Cardiovascular research

Principal Investigators: Prof. DJGM Duncker, Dr. D Merkus

Ischemic heart disease, in particular myocardial infarction, and hypertension are major causes of heart failure in western countries. Following myocardial infarction or chronic exposure to pressure-overload, the heart undergoes extensive alterations in muscle mass and geometry. This cardiac remodeling is associated with an increased likelihood of progression towards overt heart failure, particularly in the setting of an ageing population.

Research within Project Group 1 is aimed at improving our understanding of the mechanisms underlying the progression from ischemic heart disease towards heart failure in order to identify novel targets for therapy. For this purpose, our research focuses on the pathogenesis and therapy of (i) myocardial infarction as a result of ischemia-reperfusion damage, (ii) the cardiac remodeling that follows in the days-weeks after myocardial infarction, including infarct expansion and cardiac hypertrophy and dysfunction, (iii) myocardial perfusion abnormalities in post-infarct remodeled and pressure-overload hypertrophied myocardium, (iiii) pulmonary hypertension secondary to the left ventricular dysfunction produced by myocardial infarction or systemic pressure overload. Furthermore, we study (v) the effects of aging and exercise training on cardiac remodeling and dysfunction following myocardial infarction and chronic pressure overload and (vi) the influence of age on the cardiac responses to hemodynamic overload.

Principal Investigators: Dr. HMM van Beusekom, Prof. DJGM Duncker, Dr. ES Regar

In this project our focus is to study vascular wound healing with a focus on:

• the vascular response to coronary (PCI) and peripheral vascular interventions and
• treatment strategies and sequellae following experimental “ischemia and reperfusion”.

PCI studies are performed in different species as well as in disease models. We have found that these play an important role as they significantly affect the response to vascular injury and repair in both coronary and peripheral arteries. We employ simple models such as direct stenting and balloon angioplasty (injury) prior to PCI in healthy young animals, but also more complex models such as diet and Diabetes Mellitus induced or accelerated atherosclerosis. Different imaging modalities (invasive by e.g. OCT, NIRS, IVUS, and non-invasive by CT or MRI) allow us to characterize the baseline environment and to study the vascular response to drug eluting stents and scaffolds in a longitudinal setting. In these models we study the pharmacodynamics and polymer degradation behavior using drug eluting stents and biodegradable scaffolds in different vascular environments in health and disease.

Ischemia-reperfusion studies, both acute and chronic, are geared towards novel vascular (adjunctive) therapies for acute myocardial infarction. By means of invasive and non-invasive imaging and histology, we routinely characterize LV-function, and the composition and geometry of the infarct and no-reflow zones. We can successfully achieve therapy by means of local drug delivery and post-conditioning strategies. For the longitudinal studies we have set-up an early and sensitive assay for the determination of baseline infarct size and no reflow upon reperfusion. In addition and in collaboration with the clinical catheterization laboratory we are building a biobank of coronary thrombus aspirates (CorTAsk) to aid in understanding no-reflow in the clinical setting.

Principal Investigators: Prof. J Bakker, Dr. J van Bommel, Dr. DAMPJ Gommers, Prof ABJ Groeneveld, Prof. C Ince, Dr. EJO Kompanje.

Critical illness often results in multiple organ failure. Sepsis is a common source and the syndrome affects the circulation and ventilation among other vital organ functions. The research around this typical intense care syndrome is thus programmed around these topics, as can be deducted from the individual projects enumerated below. Research on the circulation in the syndrome focuses on peripheral perfusion, among others. New techniques, like side stream dark field (SDF), laser speckle imaging and near-infrared spectroscopy (NIRS) have been studied for assessing microvascular perfusion in septic patients. In order to minimize inflammatory response in mechanically ventilated septic patients, a new lung monitoring device (Electrical Impedance Tomography) is used to optimize ventilator settings. Ultimately, the syndrome can be intractable, raising ethical issues on end-of life decisions.

Principal Investigator: Dr. JJ Wentzel

Shear stress plays an important role in the pathobiology of the endothelium. Among others, it primes the endothelium for atherosclerotic plaque formation, which can be found at the low and oscillatory shear stress regions in the vasculature. However, evidence is accumulating for a role of high shear stress in plaque destabilization. This project focuses on the different (molecular) aspects of the role of low or high shear stress in the generation and destabilization of vulnerable plaques. For that reason studies are performed in an established animal model of vulnerable plaque formation as well as in patients that are treated for pathological lumen obstruction. For those studies a combination of computational fluid dynamics and advanced catheter based or non-invasive imaging techniques for the assessment of plaque composition is applied. Using the information from the before described studies, we investigate whether shear stress can contribute to prediction models of atherosclerotic plaque growth and events in a population based study.

Principal Investigators: Dr. FJH Gijsen, Dr. JJ Wentzel

Plaque rupture is in the majority of the cases the underlying cause of cardiovascular events. Plaque rupture occurs at the locations were the stress exceeds the local plaque strength. Plaques are very heterogeneous in composition and local tissue strength. However, not much is known on the biomechanical properties of the different plaque components.

In this project we investigate at which pressure and at what location the plaque would rupture by studying the local stress distribution and deformation of the different plaque components under increasing loading. Therefore, in an in vitro setup atherosclerotic plaques from patients or animal models of atherosclerosis are subjected to different pressure loadings and the local deformations are imaged using advanced imaging techniques.

This information will be used to validate computations on stress distributions in these plaques. Advances will be made in imaging of plaque deformation and (multiscale) modelling of the different plaque components.

Principal Investigators: Prof. AHJ Danser, Dr. J Essers, Dr. EJ Hoorn, Dr. AH van den Meiracker, Dr. AJM Roks, Prof. R Zietse

This project focuses on hypertension, capitalizing on four pathways to discover novel intervention pathways, namely:

• the role of aldosterone in difficult-to-treat hypertensive subjects,
• hypertension induced by angiogenesis inhibition in patients with cancer,
• the impact of genomic instability on hypertension, and vascular and renal function, and
• the regulation of volume and osmoregulation in kidneys by WNKs and exosomes

An important unifying aspect in all the above topics, apart from the common relationship with hypertension, is the involvement of the renin-angiotensin-aldosterone system (RAAS), resulting in projects that investigate angiotensin/aldosterone interaction in the kidney, the role prorenin in diabetes, the function of the (pro)renin receptor in intercalated cells, the vasodilator effects of endothelial angiotensin II type 2 receptors, the angiotensin-(1-7) / Mas receptor axis, the non-genomic effects of aldosterone in the vessel wall, and the role of RAAS and related interventions on genomic instability-related vascular and renal dysfunction. The studies concerning genomic instability involves transgenic mice with decreased DNA repair function, and are performed in close collaboration with the Dept. of Genetics and of Vascular Surgery.

Principal Investigator: Dr. A Maassen van den Brink

Migraine is a paroxysmal neurovascular disorder, which is 2-3 time more prevalent in women than in men. Currently available drugs for the acute treatment of migraine all constrict cranial blood vessels, which most likely mediates their therapeutic action. However, since these drugs may also constrict peripheral blood vessels, including the coronary artery, there is a concern about cardiac side effects and these drugs are thus contraindicated in patients with cardiovascular disease. We are investigating the neurovascular properties of prospective antimigraine drugs that may act via a primary neuronal mechanism.

This could result in a reduced coronary side-effect potential of these prospective drugs. Further, since migraine occurs more often in women and depends on hormonal fluctuations such as occurring around the menstruation, we investigate the effects of (changing levels of) female sex hormones on mechanisms implied in the pathophysiology of migraine.

Principal Investigators: Dr. KM Akkerhuis, Prof. H Boersma, Dr. K. Nieman.

Current research addresses the detection and management of heart failure and cardiogenic shock in patients with Acute Coronary Syndromes (myocardial infarction). In particular it is investigated whether impaired microcrculation in patients with acute heart failure or shock can be improved by specific interventions, and whether such interventions improve prognosis of these patients. Furthermore the implications are investigated of cardiomyopathies, in particular non-compaction cardiomyopathy.

Principal Investigator: Dr. FUS Mattace Raso

The study of the structural and functional age-related vascular changes represents a good model to unravel the complex process of senescence. We investigate mainly three items:

• The environmental and genetic determinants of vascular aging
• The consequences of vascular aging on short and long term blood pressure regulation
• The consequence of vascular aging on morbidity and mortality and its possible role in cardiovascular risk stratification

These investigations are performed within several settings, in the general population but also in specific categories of patients including persons with end stage renal disease and with a history of syncope and patients’ first signs and symptoms of dementia.

Principal Investigators: Prof. EJG Sijbrands, Prof. F Zijlstra

At the Erasmus outpatient clinic for cardiovascular genetics, family based approaches are employed to study inherited cardiovascular diseases: cardiomyopathies, congenital heart malformations, arrhythmias, dyslipidemias, diabetes mellitus, hypertension and severe premature coronary artery disease. Technical innovation is a hall mark of this research: for example, novel imaging modalities are used to identify new phenotypes and high-throughput molecular analyses are performed to identify modifier genes in addition to major locus effects.

We have identified a large number of novel genes that are associated with cardiovascular disease and related traits. We perform molecular and biochemical studies to get a better understanding of the mechanisms underlying the diseases and the complications.Our clinical research is performed in patients with very rare diseases, like β-myosin heavy chain defects in noncompaction cardiomyopathy, but also more common disorders of synthesis and processing of insulin in families with type 2 diabetes.

Principal Investigators: Prof. DWJ Dippel, Prof. PJ Koudstaal

Stroke is a heterogeneous disease, it comprises ischemic stroke, intracerebral hemorrhage and subarachnoid hemorrhage. Stroke is a high ranking cause of death and the most common cause of acquired disability in The Netherlands and Western Europe. Causes of disability include motor function and disturbances of language, memory and cognition.

Etiologic studies include genetics (Metabochip), hemostasis (von Willebrand factor, fibrinogen), glucose metabolism, cardioembolic disorders (SURTAVI), and carotid plaque morphology (PARISK).

Intervention studies include a series of multicenter RCT’s of the effect of prevention of high body temperature and fever (PAIS). Also, we conduct a large national multicenter study of the effect of intra-arterial treatment for acute ischemic stroke (MR CLEAN). Moreover, we evaluate early cognitive linguistic treatment of aphasia in a series of multicenter RCT’s (RATS).

Prognostic studies include prediction of outcome after stroke, recurrent vascular events and vascular cognitive impairment, and functional imaging (FIAT) and outcome (SPEAK) of aphasia caused by stroke in large patient-cohorts.

Data for genetic, prognostic and etiologic studies are derived from the Erasmus Stroke Study, an ongoing hospital based registry, and from the Rotterdam study, a large population based cohort study.

Principal Investigators: Prof. FWG Leebeek, Dr. MJHA Kruip

Clinical studies on bleeding disorders, including von Willebrand disease (VWD) and hemophilia, are currently performed within this theme. The Willebrand in the Netherlands (WiN) study is a nation-wide study coordinated by the Erasmus MC on the clinical aspects of von Willebrand disease. In this study over 800 patients with moderate and severe VWD have been included and currently a prospective WiN-PRO study has started. The aim of the study is to investigate the impact of the disease on quality of life and obtain more insight in diagnosis, genetic background, bleeding symptoms and disease burden. In addition we personalize treatment of bleeding disorders, using pharmacokinetic based-dosing and studying innovative treatments like gene therapy. The etiology, diagnosis and treatment of various clinical entities of venous thrombosis are also focus of our research, with special interest in thrombotic complications in patients with COVID-19 or post-coronavaccination. In collaboration with other partners we have initiated studies on prevention and treatment of arterial and venous thrombosis using different oral anticoagulant drugs, including direct factor IIa and Xa inhibitors and vitamin K antagonists. The overall aim is to optimize treatment with anticoagulants and prevent complications in different patients groups, such as patient with heart valve replacement, patients with a limited life expectancy or young aduls.

Principal Investigators: Prof. FWG Leebeek, Prof. MPM de Maat

The studies performed in this theme are focusing on the role of coagulation factors and platelets in the development of arterial thrombosis. Several case-control studies have been initiated to investigate whether hemostatic or inflammatory factors determine the risk of first and recurrent arterial thrombotic events, including stroke and acute coronary syndrome. Our special interest is on von Willebrand factor, fibrinogen and fibrinolysis. Several genetic approaches are used, including GWA, SNP and haplotype analysis. We have obtained more insight in the mechanism of fibrin formation and fibrinolysis by identifying new proteins binding to fibrin using plasma proteomics techniques. The effect of fibrin structure on the risk of thrombosis and the relationship with atherosclerosis and angiogenesis, is studied using high resolution imaging techniques.

Principal Investigators: Dr. R Bierings. Prof. FWG Leebeek

In this research theme we study secretory mechanisms in platelets and endothelial cells in the context of bleeding disorders such as Von Willebrand Disease (WVD) and inherited platelet function disorders. Specific focus is on how secretory organelles such as Weibel-Palade bodies (WPBs) in endothelial cells or alpha- and dense granules in platelets are formed and released and how defects in these systems can lead to clinical bleeding problems. We use molecular and cellular approaches such as RNAi silencing, CRISPR/Cas9 gene editing, proteomics and advanced imaging including super resolution microscopy to identify new components of the platelet and endothelial secretory machinery. We also conduct our studies in patient-derived cellular model systems, such as platelets and blood outgrowth endothelial cells (BOECs) that are isolated from several cohorts of patients with bleeding abnormalities such as the Willebrand in the Netherlands (WiN) study and from patients with genetic defects in components of the secretory machinery. Patient BOECs are also used to develop new gene therapy solutions for VWD, such as CRISPR gene correction.

Principal Investigator: Prof. N. de Jong

Ultrasound contrast agents (UCA) consist of gas microbubbles (1-10 µm) that are coated by a protein, lipid or polymer. In addition to their diagnostic value, microbubbles have great potential as local drug delivery systems. In project 16 we investigate the clinical and the more fundamental/ future use of UCA.

The clinical use includes the left ventricle opacification and myocardial perfusion during normal and stress echocardiography. Further, a clinical study (ParisK) is running to detect the presence and properties of atherosclerotic plaques in the carotid artery after administration of UCA.

Future use of UCA lies in molecular ultrasonic imaging uses tiny microbubbles that bind to cellular disease processes. These microbubbles can be functionalized using specific ligands and injected into the human body. Upon excitation by an appropriate ultrasonic field the microbubbles start to vibrate thereby acting as an ultrasound source. This source shows a very specific signature which differs to a great extend from the scattering by normal/pathological tissue. For therapy the bubble can be either loaded with the drug of choice where the drug can be locally released upon ultrasound and/or the vibrating bubble is used to enhance the uptake of the drug. Essential in this whole process is the knowledge of the vibrating bubble, the ultrasound field and the imaging capabilities of the ultrasound system.

Principal Investigators: Dr. JG Bosch, Prof. N. de Jong, Prof. AFW van der Steen

Research focuses on novel ultrasound transducers and image processing for ultrasound, with a strong accent on novel 3D cardiovascular imaging. This includes matrix transducers, electronics and new beamforming for 2D and 3D imaging of the heart, the carotid artery, the bladder etc. Moreover, image processing approaches for 3D image generation, 2D and 3D image analysis and quantification by segmentation, tracking and classification are pursued. Advanced geometric and statistical modelling is employed. Current applications include improved realtime 3D TEE imaging, 3D echocardiography analysis, stress echo, analysis of plaque vulnerability in carotid arteries, and monitoring of electrophysiological interventions with 3D ultrasound.

Principal Investigator: Prof. AFW van der Steen

Intravascular imaging is momentarily highly focusing on characterizing the composition of the atherosclerotic plaque. Charactering lipid content, plaque vascularization and thickness of thin caps are of particular interest. These characteristics discriminate a stable plaque from a rupture prone or vulnerable plaque. The latter one can cause myocardial infarctions or stroke. Plaque vascularization is measured by intravascular ultrasound in combination with ultrasound contrast agents. Several strategies are developed to characterize lipid content. These are based on optical coherence tomography or combination catheters where light and sounds are combined.

Principal Investigator: PW Serruys

The decision making process for patients with obstructive coronary artery disease requiring revascularization is evolving. Historically, patients with the most complex coronary artery disease were preferentially treated by surgical revascularization: however technological advances in percutaneous therapy have ensured that many of these patients can now receive equally effective treatment with percutaneous coronary intervention (PCI). Intertwined with these developments are a lower threshold to investigate patients with symptoms suggestive of coronary artery disease, an increasingly elderly population in need of revascularization, the changing dynamics of the doctor-patient relationship, and a greater emphasis on guideline driven patient care. Consequently decisions regarding revascularization are now more complex than ever before.

The advent of drug eluting stents (DES), which consist of a drug (immunosuppressive or antiproliferative drug), a polymer and a metallic platform, has revolutionized the practice of interventional cardiology by significantly reducing the rates of restenosis and repeat revascularization as compared to bare metal stents. Within this project, this subject is studied in detail while taking into account evolvement in stent development, as well as secular trends in acute and chronic benefits of percutanuous coronary interventions.

Principal Investigators: Dr. Ricardo Budde; Dr. Alexander Hirsch

The cardiac CT and MRI group is a joint initiative by the departments of cardiology and radiology and collaborates with several (pre)-clinical departments within the Erasmus MC.
Research activities involving CT include assessment of several technological innovations and new clinical applications, i.e. various scan protocols to reduce radiation exposure, dynamic assessment of prosthetic heart valves, CT-FFR and stress myocardial perfusion imaging to assess the hemodynamic significance of obstructive coronary disease.

Ongoing investigation into the implementation of cardiac CT in clinical practice includes the use of cardiac CT in patients with a suspicion of endocarditis, patients with stable angina (fast-track chest pain clinic), to exclude coronary disease in patients with congestive heart failure and after heart transplantation, as well as a tool for triage of acute chest pain in the emergency ward. Also the potential role of (cardiac) CT in planning minimally invasive heart valve implantations, assessment of the thoracic aorta and predicting the effect of coronary stenting is being investigated.

Cardiovascular Magnetic Resonance Imaging (CMR) has become an important imaging technique for patients with a wide variety of heart disease. Beside anatomy, quantification of function, and assessment of cardiac fibrosis, there are major breakthroughs in the last decade including flow quantification with 4D flow and tissue characterization using T1-, T2-mapping and assessment of the extracellular volume. Research activities involving CMR include several studies with non-ischemic cardiomyopathies. For example, the role of 4D flow and strain analysis in hypertrophic cardiomyopathy is studied and also the role of CMR in non-compaction cardiomyopathy is a topic of investigation. Furthermore, CMR is used in a study looking at the late cardiac toxicity of chemotherapy and radiation in patients with Hodgkin lymphoma.

Erasmus MC is an expert center for treatment of congenital heart disease and imaging is an important topic of investigation. CMR including 4D flow is used in a large study with bicuspid valve and Turner patients and also in patients with Tetralogy of Fallot and Fontan. Finally we started with exercise CMR looking at cardiac reserve during physical exercise with CMR.

Principal Investigator: Dr. ML Geleijnse

Echocardiography is the most important diagnostic tool in cardiology. Recent advances in ultrasound hardware and software have made 3-dimensional echocardiography and speckle tracking echocardiography possible. These techniques are used for estimation of left ventricular pump function according to the classically defined volumes and ejections fraction but also deformation and rotation.

Newer developments are:

• 3D trans-oesophageal echo,
• Imaging of the vasa vasorum and
• Plane-wave imaging.

Principal Investigator: Prof. A. van der Lugt (a.vanderlugt@erasmusmc.nl)

Ischemic cerebral infarcts are related to the presence of atherosclerotic disease in the carotid artery. Severity of the stenosis is a predictor of clinical symptoms and is used as parameter in the therapeutic decision as to which patients will benefit from carotid intervention. Next to stenosis severity, plaque morphology is thought to be a major determinant of cerebrovascular events.

Within this project, imaging of the atherosclerotic plaque in the carotid bifuction with multidetector CT and MRI is evaluated.

We focus on 1) The validation of imaging parameters by comparison of images with histology, 2) Development of new structural and haemodynamic parameters atherosclerortid disease, 3) Development and validation of automated measurements, 4) Prospective studies in patients and healthy volunteers to prove the additional value of plaque parameters in risk prediction, 5) Serial imaging studies to evaluate the natural course of the atherosclerotric disease, 6) Studies into the relationship between atherosclerotic plaque parameters and brain infarcts and white matter lesions on CT and MRI.

Principal Investigator: Prof. WJ Niessen (w.niessen@erasmusmc.nl)

In the management of disease, advances in imaging devices have drastically increased our capabilities to (non-invasively) study both anatomy and function. With these advances, the sheer size, complexity, and heterogeneity of imaging data available for biomedical research and clinical practice have increased enormously. To fully utilize the wealth of information available in imaging data, techniques for automated analysis and interpretation are required. In this subtheme, quantitative image analysis techniques are developed and applied to improve diagnosis, therapy planning and therapy monitoring. Application areas include cardiovascular disease, neurodegenerative diseases and oncology. In the cardiovascular domain, we e.g. quantify atherosclerotic disease from non-invasive imaging techniques, for improved diagnosis and prognosis. In the neurodegenerative domain, we perform large scale analysis of neuro imaging data, both from population imaging studies and clinical studies, to improve early detection, differential diagnosis, and prognosis of neurodegenerative disease. In oncology, we aim to improve treatment planning and predict and monitor treatment success.

Principal Investigator: Dr. J Essers

In the basic research line ‘Molecular biology of aneurysm formation‘ of the Laboratory for Experimental Vascular Surgery (LEVAS), the molecular processes that underlie aneurysm formation are investigated through close collaboration between the department of Genetics & Cell Biology and the department of Vascular Surgery. The goal of this translational research line is to decrease aneurysm related mortality and reduce the need for surgical intervention. Consequently, we focus on two research areas: 1) early detection of degenerative changes in the aortic wall, and 2) pharmacological intervention to treat aortic wall degeneration. To this end we make use of the scientific expertise and state-of-the-art infrastructure of our research institute as well as the practical implications, anonymous patient data and bio-bank of the clinical research group. This intensive collaboration ensures innovative basic research based on clear clinical relevance. This research line is embedded in the Erasmus MC research schools Medical Genetics Centre South-West Netherlands (MGC) and COEUR in collaboration with among others the departments of pharmacology, cardiology, clinical genetics, bioinformatics and biochemistry.

Principal Investigator: Prof. HJM Verhagen

Aortic pathology like aneurysms, dissections and traumatic ruptures were traditionally treated by open repair. In the last decade, endovascular technology became available as a minimally invasive alternative. Like with all other new and innovative treatment modalities, results, especially long-term, are unknown and it remains unclear whether this minimal invasive treatment is beneficial for all patients or only for the ones declared “unfit for surgery”. Furthermore, many uncertainties remain on the best indications for stentgraft placement: is it only advisable for aneurysmal disease or should it be used for all aortic pathology known to eventually lead to life-threatening dilatation of the aorta. If so, in what stage of the disease should it be used: as treatment or as prevention? Can it be seen as definitive treatment or will it turn out to be just a “bridge to surgery”? Within this project, many sides of this new treatment are being investigated.

Principal Investigator: Prof. AJJC Bogers

Technological developments in lung/thoracic surgery in the direction of video-assisted surgery as well as improvements in peri-operative care are actual issues, resulting in concentration in larger centres. Larger series and better quality of care are the result and form a sound basis for further clinical research and cooperation at international level. A multidisciplinary approach is the key to this goal. This also holds for lung transplantation for which also preclinical studies on organ preservation are undertaken. This project aims at outcome research with emphasis on clinical decision making.

Principal Investigators: Prof. PPT de Jaegere, Prof. PW Serruys

Catheter-based treatment of structural heart disease is a recent but rapidly evolving treatment modality. At present it is primarily reserved for patients with aortic stenosis who are considered poor candidate for surgical valve replacement. As a result of ongoing research and innovations in catheter technology, bioprosthestetic materials (scaffolding frame and tissue), imaging (3-4D, co-registration) in addition to operator experience, it is expected that catheter-based treatment will also be available for other forms of structural heart disease such as mitral – and aortic regurgitation, left ventricular systolic dysfunction in addition to the application of these techniques in patients who are candidate for surgical treatment.

Research in this domain will encompass 1] clinical cohort research examining the safety and efficacy, the evaluation of responder and non-responder by the definition of determinants of (clinical and technical) outcome by means of single- and multicenter collaborative efforts, 2] pathofysiologic assessment of the effects of treatment on the morphology, function and haemodynamics of various cardiac components (myocardium, valves, ascending aorta) in collaboration with the department of radiology and experimental cardiology, 3] randomised clinical comparison between catheter-based and surgical treatment of structural heart disease, 4] advanced imaging allowing 3 and eventually 4 D co-registration of the anatomy during treatment (collaboration with experimental cardiology, radiology and industry).

Focus areas: pediatric/adult patients with congenital heart disease and/or heart failure

Principal Investigator: Prof. Dr. Natasja M.S. de Groot* (n.m.s.degroot@erasmusmc.nl),

Departments involved:

• Department of Cardiology, Erasmus Medical Center
• Department of Cardiothoracic surgery, Erasmus Medical Center
• Department of microelectronics, Technical University Delft · Medical Delta Cardiac Arrhythmia Lab (https://www.medicaldelta.nl/onderzoek/medical-delta-cardiac-arrhythmia-lab)

Our research projects are aimed at 1) unravelling the pathophysiology of heart rhythm disorders 2) developing and 3) testing developing novel diagnostic tools (e.g. heart rhythm sensors, in close collaboration with TU Delft) and therapies (e.g. pharmacological therapies, neuromodulation, (catheter-based) device therapies) for cardiac arrhythmias in both experimental settings and daily clinical practice. In our department, there are on-going experimental, translational and clinical research projects. These research projects are multidisciplinary in nature and we closely collaborate with department of cardiothoracic surgery, pediatric cardiology and epidemiology.

Our patient studies are executed during cardiac surgery, electrophysiological procedures at our catheterization laboratory or the cardiology outpatient clinic. Main topics of our research include for example heart rhythm disorders in adult patients with congenital heart disease, electrical properties of the heart in pediatric patients with congenital heart disease, unravelling mechanisms of (post-operative) atrial fibrillation by visualizing and quantifying electrical properties of cardiac tissue, relating electrical function of in-vivo heart tissue with in-vitro cardiac tissue slices (in collaboration with cardiothoracic surgeon Dr. Y. Taverne, head lab of experimental cardiothoracic surgery), unravelling pathophysiology of heart rhythm disorders in patients with heart failure, staging of atrial fibrillation by bio-electrical fingerprinting and neuromodulation of heart rhythm disorders.

Heart rhythm disorders are associated with significant morbidity and mortality. Their prevalence will continue to rise and will persist to pose a major burden on society. Standard anti-arrhythmic drug therapy is often not effective in eliminating tachycardia episodes and ablative therapy is also not so successful, particularly in patients with atrial fibrillation. Heart rhythm disorders are the cardiovascular epidemic of the 21th century, due to ageing of our population and increased survival of other cardiovascular diseases which is complicated by development of various heart rhythm disorders. This necessitates research to develop preventive strategies, to improve existing treatment modalities and design novel therapies. The major reason for therapy failure is insufficient knowledge of the mechanism underlying heart rhythm disorders. In our projects, we record electrical signals directly from the surface of heart during either endovascular electrophysiological interventions or open-heart surgery. These signals are used to construct electrical ‘roadmaps’ to determine the severity of the electrical alterations. In this way, we investigate which parts of the heart are ‘electrically ill’ and could explain development of rhythm disorders. To investigate the electrical properties of the heart, we develop and test diagnostic instruments in our clinical studies. Electrical activation patterns or electrocardiogram features are correlated with clinical profiles, and blood- and tissue-based biomarkers. In addition, imaging techniques (ultrasound) are used to correlate cardiac structure with electrical alterations. In our pharmacological therapeutic studies, we test novel pharmacological drugs using bio-electrical fingerprints.

Principal Investigator: Prof. AJJC Bogers

Technological developments in surgery (and interventional cardiology as well) and peri-operative/peri-procedural care continue to evolve at a rapid pace. In particular, the field evidence with regard to the treatment of coronary artery disease and cardiac valvular disease is rapidly expanding. The search for hybrid approaches applying minimal invasive techniques continues. This is also relevant for the further development of robotic techniques. It was shown that a multidisciplinary approach delivers the best results, and collaboration between engineers, cardiologists, cardiothoracic and vascular surgeons and radiologists is the preferred and chosen route. This project aims at outcome research with emphasis on clinical decision making.

Principal Investigators: Prof. WA Helbing (w.a.helbing@erasmusmc.nl)

Treatment of congenital heart disease in early childhood has resulted in excellent survival in the pediatric age range. However, residual cardiac loading abnormalities and the effects of pre-treatment hypoxaemia may impair long term survival and quality of life. The project aims to identify early (bio)markers of suboptimal outcome following treatment in childhood and to develop new treatment modalities to improve outcome. Novel imaging methods and animal experiments are used for these purposes.

Principal Investigator: Prof. AJJC Bogers

Surgical management of congenital heart disease has improved significantly in the last decades, which has resulted in improved survival into adulthood. Thus the number of adult patients is growing. While the number of patients to be operated at young age is more or less constant, the number of patients needing an operation at adult age is increasing, both the number of primary operations as well as the number of reoperations due to residual cardiac abnormalities. In particular, abnormal loads are commonly imposed on the right ventricle or on single ventricular hearts. Residual abnormalities may cause heart failure, rhythm disturbances and may affect quality of life. Evidence-based l treatment is often lacking. Guidelines for timing of catheter intervention and surgical therapy also lack sufficient evidence. This project aims at outcome research with emphasis on assessment cardiac function in the right ventricle and in structurally abnormal hearts with conventional imaging techniques. An important part of this theme concerns these imaging techniques on one hand and improvement of clinical decision-making and therapy on the other.

Principal Investigators: Prof. RJ Stolker, Prof. H Verhagen

Cardiovascular disease is the major cause of postoperative morbidity and mortality. In Europe, 40.000.000 surgical procedures are performed every year, with a cardiovascular mortality rate of 0.3% (133.000 patients). To improve postoperative outcome, preoperative identification of patients at risk is performed using clinical risk scores, biomarkers for coronary artery disease and heart failure, and cardiac imaging. The preoperative risk assessment is linked to the intraoperative identification of acute coronary syndromes using electrocardiography and cardiac imaging as well as newly identified biomarkers. The follow-up of these patients is performed regularly, for early identification of cardiac events. The identification of a genetic predisposition in relation with biomarkers and subsequent treatment is the research line of this group.

Principal Investigators: Prof. AJJC Bogers, Prof. JJM Takkenberg

This project concerns risk modelling, decision making, innovative statistical analysis and health technology assessment of appropriate diagnostic and therapeutic measures in the area of cardio-thoracic interventions. One of the challenges for contemporary medicine is to apply evidence-based medicine and to rationally implement the available therapies in clinical practice, in the appropriate patients at the appropriate time.

Current research includes the application of longitudinal statistical models on serial data such as cardiac biomarkers and echocardiographic measurements over time for the purpose of outcome prediction, the optimization of individualized prognosis prediction through the development of novel risk models, shared decision making studies in prosthetic heart valve selection and NSCLC treatment selection, and cost-effectiveness studies of novel cardio-thoracic interventions. The results are applied in outcome research and should support clinical decision making.

Principal Investigator: Prof. H Boersma

In the past decades, significant improvement has been achieved in the management and outcome of patients with cardiovascular disease (CVD). Despite these developments, CVD still is a major cause of the loss of healthy years in The Netherlands: the annual number of fatal events is as high as 40,000. The burden of CVD is expected to increase in the decades ahead, and it is crucial to develop and improve CVD risk prediction instruments, and implement appropriate preventive and therapeutic measures. Traditionally, the assessment of CVD risk is based on global risk models. However, these models fall short, as they do not utilize contemporary knowledge on the pathophysiology of CVD. Project 36 Clinical epidemiology of cardiovascular diseases is designed to improve CVD risk assessment and risk reduction. Several concepts are currently studied: (multiple) CVD biomarkers, repeated biomarker assessment, cardiac imaging, dynamic risk modelling and simulation risk modelling.

Principal Investigator: Prof. JW Roos-Hesselink

In the Netherlands, 8 out of 1000 children are born with a congenital heart defect. Due to improved diagnostics, the introduction of the heart long machine and open heart surgery, more than 85% of these patients reach adulthood and nowadays there are 30.000 adults living in the Netherlands. Many of them have late complications, such as valvular dysfunction, arrhythmias or heart failure. In addition often surgical or catheter reintervention is necessary. Research in project 37 focuses on long-term outcome in these patients, both after surgical correction, interventional treatment or natural history. Special emphasis on psychological outcome, pregnancy and sports participation is important in this specific group of young adults. Also genetic research, imaging of the complex cardiac anatomy and biomarker studies are being conducted.