Metabolic Aspects of Cardiovascular Diseases

The role of energy metabolism (i.e., glucose and lipid metabolism) in the onset and progression of atherosclerotic CVD is evident but incompletely understood.

Knowledge gaps include:

  1. the exact interplay between metabolic organs including intestine, liver, adipose tissues, skeletal muscle and brain, including neural and hormonal pathways, in energy metabolism/CVD
  2. the role of the biological clock, in relation to the high prevalence of CVD in individuals working night shifts
  3. the role of ethnicity, given that individuals of e.g. South Asian decent (comprising 20% of the world population) are especially vulnerable to develop CVD as compared to Europids.

Therefore, within the Cardiometabolic Diseases program the role of energy metabolism in the development of obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is studied in relation to the development of atherosclerotic CVD, mainly within the research groups of Prof Rensen (ENDO), Prof Willems van Dijk (HG/ENDO) and Dr Giera (CPM). This program makes use of the full spectrum of:

  1. in vitro studies using cultured metabolic cells and organ-on-chips
  2. in vivo studies with unique radioactive lipid tracing techniques in our in house-developed APOE*3-Leiden.CETP mouse, a well-established translational model for human cardiometabolic disease
  3. intervention studies aimed at improving energy metabolism in vulnerable individuals e.g. South Asians
  4. genetic (e.g., Mendelian Randomization), metabolomic (e.g., Nightingale platform) and lipidomic (e.g., Lipidyzer) studies in large populations including the Netherlands Epidemiology of Obesity (NEO) study and UK Biobank to reveal genetic targets that are causal to energy metabolism in relation to CVD.

In this program, the role of various organs in energy metabolism is being studied in Prof Rensen’s group. For example, brown adipose tissue (BAT), a tissue that combusts glucose and lipids to generate heat in a highly circadian fashion, has recently been shown to be present and metabolically active in human adults and to considerably contribute to energy expenditure. Given that current visualization techniques for BAT are suboptimal, at the LUMC biomarkers are searched for and improved MRI/PET-CT visualization techniques are developed in collaboration with the department of Radiology (Dr. Hermien Kan?). The role of BAT in physiology is unraveled and therapeutic targets and tools including G-protein coupled receptors (GPCRs) and electrostimulation are being elucidated for as potential (chrono)therapeutic approaches (Dr Boon, Dr Kooijman). As such, the LUMC group is world-leading in the elucidation the role of BAT in CVD, which generates international attraction from collaboration partners and pharmaceutical industry. In addition, the role of:

  1. (timed) exercise in regulation of inflammatory pathways (Dr Schönke, Dr Martinez-Tellez)
  2. the gut microbiome in regulation of the gut brain (Prof Wang) and gut muscle axes (Dr Schönke, Dr Martinez-Tellez)
  3. the brain in determining the energy balance (Dr Boon) and circadian regulation of energy metabolism (Dr Kooijman) are being studied as potential therapeutic strategies to prevent and treat cardiometabolic diseases. Collectively, these research lines are expected to identify new therapeutic tools and targets to combat cardiometabolic diseases including CVD.

In addition, in this program the research in Prof Willems van Dijk’s group is aimed at understanding the dynamics of the interplay between genes and environment over the life course in the development of cardiometabolic disease (and is also embedded in the theme Lifecourse).

This is addressed by genetic epidemiological research in large cohorts with longitudinal data. These include the Doetinchem Cohort Study (DCS), NEO and the UK Biobank, Oxford Biobank and LASA. To address this, we have developed novel approaches applying mixed effects models in combination with penalized B-spline (P-spline) functions to semi-parametrically model average and trait variation with age. In addition, we apply various types of Mendelian Randomization techniques to dissect gene-gene and gene-age interactions, in collaboration with the University of Bristol (prof. Timpson). We also apply mathematical modelling with more advanced regression criteria such as orthogonal nonlinear least squares (OrNLS) to better model nonlinear relationships and define more robust and independent traits of complex and interrelated constructs such as sleep, which can subsequently be applied for genetic and Mendelian randomization analyses. The latter in collaboration with various international sleep researchers (i.e. Brigham and Women’s Hospital, prof. Redline).