Complemental impact of LDL-cholesterol levels and microbiota-derived metabolites on coronary plaque burden and composition

在心血管疾病患者中，降脂治疗是预防疾病进展的关键基石。尽管指南中指出了明确的阈值，但LDL-胆固醇水平与随后心血管事件风险降低之间存在线性关系。然而，现有的随机对照试验文献仅评价了不同的治疗策略，而不是个体LDL-胆固醇水平。相比之下，给定治疗在达到LDL水平方面的效力在个体患者水平上变化很大。目前缺乏数据，无论是个体LDL水平还是治疗策略都能改善患者结局。此外，尽管通过修改传统CVD风险因素在降低CVD负担方面取得了进展，但仍存在显著的剩余风险。可能导致动脉粥样硬化进展和CVD发展的因素之一是感染性病原体。目前的研究表明，三甲胺N-氧化物（TMAO）是肠道微生物群的代谢产物，是CVD事件的预测因子，独立于传统的CVD风险因素。然而，目前缺乏研究微生物群衍生的代谢物与冠状动脉粥样硬化负荷之间关系的可靠数据。该项目的目的是确定LDL-胆固醇水平是否影响冠状动脉斑块体积随时间的变化，无论治疗方案如何。此外，在本项目中，申请人旨在研究TMAO水平作为微生物群衍生的代谢物与脂质水平以外的不良冠状动脉斑块特征的关联。本项目包括两个主要部分，将在克利夫兰临床研究协调中心进行。在A部分中，将对10项前瞻性随机对照试验（超过5，500例接受药物治疗的患者进行连续IVUS检查）进行事后汇总分析。在本项目的B部分，申请方将在克利夫兰诊所的前瞻性患者数据库中，通过IVUS和虚拟组织学定量评价TMAO（微生物源代谢物）与冠状动脉斑块负荷和组成的相关性。申请方将进一步评估胆固醇水平和微生物群衍生代谢物对冠状动脉斑块负荷和组成的补充影响。从该项目中得出的结果将提供关于了解降脂治疗策略和LDL水平对冠心病患者疾病进展的影响的实质性见解。此外，该项目还将进一步评估肠道微生物组与冠状动脉粥样硬化的关系。结合两部分的信息，本项目可指导冠心病一级预防和二级预防的个体化治疗决策

In patients with cardiovascular diseases, lipid lowering therapy is the key cornerstone for prevention of disease progression. Despite definite thresholds as indicated in the guidelines, a linear relationship between LDL-cholesterol levels and reduction of risk for subsequent cardiovascular events exists. However, existing literature on randomized controlled trials only evaluated different treatment strategies instead of individual LDL-cholesterol levels. In contrast, the potency of a given treatment with regard to achieved LDL-levels varies considerably on an individual patient level. Currently data is lacking, whether the individual LDL-level or the treatment strategy leads to improved patient outcome. In addition, despite the advances in reducing CVD burden with modification of traditional CVD risk factors, significant residual risks remain. One of the factors that might contribute to the progression of atherosclerosis and development of CVD are infectious pathogens. Present studies have shown that trimethylamine N-oxide (TMAO), a metabolite of the gut microbiota, is a predictor of incident CVD events, independent of traditional CVD risk factors. However, robust data investigating the association of microbiota-derived metabolites with coronary atherosclerosis burden is currently lacking. The aim of this project is to determine, whether LDL-cholesterol levels influence the change in coronary plaque volume over time, irrespective of the treatment regime. In addition, in the present project, the applicant aims to investigate the association of TMAO levels as microbiota-derived metabolite with adverse coronary plaque characteristics beyond lipid levels. The present project consists of two major parts that will be performed at the Cleveland Clinic Coordinating Center for Clinical Research. Within part A, a post-hoc pooled analysis of 10 prospective randomized controlled trials with over 5,500 patients on medical therapy with serial IVUS examinations will be performed. Within part B of the project, the applicant will evaluate the association of TMAO as microbiota-derived metabolite with coronary plaque burden and composition, as quantified by IVUS and virtual histology, in a prospective database of patients from the Cleveland Clinic. The applicant will further assess the complemental impact of cholesterol levels and microbiota-derived metabolites on coronary plaque burden and composition. The results drawn from this project will give substantial insights regarding the understanding of the influence of lipid lowering treatment strategies and LDL-levels on disease progression in patients with coronary artery disease. In addition, the project will further assess the association of the gut microbiome on coronary atherosclerosis. Combining the information from both parts, the project may direct towards individualized therapy decisions in primary and secondary prevention of coronary artery disease