Cardiology, Cardiothoracic Surgery and Vascular Surgery

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Cardiology.

Description

The Cardiovascular Center Leiden (The departments of Cardiology, Cardiothoracic Surgery and Vascular Surgery) is responsible for the generation of new insights in complex cardiovascular diseases in favor of the development & implementation of new diagnostic and therapeutic modalities to further improve modern clinical care in a sustainable manner. The focus of the Center is to achieve these goals by working closely together with other professionals (national and international), insurance companies and patients. The central themes of the department are organized in care tracks with integrated research activities. By implementation of the principles of Bench to Bedside (B2B) it was possible to stimulate crossing border research activities both within the LUMC as with external partners. The Cardiovascular Center Leiden B2B program offers unique opportunities in the development of new research activities and this program also allows investigators easier access to other activities. The Cardiovascular Center Leiden B2B activities are concentrated around 5 themes: Arrhythmias, Atherosclerosis, Aneurysmatic diseases and Genetics, Congenital Heart Disease, Valvular disease, LV Dysfunction and Heart Failure.
This also implicates that the traditional organization in 4 different projects (20301, 20302,10600, and 10201) was rather artificial. Therefore in 2017 the different research activities were included in 1 project (20303) with different themes. This also reflects the fact that the performance is a real team effort and not the work of individuals and that all members of the staff work on many different projects. The integration of Cardiothoracic Surgery and Cardiology was already formalized one year ago. The next step will be to really include the department of Vascular Surgery within not only the research activities but also the clinical activities of the Cardiovascular Center Leiden.

Aim and Focus

This programme encompasses basic, clinical (both diagnostic and therapeutic) and genetic research in one of the designated themes.

Arrhythmias: within this theme (under supervision of Prof. Zeppenfeld) all clinical and basic research activities involving pathophysiology and treatment of atrial and ventricular arrhythmias are concentrated. For complex catheter ablation procedures several imaging modalities are integrated with 3-dimensional electrical mapping systems to pinpoint the anatomic structures and areas to be treated, and to improve the success of the intervention. Furthermore, many patients are treated during a surgical intervention. Especially noteworthy is the group of patients referred for LVAD implantation who simultaneously undergo an endocardial resection to prevent ventricular arrhythmias in the post LVAD implantation period.
Treatment of complex arrhythmias also involves therapy of children with serious rhythm disturbances (in cooperation with the Department of Paediatrics) and therapy of patients with genetically determined arrhythmias (in cooperation with the Department of Clinical Genetics). The quality of the program is also reflected by the number of international fellows trained in Leiden and the referral of patients from all over Europe.

Genetic factors implicated in the development of specialized conduction tissue in the heart are studied in the fetal chicken heart operated upon in ovo and in hearts of transgenic mice in collaboration with the Department of Anatomy and Embryology. Further mechanistic insights into these rhythm disturbances is derived by studies on cardiac biopsies from patients, thereby eventually providing a data set from molecule to man.

The basic science work within the laboratory of cardiology also involves the development of the so-called “Bio-ICD”: here biologists, physicians and mathematicians investigate how to enable the heart to correct arrhythmias itself by genetic modification of basic cellular electrophysiological characteristics, which is currently explored by means of optogenetics (supported by an European Research Council (ERC) starting grant). These efforts are expected to contribute to a sustainable and comprehensive improvement in the prospects of cardiac health through synthetic biomedicine.

Within this theme also the continuing evaluation of on device therapies is incorporated. Especially successful over the last decade was the research on resynchronization therapy with more than 200 publications and numerous PhD projects.
Determination of interventricular and intraventricular dyssynchrony of segmental contraction resulted in improvement of criteria for cardiac resynchronization therapy. New techniques to diagnose and quantify asynchronous contraction by speckle tracking strain analysis and evaluation of apical and basal rotation have extended the methodology to select patients for cardiac resynchronization therapy, as well as to assess the efficacy of this therapy. Research in this field will gradually shift towards patient centered health-care changes. In other words, the large-scale introduction of tele-monitoring and other E- health applications will focus (amongst others) on this group of patients.

Another important aspect is device therapy in the last phase of life: ethical aspects concerning deactivation of devices are evaluated with participation of patients and family members. Dr. van Erven wrote a national guideline on this subject.

Patients and their families at risk for cardiomyopathy and/or potentially life-threatening arrhythmias are systematically analysed and treated using standardized care tracks. Genetic counselling is provided in collaboration with the department of Genetics (Dr. Bootsma).

On a yearly basis around 15 PhD students are involved in the different research activities of the groups active in the field of arrhythmia research. With the opening (in 2019) of the new Cardiovascular Intervention Center (build next and connected to the basic science laboratory) it is expected that the link between clinical and basic research will only be strengthened. The future hybrid MR/cathlab (together with the Department of Radiology) will offer new exciting possibilities to improve substrate mapping and ablation of patients with complex arrhythmias.

Atherosclerosis, Aneurysmatic diseases, and Genetics: The work on the different aspects of atherosclerosis and the genetic basis of atherosclerosis remain of importance for the Cardiovascular Center Leiden. Many long-lasting and successful projects can be identified as the DIACARM (DIAbetes CArdiovascular Risk Management) project (involving diabetic patients who are asymptomatic for cardiovascular disease are tested thoroughly for cardiovascular risk factors (in collaboration with the Department of Endocrinology and the Department of Nephrology)), the participation in the NEO study, the GENIUS study and the ENERGIZE study. A significant number of projects is supported by the European FrameWork 7 (WP7-Health) or CVON (Dutch Heart Foundation). It is within the field of coronary atherosclerosis, in particular lipid metabolism, vascular biology, molecular plaque imaging, and novel therapeutic interventions are incorporated. To this purpose, the collaboration in the working group Leiden Vascular Medicine (LVM) and Center for Medical Systems Biology (CMSB) aims to apply innovative multidisciplinary genomics and bioinformatics to improve diagnosis, therapy and prevention of common and rare diseases. There exists a close collaboration with other partners within the Einthoven laboratory for Experimental Vascular Medicine and the Vascular and Regenerative Medicine Profile area. The focus of this research program is directed at new aspects of cell therapy and the possibilities for modulating the inflammatory and immune responses involved in regulating vascular remodeling. In recent years in particular the role of microRNAs and noncoding RNAs in vascular remodelling have gained our interest. In this respect we have established a substantial role for the non-coding RNAs of the 14q32 gene cluster in regulating various aspects of vascular remodeling. In the area of vascular remodeling in atherosclerosis and restenosis the role of inflammatory driven vascular remodeling is being investigated in research projects that are directed at vein graft disease and plaque rupture (CTTM circulating cells, CVON Genius, Moglynet EU Marie Curie H2020 Eur Joint Doctorate program, Dr Dekker Senior PostDoc NHS).

Risk stratification with the use of non-invasive imaging of coronary artery disease is another important focus in this program, aiming at integration of intravascular echocardiography, nuclear cardiology, magnetic resonance imaging (MRI), and multi-slice computer tomography (CT) in collaboration with the Department of Radiology. Important in this programme is the future routing of patients with low, intermediate, high and very high risk of cardiovascular complications.

The first of the MISSION! Programmes (Clinical Care tracks) was devoted to patients admitted with acute myocardial infarction. This guideline implementation programme includes pre-hospital, in-hospital and post-clinical phases, involving all different health care providers in the Leiden area. Family physicians and ambulance personnel have been instructed to diagnose and transport the patient suffering from acute myocardial infarction according to guideline protocols, followed by primary percutaneous coronary intervention in the cathlab. The MISSION! Programme is very successful and is now implemented in more regions in the Netherlands. Part of the MISSION! Programme includes the evaluation of long-term outcome parameters  in a number of regions in the Netherlands. The MISSION! STEMI programme resulted in numerous papers and a significant number of finished PhD project.

The recently started Benefit (a €2.5 million externally financed project) program focus on stimulating patients in life style changes by rewarding them instead of punishing them will be a game changing program in the way we achieve goals in life style adjustments together with our patients! Within this programme (together with the Department of Clinical Psychology) the activities with the city of Leiden will be included.

Within this research theme also the different activities of the cardiothoracic surgery department focusing on improved outcome of patients after surgery are included. New techniques of extra corporal circulation and ways to limit the inflammatory response are investigated in cooperation with (amongst others) the department of Intensive Care. Outcome research on total arterial revascularisation is resulting in several publications the coming years.

The treatment and underlying mechanisms of aortic pathophysiology (including atherosclerotic disease and genetic disorders (Marfan’s disease) are important projects part of this research theme. In close collaboration with many departments within the LUMC progress is made on both diagnostic and treatment options for patients with aortic disease. As vascular surgeons, cardiothoracic surgeons and cardiologists (together with interventional radiologist) are already working together on this  subject it is a logical next step to fuse the different research groups into one program. The research line “Pathogenesis and Treatment of Aneurysms” has a strong position with regard to the molecular basis of aneurysm growth and rupture, and on the best medical practices with regard to the treatment of the disease. The department has initiated and is involved in national and international multicenter RCTs on pharmacological stabilization or inhibition of the inflammatory processes during aneurysm development in the abdominal aorta (PHAST trial, AORTA trial, TEDY trial) Preclinical studies are performed in close collaboration with TNO-life sciences, the department of Molecular Medicine, Karolinska Institute, Stockholm, the James Cook University, Australia, and Ludwig-Maximillian’s University, Munich, Germany. The translational focus on inflammation and proteases is shifting towards the role of impaired repair (fibrosis) in perpetuating the disease. In close collaboration with the Departments of Vascular Surgery of the AMC and the VUMC a biobank of human aortic material is developed upon the already existing biobank of human donor aortic (in collaboration with the Department of Transplant Surgery) and coronary atherosclerotic tissue.

Patients with drug-refractory angina pectoris receive “cell” therapy to relieve angina and improve left ventricular function using autologous bone marrow-derived mononucleated cells, including mesenchymal stem cells (MSCs). These cells are injected into myocardial areas by trans arterial catheter in cooperation with the Department of Haematology. These studies have shown that cell therapy is safe, does not cause arrhythmias, contributes to relief of angina, reduces the number of segments with stress-induced ischemia, improves myocardial perfusion, and increases left ventricular diastolic and systolic function. The program is successful and currently the largest group of patients worldwide have been treated in the LUMC. The current cell therapy program is not offering the final solution only the beginning of a new era. Within the coming years new cell types have to be identified to improve the outcome of the treatment.

A CVON project on bicuspid aortopathy plays a central role in surgical decision making for patients with bicuspid valves. In collaboration with the department of Anatomy the complex (genetic) link between the bicuspid aortic valve and structure and function of the aorta is being unravelled.
The objective of the research program is to increase our understanding of the physiological and pathological of vascular remodeling and to translate this knowledge in better treatment modalities for patients suffering from pathological vascular diseases such as aneurysm formation, peripheral arterial disease, vein graft disease, shunt failure or ischemia of the lower limb. The program is strongly embedded in the Vascular and Regenerative Medicine Profile of the LUMC and in the (inter)national network with participation in several larger program consortia. Over the past years we participated in the Smartmix TeRM program, the BMM PENT program (Prof Quax was Principal Investigator of this program), CTMM as well as the Netherlands Initiative Regenerative Medicine (NIRM). Moreover, we coordinated the EU funded FP7 program Cardimmun and participated
in the Moglynet program, a Marie Curie European Joint Doctorate program. Furthermore, there is a direct (translational) link to the clinic with (nationally organized) patient related research. For that two clinical research lines are defined: 1) the ischemic limb (including regenerative medicine and intimal hyperplasia) and 2) aneurysm formation (including inflammation) to support the Top Reference care programs on these topics.

On yearly basis more than 20 PhD students are linked to the different programs involved in this theme.

Congenital Heart disease: In the research cluster entitled Congenital Heart Disease the Cardiovascular Center Leiden joined the nation-wide registry called CONCOR and is working within the CAHAL group together with the Academic Medical Center Amsterdam and the VuMC (Amsterdam). Surgeons work in both the AMC and the LUMC. Research is focused on optimal care for patients with complex congenital heart diseases (for example patients with tetralogy of Fallot, in whom replacement of the pulmonary valve should be timed dependent on the severity of right ventricular dilatation) and the introduction of new techniques to improve quality of life for this growing group of patients, as more patients will life into adulthood. The recent implantation of a ventricular assist device in a patient with a failing systemic right ventricular is an example of such an innovation. It is also an example of the need to work as a team. The surgical group has published a significant number of   papers on the evaluation of the long-term outcome after surgical interventions (Twenty-year experience with the Ross-Konno procedure. Schneider AW, Bökenkamp R, Bruggemans EF, Hazekamp MG. Eur J Cardiothorac Surg. 2016 Jun;49(6):1564-70), More than 25 years of experience in managing pulmonary atresia with intact ventricular septum. Schneider AW, Blom NA, Bruggemans EF, Hazekamp MG. Ann Thorac Surg. 2014 Nov;98(5):1680-6)). The quality of the work is also reflected by the

growing number of patients from outside the Netherlands referred for a surgical intervention and the training of international fellows in congenital heart surgery (2/year). Basic research is focused on the development of new prosthetic heart valves (supported by external organizations) The work on ECG related parameters in the congenital heart disease group is successful and resulted in a number of PhD theses. Also, the work on developmental aspects of congenital heart diseases is a part of the research program of the group. Within this theme the studies on primary and secondary pulmonary hypertension are incorporated as well. A unique project is the 3-D scanning and printing of congenital heart disease preparations (available from the 1950’s), these 3-D prints can be used as teaching tools but also (due to the material used) are made available to teach surgeons to perform complex congenital heart disease procedures. The Center invested in a number of Holo-lenses to translate the 3-D images in holograms to improve 3-D insight and to assist in teaching students and fellows.
To strengthen the group involved in studies on congenital heart disease the number of staff (now 8, cardiologists and surgeons) was increased and 6 PhD students are linked to this program.

Valvular disease: Valvular heart disease is an important subject of both clinical care and basic and clinical research. The   surgical group is dedicated to the work and internationally well recognized. The group participates in large international trials and in international training activities. The success of these interventions depends on a close collaboration with the imaging group and the availability of new techniques to improve the outcome of these procedures. The percutaneous valvular interventions are successful and contributed to the significant improvement of the quality of life of especially of the very old patients involved. With the introduction of the percutaneous aortic valve program, the percutaneous treatment of mitral valve disease and in the coming years the tricuspid program it will become possible to treat high risk patients and to improve   survival and quality of life. With the introduction of the percutaneous treatment options surgeons and cardiologist are working closely together to improve outcome. The success of the percutaneous program also heavily depends on different imaging techniques. The installation of a new Cath lab system offering the integrations of different imaging modalities in one image underlines this importance. The work on the genetical and developmental aspects of Barlow’s disease (involving the mitral valve) combined with physical aspects of this disorder is promising (Dr. Ajmone Marsan). As this disorder is common among patients with mitral valve disease it is also highly clinically relevant. Recently a Horizon 2020 funded project was started on the application of decellularized homografts for aortic valve replacement. In follow-up of this project we will de-cellularise these valves in Leiden and study the potential of regeneration of cardiac valves in this model. The Cardiovascular Center Leiden will join a large (US) surgical trial network in which multiple randomized trials will be conducted, starting with one on functional tricuspid valve surgery.

Within this program numerous PhD students and international fellows are working on both the clinical evaluation of the different programs and the introduction and evaluation of new imaging modalities.

Ventricular dysfunction and Heart Failure: In this programme novel therapies for patients with heart failure are studied. Surgical therapies to treat mitral regurgitation and to reshape the left ventricle are evaluated and an important modality to improve the outcome of patients with advanced stages of heart failure. Late outcome studies of the surgical treatment of functional mitral regurgitation are being finalized. The LVAD destination therapy program (Palmen, Tops & Beeres) is part of this theme and an important option for patients who are not a candidate for heart transplantation. Research on the adaptation of the inflammatory system to the newly implanted device has gained insight into the complications these patients. The tertiary MISSION! Heart Failure care track for the evaluation and treatment of patients with advanced stages of heart failure is    another example of a successfully implemented care track. Within this program the care and research for patients with genetic disorders causing LV dysfunction is included.  The recently started percutaneous ECMO program is also part of this research theme and focus on acute heart failure in case of a myocardial infarction and heart failure caused by massive pulmonary embolism.
Other important activities involve the participation in the NVVC-Connect Heart failure program. This national program is designed to improve care for patients with heart failure together with all professionals involved (family doctor, regional and academic cardiologists, rehab centres), patient groups and insurance companies. Recently some programs have been initiated focussing on value based health care. These programs will expand over the coming years. Many patients are already included in tele-monitoring and other E-health applications and it can be expected that this will increase over the next years. With the design and the start of the Connect 3-P program a digital network connecting patients, public and professionals will be installed and the importance of E-health is underlined.
Within this program numerous PhD students are working on both the clinical evaluation of the different programs and the introduction and evaluation of treatment options. Two PhD students are now working on the regional programs.

Cardiovascular Imaging: Advanced cardiovascular imaging was one the most important factors contributing to success of the Cardiovascular Center Leiden. Numerous new echo techniques, new applications of cardiac CT, nuclear imaging and advanced MRI techniques have been introduced (often in close collaboration with the Department of Radiology) and were used in the evaluation of new diagnostic and treatment modalities. The position of the imaging group is (both on a national and international level) well recognized and with more than 25 international fellows over the last 5 years and with continuously more than 15 PhD students very important for the scientific output of the center. 4D MRI techniques are increasingly used especially in congenital heart disease patients. 3-D printing of CT or MR derived images is a new tool which may help surgeons or interventional cardiologists to prepare complex procedures.
Advanced cardiovascular imaging will be even more important in the future as the success of new interventions depends on

the availability of 3-D integrated imaging modalities both on a cellular level as on an organ level. Furthermore, in collaboration with the department of Radiology plans are developed to build a MRI-Cathlab unit enabling simultaneous MRI and X-ray imaging which is important for example to improve the outcome of ablation and cell therapy procedures. This may also be of importance for the combined vascular interventional procedures (vascular surgery together with interventional radiologists).

Care-tracks, Patient safety, Value Based Health Care: The large number of care-tracks (MISSION! Projects) was instrumental for the success of the clinical research programme. By introducing detailed (crossing borders) care tracks and the simultaneous introduction of a fully digital patient file system (integrating all different clinical data and imaging modalities) it became  possible to evaluate the outcome of all kind of interventions. The MISSION!-STEMI programme (introduced in 2004) resulted in
1) a significantly improved patient outcome and 2) the publication of numerous papers and PhD projects, 3) dissemination of this protocol to a national level in so called regional Connect projects. Furthermore, the care tracks offer a platform for introduction and evaluation of new care interventions. Another advantage of these care-tracks is the possibility to study patient safety in detail and a number of PhD students is currently involved in these projects. By combining clinical, financial  and patient reported outcome data it is possible to evaluate the added value for patients which will be a central theme during the coming years. Part of the safety programme are the different activities involving the personnel of the Cardiovascular Center Leiden to improve awareness and culture (the We instead of I project being an example). Vascular Surgery evaluates the learning capacity and potential of mortality and morbidity meetings and complication registry programs. They also explore scientifically modern patient safety approaches (Safety II) in daily practice and training programs. Furthermore, new care interventions are prospectively evaluated using systemically so-called prospective risk analysis. As the departments involved all treat complex disorders in patients by advanced but often high-risk procedures specific crew resource management training sessions and feedback programs will be initiated and evaluated.

The Cardiovascular Intervention Center, Radiology Intervention Center and Hybrid MRI/Cathlab: After a long preparation phase the actual building activities concerning the Cardiovascular Intervention will start in 2018. Within this center the cardiothoracic operation rooms, the catheterization laboratories and 2 hybrid operation/cathlab rooms will be positioned. This is a real exciting development as it implicates that all involved will have to work together. The physical connection with the Cardiology basic science laboratory offers new possibilities and a B2B milieu which will be unique. Potentially, if possible, it would be desirable that the new Radiology Intervention Center and the Hybrid MRI/Cathlab are positioned next to this CVIC. Why is this important? It can be expected that more and more patients will be treated percutaneously or in a hybrid fashion. As cardiovascular diseases are not limited to one organ or organ system many patients need more interventions and by combining all cardiovascular treatment modalities within one center expertise will grow and outcome will improve. To be successful this new organization will cause a drastic culture change (or shock). Compared to the old (and strict) organization in separate departments barriers have to be removed as all involved will work in a patient centered manner. This of course will cause time as change will request people to leave their comfort zones. However, to remain competitive, this may be the way to go!

Teaching, Training and Culture!: Teaching, Training and Culture are important aspects of a safe and motivating environment. Within the Cardiovascular Center Leiden teaching of students is one of the key elements of the Center. It is therefore important that one of the staff members was appointed as teaching professor. The Center supported this by financing a PhD student.
Furthermore, training of care professionals is stimulated by the opening of the simulation laboratory and the numerous on-site training courses. Cultural aspects play a role in all activities of the Center and by introducing Just Culture activities (stimulated by the Head of the Department of Vascular Surgery) results of all clinical, research and teaching activities will improve.
Important to note that the three program leaders are all active within the medical specialist training programs on a national level. It can be expected that a dedicated research group will be installed chaired by the head of vascular surgery. To stimulate the development of non-medical skills staff members, residents and PhD students are stimulated to follow leadership development and health care economic coursed and some are following master courses organized by the London School of Economics and IESEG Paris.

Society: The Cardiovascular Center Leiden is anchored within the society and feels a strong obligation to play an important role to improve health and improve prognosis of patients with cardiovascular disease. Examples are the Women and Heart disease campaign to increase awareness that women can get a myocardial infarction; the Heart-Vascular Disease Café’s (together with the patient group) and the Taskforce QRS initiative to stimulate resuscitation training sessions on schools and for example sports clubs. At this time more than 1500 students from 10-18 years have been trained already!

Position in international content

As discussed based on the comments of the international committee in 2012 the departments of Cardiothoracic Surgery, Cardiology and Vascular Surgery decided to reshape the research profile. In short research programs 20301, 20302, 10600 and 10201 are fused into one large project with 5 different themes
The overall departmental CWTS analysis scores improved over the last 10 years on almost all different parameters and reflects a significant scientific output. Both on a national and international level there are many collaborations and many staff members are active within the national and international groups involved.

Future themes

By improving integration of several imaging modalities (intravascular echocardiography, nuclear cardiology, MRI, multislice CT, and NOGA) we aim to optimize diagnosis and interventions in patients with complex atrial and ventricular arrhythmias, as well as in patients with atherosclerosis, structural heart disease (either valvular of congenital) and/or heart failure to improve prognosis. More programmes will be developed to implement current guidelines for specific patient groups, thereby improving patient care with respect to diagnosis and therapy. Genetic studies in large patient groups, such as collected in the GENDER/CONCOR study, will provide information about molecular processes that are implicated in restenosis after successful percutaneous coronary intervention. Cell research will lead to better selection of cell types and matrix components, choice of pre-treatment of stem cells to guide differentiation, electrical properties and contractile capacities, and increase the number of stem cells that after injection remain present in the myocardium. Important future themes are the “Bio-ICD” programme and expanded ‘care at home’ via eHealth to monitor, educate and coach patients with respect to lifestyle and disease. Furthermore, patient participation will be important to improve empowerment and to help us develop new patient centered therapeutic options.

Cohesion within LUMC

In this programme the Cardiovascular Center Leiden cooperates intensively with (amongst others) the Departments of Anatomy and Embryology, Molecular Cell Biology, Haematology, Radiology, Nuclear Medicine and Genetics, Clinical Genetics, Clinical Epidemiology and Public Health. The collaborations in the working group Leiden Vascular Medicine (LVM) and Center for Medical Systems Biology (CMSB) (aiming to apply innovative multidisciplinary genomics and bioinformatics to improve diagnosis, therapy and prevention of common and rare diseases) are examples of the importance of working together within the LUMC. The cell therapy programme is firmly embedded in the profile area Vascular and Regenerative Medicine LUMC. Its scope ranges from basic molecular research to clinical application through involvement of various preclinical and clinical LUMC departments.

Furthermore, to strengthen its position the Cardiovascular Center Leiden is working together with patient groups, primary care physicians, insurance companies and regional cardiologist to develop crossing borders care tracks, install a regional triage center for acute cardiac care and develop a regional training program for residents in cardiology offering them a really individualized schedule.

The Cardiovascular Center Leiden is working closely together with physicians from the large regional hospitals and it can be expected that especially the collaboration with the groups of the large hospitals in The Hague will result in the formation of the Cardiovascular Center South-West Network. Although, on the long term, it may even result in founding a dedicated Academic Cardiovascular Center for the coming years this will be a functional network where professionals may work at different locations and use the specific facilities of each location.