Dietary prevention of cholesterol induced trained immunity in early atherosclerosis

About the project

Maintenance of lifetime low plasma levels of LDL-C is associated with low lifetime risk of CVD. The evidence for this notion is provided from both genetic studies and from population living a preindustrial lifestyle. In contrast, children with genetically elevated cholesterol [Familial Hypercholesterolemia (FH)] have increased inflammation and clinical signs of increased atherosclerosis (e.g. increased intima-media thickness) already from 8-10 years of age. Strategies to reduce lipid levels and atherosclerosis initiation in childhood/young adulthood may seem well suited for reducing the lifelong exposure LDL-C. Understanding the complexity of individual differences in LDL-C and immune responses to intervention is key to understanding why dietary components benefit some patients more than others. In addition, understanding the molecular mechanisms will be important in the pursuit of future personalized therapeutic strategies. 

Objectives

The overall goal of the current project is to optimize and individualize CVD prevention starting with early dietary prevention.  

We hypothesize, that dietary modulation that reduces early cholesterol load in childhood will alleviate enhanced inflammatory responses caused by pre-activated monocytes (trained immunity) and subsequently lead to reduced atherosclerotic events. 

  1. Determine and identify markers of early cholesterol load and trained immunity and identify treatment targets.
  2. Examine how dietary PUFAs [n-6 Fatty acids (FA) and n-3 FA] affect markers and drivers of atherosclerosis development e.g. lipid- induced inflammation and genome– and epi-transcriptome instability.
  3. Investigate if PUFAs (n-6 FA and n-3 FA) can influence biological and metabolic pathways including markers of trained immunity, differently among LDL-C responders and non-responders using existing data and in a new proof of concept study.

Our ambition is to advance our understanding of the significance of a common condition (hypercholesterolemia) and to determine how early prevention by diet can improve health. It is challenging to communicate the concept of the accumulated risk associated with hypercholesterolemia to the general population and to the younger population, as high LDL-C levels are rarely associated with symptoms prior to disease onset. Thus, an active strategy for preventing cholesterol accumulation in younger subjects will redefine primary prevention practices to reduce future cardiovascular events which are usually only initiated in adult age.

Background

Poor dietary habits are one of the major contributors to non-communicable diseases world-wide. In 2017, diet was found to be responsible for as many as 11 million deaths globally. Cardiovascular disease (CVD) is the number one killer in the world, and atherosclerosis is its main underlying cause. The major challenge today is that prevention of atherosclerosis is initiated too late during disease progression. 

The concept of a total lifelong cholesterol burden defining the risk of CVD has developed over the last years and suggests that even relatively small differences in absolute cholesterol levels may contribute substantially to the total life-long cholesterol burden. Importantly, a large part of the accumulated cholesterol burden prior to CVD is obtained in childhood and young adulthood, making these periods well suited for reducing the lifelong exposure of cholesterol. Patients with established CVD continue to have a large burden of atherosclerosis despite substantial lower cholesterol levels, and they remain at high risk for new cardiovascular events. This suggests that the cholesterol-lowering treatment may not be sufficient for completely reversal of the atherosclerosis when initiated at this late stage. 

Financing

The Throne Holst Foundation for Nutrition Research

Cooperation

  • Associate professor Jeanine Roeters van Lennep, MD, PhD. Erasmus Medical Centre, Dep. Internal Medicine, Rotterdam. The Netherlands
  • Professor Niels Riksen (MD, PhD),  Radboud University, Medical Centre (Radboudumc), Nijmegen
Published Sep. 24, 2021 2:22 PM - Last modified Sep. 24, 2021 2:22 PM