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。尽管指南中有明确的阈值，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只评估了不同的治疗策略，而不是个体ldl -胆固醇水平。相反，对于达到的低密度脂蛋白水平，给定治疗的效力在个体患者水平上有很大差异。目前缺乏关于个体ldl水平或治疗策略是否能改善患者预后的数据。此外，尽管通过改变传统的心血管疾病危险因素在减少心血管疾病负担方面取得了进展，但仍存在显著的残留风险。可能导致动脉粥样硬化进展和心血管疾病发展的因素之一是感染性病原体。目前的研究表明，肠道微生物群的代谢物三甲胺n -氧化物（TMAO）是CVD事件发生的预测因子，独立于传统的CVD危险因素。然而，研究微生物衍生代谢物与冠状动脉粥样硬化负担之间关系的可靠数据目前尚缺乏。该项目的目的是确定ldl -胆固醇水平是否随时间影响冠状动脉斑块体积的变化，而不考虑治疗方案。此外，在本项目中，申请人旨在研究TMAO水平作为微生物衍生代谢物与血脂水平以外的不良冠状动脉斑块特征的关系。目前的项目包括两个主要部分，将在克利夫兰诊所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进行事后汇总分析，该试验涉及5,500多名接受药物治疗并进行连续IVUS检查的患者。在该项目的B部分，申请人将评估TMAO作为微生物衍生代谢物与冠状动脉斑块负荷和组成的关系，通过IVUS和虚拟组织学量化，在克利夫兰诊所的前瞻性患者数据库中。申请人将进一步评估胆固醇水平和微生物衍生代谢物对冠状动脉斑块负荷和组成的互补影响。该项目得出的结果将为了解降脂治疗策略和ldl水平对冠状动脉疾病患者疾病进展的影响提供实质性见解。此外，该项目将进一步评估肠道微生物群与冠状动脉粥样硬化的关系。结合这两部分的信息，该项目可能会指导冠状动脉疾病一级和二级预防的个性化治疗决策

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