Coronary plaque changes with statin and colchicine among people with high polygenic risk- a mechanistic pilot study

他汀类药物和秋水仙碱对高多基因风险人群的冠状动脉斑块变化——一项机制试点研究

• 批准号: 10736120
• 负责人: Akl C Fahed
• 金额: $ 83.44万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736120
• 关键词: Address; Affect; American Heart Association; Anti-Inflammatory Agents; Atherosclerosis; Attenuated; Biological Markers; Blood; Blood Vessels; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Clinic; Clinical; Clinical Trials; Colchicine; Combined Modality Therapy; Coronary; Coronary Arteriosclerosis; DNA; Data; Dedications; Development; Disclosure; Dose; Double-Blind Method; Event; Family; Fatty acid glycerol esters; Flying body movement; Genetic Predisposition to Disease; Genomic medicine; Health education; Health system; Hospitals; Image; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Intervention; Investigation; LDL Cholesterol Lipoproteins; Life; Lipids; Longitudinal Studies; Low-Density Lipoproteins; Matched Group; Measures; Myocardial Infarction; Participant; Pathway interactions; Patients; Persons; Pharmacological Treatment; Phenotype; Pilot Projects; Population; Primary Care; Protocols documentation; Randomized; Recording of previous events; Recurrence; Risk; Risk Factors; Risk Reduction; Rupture; Site; Target Populations; Testing; Variant; X-Ray Computed Tomography; attenuation; biobank; cardiovascular health; cardiovascular risk factor; clinical practice; clinical risk; cohort; coronary computed tomography angiography; coronary plaque; genome-wide; high risk; implementation study; indexing; innovation; interest; middle age; pharmacologic; polygenic risk score; prevent; primary endpoint; prospective; randomized trial; rosuvastatin; treatment group

Project Summary Genome-wide polygenic score for coronary artery disease (CAD) identifies 20% of the population with more than double the average risk. Those individuals are not identified by clinical risk factors or family history, yet they derive the greatest relative and absolute benefit from LDL-cholesterol lowering therapy. A key barrier to the use of polygenic score in clinic to prevent CAD is the lack of prospective implementation studies that quantify and characterize coronary atherosclerosis in individuals with high polygenic risk and reverse it using pharmacological interventions. LDL-cholesterol pathways account for only a small proportion of risk, and other mechanisms such as inflammation are of interest. Low dose colchicine has been shown to reduce the risk of cardiovascular evens in patients with stable coronary artery disease, but the exact mechanism of how colchicine affects coronary plaque is unknown. Our proposal addresses those gaps and leverages recent innovations in genomic medicine, biobank data, and coronary imaging for plaque characterization, through a genomic medicine implementation study of returning results to hospital biobank participants followed by a mechanistic clinical trial of rosuvastatin and colchicine using biomarkers and coronary plaque phenotypes on noninvasive coronary CT angiography (CCTA). We already identified a target population from our hospital biobank consisting of several thousand individuals who have no known cardiovascular disease, are not on lipid lowering or anti-inflammatory therapy, and have a high polygenic score defined as top 20% of the distribution. In AIM1, we will return a high polygenic risk score result to 300 participants and assess baseline and one-year cardiovascular health compared to a matched group from the MGH Primary Care Cohort. In AIM2, we will measure lipid and inflammatory biomarkers and perform CCTA on the 300 participants to study coronary plaque volumes and high-risk features, and their association with cardiovascular health and lipid and inflammatory biomarkers among individuals with high polygenic risk. In AIM3, we will determine if combination therapy with statin and low dose colchicine – compared with statin alone – favorably modulates progression and composition of coronary atherosclerosis in individuals with high polygenic score in a mechanistic pilot study of 150 participants followed for one year. This study will provide a framework for identification, disclosure, and reversal of subclinical coronary atherosclerosis in individuals with high polygenic risk and inform the mechanism by which low dose colchicine reduces cardiovascular events through longitudinal phenotyping of coronary plaque.

项目摘要 冠状动脉疾病（CAD）的全基因组多基因评分确定了20％的人口 比平均风险两倍。这些人尚未通过临床风险因素或家族史来确定 它们从LDL-胆固醇降低疗法中获得了最大的相对和绝对益处。 在诊所中使用多基因评分以防止CAD的关键障碍是缺乏前瞻性实施 量化和表征高多基因风险和 使用药物干预措施将其反转。 LDL-胆固醇途径仅占一小部分 风险和其他机制（例如创新）引起了人们的关注。低剂量的秋水仙碱已显示为 降低稳定冠状动脉疾病患者心血管ev的风险，但确切的 秋水仙碱如何影响冠状斑块的机制尚不清楚。 我们的建议解决了基因组医学，生物库数据和 通过基因组医学实施研究，用于斑块表征的冠状动脉成像 结果是医院生物库参与者，然后进行了余星和秋水仙碱的机械临床试验 使用生物标志物和冠状斑块表型在非侵入性冠状动脉血管造影（CCTA）上。 我们已经从我们的医院生物库中确定了目标人群，由数千人组成 没有已知心血管疾病的人，不接受脂质降低或抗炎疗法，并且具有 高多基因评分定义为分布的最高20％。在AIM1中，我们将返回高多基因风险评分 与匹配相比，有300名参与者和评估基线和一年的心血管健康结果 来自MGH初级保健队列的组。在AIM2中，我们将测量脂质和炎症生物标志物以及 对300名参与者进行CCTA，以研究冠状动脉斑块量和高风险功能及其 与患有较高患者的心血管健康以及脂质和炎症生物标志物相关联 多基因风险。在AIM3中，我们将确定与他汀类药物和低剂量秋水仙碱的联合疗法 - 与单独汀类药物相比 - 有利地调节冠状动脉粥样硬化的进展和组成 在150名参与者的机械初步研究中，多基因得分高的个体紧随其后一年。这 研究将为亚临床冠状动脉粥样硬化的识别，披露和逆转提供一个框架 在具有高多基因风险的个体中，低剂量秋水仙碱可降低的机制 心血管事件通过冠状动脉斑块的纵向表型。