus 189.22 kPa; P=0.0278) and 48% (0.2267 versus 0.1527 kPa; P=0.0476) higher than that for no-rupture plaques, respectively. The mean values of maximum flow shear stresses for ruptured and no-rupture plaques were 145.02 dyn/cm2 and 81.92 dyn/cm2 (P=0.1111), respectively. However, the flow shear stress difference was not statistically significant.
Conclusions: This preliminary case-control study showed that the ruptured plaque group had higher mean maximum stress and strain values. Due to our small study size, larger scale studies are needed to further validate our findings.
{"title":"Plaque Ruptures Are Related to High Plaque Stress and Strain Conditions: Direct Verification by Using In Vivo OCT Rupture Data and FSI Models.","authors":"Chen Zhao, Rui Lv, Akiko Maehara, Liang Wang, Zhanqun Gao, Yishuo Xu, Xiaoya Guo, Yanwen Zhu, Mengde Huang, Xiaoguo Zhang, Jian Zhu, Bo Yu, Haibo Jia, Gary S Mintz, Dalin Tang","doi":"10.1161/ATVBAHA.124.320764","DOIUrl":"10.1161/ATVBAHA.124.320764","url":null,"abstract":"<p><strong>Background: </strong>While it has been hypothesized that high plaque stress and strain may be related to plaque rupture, its direct verification using in vivo coronary plaque rupture data and full 3-dimensional fluid-structure interaction models is lacking in the current literature due to difficulty in obtaining in vivo plaque rupture imaging data from patients with acute coronary syndrome. This case-control study aims to use high-resolution optical coherence tomography-verified in vivo plaque rupture data and 3-dimensional fluid-structure interaction models to seek direct evidence for the high plaque stress/strain hypothesis.</p><p><strong>Methods: </strong>In vivo coronary plaque optical coherence tomography data (5 ruptured plaques, 5 no-rupture plaques) were acquired from patients using a protocol approved by the local institutional review board with informed consent obtained. The ruptured caps were reconstructed to their prerupture morphology using neighboring plaque cap and vessel geometries. Optical coherence tomography-based 3-dimensional fluid-structure interaction models were constructed to obtain plaque stress, strain, and flow shear stress data for comparative analysis. The rank-sum test in the nonparametric test was used for statistical analysis.</p><p><strong>Results: </strong>Our results showed that the average maximum cap stress and strain values of ruptured plaques were 142% (457.70 versus 189.22 kPa; <i>P</i>=0.0278) and 48% (0.2267 versus 0.1527 kPa; <i>P</i>=0.0476) higher than that for no-rupture plaques, respectively. The mean values of maximum flow shear stresses for ruptured and no-rupture plaques were 145.02 dyn/cm<sup>2</sup> and 81.92 dyn/cm<sup>2</sup> (<i>P</i>=0.1111), respectively. However, the flow shear stress difference was not statistically significant.</p><p><strong>Conclusions: </strong>This preliminary case-control study showed that the ruptured plaque group had higher mean maximum stress and strain values. Due to our small study size, larger scale studies are needed to further validate our findings.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-05-16DOI: 10.1161/ATVBAHA.124.320790
Matthew W Ellis, Muhammad Riaz, Yan Huang, Christopher W Anderson, Marie Hoareau, Xin Li, Hangqi Luo, Seoyeon Lee, Jinkyu Park, Jiesi Luo, Luke D Batty, Qunhua Huang, Colleen A Lopez, Dieter P Reinhardt, George Tellides, Yibing Qyang
Background: A series of incurable cardiovascular disorders arise due to improper formation of elastin during development. Supravalvular aortic stenosis (SVAS), resulting from a haploinsufficiency of ELN, is caused by improper stress sensing by medial vascular smooth muscle cells, leading to progressive luminal occlusion and heart failure. SVAS remains incurable, as current therapies do not address the root issue of defective elastin.
Methods: We use SVAS here as a model of vascular proliferative disease using both human induced pluripotent stem cell-derived vascular smooth muscle cells and developmental Eln+/- mouse models to establish de novo elastin assembly as a new therapeutic intervention.
Results: We demonstrate mitigation of vascular proliferative abnormalities following de novo extracellular elastin assembly through the addition of the polyphenol epigallocatechin gallate to SVAS human induced pluripotent stem cell-derived vascular smooth muscle cells and in utero to Eln+/- mice.
Conclusions: We demonstrate de novo elastin deposition normalizes SVAS human induced pluripotent stem cell-derived vascular smooth muscle cell hyperproliferation and rescues hypertension and aortic mechanics in Eln+/- mice, providing critical preclinical findings for the future application of epigallocatechin gallate treatment in humans.
{"title":"De Novo Elastin Assembly Alleviates Development of Supravalvular Aortic Stenosis-Brief Report.","authors":"Matthew W Ellis, Muhammad Riaz, Yan Huang, Christopher W Anderson, Marie Hoareau, Xin Li, Hangqi Luo, Seoyeon Lee, Jinkyu Park, Jiesi Luo, Luke D Batty, Qunhua Huang, Colleen A Lopez, Dieter P Reinhardt, George Tellides, Yibing Qyang","doi":"10.1161/ATVBAHA.124.320790","DOIUrl":"10.1161/ATVBAHA.124.320790","url":null,"abstract":"<p><strong>Background: </strong>A series of incurable cardiovascular disorders arise due to improper formation of elastin during development. Supravalvular aortic stenosis (SVAS), resulting from a haploinsufficiency of <i>ELN</i>, is caused by improper stress sensing by medial vascular smooth muscle cells, leading to progressive luminal occlusion and heart failure. SVAS remains incurable, as current therapies do not address the root issue of defective elastin.</p><p><strong>Methods: </strong>We use SVAS here as a model of vascular proliferative disease using both human induced pluripotent stem cell-derived vascular smooth muscle cells and developmental <i>Eln</i><sup>+/-</sup> mouse models to establish de novo elastin assembly as a new therapeutic intervention.</p><p><strong>Results: </strong>We demonstrate mitigation of vascular proliferative abnormalities following de novo extracellular elastin assembly through the addition of the polyphenol epigallocatechin gallate to SVAS human induced pluripotent stem cell-derived vascular smooth muscle cells and in utero to <i>Eln</i><sup>+/-</sup> mice.</p><p><strong>Conclusions: </strong>We demonstrate de novo elastin deposition normalizes SVAS human induced pluripotent stem cell-derived vascular smooth muscle cell hyperproliferation and rescues hypertension and aortic mechanics in <i>Eln</i><sup>+/-</sup> mice, providing critical preclinical findings for the future application of epigallocatechin gallate treatment in humans.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11209776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-26DOI: 10.1161/ATVBAHA.124.320142
Ravichandran Ramasamy, Alexander Shekhtman, Ann Marie Schmidt
{"title":"RAGE/DIAPH1 Axis and Cardiometabolic Disease: From Nascent Discoveries to Therapeutic Potential.","authors":"Ravichandran Ramasamy, Alexander Shekhtman, Ann Marie Schmidt","doi":"10.1161/ATVBAHA.124.320142","DOIUrl":"10.1161/ATVBAHA.124.320142","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11210684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-26DOI: 10.1161/ATVBAHA.124.321157
Anna L Pouncey, Janet T Powell
{"title":"Through the Smoke Screen Clearly.","authors":"Anna L Pouncey, Janet T Powell","doi":"10.1161/ATVBAHA.124.321157","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321157","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454840","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 : 2024-07-01Epub Date: 2024-06-26DOI: 10.1161/ATVBAHA.124.319396
Kenji Kawai, Rika Kawakami, Aloke V Finn, Renu Virmani
{"title":"Differences in Stable and Unstable Atherosclerotic Plaque.","authors":"Kenji Kawai, Rika Kawakami, Aloke V Finn, Renu Virmani","doi":"10.1161/ATVBAHA.124.319396","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.319396","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454832","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 : 2024-07-01Epub Date: 2024-05-30DOI: 10.1161/ATVBAHA.124.319845
Peter William Jones, Ziad Mallat, Meritxell Nus
Atherosclerosis is a complex inflammatory disease in which the adaptive immune response plays an important role. While the overall impact of T and B cells in atherosclerosis is relatively well established, we are only beginning to understand how bidirectional T-cell/B-cell interactions can exert prominent atheroprotective and proatherogenic functions. In this review, we will focus on these T-cell/B-cell interactions and how we could use them to therapeutically target the adaptive immune response in atherosclerosis.
动脉粥样硬化是一种复杂的炎症性疾病,适应性免疫反应在其中发挥着重要作用。虽然 T 细胞和 B 细胞在动脉粥样硬化中的总体影响已相对确定,但我们才刚刚开始了解 T 细胞/B 细胞的双向相互作用如何发挥突出的动脉粥样硬化保护和致动脉粥样硬化功能。在这篇综述中,我们将重点讨论这些 T 细胞/B 细胞相互作用,以及如何利用它们来治疗动脉粥样硬化中的适应性免疫反应。
{"title":"T-Cell/B-Cell Interactions in Atherosclerosis.","authors":"Peter William Jones, Ziad Mallat, Meritxell Nus","doi":"10.1161/ATVBAHA.124.319845","DOIUrl":"10.1161/ATVBAHA.124.319845","url":null,"abstract":"<p><p>Atherosclerosis is a complex inflammatory disease in which the adaptive immune response plays an important role. While the overall impact of T and B cells in atherosclerosis is relatively well established, we are only beginning to understand how bidirectional T-cell/B-cell interactions can exert prominent atheroprotective and proatherogenic functions. In this review, we will focus on these T-cell/B-cell interactions and how we could use them to therapeutically target the adaptive immune response in atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141173655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-05-30DOI: 10.1161/ATVBAHA.124.319844
James W O'Brien, Ayden Case, Claudia Kemper, Tian X Zhao, Ziad Mallat
The adaptive immune system plays an important role in the development and progression of atherosclerotic cardiovascular disease. B cells can have both proatherogenic and atheroprotective roles, making treatments aimed at modulating B cells important therapeutic targets. The innate-like B-cell response is generally considered atheroprotective, while the adaptive response is associated with mixed consequences for atherosclerosis. Additionally, interactions of B cells with components of the adaptive and innate immune system, including T cells and complement, also represent key points for therapeutic regulation. In this review, we discuss therapeutic approaches based on B-cell depletion, modulation of B-cell survival, manipulation of both the antibody-dependent and antibody-independent B-cell response, and emerging immunization techniques.
适应性免疫系统在动脉粥样硬化性心血管疾病的发生和发展过程中扮演着重要角色。B 细胞既能诱发动脉粥样硬化,也能保护动脉粥样硬化,因此,旨在调节 B 细胞的治疗方法是重要的治疗目标。先天性类 B 细胞反应通常被认为具有动脉粥样硬化保护作用,而适应性反应对动脉粥样硬化的影响则好坏参半。此外,B 细胞与适应性和先天性免疫系统成分(包括 T 细胞和补体)的相互作用也是治疗调节的关键点。在这篇综述中,我们将讨论基于 B 细胞耗竭、B 细胞存活调节、抗体依赖性和抗体非依赖性 B 细胞反应操控以及新兴免疫技术的治疗方法。
{"title":"Therapeutic Avenues to Modulate B-Cell Function in Patients With Cardiovascular Disease.","authors":"James W O'Brien, Ayden Case, Claudia Kemper, Tian X Zhao, Ziad Mallat","doi":"10.1161/ATVBAHA.124.319844","DOIUrl":"10.1161/ATVBAHA.124.319844","url":null,"abstract":"<p><p>The adaptive immune system plays an important role in the development and progression of atherosclerotic cardiovascular disease. B cells can have both proatherogenic and atheroprotective roles, making treatments aimed at modulating B cells important therapeutic targets. The innate-like B-cell response is generally considered atheroprotective, while the adaptive response is associated with mixed consequences for atherosclerosis. Additionally, interactions of B cells with components of the adaptive and innate immune system, including T cells and complement, also represent key points for therapeutic regulation. In this review, we discuss therapeutic approaches based on B-cell depletion, modulation of B-cell survival, manipulation of both the antibody-dependent and antibody-independent B-cell response, and emerging immunization techniques.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141173698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-05-23DOI: 10.1161/ATVBAHA.123.320287
Mark Trinder, Lubomira Cermakova, Isabelle Ruel, Alexis Baass, Martine Paquette, Jian Wang, Brooke A Kennedy, Robert A Hegele, Jacques Genest, Liam R Brunham
Background: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH.
Methods: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease.
Results: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant.
Conclusions: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.
{"title":"Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia.","authors":"Mark Trinder, Lubomira Cermakova, Isabelle Ruel, Alexis Baass, Martine Paquette, Jian Wang, Brooke A Kennedy, Robert A Hegele, Jacques Genest, Liam R Brunham","doi":"10.1161/ATVBAHA.123.320287","DOIUrl":"10.1161/ATVBAHA.123.320287","url":null,"abstract":"<p><strong>Background: </strong>Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH.</p><p><strong>Methods: </strong>We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease.</p><p><strong>Results: </strong>Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant.</p><p><strong>Conclusions: </strong>Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}