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Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances. 合并血脂紊乱的基因结构与临床结果
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-05 Epub Date: 2024-06-03 DOI: 10.1161/CIRCRESAHA.123.323973
Thomas Gilliland, Jacqueline S Dron, Margaret Sunitha Selvaraj, Mark Trinder, Kaavya Paruchuri, Sarah M Urbut, Sara Haidermota, Rachel Bernardo, Md Mesbah Uddin, Michael C Honigberg, Gina M Peloso, Pradeep Natarajan

Background: Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort.

Methods: Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data.

Results: Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P=2×10-16), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P=2.6×10-12). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia.

Conclusions: Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.

背景:脂蛋白异常血症通常涉及多种血脂特征的同时失调。我们的目的是评估基于普通人群的队列中合并血脂紊乱的表型和遗传特征:方法:在英国生物数据库(UK Biobank)参与者中,如果没有流行性冠状动脉疾病,我们使用血脂和载脂蛋白 B 浓度将其归入 6 种可重复且相互排斥的脂蛋白异常亚型中的一种。使用 Cox 比例危险模型估算了每个亚型的冠心病发病风险。对每个亚型进行了全表型分析和全基因组关联研究,然后进行了硅学因果基因优先排序和遗传率分析。此外,还利用全外显子组序列数据评估了孟德尔血脂紊乱病因基因中破坏性变异的发生率:结果:在 450 636 名英国生物库参与者中,有 63 人(0.01%)患有血脂紊乱:63人(0.01%)患有乳糜微粒血症;40 005人(8.9%)患有高胆固醇血症;94 785人(21.0%)患有合并高脂血症;13 998人(3.1%)患有残余高胆固醇血症;110 389人(24.5%)患有高甘油三酯血症;49人(0.01%)患有混合型高甘油三酯血症和高胆固醇血症。在11.1(10.4-11.8)年的中位数(四分位数间距)随访期间,不同亚型的冠心病发病风险各不相同,其中合并高脂血症的风险最大(危险比为1.92 [95% CI, 1.84-2.01];P=2×10-16),即使考虑到非高密度脂蛋白胆固醇(危险比为1.45 [95% CI, 1.30-1.60];P=2.6×10-12)。全基因组关联研究揭示了与脂蛋白血症亚型显著相关的 250 个位点,其中 72 个位点(28.8%)在之前的单一血脂性状全基因组关联研究中未被检测到。在脂蛋白血症患者中,孟德尔血脂变异携带者很少见(2.0%),但多基因遗传率很高,从残余高胆固醇血症的23%到合并高脂血症的54%不等:结论:对多种血脂异常的同时评估揭示了不同脂蛋白异常亚型的冠心病风险和遗传结构的细微差别。这些发现强调了超越单一血脂特征以更好地了解血脂和脂蛋白综合表型及其对疾病风险影响的重要性。
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引用次数: 0
TRIM35: A Proposed Gateway to p53-Induced Heart Failure Pathogenesis. TRIM35:p53诱导心力衰竭发病机制的拟议通道。
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-05 Epub Date: 2024-07-04 DOI: 10.1161/CIRCRESAHA.124.324792
Chang Jie Mick Lee, Roger S-Y Foo
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引用次数: 0
Exploring the Function of Epicardial Cells Beyond the Surface. 探索心外膜细胞表面之外的功能
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-05 Epub Date: 2024-07-04 DOI: 10.1161/CIRCRESAHA.124.321567
David Wong, Julie Martinez, Pearl Quijada

The epicardium, previously viewed as a passive outer layer around the heart, is now recognized as an essential component in development, regeneration, and repair. In this review, we explore the cellular and molecular makeup of the epicardium, highlighting its roles in heart regeneration and repair in zebrafish and salamanders, as well as its activation in young and adult postnatal mammals. We also examine the latest technologies used to study the function of epicardial cells for therapeutic interventions. Analysis of highly regenerative animal models shows that the epicardium is essential in regulating cardiomyocyte proliferation, transient fibrosis, and neovascularization. However, despite the epicardium's unique cellular programs to resolve cardiac damage, it remains unclear how to replicate these processes in nonregenerative mammalian organisms. During myocardial infarction, epicardial cells secrete signaling factors that modulate fibrotic, vascular, and inflammatory remodeling, which differentially enhance or inhibit cardiac repair. Recent transcriptomic studies have validated the cellular and molecular heterogeneity of the epicardium across various species and developmental stages, shedding further light on its function under pathological conditions. These studies have also provided insights into the function of regulatory epicardial-derived signaling molecules in various diseases, which could lead to new therapies and advances in reparative cardiovascular medicine. Moreover, insights gained from investigating epicardial cell function have initiated the development of novel techniques, including using human pluripotent stem cells and cardiac organoids to model reparative processes within the cardiovascular system. This growing understanding of epicardial function holds the potential for developing innovative therapeutic strategies aimed at addressing developmental heart disorders, enhancing regenerative therapies, and mitigating cardiovascular disease progression.

心外膜以前被视为心脏周围的一个被动外层,现在被认为是心脏发育、再生和修复的重要组成部分。在这篇综述中,我们将探讨心外膜的细胞和分子构成,重点介绍心外膜在斑马鱼和蝾螈的心脏再生和修复中的作用,以及心外膜在哺乳动物幼年和成年后的激活过程。我们还考察了用于研究心外膜细胞功能以进行治疗干预的最新技术。对高度再生动物模型的分析表明,心外膜在调节心肌细胞增殖、短暂纤维化和新生血管方面至关重要。然而,尽管心外膜具有解决心脏损伤的独特细胞程序,但目前仍不清楚如何在非再生哺乳动物体内复制这些过程。心肌梗死期间,心外膜细胞分泌信号因子,调节纤维化、血管和炎症重塑,从而不同程度地增强或抑制心脏修复。最近的转录组学研究验证了心外膜在不同物种和发育阶段的细胞和分子异质性,进一步揭示了心外膜在病理条件下的功能。这些研究还深入揭示了源自心外膜的调控信号分子在各种疾病中的功能,这可能会带来新的疗法和心血管修复医学的进步。此外,研究心外膜细胞功能所获得的洞察力也促进了新技术的发展,包括使用人类多能干细胞和心脏器官组织来模拟心血管系统内的修复过程。人们对心外膜功能的了解不断加深,有望开发出创新的治疗策略,以解决心脏发育障碍、增强再生疗法和缓解心血管疾病进展。
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引用次数: 0
Phosphodiesterase Inhibitors in Cerebrovascular Perfusion and Pulsatility. 磷酸二酯酶抑制剂在脑血管灌注和脉动中的作用
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-05 Epub Date: 2024-07-04 DOI: 10.1161/CIRCRESAHA.124.324954
Jesus D Melgarejo
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引用次数: 0
Residences in Historically Redlined Districts in New York City Area Have More Indoor Particulate Air Pollution Potentially Reducible by Portable Air Cleaners. 纽约市地区历史上被划为红线区的住宅有更多的室内微粒空气污染,而便携式空气净化器有可能消除这些污染。
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-06-21 Epub Date: 2024-05-17 DOI: 10.1161/CIRCRESAHA.124.324486
Jacob R Blaustein, Heewon Alexandra Moon, Clarine Long, Luke J Bonanni, Terry Gordon, Lorna E Thorpe, Jonathan D Newman, Sharine Wittkopp
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引用次数: 0
From Grafts to Genes: Shaping Heart Care With Next-Generation Therapies. 从移植到基因:用新一代疗法塑造心脏护理。
IF 16.5 1区 医学 Q1 Medicine Pub Date : 2024-06-21 Epub Date: 2024-06-20 DOI: 10.1161/CIRCRESAHA.124.324573
Monika M Gladka
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引用次数: 0
G Protein-Coupled Receptors: A Century of Research and Discovery. G 蛋白偶联受体:一个世纪的研究与发现
IF 16.5 1区 医学 Q1 Medicine Pub Date : 2024-06-21 Epub Date: 2024-06-20 DOI: 10.1161/CIRCRESAHA.124.323067
Samuel Liu, Preston J Anderson, Sudarshan Rajagopal, Robert J Lefkowitz, Howard A Rockman

GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and β-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of β-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.

GPCR(G 蛋白偶联受体)又称 7 跨膜结构域受体,是人类基因组中最大的受体家族,有 800 多个成员。GPCR 几乎调控着人类生理和疾病的方方面面,因此是治疗心血管疾病的重要药物靶点。GPCR 具有由 7 个跨膜 α-螺旋组成的保守结构,可与异三聚 G 蛋白、GPCR 激酶和 β-阻遏蛋白结合,通过第二信使和其他细胞内信号通路促进下游信号传导。GPCR 药物的开发带来了重要的心血管疗法,如治疗心力衰竭和高血压的 β 肾上腺素能和血管紧张素 II 受体拮抗剂,以及用于减少不良心血管事件和其他新兴适应症的胰高血糖素样肽-1 受体激动剂。在 GPCR 机理研究和基于结构的药物设计取得进展的推动下,心血管和心血管代谢疾病领域的 GPCR 药物开发仍然备受关注。本综述回顾了 GPCR 研究的丰富历史,包括临床使用的 GPCR 药物的现状,并重点介绍了新发现的 GPCR 生物学方面以及未来有希望的研究方向。随着调节 GPCR 信号的更多机制被发现,针对这些无处不在的受体的新策略为心血管医学领域带来了巨大的希望。
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引用次数: 0
o8G Site-Specifically Modified tRF-1-AspGTC: A Novel Therapeutic Target and Biomarker for Pulmonary Hypertension. o8G 位点特异性修饰的 tRF-1-AspGTC:肺动脉高压的新型治疗靶点和生物标记物。
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-06-21 Epub Date: 2024-05-15 DOI: 10.1161/CIRCRESAHA.124.324421
Junting Zhang, Yiying Li, Yuan Chen, Jianchao Zhang, Zihui Jia, Muhua He, Xueyi Liao, Siyu He, Jin-Song Bian, Xiao-Wei Nie

Background: Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling.

Methods: Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine -modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH.

Results: This modification occurs at the position 5 of the tRF-1-AspGTC (5o8G tRF). Inhibition of the 5o8G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o8G tRF retargeted mRNA of WNT5A (Wingless-type MMTV integration site family, member 5A) and CASP3 (Caspase3) and inhibited their expression. Ultimately, BMPR2 (Bone morphogenetic protein receptor 2) -reactive oxygen species/5o8G tRF/WNT5A signaling pathway exacerbated the progression of PH.

Conclusions: Our study highlights the role of site-specific 8-oxoguanine-modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o8G tRF as a potential innovative marker for diagnosing this disease.

理由:缺氧和氧化应激有助于肺动脉高压(PH)的发展。tRNA衍生片段在RNA干扰和细胞增殖中发挥重要作用,但它们在PH发展中的表观转录作用尚未得到研究:我们旨在深入了解氧化应激诱导的 8-氧鸟嘌呤在肺血管重塑中的作用机制:通过小 RNA 修饰阵列分析和定量聚合酶链反应,发现 PH 患者的肺组织和血清中 8-氧鸟嘌呤修饰的 tRF-1-AspGTC 明显上调。这种修饰发生在 tRNA 衍生片段种子区的第五个 8-氧代鸟嘌呤(5o8G)tRF 上。抑制 5o8G tRF 可逆转缺氧诱导的肺动脉平滑肌细胞增殖和凋亡抵抗。进一步研究发现,5o8G tRF 重定向了 WNT5A 和 CASP3 的 mRNA,并抑制了它们的表达。最终,BMPR2(骨形态发生蛋白受体 2)-活性氧/5o8G tRF/WNT5A 信号通路加剧了 PH 的进展:我们的研究强调了特异位点8-氧鸟嘌呤修饰的tRF在促进PH发展中的作用。我们的研究结果为治疗 PH 提供了一条很有前景的治疗途径,并建议将 5o8G tRF 作为诊断这种疾病的潜在创新标记物。
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引用次数: 0
Meet the First Authors. 认识第一作者
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-06-21 Epub Date: 2024-06-20 DOI: 10.1161/RES.0000000000000678
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引用次数: 0
EnFUSiasm for Healing: Ultrasound Neuromodulation in PAH. EnFUSiasm for Healing:PAH 中的超声神经调制。
IF 16.5 1区 医学 Q1 Medicine Pub Date : 2024-06-21 Epub Date: 2024-06-20 DOI: 10.1161/CIRCRESAHA.124.324791
Olga Rafikova, Joel James, Tatiana V Kudryashova
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引用次数: 0
期刊
Circulation research
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