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

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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