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.

项目概要 冠状动脉疾病 (CAD) 全基因组多基因评分确定 20% 的人群患有更多冠心病 这些人的风险是平均风险的两倍，但尚未通过临床风险因素或家族史来识别。 他们从低密度脂蛋白胆固醇降低疗法中获得最大且相对的益处。 在临床上使用多基因评分预防 CAD 的一个关键障碍是缺乏前瞻性实施 量化和表征具有高多基因风险的个体的冠状动脉粥样硬化的研究 使用药物干预来逆转它仅占一小部分。 低剂量秋水仙碱已被证明具有风险和其他机制（例如炎症）。 降低稳定性冠状动脉疾病患者心血管事件的风险，但确切的 秋水仙碱影响冠状动脉斑块的机制尚不清楚。 我们的提案解决了这些差距，并利用了基因组医学、生物库数据和 通过基因组医学实施研究返回斑块特征的冠状动脉成像 向医院生物库参与者提供结果，随后进行瑞舒伐他汀和秋水仙碱的机械临床试验 在无创冠状动脉 CT 血管造影 (CCTA) 中使用生物标志物和冠状动脉斑块表型。 我们已经从我们的医院生物库中确定了由数千人组成的目标人群 没有已知的心血管疾病，未接受降脂或抗炎治疗，并且有 高多基因评分定义为分布的前 20%，在 AIM1 中，我们将返回高多基因风险评分。 向 300 名参与者提供结果，并与匹配的参与者相比评估基线和一年的心血管健康状况 来自 MGH 初级保健队列的小组在 AIM2 中，我们将测量脂质和炎症生物标志物并 对 300 名参与者进行 CCTA，以研究冠状动脉斑块体积和高风险特征及其 与心血管健康以及高脂血症个体中的脂质和炎症生物标志物的相关性 在 AIM3 中，我们将确定他汀类药物和低剂量秋水仙碱的联合治疗是否 – 与单独使用他汀类药物相比——有利地调节冠状动脉粥样硬化的进展和成分 在一项由 150 名参与者参与的机械试点研究中，对多基因得分高的个体进行了为期一年的跟踪。 研究将为亚临床冠状动脉粥样硬化的识别、披露和逆转提供框架 在具有高多基因风险的个体中，并告知低剂量秋水仙碱减少的机制 通过冠状动脉斑块的纵向表型分析心血管事件。