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 CardiologyThoraxcenter, 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

ConsortiumUniversity Medical Center UtrechtMichiel Bots Clinical Epidemiology / GP PracticesTim Leiner RadiologyArjan Brenkman Metabolic DiseasesPaul de Bakker Genomics (Broad Institute)

Maastricht Medical CenterGeert-Jan Dinant General Practitioner / GP Practices

Erasmus MCJaap Deckers Cardiologist Myriam Hunink Radiology / CE analysis

Other UMC’s, Bronovo Hospital, GP Practices Rotterdam and Nijmegen

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.

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.

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 CTAUsual care

>400

Statin 40 mgACE 4 mgASA 80 mg

1

2

3

46

5

Translation

plasmPBMCgranulocytes

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- F2 – 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

Focus Areas Dutch Heart FoundationGender 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 agingElderly 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.

PreventionNo comments needed: goes without saying

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

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…