Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases

A large number of cardiovascular events are not prevented by current therapeutic regimens. In search for additional, innovative strategies, immune cells have been recognized as key players contributing to atherosclerotic plaque progression and destabilization. Particularly the role of innate immune cells is of major interest, following the recent paradigm shift that innate immunity, long considered to be incapable of learning, does exhibit immunological memory mediated via epigenetic reprogramming. Compelling evidence shows that atherosclerotic risk factors promote immune cell migration by pre-activation of circulating innate immune cells. Innate immune cell activation via metabolic and epigenetic reprogramming perpetuates a systemic low-grade inflammatory state in cardiovascular disease (CVD) that is also common in other chronic inflammatory disorders. This opens a new therapeutic area in which metabolic or epigenetic modulation of innate immune cells may result in decreased systemic chronic inflammation, alleviating CVD, and its co-morbidities

The challenge of choosing in cardiovascular risk management

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. For many years guidelines have listed optimal preventive therapy. More recently, novel therapeutic options have broadened the options for state-of-the-art CV risk management (CVRM). In the majority of patients with CVD, risk lowering can be achieved by utilising standard preventive medication combined with lifestyle modifications. In a minority of patients, add-on therapies should be considered to further reduce the large residual CV risk. However, the choice of which drug combination to prescribe and in which patients has become increasingly complicated, and is dependent on both the absolute CV risk and the reason for the high risk. In this review, we discuss therapeutic decisions in CVRM, focusing on (1) the absolute CV risk of the patient and (2) the pros and cons of novel treatment options.Cardiolog

From targeting major cardiovascular players to precision medicine

Atherosclerosis is a multifactorial and complex disorder. This thesis focusses on three of the major players in the initiation and progression of atherosclerotic cardiovascular disease (CVD): inflammation, low density lipoprotein (LDL) cholesterol and lipoprotein(a) [Lp(a)]. This thesis aims to increase understanding of who is at risk, what is driving the risk and how to target the risk in order to reduce the burden of CVD. In part I we discuss the role of LDL- cholesterol, Lp(a) and inflammation in initiation and progression of atherosclerotic cardiovascular disease (CVD) and their role in cardiovascular risk of patients. After identification of the major players in atherosclerosis in part I, part II comprises different strategies targeting these major players. Here, the effects of both anti-inflammatory drugs and cholesterol lowering drugs are evaluated on arterial wall inflammation in different patient groups (as assessed by 18FDG PET-CT). Furthermore, we target Lp(a) both in vitro and ex vivo, with effects measured on endothelial cells as well as monocytes. An increasing number of therapeutic interventions can target the major players in order to reduce CVD. Accurate cardiovascular disease prediction is essential to balance risk and potential benefits of novel therapeutic options. Part III of this thesis works towards a patient tailored approach for cardiovascular risk. In line, we discuss novel therapeutic options in cardiovascular risk management and supply an overview of the pros and cons of these new drugs

[Anti-inflammatory therapy in cardiovascular disease; from hypothesis to future guideline?]

Atherosclerosis is a lipid-driven inflammatory disease, in which both lipids and inflammation can be considered treatment targets. The CANTOS-trial, using the IL-1β monoclonal antibody canakinumab, has proven the concept of targeting inflammation to reduce cardiovascular risk. In contrast, the anti-inflammatory drug methotrexate failed to show cardiovascular benefit. Colchicine is a drug used in gout patients, acting as a non-selective inflammasome inhibitor. The COLCOT-trial uncovered a significant reduction in ischemic cardiovascular events in subjects following an acute myocardial infarction, which was recently confirmed in the larger LoDoCo2-trial in stable coronary heart disease. Guideline committees will have to decide whether the trials have supplied sufficient evidence to implement the routine use of colchicine in the guidelines for cardiovascular risk management. These convincing endpoint trials have paved the way for tailored treatment regimens, comprising anti-inflammatory agents besides currently established treatment modalities in CVRM