Speakers Detail: BHF CRE and Cambridge Cardiovascular Research Symposium 2026
Distinguished guest speaker: Marianna Fontana, University College London
Understanding Mechanisms and Precision Treatment of Transthyretin Amyloid Cardiomyopathy
Amyloid cardiomyopathy, particularly transthyretin (ATTR) amyloidosis, has undergone a profound therapeutic transformation over the past decade. Initial strategies focused on reducing the production of misfolded transthyretin through gene silencers and stabilisers, effectively slowing disease progression and improving outcomes. However, these approaches do not address the substantial burden of pre-existing amyloid deposits within the myocardium, which continue to drive cardiac dysfunction, particularly in advanced disease.
Emerging therapies now aim to enhance amyloid clearance, representing a complementary and potentially transformative approach. These agents are designed to target and remove fibrillar deposits, leading to a distinct pattern of cardiac remodelling characterised by structural changes and improved haemodynamic function. This shift has also prompted a re-evaluation of how treatment response is assessed, moving beyond traditional global metrics towards integrated measures that more accurately reflect myocardial substrate and function.
This talk will explore the evolving understanding of disease mechanisms in ATTR cardiomyopathy, from amyloid production to clearance, and discuss how these insights are shaping a more precise, mechanism-driven therapeutic paradigm. Ultimately, combining suppression of amyloid formation with active removal of existing deposits may offer the greatest opportunity to modify disease trajectory and improve patient outcomes.
SESSION 1: NEW INSIGHTS FROM MULTIMODALITY STUDIES IN CARDIOVASCULAR AND CARDIOMETABOLIC DISEASE
Samuel Lambert, Cardiovascular Epidemiology Unit, University of Cambridge
Liver fat accumulation Contributes to Discordant Genetic Risk Between Coronary Artery Disease and Type 2 Diabetes
Type 2 diabetes (T2D) and coronary artery disease (CAD) frequently co-occur, yet our understanding of their shared biology remains incomplete. We investigated this comorbidity pair using the largest available multi-ancestry GWAS datasets. Using PLACO and colocalization analyses, we identified 154 genetic loci shared between T2D and CAD, including 42 novel loci. Despite the positive association between these two diseases, 57 genetic loci showed discordant effects between them, accounting for the majority of the newly discovered signals. To characterise shared risk pathways, we extended variant-clustering approaches to a multi-disease framework, grouping shared variants by their effects on intermediate cardiometabolic traits and identifying seven genetic clusters. Clusters enriched for discordant variants were predominantly linked to liver fat and circulating lipids, a finding we confirmed using individual-level metabolomics data and disease outcomes from UK Biobank. Mendelian randomization analyses further suggest a causal role for liver fat in mediating opposing genetic risk for T2D and CAD. Together, these results highlight liver fat as a key biological driver of discordant disease risk and motivate future research into liver-centred pathways as a target for precision prevention and management of both conditions.
Antonio Vidal Puig, Institute of Metabolic Science, University of Cambridge
Cardiometabolic Disease as a Systems Problem: A Vision for Cambridge and Beyond
Cardiometabolic disease is conventionally attributed to excess adiposity, yet this framing cannot account for the profound heterogeneity in disease risk and trajectory across individuals and populations. I propose a reframing: cardiometabolic disease as a failure of systemic metabolic resilience, arising when coordination across organs and tissues breaks down.
Central to this framework is the concept of adipose tissue expandability. Our work demonstrates that the capacity to safely buffer lipid surplus, not the absolute amount of fat, is a primary determinant of metabolic health. When this buffering capacity is overwhelmed, lipid spillover triggers ectopic deposition, immune activation, and fibro-inflammatory cascades across the liver, vasculature, heart, and skeletal muscle. This cascade underlies the convergent pathophysiology of MASLD, HFpEF and type 2 diabetes.
We further integrate evidence that metabolic homeostasis depends on dynamic inter-organ communication, mediated by extracellular vesicles, lipid mediators, and metabolite signalling, that coordinates energy utilisation and adaptive responses to stress. When these networks are disrupted, physiological flexibility gives way to pathological rigidity, amplifying disease progression across multiple organ systems simultaneously.
Cardiometabolic disease, therefore, is not a single-organ disorder but an emergent property of a dysregulated system. This has profound implications. Biologically, it demands multi-scale, human-centred strategies that integrate deep phenotyping, multi-omics, and next-generation experimental models, including organoids and organ-on-chip platforms. Therapeutically, it shifts focus from isolated molecular targets toward restoring network resilience: improving adipose buffering capacity, endothelial metabolism, and inter-organ crosstalk.
I will close with a vision for Cambridge as a global centre for systems cardiometabolic research, uniting mechanistic discovery with translational infrastructure and international partnerships, particularly across Asia, where cardiometabolic disease manifests at lower adiposity thresholds and offers unique insights into the biology of resilience and susceptibility.
Mayank Dalakoti, Cardiovascular Epidemiology Unit, University of Cambridge
Cardiometabolic Disease Prevention from a Global Context
Cardiometabolic diseases are leading causes of global morbidity and mortality, yet their determinants vary substantially across populations. South Asian populations experience a disproportionate burden, with earlier onset compared with White European populations, alongside a relative lack of representative data. Traditional risk factors such as obesity, hypertension, and dyslipidaemia do not confer uniform risk across ethnic groups, and emerging factors such as metabolic dysfunction–associated steatotic liver disease (MASLD) interact with biological and environmental determinants in population-specific ways.
This talk will explore cardiometabolic disease epidemiology and prevention from a global perspective. Ongoing recruitment of deeply phenotyped multi-ethnic cohorts aims to characterise subclinical disease using a systems biology approach. Preliminary findings from the BELIEVE cohort in Bangladesh will be presented, focusing on key determinants of cardiometabolic disease, including lipoprotein(a) and liver fat. This body of work supports a shift towards more inclusive, population-informed prevention strategies that integrate biological and social determinants of health in an increasingly diverse world.
SESSION 2: PREVENTION, TREATMENT AND REGENERATION IN HEART FAILURE
Lay Ping Ong, Department of Pharmacology, University of Cambridge
Form and Function of the Regenerated Rat Heart: Cx43 Reveals a Druggable Axis Linking Regeneration to Rhythm Control
Myocardial infarction (MI) results in the irreversible loss of up to one billion cardiomyocytes, driving progressive heart failure—a major unmet clinical need. Human embryonic stem cell (hESC)-derived cardiomyocytes offer a promising strategy for cardiac remuscularisation; however, clinical translation is limited by incomplete graft integration and the risk of life-threatening arrhythmias. The mechanisms governing safe electrical coupling between graft and host myocardium remain poorly defined.
Here, we applied an integrative multi-omics framework to map graft–host interactions in a chronic heart failure rat model receiving distinct cellular therapies. Using spatial transcriptomics and single-nucleus RNA sequencing, we identified Connexin-43 (Cx43) as a key determinant of electrical stability at the graft–host interface, enriched within pro-regenerative niches.
To bridge structure and function, we performed 3D reconstruction of serial heart sections, linking Cx43 polarisation with myofibre alignment and tissue-level architectural integration. This demonstrated that organised Cx43 junctions underpin anisotropic conduction and coordinated contraction, providing mechanistic evidence that electrical stability is intrinsically coupled to structural regeneration.
To translate these findings, large-scale phenotypic screening in human iPSC-derived cardiomyocytes using FDA-approved compounds identified cAMP/PKA signalling as a key regulator of Cx43 trafficking and phosphorylation, revealing a druggable pathway to enhance electrical integration and suppress arrhythmogenesis.
Collectively, this work establishes a unifying framework linking regeneration, electrical stability, and functional outcomes. Mechanistic insights from cardiac regeneration revealed Cx43 kinetics as a tractable therapeutic axis, offering a new strategy to treat arrhythmias and heart failure beyond cell therapy alone.
Ana Vujic, Department of Medicine, University of Cambridge
Exercise and Cardiometabolic Disease
Heart failure with preserved ejection fraction (HFpEF) is driven by cardiometabolic stress and systemic immune dysregulation, yet effective disease-modifying therapies remain limited. Here, we investigated whether structured exercise training reverses HFpEF-associated diastolic dysfunction through coordinated cardiac and immune remodelling in a two-hit murine model induced by high-fat diet (HFD) and Nω-nitro-L-arginine methyl ester (L-NAME).
HFD/L-NAME mice developed a HFpEF-like phenotype characterised by impaired diastolic function, increased myocardial stiffness, and reduced exercise capacity, while systolic function was preserved. Structured exercise training improved diastolic function parameters and partially restored ventricular compliance without affecting systolic performance.
Mechanistically, single-cell transcriptomic profiling of haematopoietic and immune compartments revealed exercise-induced reprogramming of bone marrow immune niches, associated with altered myelopoietic trajectories and reduced transcriptional signatures of pro-inflammatory myeloid activation. These changes were accompanied by reduced abundance of circulating pro-inflammatory myeloid populations, consistent with attenuated myeloid mobilisation. Systemically, exercise was associated with suppression of inflammatory gene expression programmes, supporting a coordinated reduction in immune activation along the bone marrow–heart axis.
Collectively, these findings identify exercise as a systems-level intervention that ameliorates HFpEF-associated diastolic dysfunction through integrated remodelling of haematopoietic output, immune cell state transitions, and systemic inflammatory transcriptional programmes in cardiometabolic HFpEF.
Robert Fletcher, Cardiovascular Epidemiology Unit, University of Cambridge
Contemporary Epidemiology of Hospitalised Heart Failure with Reduced vs Preserved Ejection Fraction in England
Alarming reports from the USA have revealed concerning trends in heart failure mortality from 1999 to 2021, seemingly despite the introduction of new guideline-recommended treatments over this period. Until recently, it was unclear whether such trends extended to other settings, although combined with new evidence of rising heart failure incidence and prevalence across high income countries, they may signal cause for concern and hold major implications for health services.
In England, whole-population electronic health records have enabled the study of heart failure epidemiology on a broad scale. Unique linkage to heart failure audit data has further allowed for the phenotyping of heart failure cases into preserved and reduced ejection fraction subtypes, which differ markedly in their pathophysiology, clinical outcomes, and responses to available treatments.
These data thus provide unique evidence to improve our understand of the clinical outcomes, co-existing chronic medical conditions, and population-level treatment implementation in patients with heart failure with reduced and preserved ejection fraction.
EXTRA SESSIONS
Laura Donnelly, Cambridge Enterprise and Ash Earl, Gill Jennings & Every LLP
From Ideas to Impact: Making The Most of Your IP
Laura is an Associate Director in the Technology Development & Licensing Team at Cambridge Enterprise, where she works to commercialise technologies from across the life sciences. She has experience in identifying, managing, developing and commercialising IP and has worked on a variety of deals to spin-out companies and multi-national corporations, including T-Therapeutics, Evoralis and NoBACZ Healthcare. As part of her role at Cambridge Enterprise, Laura was seconded as a Business Development Manager at one of Cambridge Enterprise’s spin-out companies, Biomodal, and has sat on the board of multiple spin-out companies. Laura did a postdoc in cardiovascular research, has a PhD in Biochemistry from the University of Manchester and a BSc in Biochemistry from the University of York.
Ash is a European and UK Patent Attorney and advises clients in the pharmaceutical and chemistry sectors. He became dual qualified in 2020 and has been in the profession for more than a decade. His practice focuses on patent portfolio development, patent strategy, and post-grant validity proceedings at the European Patent Office. He specialises in small molecule pharmaceuticals and has advised clients on patent matters relating to pre-clinical candidates, clinical candidates and approved drugs. Ash also has technical expertise in fields of chemistry outside of pharmaceuticals, including materials for bioprosthetic valves, battery materials, polymer chemistry and consumer products.
James Leiper, Director of Research, British Heart Foundation
BHF Research Strategy- Our portfolio of Funding Opportunities
The British Heart Foundation (BHF) has set out an ambitious research strategy to accelerate progress against cardiovascular disease, from early discovery through translation, clinical studies and implementation in practice. Launched in May 2025, the strategy is guided by three principles: diversifying the science base, partnering to tackle specific challenges, and leveraging additional skills, technology and funding to increase impact. These priorities are reflected in a strengthened portfolio of grant schemes designed to enable bold ideas, with expanded funding levels for project, programme and translational awards, faster “pump‑priming” support to de‑risk translational work, and enhanced opportunities for late‑stage clinical studies.
A major new element is the Cardiovascular Grand Challenge, intended to catalyse ambitious, cross‑disciplinary programmes and create opportunities for step‑change advances; the programme aims to make at least one award of up to £10m over up to five years. The first Cardiovascular Grand Challenge focuses on artificial intelligence in transforming cardiovascular health “from discovery to clinical practice”, underpinning new approaches to identifying and studying mechanisms, prevention, diagnosis, risk prediction and therapeutics. Enhancing the research funding portofolio, the BHF Healthcare Implementation Fund supports measurable improvements in service delivery for people with cardiovascular disease, currently offering up to £350k for projects that reduce admissions or readmissions, enhance patient flow, optimise resources, implement new technologies, and strengthen communication and collaboration.
Supporting the brightest minds remain central to our strategy. BHF reviewed all the personal support schemes to ensure appropriate support at every career phase. We currently offer PhD opportunities, and career‑stage opportunities from early career fellowships (for discovery scientists and clinicians in training) through senior fellowships and research professorships.
Finally, the BHF continues investment in critical research infrastructure and collaboration, across universities, NHS services and industry globally, including thematic and regional Research Excellence Networks, multinational clinical trials initiatives, and international partnership awards.
Rouchelle Sriranjan, Department of Medicine, and Nick Evans, Department of Clinical Neurosciences, University of Cambridge
East of England patient and public Involvement and Engagement in cardiovascular research
Rouchelle is a NIHR clinical lecturer in Cardiology at the University of Cambridge. Her clinical sub-speciality is interventional cardiology. Her current research programme aims to examine novel anti-inflammatory therapies in the context of atherosclerosis through phase 2 and 3 clinical trials. She also employs experimental medicine approaches such as the use of imaging biomarkers and immunophenotyping in the context of these trials. She has done extensive PPIE across the region and internationally. Nick is a senior clinical lecturer and a Consultant in Stroke Medicine. He has founded the ASPIRE PPIE project and is the PPIE lead at the HLRI. Rouchelle and Nick will talk about newly launched East of England Cardiovascular and Respiratory PPIE network and the PPIE work done across the region.
SESSION 3: SMALL VESSEL DISEASE AND DEVELOPMENT
Wei Li, Department of Medicine, University of Cambridge
Does endoglin play a role in endothelial and adipose tissue crosstalk?
Loss-of-function germline mutations in endoglin (ENG) cause hereditary haemorrhagic telangiectasia (HHT) and contribute to pulmonary arterial hypertension (PAH), two debilitating vascular disorders for which there is currently no cure. Not all ENG mutation carriers develop PAH or HHT; disease manifestation often requires a second hit, with inflammation being a well-recognised trigger. While ENG mutations are known to drive endothelial dysfunction - the initiating event in PAH and HHT - whether ENG also contributes to the second-hit mechanism is poorly understood.
ENG is a single-pass transmembrane protein that is highly expressed in endothelial cells and is essential for many fundamental endothelial functions, including angiogenesis. ENG is also abundantly expressed in several other cell types; however, its roles outside the vascular endothelium remain largely unexplored.
In this presentation, I will discuss published studies alongside our own experimental findings, incorporating human, in vivo, and in vitro data, which suggest a previously unrecognised role for ENG in adipose tissue homeostasis. Healthy adipose tissue requires tightly regulated angiogenesis, pointing to a potential role for ENG in adipose-endothelial crosstalk. Adipose tissue dysfunction is a well-documented source of chronic low-grade inflammation. I propose that, in PAH pathogenesis, ENG mutations not only drive endothelial dysfunction but also promote adipose tissue dysfunction and inflammation, thereby contributing to the second hit required for disease progression.
Maria Köhne, Cambridge Stem Cell Institute
Spatiotemporal Benchmarking of Endocardial Sprouting and State Dynamics During Human Coronary Vessel Development
The endocardium is a recognised contributor to coronary vessel development in animal models, but the timing, spatial pattern, and mechanisms regulating endocardial state transitions during this process remain poorly defined in humans. Here, we combined transcriptomic profiling, spatial transcriptomics, and immunofluorescence across the developing human fetal heart to define the window of coronary vessel emergence and the accompanying endocardial changes.
We identify a discrete angiogenic window during which coronary endothelial cells first emerge and expand in the human heart. Spatial analyses localise this process to the ventricular wall and interventricular septum, with septal vascularisation initiating around 6 post-conception weeks and progressing through 7–9 post-conception weeks. Across this window, integrated transcriptomic analyses identify time-dependent changes in endocardial and coronary endothelial gene expression.
To investigate candidate regulators of these transitions, we integrated time-resolved signalling and gene regulatory network analyses. These nominate PDGFRB as a transient endocardial enriched receptor that is downregulated after the early angiogenic phase. In an hESC-derived endocardial model, siRNA-mediated loss-of-function perturbation of PDGFRB increased endocardial, endothelial, and coronary-associated gene expression, supporting PDGFRB as a candidate regulator of early endocardial state transitions.
Together, these findings define when and where coronary endothelial cells first emerge in the human heart and identify regulatory changes associated with this process. By defining the developmental window and candidate regulators linked to coronary endothelial emergence, this work provides a framework for improving stem cell-based models of human coronary vessel development, for modelling diseases involving defective coronary or endocardial development, and for guiding strategies to generate coronary-like endothelial cells for regenerative vascular repair.
Oriane Marguet, Department of Clinical Neurosciences, University of Cambridge
Inflammation and Cerebral Small Vessel Disease Severity - Insights from the INSVD study
Cerebral small vessel disease (CSVD) causes a quarter of all strokes and is the main cause of vascular dementia. Increased evidence has implicated inflammation in its pathophysiology; however, whether it is causally related and can be therapeutically targeted is uncertain. The INSVD study is a prospective longitudinal cohort study performed in Cambridge and Nijmegen, Netherlands, funded by a joint BHF-Dutch Heart Foundation grant, to determine whether immune dysregulation predicts CSVD progression. The primary outcome is brain white matter microstructural integrity, measured using diffusion-tensor imaging, the most sensitive imaging marker of white matter damage in CSVD. We report baseline cross-sectional analysis with multiple immune markers.
202 patients with symptomatic CSVD were recruited and underwent MRI scanning and blood draw. Mean diffusivity peak heigh (MD-PH) was computed from diffusion-tensor imaging. We collected traditional neuroimaging CSVD markers (white matter hyperintensity volume, lacunes, perivascular space volume, cerebral microbleeds) and blood-brain barrier permeability measures via dynamic-contrast enhanced MRI.
Multiple immune markers were collected: (1) CyTOF on whole blood to evaluate the relative abundance of immune populations. (2) Plasma inflammatory markers using Olink proteomics. (3) Peripheral blood mononuclear cells stimulated with LPS, Pam3Cys, and LPS+nigericin to assess cytokine production capacity. Partial Spearman correlations between imaging and immune markers were computed.
MD-PH was associated with the relative abundance of CD4+ MAIT/NKT T-cells (rs=0.20, p=0.043), conventional CD8+ αβ T-cells (rs =0.22, p=0.028), nonclassical and classical monocytes (rs =0.26, p=0.0048 and rs =-0.23, p=0.028), and dendritic cells (rs =0.27, p=0.0048).There was no association between MD-PH and Olink markers nor cytokine production capacity. Few associations were observed between traditional CSVD markers and immune markers, and none between blood-brain barrier permeability and immune markers.
Conclusion:White matter microstructural integrity was associated with a circulating immune cell composition suggesting immune involvement beyond soluble inflammatory markers.
SESSION 4: INHERITED, ACQUIRED AND IMMUNE DRIVERS OF CVD
Emanuele Di Angelantonio, Cardiovascular Epidemiology Unit, University of Cambridge
Integrating imaging and genetic markers in cardiovascular risk stratification
Current risk prediction models based on traditional clinical factors are widely used, yet their ability to accurately identify risk in asymptomatic individuals remains suboptimal. Strategies integrating genomic and imaging data may enable more precise and individualised prevention pathways. CVRISK-IT is a large multicentre, randomized Italian trial designed to evaluate whether advanced cardiovascular risk assessment improves preventive care beyond standard approaches. In the first phase, 30,000 adults aged 40–80 years without prior CVD or diabetes undergo clinical evaluation, laboratory profiling, and conventional risk estimation using SCORE2 or SCORE2-OP. Eligible participants then proceed to a second phase in which approximately 12,000 individuals are randomised to one of four strategies: standard care, imaging-guided risk assessment, polygenic risk score (PRS)-guided assessment, or a combined imaging plus PRS strategy. The primary objective is to determine whether these enhanced strategies improve estimated 10-year cardiovascular risk and optimize implementation of preventive interventions. Secondary outcomes include treatment adherence, lifestyle modification, risk factor control, and long-term clinical events. CVRISK-IT represents a large-scale initiative in precision prevention, with the potential to redefine contemporary cardiovascular risk assessment. By integrating traditional factors with genetic predisposition and subclinical disease imaging, the study may provide a scalable model for more effective, personalized prevention in routine clinical practice.
Paul Carter, Department of Medicine, University of Cambridge
Clonal haematopoiesis in cardiovascular disease: how the genetic driver, sex, and disease context matter
Clonal haematopoiesis of indeterminate potential (CHIP) is the age-related expansion of haematopoietic cells carrying pre-leukaemic mutations that confer a proliferative advantage. It affects ~20% of septuagenarians and is associated with increased cardiovascular disease (CVD), likely mediated by mutant pro-inflammatory myeloid cells. CHIP arises from mutations in over 50 genes, with DNMT3A, TET2, and JAK2 accounting for over 70%. Despite their distinct, and sometimes opposing functions, CHIP is often considered as a single entity, with shared CVD mechanisms. The directionality of this relationship remains unclear, and cardiovascular inflammation has been proposed as a potential driver of clonal expansion.
Using multimodal approaches, we show that CHIP driven by different mutations has distinct pathophysiology and consequences. Combining experimental models with Mendelian randomisation, we find that systemic inflammation and atherosclerosis are unlikely to drive CHIP. Instead, CHIP promotes CVD in a gene- and sex-dependent manner. DNMT3A-driven CHIP associates with atrial dilatation and increased atrial fibrillation risk. In contrast, enhanced NLRP3 inflammasome activation and cytokine release are specific to TET2-driven CHIP, with increased atherogenesis only in female mice with Tet2 mutations; whether this contributes to the late-life rise in atherosclerotic disease in women warrants further investigation
Despite its clinical significance, no therapies currently exist to prevent CHIP or its consequences. We present epidemiological and experimental evidence that various cardiovascular medications may limit clonal expansion, offering dual benefit in CHIP. Establishing treatments that alter its clinical trajectory will be key to integrating testing into practice and such developments should focus on CHIP as distinct mutational subtypes.
James 0`Brien, University of Cambridge
The Impact of Modulating the Adaptive Immune System on the B Cell Repertoire in Acute Coronary Syndromes
Atherosclerotic cardiovascular disease (ASCVD) remains a leading driver of illness and death globally, with inflammation playing a fundamental role in disease development. While immunotherapies targeting the innate immune system have shown limited success and increased infection susceptibility, attention has shifted toward modulating the adaptive immune response. Low-dose interleukin-2 (IL-2LD) therapy can preferentially expand regulatory T cells (Tregs) and reduce vascular inflammation in acute coronary syndrome (ACS) patients, though its broader effects on B cell function remain incompletely understood.
In the LILACS trial, we used single-cell RNA and B cell receptor (BCR) sequencing to examine how IL-2LD affects B cell clonal dynamics, phenotype, and isotype switching in ACS patients. Our results show that IL-2LD triggers reduced clonal expansion across most B cell populations, except plasmablasts, which exhibited an enhanced regulatory B cell (Breg) profile and BCR activation. Notably, IL-2LD drives a marked shift toward IgA production—an antibody critical for mucosal defence—while placebo preferentially induces IgG switching. Cell–cell communication analysis identified the transforming growth factor beta (TGF-β) pathway as central to this effect, with in vitro studies confirming that Tregs promote IgA class switching through TGF-β signalling—an effect diminished by TGF-β blockade.
These findings suggest that IL-2LD therapy in ACS may provide an anti-inflammatory benefit while potentially safeguarding antimicrobial mucosal defences, thereby reducing infection risk typically associated with immunomodulation. Our research offers mechanistic insight into IL-2LD's immunomodulatory actions, highlighting its capacity to achieve immune regulation without compromising host protection. This work supports further exploration of IL-2LD as a cardiovascular disease treatment.
Distinguished guest speaker: Muredach Reilly MB MS, Columbia University, Irving Medical Center, New York
Stromal Cells in Atherosclerosis: A Genomics Perspective
Recent work by the Reilly group on how atherosclerosis is a tumor-like disease of smooth muscle cells (SMC) will be reviewed and implications considered. Two novel findings will be presented. First, to define the phenotypic diversity and regulation of SMCs including SMC-foam cells in atherosclerosis, we performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and bulk RNA sequencing in SMC lineage-tracing Ldlr-/- mice. Single-cell multi-omics revealed cellular heterogeneity within atherosclerotic plaques, including rare SMC-derived macrophage-like cells, confirmed by immunohistology. We also identified that SMC-derived foam cells comprised approximately 70% of all foam cells in lesions. These cells exhibited activation of gene programs for lipid metabolism, proliferation, and tumor-like features. The transcription factor Bhlhe40 emerged as a master regulator of this phenotypic transition. Knockdown of Bhlhe40 suppressed SMC phenotypic switching and foam cell characteristics, underscoring its potential to drive SMC modulation. Second, we used SMC lineage tracing with scRNA-seq, spatial transcriptomics, and histological analyses in Myh11 CreERT2; Ldlr–/–; Rosa26 ZsGreen1 mice to define which cell types drive plaque remodeling during 20 weeks of LDL-C lowering. LDL-C reduction triggered early resolution of inflammation, a buildup of collagen and thickening of the fibrous cap, without significant lesion area regression. scRNA-seq showed that this transition coincided with a selective expansion of fibroblast subpopulations, most prominently Pi16⁺CD26⁺ and Mmp3⁺Fmod⁺ fibroblasts. Both fibroblast subsets engaged robust collagen biosynthetic programs but differed in activation dynamics and spatial context. Master regulator analysis highlighted Klf3 as a pivotal transcription factor maintaining the Pi16⁺CD26⁺ phenotype. Computational modeling predicted that loss of Klf3 would shift fibroblasts toward an Mmp3⁺Fmod⁺ state. Concordantly, Klf3 silencing in mouse and human aortic fibroblasts reduced collagen expression, proliferation, and migration. scRNA-seq and spatial analyses of human carotid atherosclerosis revealed conserved fibroblast diversity and KLF3 enrichment within fibrous cap. This work suggests a key role for specific fibroblast subtypes in plaque remodeling during LDL-C lowering.