Atherogenesis / percutaneous coronary intervention

The cardiac catheterisation laboratory has a large share in the scientific research of the Department of Cardiology. In particular, vascular wall research takes an important place. For this research several techniques are being used: besides traditional coronary angiography, intravascular echo, flow reserve/Doppler techniques, quantitative analysis of intravascular echocardiovascular images and 3-D reconstruction of these images are performed, the latter two in cooperation with LKEB (Department of Radiology). 

The introduction of (drug eluting) stents and the glycoprotein llb/llIa receptor antagonists have led to an increase of the success rate of complex PTCA procedures and to a decrease of the number of acute complications. The long-term results have improved as well and the clinical restenosis rate (after 9 months) has declined over the years from >30% to <10%! The introduction of these treatment modalities now allows treatment of patients who could not be treated in the past or only by means of a coronary artery bypass operation.  

Clinical scientific research within the Cluster Atherogenesis/Percutaneous Coronary Interventions is directed to "optimized patient care research" together with “translational research, from bench to bedside”. It is set up as a systematic collaboration between the clinic and the preclinical/scientific research laboratories. On the one hand this approach is integrated in an embedding organizing structure, i.e. Leiden Vascular Medicine (LVM) and the Theme Group Vascular Medicine, on the other hand a large number of spontaneous innovative initiatives/projects from the “floor” are encouraged and built in the program of LVM/Vascular Medicine later on.
At the Department of Cardiology in the LUMC this model is now working as a scientific research system called “translational cardiology/biology”. This involves a cooperation between the clinical departments of a/o Cardiology, Endocrinology, Nephrology, Internal Medicine/Gerontology, (Thorax)surgery and Radiology, and the preclinical departments of a/o TNO Prevention and Health, Sylvius Laboratory, Leiden Amsterdam Center for Drug Research/Biopharmacy and Embryology & Anatomy. This cooperation is now raising a significant scientific spin-off. In addition to this cooperation there is a flourishing collaboration with other research groups, national as well as international. 

"Optimized patient care research" together with “translational research, from bench to bedside” comprises several closely related lines of investigation. The clinical investigation on the effectiveness of intracoronary stents in high risk patients/complex procedures is an important part of the department's research. Recently large randomized studies (a.o. the Mission Stent-, Endeavor- and ARTS studies) investigating the use of drug eluting stents have been completed. New studies are being initiated particularly with regard to the so called “drug eluting stents” probably capable of reducing restenosis rates to <10%. The first implants have been applied in 2003 in selected patients, like diabetic patients and other groups with (expected) high restenosis rates, as well as in (inter)national trial setting. Current research focuses on use of drug-eluting stents in selected patient groups.
A large regional project in which patient care is optimized according to the latest guidelines and in which research is an integrated part, is the MISSION! project. Here triage of myocardial infarction patients starts already at home and patients with eligible myocardial infarctions are then directly transported to the department of Cardiology of the LUMC for immediate primary PTCA of the occluded coronary artery. At the cathlab the patients are randomized to a regular stent or a novel drug eluting stent, followed by a 1 year standardized intensive follow-up program including standard- of-care medical therapy as well as revalidation. This protocol is developed in close cooperation with the regional ambulance services, general practitioners, cardiologists and others in the region. Mission! has made a very successful start and very favourably 1 year results are now available.  

Another patient care driven research project that is now being initiated is “Focus on Women and Atherosclerotic Cardiac Disease”. Women are now acknowledged to often present with different symptoms than men, with more aspecific complaints and a different presentation of the disease with regard to anamnesis as well as type of coronary atherosclerosis. Since the correct diagnosis here is often missed working along the general guidelines (mostly designed for men), it seems therefore mandatory that an integrated pathway of disease detection and management with long term follow-up is established, which are the goals of the project “Women and Atherosclerotic Cardiac Disease”. 

An integrated research plan with regard to atherosclerosis and restenosis is now fully operational including  clinical as well as preclinical lines, in cooperation with the TNO Prevention and Health, Sylvius Laboratories, Gorlaeus/Biopharmacy Laboratories and the Center for Medical Systems Biology (SMSB), with funding by the Netherlands Heart Foundation and industrial grants. 

Focus of translational research

The research is divided into two main branches.
1. Atherosclerosis research;
2. Restenosis after percutaneous transluminal coronary angioplasty (PTCA) research. 

Since both clinical and preclinical programs are integrated, animal research is performed in ApoE*3-Leiden transgenic mice which express human-like atherosclerosis and restenosis when fed a high-fat diet. The lesions are highly representative for human lesions and suitable for systemic drug therapy as well as the newly by us developed locally acting drug eluting cuffs. Examples of human atherosclerosis and restenosis studies under auspices of Leiden are ICIN/NHF studies, such as the Regression Growth Evaluation Statin Study (REGRESS), the Genetic Determinants of Restenosis study (GENDER) and the Prospective Study of the Elderly at Risk (PROSPER). These studies are designed to clarify the dynamics and genetic/molecular backgrounds of atherosclerosis and restenosis, respectively, in order to provide a better risk stratification and more tailored therapy. The studies include discovery of new pathways by metabolomics and pharmacogenomics. These studies on genetics/epigenetics/metabolomics are performed in close cooperation with the Department of Clinical Epidemiology, Nephrology and Elderly Medicine.
An epidemiological/statistical research program has been funded to allow proper analysis of the enormous number of genetic data now coming available. The Leiden “combined pancreas-kidney transplantation” research protocol is providing unique data showing that, in patients with end-stage renal failure due to diabetes type 1, a combined pancreas-kidney transplantation is indeed superior to kidney transplantation alone, with regard to progression of coronary atherosclerosis and long-term survival. Furthermore a new Plexus Outpatient Clinic has been initiated, in cooperation with the Department of Endocrinology, for cardiovascular screening of patients with type II diabetes. Goals are to set up a frontline cardiovascular screening program, integrated in routine patient care, where 1) innovating detection/treatment methods are being applied, 2) top reference patient care is carried out, and 3) a clinical research program is established.
Other research projects in humans are hemodynamic investigations (a/o conductance catheter) and new devices such as Therox therapy, i.e. intracoronary administration of hyperbaric oxygen in the (sub)acute phase of an evolving myocardial infarction.
Imaging research by means of MRI, Multislice CT (a rapidly growing research line), Tissue Doppler Echo imaging and molecular imaging of atherosclerosis is essential to be able to evaluate the dynamics of atherosclerosis and restenosis. Therefore new developments in these fields are continuously implemented and investigated in studies. In this field especially MRI projects of measuring blood flow through bypass grafts and recipient coronary arteries has been very successful (Magic Flow project) and multi-slice CT scan studies evaluating coronary atherosclerosis and restenosis after PTCA/stenting in high risk subgroups and in patients with hypertension and diabetes are very successful.
Atherosclerosis research in transgenic mice comprises the anti-atherosclerotic synergy of combined statin + calcium channel blocker or angiotensin II receptor antagonist therapy (CASSIA and ASIRA studies), as well as the evaluation of various novel compounds still in the developmental stage in humans such as PPAR alfa-gamma agonist and cholesteryl-ester transfer protein inhibitors. Other  projects include the evaluation of the influence of C-reactive protein (cause or consequence) on the development of atherosclerosis and the impact of smooth muscle cells on plaque calcification and the impact of antirestenotic drugs delivered by the newly developed drug eluting cuff, which now turns out to be a very successful program sponsored by the NHF. A new project studies the efficacy of local gene therapy using gene constructs delivered to the vessel wall by electroporation. All these experimental projects are carried out in close cooperation with TNO Prevention and Health and LUMC laboratories.

Perspectives

1. Enhancement of the link between clinical and preclinical research in atherosclerosis and restenosis research by means of an integrated approach of vascular cardiology/biology by integrated clinical and preclinical research lines. This approach should provide a better risk stratification strategy and a better-tailored therapy for the individual patient as well as provide new targets for therapy. Optimized patient care protocols such as MISSION! the DIAbetes Cardiovascular Risk Management (DIACARM) (in close coorperation with the departments of Endocrinology and Nephrology) and Women with Atherosclerotic Cardiac Disease, in which research is systematically embedded, are an important tool in this respect.
2. Non-invasive imaging of (unstable) atherosclerosis and restenosis by means of a combination of macro- and micro-imaging. This should lead to (molecule) targeted anti-atherosclerosis/anti-restenosis therapy.