Dr Thomas Agbaedeng

From cardiometabolic risk to causal mechanism: a human-cardiomyocyte platform for obesity-driven heart failure

Abstract:

Obesity is now the dominant modifiable driver of heart failure, particularly HFpEF, yet the causal link between adipose-derived signals and human cardiomyocyte dysfunction is still poorly resolved. In this talk, I will first show how my work has moved cardiometabolic disease from association to mechanism, using human genetics, single-cell and spatial multi-omics, and CRISPR-based perturbation to fine-map non-coding regulatory variants and identify disease-relevant cell states in vascular and immune compartments. I will then present my proposed King’s BHF Centre programme, which applies the same logic to the obese, failing heart. In year one, I will use human iPSC-derived cardiomyocytes to assess perturbations with harmful and protective adipokines. I will profile the transcriptional response with low-cost DRUG-seq, anchor candidate regulators against published bulk and single-nucleus heart failure datasets, and test causality and reversibility with CRISPRi/a against pre-specified calcium-handling and electrophysiology endpoints. The deliverables are deliberately staged to support an intermediate fellowship: a reproducible adipokine-induced dysfunction phenotype, a cardiomyocyte-intrinsic disease-concordant module, and proof-of-concept rescue at a small number of high-confidence nodes. Year two extends to paracrine adipose-to-cardiomyocyte models and positions the programme to expand into chromatin mechanisms, 3D engineered tissues, and patient-derived models in alignment with the King’s BHF Centre.

Biography:

Dr Thomas Agbaedeng is a cardiovascular functional genomics researcher at the University of Oxford, where he integrates CRISPR genome and epigenome engineering with single-cell and spatial multi-omics to map and perturb non-coding regulators of human cardiovascular disease. He trained at the University of Brighton (BSc Hons) and was awarded a PhD in Medicine at the University of Adelaide in 2019 for ovine work defining how adiposity reshapes atrial and ventricular substrate. His PhD was recognised by six Young Investigator Awards, including 1^st Prize at the European Heart Rhythm Association Congress and an Achievement Award at the European Society of Cardiology Congress. As a Novo Nordisk Postdoctoral Research Fellow at Oxford (2021–2025), he built a human variant-to-mechanism pipeline in primary vascular and immune cells, leading to mapped vascular smooth muscle cell-specific enhancer networks driving cholesterol-induced phenotypic reprogramming (biorXiv), the identification of a lipid-handling macrophage subpopulation that concentrates coronary artery disease genetic risk (Circulation Research, 2024), and an invited Circulation editorial on cardiac epigenetic regulation after myocardial infarction. He has authored 27 peer-reviewed papers (h-index 18), secured over £700k in competitive funding as principal or co-investigator, and is an Oxford Saïd Ideas-2-Impact Fellow. He currently leads experimental delivery for the EIC-funded SeCURE consortium on iPSC-derived neurovascular models for gene therapy delivery, while developing his independent programme on how obesity-linked paracrine signals reprogramme cardiomyocytes in heart failure.

Association:

Thomas Agbaedeng — Centre for Human Genetics

 

Dr Michaeljohn Kalakoutis

Combining mechanobiology with transcriptomics to uncover how mechanisms of contraction regulate transcriptional signatures in the beating heart.

Abstract:

Cardiac muscle adapts to meet the mechanical demands placed upon it throughout a person’s lifetime, which is an important determinant of cardiac physiology and pathology.

Structural remodelling can improve cardiac function, such as following exercise. In contrast, conditions such as ageing or adverse mechanical stress can contribute to the development of a pathological phenotype. Mechanical forces are increasingly recognised as an important regulator of tissue remodelling and subsequent disease progression. However, little is known about how key mechanistic regulators of cardiac contraction, namely sarcomeric protein and biochemical interactions, contribute to the transcriptional signalling which underlies cardiac tissue adaptation. In this presentation I will propose a research programme which combines my expertise in mechanobiology with transcriptomic approaches to determine how the mechanism of contraction regulates transcriptional signalling in contracting heart tissue. First, I will outline the breadth of my experience in mechanobiology, ranging from investigating the cause of age-related muscular weakness in human single skeletal muscle fibres, to using biophysical techniques to study the mechanism of contraction in the cardiac sarcomere.

Second, I will outline my research proposal to combine experiments manipulating the mechanism of contraction in intact mammalian cardiac tissue with transcriptomic analysis. The long-term aim of this research programme is to determine whether

modulating mechanisms of cardiac contraction can be used as a therapeutic tool to induce transcriptional signatures which promote beneficial structural remodelling in the heart.

Biography:

Dr Michaeljohn Kalakoutis was awarded his PhD at King’s College London (KCL), for which he studied the contractility of human single skeletal muscle fibres from young and elderly cohorts to investigate the cause of age-related muscular weakness. This was followed by postdoctoral work at the Karolinska Institute studying the role of oxidative stress in muscular weakness associated with inflammation (rheumatoid arthritis), using live cell imaging of redox sensitive biosensors in single muscle fibres. Following a career break to complete mandatory military service, he took up his current postdoctoral position at KCL in the lab of Professor Malcolm Irving, using fluorescence polarization and X-ray diffraction to study the regulatory mechanisms of contraction in both intact and demembranated cardiac and skeletal muscle. Dr Kalakoutis aims to combine his expertise in mechanobiology with transcriptomic analysis to determine how transcriptional signatures which cause cardiac muscle remodelling are regulated by mechanisms of contraction.

Association:

Michaeljohn Kalakoutis - King's College London