Risk Of CArdiovascular disease in DEpressed individuals – ROCADE

Works achieved over these last 30 months
(1) Cleaning and quality control of the whole database for the echotracking data by P2: of the 10 157 included subjects, data are usable for 9213 subjects. (2) Investment in a high sensitivity equipment to measure circulating biomarkers in such a healthy population. (3) Recruitment by P3 of a dedicated ingeneer for the biomarkers assessment. (4) Biomarkers assessment by P3 achieved for the first 5000 participants (CRP, IL6, IL 10, BNP) and for the first 2500 participants (troponin that required a different technology) by Sept 2018. The assessment of all the biomarkers for the whole cohort is planned to be finalized by June 2019 (5) Ongoing follow-up of the cohort with participation rates between 85 and 89%. The 6-year follow up is over and its quality control is under way. Ongoing adjudication of the CVD events (n=586 by Sept 2018).

We have started investigating vulnerability 1 and 2. We have first addressed the clinical relevance of the cardiovascular health for subclinical events (ATVB 2016) in PPS3, and for incident CVD events (JACC 2017) and dementia (JAMA 2018) outside PPS3. In parallel, within PPS3, we showed that depression and more generally psychological and socieconomic factors were related to lower odds of
achieving optimal cardiovascular health (Heart 2017, Int J Cardiol 2018). Regarding the vascular vulnerability, we have shown that depression was related to autonomic dysfunction as evaluated by lower (neural) BRS (Atherosclerosis 2016). To address the clinical relevance of the neural BRS, we have shown in PPS3 that people with exaggerated systolic blood pressure in response to a moderate exercise (a marker of future hypertension and mortality) had alteration in their neural BRS (Eur heart J 2018). Last, we just published the results on the longitudinal association between baseline carotid stiffness and incident depression (Biol Psychiatry 2019).

We will start investigating the association between blood biomarkers and incident depression (molecular vulnerability). Then, using the validated CVD events, we will quantify to which extent the 3 explored vulnerabilities (lifestyle, vascular/autonomous dysfunction and molecular) explain part of the increased CVD risk in the presence of depression.

1. Thomas T van Sloten, Pierre Boutouyrie, Muriel Tafflet, et al. Carotid artery stiffness and incident depressive symptoms: The Paris Prospective Study 3. Biol Psychiatry 2019 Mar 15;85(6):498-505.
2. Sharman JE, Boutouyrie P, Perier MC, et al. Impaired baroreflex sensitivity, carotid stiffness, and exaggerated exercise blood pressure: a community-based analysis from the Paris Prospective Study III. Eur Heart J. 2018 Feb 14;39(7):599-606. (IF: 23)
3. Thomas T van Sloten, Pierre Boutouyrie, et al. Body silhouette trajectories across the lifespan and vascular aging: The Paris Prospective Study 3. Hypertension 72:1095-1102 (IF: 6,8)
4. Poirat L, Gaye B, Perier MC, et al. Perceived stress is inversely related to ideal cardiovascular health: The Paris Prospective Study III. Int J Cardiol. 2018 Jun 12. pii: S0167-5273(17)36832-8.
5. Simon M, Boutouyrie P, Narayanan K, et al. Sex disparities in ideal cardiovascular health. Heart. 2017 Oct;103(20):1595-1601.
6. Empana JP, Prugger C, Thomas F, et al. Serotonin and norepinephrine reuptake inhibitors antidepressant use is related to lower baroreflex sensitivity independently of the severity of depressive symptoms. A community-study of 9213 participants from the Paris Prospective Study III. Atherosclerosis. 2016 Aug;251:55-62.
7. Gaye B, Mustafic H, Laurent S, et al. Ideal Cardiovascular Health and Subclinical Markers of Carotid Structure and Function: The Paris Prospective Study III. Arterioscler Thromb Vasc Biol. 2016 Oct;36(10):2115-24
8. Gaye B, Prugger C, Perier MC, et al. High level of depressive symptoms as a barrier to reach an ideal cardiovascular health. The Paris Prospective Study III. Sci Rep. 2016 Jan 8;6:18951. doi: 10.1038/srep18951

Aims: ROCADE is a 4-year project conducted in the primary prevention setting aiming to explore simultaneously 3 putative and inter related diseases processes that could partly explain the increased risk of cardiovascular disease (CVD) in depressed individuals and/or antidepressants (ATD) users. Hypothesis 1 will address a behavioural vulnerability evaluating the combined contribution of lifestyle and cardiovascular risk factors using the novel concept of ideal cardiovascular health. Hypothesis 2 will address a molecular vulnerability by measuring a panel of 4 inflammatory and non-inflammatory blood biomarkers involved in relevant CVD disease pathways. Hypothesis 3 will address a vascular vulnerability together with autonomic dysfunction by measuring arterial stiffness and baroreflex sensitivity using high-precision carotid echotracking techniques and by evaluating novel heart rate parameters.
Methods: ROCADE will be conducted in the Paris Prospective Study 3 (PPS3), a contemporary observational community-based prospective cohort that has recruited 10 157 subjects aged 50-75 (40% women) between 2008-2012. By 2018, representing between 6.5 and 8.5 years of follow-up, 720 deaths and 587 vascular events are expected. High-precision carotid echotracking has been conducted in the whole cohort providing data on structural and functional arterial stiffness parameters and the baroreflex sensitivity. Heart rate has been continuously recorded during 2 ½ hours including during a 2 minutes step test so that non-standard heart rate parameters with robust clinical relevance and reflecting autonomic dysfunction will be investigated in addition to standard heart rate variability parameters. A large unthawed biobank is available and inflammatory (CRP and IL-6) and non-inflammatory biomarkers reflecting cardiomyocyte damage (hyper-sensitive troponin I) and cardiac stress (NT-proBNP) will be measured. A replication analysis will be conducted in the Maastricht cohort. All statistical analysis will be centralized at INSERM U970, Paris (coordination team).
The consortium: it is led by JP Empana, INSERM Research Director at INSERM U970 (P1, coordination team), principal investigator of the PPS3 and who is a recognized expert in the field of blood biomarkers. P1 also comprised X Jouven who is a world leader in the epidemiology of sudden cardiac death and who is coordinating the Sudden Death Expertise Centre since 2011. P2 is composed of P Boutouyrie and S Laurent, 2 world leaders on arterial wall mechanics, and who have coordinated the carotid echotracking measures of PPS3. P3 includes the INSERM Cochin Platform directed by M Andrieu who has longstanding experience in the conduct of multiplex assessment. Collaborators include the PRB-HEGP (PPS3 biobank storage), CD Steehouwer (Maastricht cohort) and C Lemogne (Department of psychiatry, HEGP). This multidisciplinary consortium has already 10 years of collaboration and common publications.
Work packages (WPs): WP1 is dedicated to coordination (P1, Empana), WP2 to biomarkers assessments (P1&P3), WP3 to carotid echotracking (P2), WP4 to Holter recording (P1, Jouven), WP5 to follow-up (P1) and WP6 to statistical analysis and drafting manuscripts (P1,P2, P3 and collaborators).
Expected results: 1.To identify relevant disease process contributing to the increased risk of CVD in depressed individuals. 2. To clarify the respective role of depressive symptoms and ATD use in the occurrence of CVD. 3. To identify targets for prevention of CVD in depressed individuals.
Feasability: 1. Availability of baseline data. 2. WPs can be run in parallel. 3. A 90% rate of follow-up. 4. External replication. 5. Existing published preliminary results from the consortium supporting research hypotheses. 6. 10 years of collaboration within the consortium
Budget required to ANR: 442 k€ (overheads excluded): 256 k€ for P1, 80 k€ for P2 and 106 k€ for P3.