Programme leader: Prof. Dr. A. de Roos
Analysis of congenital and acquired cardiovascular diseases using state-of-the-art imaging technology.
Aim and focus
In the cardiovascular research program we study congenital and acquired cardiovascular diseases using state-of-the-art imaging technology, including MRI, CT, ultrasound and nuclear medicine techniques. The research is organized according to a matrix system with disease-oriented themes on one axis and imaging modalities and image post-processing on the other axis. Principal investigators are responsible for each subproject. The program is characterized by close interactions between themes with a biomedical and technological focus, where technological innovation meets clinical application. The development of innovative imaging technology is directly linked to clinical feasibility studies. The research is based on multidisciplinary collaboration involving many disciplines, including internal medicine/endocrinology, vascular medicine, epidemiology, cardiology, pediatric cardiology, electrical engineering and computer science.
Position in international context
The cardiovascular research group is internationally well acknowledged and positioned. Recently prof. Neubauer from Oxford evaluated a cardiovascular MRI program proposal from our group and characterized the project group as follows: “This proposal comes from one of the very top groups in biomedical imaging development and application. External evaluation by dr. Neubauer stated “ Drs de Roos, Lamb and colleagues have been at the forefront of the field for well over two decades and have already contributed many seminal papers in the field. They clearly rank amongst the very top in this area worldwide, as reflected by their H-indexes, Prof. de Roos (68] and prof. Lamb (44). In addition, several algorithms and software packages developed by the LKEB (Image Processing group) have been marketed worldwide, and have become de-facto standards in the field: 4 out of the 5 existing vendors of IVUS and OCT equipment sell LKEB software along with their equipment. In addition, LKEB participates in several international trials by tailoring algorithms to the quantification needs on these studies.
Content / highlights / achievements
- New and existing research lines will continue and expanded. Main themes: 1. CT in coronary artery disease; 2. CT and MRI in diagnosis and work-up of pulmonary embolism and thrombus imaging; 3. Ultrasound in thrombus imaging; 4. MRI in ischemic heart disease; 5. Congenital heart disease; 6. High-field vascular MRI at 7T; 7. Molecular vascular imaging and lung cancer; 8. CT/MRI in obesity and diabetes; 9. Technical innovation in acquisition and post-processing and image fusion; 10. Integration of multi-organ imaging (heart-brain connection) and oncology. Some new aspects of ongoing research are highlighted below.
- Research grants (incl. Netherlands Heart Foundation, CTMM, STW) and awards have recently been provided to the research line for developing innovative MRI applications in cardiovascular disease (grant for research on pulse wave velocity (PWV)). Dr. H.J. Lamb became principal investigator on an industrial grant for evaluating the effect of medication on myocardial triglycerides in diabetes (NOVO grant 350.000€). The Netherlands Heart Foundation has provided a grant for direct thrombus imaging by MRI in collaboration with vascular medicine. Grant applications on similar projects have been submitted or are in preparation using a multidisciplinary approach.
- For image processing, we recently received 4 STW grants with a total budget of 1.8 M€ for development of image analysis methods for 4D flow MRI, for whole-body MRI, for intracranial aneurysms in MRI and for carotid plaque classification. Also, 2 ZonMW grants, 2 Eurostars grants and 2 European Joint Program Initiative grants were funded. One of these European projects (MEDIATE) received several awards, among others for maximum business impact. Five Chinese Scholarship Council (CSC) grants were awarded to Chinese PhD students pursuing their PhD at LKEB. Eight PhD theses were defended between 2012 and 2014. In addition, several LKEB developed software packages are currently marketed worldwide in collaboration with Medis medical imaging systems, and are regarded as standards in the field. This has resulted in a steady inflow of royalty funding over the past decade. LKEB also participates in international standardization committees that formulate best practices for intravascular OCT and IVUS acquisition and analysis; this has led to top-cited publications. The current lines of clinical research will be continued and expanded to other applications like pulmonary imaging. Multi-organ imaging The key imaging strategy for this project is multi-organ imaging using innovative MRI techniques that are not yet routinely used and are not yet integrated in a comprehensive imaging strategy. Initial studies have validated the MRI techniques in studies focusing on a single organ and have not implemented these innovative techniques in a comprehensive protocol for multi-organ imaging. Observational multi-organ studies will be performed to demonstrate proof of concept and associations between disease manifestations. MRI techniques will be implemented and optimized when necessary.
At present, we are deploying these multi-organ imaging approaches along two main axes of clinical application:
1. The Heart-Brain Connection (CVON project in conjunction with neurovascular research).
The cardiovascular and neuro imaging research lines are converting on a new research focus, exploring the heart-brain interaction in various diseases that may lead to neurocognitive decline. The hypothesis is that the combined effects of cardiac dysfunction, atherosclerotic burden and carotid occlusive disease are important and potentially reversible, but underestimated causes of vascular cognitive impairment offering an excellent opportunity for treatment. A comprehensive MRI protocol will be applied using innovative as well as validated techniques. This protocol will provide information on blood flow characteristics measured in the aorta as well as the first generation pathway towards the brain, heart function, carotid artery disease and cerebral pathology. The systolic pressure or blood flow wave propagates as a pulse wave from the left ventricle through the arterial system and is subsequently transmitted to the arterioles in the brain. Abnormal wave propagation may be harmful to the end organs when forward and reflecting waves transmit excessive pulsatile energy into these organs, potentially damaging the endothelium and smooth muscle cells. Many pathophysiological processes involve stiffening of the vessel wall, which leads to abnormal wave propagation. Additionally, an increase in arterial stiffness will result in a deficient absorption of the pulse wave itself. Especially the brain is a vulnerable end organ, as it has a low-resistance vascular bed and is passively perfused throughout systole and diastole. In addition to PWV-assessment for global and regional arterial wall stiffness evaluation, wave analysis is performed to obtain further information on the hemodynamic impact of arterial wall stiffening and its association to end organ damage. Separation of flow waves into forward and backward propagating components using Fourier transformation and linear wave analysis provide quantitative measures such as the propagation and reflecting coefficients, input impedance and the augmentation, pulsatility and resistance indices. These parameters are related to the vascular function and the hemodynamic load on the end organs and may provide novel markers with predictive value for cerebral dysfunction and damage.
2. Obesity and Diabetes
We are developing a multi-organ imaging and quantification approach for analyses of the pathophysiology of obesity and diabetes. This approach consists of imaging strategies to image end-organ damage due to these diseases, for instance:
- Imaging Fatty Liver: MRI techniques for assessing liver steatosis are now routinely used. Single-voxel liver spectroscopy is the reference method for estimating liver steatosis. However, single-voxel spectroscopy interrogates a single, large voxel (2x2x2 cm) and therefore provides no volumetric assessment of the fat content of the liver. It is well known that hepatic steatosis is often heterogeneous, thus limiting the value of single-voxel spectroscopy. We will implement MRI for measuring heterogeneous liver steatosis and fibrosis. To this end, we will develop and validate 2-dimensional chemical shift MRI for assessing liver steatosis volumetrically. Improved acquisition schemes using T1-independent, T2*-corrected techniques will be implemented at 3T. In addition, proton-decoupled 31 P 3T MR spectroscopy shows promise in the differentiation of non-alcoholic fatty liver disease (NAFLD) stages. Therefore, also P-31 liver spectroscopy will be implemented to measure NADPH as a biomarker of nonalcoholic steatohepatitis (NASH) as validated in initial studies. Molecular imaging using USPIO contrast agents may also become helpful to characterize the transition from simple steatosis to NASH. The added benefit of these volumetric techniques is the simultaneous quantification of iron in the liver.
- Imaging Liver Fibrosis: Studies have shown that the apparent diffusion coefficient (ADC) of cirrhotic liver is lower than that of normal liver. We aim to implement chemical shift MRI for assessing liver fat accumulation and diffusion-weighted MRI at 3T for assessing liver fibrosis. The apparent diffusion coefficient (ADC) assessed with diffusion-weighted MRI is significantly correlated with the liver fibrosis score. We will implement diffusion-weighted MRI for estimating the degree of liver fibrosis.
- Imaging Fat Deposits: Currently, estimates of visceral fat, subcutaneous fat and pericardial fat are based on single-slice approaches at predefined anatomic levels. It is known that fat deposits may vary regionally and therefore it is desirable to have a three-dimensional volumetric measurement of the various fat deposits. We will develop imaging protocols for 3D visualization of the various fat deposits throughout the body. Also, techniques for automated volume assessment of abdominal fat deposits will be developed.
- Imaging the aortic anatomy, flow and stiffness: MRI has previously been used to describe wall stiffness regionally in the aorta by means of the aortic PWV. In this project, we have developed MRI tools for measuring regional aortic wall stiffness and wall thickness. Aortic wall stiffness may be affected in patients with obesity and DM2 early in the disease process, as well as in patients with connective tissue disease such as Marfan syndrome. Wall stiffening results in abnormal pulse wave propagation which may be harmful to the end organs when forward and reflecting waves transmit excessive pulsatile energy into these organs, potentially damaging the endothelium and smooth muscle cells. Many pathophysiological processes of cardiovascular diseases involve stiffening of the arterial vessel wall, which leads to abnormal wave propagation. Central aortic wall stiffening may be the starting point of a negative cascade of end organ damage and has been reported as an important risk factor for various expressions of end organ damage and dysfunction in the heart, kidney and brain.
- Imaging cardiac anatomy and flow: the current research group has an excellent track record in developing novel imaging methodologies to evaluate cardiac function and flow. In the past period, the group has established itself as an internationally leading center for MR acquisition and analysis of intra-cardiac flow, as evidenced by several high-profile publications and (inter)-national collaborations on this subject. The novel acquisition and analysis developments in this program enable an integrative approach to assessment of obesity, heart failure and diabetes related diseases.
LUMC has a strong tradition in image analysis for image-guided cardiovascular interventions. This is evidenced by the fact that LKEB software is used in countless clinical research studies worldwide. This has resulted in market introductions of novel drugs (as recently evidenced by a Lancet paper), and in evaluation of novel medical devices. In the next few years, we aim to investigate technologies for 1) characterization of plaque morphology using CT, IVUS and OCT in relation to follow-up CT angiography data, 2) automatic evaluation of stent deployment from OCT to support clinical evaluation of novel stenting devices and 3) integration of estimates of Fractional Flow Reserve from non-invasive imaging data, and 3D correlation of in-vivo and ex-vivo plaque morphology, and finally: MRI-based planning and execution of cardiac ablation procedures.
Cohesion within LUMC
There is extensive experience in the Department of Radiology at Leiden University Medical Center (LUMC) with implementation and validation of innovative MRI techniques that form the basis of this research. Collaboration with the manufacturer (Philips Medical Systems) is well established and is important to explore these techniques.
Locally this project is embedded in collaboration between multiple departments, including internal medicine (vascular medicine), endocrinology, (pediatric) cardiology, pulmonology, nephrology, clinical epidemiology. The NEO (Netherlands Epidemiology of Obesity) study in obesity has been designed in our center as a multidisciplinary research project involving 10 local departments as well as other Dutch universities. The NEO study is a population-based cohort study that will include 6000 overweight and obese individuals aged 45 to 65 years. As part of the NEO study participants undergo a standard MRI protocol that involves spectroscopy of the liver for assessing liver steatosis, IMT of carotids and MRI-based aortic compliance measurements of the entire aorta.