Coronary Vasculature Repair Consortium: Preservation and restoration of the coronary vasculature to limit myocardial damage after PCI-treated myocardial infarction.

1. Coronary Vasculature Repair Consortium: Preservation and restoration of the coronary vasculature to limit myocardial damage after PCI-treated myocardial infarction. Preclinical: Prof. Dr. Anton J.G. Horrevoets Molecular Cell Biology and Immunoloy VU Medical Center Clinical: Prof. Dr. Felix Zijlstra Head Cardiology Erasmus Medical Center

2. EUR: Prof. Dr. F. Zijlstra (Cardiology, clinical trials); Prof. Dr. WJ. van der Giessen (Exp. Cardiology, porcine models) VUMC: Prof. Dr. AJG Horrevoets (Cell biology/genomics/ mononuclear cells), Dr. N van Royen (Cardiology, bedside-to-bench, porcine models) UMCU: Prof. dr. DPV. de Kleijn (Exp. Cardiology/proteomics/biomarkers) Dr. SAJ. Chamuleau (Cardiology, stem cells, Porcine models) AMC: Prof. dr. JJ. Piek (Cardiology), Prof. Dr. ET van Bavel (Medical Physics and Engineering) LUMC: Prof. dr. PHA. Quax (neovascularization, inflammatory cells, mouse models) UMCG: Prof. dr. WH. van Gilst (Pharmacology, clinical trials) UMCN: Dr. G. Rongen (Pharmacology, Ischemia/Reperfusion Injury) MUMC Dr. WM. Blankensteijn (Cell Biology, signal transduction) Consortium: 8 UMCs

3. Health Care problem Following successful PCI to restore epicardial flow, insufficient restoration of the myocardial microvasculature in 30-40% of patients and excessive influx of cells of the innate immune system, both enlarge infarct size and scarring, thus promoting ventricular dysfunction, re-infarction and development of heart failure. Objectives: Recovery and repair interventions on the coronary vasculature and control of leukocyte recruitment and phenotype during different stages after AMI PCI-treatment will have beneficial effects on myocardial morphology and functional performance during prolonged follow-up and will prevent heart failure.

4. Research questions NO-REFLOW: Prevention of no-reflow by microvascular obstruction and of ischemia reperfusion injury by pharmacological modulation, especially in the context of diabetes, will have added benefit to improved reperfusion. PROGRAMMING MONONUCLEAR CELLS: Control of leukocyte recruitment and phenotype during different stages after AMI PCI-treatment will enhance endocardial perfusion and have beneficial effects on myocardial morphology and functional performance during prolonged follow-up and will prevent heart failure.

5. Research plan 1. COAGULATION: WP leader Wim van der Giessen targets acute microvascular obstruction 2. I/R INJURY: WP leader Gerard Rongen targets vascular and cardiac tolerance to deleterious consequences of early reperfusion 3. INFLAMMATION: WP leader Niels van Royen targets post-AMI leukocyte infiltration and programming 4. ANGIOGENESIS/ ARTERIOGENESIS: WP leader Paul Quax targets arteriolar and capillary damage and repair 5. LONGITUDINAL: WP leader Dominique de Kleijn targets identification of biomarkers and testing longitudinal effects of treatment

6. Translation Application covers the full axis: -Multi-center clinical trial with registered pharma -Longitudinal porcine model to test targets from previous research -Discovery of diagnostic and druggable targets from patient material -Mechanistic studies in vitro cell/vessel culture and small animals

7. Focus areas Dutch Heart Foundation Bedside to bench approach allows subanalyses of gender issues, metabolic disorders and aging, based on the scale of multicentre clinical trials. Metabolic disorders and age will be specifically addressed in animal models, notably diabetes and hypercholesterolemia. Gender issues in relation to in-hospital death, ACS, coagulation/platelet aggregation, mononuclear cell response and myocardial salvage will be addressed systematically at large scale for the first time, and includes female-specific risc factors like pregnancy-related DM and HT, time to menopause etc, in relation to quantitative MRI-outcome (coordinated by Yolande Appelman, head Catherization, VUMC).

8. Perspective The consortium combines intervention cardiology and its related basic research (publication track record) in the Netherlands, from all 8 UMCs, with strong liaison in ICIN Through ICIN might participate as single partner in new intervention cardiology network to be established within Europe

9. Strengths of the proposal: Covers full translational axis Explores novel ways to program mononuclear cell phenotype at different stages after PCI in a longitudinal fashion, at forefront of scientific progress Both Multi center clinical trial, small investigator-initiated trials and porcine animal model will yield quantitative MRI data on myocardial damage and salvage on 3-months follow-up, in addition to clinical and functional outcome parameters Influence of metabolic comorbidities and gender will be sub-analysed, and together with quantitative MRI data allows systems biology analysis Novel diagnostic functional biomarkers from patient material obtained at PCI will identify personalized adjunctive therapies