Speaker Abstracts and Itinery 2023

Cambridge Cardiovascular / BHF Cambridge CRE annual symposium 2023
09:20	Dr Genevieve Cezard Genevieve_Cezard.jpg The impact of vaccination on the association of Covid-19 diagnosis with cardiovascular diseases
The incidence of cardiovascular diseases increases after COVID-19 diagnosis. How COVID-19 vaccination and different SARS-CoV-2 variant eras impact on this increase is unclear. We aim to quantify associations between COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras in England. Data were analysed within the OpenSAFELY platform which links primary care, hospital, death, COVID-19 testing and vaccination records for ~40% of the English population. We found that vaccination attenuates the elevated incidence of arterial and venous thrombotic events after COVID-19. Our results also suggest that different SARS-CoV-2 variants did not markedly affect cardiovascular risk after COVID-19.
09:35	Dr Carles Foguet Carles_Foguet.jpg Genetically personalised organ-specific metabolic models: A new tool to characterise how genetic variants condition metabolic phenotypes
Understanding how genetic variants influence disease risk is one of the major challenges in genetics. To address it, we developed a model-driven framework to leverage human genome-scale metabolic networks to define how genetic variants affect biochemical reaction fluxes across major human tissues. As proof of concept, we built personalised organ-specific metabolic flux models for over 500K individuals and performed a fluxome-wide association study (FWAS) to identify metabolic fluxes associated with complex traits and disease risk. We highlight how genetically personalised metabolic models can identify metabolic processes mechanistically linked to common human diseases.
09:50	Dr Lisa Pennells lisa_pennells.jpg SCORE2-Diabetes: new calibrated models to estimate 10-year risk of cardiovascular disease in individuals with type 2 diabetes in Europe
Cardiovascular disease primary prevention guidelines generally advocate estimation of 10-year CVD risk in individuals with Type-2 diabetes to inform treatment decisions. However, available risk models for this population have limitations. In particularly, they are not systematically ‘recalibrated’ to reflect substantial variation in CVD rates across Europe. SCORE2-Diabetes was derived by extending the SCORE2 general population CVD risk algorithms with diabetes-related risk predictors, and recalibrated to four European risk regions. SCORE2-Diabetes should improve CVD risk estimation accuracy in individuals with Type-2 diabetes across Europe and, since it extends on SCORE2, provides alignment in risk prediction for those with and without diabetes.
10:05	Dr Spencer Keene spencer_keene.jpg The long-term risk of stroke and cardiovascular disease in patients after coronavirus infection compared with influenza/pneumonia
Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to systemic inflammation and thrombosis. Soon after infection, there is an increased risk of both arterial and venous thromboembolism. We sought to compare the longer-term risks of arterial and venous thromboses COVID-19 with the risk after influenza or pneumonia in linked primary and secondary care electronic health records for the whole population of Wales. The vascular risk of COVID-19 has been particularly prominent in discussions about the illness, and it is important to compare them so that policy responses can be proportionate.
10:25	Prof Nicole Soranzo Nicole_Soranzo.jpg Endothelial cell and other large-scale single cell RNA analyses

10:40	Mr Bernard Cho Bernard_Cho.jpeg Association of Vascular Risk Factors and Genetic Factors with Penetrance of Variants Causing Monogenic Stroke
It is uncertain what factors are associated with penetrance of variants causing monogenic cerebral small vessel disease (cSVD). In this UK Biobank study of 454,756 participants, NOTCH3, HTRA1, and COL4A1/2 variants causing monogenic cSVD were associated with increased stroke and dementia risk. Cardiovascular risk factors were found to be associated with penetrance of these variants. Our results support the hypotheses that cardiovascular risk factor control may improve disease prognosis in individuals with monogenic cSVD variants, and that identifying individuals early in life before symptom onset may help reduce stroke and dementia risk.
10:55	Dr Stefan Graf Stephan_Graf.jpg Dysregulated molecular networks of rare vasculopathies
Whole genome sequencing has become a routine tool in genomic medicine. Population-scale sequencing facilitates the identification of pathogenic sequence variation and its effects on biological function disrupting the underlying molecular genetic networks. Diagnostic yields, however, are still low and very variable between different conditions. The unexplained missing heritability is evident in frequently observed incomplete penetrance and variable expressivity. Multi-omics data integration bears the hope to decipher the remaining molecular genetic and ‘omic architecture of human disease. I will summarise the progress being made and discuss current opportunities and challenges exemplified by two rare vasculopathies, pulmonary hypertension and small vessel disease.
11:40	Dr Emma Yu Emma_Yu.jpeg Mitochondrial regulation of atherosclerosis
Atherosclerotic plaques and plaque-derived vascular smooth muscle cells (VSMCs) show significant mitochondrial dysfunction. Cardiolipin is an important phospholipid of the mitochondrial inner membrane and is required for respiratory efficiency. Tafazzin is a nuclear-encoded trans-acylase that acylates immature monolysocardiolipin to mature cardiolipin. However, the role of tafazzin in regulating VSMC mitochondrial function and atherogenesis is unclear. In this study we show that tafazzin expression is decreased in human plaque-derived VSMCs and is negatively regulated by microRNA 125a-5p. Defective tafazzin decreases mitochondrial respiration, increases apoptosis and promotes atherosclerosis. Tafazzin and/or its substrate cardiolipin are potential new therapeutic targets in atherosclerotic disease.
11:55	Mr Semih Bayraktar semih_bayraktar.jpg High resolution single cell analysis of the developing human heart and the great vessels
The human heart is composed of various cell types that collectively support its homeostasis. Here, we generated a high-resolution multi-omic atlas of the first and second trimester human heart and great vessels using single cell RNA and single nuclei multiome (RNA+ATAC) sequencing, as well as spatial transcriptomics. We defined +60 cell types with distinct identity, function, or location specific signatures, such as the cardiomyocytes of different chambers and the vessel constituents specific to coronary or great vessels. Collectively, our analysis provides the most comprehensive cardiac developmental atlas to date and will provide insights into function in health and disease.
12:10	Dr Meritxell Nus Marginal Zone B cell - T follicular helper cell interactions protect from atherosclerosis
The adaptive immune response plays an important role in atherosclerosis. In response to a high fat/high cholesterol diet, marginal zone B (MZB) cells activate an atheroprotective programme regulating the differentiation of T follicular helper (Tfh) cells. Lack of MZB cells lead to the accumulation of “abnormal” Tfh. However, the direct role of Tfh cells in atherosclerosis remains poorly understood. Here, using an atherogenic mouse model with specific deletion of Tfh cells, we show that absence of Tfh leads to an accumulation of “abnormal” MZB cells unable to secrete “natural” IgM antibodies. Our findings could have important pathophysiological and therapeutic implications.
12:25	Dr Xuan Li Regulation of microtubule function in ischaemic heart failure
Heart failure is the leading cause of morbidity and mortality worldwide, and myocardial infarction (MI) is the main cause of ischaemic heart failure. Existing drugs that improve inotropy act through calcium-dependent mechanisms, and are of limited clinical use due to their severe adverse effects. Microtubule detyrosination is a recently discovered mechanism that regulates cardiomyocyte contractility in a calcium-independent manner. We are studying how microtubule detyrosination is mechanistically regulated after myocardial infarction. Targeting the regulatory players on this pathway will provide a strong translational basis on how to regulate microtubule detyrosination to improve cardiomyocyte contractility after MI.
14:15	Prof Toni Vidal Puig antonio_vidal-puig.jpg Lipid metabolism in macrophages and cardiometabolic risk
Our research program focuses on the role of macrophage lipid metabolism and metabolic inflammation in obesity. Our research has identified that adipose tissue macrophages (ATMs) experience metabolic inflammation due to impaired cellular lipid metabolism, contributing to obesity-associated cardiometabolic comorbidities (CMCs). We focus on the pathogenic relevance of three interconnected pathways that regulate macrophage lipid metabolisms programme which have the potential to identify new evidence-based targets for developing drugs to prevent or reverse obesity-associated CMCs and identify mechanistically-based diagnostic, prognostic and therapy response biomarkers that can stratify obese patients based on their susceptibility to cardiometabolic risk.
14:30	Prof Roger Foo roger_foo.jpg Target discovery through cardiac epigenetics

14:45	Dr Albert Koulman albert_koulman.jpg Quantitative lipidomics, yielding biomarkers for lifestyle nutrition and disease risk
The concentration of lipids in the circulation and in tissues is tightly regulated, but the complexity and redundancy in lipid biochemistry allows the body to constantly change and adapt lipid concentrations to respond to changes in nutrition, lifestyle and physiological processes. Lipids are therefore a rich source for biomarkers, both for short-term and long-term processes. Through the use of quantitative lipidomics we can translate and validate candidate lipid markers. In the talk I will highlight the current state of quantitative lipidomics, show examples of candidate lipid biomarkers and how these can be translated from animal models to humans
15:00	Dr Ana Vujic Interference with mitochondrial RET-ROS generation results in metabolic changes and heart failure with preserved ejection fraction (HFpEF)
Heart failure with preserved ejection fraction (HFpEF) is a major public health problem with high morbidity and mortality, and is rising in prevalence. Patients with HFpEF are more likely to suffer from metabolic comorbidities, compared to patients with primarily a systolic dysfunction, suggesting that distinct risk factors and pathological mechanisms underlie these conditions. Mitochondrial abnormalities such as alteration of the mitochondrial oxidative function, bioenergetic starvation and excessive generation of mitochondrial reactive oxygen species (ROS), have been implicated in the pathophysiology of HFpEF, however the exact relationship is unknown. Here, we show that interference with reverse electron transport (RET)-ROS production in vivo, accomplished via a G13997A mtDNA mutation in the ND6 subunit of complex I (ND6-P25L), induces an obese phenotype, pathological cardiac hypertrophy, reduced exercise tolerance and diastolic dysfunction, hallmarks of human HFpEF. Furthermore, exercise-induced alteration in lipid handling is associated with improvement of diastolic dysfunction. In summary, these data provide a valuable model for studying the role of mitochondrial function and metabolic impairments in HFpEF.
15:20	Dr Kevin Woollard kevin_woolard.jpg Target discovery and development for cardio renal diseases
Dr Kevin Woollard talk will highlight AstraZeneca’s ambition for treating cardio renal disease patients. I will show impact of SGTL2 inhibitors on heart failure and CKD and describe design of next generation therapeutics to stop, reverse or cure cardio renal diseases. I will briefly highlight strategies of target identification and validation in this space and focus on cardio renal immunology as an exciting area of investigation.
15:35	Dr Rouchelle Sriranjan rouchelle_sriranjan.jpg Immune modulation in ACS: The IVORY trial
Inflammation plays a pivotal role in the initiation and progression of atherosclerosis, which accounts for an overwhelming majority of cardiovascular events. The Low-dose Interleukin 2 (IL2) for the reduction of vascular inflammation in acute coronary syndromes (IVORY) study is a phase II double blind placebo controlled clinical trial that looks at immune modulation mediated through the adaptive immune system (specifically T regulatory cells), in patients presenting with ACS. It brings together aspects of drug development such as repurposing currently licenced drugs and the use of imaging biomarkers to accelerate the translation of science from the bench to the bedside.
15:50	Dr Andrej Corovic Andrej_Corovic.jpg Somatostatin receptor PET/MR imaging of inflammation post-myocardial infarction
After myocardial infarction (MI), inflammation and its resolution modulate the extent of myocardial damage. Specifically, an excessive or prolonged “pro-inflammatory” phase may contribute to adverse cardiac remodelling. Non-invasive imaging of post-MI inflammatory and repair processes is potentially of use in the development pipeline of novel immunomodulatory therapies as well as in the risk stratification of patients for their deployment. 68Ga-DOTATATE is a PET tracer that binds to somatostatin receptor 2 (SST2), which has been shown to be upregulated in “pro-inflammatory” macrophages. In this first prospective study of 68Ga-DOTATATE PET/MRI in patients after MI, we show that 68Ga-DOTATATE tracks resolving myocardial inflammation. Ongoing work as part of this study seeks to confirm the cellular origin of infarct-related 68Ga-DOTATATE PET signal and SST2 expression within inflamed myocardial tissue and test its longer-term association with ischaemic myocardial remodelling.
16:05	Dr Robin Brown Robin_Brown.jpg Central and peripheral inflammation in cerebral small vessel disease
My work investigates the role of novel disease processes in cerebral small vessel disease (SVD), a common reason for stroke and the most significant cause of vascular dementia. I use contrast-enhanced MRI to image the blood-brain barrier, and PET imaging, using a radioligand that binds to microglia as a proxy for neuro-inflammation, to investigate the role of these processes in SVD. I will discuss the relationship between these advanced neuroimaging markers and overt brain lesions and neuropsychometric performance in a cohort of SVD patients, and the extent to which they predict radiological and clinical progression.
16:50	Prof Borja Ibanez - Distinguished Lecturer CNIC: Spanish National Centre for Cardiovascular Research borja_iibanez.jpg Mitochondria-targeted therapies for anthracycline cardiotoxicity
Borja Ibáñez (Madrid,1975) combines research activities as Scientific Director of the Spanish National Center for Cardiovascular Research (CNIC) with clinical activities as an interventional cardiologist at the University Hospital Fundación Jiménez Díaz. He was trained in Spain and in the USA (Mount Sinai Heart, NY). His research is at the verge of the basic and clinical arena, mainly in the fields of MI, heart failure and lately to cancer therapy‐induced cardiotoxicity. He is the co‐PI of the large PESA project, focused on the primary prevention of atherosclerosis. He is the PI of several multicenter clinical trials. He served as the Chairperson of the 2017 European Society of Cardiology (ESC) STEMI Clinical Practice Guidelines and is Chairperson of the forthcoming ESC guidelines for Acute Coronary syndromes. He is the PI coordinator of several national and international projects, including H2020‐funded grants highlighting an active ERC consolidator grant called “MATRIX” (Novel mitochondria‐targeted therapies for anthracycline‐induced cardiotoxicity), and a H2020‐HEALTH project called “RESILIENCE”. He has published more than 350 scientific publications in high‐impact journals. His H‐index (scholar) is 73, and his works have received more than 50,000 citations. He has received numerous awards for his scientific merits, including the Banco de Sabadell, Constantes y Vitales, Princesa de Girona, and Fundación Jesús Serra among others.