The document outlines a research initiative focused on improving the prevention and management of cardiovascular disease (CVD) in asymptomatic individuals at intermediate risk by integrating imaging, clinical, and biological data. It emphasizes the need for a more tailored approach to identify high-risk individuals effectively and address gender-specific factors influencing CVD. The study aims to enhance risk stratification and clinical outcomes through innovative methodologies, including systems biology and novel biomarkers.

1. Combining Atherosclerosis Imaging and New and Novel Markers in Asymptomatic Subjects at Intermediate CVD Risk: Implications for Pathophysiology, Prediction and Prevention. Jaap W. Deckers, MD, PhD, Associate Professor of Cardiology Thoraxcenter, Department of Cardiology, Erasmus MC Michiel L. Bots, MD, PhD, Professor of Epidemiology of Cardiovascular Disease Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht

2. Consortium University Medical Center Utrecht Michiel Bots Clinical Epidemiology / GP Practices Tim Leiner Radiology Arjan Brenkman Metabolic Diseases Paul de Bakker Genomics (Broad Institute) Maastricht Medical Center Geert-Jan Dinant General Practitioner / GP Practices Erasmus MC Jaap Deckers Cardiologist Myriam Hunink Radiology / CE analysis Other UMC’s, Bronovo Hospital, GP Practices Rotterdam and Nijmegen

3. Health Care Problem Currently, most patients with (recognized or established) CVD receive appropriate medical care Prevention – further reduction of CVD incidence - should be number one priority Correct identification of men and women at risk is crucial but existing risk models – high risk strategy – have low diagnostic yield Since CVD occurs mainly in subjects at intermediate risk, the correct identification of men and women in this category who will develop CVD is crucial, but this is – as of now – not possible An integrated approach – combining clinical, imaging and biological data – is thus urgently needed to better “tailor” preventive measures and therapy.

4. Three Major Research Questions 1. An algorithm of coronary imaging – leading to CVD risk reclassification in >50% – followed by tailored cardiovascular risk factor management will reduce cardiovascular events compared to ‘care as usual’ in subjects at intermediate CVD risk; 2. Added to traditional risk factors, measurement of coronary atherosclerosis and assessment of novel biomarkers by a systems biology approach (proteomics, metabolomics and genomics) will be able to distinguish high- from low-risk subjects; 3. Such an integrated systems biology approach will identify disease-causing mechanisms responsible for the presence and extent of coronary atherosclerosis and the occurrence of new cardiovascular events.

5. Research Plan CAC independent and strong (RR 3) risk factor Very high rate of re-classification (>50%) However, no evidence that CAC measurement improves prognosis 12.000 healthy men and women at intermediate CV risk (SCORE) >100 ≤ 100 Randomisation in two groups Clinical outcome Statin 40 mg Coronary Calcium Score and CTA Usual care >400 Statin 40 mg ACE 4 mg ASA 80 mg 1 2 3 4 6 5

6. Translation plasm PBMC granulocytes biobank Nested case-control study (3*250) to determine risk profile using systems biology approach Metabolomics Unique inflammatory lipid platform; 120 eicosanoids detected and quantified in a single measurement - F 2 – Isoprostanes; attractive markers of oxidative stress and risk Proteomics - Validation of known bloodcel and plasm markers Genomics Targeted sequencing of genes associated with CAD/MI

7. Focus Areas Dutch Heart Foundation Gender Our study will determine gender-specific risk factors, disease mechanisms and clinical CVD presentations in about 6.000 women (and the same number of men) between 55 and 70 years of age and will thus be able to relate gender-specific patho-physiological processes and their clinical impact. Healthy aging Elderly men and women at intermediate CVD risk constitute the majority of Dutch subjects. The results of our research will have direct and immediate bearing on clinical practice and subsequent management of these persons. Prevention No comments needed: goes without saying

8. In perspectief (persoonlijk) Het kostte twee jaar om het onderzoeksvoorstel te formuleren. Sinds februari (eerste bijeenkomst CVON) sterke impuls ontstaan voor de benodigde (en door de Gezondheidsraad vereiste) Nederlandse samenwerking. Als klinisch onderzoeker enorm onder de indruk geraakt van enthousiasme, kennis en kunde van de overige disciplines (“Omics” en ook huisartsen) binnen het huidige consortium. Ten aanzien van Europa / Kaderprogramma: relatief eenvoudig om tot een mono-disciplinair onderzoeksvoorstel te komen (is ook gebeurd), maar opzetten van translationeel onderzoek moeilijker. Samenwerking met de USA (NHBLI, RCT) is onderwerp van discussie

9. Waar staan we na afloop van dit onderzoek: De invloed van de meting van de kalkscore op de prognose en de betekenis van biologische factoren bij ontstaan en progressie van hart- en vaatziekten bij mannen en vrouwen zijn bekend. De identificatie van individuen met een hoog risico op HVZ is sterk verbeterd waardoor preventieve maatregelen op maat (direct) geeffectueerd kunnen worden (“will change clinical practice”). Tot slot…