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Empowering the Future: The Importance of Recognizing Early Career Scientists in JACC: Basic to Translational Science 为未来赋能:在《JACC.Basic to Translational Science》杂志上表彰早期职业科学家的重要性:从基础科学到转化科学
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-01 DOI: 10.1016/j.jacbts.2024.07.002
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引用次数: 0
Association Between Clonal Hematopoiesis and Left Ventricular Reverse Remodeling in Nonischemic Dilated Cardiomyopathy 克隆性造血与非缺血性扩张型心肌病左心室逆重塑之间的关系
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-01 DOI: 10.1016/j.jacbts.2024.04.010

Although clonal hematopoiesis of indeterminate potential (CHIP) is an adverse prognostic factor for atherosclerotic disease, its impact on nonischemic dilated cardiomyopathy (DCM) is elusive. The authors performed whole-exome sequencing and deep target sequencing among 198 patients with DCM and detected germline mutations in cardiomyopathy-related genes and somatic mutations in CHIP driver genes. Twenty-five CHIP driver mutations were detected in 22 patients with DCM. Ninety-two patients had cardiomyopathy-related pathogenic mutations. Multivariable analysis revealed that CHIP was an independent risk factor of left ventricular reverse remodeling, irrespective of known prognostic factors. CHIP exacerbated cardiac systolic dysfunction and fibrosis in a DCM murine model. The identification of germline and somatic mutations in patients with DCM predicts clinical prognosis.

虽然不确定潜能克隆性造血(CHIP)是动脉粥样硬化疾病的不良预后因素,但它对非缺血性扩张型心肌病(DCM)的影响却难以捉摸。作者对198名DCM患者进行了全外显子组测序和深度靶向测序,检测到了心肌病相关基因的种系突变和CHIP驱动基因的体细胞突变。在22名DCM患者中检测到25个CHIP驱动基因突变。92名患者存在心肌病相关的致病基因突变。多变量分析显示,无论已知的预后因素如何,CHIP都是左心室逆向重塑的独立风险因素。在 DCM 小鼠模型中,CHIP 加剧了心脏收缩功能障碍和纤维化。在DCM患者中识别种系突变和体细胞突变可预测临床预后。
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引用次数: 0
Reduced Stroke Volume and Brain Perfusion Drive Postural Hyperventilation in Postural Orthostatic Tachycardia Syndrome 体位性正位性心动过速综合征患者脑卒中量减少和脑灌注减少驱动体位性过度换气
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-01 DOI: 10.1016/j.jacbts.2024.04.011

Postural hyperventilation has been implicated as a cause of postural orthostatic tachycardia syndrome (POTS), yet the precise mechanisms underlying the heightened breathing response remain unclear. This study challenges current hypotheses by revealing that exaggerated peripheral chemoreceptor activity is not the primary driver of postural hyperventilation. Instead, significant contributions from reduced stroke volume and compromised brain perfusion during orthostatic stress were identified. These findings shed light on our understanding of POTS pathophysiology, emphasizing the critical roles of systemic hemodynamic status. Further research should explore interventions targeting stroke volume and brain perfusion for more effective clinical management of POTS.

体位性过度通气被认为是体位性正位性心动过速综合征(POTS)的病因之一,但呼吸反应增强的确切机制仍不清楚。这项研究挑战了目前的假设,揭示了夸张的外周化学感受器活动并不是体位性过度通气的主要驱动因素。相反,在正立应激过程中,中风量减少和脑灌注受损对其有重大贡献。这些发现揭示了我们对 POTS 病理生理学的理解,强调了全身血液动力学状态的关键作用。进一步的研究应探索针对脑卒中容量和脑灌注的干预措施,以便对 POTS 进行更有效的临床治疗。
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引用次数: 0
LL-37: A Direct Link Between Inflammation and Myocardial Infarction LL-37:炎症与心肌梗死之间的直接联系
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-01 DOI: 10.1016/j.jacbts.2024.05.007
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引用次数: 0
A Novel Pathway of Platelet Activation in ACS Mediated by LL-37 Immunoglobulin G Autoantibody Immune Complexes 由 LL-37 免疫球蛋白 G 自身抗体免疫复合物介导的 ACS 中血小板活化的新途径
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-01 DOI: 10.1016/j.jacbts.2024.04.012

The cathelicidin antimicrobial peptide LL-37 is a self-antigen in neutrophil extracellular traps that provokes autoantibody responses in autoimmune/autoinflammatory conditions. LL-37 immunoglobulin (Ig) G autoantibody levels were measured in subjects with and without atherosclerotic cardiovascular disease assessed using the coronary artery calcium score, in patients who had a future myocardial infarction and in a cohort of acute coronary syndrome (ACS) patients. LL-37 IgG levels were not associated with coronary artery calcium score, but future myocardial infarction patients had significantly higher LL-37 IgG at baseline. Reduced LL-37 IgG in ACS was associated with increased LL-37 IgG–immune complex. ACS plasma increased activated CD62P+ platelets from healthy donors mediated in part by LL-37 IgG–immune complexes and platelet Fc gamma receptor 2a.

柔毛苷抗菌肽 LL-37 是中性粒细胞胞外捕获器中的一种自身抗原,在自身免疫/自身炎症情况下会引起自身抗体反应。在使用冠状动脉钙化评分评估患有和未患有动脉粥样硬化性心血管疾病的受试者、未来发生过心肌梗死的患者以及急性冠状动脉综合征(ACS)患者队列中测量了 LL-37 免疫球蛋白 (Ig) G 自身抗体水平。LL-37 IgG 水平与冠状动脉钙化评分无关,但未来心肌梗塞患者的基线 LL-37 IgG 水平明显更高。ACS 患者 LL-37 IgG 的降低与 LL-37 IgG 免疫复合物的增加有关。ACS 血浆增加了健康捐献者的 CD62P+ 活化血小板,部分原因是 LL-37 IgG 免疫复合物和血小板 Fc γ 受体 2a 的介导。
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引用次数: 0
Human Aortic Stenotic Valve-Derived Extracellular Vesicles Induce Endothelial Dysfunction and Thrombogenicity Through AT1R/NADPH Oxidases/SGLT2 Pro-Oxidant Pathway 人主动脉瓣狭窄衍生的细胞外囊泡通过 AT1R/NADPH 氧化酶/SGLT2 促氧化剂途径诱导内皮功能障碍和血栓形成
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-01 DOI: 10.1016/j.jacbts.2024.02.012

Pathological tissues release a variety of factors, including extracellular vesicles (EVs) shed by activated or apoptotic cells. EVs trapped within the native pathological valves may act as key mediators of valve thrombosis. Human aortic stenosis EVs promote activation of valvular endothelial cells, leading to endothelial dysfunction, and proadhesive and procoagulant responses.

病理组织会释放多种因子,包括活化或凋亡细胞脱落的细胞外囊泡 (EV)。滞留在原生病理瓣膜内的 EVs 可能是瓣膜血栓形成的关键介质。人类主动脉瓣狭窄 EVs 可促进瓣膜内皮细胞的活化,导致内皮功能障碍以及促粘附和促凝血反应。
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引用次数: 0
Novel Tryptophan Hydroxylase Inhibitor TPT-001 Reverses PAH, Vascular Remodeling, and Proliferative-Proinflammatory Gene Expression 新型色氨酸羟化酶抑制剂 TPT-001 可逆转 PAH、血管重塑和增殖-炎症基因表达
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-01 DOI: 10.1016/j.jacbts.2024.04.006

The serotonin pathway has long been proposed as a promising target for pulmonary arterial hypertension (PAH)—a progressive and uncurable disease. We developed a highly specific inhibitor of the serotonin synthesizing enzyme tryptophan hydroxylase 1 (TPH1), TPT-001 (TPHi). In this study, the authors sought to treat severe PAH in the Sugen/hypoxia (SuHx) rat model with the oral TPHi TPT-001. Male Sprague Dawley rats were divided into 3 groups: 1) ConNx, control animals; 2) SuHx, injected subcutaneously with SU5416 and exposed to chronic hypoxia for 3 weeks, followed by 6 weeks in room air; and 3) SuHx+TPHi, SuHx animals treated orally with TPHi for 5 weeks. Closed-chest right- and left heart catheterization and echocardiography were performed. Lungs were subject to histologic and mRNA sequencing analyses. Compared with SuHx-exposed rats, which developed severe PAH and right ventricular (RV) dysfunction, TPHi-treated SuHx rats had greatly lowered RV systolic (mean ± SEM: 41 ± 2.3 mm Hg vs 86 ± 6.5 mm Hg; P < 0.001) and end-diastolic (mean ± SEM: 4 ± 0.7 mm Hg vs 14 ± 1.7 mm Hg; P < 0.001) pressures, decreased RV hypertrophy and dilation (all not significantly different from control rats), and reversed pulmonary vascular remodeling. We identified perivascular infiltration of CD3+ T cells and proinflammatory F4/80+ and CD68+ macrophages and proliferating cell nuclear antigen–positive alveolar epithelial cells all suppressed by TPHi treatment. Whole-lung mRNA sequencing in SuHx rats showed distinct gene expression patterns related to pulmonary arterial smooth muscle cell proliferation (Rpph1, Lgals3, Gata4), reactive oxygen species, inflammation (Tnfsrf17, iNOS), and vasodilation (Pde1b, Kng1), which reversed expression with TPHi treatment. Inhibition of TPH1 with a new class of drugs (here, TPT-001) has the potential to attenuate or even reverse severe PAH and associated RV dysfunction in vivo by blocking the serotonin pathway.

长期以来,人们一直认为血清素通路是治疗肺动脉高压(PAH)--一种进行性和无法治愈的疾病--的有希望的靶点。我们开发了一种高度特异性的血清素合成酶色氨酸羟化酶 1 (TPH1) 抑制剂 TPT-001 (TPHi)。在这项研究中,作者试图用口服 TPHi TPT-001 治疗苏根/缺氧(SuHx)大鼠模型中的严重 PAH。雄性 Sprague Dawley 大鼠被分为 3 组:1)ConNx,对照组;2)SuHx,皮下注射 SU5416 并暴露于慢性缺氧环境 3 周,然后在室内空气中暴露 6 周;3)SuHx+TPHi,SuHx 动物口服 TPHi 治疗 5 周。进行闭胸左右心导管检查和超声心动图检查。对肺部进行组织学和 mRNA 测序分析。与发生严重 PAH 和右心室(RV)功能障碍的 SuHx 暴露大鼠相比,经 TPHi 处理的 SuHx 大鼠的 RV 收缩压(平均值 ± SEM:41 ± 2.3 mm Hg vs 86 ± 6.5 mm Hg;P < 0.001)和舒张末压(平均值 ± SEM:4 ± 0.7 mm Hg vs 14 ± 1.7 mm Hg;P <;0.001),减少了 RV 肥厚和扩张(与对照组大鼠相比均无显著差异),并逆转了肺血管重塑。我们发现 CD3+ T 细胞和促炎 F4/80+ 及 CD68+ 巨噬细胞以及增殖细胞核抗原阳性肺泡上皮细胞的血管周围浸润均受到 TPHi 治疗的抑制。对 SuHx 大鼠进行的全肺 mRNA 测序显示,与肺动脉平滑肌细胞增殖(Rpph1、Lgals3、Gata4)、活性氧、炎症(Tnfsrf17、iNOS)和血管舒张(Pde1b、Kng1)相关的基因表达模式各不相同,TPHi 治疗可逆转这些基因的表达。用一类新药(此处为 TPT-001)抑制 TPH1 有可能通过阻断血清素通路,减轻甚至逆转体内严重 PAH 和相关的 RV 功能障碍。
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引用次数: 0
The Uses and Misuses of Mendelian Randomization in Clinical and Translational Science 孟德尔随机化在临床和转化科学中的应用与误用
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-01 DOI: 10.1016/j.jacbts.2024.06.005
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引用次数: 0
Genetics and Pharmacogenetics of Atrial Fibrillation 心房颤动的遗传学和药物遗传学
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-01 DOI: 10.1016/j.jacbts.2023.12.006

The heritability of atrial fibrillation (AF) is well established. Over the last decade genetic architecture of AF has been unraveled by genome-wide association studies and family-based studies. However, the translation of these genetic discoveries has lagged owing to an incomplete understanding of the pathogenic mechanisms underlying the genetic variants, challenges in classifying variants of uncertain significance (VUS), and limitations of existing disease models. We review the mechanistic insight provided by basic science studies regarding AF mechanisms, recent developments in high-throughput classification of VUS, and advances in bioengineered cardiac models for developing personalized therapy for AF.

心房颤动(房颤)的遗传性已得到公认。过去十年间,全基因组关联研究和基于家族的研究揭示了心房颤动的遗传结构。然而,由于对遗传变异背后的致病机制了解不全面、对意义不确定的变异进行分类面临挑战以及现有疾病模型的局限性,这些遗传学发现的转化工作一直滞后。我们回顾了基础科学研究就房颤机制提供的机理见解、高通量 VUS 分类的最新进展以及用于开发房颤个性化疗法的生物工程心脏模型的进展。
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引用次数: 0
Clopidogrel-Mediated P2Y12 Inhibition According to Renal Function in Patients With Diabetes Mellitus and CAD 根据糖尿病和冠心病患者的肾功能确定氯吡格雷介导的 P2Y12 抑制作用
IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-07-01 DOI: 10.1016/j.jacbts.2024.03.003

This prospective ex vivo and in vitro pharmacodynamic (PD)/pharmacokinetic investigation was conducted in patients with diabetes mellitus with (n = 31) and without chronic kidney disease (n = 30). PD assessments included platelet reactivity index, maximum platelet aggregation, and P2Y12 reaction units. Ex vivo pharmacokinetic assessments included plasma levels of clopidogrel and its active metabolite. In vitro PD assessments were conducted on baseline samples incubated with escalating concentrations of clopidogrel and its active metabolite. Among patients with diabetes mellitus treated with clopidogrel, impaired renal function was associated with increased maximum platelet aggregation. This finding could be attributed partially to upregulation of the P2Y12 activity without differences in drug absorption or metabolism. (Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus; NCT03774394)

这项前瞻性体内外药效动力学(PD)/药代动力学研究是在患有慢性肾病的糖尿病患者(31 人)和不患有慢性肾病的糖尿病患者(30 人)中进行的。PD 评估包括血小板反应指数、最大血小板聚集和 P2Y12 反应单位。体内药代动力学评估包括氯吡格雷及其活性代谢物的血浆水平。体外药代动力学评估是在基线样本与浓度不断升高的氯吡格雷及其活性代谢物培养后进行的。在接受氯吡格雷治疗的糖尿病患者中,肾功能受损与最大血小板聚集增加有关。这一发现可部分归因于 P2Y12 活性的上调,而药物的吸收或代谢并无差异。(慢性肾病对糖尿病患者氯吡格雷效果的影响;NCT03774394)
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引用次数: 0
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JACC: Basic to Translational Science
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