Posters will be presented during the morning break and in 2 sessions during the lunchbreak from 13:15 - 14:15
Presenter: Aminder Singh (poster 14)
Combining complex stem cell models and multiomics to reveal causality of aortic disease genetic variants
Presenter: Campbell Wolford (poster 36)
Discovery of Novel Metabolic Pathways and Therapeutic Targets for Type 2 Diabetes Through Plasma Metabolome-wide Mendelian Randomization
Authors: Campbell Wolford, Adam Butterworth
Understanding how individual metabolites influence cardiometabolic risk offers valuable insights for therapeutic development. However, previous research has been limited by the narrow scope of metabolites examined. To overcome this limitation, we conducted a Mendelian Randomization (MR) analysis of 604 plasma metabolites, assessing their genetically predicted associations with type 2 diabetes (T2D) risk and glycaemic traits.
To evaluate the impact of pleiotropy on these associations, we employed conservative and liberal sets of “trans” metabolite quantitative trait loci as instruments. Our analysis identified 94 metabolites with significant genetically predicted associations with T2D risk and glycaemic outcomes, many of which replicate across multiple outcomes. Through a series of sensitivity analyses, reverse causation tests, and Bayesian colocalisation, we excluded associations that violated MR assumptions, prioritising 19 metabolites. Nine of which have previously established etiological links to cardiometabolic-renal disorders.
By assessing the pleiotropic potential of individual genetic instruments, we classified the metabolite associations into three confidence groups, with five metabolites emerging in the high-confidence set for their causal effect on T2D. We enhanced the translational impact of our study by integrating these prioritised metabolites with evidence from in vitro and in vivo experiments, proposing plausible mechanisms and therapeutic opportunities. Notably, our findings further support the role of lysophosphatidylcholines in T2D management strategies. Ultimately, our study deepens our understanding of metabolite-based interventions for cardiometabolic disease and underscores the translational promise of metabolome-wide MR in identifying genetically prioritised therapeutic targets.
Presenter: Chief Ben-Eghan (poster 32)
Multi-ancestry vQTL inquiry into the human proteome
Authors: Chief Ben-Eghan, Scott Ritchie, Elodie Persyn, Carles Foguet, Stephen Burgess, Mike Inouye
Background: Variance quantitative trait loci (vQTLs) influence trait variance in complex traits and can serve as proxies for gene-environment interactions. Their contribution towards the genetic architecture of complex traits has only recently been explored, albeit not exhaustively. Here, we investigate their role in the circulating human proteome across diverse ancestries.
Methods: We mapped vQTLs for 2,826 proteins in the UK Biobank (UKB; N=52,076) using the median-based Levene’s test (for homogeneity of variances), implemented in OSCA. We identified population-specific and shared cis-acting protein vQTLs in unrelated participants of European (EUR; N=45,486), African (AFR; N=1,336), and South-Asian (SAS; N=933) ancestries. Finally, we assessed whether protein vQTLs independently influence coronary artery disease (CAD) and Type 2 diabetes (T2D) risk using cis-multivariable MR (MVMR) implemented in Robust-PCGMM.
Results: We identified 2,042 independent cis-acting vQTLs (PEUR=6.2E-11, Pnon-EUR=5.0E-08), including EUR (1,885; 748 proteins), AFR (98; 83 proteins), and SAS (59; 53 proteins). Among these, 4.7%, 21%, and 6%, respectively, exhibited vQTL effects exclusively (p > 0.05 for main effects), with 29 proteins sharing cis-vQTLs across all ancestries. In the EUR, we identified 530 proteins with distinct causal variants for main and variance effects (colocalization H3). MVMR revealed that trait variance influenced CAD and T2D risk independently of main effects for some key proteins: LPA, PCSK9, VAMP5, and FN1 (CAD) and ANGPTL4 (T2D) (p < 1E-03, both effects).
Conclusion: Our findings provide new insights into how vQTLs shape the genetic architecture of complex traits, highlighting trait variance as an independent causal risk factors for CAD and T2D.
Presenter: Genevieve Cezard (poster 23)
Impact of COVID-19 diagnosis on the association between age at diagnosis of diabetes and incidence of cardiovascular diseases in England
Authors: Genevieve Cezard, Wen Shi, Chimweta Chilala, Ewan Walker, Tom Bolton, Fionna Chalmers, Lisa Pennells, Elena Raffetti, Rachel Denholm, Emanuele Di Angelantonio, Angela Wood, and Stephen Kaptoge on behalf of the CVD-COVID-UK/COVID-IMPACT consortium and the Diabetes Data Science Catalyst
Background
A younger age at diagnosis of diabetes is associated with increased risk of cardiovascular disease (CVD). People with diabetes had worse outcomes during COVID-19 pandemic but no studies have analysed the impact of COVID-19 on CVD incidence by age at diagnosis of diabetes.
Methods
We analysed linked health records (primary care, hospitalisation, mortality, COVID-19 infection and vaccination) available through the NHS Secure Data Environment. We included people aged 40 years and over living in England on January 1st 2022, and without prior CVD. We calculated hazard ratios for ten CVD outcomes separately for type 2 and type 1 diabetes by age at diagnosis and tested for interaction with COVID-19 diagnosis using Cox regression models stratified by sex and region and adjusted for age, ethnicity, deprivation, BMI, smoking and vaccination status.
Results
Among 30.6 million people, 4.3 million (14%) had a history of COVID-19 diagnosis before 2022. There was a strong relationship between earlier age at diagnosis (for type 2 and type 1 diabetes) and increased risk of CVD outcomes, which was broadly quantitatively similar by previous COVID-19 diagnosis, despite statistically significant interactions observed between COVID-19 and age at diagnosis of type 2 diabetes for arrythmias, coronary heart disease, heart failure, stroke and composite CVD outcomes.
Conclusion
We found a strong relationship between age at diagnosis of diabetes and incidence of CVDs. Our findings highlight the continued need for public health approaches to prevent early onset of diabetes in the general population.
Acknowledgements
This work was carried out with the support of the BHF Data Science Centre led by HDR UK (BHF Grant no. SP/19/3/34678). This study made use of de-identified data held in NHS England’s Secure Data Environment service for England and made available via the BHF Data Science Centre’s CVD-COVID-UK/COVID-IMPACT consortium. This work used data provided by patients and collected by the NHS as part of their care and support. We would also like to acknowledge all data providers who make health relevant data available for research.
Presenter: Hasanga Manik Purage (poster 34)
Heterogeneity of genetic effect sizes according to local ancestry probabilities and impact on cardiovascular disease association
Authors: Hasanga D. Manikpurage, Michael Wu, Xilin Jiang, Scott C. Ritchie, Elodie Persyn, Chief Ben-Eghan, Loïc Lannelongue, Yang Liu, Yu Xu, Sam A. Lambert, Michael Inouye
Background: While genome-wide association studies (GWAS) have largely assessed the overall ancestry group of an individual, the effects of local, haplotype-level ancestries within individuals has been underexplored. The extent to which heterogeneity in local ancestry (LA) modifies the effects of GWAS loci has important implications for how we think about genetic architecture, therapeutic target prioritisation and polygenic scores. Here, we sought to describe ancestry-specific effect modification on already described coronary artery disease (CAD)-loci.
Material/Methods: A supervised LA inference pipeline (SparsePainter) was applied to imputed genotype data of an initially random subset of UK Biobank (n=200,000; to be scaled to full 487,000). Using the 1000 Genomes reference panel, 26 sub-ancestries (spanning 5 continental ancestries) were considered to infer LA probabilities for ~2.7 millions of SNPs for each individual. Using the identified CAD-loci from the latest CARDIoGRAMplusC4D GWAS, mean LA probabilities were available for 140 lead genetic variants. Association for myocardial infarction (MI) prevalence were assessed using logistic regression models, including variants allelic dosage and LA probabilities.
Results: Preliminary results show distinct genetic effect modification observed on several loci when specific LA probabilities were incorporated in regression models. For example, at the LDL receptor locus, LAs from sub-populations across East Asia showed significantly attenuated effect sizes for MI compared to other LAs. Similar results were obtained for other loci and other ancestries (e.g. PCSK9 in Africans and South Asians, ILR6 in South Asians).
Conclusion: LAs at CAD-loci significantly change the effects of established risk alleles. This may have important implications for equitable genomic medicine.
Presenter: Stephen Watt (poster 29)
Comparative systems genetics of endothelial and immune cells reveals shared and distinct pathways in cardiovascular disease
Authors: Stephen Watt, Matiss Ozols, Arianna Landini, Kevin Bin Liu, Sodbo Sharapov, Daniela Zanotti, Gabriela Ivanova, Charles Solomon, Xu Dong Yang, Tolulope Balogun, Nicole Staudt, Wei Li, Tom Webb, David McVey, Nick Morrell, Stefan Gräf, Shu Ye, Nicola Pirastu, Nicole Soranzo, Mattia Frontini
Cardiovascular disease (CVD) is an umbrella term used to describe disease of the heart and blood vessels. The endothelial lining of blood vessels is the point of contact between blood and the vasculature, and how it responds to environmental insults could determine the progression of disease. CVD has a considerable immune component, with genome wide association studies (GWAS) identifying hundreds of risk loci associated with both CVD and autoimmune disease, many of which converge on the same candidate genes.
To investigate the genetic mechanisms at CVD loci we generated a new molecular quantitative trait loci (molQTL) dataset including; gene expression, open chromatin and enhancer activity in human umbilical vein endothelial cells (HUVEC) from a panel of 100 donors. We integrated this with previously published QTL data from our laboratory generated in three immune cell types; monocytes, neutrophils, and naïve T lymphocytes. We performed colocalisation analysis between molQTLs and 17 cardiovascular disease GWAS, including Coronary Artery Disease and Atrial Fibrillation. In addition, to directly test genetic effects on endothelial barrier integrity we used Electric Cell-substrate Impedance Sensing (ECIS) as a quantitative trait to perform genetic association analysis.
We resolved hundreds of risk loci in both endothelial and immune cells, both highly pleiotropic loci that were shared across cell types and traits, and loci that were restricted to cell type relevant pathways. As an example using our molQTL and ECIS data we identified a novel isoform QTL at the IGF2BP3 gene which has recently been shown to protect against endothelial dysfunction.
Acknowledgements: BHF RE/18/1/34212, BHF FS/18/53/33863
Presenter: Yu Zhang (poster 12)
Targeting microtubule post-translational modification in thoracic aortic aneurysm and dissection
Authors: Yu Zhang, Jia Hu, Xuan Li, M.D.
Thoracic aortic aneurysm and dissection (TAAD) represents a critical cardiovascular pathology characterized by progressive weakening of the aortic wall, frequently culminating in catastrophic aortic rupture. Emerging evidence implicates vascular smooth muscle cell (VSMC) dysfunction as a core pathogenic mechanism, particularly through impaired contractile function and aberrant extracellular matrix remodeling. Microtubules are important components of the cytoskeleton and participate in many cell processes. However, the specific contribution of microtubule homeostasis to TAAD pathogenesis remains unexplored. Our investigation reveals significant alterations in the post-translational modification (PTM) profile of α-tubulin in human TAAD specimens, with immunohistochemical and biochemical analyses demonstrating marked elevation of acetylation and detyrosination level compared to healthy aortic tissues. Complementary proteomics data of human TAAD disease identified dysregulation of microtubule-associated proteins – key regulators of microtubule stability and mechanotransduction. These modifications predict enhanced microtubule rigidity and impaired dynamic remodeling, which may compromise VSMC contractility through aberrant force transmission. Therefore, we hypothesize that this PTM-driven cytoskeletal instability likely establishes a self-reinforcing cycle of mechanical stress susceptibility, extracellular matrix degradation, and hemodynamic overload – critical determinants of aortic wall failure in TAAD. Our findings position microtubule homeostasis as a novel molecular axis in TAAD pathogenesis, suggesting potential therapeutic targets through pharmacological modulation of tubulin PTM balance.
Presenter: Adriana Zainurin (poster 5)
Microglial activation predicts hippocampal atrophy but not incident cognitive impairment in cerebral small vessel disease
Authors: Adriana Zainurin, Robin B Brown, Daniel J Tozer, Hugh S Markus
Background: Cerebral small vessel disease (CSVD) is the most prevalent pathology involved in vascular cognitive impairment (VCI). Hypothesised pathogenic mechanisms of VCI include microglial activation (neuroinflammation) and blood-brain barrier (BBB) leakage, but the longitudinal relationship between such processes and VCI in CSVD is underexplored.
Aim: To determine whether microglial activation and BBB leakage at baseline predicted hippocampal atrophy and cognitive impairment over a one-year and four-year follow-up respectively.
Methods: The study involved a prospective follow-up cohort of 77 patients with symptomatic CSVD (sporadic CSVD, n = 57; monogenic CSVD, n = 20). Positron emission tomography (PET) was used to measure microglial activation using the translocator protein radioligand 11C-PK11195 (“PK binding”). BBB leakage was measured using dynamic contrast enhanced MRI (DCE-MRI). Hippocampal atrophy was estimated using percentage volume changes between baseline and one-year follow-up. Cognitive performance was assessed at 4 years post-baseline.
Results: Cox proportional hazards analyses showed no significant associations between PK binding and BBB permeability with cognitive impairment over 4 years. Linear regression analysis showed that greater PK binding at baseline was associated with greater hippocampal atrophy (p = 0.001, 95% confidence interval = -0.7, -0.18) at one year. There were no associations between DCE-MRI markers and atrophy in the hippocampus.
Conclusion: Our findings suggest that microglial activation may play a role in the onset of hippocampal atrophy, particularly at an earlier stage of CSVD progression, but more data from studies with a longer follow-up period and a larger sample size is required.
Acknowledgements: Recruitment was supported by the National Institute for Health Research Clinical Research Network. Data collection was assisted by the staff at Wolfson Brain Imaging Centre.
Presenter: Matthew Batty (poster 13)
The role of macrophage tafazzin in atherosclerosis
Authors: Matthew Batty, Cindy Dong, Nichola Figg, Lauren Kitt, Martin Bennett, Emma Yu
Background: Mitochondrial respiration is reduced in atherosclerotic plaques but the factors that drive this are unclear. Tafazzin, a mitochondrial transacylase, is essential for the maturation of cardiolipin, a key component of the inner mitochondrial membrane. However, the role of tafazzin in regulating macrophage function and its contribution to atherosclerosis is unknown.
Objectives:
- To characterise macrophage tafazzin expression in atherosclerotic plaques
- To investigate the effect of tafazzin on macrophage function and atherogenesis
Methods: Tafazzin expression in human atherosclerotic plaques was assessed using qPCR and immunohistochemistry. The functional role of tafazzin was investigated through siRNA silencing in THP-1 macrophages. Apolipoprotein E deficient (ApoE-/-) mice expressing a catalytically inactive mutant tafazzin (TazH69Q) under the CD68 macrophage promoter were generated for in vivo and in vitro analysis.
Results: Tafazzin mRNA expression was decreased in human plaques compared to normal aortic tissue. Immunohistochemistry showed decreased tafazzin expression in CD68+ macrophages in human plaque cores. Silencing tafazzin in THP-1 macrophages reduced mitochondrial respiration, mitochondrial membrane potential, efferocytosis and proliferation and increased oxidative stress. Macrophages from CD68-TazH69Q/ApoE-/- mice exhibited decreased respiration and efferocytosis yet had increased pro-inflammatory cytokine release and oxidative stress. After 14 weeks of high fat diet, aortic plaque area was increased in ApoE-/- mice transplanted with CD68-TazH69Q/ApoE-/- bone marrow.
Conclusion: Our findings demonstrate that tafazzin is critical for macrophage function. Macrophage tafazzin inactivation causes mitochondrial dysfunction and exacerbates plaque burden. Tafazzin downregulation in plaque macrophages may be an important factor in disease progression, offering new insights into the mechanisms underlying atherogenesis.
Acknowlegements: This work was supported by British Heart Foundation grants FS/4yPhD/F/21/34156A, FS/19/2/34017 and the BHF Centre for Research Excellence
Presenter: Nikolai Pakhomov (poster 21)
Apabetalone protects vascular smooth muscle cells against chemotherapy treatment
Presenter: Peter Jones (poster 37)
Sexual dimorphism in T follicular helper function in atherosclerosis
Authors: Peter Jones, Despina Giakomidi, James Harrison, Judhell Manansala, Katie Law, Leanne Masters, Nichola Figg, Josef Peninger, Mike Murphy, Thomas Krieg, Ana Vujic, Ziad Mallat, Meritxell Nus
Adaptive immunity plays an important role in atherosclerosis. We previously demonstrated extrafollicular Marginal Zone B (MZB)-T follicular helper (TFH) cell interactions protect from atherosclerosis. Preliminary results indicate that MZB cells regulate TFH differentiation through metabolic reprogramming. Specifically, we found that several members (like ND6) and regulators (like Aif1) of the respiratory complex I may have an important role in TFH differentiation. Hence, we aim to investigate the impact of targeting Aif1 and ND6 on TFH functions and thereby atherosclerosis.
Methodology: We generated atherosclerotic (Ldlr-/-Rag2-/-) mouse models with TFH-specific Aif1 and ND6-P25L deletion through mixed bone marrow transplant.
Results: TFH-specific Aif1 deletion reduced TFH and GC B cells but not MZB cell numbers. In females, this led to a decrease in atheroprotective ox-LDL IgM titres and thereby increased atherosclerosis. Conversely, males had reduced atherogenic ox-LDL IgG antibodies and atherosclerosis. Unexpectedly, targeting ND6-P25L mice did not change TFH, GC B or MZB cell numbers or atherosclerosis in comparison to WT mice.
Conclusion: Aif1 but not ND6 is necessary for TFH differentiation in atherosclerosis. This could be explained because Aif1 deletion led to a significant decrease in ROS production and NADH levels, while ND6 KO mouse did not affect NADH levels.
We have found a sexual dimorphism on the role of Aif1 in TFH differentiation. In females, Aif1 is necessary for TFH extrafollicular IgM response while in males for the TFH-GC B cell response and the formation of IgG antibodies. Further experiments are necessary to explain this sexual dimorphism.
Acknowledgements: This work was funded by the BHF Fellowship FS/20/23/34784 and Project Grant PG/22/10898.
Presenter: Qiyu Tang (poster 15)
Autophagy regulates senescence-associated secretory phenotype (SASP) and cell senescence by mediating the degradation of CDKN1A/p21 and CDKN2A/p16 through SQSTM1/p62-mediated selective autophagy in myxomatous mitral valve degeneration
Authors: Qiyu Tang, Keyi Tang, Greg R. Markby, Maciej Parys, Kanchan Phadwal, Brendan M. Corcoran and Vicky E MacRae
Myxomatous mitral valve degeneration (MMVD) is one of the most important age-dependent degenerative heart valve disorders in both humans and dogs. It is characterized by the aberrant remodeling of extracellular matrix (ECM), regulated by senescent myofibroblasts (aVICs) transitioning from quiescent valve interstitial cells (qVICs), primarily under TGFB1/TGF-β1 control. In the present study, we found senescent aVICs exhibited impaired macroautophagy/autophagy as evidenced by compromised autophagy flux and immature autophagosomes. MTOR-dependent autophagy induced by rapamycin and torin-1 attenuated cell senescence and decreased the expression of cyclin-dependent kinase inhibitors (CDKIs) CDKN2A/p16INK4A and CDKN1A/p21CIP1. Furthermore, induction of autophagy in aVICs by ATG (autophagy related) gene overexpression restored autophagy flux, with a concomitant reduction in CDKN1A and CDKN2A expression and senescence-associated secretory phenotype (SASP). Conversely, autophagy deficiency induced CDKN1A and CDKN2A accumulation and SASP, whereas ATG re-expression alleviated senescent phenotypic transformation. Notably, CDKN1A and CDKN2A localized to autophagosomes and lysosomes following MTOR antagonism or MG132 treatment. SQSTM1/p62 was identified as the autophagy receptor to selectively sequester CDKN1A and CDKN2A cargoes for autophagic degradation. Our findings are the first demonstration that CDKN1A and CDKN2A are degraded through SQSTM1-mediated selective autophagy, independent of the ubiquitin-proteasome pathway. These data will inform development of therapeutic strategies targeting cell senescence and SASP for the treatment of canine and human MMVD, and for the treatment of Alzheimer disease, Parkinson disease and other age-related degenerative disorders. (Link for this latest published paper: https://doi.org/10.1080/15548627.2025.2469315)
Acknowledgements: We would like to acknowledge acquisition of electron microscopy images at the Roslin Institute 3D Electron Microscopy Facility and sample processing for electron microscopy at the Kings Buildings Scanning and Transmission Electron Microscopy Facility. V.E.M is a member of the International Network on Ectopic Calcification (INTEC; itnintec.com).
Presenter: Sebnem Oc (poster 17)
Investigation of clonal VSMC proliferation in humans through combinatorial lineage and identity mapping
Presenter: Anna Pullinger (poster 9)
A model of accelerated vascular aging using human pluripotent stem cells
Authors: Anna Pullinger, Aishwarya Jacob, Semih Bayraktar, Irina Mohorianu, Maria Köhne, Anthony Davenport, Sanjay Sinha
Aging vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of several age-associated cardiovascular conditions such as atherosclerosis. However, studying cellular aging in humans remains challenging due a lack of suitable in vitro models. To meet this need, we have created an “aging-in-a-dish” VSMC model using induced pluripotent stem cell (iPSCs) derived from a patient with Hutchinson-Gilford Progeria Syndrome (HGPS), a disorder characterised by premature vascular aging and atherosclerosis. We hypothesise that insights from HGPS can inform novel therapeutic strategies for age-associated vascular diseases. We used CRISPR-Cas9 gene editing to correct the disease-causing LMNA mutation in HGPS-iPSCs, creating an isogenic control cell line. We then used these to generate VSMCs of the lateral plate mesoderm lineage: a cell type relevant for several vascular pathologies including coronary artery disease. RT-PCR and immunoblotting confirmed expression of the disease-causing protein progerin was ameliorated in isogenic control VSMCs. Extensive characterisation of HGPS-VSMCs showed detectable signs of accelerated aging including epigenetic alterations (reduced H3K9me3) and dysmorphic nuclei which were reduced by CRISPR correction. Transcriptomic analysis highlighted alterations in extracellular matrix production (ECM), a biological process which is difficult to fully recapitulate in 2D cultures. To overcome this limitation, we are developing 3D engineered vascular tissues to model changes in ECM dynamics and mechanical properties in HGPS-VSMCs and perform proteomic analyses. This model may identify potential new therapeutic targets in accelerated and physiological aging whilst providing a platform for drug testing with higher physiological relevance than a 2D monoculture.
Acknowledgements: British Heart Foundation
Presenter: Anne Frølund Grangaard (poster 18)
Building a pipeline for large-scale phenotypic drug screen with hESCs-Cardiomyocytes – lessons learnt
Presenter: Chun Hao Wong (poster 24)
Arrayed CRISPR screening at the MRC-AZ-University of Cambridge Joint Functional Genomics Screening Laboratory (FGSL)
Authors: Antigoni Gogolou, Shaun Maguire, Ben Pearson, Nicola McCarthy, Davide Gianni, Ulrike Künzel, Chun Hao Wong
The FGSL, a newly established joint venture between the Milner Therapeutics Institute at the University of Cambridge, AstraZeneca and the Medical Research Council (MRC), aims to combine the strengths of academia and industry to accelerate the development of biomarkers and therapeutics through functional interrogation of the genome at scale. We aimed to form collaborations with UK-based researchers to identify novel gene targets in healthy development and disease.
The FGSL leverages the unique features of arrayed screening, whereby individual genes are targeted via CRISPR/Cas9 in a plate-based format, to uncover the complexity of phenotypic signatures in human cell models. To do this, the laboratory is equipped with a high-throughput screening platform that enables automated liquid handling and acquisition of high-content endpoints including microscopy and flow cytometry.
Academic researchers, small- and medium-sized enterprises (SMEs), and industries from across the UK can propose arrayed CRISPR screening projects in complex human cell models outside of oncology such as organoids, co-cultures, primary and iPSC-derived cells. A bi-annual call for proposals for CRISPR screens is open with the next review deadline on 11th May 2025. Successful applicants will enter into a collaboration agreement with the University of Cambridge and in some cases with AstraZeneca to execute the screen, which will be carried out by FGSL scientists on our automated arrayed CRISPR screening platform. Funding is available for UK-based academics. To learn more about the screening lab and how to apply, please visit our poster.
Presenter: Jack Palmer (poster 40)
Deciphering gene regulatory networks that govern cardiomyocyte maturation in vitro
Authors: Jack A. Palmer, Kazumasa Kanemaru, James Cranley, Jonathan Lee, Chun-Ka Wong, Noémie Combémorel, Nadav Yayon, Valentina Migliori, Michaela Bruntraeger, Nneka Anyanwu, Freddy Wong, Sandeep S. Rajan, Amy Yeung, Sanjay Sinha, Andrew R. Bassett, Richard C. V. Tyser, Sarah A. Teichmann
Recent single-cell atlases of the human developing and adult heart have provided unprecedented
resolution of cardiac cells. Cardiomyocytes, a major cell type of the heart, have been
profiled to reveal a spectrum of phenotypes, from contractile to conductive. However, in vitro
models of cardiomyocytes retain foetal characteristics and lack the maturity observed in vivo, limiting their therapeutic application.
In this project, I am leveraging human heart atlases to predict key signalling molecules that drive cardiomyocyte maturity in vivo. These candidate molecules are used to carry out in vitro perturbations of human pluripotent stem cell derived cardiomyocytes, followed by single cell multiome sequencing (paired scRNA-seq and scATAC-seq) to benchmark perturbed cells against in vivo cardiomyocytes states. In perturbed cells that exhibit a mature phenotype, gene expression and chromatin data will be used to discover gene regulatory networks that govern cardiomyocyte maturation in vitro, including key transcription factors. Such networks can be further probed to enhance in vitro cardiomyocyte models for therapeutic use.
Presenter: Lay Ping Ong (poster 41)
Cellular therapy for the chronically failing heart – benefits of multicellularity?
Presenter: Rahul Manamperige (poster 10)
The role of HIF-2 in hypoxic programming of the sympathoadrenal system
Authors: Rahul Manamperige, Dino A Giussani, Peter Ratcliffe, James Nathan, Emma Hodson
Normal development occurs in an environment of physiological hypoxia, but more severe hypoxia has pathological consequences. Gestational hypoxia causes sympathetic hyperinnervation and cardiovascular dysfunction in the fetus and post-natal offspring. Similar phenomena may contribute to acquired cardiovascular pathologies, like heart failure or hypertrophy, which are associated with metabolic stress, cardiac sympathetic re-programming and reactivation of fetal cell states. Hypoxic effects on developmental programming are poorly understood but could form therapeutic targets.
Hypoxia-inducible factors (HIF-1/HIF-2) are oxygen-regulated transcription factors that maintain adaptive cardiorespiratory physiology but are also widely active in the embryo. The vertebrate-specific HIF-2 is highly expressed in developing sympathoadrenal tissues and is essential for fetal catecholaminergic homeostasis. Together with clinical observations that HIF-2 activating mutations cause catecholamine cell tumours (phaeochromocytoma/ paraganglioma) this suggests a developmental role. We hypothesize that HIF-2 regulates sympathoadrenal development, with excess activation drivfing sympathetic dysfunction and its cardiovascular consequences.
We have developed models to study how HIF activation affects development of sympathetic neurons and chromaffin cells using differentiation of human embryonic stem cells, alongside parallel experiments on chicken embryos as an in vivo system free from materno-placental confounders. These models allow us to dissect hypoxia-induced effects from isolated HIF activation via pharmacological or genetic interventions, including inducible expression of HIF-2 gain-of-function mutants mimicking clinical pathogenic variants.
We present validation of our experimental systems, which enable precise characterisation of HIF-dependent effects at each stage of sympathoadrenal development and provide a platform to assess the translational potential of clinically licensed HIF-active drugs in therapeutic sympathetic reprogramming.
Acknowledgements: Funded by the Wellcome Trust and The British Heart Foundation
Presenter: Rowda Dahir (poster 1)
Regeneration of the mouse heart 7-days Post-Myocardial Infarction through the activation of Myc and Cyclin T1.
Authors: Rowda Dahir, Alby Biju , Aleksandra Boikova , Dr. Adam Seaton, Dr.Catherine Wilson
Adult mammalian hearts have a poor intrinsic ability to regenerate following an injury. During myocardial infarction (MI), the lost contractile cardiomyocytes are replaced with a non-contractile fibrotic scar. These changes result in impaired contractility and loss of function which eventually progresses towards heart failure. Current treatment options tackle the reduced cardiac output and slow down the progression of the disease but the only curative intervention for heart failure is heart transplantation. Therefore, there is an unmet need to develop new regenerative therapies. One novel regenerative method to replace lost cardiomyocytes is via stimulating endogenous mechanisms that can elicit proliferation from pre-existing cardiomyocytes. Previously, we have shown transient and localised co-expression of Myc and Cyclin T1 at the site of injury one day post-MI, induces cardiomyocyte proliferation and functional recovery of adult mouse hearts in vivo. However, whether the treatment could drive recovery at later time points had not been determined. Here, we investigated whether transient, localised co-expression of Myc and Cyclin T1 at 7 days post-MI, could elicit adult cardiomyocyte proliferation and functional recovery. We show expression of Myc and Cyclin T1 in cardiomyocytes drives cell cycle with no significant changes to apoptosis. We determined scar size and showed improvement in left ventricular function which indicates that Myc and Cyclin T1 can successfully drive cardiac repair in pathologically remodelled injured hearts.
Acknowledgements: Department of Pharmacology, MRC Toxicology Unit, Newnham College, British Heart Foundation
Presenter: Adriana Córdova-Casanova (poster 2)
Maternal obesity during pregnancy disrupts iron homeostasis and promotes fetal hypoxia in the mouse
Authors: Adriana Córdova-Casanova, Isabella Inzani, Dino A Giussani, Denise S Fernandez-Twinn, Susan E Ozanne
Research in both humans and animals has consistently demonstrated that diverse complications during pregnancy impact on the risk of chronic diseases in the offspring. In many settings, over half of women are either overweight or living with obesity during pregnancy. This has short- and long-term impacts on offspring health. The mechanisms mediating changes in the fetal environment that may trigger developmental origins of future cardiometabolic risk in the offspring are not fully elucidated. In this study, using an established mouse model, we aimed to determine whether obesity during pregnancy causes fetal hypoxia and to explore potential underlying mechanisms. We showed that fetal hypoxia is a key component of the in utero obesogenic environment at e13.5 / 0.7 of gestation. Concomitantly, obese dams exhibit low iron levels, higher circulating hepcidin and CRP. We also showed that the placental structure and efficiency is not affected by maternal obesity at e13.5, suggesting that the reduction in oxygen delivery to the fetus was not a consequence of placental dysfunction at this stage of gestation. We conclude that maternal obesity-induced iron deficiency and fetal hypoxia are important mechanisms by which obesity during pregnancy impacts on offspring health. Furthermore, iron deficiency in mothers with obesity is a tractable therapeutic target for intervention that could prevent transmission of poor cardiometabolic health from mother to child.
Acknowledgements: British Heart Foundation (BHF): Dino A Giussani, Denise S Fernandez-Twinn, Susan E Ozanne RG/17/12/33167; UKRI | Medical Research Council (MRC): Denise S Fernandez-Twinn, Susan E Ozanne MRC_MC_UU_00014/4. Izabella Inzani was a recipient of a British Heart Foundation PhD studentship (FS/18/56/35177) and Adriana Córdova is the recipient of a -Beca Postdoctorado en el Extranjero- fellowship (ANID #74220049).
Presenter: Skaai Davison (poster 38)
Translatable Programming of Cardiovascular Dysfunction in Adult Offspring in an Ovine Model of Maternal Obesity During Pregnancy
Authors: Skaai H. Davison, Rachael C. Crew, Youguo Niu, Sage G. Ford, Clement L. Cahen, Anna L. K. Cochrane, Michael P. Murphy, Susan E. Ozanne, Dino A. Giussani
Introduction:
Mechanisms linking maternal obesity with cardiovascular risk in offspring remain unclear. Since sheep and humans share key milestones in cardiovascular development (Morrison et al. AJP 315: R1123, 2018), ovine models provide high translational value for studying prenatal origins of cardiovascular dysfunction. We established a novel ovine model to test whether maternal obesity induces sex-dependent alterations in cardiovascular function in adult offspring.
Methods:
Welsh Mountain ewes were fed either a control diet (C) (200g concentrate/day + ad libitum hay) or an obesogenic diet (OB) (ad libitum concentrate + hay) 60 days pre-pregnancy and throughout gestation. Male (C, n=6; OB, n=8) and female (C, n=6; OB, n=4) lambs were weaned at 3 months and raised to adulthood. At 9 months, lambs underwent surgical implantation of vascular catheters and a femoral artery Transonic flow probe under general anaesthesia. After 5 days recovery, cardiovascular responses to i.a. phenylephrine (PE) bolus doses or i.v. sodium nitroprusside infusion (SNP) were assessed.
Results:
Male (C vs. OB, mean pressure 90.4±2.9 vs. 97.2±1.3 mmHg) and female (80.8±0.3 vs. 88.9±0.9 mmHg) lambs of obese pregnancy were hypertensive (P<0.05). Male OB lambs showed sensitised PE pressor responses and enhanced tachycardia during SNP (Fig. 1), signifying sympathetic baroreflex hypersensitivity (C vs. OB, D heart rate at 10 min infusion: -5.5±3.6 vs. 34.8±5.0 beats.min-1, P<0.05).
Conclusions:
Maternal obesity during pregnancy programmes sex-dependent cardiovascular dysfunction in adult offspring in an ovine model of improved translational potential. Heightened vasoconstrictor reactivity and baroreflex gain in males may contribute to their increased cardiovascular disease risk.
Acknowledgements: Supported by the MRC
Presenter: Ankur Saini (poster 6)
The Compelling Link Between Exercise-Induced Immune System Adaptation and HFpEF
Authors: Ankur Saini, Amanda Rodgers, Lauren Kitt, Sebnem Oc, Nichola Figg, Olga Sauchanka, Meritxell Nus Chimeno, Helle F Jorgensen, Murray Clarke, Thomas Krieg, and Ana Vujic
Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and is characterized by a left ventricular ejection fraction ≥50%. HFpEF is often associated with comorbidities such as obesity, hypertension, and type 2 diabetes, leading to chronic low-grade systemic inflammation that fuels disease progression. While some therapies have shown promise, there remains a critical need for treatments that directly target the inflammatory mechanisms driving HFpEF. Exercise is well known for its cardiovascular benefits, and recent studies highlight its role in immune modulation. However, the precise molecular and cellular mechanisms underlying these effects remain unclear. In this study, we investigated exercise-induced immune reprogramming in HFpEF using a two-hit mouse model (60% high-fat diet + L-NAME). Echocardiographic assessments confirmed that exercise preconditioning did not prevent HFpEF progression. To explore potential therapeutic effects, we transplanted bone marrow-derived cells (BMDCs) from exercise-trained mice into HFpEF models. While BMDC transplantation during HFpEF development induced systemic changes without improving cardiac function, intervention after pathology onset led to structural and functional cardiac recovery. Immunofluorescence analyses revealed a reversal of cardiomyocyte hypertrophy. Further multi-omic analyses of bone marrow and immune cell trajectories in the heart and spleen will provide deeper insights into the immune mechanisms underlying exercise-induced cardioprotection.
Presenter: Siyuan Chen (poster 25)
Identify risk-factor-specific cell types that mediate the impact of diabetes, obesity, lipid, and blood pressure on coronary artery disease
Authors: Siyuan Chen, Michael Inouye, Xilin Jiang
Coronary artery disease (CAD) has multiple risk factors, including obesity, blood pressure, type 2 diabetes (T2D), and LDL-cholesterol (LDLC). However, whether these risk factors elevate CAD risk through distinct or shared cellular mechanisms remains unclear. In this study, we used both GWAS data and single-cell RNA sequencing data and developed an integrative framework that combines GWAS-by-subtraction (Demange et al. 2021 Nat. Genet.) and sc-linker (Jagadeesh & Dey et al. 2022 Nat. Genet.) to link causal cell types to CAD mediated by each risk factor. We use realistic simulations to validate our methods. We applied our method to five large GWAS studies (CAD, BMI, systolic blood pressure, T2D, and LDLC) and single-cell RNA sequencing data from 50 tissues and 353 cell types. We identified 34 cell types mediating T2D-elevated CAD risk, 22 mediating BMI-elevated CAD risk, and 43 mediating LDLC-elevated CAD risk (FDR threshold = 0.05). Specifically, T2D mainly conveys CAD risk through brain cell types, including oligodendrocytes in the anterior cingulate cortex, inhibitory neurons in the brain temporal lobe, and neurons in the central nervous system. For BMI-mediated and LDLC-mediated CAD risk, our method mainly prioritizes brain and colon cell types. Using tissue-level bulk RNA-seq data, we found majority of our signals could not be explained by tissue-specific gene expression profiles, which presents within-tissue heterogeneity. Our findings identify shared and distinct cellular mechanisms underlying distinct CAD risk factors and provide a foundation for advancing precision medicine approaches targeting specific cell types.
Presenter: Amy Wharmby (poster 42)
A single-centre initial experience with the Aurora™ Extravascular Defibrillator
Authors: Amy Wharmby, Claire Martin and Greg Mellor
Background: The Aurora™ extravascular (EV) implantable cardioverter defibrillator (ICD) can be used as an alternative to a transvenous or subcutaneous ICD. The single lead is implanted substernally avoiding vasculature and permits defibrillation, anti-tachycardia pacing and pause-prevention pacing.
Methods: A UK single-centre retrospective audit of the Aurora™ EV ICD device implanted over 12 months from January 2024 utilising health records and Carelink™.
Results: A total of 18 patients underwent EV ICD implantation, 34% female, age 43.1±16.5 years old, 44% primary prevention and LVEF 45.7%±15.3. Pre-implant imaging was conducted in 83.3% of patients. Defibrillation threshold testing (DFT) was conducted in 17 patients at implant, with successful defibrillation of ventricular arrhythmia (VA) in 94.1% at 30J. True shock impedance 71±18 ohms vs. sub-threshold 66±14 ohms. The first episode of noise occurred between 1- and 37-days. Noise episodes were recorded in 44.4% of patients, non-physiological (62.5%) and physiological (37.5%) sources, consequently, 25% of episodes required re-programming. Two dislodgments were observed, one patient the lead rotated 180 degrees but with no impact on sensing and successful re-DFT and second patient displacement in the pleural space. Two patients received successful shock therapy for VA. No inappropriate therapy to report. With regards to follow-up, 50% required at least 1 additional follow-up prior to the first remote follow-up 2 weeks post implant. Beyond this 38.9% required a further review between 6-8 weeks.
Conclusion: Our initial single centre experience indicated comparable outcomes to that of Pivotal study, showing the EV ICD to be a safe and effective system.
Presenter: Anirudh Krishnakumar (poster 39)
Safety and Acute Efficacy of the Affera Mapping and Ablation System for Atrial Ablation
Authors: Anirudh Krishnakumar*, Aniruddh Prabhu*, Sarah Zeriouh, Flavio Mendonca, Martyna Skrzynska-Kowalczyk, James Cranley, Parag Gajendragadkar, Patrick Heck, Greg Mellor, Claire A. Martin
*Joint first authors
Introduction:
Pulsed Field (PF) Ablation is a nonthermal technique using high-voltage electrical pulses to induce cell death by electroporation. Preclinical and clinical evidence show PF allows selective ablation of myocardial tissue. We evaluated the safety and efficacy of the novel Affera catheter (Medtronic) for atrial ablation.
Methods:
This prospective study included patients undergoing ablation at the first UK centre using Affera. Procedures were performed with the Sphere-9 (a multi-purpose dual-energy and mapping catheter). 3D electroanatomic mapping was conducted before and after ablation (Figure 1). Endpoints included lack of arrhythmia inducibility, pulmonary vein isolation (PVI) and bidirectional block across linear lesions.
Results:
40 patients were treated between April-December 2024. Patient characteristics: age 60.6±11.5 years, 21 female, BMI 30.7±5.7 kg/m², LVEF 55.1±10.4%, CHADS2VASC2 1.3±0.9. Primary arrhythmias: Paroxysmal Atrial Fibrillation (n=14), Persistent Atrial Fibrillation/Macroreentrant Atrial Tachycardia (n=22), Typical Flutter (n=2), and Focal Atrial tachycardia (n=2). Lesions included: PVI (n=29), cavotricuspid isthmus line (n=20), posterior wall isolation (n=18), mitral line (n=7), roof line (n=1), superior vena cava isolation (n=2), and bicaval line (n=1). One case experienced acute PV reconnection requiring further ablation; all other lesions were successful. Two patients experienced pericardial effusion. Follow-up data was available for 13 patients of which one experienced arrhythmia recurrence.
Conclusion:
Atrial ablation with Affera demonstrates promising efficacy, acute safety, and efficient workflow with rapid lesion creation. Further data will be collected, evaluating long-term safety and lesion durability.
Acknowledgements:
With thanks to Dr. Claire Martin and the Electrophysiology Department at Royal Papworth Hospital, UK
Presenter: Dorisa Gil (poster 4)
Getting into platelets: the potential of protein transduction domain tags to study the roles of small GTPases in platelets
Authors: Dorisa L. A. Gil, Mareike Posner, Clett Erridge, Nicholas Pugh
Platelets are anuclear blood cells central to haemostasis following vascular injury and thrombosis. The study of their function and signal transduction pathways is therefore essential in the development of novel anti-thrombotic strategies.
As anuclear cells, conventional in vitro molecular techniques are not suited to platelet study, making pharmacological approaches and transgenic mice the go-to techniques. However, these methods may not always be possible or applicable to humans. There are several small GTPases in the platelet proteome which have therefore not been studied. New technology is needed to facilitate research into the roles these have in platelets.
Protein-transduction domain (PTD) tags have been shown to enable delivery of full-length proteins into a variety of cell types, but the potential for PTD-tagged recombinant proteins to study platelets has yet to be investigated in detail. We hypothesise that successful transduction of constitutively active signalling proteins into the platelet cytosol would mimic the effects of activation of the endogenous protein following platelet activation.
Preliminary data has tested the effects of recombinant, purified TAT-tagged CDC42 protein on platelets using light transmission aggregometry. Treatment with constitutively active CDC42 (CDC42-G12V), but not wild type or dominant negative (CDC42-T17N), results in aggregometry traces suggestive of shape change, consistent with a bioactive response. These data show promise for the use of PTD-tagged recombinant proteins as novel reagents to study the roles of small GTPases in platelets. Further research will investigate this concept using GTPases with unknown roles, aiming to enhance understanding of the platelet proteome and signal transduction pathways.
Acknowledgements: This work was supported by the British Heart Foundation
Presenter: Emily Capes (poster 8)
Investigation of the mechanisms and significance of degranulation-dependent Zn2+ release following platelet activation
Authors: Emily M Capes, Havovi Chichger, Joanna-Marie Dear, Matthew T Harper, Nicholas Pugh
Following vascular injury or pathogenic thrombosis formation, platelet activation results in the release of bioactive agents including zinc (Zn2+) that acts as a platelet agonist. Zn2+ has been found to accumulate in atherosclerotic plaques to levels six-fold greater than surrounding tissues, potentially providing a reservoir accessible to haemostatic processes following plaque rupture. Sub-activatory concentrations (30µM) of Zn2+ potentiate platelets to activation by conventional agonists. These concentrations are not considerably greater than basal plasma Zn2+ (0.5-1µM) and could feasibly be attained as a result of platelet degranulation, cell damage, or atherosclerotic plaque rupture. The aim of this work was to investigate the mechanisms involved in of Zn2+ induced platelet aggregation, and to quantify the total Zn2+ released from platelets following activation.
Experiments were performed to investigate of the effects of Zn2+ on buffer components in calcium-free Tyrodes buffer. Platelet activation was measured in washed human platelet suspensions using light transmission aggregometry and flow cytometry. Zinc release was quantified using optical emission spectroscopy and colorimetric assay. It was found that Zn2+ induced platelet aggregation was aberrated in the absence of phosphate in the buffer whilst all other normal platelet responses were maintained. Optical emission spectroscopy quantified Zn2+ release from platelets following activation. Further investigations will quantify total Zn2+ released from platelets after stimulation from various agonists.
Presenter: Jason Sangha (poster 35)
Coronary plaque structural stress derived from AI-based segmentation of OCT images independently predicts future non-culprit lesion MACE
Authors: Jason Sangha, Yuan Huang, Sophie Gu, Michael Roberts, Martin Bennett
Background
Non-culprit lesions are responsible for a significant proportion of downstream MACE1, 2. High-risk anatomical features have a positive predictive value for MACE of just 5-10%3. To augment image-based prediction of future MACE, we have developed a novel method wherein we couple AI-based segmentation of optical coherence tomography images (‘AutoOCT’) to finite element analysis (FEA) to derive circumferential wall stress (plaque structural stress; PSS).
Methods
We have previously coupled virtual histology intravascular ultrasound (VH-IVUS) to FEA to derive PSS4, and this has been correlated with MACE5. We first validated the novel AutoOCT-based method against this established technique by manually co-registering VH-IVUS and AutoOCT images from the IBIS-4 trial6 using two expert readers and comparing PSS outputs. To correlate Auto-OCT derived PSS with MACE, we utilise 32 LAD OCT pullbacks with 3,333 frames from the CLIMA study3. The primary composite clinical endpoint was cardiac death or LAD segment MI at 1-year. OCT images were first segmented for plaque components using the AutoOCT deep learning AI modules before reconstruction in MATLAB, meshing and FEA simulation using ADINA to generate PSS. We investigated the pullback-wise median of frame-level peak PSS in the plaque regions.
Results
For validation, we matched 221 VH-IVUS and AutoOCT frames from 17 pullbacks from 17 patients and found significant associations in median PSS (Spearman rho 0.68, p<0.0001; Figure 1). In multivariate linear models, adjusting for lumen area, PSS was 22.5kPa higher (p=0.005; Figure 2) in MACE patients. In ROC curve analyses, PSS combined with lumen area (LA) generated an AUC of 0.87 for MACE prediction (Figure 3).
Conclusion
Fully automatic biomechanical phenotyping of non-culprit lesions improves identification of plaques prone to future destabilisation.
Presenter: Ji-Eun Lee (poster 16)
Assessing mitochondrial morphology using high-throughput fluorescence imaging in combination with a novel deep learning segmentation method
Authors: Ji-Eun Lee, Agustina Salis Torres, Abhinanda Punnakkal, April Tan, Justyna Cholewa-Waclaw, Amirhossein Kardoost, Craig Leighton, Janelle Leong, Daniel Greenslade, Dilip K. Prasad, Alison Hulme, Casten Marr, Mathew H. Horrocks, Vicky E. MacRae
Vascular calcification (VC) is a critical pathophysiological process contributing to cardiovascular disease (CV), with mitochondrial dysfunction playing a pivotal role in its progression. Mitochondria are vital for energy production, cell signalling and apoptosis, and their structure varies with cell processes. The morphology of mitochondria is a critical indicator of their functions, as determined by mitochondrial fusion and fission. Here, we have developed a high-content imaging pipeline to assess mitochondrial morphology in primary vascular smooth muscle cells (VSMCs) using high-throughput spinning disk confocal imaging in combination with a novel deep learning segmentation model (MitoSegNet). Our data show the use of MitoSegNet and AI analysis can quantify vast amounts of data on complex mitochondrial morphology and can detect subtle changes in mitochondrial morphology successfully across multiple experimental conditions. Furthermore, we demonstrate our high-throughput imaging platform can be used to quantitatively assess mitochondrial dysfunction and in-depth study mitochondrial dysfunctions associated with CV. This approach will provide new insights into not only the study of mitochondrial mechanisms underlying VC but also establishment of a scalable platform for drug screening and therapeutic targeting.
Acknowledgements: This work was funded by the BBSRC and the British Heart Foundation
Presenter: Justin Braver (poster 20)
Is cardiac rehabilitation beneficial following transcatheter aortic valve implantation (TAVI)?
Authors: Justin Braver, Thomas Marwick, John Nolan, Angela Wood
Introduction. Cardiac rehabilitation (CR) programs provide substantial benefits and are endorsed by international guidelines for acute coronary syndromes (ACS), heart failure (HF) and following coronary revascularization procedures. However, evidence on CR rates and its potential benefits for patients undergoing transcatheter aortic valve implantation (TAVI) remains very limited.
Purpose. To characterise CR rates following TAVI procedures across England and evaluate the association between CR and patient outcomes.
Methods. Retrospective, cohort study, using whole-population electronic health records for 57 million individuals in England. Adults aged 18 years or older who underwent a TAVI procedure between 1 January 2018 and 31 March 2023 were included. Patients exposed to CR were compared to those not exposed, adjusting for demographic characteristics, clinical factors and complications with the index TAVI procedure. Primary outcome was unplanned HF hospital readmission, assessed using a competing risk analysis with death. Secondary outcomes included all-cause mortality and all-cause rehospitalization.
Results. Among 24,950 individuals with a TAVI procedure (56% male, mean age 81 years and 95% white ethnicity), fewer than one in twenty attended CR (n=1,090, 4.4%). CR rates increased from 2018 (1.73 per 10,000 person days of follow-up) to 2022 (2.93 per 10,000 person days of follow-up). All-cause and HF rehospitalization rates beyond 180 days were comparable between the exposed and unexposed groups: 49.7% (n=355) vs. 56.2% (n=8,605) for all-cause rehospitalization and 7.4% (n=75) vs. 9.2% (n=1,995) for HF rehospitalization. Similarly, all-cause mortality beyond 180 days did not differ between the exposed (n=300, 28.7%) and unexposed (n=7,510, 33.2%) groups. After adjustment, no significant associations were observed between exposure to CR and HF rehospitalization, all-cause rehospitalization, or all-cause mortality (p>0.05).
Conclusion: The benefit of CR following TAVI remains uncertain. Further prospective research is required.
Presenter: Lewis Spurrier-Best (poster 11)
Novel GPCR in the lung endothelium regulates VEGF-mediated angiogenic processes
Authors: Lewis Spurrier-Best, Havovi Chichger
Introduction: Respiratory diseases account for ~10% of European hospital admissions. Angiogenesis is implicated in various lung pathologies, notably pulmonary hypertension, and cancer, but also conditions including COPD and pulmonary fibrosis. The bitter taste receptor T2R14 is expressed in the lung microvascular endothelium, and its agonists disrupt endothelial barrier function, however, there are no studies which investigate the impact of T2R14 on angiogenic processes.
Research Question: To investigate the role of the novel T2R14 antagonist, LW129, on angiogenic processes within primary human pulmonary microvascular endothelial cells (HPMECs).
Methods: Primary HPMECs were treated with varying concentrations of LW129. Cell viability was assessed using MTT and proliferation assays. Angiogenic processes were evaluated via tube formation assays (MatrigelTM) and cell migration assays. The impact of LW129, in the presence and absence of VEGF, was examined.
Results: MTT assays revealed LW129 toxicity at concentrations above 10 μM, likely due to off-target effects. At concentrations from 1 nM -1 μM, LW129 increased HPMEC viability which was largely mirrored by proliferation assay findings. Both tube formation and cell migration assays showed no significant impact of LW129 alone, however, the antagonist significantly reduced VEGF-induced tube formation and migration.
Conclusion: While LW129 increases HPMEC proliferation at low concentrations, it does not significantly promote angiogenesis. Furthermore, it appears to attenuate VEGF-mediated angiogenic responses. These findings suggest a role for T2R14 in regulating angiogenesis in the lung microvasculature and indicate a potential role for antagonists for pro-angiogenesis pathologies.
Acknowledgements: Prof Nicholas Pugh, Dr Clett Erridge, Dr Mareike Posner, Cambridge Philosophical Society
Presenter: Owen Taylor (poster 19)
Tailoring Graphic Communication of Cardiovascular Disease Risk to Mitigate Inequalities in Clinical Decision Making and Primary Prevention: A Systematic Review and Qualitative Study
Authors: Owen A Taylor, Carmen Petitjean, Elena Raffetti, Claire Coffey, Martha Kingsley, Melinda Carrington, Rebecca Dennison, Angela M Wood
To optimise graphic formats for communicating cardiovascular disease (CVD) risk in primary prevention, we employed two complementary approaches. First, a systematic review investigated graphic communication of phenotypic risk for CVD or cancer primary prevention. A comprehensive search (01/01/2000–29/01/2024) across several databases identified 53 studies (n=17,457). A taxonomical framework was derived to synthesise heterogeneous data. No single graphic format outperformed others across five outcome categories: Knowledge and Understanding, Preferences and Satisfaction, Health and Behaviour Outcomes, Emotional and Psychological Outcomes, and Decision Quality and Decision-Making Capacity. Quantitative bar graphs yielded higher Knowledge and Understanding and Preference and Satisfaction than non-visual formats, while icon arrays with gender-specific anthropometric icons were most effective among individuals with lower numeracy and graph literacy. Moreover, combining graphic with non-graphic visuals improved Health and Behaviour Outcomes regardless of education or health literacy. Second, an international qualitative study (n=36) using semi-structured interviews prioritised recruitment of underserved populations, balanced by diabetes status and location: Australia and the UK. Participants evaluated risk visuals to communicate phenotypic, polygenic and coronary artery calcium (CAC) scores based on design features such as colour, framing and iconography. Although population distribution curves for polygenic risk sometimes hindered understanding, CAC illustrations, bar graphs and visual analogue scales were favoured for clarity, especially among those with limited graph literacy. Integrating evidence from both studies supports a tailored, user-centred approach to risk communication to foster informed decision-making and reduce health disparities. Further research is warranted to refine and evaluate the long-term impact of graphic and visual risk formats.
Acknowledgements: OAT is supported by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312) [*]. *The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. OAT is supported by Cambridge BHF Centre of Research Excellence (RE/18/1/34212) and the BHF Chair Award (CH/12/2/29428). OAT is supported by core funding from the: British Heart Foundation (RG/18/13/33946).
Presenter: Ruby Baxter (poster 28)
Reported TMEM16F inhibitors do not block platelet phosphatidylserine exposure
Authors: Ruby Baxter, Cameron Bicknell, Milena Malcharek, Matthew Harper
Background: Pro-coagulant platelets expose phosphatidylserine (PS), promoting thrombin generation in thrombosis and haemostasis. TMEM16F is the ‘scramblase’ responsible for PS exposure. Inhibition of TMEM16F and therefore PS exposure could be a novel approach to prevent thrombosis. Although several drugs are reported to inhibit TMEM16F, there is limited evidence of their efficacy with platelets.
Aims: Assess the efficacy of reported TMEM16F inhibitors on platelet PS exposure.
Methods: Platelets were incubated with reported TMEM16F inhibitors before stimulation with thrombin and CRP-XL or A23187. PS exposure was measured with Annexin V (AnV) and mitochondrial membrane potential was measured with TMRM, via flow cytometry.
Results: Abamectin and niclosamide reduced the percentage of AnV-positive platelets following thrombin and CRP-XL stimulation but not following A23187. The MFI of the AnV-positive population was unchanged suggesting that there was no reduction in the extent of PS on the platelet surface. Abamectin reduced degranulation and αIIbβ3 integrin activation with stimulation showing inhibition of platelet activation which could account for the reduction in the percentage AnV-positive platelets. Niclosamide incubation resulted in loss of TMRM fluorescence in the absence of stimulation to a similar extent as CCCP (a mitochondrial uncoupler). CCCP similarly reduced the percentage of AnV-positive platelets with thrombin and CRP-XL stimulation, suggesting that niclosamide could also be a mitochondrial uncoupler.
Conclusions: Reported TMEM16F inhibitors do not selectively inhibit platelet PS exposure in repsonse to stimulation. Abamectin and niclosamide showed a reduction in AnV-positive platelets with thrombin and CRP-XL treatment, but this can be attributed to off-target effects.
Acknowledgements: Thank you to the British Heart Foundation for their funding. Thank you to the kind volunteers who donate blood to the Harper group.
Presenter: Rui Li (poster 31)
LUMEN–A Deep Learning Pipeline for Analysis of the 3D Morphology of the Cerebral Lenticulostriate Arteries from Time-of-Flight 7T MRI
Authors: Rui Li, Soumick Chatterjee, Yeerfan Jiaerken, Chethan Radhakrishna, Philip Benjamin, Stefania Nannoni, Daniel J. Tozer, Hugh S. Markus, Christopher T. Rodgers
The lenticulostriate arteries (LSA) supply critical subcortical brain structures and are affected in cerebral small vessel disease (CSVD). Changes in their morphology are linked to cardiovascular risk factors and may indicate early pathology. 7T Time-of-Flight MR angiography (TOF-MRA) dramatically enhanced LSA visualisation. We aimed to develop a semi-automatic pipeline for quantifying 3D LSA morphology from 7T TOF-MRA in CSVD patients.
We used data from a local 7T CSVD study. Our pipeline, LUMEN, comprises two stages: vessel segmentation and LSA quantification. For segmentation, we fine-tuned a deep learning model, DS6, and compared it against a classical Frangi filter-based pipeline, MSFDF. For quantification, centrelines of LSAs within the basal ganglia were extracted to compute branch counts, length, and tortuosity. This pipeline was applied to 69 subjects, with results compared to traditional analysis measuring LSA morphology on 2D coronal maximum intensity projection (MIP) images.
For vessel segmentation, the fine-tuned DS6 model achieved a mean test Dice score of 0.814±0.029, outperforming MSFDF on Dice score, sensitivity, and balanced average Hausdorff distance. Visual inspection confirmed that DS6 was more sensitive in detecting LSA branches with weak signals. Across 69 subjects, the pipeline identified 23.5±8.5 LSA branches on average. Mean branch length inside the basal ganglia was 26.4±3.5mm, and mean tortuosity 1.5±0.1. Extracted LSA metrics from 2D MIP analysis and our 3D analysis showed fair to moderate correlations. Outliers highlighted the insufficiency of 2D MIP analysis.
This open-source deep-learning-based pipeline offers a validated tool quantifying 3D LSA morphology in CSVD patients from 7T-TOF-MRA for clinical research.
Presenter: Spencer Keene (poster 27)
SCORE2-HF risk prediction algorithms: New models to estimate 10-year risk of incident heart failure in Europe
Authors: Spencer Keene, Stephen Kaptoge, Wen Shi, Chimweta Chilala, Jennifer Lees, Tessa Reitsma, Nathalie Conrad, Massimo Piepoli, Charlotte Andersson, Steven Hageman, Jannick Dorresteijn, Frank Visseren, Angela Wood, Emanuele Di Angelantonio, and Lisa Pennells, on behalf of the SCORE2-HF working group and ESC Cardiovascular Risk Collaboration
Heart failure (HF) is a life-threatening condition affecting over 60 million people globally. The European Society of Cardiology recommends the SCORE2, SCORE2-OP, and SCORE2-Diabetes risk scores to estimate individual cardiovascular disease (CVD) risk and guide preventive intervention in primary care. However, these models do not incorporate the risk of non-fatal HF.
We derived SCORE2-HF, a prediction model to estimate 10-year risk of incident HF in European adults aged 40 years and over without prior CVD or HF, using data from >450,000 individuals with >12,000 HF events from the UK Biobank and multiple European/North American cohorts. Sex-specific, competing risk-adjusted models incorporated age, smoking status, systolic blood pressure, antihypertensive treatment, body mass index, estimated glomerular filtration rate, and diabetes (including age at diagnosis and HbA1c). SCORE2-HF was recalibrated to accurately reflect HF incidence in Europe, using population CVD mortality statistics from the World Health Organisation, and HF incidence from representative data sources.
SCORE2-HF showed excellent calibration and discrimination when externally validated in 1.23 million individuals with 33,755 HF events from the Clinical Practice Research Datalink (C-index: 0.819 [0.817-0.821]). SCORE2-HF risk estimations varied importantly across individuals with different levels of modifiable risk factors (Figure 1). Furthermore, SCORE2-HF provided meaningful risk stratification within existing guideline-recommended CVD risk categorisations using SCORE2 risk models (Figure 2), indicating complementary value in additionally using SCORE2-HF scores to guide preventive intervention.
SCORE2-HF was derived, recalibrated, and validated to estimate 10-year risk of incident HF in European countries, and should enhance identification of individuals at high HF risk.
Presenter: Stelios Boulitsakis Logothetis (poster 22)
Multi-disease risk models to target concomitant diseases and their interactions: Insights on cardio-renal-metabolic syndrome in England
Authors: Stelios Boulitsakis Logothetis, Niels Peek, Angela Wood
Introduction
Clinical risk prediction models typically focus on a single disease, overlooking clusters of conditions with shared pathophysiology and treatments. Accounting for these relationships could improve disease prevention and health outcomes.
This study develops multi-disease models to jointly predict cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic disorders like diabetes—collectively termed cardio-renal-metabolic syndrome. These conditions share risk factors, intervention effects, and contribute to premature mortality. We aim to extract insights into disease progression in the English population and lay the groundwork for individualised multi-disease prediction models.
Methods
We modelled disease progression as a state transition process, using a multi-state model to predict 5-year incident CVD and CKD, with diabetes as a risk factor and death as a competing risk. Transition intensities were estimated using Cox proportional hazards sub-models.
We analysed electronic health records from NHS databases, covering 48.65 million eligible adults. Diagnoses, lab measurements, and treatments were included, with missing data multiply imputed. To ensure computational feasibility, we coarsened the time scale and restricted predictors to well-established risk factors.
Results
Among eligible adults, 394,555 had concomitant CVD and CKD. CKD incidence after CVD was twice that of CVD after CKD (24.73 vs. 12.85 per 1000 person-years). Cox models achieved a concordance index of 0.882. Nearly all predictors had significant association with every state transition. Smoking was the strongest predictor (HR: 2.14–2.69).
Conclusion
We demonstrated national-scale joint modelling of cardio-renal-metabolic syndrome. Future work will refine individual-level predictions and explore machine learning to overcome computational limitations of classical approaches when using whole-population electronic health records.
Acknowledgements
Tom Bolton, Rob Fletcher, Nick Hirschmuller, Spencer Keene, Carmen Petitjean, Alexia Sampri, Elena Raffetti, Isabel Walter
Presenter: Wen Shi (poster 30)
Burden of cardiovascular diseases from 2020 to 2024: a national cohort in NHS England
Authors: Wen Shi, Elias Allara, Tom Bolton, Fionna Chalmers, Elena Raffetti, Genevieve Cezard, Spiros Denaxas, Angela Wood, William Whiteley on behalf of the CVD-COVID-UK/COVID-IMPACT Consortium
Background: Regular estimates of epidemiological statistics are useful for public health. We estimated prevalence, incidence, 30-day mortality and post-diagnosis 30-day to 1-year rate of myocardial infarction (MI) or ischaemic stroke.
Methods: We used primary and secondary care electronic health records (EHR), mortality and disease registries from 2020 to 2024 in the NHS England Secure Data Environment to generate estimates for 79 cardiovascular diseases. We performed crude analyses by COVID-19 periods, sensitivity analyses by data sources and subgroup analyses adjusted for sex, age, ethnicity, deprivation, region, comorbidity. Results were weighted by ONS census population estimates.
Results: Our population size was 56.2 - 57.5 million. We observed reduced incidence and increased mortality for almost all diseases during the first COVID-19 wave in early 2020 and increasing trends for diseases like hypertension afterwards (Fig 1). Adjusted estimates were generally higher in older than younger people, in men than women, in people more than less deprived, and in people with more comorbidities than fewer (Fig 2). There were higher incidences of hypertension and ischaemic heart disease in Asian and Black compared to White British (Fig 3). Some Integrated Care Boards in the West and North-East tend to have much higher mortality of MI (Fig 4). Sensitivity analyses showed that different data sources complement each other to provide a more comprehensive picture of disease burden (Fig 5).
Conclusion: Regular epidemiological estimates can be produced with linked EHR, which exposes patterns overtime and among subgroups. Provisioning such estimates for public health planning should be prioritised.
Acknowledgements: Protocol reviewers (researchers): Alice Hosking, Kamlesh Khunti, Chris Tomlinson, Ami Banerjee, Kazem Rahimi, Sara Khalid, Jayati Das-Munshi, Steffen Peterson. Protocol reviewers (public and patient contributors): Simon Frain, Ben Bray. This work was carried out with the support of the BHF Data Science Centre led by HDR UK (BHF Grant no. SP/19/3/34678). This study made use of de-identified data held in NHS England’s Secure Data Environment service for England and made available via the BHF Data Science Centre’s CVD-COVID-UK/COVID-IMPACT consortium. This work used data provided by patients and collected by the NHS as part of their care and support. We would also like to acknowledge all data providers who make health relevant data available for research.
Presenter: Will Watson (poster 33)
Phosphorous-31 Magnetic Resonance Cardiac Spectroscopy at 3 Tesla: Initial Experience at Papworth
Authors: Will Watson, Clare Goldsmith, Ukpong Antigha, Jabrane Karkouri, Andrew Gill, Christopher Rodgers
Aim: To develop a system for phosphorous-31 cardiac magnetic resonance spectroscopy using a 15cm surface coil at 3 Tesla rapidly and in patient comfort. Previous applications have used large, heavy coils or involved participants lying prone.
Methods: Nine healthy volunteers were recruited (age 25-52 years old, mean BMI 25.7). A 3 Tesla CMR system (Prisma, Siemens, Germany) was used. Participants were positioned supine with a 15cm loop surface coil (Pulseteq, UK) positioned over the heart. A 3D chemical shift imaging sequence with ultra-short echo time (UTE-3DCSI) was used to acquire cardiac spectra, with saturation bands positioned over skeletal muscle and liver. A cardiac voxel from the basal septum was used for analysis and analysed using the OXSA toolkit in Matlab. Phosphocreatine / ATP ratio was calculated using the peak amplitude of phosphocreatine divided by the average of the three ATP peaks, and corrected for blood pool contamination by adjusting for the diphosphoglycerate peak.
Results: Average PCr/ATP ratio was 1.89 ± 0.23, and blood corrected PCr/ATP was 2.13 ± 0.21.
Conclusions: Blood corrected PCr/ATP is consistent with other series in healthy volunteers, indicating successful collection of cardiac data. This represents a sequence that allows for acquisition of these data in 15 minutes in relative comfort.
Future directions: This approach may be applied to patients with cardiac disease for investigation of myocardial energetics.
