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Landelijke thematische consortia Overzicht ten behoeve van het gezamenlijke financieringsprogramma van de Hartstichting, British Heart Foundation en Deutsches Zentrum für Herz-Kreislauf-Forschung 2021. Overzicht landelijke thematische consortia – februari 2021
Inleiding
Onderzoeksvoorstellen die in 2021 in het kader van het gezamenlijke financieringsprogramma van de
Hartstichting, British Heart Foundation (BHF) en Deutsches Zentrum für Herz-Kreislauf-Forschung
(DZHK) worden ingediend en waaraan Nederlandse onderzoekers meedoen moeten bijdragen aan en
samenwerken met landelijke thematische consortia. De consortia die hiervoor in aanmerking komen zijn
onderdeel van de Dutch CardioVascular Alliance.
In dit document vindt u de consortia die voor deze samenwerking in aanmerking komen, een
samenvatting van het onderzoeksprogramma en contactgegevens van de onderzoeksleiders.
Thema Consortium Onderzoeksleiders
Atherosclerose GENIUS-II Prof. dr. J. Kuiper
Prof. dr. E. Stroes
Genetische Hartziekten ARENA-PRIME Prof. dr. Y. Pinto
Prof. dr. L. de Windt
DOUBLE DOSE Prof. dr. R. de Boer
Prof. dr. J. van der Velden
Hartritmestoornissen PREDICT-2 Prof. dr. A. Wilde
Prof. dr. M. Vos
Hart-brein connectie HBC-X Prof. dr. G. Biessels
Prof. dr. M. Daemen
Pulmonaire hypertensie PHAEDRA-IMPACT Prof. dr. M Goumans
Prof. dr. H.J. Bogaard
Aangeboren hartafwijkingen OUTREACH Prof. dr. W. Helbing
Prof. dr. M. Hazekamp
Prof. dr. J. Bakkers
Hartfalen (HFpEF) RECONNEXT Prof. dr. D. Duncker
Prof. dr. M Verhaar
Hart- en vaatziekten bij IMPRESS Prof. dr. H. den Ruijter
vrouwen Prof. dr. H. Boersma
Hart- en vaatziekten en het IN-CONTROL II Prof. dr. F Kuipers
microbioom Prof. dr. N. Riksen
Regeneratie van het hart Cardiovascular Moonshot Prof. dr. P, Doevendans
(RegMed XB) Prof. dr. C. Bouten
Prof. dr. M.J. Goumans
Dr. B. Mees
Beroerte CONTRAST Prof. dr. D. Dippel
Prof. dr. C. Majoie
Overzicht landelijke thematische consortia – februari 2021GENIUS-II: Generating the best evidence-based pharmaceutical targets and drugs for
atherosclerosis II
Research leaders Prof. dr. J. Kuiper: j.kuiper@lacdr.leidenuniv.nl
Prof. dr. E. Stroes: e.s.stroes@amsterdamumc.nl
This GENIUS II proposal is built on the most promising targets identified in GENIUS I which we now
aim to move towards clinical application. As such, GENIUS II builds on our unique integration of
knowledge on dyslipidemia and the immune response as a consequence of dyslipidemia. The work is
divided into four distinct work packages that represent the logical steps in drug development and
accordingly each of the selected targets from GENIUS I to be studied was carefully placed into this
track. Studies will include the actual testing of the effectiveness of small molecules, monoclonal
antibodies and siRNA that modulate selected targets. The investigations will range from in vitro to in
vivo analyses to improve mechanistic insight and druggability, and test effects on atherosclerosis. For
five targets we already defined small molecules and a monoclonal that affect our targets. These drug
leads will be further translated along toxicity studies and proof-of-pharmacology studies. We already
identified three drugs affecting the current foremost targets of GENIUS I and we will study whether
they can be efficiently applied to reduce atherosclerotic parameters in First-In-Human clinical studies.
This will be possible through additional help of our industrial partners. In all studies, we will address
gender specificity. Next to directly building on GENIUS I drug targets and drug leads, we want in this
regard also take advantage of the most recent innovative developments to find new druggable targets
in cells of male and female atherosclerotic lesions as well as in circulating cells (immunophenotyping
and single cell sequencing.) This is also expected to lead to the identification of novel gender specific
biomarkers that can facilitate identification of disease progression and improve diagnosis. Our talent
program is designed in such a way that all young talent working on GENIUS II will gain insight in the
opportunities and challenges of developing drugs for cardiovascular disease. Overall, GENIUS II will
focus on translating knowledge towards a clinical application.
Overzicht landelijke thematische consortia – februari 2021ARENA-PRIME: Towards Personalised Medicine in the Clinic: Novel RNA Therapies aimed at
heritable forms of treatment-resistant Heart Failure.
Research leaders: Prof. dr. Y. Pinto: y.pinto@amsterdamumc.nl
Prof. dr. L. de Windt: l.dewindt@maastrichtuniversity.nl
The former ARENA programme contributed to the discovery and elucidation of prominent mechanisms
by which different cardiac RNA species (microRNAs, lncRNAs and circular RNAs) are involved in
development and progression of diverse forms of heart failure (HF). Importantly, ARENA installed a
national framework that successfully connected to European partners. Our current proposal shifts its
focus towards forms of HF that are resistant to current HF treatment. In previous decades, generally
applied therapies substantially improved survival of HF patients. Still, in a minority of patients, these
treatments fail to halt the progression of the disease. This particularly concerns younger patients with
forms of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). ARENA-PRIME
takes the individual disease mechanism of DCM caused by mutations in the RBM20 and LMNA genes
as well as ACM caused by mutations in the DSGL2 and PKP2 genes as forms of treatment-resistant
HF to develop novel RNA therapies tailored to the individual disease. Within ARENA we recently
identified additional mechanisms by which mutations in RBM20 cause hereditary HF. This discovery
forms the basis of WP1 where we test FDA-approved compounds to prevent myocyte calcium
overload to ameliorate ventricular arrhythmias in RBM20-DCM. Next, we capitalize on the knowledge
gained in ARENA on inhibitory RNAs to develop novel smart-siRNAs to inhibit mutated alleles with just
a few siRNAs, avoiding the need to generate an siRNA for each discrete mutation. We will use this
technology to target the toxic allele that results from LMNA mutations to treat LMNA-DCM (WP2).
Furthermore, we will investigate multiple innovative strategies to treat ACM caused by mutations in the
DSGL2 and PKP2 genes: allele-specific short hairpin RNAs, antimiRs and FDA-approved compounds
(WP3). Our translational work packages are complemented with state-of-the-art delivery-technologies
based on AAV vectors and antibody conjugation (WP4). Finally, we connect the national wealth of
heart tissue collections to novel high-end sequencing technologies like single-cell sequencing to
further explore disease mechanisms (WP5). Upon completion of this programme, we anticipate to
achieve clinical proof-of-principle of the new RBM20 therapy and preclinical proof-of-concept of LMNA,
DSGL2 and PKP2 directed therapies on a path towards clinical reality.
Overzicht landelijke thematische consortia – februari 2021DOUBLE-DOSE: Double Dose of energy and efforts of the national DOSIS consortium
Research leaders Prof. dr. R. de Boer: r.a.de.boer@umcg.nl
Prof. dr. J. van der Velden: j.vandervelden1@amsterdamumc.nl
Inherited cardiomyopathies affect tens of thousands of people in the Netherlands and cause severe
symptoms and an increased risk of sudden cardiac death. The most common forms are hypertrophic
(HCM) and dilated cardiomyopathy (DCM). The genetic mutation alone is not sufficient to predict
clinical course, therefore our previous DOSIS consortium investigated the interaction between
mutation and external factors. Importantly we found that cardiomyopathy-mutations induce metabolic
stress and that secondary metabolic stress, such as obesity accelerates disease progression.
This has led to the DOUBLE-DOSE hypothesis that metabolic stress represents the central
pathomechanism of early and late cardiac dysfunction in HCM and DCM. Therapeutically targeting this
may prevent or cure cardiomyopathies.
Our consortium is expanded with researchers with a strong clinical focus on DCM in children and
adults, further strengthening our expertise and access to clinically well-defined patient cohorts. We will
establish biobanks of serum and tissue as well as of induced pluripotent stem cell-derived
cardiomyocytes (iPSC-CMs) from patients. We have already established mouse models of the most
prevalent cardiomyopathy-causing mutations in the Netherlands.
Linking clinical data, patient samples and our experimental models we will define the mechanism of
how obesity and muscle adiposity cause endothelial and cardiomyocyte dysfunction in mutation
carriers. We will also unravel the mechanism by which cardiomyopathy-causing mutations lead to
ultrastructural changes in cardiomyocytes. These changes cause impaired metabolism, contraction
and relaxation defects, and disturbed communication with other cells in the heart.
Making use of our extensive patient cohorts and the findings from DOSIS and we will optimize care for
cardiomyopathy patients. We will quantify the cost-effectiveness of current diagnostics and clinical
care from both patient and societal perspective. Furthermore, we will translate our findings that
metabolic alterations are central to cardiomyopathies, by initiating at least one clinical trial based on
treatment(s) that reduce metabolic stress.
The DOUBLE-DOSE program will establish serum, tissue and iPSC-CMs biobanks from a large set of
cardiomyopathy patients. We will provide mechanistic pre-clinical and clinical insight into the link
between metabolic stress and cardiomyopathy pathophysiology, and translate these findings to
optimize diagnosis and care of cardiomyopathy patients.
Overzicht landelijke thematische consortia – februari 2021PREDICT-2: Predicting sudden cardiac arrest
Research leaders Prof. dr. A. Wilde: a.a.wilde@amsterdamumc.nl
Prof. dr. M. Vos: m.a.vos@umcutrecht.nl
Sudden cardiac arrest (SCA) continues to be a major public health problem, representing almost 20%
of all deaths in industrialized societies. SCA accounts for ~50% of all heart disease deaths, an
important subset of which consists of individuals not previously diagnosed with heart disease. The
devastating psycho-social impact on society and on families of victims often still in their prime, is
obvious. Ventricular fibrillation (VF) is the most common arrhythmia causing SCA. VF leads to death
within minutes if left untreated, yet occurs out-of-hospital in the vast majority, resulting in survival rates
of only 5-20%. Clearly, prevention is key to solving this important public health problem. However, our
ability to prevent SCA is at present hindered by our gap in knowledge of causes and mechanisms of
SCA. Moreover, genetic and non-genetic modulatory factors, including gender, age, co-morbidities,
and lifestyle are expected to mediate SCA risk, but their contribution are still unknown. PREDICT2
brings together renowned PIs with expertise in epidemiological, clinical, genetic, and functional studies
to identify factors causing SCA, understand their underlying mechanisms and use these insights to
construct strategies to prevent and treat SCA. They will crucially build on the foundations laid in
PREDICT1 which involved, amongst others, the accrual of large cohorts of highly characterized
patients and the generation of preclinical disease models and insights. Research will focus on the
inherited arrhythmia syndromes, generally considered paradigms for the understanding of the
arrhythmogenic substrate in the more frequent cardiac syndromes associated with SCA. Specifically,
PREDICT2 will:
(1) Identify genetic and non-genetic factors that conspire to determine risk for SCA and use these to
construct risk prediction algorithms for personalized risk assessment in the individual patient;
(2) Conduct functional studies to identify mechanisms underlying SCA to enable the development of
new risk stratification and therapeutic strategies;
(3) Conduct clinical studies, assessing risk
Overzicht landelijke thematische consortia – februari 2021HBC-X: Heart Brain Connection - crossroads
Research leaders Prof. dr. G. Biessels: g.j.biessels@umcutrecht.nl
Prof. dr. M. Daemen: m.j.daemen@amsterdamumc.nl
Cardiovascular disease and dementia are closely related. Cognitive impairment is common among
people with cardiac or cerebrovascular disease and one in three dementia cases is attributable to
vascular injury. This potentially preventable vascular burden in cognitive decline and dementia is
referred to as Vascular Cognitive Impairment (VCI). From 2013, the Heart Brain Connection (HBC1)
programme focuses on the role of haemodynamic abnormalities along the heart-brain axis in VCI. We
have established a unique multidisciplinary network to address aetiology, assessment, and
management of VCI from the heart to the brain using advanced research tools, with strong roots in
clinical care. Our findings confirm the importance of the heart-brain axis in VCI and support the
aetiological role of haemodynamic factors, although this likely involves more than cerebral
hypoperfusion. Our new HBC crossroads(HBCx) programme will therefore address additional
important haemodynamic factors, including blood pressure and cerebrovascular reactivity, and
venous, valvular, rhythm, and endothelial abnormalities. Converging evidence from epidemiological,
clinical, and autopsy studies also shows that the impact of haemodynamics and cardiovascular
disease in VCI needs to be considered in the context of common comorbidities. In the brain, Alzheimer
pathology frequently co-occurs with vascular injury. In the heart, atrial fibrillation(AF) is a common
vulnerability factor for VCI. HBCx will also address these factors. Our overall hypothesis is that the
interplay between haemodynamics and vulnerability factors, in particular AF
and amyloid, determines functional and structural brain changes in VCI and provides leads for
treatment
Overarching objectives are to:
Further establish the role of haemodynamics in VCI, also beyond hypoperfusion
Establish the role of common vulnerability factors for VCI(AF and amyloid) in interplay with
haemodynamics(i.e. crossroads)
Implement the HBC concept in diagnosis and treatment of VCI in routine patient care HBCx
builds on the strong, multidisciplinary, translational research community and infrastructure
established in HBC1. We foster our young talents, connect with other research consortia, and
involve patients and clinicians in order to advance the HBC concept in the diagnosis and
treatment of VCI. Our ambitions are to identify treatable targets, translate research tools to
diagnostic applications, and provide integrated heart-brain care for patients with VCI.
Overzicht landelijke thematische consortia – februari 2021PHAEDRA-IMPACT: Pulmonary hypertension and associated right heart failure: improved
outcomes through precision medicine, advanced modelling and early detection.
Research leaders Prof. dr. M. Goumans: m.j.goumans@lumc.nl
Prof.dr. H.J. Bogaard: hj.bogaard@amsterdamumc.nl
Pulmonary hypertension, or increase in pulmonary blood pressure, remains a fatal condition since
there are no known effective interventions to reverse pulmonary vascular remodelling or to prevent
right heart failure. In the past five years, the PHAEDRA consortium made important steps towards
solving this health care problem. Compounds were identified which, through modulation of the
transforming growth factor-β (TGFβ)/bone morphogenetic protein balance, could restore endothelial
function in vitro and reverse pulmonary vascular remodelling in vivo. A proof-of-concept trial was
started with one of these drugs, 6-mercaptopurine. Biomarkers were identified to facilitate early and
accurate diagnosis and precision medicine treatment. PHAEDRA-IMPACT will continue the pursuit of
improved outcomes in PH via the following objectives: First, PHAEDRA-IMPACT will contribute to the
early detection of treatable PH through the application of non-invasive risk scores in combination with
imaging and simple blood tests that can detect pre-capillary PH. Second, PHAEDRA-IMPACT will
contribute to the identification of the right drug for the right patients, using a precision medicine
strategy based on advanced imaging and biomarker collection. The underlying hypotheses here are
that antiproliferative drugs will only be beneficial in patients with high rates of lung vascular
proliferation, and also that high rates of proliferation are most likely restricted to relatively early stages
of the disease or are only intermittently present in patients. Our studies will tell us how to use targeted
treatments in patient subgroups, and will help understand why disease development and progression
is so variable between subjects who are similarly predisposed to developing PH, such as survivors of
acute pulmonary embolism and BMPR2 mutation carriers. A better understanding of predisposing
factors and second hits, will aid in developing new drugs and preventive strategies, as well as in early
recognition of disease development. Third, we will study interactions between the ”sick lung
circulation” and the failing right heart in pulmonary hypertension, in order to develop new treatments to
specifically improve right heart pressure adaptation. We will use patient material in innovative 3D
culture models of lung and heart tissue to unravel mechanisms of disease in PH and to identify new
possible ways of treatment.
Overzicht landelijke thematische consortia – februari 2021IN-CONTROL II: Inflammatory Reprogramming by Ageing and Microbiome – Targets for
Treatment of Cardiovascular Disease
Research leaders Prof. dr. F Kuipers: f.kuipers@umcg.nl
Prof. dr. N. Riksen: niels.riksen@radboudumc.nl
The current IN-CONTROL II proposal is built on the strong fundaments provided by our successful IN-
CONTROL I consortium, that unequivocally demonstrated the role and relevance of the microbiome in
the development of low-grade inflammation, a hallmark of atherosclerotic cardiovascular diseases, as
well as for a number of other risk factors including plasma levels of lipids and microbiome-derived
metabolites. These insights are of great relevance to halt the rise in cardiovascular disease-related
deaths in our ageing and increasingly overweight population. The consortium, in this next phase, aims
therefore to shift from association to causality, from population-based cohorts to patient groups with
atherosclerotic cardiovascular disease (CVD) and from observation to intervention. In this transition,
we will also take advantage of recent developments in the network of the consortium, delineating
cellular senescence as a druggable target for the broad spectrum of age-related chronic diseases,
including cardiovascular diseases, and identification of components of the bile acid-signaling system
for this purpose. IN-CONTROL II will seek to i. unravel the mechanisms driving ‘trained immunity” in
patients, taking into account the impact of senescence, age, gender and obesity, ii. elucidate the
interactions between microbiome-derived signals (aromatic amino acids and their metabolites,
(secondary) bile acids) and (immune) senescence in the etiology of obesity-related cardio-metabolic
diseases, and iii. to pursue and to identify new therapeutic targets and to design novel
pharmacological and microbiome-based therapies to counteract inappropriate induction of trained
immunity and inflammatory processes in cardiovascular disease. To do so, we will perform proof-
ofprinciple trials in well-defined patient groups, and make use of state-of-the-art experimental
procedures, e.g., systems biology concepts, single cell sequencing, innovative animal models, small
animal imaging for cardiac function, next generation –omics and in vivo quantification of metabolic
fluxes (fluxomics). A talent program will be put in place to allow all young researchers within the
consortium to benefit from the infrastructure provided by the consortium, including its extended
network, and to gain insight into all aspects associated with design and development of new treatment
modalities for cardiovascular disease. Hence, IN-CONTROL II will have a strong focus on rapid
translation of new concepts towards clinical application.
Overzicht landelijke thematische consortia – februari 2021IMPRESS: national collaborative knowledge platform to impact on sex- and gender sensitive
cardiovascular medicine.
Research leaders Prof. dr. H. den Ruijter: H.M.denRuijter-2@umcutrecht.nl
Prof. dr. ir. H. Boersma: h.boersma@erasmusmc.nl
In the Netherlands, annually, 20,000 women die from cardiovascular diseases. IMPRESS is a Dutch
national consortium established to improve the care of women with cardiovascular disease. We will
collect, summarize and disseminate existing knowledge, and, where possible, implement evidence
into practice. We will also stimulate and initiate research to help fill in the current knowledge gaps.
In recent years, a broad range of studies have been conducted on cardiovascular disease in women,
and our knowledge on the matter has considerably improved. However, information on study results is
difficult to find for patients, doctors and other stakeholders. IMPRESS will collect, distribute and
implement existing knowledge on cardiovascular disease and -health in women, through a national
Knowledge Platform to be established.
Previous research and practical experience show that many women present with symptoms that are
unclear as to whether they are a manifestation of heart disease. For example, those symptoms could
also fit well with general menopausal symptomatology. It is therefore a challenge for general
practitioners to determine who should be referred for further investigation by a cardiologist.
Unfortunately, the correct diagnosis is regularly missed, or it takes too long before the final diagnosis
is made. We will investigate whether and how the diagnostic process in women with symptoms of
heart disease can be improved. We will pay attention to physical, psychosocial and ethnic-cultural
aspects.
Non-obstructive cardiovascular disease is the collective name for vascular spasms and problems in
the small blood vessels of the heart. This form of heart disease is more common in women than in
men. Patients with non-obstructive cardiovascular disease have an impaired quality of life and a
poorer prognosis than patients without cardiovascular disease. It is therefore important to diagnose
this condition in time. IMPRESS will conduct research into non-obstructive heart disease in women
who are referred to the cardiologist. Usually advanced imaging is then applied, such as "Magnetic
Resonance Angiography" or a heart catheterization, in highly specialized cardiology centers. We will
investigate which diagnostic instruments can best (cost-effective) be used in practice. We will also
study whether the symptoms of non-obstructive cardiovascular disease can be eliminated by certain
drugs. Finally, we will conduct experimental research into the immune system and the heart cell
function. Results of these studies help us to better understand cardiovascular disease in women, with
the ultimate goal to prevent disease occurrence and -manifestation in the future.
Overzicht landelijke thematische consortia – februari 2021OUTREACH: Outflow tract related aging with congenital heart defects: identifying causes and
mechanisms of myocardial and large vessel wall adaptation, predictors for long term outcome
and targets for improved treatment.
Research leaders Prof. dr. W. Helbing: w.a.helbing@erasmusmc.nl
Prof. dr. M. Hazekamp: m.g.hazekamp@lumc.nl
Prof. dr. J. Bakkers: j.bakkers@hubrecht.eu
Treatment of congenital heart disease (ConHD) is one of the successes of the 20th century.
Unfortunately, the 3.8 million ConHD patients in Europe have a high risk of developing heart failure,
arrhythmias, sudden cardiac death (SCD) or (potentially fatal) blood vessel dilatation or stenosis
relatively early in life. To reduce the burden of cardiovascular morbidity in the aging ConHD patient we
must recognize these late complications earlier and treat them better. Our research will focus on the
group of patients with anomalies of the outflow tract: the connection between the heart chambers and
the great arteries to lungs and body. These outflow tract defects include disorders such as
transposition of the large arteries (TGA), tetralogy of Fallot (ToF) and aortic stenosis (AoSt). Almost
half of the patients with ConHD fall into this category. Our ambition is to develop new methods for
better understanding, earlier recognition and improved treatment of the above mentioned problems. In
this research proposal we will continue with previously acquired knowledge in three existing ConHD
research consortia. With our research we will improve knowledge of heart rhythm disorders,
abnormalities of the coronary arteries, weakening of the large blood vessels and function loss of the
heart chambers. Within 5 years we want to know which control mechanisms are involved in early
development and later weakening of the wall of the large arteries. Factors will be tested that
strengthen the heart muscle cells and improve vascularization, and a method to apply them. We want
to understand better new anomalies of the coronary arteries late after surgery of TGA. We will have
created risk profiles for earlier recognition in the three largest groups (TGA, ToF, AoSt). New is that
we will use measures that link the function of the heart to the blood flow in the large vessels in our risk
profiles. The treatments that we will test also focus on effects of exercise on healthy aging with
ConHD. The results of our research will be made available in online information portals for patients,
parents and caregivers and doctors.
Overzicht landelijke thematische consortia – februari 2021RECONNEXT: Renal connection to microvascular disease and heart failure with preserved
ejection fraction: the next phase
Research leaders Prof. dr. D. Duncker: d.duncker@erasmusmc.nl
Prof. dr. M. Verhaar: m.c.verhaar@umcutrecht.nl
Heart failure (HF) is a major health care problem with high mortality. Although significant advances
have been made in the treatment of HF patients with reduced ejection fraction (EF), this is not true for
HF patients with preserved EF (HFpEF). In 2015 we initiated a consortium focusing on the renal
connection to microvascular disease and HFpEF (RECONNECT). In the past 5 years, RECONNECT
has demonstrated that impaired kidney function is a strong risk factor for mortality in HFpEF, and has
generated two HFpEF diagnostic prediction rules for use in general practice. Moreover, RECONNECT
has yielded novel insights into the mechanisms by which chronic kidney disease (CKD) and its
systemic consequences, through an effect on the microcirculation, contribute to HFpEF. Our dedicated
in-vitro and animal models and patient-cohorts yielded convincing data supporting our hypothesis that
inflammation and the consequent coronary microvascular dysfunction play a central role in the
pathogenesis of CKD-associated HFpEF. Thus, our consortium identified several potential targets for
therapy, including markers of inflammation (TNFα, IL6), reactive oxygen species (OPLAH),
microvascular dysfunction (reduced NO-bioavailability, SGLT2, H2S/STS), fibrosis (TGF-β signaling:
GDF-15, Activin A), mitochondrial dysfunction (trimetazidine, iron) and cardiomyocyte myofilament
dysfunction (heat shock protein activation: GGA). In addition, we established a strong translational
pipeline to discover novel targets and bring these to clinical testing via preclinical models.
In RECONNEXT we will use and expand this pipeline to (pre)clinically investigate targets identified
during RECONNECT as well as novel targets. In addition, we continue to explore in-depth the
molecular mechanisms linking CKD to HFpEF. By combining epidemiology with mechanistic ex- and
in-vivo studies, we will evaluate renal drivers of HFpEF and elucidate the mechanisms that contribute
to microvascular dysfunction and inflammatory-microvascular-cardiomyocyte crosstalk. We use state-
of-the-art techniques, including functionomics, metabolomics, proteomics, single nucleus sequencing,
and epigenetics. Following a stratified approach, RECONNEXT will investigate novel drug targets of
HFpEF in our unique CKD-HFpEF models. We will perform targeted clinical interventions in focused,
well-phenotyped patient-groups. RECONNEXT will enhance our mechanistic insight in the renal
drivers of HFpEF and provide a basis for future large-scale intervention trials, ultimately allowing new
prognostic and therapeutic solutions for HFpEF patients.
Overzicht landelijke thematische consortia – februari 2021Cardiovascular Moonshot of RegMed XB: Regeneration of the human heart.
Research leaders Prof. dr. P Doevendans. p.doevendans@umcutrecht.nl
Prof. dr. M.J. Goumans: m.j.goumans@lumc.nl
Prof. dr.C. Bouten: c.v.c.bouten@tue.nl
Dr. B. Mees: barend.mees@mumc.nl
The cardiovascular moonshot of RegMed XB is a comprehensive program based on the concept that
we should be able to create a cardiac (re-)generative therapy that suits best the individual patient. One
approach is to restore the heart function outside of the body (ex vivo). The advantage of this method is
that we can solely treat the heart and assess cardiac function during treatment. During the time the
heart is outside the body, the body will be connected to a heart-lung machine. After restoring the
heart, it will be re-implanted. With this approach, gene therapy to cure hereditary diseases will also
become possible. The researchers aim to stimulate the body’s own regenerative capacity including, for
example, improving the contractility and perfusion of the heart muscle, repair or replacement of
coronary arteries and heart valves.
The cardiovascular moonshot is divided in different steps, also called milestones. They are called
milestone since they are major progress points on of which achievements areneeded for the
moonshot. The first milestone focuses on keeping a beating heart healthy and functioning for up to 7
days in a bioreactor outside of the body. During this time, the heart can be repaired. The main goal is
to restore the damaged heart using regenerative medicine solutions. This can vary from restoring for
instance the muscular function to dealing with atherosclerotic damage.
RegMed XB partners are working together to create new solutions for multiple cardiovascular
diseases. The ultimate goal and the in-between steps can create therapies for many patients with
different cardiovascular conditions, such as coronary artery disease and untreatable arrhythmias.
Overzicht landelijke thematische consortia – februari 2021Contrast: Collaboration for New Treatments of Acute Stroke.
Research leaders Prof. dr. D. Dippel. d.dippel@erasmusmc.nl
Prof. dr. C. Majoie: c.b.majoie@amsterdamumc.nl
In MR CLEAN we have recently shown that intra-arterial therapy (IAT) with the use of a retrievable
stent improves outcome in selected patients with acute ischemic stroke (AIS) and a proximal
intracranial artery occlusion. This benefit has been confirmed in four other trials. Still, major challenges
in the treatment of acute stroke remain. First, still two thirds of the patients treated with IAT in MR
CLEAN were dead or dependent at 3 months. Secondly, only 10% of patients with AIS are eligible for
IAT to date. And thirdly, about 15% of all strokes are intracerebral hemorrhages (ICH), for which
treatment options are very limited.
CONTRAST aims 1. To achieve faster optimal stroke treatment for more patients; 2. To develop and
test new treatments for a broad population of patients with ischemic stroke or ICH; and 3. To broaden
the indication for IAT and increase its benefits.
These aims will be reached through joined efforts of basic and clinical scientists. We will perform five
large acute stroke trials to test novel treatment strategies, including 1. pre-hospital augmentation of
collateral blood flow and blood pressure reduction; 2. antithrombotics to prevent microvascular
occlusion after IAT; 3. immediate IAT without preceding thrombolysis; 4. IAT in the 6 to 12 hour time
window; and 5. microsurgical hematoma evacuation and dexamethasone in patients with ICH. We will
1. aim to identify patients who will benefit from these interventions through advanced imaging; and 2.
we will develop novel stroke treatments with animal models, in combination with data from our clinical
biobank, which stores blood, plasma and thrombi; and 3. apply discrete event modelling (DES) with
data from the trials, to optimize stroke care.
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