Epidemiology of sleep complaints and cardiovascular disease in the community – EPICARSLEEP

EPICARSLEEP combines the baseline and follow-up data of two contemporary observational community-based prospective cohorts: the Paris Prospective Study 3 (PPS3) in France, and the CoLaus/ HypnoLaus study in Switzerland. Altogether, the two studies represent 17 000 subjects (40% women) aged 50-75 (PPS3) and 35-75 (CoLaus/HypnoLaus), with a follow-up time between 9 and 13 years by 2021. A total of 338 strokes and 638 coronary events and 471 deaths are expected. In both cohorts, sleep duration, insomnia complaints and subjective daytime sleepiness have been assessed at different time points using similar standardized questionnaires (Pittsburg Sleep Quality Index and Epworth sleepiness scale). Additional common variables include: socioeconomic data at the individual level; classical CVD risk factors; depressive symptoms; inflammatory (hsCRP and IL-6) and non-inflammatory (BNP, troponins) biomarkers. Some data are cohort specific: high-precision carotid echotracking and Holter recordings for the PPS3 and polysomnographic data for the CoLaus/HypnoLaus study. In addition, using a case control approach combining data from the 2 cohorts, we will explore whether a panel of circulating microRNA can identify pathways contributing to the occurrence of CVD in subjects with and without sleep disorder breathing.

As of March 25 2019, most data have been harmonized across the 2 studies.
Furthermore, a first published result has addressed the lifestyle and cardiovascular risk factors hypothesis by using the concept of primordial prevention investigating the association between cardiovascular health (based on 7 risk factors categorized in poor, intermediate and ideal level) and the different sleep complaints. In both cohorts, we observed that higher level of cardiovascular health was associated with a lower risk of sleep disorder breathing and excessive daytime sleepiness in a graded manner. No clear association was found with sleep duration or insomnia symptoms.
In addition, regarding the molecular hypothesis, we have measured a panel of 180 circulating microRNAs per patient in sleep disorder breathing patients with (case) and without CVD (control). We are currently analyzing the data. On this same molecular hypothesis, we are finalizing the measurement in PPS3 of the inflammatory (hs-CRP and Il6) and non inflammatory (BNP and hs-troponin) biomarkers in the whole cohort; these markers are already available in CoLaus

We plan to finalize the analysis on the microRNAs and to start investigating the role of inflammatory and non inflammatory biomarkers.We also plan to start investigating in PPS3 only the role of arterial stiffness and baroreflex sensitivity, with an extension in the Maastricht cohort.
On the mid term we will explore the association of the sleep complaints with the outcomes (CVD and mortality) and thereafter test to which extent, the 4 disease pathways mentioned above mediate part of the increased risk of CVD associated with these sleep complaints.

Nadine Häusler, Quentin Lisan, Thomas Van Sloten, José Haba-Rubio, Marie-Cécile Perier, Frederique Thomas, Nicolas Danchin, Catherine Guibout, Pierre Boutouyrie, Raphaël Heinzer, Xavier Jouven, Pedro Marques-Vidal, Jean-Philippe Empana.Cardiovascular Health and Sleep Disturbances: Results From two Population-based Cohort Studies. Heart 2019 (accepted)

Lisan Q, Tafflet M, Thomas F, Boutouyrie P, Guibout C, Haba-Rubio J, Climie R, Périer MC, Van Sloten T, Pannier B, Marques-Vidal P, Jouven X, Empana JP. Body Silhouette Trajectories Over the Lifespan and Insomnia Symptoms: The Paris Prospective Study 3.Sci Rep. 2019 Feb 7;9(1):1581.

Lisan Q, Tafflet M, Charles MA, Thomas F, Boutouyrie P, Guibout C, Haba-Rubio J, Périer MC, Pannier B, Marques-Vidal P, Jouven X, Empana JP. Self-reported body silhouette trajectories across the lifespan and excessive daytime sleepiness in adulthood: a retrospective analysis. The Paris Prospective Study III. BMJ Open. 2018 Mar 27;8(3):e020851.

Aims: EPICARSLEEP is a 4-year project in the primary prevention setting aiming to explore simultaneously four inter-related disease pathways (vulnerabilities) that could explain the increased risk of cardiovascular disease (CVD) in individuals with sleep complaints. Hypothesis 1 will address behavioral vulnerability by evaluating the combined contribution of lifestyle and cardiovascular risk factors using the novel concept of ideal cardiovascular health. Hypothesis 2 will address psychosocial vulnerability by exploring depression and socio economic factors at the individual and contextual levels. Hypothesis 3 will address molecular vulnerability by investigating inflammatory and non-inflammatory blood biomarkers and a large array of plasma microRNAs on baseline frozen samples. Hypothesis 4 will address vascular vulnerability and autonomic dysfunction by analyzing arterial stiffness and baroreflex sensitivity using state-of-the-art methods (high-precision carotid echotracking) and by evaluating novel heart rate parameters on Holter recordings.
Methods: EPICARSLEEP combines the baseline and follow-up data of two contemporary observational community-based prospective cohorts: the Paris Prospective Study 3 (PPS3) in France, and the CoLaus/ HypnoLaus study in Switzerland. Altogether, the two studies represent 17 000 subjects (40% women) aged 50-75 (PPS3) and 35-75 (CoLaus/HypnoLaus), with a follow-up time between 9 and 13 years by 2021. A total of 338 strokes and 638 coronary events and 471 deaths are expected. In both cohorts, sleep duration, insomnia complaints and subjective daytime sleepiness have been assessed at different time points using similar standardized questionnaires (Pittsburg Sleep Quality Index and Epworth sleepiness scale). Additional common variables include: socioeconomic data at the individual and contextual level; classical CVD risk factors; depressive symptoms; inflammatory (hsCRP and IL-6) and non-inflammatory (BNP, troponins) biomarkers. Some data are cohort specific: high-precision carotid echotracking and Holter recordings for the PPS3 and polysomnographic data for the CoLaus/HypnoLaus study.
Main tasks to be done include: 1) data harmonization, 2) the assessment of plasma microRNA using the largest chip available (n=752 microRNAs) in both cohorts and hs-troponin I in PPS3 and 3) heart rate parameters analysis and interpretation (PPS3) 4) completion of follow-up in both studies.
Work packages (WPs): WP1 is dedicated to coordination; WP2 to data harmonization, WP3 to Holter recording analysis, WP4 to biomarker assessments, WP5 to follow-up completion and WP6 to statistical analysis and drafting manuscripts.
The consortium is coordinated by JP Empana, who is Research Director at INSERM U970, principal investigator of the PPS3. EPICARSLEEP gathers experts in cardiovascular and sleep epidemiology. It includes 5 academic partners: INSERM U970, team 4 (leader JP Empana), INSERM U970, team 7 (leader: P Boutouyrie), INSERM U1016 (leader: M Andrieu), CHU de Lausanne (leader PM Vidal), and Investigation and Research centre on sleep of Lausanne (R Heinzer et JH Rubio).
Expected results: we expect to 1) identify the determinants of the most common sleep complaints such as insomnia, excessive daytime sleepiness and of sleep duration; 2) assess the associations between sleep complaints and sleep duration with incident CVD; 3) identify relevant disease processes contributing to the increased risk of CVD in subjects with sleep complaints and 4) identify targets for prevention of CVD in subjects with sleep complaints.
Conclusion: EPICARSLEEP will be the largest cohort worldwide in the field of sleep epidemiology. This joint collaboration including 17 000 subjects extremely well-phenotyped and followed for 9 to 13 years will provide an unique opportunity for assessing the effects of sleep duration, sleep complaints and disturbed sleep on the incidence of CVD.
Budget required to ANR: 479 900 € (overhead excluded)