Previous awards (ICRPA)

UK: Dr Alicia D’Souza, Imperial College London
BHF awarded: £445,151.00 (IA/F/24/275114)

The Netherlands: Dr Gerard Boink, Amsterdam UMC
DHF awarded: €499,488.50

Germany: Professor Constanze Schmidt, University Hospital Heidelberg
DZHK awarded: €499,925.00

France: Dr Jason Bayer, University of Bordeaux
LDF awarded: €499,520.00

Over 15 million people in Europe live with heart failure (HF) and many deaths in HF patients are due to dysfunctional activity of the electrical wiring system of the heart. The currently available treatment of surgical pacemaker implantation does not always work well and, importantly, does not resolve the underlying problem.

In this study, we are proposing a new ‘gene therapy’ approach to correct these electrical conduction issues. Our idea is to use a virus that we have developed to deliver specific genes that repair slowed conduction in HF. We have collected data showing that this may improve heart function safely and effectively, and we will test this in animals with HF.

We will study how the delivered genes alter heart cell behaviour and electrical activity and whether they improve the health of HF animals. We will use advanced computer models to test how our gene therapies will work in HF patients and perform the first detailed studies in human heart tissues to further understand the cause of abnormal electrical function and the capacity of gene therapy to repair it. If successful, our studies will lead to a new treatment that restores heart function and survival in HF patients.

Dysfunction of the ventricular conduction system (VCS) and asynchronous ventricular activation is an important determinant of mortality in heart failure (HF) patients. Current treatment for VCS disease in HF is limited to surgical implantation of an electronic pacemaker in cardiac resynchronisation therapy, however success rates are suboptimal, and there is a clinical need for refined and minimally invasive therapies.

In this application, we propose gene therapy as a new strategy to normalise conduction abnormalities in HF. We hypothesise that permanent modification of conduction properties by adeno-associated virus (AAV)9-mediated targeting of its known molecular determinants will safely and effectively normalise conduction abnormalities and improve HF outcomes.

To test this hypothesis, first we will build on recent data collected in our laboratories and elsewhere showing that ventricular conduction in heart disease can be improved by increasing either cardiac sodium current conductance, improving trafficking of the gap junction protein Connexin 43 to intercalated discs, or increasing expression of the transcription factor Tbx5.

We will conduct preclinical testing of AAV-mediated gene therapy directed to these known conduction-promoting targets in translationally relevant murine and porcine models of HF, and in human hearts ex vivo with the following specific aims:

• Aim 1: Define the optimal gene therapy targeting and delivery strategy for normalisation of conduction in HF
• Aim 2: Examine the precise downstream mechanisms by which the gene therapy targets modulate the cellular electrophysiology and molecular profile of the ventricular myocardium
• Aim 3: Utilise state-of-the-art multi-scale computational approaches to optimise the delivery of gene therapy to humans, and investigate the impact of specific gene therapy targets on conduction in the myocardium and VCS. Successful completion of these aims will be a significant step towards clinical translation of a potentially life-saving therapy.

To refine and enhance the translatability of our findings, in Aim 4 we will perform the first study of the function and molecular signature of the VCS in failing and non-failing human hearts at unmatched scale and resolution, coupling spatial transcriptomics with advanced optical mapping, imaging and computational techniques. These data will yield novel insight into VCS disease in humans and promote spin-off projects addressing a broader range of VCS-targeting gene therapies. In sum, our studies will provide first proof-of-principle for gene therapy in normalising conduction defects in HF and pave the way for further novel mechanism-based treatments for VCS disease.

UK: Dr Luigi Venetucci, University of Manchester
BHF awarded: £464,394.25 (IA/F/24/275141)

The Netherlands: Dr Christian van der Werf, Amsterdam UMC
DHF awarded: €466,482.33

France: Dr Julien Barc, The National Institute for Health and Medical Research (INSERM)
LDF awarded: €499,900.00)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) can cause irregular beating of the heart and sudden death especially in young people. CPVT is caused by a faulty gene and can affect several people within a family. Using a blood test, we can find all the family members who have the faulty gene, but we cannot say which ones will have irregular beating and die. Some drugs reduce the irregular beating of the heart, but they do not always work and sometimes make patients feel unwell.

In this study, a team of established and complementary researchers in CPVT from the Netherlands, France and the United Kingdom will address these problems. The team will establish whether blood tests and detailed analysis of the heart tracing could help us finding which people/patients/persons with the genetic defect are going to have irregular heart beating. The team will also test new drugs to stop the irregular heart rate and will also test whether increasing the speed of the normal heart rate can reduce the occurrence of irregular heart beating.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmia syndrome characterized by adrenergically-mediated ventricular arrhythmias and arrhythmic events (AE), including sudden cardiac death. In most patients, mutations in the gene encoding the cardiac ryanodine receptor are identified. In untreated patients, CPVT is associated with significant morbidity and mortality. Despite the significant improvements in the diagnosis and treatment of CPVT achieved over the last 15 years, there are still several aspects of the management of CPVT that need significant improvement.

In this project, we will focus on three main aspects:

1. Identification of clinical markers to better stratify the risk of AEs and assess the association between baseline heart rate and ventricular arrhythmias at the exercise stress test.
2. Deciphering the genetic architecture of CPVT and more particularly identify the factors that modulate disease penetrance and expressivity as well as those sharing a genetic correlation with heart rate.
3. Lack of specific treatments to correct the altered function of the cardiac ryanodine receptor.

To address these challenges, we have assembled a multidisciplinary team:

Dr. Christian Van der Werf (Amsterdam UMC, Amsterdam) will lead the clinical studies. He co-directs the largest international registry of patients with CPVT worldwide and has extensive experience in clinical trials and registry studies in CPVT. Dr. Van der Werf conducted a retrospective study and identified novel risk markers associated with CPVT that will be combine with genetic risk score.

In addition, we will lead prospective studies to assess the association between resting heart rate and (exercise-induced) ventricular arrhythmias. Finally, he will also lead exercise test-based studies to assess the efficacy of new treatment strategies we will identify in basic science studies.

Dr. Julien Barc, (l’institut du thorax, Inserm, Nantes) will lead the genomic study. He has extensive experience in performing large-scale genomic studies. He will lead and supervise a case-control genome-wide association study to identify variants conferring risk and build a polygenic risk score.

The studies on novel treatments will be led by Dr. Luigi Venetucci, based at the University of Manchester, and Dr. Jerome Montnach (l’institut du thorax, Inserm, Nantes). Dr. Venetucci has extensive experience in preclinical studies on mouse models of CPVT and clinical management of patients with CPVT. He will lead and supervise a preclinical study on mouse models of CPVT to test the antiarrhythmic efficacy of R-carvedilol, R-3-hydroxy carvedilol and R-4'-hydroxycarvedilol.

Dr. Montnach developed novel photopharmacology approaches to modulate autonomic nervous system function and heart rate. He will lead studies to determine whether a photopharmacology approach can be utilized to treat CPVT.

Both Dr. Montnach and Dr. Venetucci will also supervise in vitro studies to validate findings from the genomic studies. These in vitro studies will be performed on inducible pluripotent stem cells derived cardiomyocytes and tissue slices from mouse hearts.

France: Professor Nabila Bouatia-Naji, The National Institute for Health and Medical Research (INSERM)
LDF awarded: €499,648.00)

The Netherlands: Professor Linda van Laake, Utrecht UMC
DHF awarded: €499,305.00)

Germany: Dr Thorsten Kessler, German Heart Centre Munich
DZHK awarded: €489,329.61

Spontaneous coronary artery dissection (SCAD) is a condition in which the blood vessels supplying the heart suffer a tear in the vessel wall. This leads to a heart attack, which can result in severe pain and a deterioration in the function of the heart. In contrast to coronary heart disease, which is particularly common in elderly, SCAD is not triggered by deposits of e.g. blood fats in the vessel wall. In contrast, it affects women at a young age without risk factors. The causes of SCAD are unknown.

This research project aims to unravel the causes of SCAD using a molecular translational approach. Our international team will extend our genetic studies to identify the causal hereditary risk factors for SCAD. We will study these genetic factors in coronary vessels of SCAD patients who underwent a cardiac transplant. Also, we will investigate the function of these hereditary risk factors in cell cultures. To understand why younger women are affected by the disease at a younger age, we will investigate how sex hormones influence SCAD.

The research project aims to contribute to a better understanding of SCAD and thereby pave the way towards identification of novel targets for treatment.

Cardiovascular disease in women is a recognised area of unmet research need. This is due, in part, to key sex-specific differences in the causes of acute myocardial infarction (MI). There are significant knowledge gaps regarding female-dominant mechanisms due to the underrepresentation of women in CAD clinical trials and biobank studies.

Spontaneous coronary artery dissection (SCAD) is a unique cause of MI affecting predominantly young women who represent 90% of the patients. Although less common than atherosclerotic MI, SCAD is estimated to account for up to 35% of events in female patients under 60 years, and is also a leading cause of postpartum MI. The pathophysiology of SCAD differs markedly from atherosclerotic MI. It is caused by the development of a tracking intramural haematoma in the coronary artery, leading to coronary insufficiency. Current management and treatment for SCAD do not consider its specific early onset or different pathophysiology.

Evidence based on our recent genetic studies supports high polygenicity for SCAD that is not fully identified, and a prominent role of genes related to vascular smooth muscle cells (VMSCs) biology. VSMC plasticity in the context of SCAD arterial lesions, and in comparison, with atherosclerosis, has never been studied to date. We recognised the lack of pathophysiologic translation of the novel and recently acquired genetic knowledge about SCAD as a limiting step toward the development of targeted preventive and therapeutic strategies for this woman predominant form of MI.

ID-SCAD aims to unravel causal genes and specific biological mechanism of SCAD using an integrated translational approach based on human genetics. We hypothesize that dysregulated VSMCs plasticity plays a key role in SCAD and that sex components may affect the function of SCAD genes and explain the high prevalence in women, as compared to men. Our project’s objectives will implement a highly experimental and cutting-edge analytical setting led by well-established and internationally recognized leaders in clinical cardiology, cardiovascular genetics and vascular biology, with an established track in women’s specific cardiovascular risk.

Our specific aims are i) to improve genetic knowledge for risk prediction acceleration and druggable targets identification for SCAD, ii) to delineate the functional role of SCAD genes in vascular tissues through the investigation of 2D and 3D in vitro cell models, including patients’ derived vascular cells and coronary specific differentiated induced pluripotent stem cells; and iii) to examine how sex components, namely sex chromosomes and sex hormones signalling affect gene expression and function in VSMCs. We are confident to build on our expected results to translate this multi-disciplinary investigation from a highly qualified and experienced group of researchers to potential druggable targets that are urgently needed.

BI-PATH

Bi-national investigation of placental pathology and maternal cardiovascular health (4 Years)

UK: Professor Abigail Fraser, University of Bristol
BHF awarded: £476,620.35 (IA/F/23/275057)

The Netherlands: Dr Casper Mihl, Cardiovascular Research Institute Maastricht
DHF awarded: €499,224.

Lay summary

Cardiovascular disease (CVD) is a leading cause of death in women but is understudied, under-recognised, underdiagnosed, and undertreated. Common complications of pregnancy that involve the placenta include preeclampsia, gestational hypertension, preterm delivery, and foetal growth restriction. Women who had a placenta related complication have a two-fold increased risk of CVD in later life. Maternal Vascular Malperfusion (MVM) is a group of lesions found in the placenta that resembles CVD. MVM may therefore indicate that women have a higher risk of heart disease and stroke in later life, and those women who have a pregnancy with both a complication and MVM may have the highest CVD risk.

In BI-PATH, we bring together two globally unique collections of placentas, with linked data on maternal health in pregnancy, cardiovascular health decades after delivery and genetic data. This will enable us to improve understanding of the relationship between MVM, clinical complications of pregnancy and long term maternal cardiovascular health and to determine whether the placenta can be used to better identify young women at high-risk of CVD, at an age in which they can benefit from interventions to reduce that risk and to avoid overmedicalisation in low-risk women.

Scientific summary

Placental syndromes including hypertensive disorders of pregnancy, preterm birth and fetal growth restriction are robustly associated with a two-fold increased risk of maternal cardiovascular disease in later life. Maternal Vascular Malperfusion (MVM) are placentas lesions caused by the failure of the spiral arteries to adequately remodel and are found more frequently in placentas from pregnancies affected by these syndromes than in placentas from pregnancies unaffected by clinical syndromes. We hypothesize that women with a history of both placental syndromes and MVM are at a particularly high-risk of cardiovascular disease (CVD) in later life. In other words, the placenta may constitute a non-invasive source of information about a woman’s future risk of CVD, presenting at an age where interventions to mitigate this risk can be implemented.

In BI-PATH we will bring together two globally unique and complimentary placenta collections from the prospective UK ALSPAC and Dutch PEARLS studies. In both, we will determine the presence or absence of Maternal Vascular Malperfusion (MVM). The newly generated placental pathology data will be linked with existing detailed data on maternal health before and during pregnancy, measures of maternal subclinical systemic atherosclerosis and CVD risk factors up to 25 years post-partum, and genetics. This singular dataset will enable us to investigate the relationships between MVM (and its subtypes), clinical placental syndromes, and their joint associations with intermediate measures of maternal cardiovascular health and cardiovascular risk factors across the life course and to formally assess MVM’s predictive value in relation to intermediate cardiovascular phenotypes.

We will also use linked genetic data in Mendelian randomization to investigate the causal relationships between MVM, clinical placental syndromes and measures of cardiovascular health. These investigations will identify potential prevention and treatment approaches to improve women’s cardiovascular health in pregnancy and beyond.

HeartDisc

Understanding the mechano-signalling role of the Z-disc in the pathogenesis of Hypertrophic Cardiomyopathy (4 Years)

Germany: Dr Claudia Crocini, Charité – Universitätsmedizin, Berlin
DZHK awarded: €500,000

UK: Dr Katja Gehmlich, University of Birmingham
BHF awarded: £499,927.25 (IA/F/23/275037)

The Netherlands: Dr Diederik Kuster, Amsterdam UMC
DHF awarded: €499,787

Lay summary

In this research project we aim to better understand what goes wrong in Hypertrophic Cardiomyopathy, an inherited heart muscle disease. This disease causes hearts to become bigger and stiffer. Some patients develop life-threatening heart rhythm problems, similar to the ones that made Christian Eriksen collapse during a Euro2020 football match. In this proposal we will focus our attention on structures called the Z-discs. They are part of the contractile apparatus and crucial for sensing and responding to the forces generated during each contraction of the heart muscle. Importantly, the Z-discs link the contractile apparatus to the management centre (the nucleus) and the energy powerhouses (the mitochondria) of the heart muscle cells via scaffolds called the cytoskeleton. We have previously observed structural and composition changes in the Z-discs, as well as in the cytoskeleton of patients with the disease. In this project, we want to explore exactly how the Z-discs sense and respond to changed contractions and what the consequences are on the cytoskeleton, energy production and management activities in the nucleus. We will use the insights of our research to test whether reversing these changes with drugs could improve the heart and hence be a treatment option for the disease.

Scientific summary

The health problem: Hypertrophic Cardiomyopathy (HCM) is an inherited heart muscle condition, associated with diastolic dysfunction and sudden cardiac death, making it a leading cause for mortality in the young. The underlying patho-mechanisms are cellular hypertrophy and increased, but energy-inefficient contractility. Hence altered muscle mechanics are a prominent feature of HCM. Our pilot data from human samples shows that the Z-disc, a specialised structure in the contractile units, is changed in its protein composition, phosphorylation, and structure in HCM, even when the disease-causing genetic variant is in a thick filament protein.

Hypothesis: We postulate that the Z-disc is a central mechano-signalling hub in cardiomyocytes. It acts as a sensor, detecting and responding to altered mechanics in HCM. Through a series of structural changes, protein composition alterations, and post-translational modifications, the Z-disc initiates a cascade of events that lead to rearrangement of the cytoskeleton within the cardiomyocyte. These changes are further transmitted to other cellular compartments, including the nucleus and mitochondria. As a result, HCM-specific transcriptional profile and mitochondrial dysfunction occur and contribute to hypertrophic remodelling.

Our Approach: This proposal brings together a uniquely-equipped team of cell biologists, mechano-biologists, and clinicians. Collectively, we have the knowledge and diverse perspectives to effectively address the importance of Z-disc mechano-signalling in HCM. Together we provide various HCM-relevant models and two extensive biobanks of human samples. The proposal builds on our insights from human HCM samples, mouse and cellular models that show a wide-range of HCM-specific changes in cytoskeletal, nuclear, and mitochondrial function. Unifying these observations, we propose that these pathological changes in HCM are driven by aberrant Z-disc mechano-signalling. We will combine analyses of human HCM material with mechanistic investigations of human models (induced pluripotent stem cell derived cardiomyocytes, engineered heart tissue and cardiac tissue slices) and in vivo mouse models of HCM. Through this integrated approach we will reveal how mechano-signalling at the Z-disc is affected by contractility, which proteins are key mediators, what the downstream consequences are on the cytoskeleton and how these changes affect mitochondrial function and gene expression in the nucleus. We will then exploit the novel pathways and key player/s of the Z-disc mechano-signalling to test potential interventions. For this, we will test how modulation targeting Z-disc mechano-signalling and downstream signalling can revert patho-mechanisms of HCM, using cellular model systems, experimental setups derived from HCM patient material and an in vivo model.

Benefits: Our overarching goal is to identify Z-disc therapeutic targets for the treatment of HCM. Importantly, this could be relevant to both the form of HCM caused by pathogenic sarcomeric variants and the polygenic, ‘sarcomere-negative’, form of the condition. Moreover, understanding the role of Z-disc mechano-signalling to maintain normal cardiac function could be explored to develop therapeutic avenues for other heart muscle conditions, including other forms of heart failure. The team will collaborate closely throughout the project and iteratively integrate new findings from the different partner sites and models. This unique approach will accelerate our research process, avoid duplication of efforts, and expedite discovery.

SHIFT-DCM

Decoding oxidative stress mechanisms in dilated cardiomyopathy: Shifting progressive impairment to cardioprotection (4 Years)

UK: Dr Joseph Burgoyne, King’s College London
BHF awarded: £447,760.94 (IA/F/23/257048)

Germany: Dr Lukas Cyganek, University Medical Center, Goettingen
DZHK awarded: €499,730

The Netherlands: Dr Monika Gladka, Amsterdam UMC
DHF awarded: €499,538

Lay summary

Dilated cardiomyopathy (DCM) is a severe and prevalent condition characterized by the weakening and enlargement of the heart muscle, which impairs its ability to effectively pump blood throughout the body. This ultimately leads to heart failure, a life-threatening condition. To address the urgent need for improved treatments, our study aims to delve into the intricate mechanisms underlying DCM and develop novel therapeutic strategies.

By leveraging advanced technologies and cutting-edge approaches, we will unravel the common pathways and factors contributing to the development and progression of DCM. Through comprehensive investigations, we seek to gain a deeper understanding of the processes that lead to heart failure in DCM patients. This knowledge will guide us in identifying new therapeutic targets and designing innovative strategies to intervene and halt disease progression.

Our study holds the potential to transform the management of DCM by uncovering critical insights into its pathogenesis and identifying novel therapeutic approaches. By bridging the gap in our understanding of this complex condition, we aim to pave the way for the development of effective treatments that can significantly improve patient outcomes and quality of life.

Scientific summary

Dilated cardiomyopathy (DCM) is a prevalent cause of heart failure, yet the prognosis for patients with DCM remains poor. To address this critical unmet need for new treatments, our consortium aims to leverage cutting-edge techniques and technologies to identify novel advanced therapies. Specifically, our approach focuses on targeting conserved deleterious oxidant signaling pathways, which play a crucial role in the pathogenesis of common genetic forms of DCM. By modulating these pathways, we aim to limit oxidative damage and restore proper cardiac function.

Our research strategy encompasses a multidimensional approach, integrating human and mouse models to explore the complex mechanisms underlying DCM. First, we will utilize proteomics and bioinformatics approaches to map conserved deleterious redox signaling networks associated with DCM. This comprehensive analysis will allow us to identify key molecular targets and signaling pathways that contribute to disease pathogenesis. By gaining a deeper understanding of these processes, we can develop targeted strategies to intervene and disrupt the harmful oxidative stress responses.

In parallel, we will employ human models to identify therapeutic microRNAs that possess cardioprotective properties. MicroRNAs are small RNA molecules that can modulate gene expression and regulate multiple genes within signaling pathways. By targeting these microRNAs, we can potentially normalize dysregulated signaling pathways, thereby restoring normal cardiac function and mitigating disease progression in DCM.

Further, we will leverage advanced genome editing technologies to translate these findings into therapeutic interventions by employing CRISPR-Cas9 DNA base-editing and prime-editing. These powerful tools enable precise modifications in the DNA sequence, offering the potential to modulate specific genetic elements involved in disease processes. By utilizing these technologies, we can selectively target and modify conserved deleterious redox signaling components, thereby providing a novel approach for therapeutic intervention in DCM.

Ultimately, by elucidating the intricate network of deleterious oxidant signaling and identifying therapeutic microRNAs, we aim to pave the way for personalized and targeted treatments for patients with DCM. The anticipated outcomes of this project include a greater understanding of DCM pathogenesis, the identification of new therapeutic targets, and the development of advanced therapies that hold promise for improving patient outcomes and quality of life.

Our research strategy combines state-of-the-art techniques, multidisciplinary approaches, and cutting-edge technologies to address the unmet need for new treatments in DCM. Through our collaborative efforts, we aim to make significant advancements in the field, contributing to the development of innovative therapies and ultimately improving the lives of patients affected by this devastating condition.

Treat-ATHERO

Unlocking the full potential of regulatory T cells to combat atherosclerotic cardiovascular disease (4 Years)

The Netherlands: Dr Amanda Foks, Universiteit Leiden
DHF awarded: €499,987

UK: Dr Tian Zhao, University of Cambridge
BHF awarded: £497,726 (IA/F/23/275046)

Lay summary

Narrowing of the blood vessels causes reduced blood flow to important organs like the heart and brain, which for sufferers, results in chest tightness on exertion (angina), heart attacks, and strokes. The narrowings are caused by a disease process called atherosclerosis which, despite medical advances, is the leading cause of deaths globally and can lead to long-term disability. Atherosclerosis is due to a combination of fatty deposits within the blood vessel walls and the immune system’s long-term over-reaction to the deposits, called inflammation. However, we still do not have any successful treatments to target this inflammation. In our previous clinical trial, we successfully used for the first time interleukin-2, an important messenger hormone, in patients with heart attacks to increase a group of immune cells that suppress inflammation. In animal models, this leads to reduced atherosclerosis, heart attacks, and strokes. In this study we want to understand in more detail how these immune cells function in the actual blood vessel narrowing and develop the next generation of drugs to target these immune cells and treat patients with heart attacks and strokes.

Scientific summary

Atherosclerosis is characterised by chronic inflammation however, there are currently no targeted immune-modulatory therapies licensed to treat this condition. Breakthrough anti-inflammatory interventions to treat unstable atherosclerosis are thus urgently needed. Regulatory T cells (Tregs) are essential for immune homeostasis. Pre-clinical models have shown that Tregs decrease atherosclerosis progression and promote myocardial healing. Furthermore, patients after a myocardial infarction (MI) have reduced Tregs. Administrating low-dose interleukin-2 (ld-IL2) can increase Tregs in patients. Our recent clinical trial showed that ld-IL2 is safe and well-tolerated in patients with MI, and established a dose which selectively increased Treg numbers. Using single-cell RNA-sequencing (scRNA-seq) on circulating immune cells, we found a gene signature consistent with increased suppressive function and survival of Tregs. However, whether changes in circulating Tregs are mirrored in atherosclerotic plaques is unknown.

Currently, we are assessing the effect of administering ld-IL2 on patient plaque immune cells, and particularly Tregs. We are performing this by recruiting patients before their elective carotid endarterectomy and randomising them to either ld-IL2 treatment or control. Carotid plaques obtained at surgery will be analysed using scRNA-seq to study plaque immune cells. In this proposal, we wish to expand this work to understand in greater detail what regulates Treg residency and function within plaques, and how is this affected by IL2 therapy by performing spatial transcriptomics and T cell receptor profiling. We will test critical pathways found in patients in atherosclerotic mice models using conditional knockouts. This enhanced understanding of resident Treg biology will set the stage to test the next generation of IL2 molecule which has single-chain fragment variable (scFV) formulation in which a scaffold bound to a scFv derived from the prototypic E06 anti-oxidation-specific epitope phosphocholine (PC) antibody. This will allow more precise targeting of plaque-based Tregs with a longer therapeutic half-life.

We will test this molecule in aged mice models of atherosclerosis which more closely represents human atherosclerosis acting as an important step for human translation. Moreover, using state-of-the-art ex vivo human plaque cultures we will establish whether this next-generation IL2 molecule can expand tissue-residing Tregs and directly contribute to inhibition of the local inflammation. Collectively, by unravelling the critical mechanisms of Treg alteration in clinical patients and discovering the effect of modulating causal pathways in pre-clinical models, we will harness the full anti-atherosclerosis potential of Tregs and turn our discoveries into treatments for patients in the near future.

PROMETHEUS

Pulmonary hypertension induced Right heart failure: Occurrence of genetic variations and disturbed BMP & TGF-β signalling explaining impaired mechanotransduction and heterogeneous adaptation to pressure overload (4 Years)

The Netherlands: Professor Frances S, de Man, Amsterdam University Medical Centers
DHF awarded: €499,923

Germany: Professor Soni Pullamsetti, Max Planck Institute for Heart and Lung Research
DZHK awarded: €500,000

UK: Professor Andrew Swift, University of Sheffield
BHF awarded: £469,272 (SP/F/23/150050)

Lay summary

Right heart failure is the number one cause of death in patients with pulmonary arterial hypertension (PAH). PAH is a disease characterised by an increased blood pressure in the pulmonary arteries. The right heart that pumps blood through the pulmonary artery for oxygenation in the lungs, needs to adapt to this increased pressure overload in PAH-patients. Intriguingly, the right heart of some patients develops right heart failure whereas the right heart of other patients are able to adapt to a similar amount of pressure overload. This suggests that genetic variants may determine the adaptation capacity of the right heart. Therefore, we will identify in the PROMETHEUS study the genetic variants that are associated with right heart adaptation and determine how they influence cardiac adaptation to pressure overload in several models of right heart failure.

Scientific summary

The ability of the right ventricle to adapt to an increased pressure overload determines survival in pulmonary arterial hypertension (PAH) patients. Genetic variants in the bone morphogenetic protein (BMP) and transforming growth factor beta (TGF-β) are highly prevalent in PAH-patients. BMP/ TGF-β signalling are essential for mechanotransduction in other tissues. Whether genetic variants and disturbed BMP/ TGF-β signalling explains impaired mechanotransduction and the heterogeneous right ventricular (RV) adaptation observed in PAH patients remains elusive and subject of the PROMETHEUS-study. We use a translational approach: WP1. Identify gene variants associated with RV adaptation using whole genome sequencing (WGS) and cardiac magnetic resonance imaging of healthy subjects (UK Biobank) and PAH-patients. WP2. Assess the role of disturbed BMP/TGF-β signalling on RV and left ventricular pressure overload using transgenic mice models. WP3. Determine the effect of disturbed BMP/ TGF-β signalling on mechanotransduction in patient derived induced pluripotent stem cells in 2D and 3D cell culture models.

MegaCardiocyte

Discovering the microvascular landscape from a platelet perspective – mapping a blood-bone marrow-heart axis to identify therapeutic targets for heart failure (4 Years)

UK: Dr Mairi Brittan, University of Edinburgh
BHF awarded: £394,056 (SP/F/23/150051)

Germany: Dr Tobias Petzold, LMU Munich
DZHK awarded: €497,454

The Netherlands: Dr Judith Cosemans, CARIM, Maastricht University
DHF awarded: €499,818

Lay summary

Despite impressive advancements in the treatment of Heart Failure upon a myocardial infarction, another form of Heart Failure -with a preserved Ejection Fraction (HFpEF) -affects an equally large group of patients and has no available treatment. Instead of the large vessels being affected, a hallmark of myocardial infarction, in HFpEF the smallest vessels are dys-functional. There are currently no therapies sufficiently improving the functioning of these small vessels, partly because of unknown biological mechanisms causing their dysfunction. The MegaCardiocyte consortium proposes that blood platelets, normally responsible for clot-ting upon injury, are affected and drive small vessel dysfunction and heart failure. The aim of our studies is to show that this is indeed the case, and to identify novel targets for therapy.

Scientific summary

Heart Failure with a preserved Ejection Fraction (HFpEF) affects >64 million patients worldwide and has no treatment. Microvascular dysfunction (MVD) is considered the steppingstone to HFpEF, and immune functions are affected including a hyperactivation of neutrophils. The MegaCardiocyte consortium proposes that platelets are novel therapeutic targets to improve MVD in HFpEF. Platelets affect microvascular functions. Jointly, we bring innovative pilot data showing 1) thrombopoiesis is affected upon heart failure and neutrophils play a crucial role; 2) HFpEF patients have reduced cardiac perfusion and aberrant platelet activation; 3) implication of candidate noncoding RNAs in MVD during heart failure. Using state-of-the-art human and mouse models and exchanging expertise between the centra, we will unravel the contribution of neutrophils and platelets to MVD in HFpEF, and come to novel ncRNA-based therapeutic targets.

Prot4CVD

Translational proteomics for cardiovascular diseases: from population prediction to clinical and therapeutic applications (4 Years)

UK: Professor Adam Butterworth, University of Cambridge
BHF awarded: £498,174 (SP/F/23/150048)

Germany: Professor Claudia Langenberg, Charité – Universitätsmedizin Berlin
DZHK awarded: €499,834

Lay summary

If genes are ‘blueprint’ for the human body, proteins are the ‘actors’ that implement the blueprint. We will bring together leading cardiologists and scientists from Germany and the UK to jointly study measurements of thousands of proteins in 200,000 people with and without heart disease and related conditions. This will enable powerful, systematic examination of the value these protein measurements can bring for doctors and drug companies. Many of these proteins have never been studied at this scale, as their measurement has only recently become possible. It is therefore likely that new combinations of these proteins can predict who is likely to have a heart attack or stroke (or do worse after suffering these events), improving on current prediction tools that doctors use. Our findings will be made available in webtools so that the research community, doctors and drug companies can ultimately improve the lives of patients and populations.

Scientific summary

Measurements of thousands of proteins in large-scale population and patient cohorts provides the opportunity to improve prediction, prognosis, and prevention of atherosclerotic cardiovascular disease (CVD). Our new bi-national partnership will combine world-leading proteomic datasets comprising 200,000 participants with up to 7,000 measured proteins. We will apply our leading expertise in proteomics, multiomics and CVD research to perform systems medicine analyses that integrate proteomic, genomic, and clinical data to improve understanding of disease. We will compare results across primary and secondary care settings, proteomic assay platforms, sex, ethnicities and geographies to deliver robust, reproducible and generalizable insights. Our findings will enhance CVD risk prediction to inform clinical practice and identify putative therapeutic targets to inform drug development programmes, ultimately leading to improvements to CVD prevention and management. We will rapidly disseminate results through an open-access resource to provide additional value to the broader scientific community and enhance future cardiovascular research worldwide.

PLAK-TALK

Intercellular communication pathways in atherosclerosis and plaque destabilisation (4 Years)

Germany: Professor Lars Maegdefessel, Technical University Munich
DZHK awarded: €499,800

UK: Dr Jason Tarkin, University of Cambridge
BHF awarded: £499,709 (SP/F/23/150049)

The Netherlands: Professor Marit Westerterp, University Medical Center Groningen
DHF awarded: €499,968

Lay summary

Cardiovascular disease is a major global health issue. Most individuals who have heart attacks and strokes are unaware of their underlying condition before they suddenly develop symptoms. Better ways to identify people most at risk of these sudden events, and better ways of preventing them from occurring, are urgently needed. Research has shown that cells in the body that cause inflammation can increase the risk of developing “fatty plaques” (due to atherosclerosis) in the heart and neck arteries that are more likely to “break” (rupture) and block off blood flow to the heart or brain, than other more stable plaques. We will study how certain immune cells (T cells) communicate with other artery cells (smooth muscle cells) that are needed to protect plaques from becoming weakened and rupturing. Identifying these links will help to design new treatments that can stabilise plaques and stop heart attacks and strokes before they occur.

Scientific summary

Mechanisms of atherosclerotic plaque destabilisation leading to acute rupture or erosion events remain incompletely understood. The structural integrity of the fibrous cap is heavily influenced by the inflammatory milieu of the plaque microenvironment. Identification of key intercellular communication pathways linking plaque structural and immune cells is needed to better understand cellular plasticity and phenotypic behaviours. Having extensively profiled atherosclerotic plaques, we believe the crosstalk between T cells and vascular smooth muscle cells to be crucially important for plaque stability and have identified attractive targets for therapeutic intervention and imaging. In the PLAK TALK study, we will examine interactions between these and other plaque cells, using a three-pronged multi-disciplinary approach comprised of animal and human ex vivo, in vitro, and in vivo experiments to link molecular mechanisms and cellular interactions with clinically measurable imaging and blood-based biomarkers. Ultimately, this translational research will open new diagnostic and therapeutic avenues for cardiovascular disease.

ReGenLnc

Exploiting endothelial long non-coding RNAs to promote regenerative angiogenesis in the damaged myocardium (4 years)

UK: Professor Andy Baker, University of Edinburgh
BHF awarded: £357,132 (SP/F/22/150029)

The Netherlands – Professor Reinier Boon, University of Amsterdam
DHF awarded: €369,970

Germany: Professor Ralf Brandes, Goethe-University Frankfurt
DZHK awarded: €395,900

Lay summary

Scientific summary

CONTROL SVD

Immune cell reprogramming and neuroinflammation in cerebral small vessel disease (4 years)

The Netherlands: Professor Frank-Erik de Leeuw, Radboud University
DHF awarded: DHF €506,379)

UK: Professor Hugh Markus, University of Cambridge
BHF awarded: £1,081,396 (SP/F/22/150028)

Lay summary

Cerebral small vessel disease (SVD) causes a quarter of strokes and is a major cause of dementia. Despite its importance, we have few treatments for SVD. Recent evidence suggests a dysregulated immune response occurs in SVD. In this programme we will follow up patients with SVD to characterize the abnormalities in the immune system both in the blood, and also in the brain using advanced brain imaging, and work out how these relate to disease progression. This information will allow us to design drug interventions to inhibit this inflammation and we hope improve outcome by reducing stroke and dementia.

Scientific summary

Increasing evidence implicates inflammation, both systemic and central nervous system (CNS), in cerebral small vessel disease (SVD), but which aspects of the dysregulated immune response relate to disease progression and could be targeted therapeutically remains undetermined. In a cohort of well characterised patients with SVD (N=200) we will determine the nature of the dysregulated immune response, and how it is related to disease progression using multimodal MRI. We will further determine the relationship between the systemic and CNS immune responses using [¹¹C]PK11195. Positron emission tomography and cerebrospinal fluid examination. Using Mendelian randomisation techniques we will investigate causality between specific components of the immune system, and SVD. Our programme will determine which components of the dysregulated immune system in SVD relate to disease progression and allow rational design of intervention studies targeting these components to reduce recurrent stroke and cognitive decline.

COOLBAT

A cool battle: cold as a therapeutic strategy to comBAT cardiovascular diseases (4 years)

The Netherlands: Dr Mariëtte Boon, Leiden University
DHF awarded: €674,249

UK: Professor Michael Symonds, University of Nottingham
BHF awarded: £272,289 (SP/F/22/150031)

Lay summary

Cold exposure boosts energy metabolism, resulting in increased burning of sugar and fat, and positively impacts immune function. In this project, we will study whether daily bouts of cold exposure can improve the cardiovascular risk profile in individuals with elevated risk for cardiovascular diseases. In addition, we aim to identify the best way to implement more exposure to cold in daily life, how COOL is that?

Scientific summary

Cold exposure enhances thermogenesis in BAT and skeletal muscle. While cold acclimation improves insulin sensitivity in T2DM patients, its effect on cardiovascular risk factors in humans at risk for as CVD and the feasibility to implement cold exposure in clinical practice remain unclear. In a complementary collaboration between LUMC, AUMC and University of Nottingham, we will optimize application of repeated daily bouts of cold exposure in clinical practice. We will perform studies in several patient groups assessing e.g., glucose and lipoprotein metabolism, (ectopic) fat accumulation and immune cell phenotype and inflammatory signalling in response to cold treatment. We will also develop an app to implement cold treatment in daily life and assess long-term effects of daily cold bouts on cardiometabolic risk factors and intima-media thickness. We anticipate that this project will unravel whether and by which mechanisms cold treatment can improve cardiometabolic health.

I-CARE

Quantitative-imaging in cardiac transthyretin amyloidosis (4 years)

UK: Professor Marc Dweck, University of Edinburgh
BHF awarded: £393,675 (SP/20/3/35123)

Germany: Professor Fabian Siepen, University of Heidelberg
DZHK awarded: €280,800

The Netherlands: Professor Riemer Slart, University of Groningen
DHF awarded: €416,112

Lay summary

Transthyretin amyloid cardiomyopathy (ATTR-CM), is a heart muscle disease that’s stops the heart muscle working properly. With an ageing population, it is increasingly common but untreated, it has a poor prognosis. Several novel expensive treatments have become available, although we do not understand exactly how they work and why some patients respond, and others do not. The challenge is to develop better methods for monitoring the effects of these treatments, maximizing their benefits and cost-effectiveness. In I-CARE we aim to bring a new imaging technique, named 18F-fluoride PET, to the clinic and thereby improve the care of patients with ATTR-CM.

Scientific summary

ATTR-CM is a cardiomyopathic process with increasing prevalence due to an ageing population. It is a challenging condition to diagnose and has traditionally been associated with a dire prognosis. A new transthyretin stabiliser, tafamidis, has been developed that holds major promise in transforming the natural history of ATTR-CM. However, this drug is expensive and requires a precision medicine approach to maximise clinical efficacy and cost effectiveness.

In I-CARE, we have assembled a unique multidisciplinary team with world leading expertise in amyloidosis, cardiology, and multi-modality imaging. Specifically, I-CARE aims to develop 18F-fluoride PET for the accurate early diagnosis of ATTR-CM and quantification of disease burden, thereby allowing us for the first time to track disease progression and response to therapy. We believe I-CARE will deliver a step-change in the clinical pathway for ATTR-CM allowing tailored, patient-centred treatment of this previously fatal clinical condition using a novel one-stop imaging technique.

GenUCA

The Genomic basis of Unexplained Cardiac Arrest (4 years)

UK: Professor Elijah Behr, St George’s University of London
BHF awarded: £1,055,434 (SP/20/4/35124)

Germany: Professor Martin Borggrefe, University of Manheim
DZHK awarded: €452,000

The Netherlands: Professor Connie Bezzina, University of Amsterdam
DHF awarded: €350,112

Lay summary

One in twenty people who suffer a life-threatening heart rhythm abnormality (cardiac arrest) will have no clear explanation. Treatment options are limited and there may be hidden risk for relatives. We will study the largest group of unexplained cardiac arrest survivors ever collected to better understand the causes. We will perform in-depth genetic testing to uncover inheritable risk factors for cardiac arrest. Genetic discoveries will be studied in genetically altered human cells and mice to identify underlying mechanisms and targets for new medicines. We expect to identify new and improved ways to prevent sudden death in patients and their relatives.

Scientific summary

Unexplained cardiac arrest (UCA) accounts for 5-7% of out-of-hospital cardiac arrests. There are three sub-phenotypes currently recognised: Early Repolarisation Syndrome; Short-Coupled Torsades de Pointes/Ventricular Fibrillation (VF); and idiopathic VF. Underlying arrhythmia mechanisms are diverse and include delayed depolarisation, premature repolarisation; and/or triggered activity, the causes of which are unknown although there is genetic susceptibility.

We will leverage existing international collaborations to gather the largest single cohort of UCA survivors for whole genome sequencing and association studies to identify underlying rare and common variation. We will correlate genetic findings with dynamic heart rate related and autonomic ECG parameters on 12 lead 24-hour ambulatory ECG monitoring to clarify underlying mechanisms. We will study novel genetic associations in mouse and human induced pluripotent stem cell derived cardiomyocyte models to understand their molecular basis and identify druggable targets for future research. We aim to improve patient categorisation, risk prediction management and therapeutics.

DnAFiX

DNA damage in cytoskeletal protein mutation-induced atrial fibrillation: a guide to novel treatment and screening targets (4 years)

The Netherlands: Professor Bianca Brundel, University of Amsterdam
DHF awarded: €666,076

Germany: Professor Niels Voigt, University of Göttingen
DZHK awarded: €520,000

Lay summary

Atrial fibrillation (AF) is the most common cause for abnormal heart rhythm, particularly in persons older than 65 years, but often occurs in younger persons. In younger persons, AF may be due to a genetic cause. We identified AF families carrying changes (mutations) in genes encoding cytoskeletal proteins, the building blocks of heart-cells. Recent findings from our team suggest that these mutations cause DNA damage in atrial-cells and thereby drive AF. This project aims to uncover the exact mechanism how cytoskeletal protein mutations cause DNA damage and AF and test several (marketed) drugs to develop novel therapies for (genetic) AF patients.

Scientific summary

Atrial fibrillation (AF), the most common progressive cardiac rhythm disorder, is associated with serious complications such as stroke and heart failure. Although common risk factors, including hypertension, diabetes and obesity, frequently underlie AF onset, in ~20% of the AF population, AF has a genetic cause. We identified AF families carrying mutations in cytoskeletal protein lamin A/C, desmin and desmoplakin, which have a strong association with dilated and peripartum cardiomyopathy.

How mutations in cytoskeletal proteins exactly drive AF onset is unknown, but accumulating evidence indicates that they cause cytoskeletal disruption, DNA and mitochondrial damage and subsequent cardiomyocyte dysfunction. Interestingly, we recently published on the prominent role of DNA damage to drive the energy consuming repair mechanism PARP1, thereby resulting in mitochondrial dysfunction and (non-genetic) AF. Here, we aim to uncover the role of the DNAdamage-PARP1-mitochondrial pathway in cytoskeletal protein mutation-induced AF and identify novel druggable and diagnostic targets in AF.

Genetic discovery-based targeting of the vascular interface in atherosclerosis (4 years)

Germany: Professor Jeanette Erdmann, University of Lübeck
DZHK awarded: €1,200,000

UK: Professor Hugh Watkins, University of Oxford
BHF awarded: £1,071.117 (SP/19/2/34462)

Lay summary

This collaborative project aims to help understand how our genes affect our risk of heart disease. Studies involving large groups of people with and without heart disease have identified changes in the DNA code that are more frequent in people with the disease. We found many of these DNA changes are in genes involved in the wall of our blood vessels, an important biological system in the development for heart disease. We will combine innovative computational and experimental methods to investigate these genes in great detail to understand how exactly they affect disease risk, and to translate this knowledge into new treatments.

Scientific summary

Population-scale genetic analysis has transformed our understanding of the contribution of genetic variation to coronary artery disease (CAD). However, a major challenge in unlocking the potential of these genomic studies is in translating the genetic associations into causal biology and actionable clinical insights.

In unbiased bioinformatics analyses, we identified many of the genes at CAD risk loci discovered by genomic studies to be implicated in the vascular interface, comprising mechanotransduction, smooth muscle cell phenotype switching, and inflammatory cell recruitment. We will combine our leading expertise in computational and experimental methods to (1) systematically identify the key driver genes at these loci; (2) establish the molecular, cellular, and physiological mechanisms of the genes; and (3) define interactions within functional pathways.

Together, the findings will provide a clearer understanding of the biological processes at the vascular interface leading to CAD and nominate targets for therapeutic development, laying the foundations for prevention approaches.

Spatially resolved cellular and molecular drivers of cardiac remodelling in healthy and failing hearts (3 years)

Germany: Professor Norbert Hübner, Max Delbrück Center for Molecular Medicine
DZHK awarded: €962,170

UK: Dr Michela Noseda, Imperial College London
BHF awarded: £866,059 (SP/19/1/34461)

Lay summary

Heart failure is a severe disease with a defective pump function that often results in heart transplantation. A heart is made of billions of cells which must properly work together. During heart failure functional changes arise due to modifications of cells that form the heart. We want to apply new leading-edge technologies to analyse thousands of individual cells at once to study the precise cell composition of different heart compartments and, importantly, the changes leading to heart failure. We expect to identify new disease markers and therapeutic targets for enlarged (dilated cardiomyopathy, DCM) and thickened (hypertrophic cardiomyopathy, HCM) failing hearts.

Scientific summary

Heart failure is a leading cause of death and disability. Normal function of the four-chambered human heart relies on highly heterogeneous cell populations with specialized functions governed by differential gene expression. However, the precise composition of cardiac cell populations, the complex genomic architecture of individual cells and stress associated changes therein are incompletely understood.

Through our consortium, we have access to human ‘healthy’ (brain dead donors) and DCM/HCM heart samples and induced pluripotent stem cells (hiPSC). We will compare multiple anatomical regions and will characterize cardiac cell states and types, their expression networks and cellular circuits, and locate these in 3D space. We will perform functional analysis in hiPSC derived 3D engineered heart tissue. By comparing changes between non-failing hearts, DCM, and HCM, we will discern fundamental causes of maladaptive cardiac remodelling, characterize heterogeneous cellular responses in different disease aetiologies, and infer new strategies to limit these.