Research Concept
In CARDDIAB, the causes and consequences of the impaired interaction of the cardiovascular system and glucose metabolism in their early, advanced and late manifestations will be investigated in humans.
The aim of the project is to translate preclinical and clinical findings into medical practice by intensifying interdisciplinary cooperation. It will lead to the use of new concepts for maintaining the health of the population and of tailored therapies for high-risk groups and patients.
Cardiovascular diseases already pose the highest risk of morbidity and mortality, and this trend is continuing to rise. Type 2 diabetes mellitus is the most common metabolic disease worldwide. It already affects 25% of the elderly German population and will increasingly affect younger people in the future. Both disease areas show striking similarities, not only in their epidemiology but also in their pathophysiology and progression. Firstly, the majority of people with diabetes die as a result of cardiovascular disease. Secondly, more than 50% of all patients who experience acute myocardial infarction already have glucose metabolism disorders (prediabetes or diabetes) or develop diabetes in the course of a myocardial infarction. Due to the high prevalence and societal relevance of both disease areas, transdisciplinary and translational studies in healthy and diseased test persons specifically at the interface of cardiovascular, metabolic and diabetology disorders are urgently needed for medical, social and economic reasons.
The WHO defines health in terms of well-being and the absence of disease. However, this disease-focused "exclusion diagnosis" of health does not do justice to the physiology and pathophysiology of lifelong and age-dependent changes in cardiovascular function and glucose metabolism. They are determined by the complex interaction of genotype/phenotype and our environment. For this reason, humans are thought to have a cardiometabolic continuum with networks that are fine-tuned throughout their lifetime by means of ‘relay switches’. These switches (known as ‘bioswitches’) determine, among other things, the (ir-)reversible transition from a healthy to a prediseased and ultimately to a diseased state.
Decades before type 2 diabetes is manifested, complex metabolic disorders (prediabetes) are already present, the common feature of which is insulin resistance. In about one third of patients with myocardial infarction, their – often previously unknown – diabetes manifests at the same time. CARDDIAB therefore investigates preclinical functional disorders (prediseases) that manifest at an early age, along with their signalling pathways in apparently healthy individuals. The aim is to detect functional disorders at an early stage and thus to enable the preservation of health.
In contrast, the transition from metabolic and cardiovascular health to disease (point of no return) is defined by irreversible changes, such as microvascular damage and impairment of autonomic nerves (cardiac autonomic neuropathy) as they occur in severe insulin deficient diabetes (SIDD). Despite some known mechanisms, such as ectopic fat storage, lipotoxicity, inflammation, mitochondrial mismatch and oxidative – and endoplasmic reticulum (ER) – stress, the pathophysiology is still poorly understood.
CARDDIAB's research programme focuses on three main topics for identifying relay switches, biomarkers and targets for pharmacotherapeutic, medical device and behavioural prevention and intervention in the human cardiometabolic continuum (in green).
- Common mechanisms for maintaining cardiovascular and metabolic health.
- Interaction between pathophysiology of metabolic and cardiovascular disorders for identification of novel relay switches for early comprehensive intervention in diabetes-associated cardiovascular disorders.
- Identification of subphenotypes at specific risk of metabolic/cardiovascular disease and development of tailored prevention and therapy (precision medicine).
Cardiometabolic phenotyping
CARDDIAB investigates the cardiometabolic continuum using an innovative in vivo approach. The scientific concept is based on the analysis of dynamic fluxes of metabolic pathways in organ- and cell-specific networks instead of only measuring static concentrations of biomarkers. This requires a specific infrastructure for intensive cardiometabolic phenotyping of healthy and diseased individuals. The two essential methodological components are novel flux imaging and fluxomics.
Flux imaging: spectroscopy & hybrid imaging
State-of-the-art imaging techniques and spectroscopic methods form the basis for in-depth cardiometabolic in vivo phenotyping (deep phenotyping). Flux imaging allows for in vivo visualisation of flux rates in substrate and energy metabolism. These metabolic flux analyses using high-field magnetic resonance (MR) techniques provide a unique opportunity to observe metabolic processes in a live, non-invasive environment, while at the same time providing high-resolution information on myocardial structure and function. Labelled stable isotopes and hyperpolarised 13C tracers will be used for real-time analysis of metabolic processes, enabling unprecedented, highly sensitive quantification of tissue-specific metabolic activity and paving the way for precise cardiometabolic diagnostics and individualised treatment.
The long-term goal is to bring together locally established innovative methods for determining energetics, metabolism and inflammation. To identify mechanisms and biomarkers for the interaction of cardiovascular and metabolic health, these methods will be advanced in small animals, then implemented in large animals under preclinical conditions, and finally transferred to the human situation.
Fluxomics
The previously described flux imaging concept is related to a comprehensive fluxomics analysis, which considers metabolic networks by means of metabolomics, genomics and novel cell-omics analysis techniques (CyTOF). In terms of the methodological concept, the focus here is not on determining metabolites in a traditional manner, but on analysing flux rates in signalling pathways of metabolism and cardiovascular networks. Mass spectroscopic techniques will be used to investigate metabolites (metabolomics), proteins (proteomics) and lipids (lipidomics) of relevant signalling pathways together with (immune) cell analyses in circulating cells (mass cytometry) as well as tissue-stable cells (mass histology) from biopsies of preclinical model organisms and volunteers. These will be combined with genomic analyses ((epi)-genomics and single cell sequencing).
The aim is to identify novel markers within metabolic networks at defined points in time and as flow rates in observational and intervention studies that are significant for the pathogenesis of cardiometabolic diseases. These markers will help to (i) characterise novel subphenotypes with specific therapeutic needs, (ii) define specific relay switches in the manifestation of the disease state, (iii) monitor disease progression with and without intervention, and (iv) optimise risk prediction and stratification.