The vicious inflammatory circle in atherosclerosis

Despite medical advances, cardiovascular disease (CVD) is the leading cause of death and disability worldwide. The fast majority of CVD is caused by atherosclerosis: a narrowing of the blood vessels (arteries) caused by the build up of lipids and immune cells in the arterial wall. The current treatment of atherosclerotic CVD focuses on reducing lipid accumulation in the arterial wall using lipid-lowering drugs. However, to date, there are no clinically available anti-inflammatory therapies preventing the invasion of immune cells into the arterial wall. Using a unique combination of translational methods, this thesis provides a framework for approaching the therapeutic challenge of residual inflammatory risk in CVD patients.
Part I of this thesis shows that hypercholesterolemia itself influences hematopoietic stem cell behavior in patients, and thereby exerts inflammatory effects even beyond normalization of cholesterol levels, and moreover, beyond the lifespan of circulating monocytes. Also, ischemic events such as a heart attack aggravates arterial wall inflammation by promoting the production of monocytes. Summarizing, these findings identify LDL-cholesterol as instigator of a vicious inflammatory circle that is formed by the bone-marrow-vascular-axis. Part II of this thesis learns us that inadequately lowered lipoprotein(a) plasma levels drive persistent inflammation, even on a background of normal to (very) low plasma LDL-cholesterol levels.
Concluding, this thesis emphasizes that with the upcoming of new anti-inflammatory regimens and specific Lp(a)-lowering drugs, recognizing the different drivers of residual inflammatory risk is pivotal, as they require their own specific therapeutic intervention beyond LDL-cholesterol-lowering.