The PESA-CNIC-Santander Study (Progression of Early Subclinical Atherosclerosis)

Transcription

1 XXXIV LECCIÓN MEMORIAL Fundación Fernández-Cruz Today Moving Frontiers to Stay Healthy and Living Well Forever The PESA-CNIC-Santander Study (Progression of Early Subclinical Atherosclerosis) Antonio Fernández-Ortiz

2 What is PESA-CNIC-Santander? Longitudinal, prospective cohort study that includes 4184 asymptomatic middle-aged (40 to 54 years old) male and female employees of the Banco Santander in Madrid for a total of 6 years of follow-up

3 Objectives: To characterize the presence, location and progression of plaques in the early phases of subclinical atherosclerosis To study the association between the presence and progression of subclinical atherosclerosis with traditional and emerging cardiovascular risk factors ( omics ) To evaluate the influence of lifestyle behaviors (diet, physical activity and sleep patterns) and psychosocial factors on the prevalence and progression of subclinical atherosclerosis To characterize plaque composition and inflammation using PET/MRI in a subgroup of pts

4 PESA in the context of CNIC primary secondary primodial AWHS CVD prevention

5 Investigators: Valentín Fuster (Chairman) Antonio Fernández-Ortiz Agustín Mocoroa Borja Ibáñez Vicente Andrés Alberto Sanz STEERING COMMITTEE PESA Principal Investigator PESA Scientific Coordinator Bank of Santander Leader CNIC Director Clínical Res Dpt CNIC Director Basic Res Dpt CNIC Managing Director DEDICATED COMMITTEES Javier Sanz Basic & Advance Imaging José María Ordovás Systems Biology & Lifestyle Enrique Lara Systems Biology & Biomarkers Héctor Bueno Clinical Events Adjudication José Manuel García-Ruiz Statistics & Data Management Laura García Leal PESA Project Manager

6 PESA in context Subclinical atherosclerosis cohorts Carotids Coronaries Femorals Low-risk High-risk Low-risk High-risk Low-risk High-risk 2D-US (IMT) yo 2D-US MRI yo 2D,3D-US yo CACS yo CACS yo CACS yo

7 PESA in context Subclinical atherosclerosis cohorts Carotids Coronaries Femorals Low-risk High-risk Low-risk High-risk Low-risk High-risk 2D,3D-US 4066 PET/MR yo 2D-US (IMT) yo 2D-US MRI yo 2D,3D-US yo CACS yo CACS yo CACS yo CACS yo 2D,3D-US 4066 PET/MR yo

8 PESA study flow: We are here ISO 9001 A.Fernandez-Ortiz, JJ Borreguero, JL Peñalvo et al. Am Heart J 2013; 166:990-8

9 2D-Ultrasound Intima-media thickness C YV YV Blood-intima interface CCA CCA ICA media-adventitia interface Normal IMT (IMT= 0.6mm) Abnormal IMT (IMT= 1.05 mm) YV Presence of plaque (yes/no, number, size) ICA CCA Plaque definition: focal protrusion into the lumen >0.5 mm or >50% of the surrounding IMT or a diffuse thickness >1.5 mm.

10 Definition of Subclinical Atherosclerosis Subclinical atherosclerosis was defined as the presence of atherosclerotic plaques in the carotid, aortic, or iliofemoral territories or CACS 1. Extension of subclinical atherosclerosis was defined according to the number of vascular sites affected (right carotid, left carotid, abdominal aorta, right iliofemoral, left iliofemoral, and coronary arteries). Participants were classified as disease free (0 vascular sites affected) or as having focal (1 site), intermediate (2 3 sites), or generalized (4 6 sites) atherosclerosis. Fernández-Friera L, et al. Circulation. 2015;131:

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12 Demographics & Risk Factors Fernández-Friera L, et al. Circulation. 2015;131:

13 CV Risk Profile & Gender # CVRF (63.3%) (36.7%) N=2,586 Mean age 46.8 y N=1,503 Mean age 45 y 0 34,6 % 59,9 % 1 43,3 % 31,1 % 2 18,6 % 8,2 % >2 3,4 % 0,7 % Fernández-Friera L, et al. Circulation. 2015;131:

14 Prevalence of subclinical atherosclerosis by vascular territory 36.9% CAROTID ARTERIES Presence of plaque 24.1% 26.1% CORONARY ARTERIES Calcium score>=1 4.5% 27.2% ABDOMINAL AORTA 22.8% Presence of plaque 54.3% 30.1% ILIO-FEMORAL ARTERIES Presence of plaque Subclinical disease 2D-us 64.1% 72.3% 1 vascular territory 1 plaque 49.9% Fernández-Friera L, et al. Circulation. 2015;131:

15 Prevalence of subclinical atherosclerosis by age and sex in each vascular territory Fernández-Friera L, et al. Circulation. 2015;131:

16 Systemic extent of subclinical atherosclerosis by age and gender Female *Vascular sites: right carotid, left carotid, abdominal aorta, right ilio-femoral, left ilio-femoral, coronary arteries (CACS 1)

17 Distribution of subclinical atherosclerosis according to FHS risk categories Fernández-Friera L, et al. Circulation. 2015;131:

18 3D-Ultrasound 3D-US of carotids and femorals Plaque volume (mm 3 ) H Sillesen, V Fuster, E Falk, P Muntendam 2009 (BioImage Study)

19 Plaque burden (mm 3 ) assesed by 3D-ultrasound & age and gender López-Melgar B, et al. (London ESC 2015)

20 Subclinical atherosclerosis & dietary patterns Peñalvo JL, et al (non published data)

21 PESA study flow: We are here ISO 9001 A.Fernandez-Ortiz, JJ Borreguero, JL Peñalvo et al. Am Heart J 2013; 166:990-8

22 Advanced Imaging Hybrid system: PET/MR PET MR ROTATE TABLE

23 Lipid-rich plaque MR images: characterization T1w: Hiperintense T2w: Hipointense Fibrous-rich plaque T1w: Isointense T2w: Hiperintense

24 RIGHT CAROTID ARTERY UPTAKE Image fusion: 18 FDGPET/RM

25 PESA: initial results Alícuotas Tipo de tubo Tipo de alícuotas 1 tubo de EDTA 9mL 8 alícuotas de 600µl de sangre EDTA 2 alícuotas de 600µl de buffy coat 3 alícuotas de 0.3ml de DNA aislado 1 tubo de EDTA de 9 ml 8 alícuotas de 600µl de plasma 1 tubo de gel de 7.5mL 8 alícuotas de 600µl de suero 1 tubo paxgene de 2.5mL 2 alícuotas de 5mL de RNA sin aislar Volumen total: 28mL 32x4066x3= stored samples!! *** Blood sampling

26 Emerging cardiovascular risk factors Epigenome (Epigenetic marks)

27 Plasmatic proteomic biomarkers for early atherosclerosis Project objectives: To develop a novel semi-targeted quantitative proteomics technique that would combine in the same analysis the multiplexing quantitative power of DDA (TMT- 10-plexed) with the higher sensitivity of PRM for pre-selected precursor candidates, and, to overcome the ratio-compression effect of the MS2-based multiplexed techniques, with the MS3 multi-notch capability of the new MSinstruments. To apply the newly developed technology to a cohort of 140 individuals from the PESA study, expecting to discover new early ASCVD protein biomarkers. To establish a new panel of protein biomarkers that associates with early-onset ASCVD. CNIC: J. Vázquez, E. Calvo, E. Bonzón

28 Searching for novel biomarkers in CVD Role of metabolomics

29 Telomeres & Subclinical Atherosclerosis Objective: Investigate how leukocyte telomere length (LTL) and the rate of telomere ablation relate to atherosclerosis initiation and progression. telos: parte Los telómeros son capuchones que protegen los extremos de los cromosomas. Contienen una secuencia de ADN repetida muchas veces y proteínas asociadas que son necesarias para mantener su integridad. La enzima telomerasa es esencial para el mantenimiento de la longitud de los telómeros. TELÓMERO meros: final PESA participants - 6 ml of additional blood sample for PBMC isolation using Hystopaque followed by freezing in 80% FBS 20% DMSO Valentín Fuster, Vicente Andrés, María Blasco et al.

30 TAN SNIP TRANS-ATLANTIC NETWORK TO STUDY STEPWISE NONINVASIVE IMAGING AS A TOOL FOR CARDIOVASCULAR PROGNOSIS & PREVENTION Valentín Fuster AIM 1: Interventional Sub-study of PESA cohort study JM Castellano, JM Fernández-Alvira Objective: study whether a personalized worksite-based lifestyle intervention, driven by imaging data (2D and 3D-us and CT-scan) results in changes in health behavior, improved control of risk factors and reduced progression of subclinical atherosclerosis plaque burden (SAPB). AIM 4: Validation and discovery of novel biomarkers (omics) J. Vázquez, JM Ordovás Objective: Develop novel algorithms that incorporate omics, SAPB, and established FRS to improve personalized risk assessment

31 TANSNIP AIM1 INTERVENTION: 12 x 1-hour personalized lifestyle counseling Activity monitor to selfmonitor physical activity Sit-to-stand workstation at their workplace

32 TANSNIP AIM1 DESIGN TANSNIP AIM4 Blood samples

33 Supported by a Spanish Ministery Of Health Grant (FIS 2015) Subclinical Myocardial Disease by Cardiac Magnetic Resonance Imaging and its Association with Atherosclerosis Burden L. Fernández-Friera, B. Ibañez Objectives: - To determine the relationship between subclinical myocardium damage determined by pre and post-equilibrium contrast T1 and T2-mapping using cardiac MR and subclinical atherosclerosis burden. Study population 950 individuals who had baseline vascular PET/MRI and will returned for follow-up vascular MRI to CNIC - To characterize the associations of traditional and emerging CV risk factors, including genetics and omics, with LV structural, functional and tissuecomposition changes, mainly fibrosis and inflammation, in a large-population based study.

34 Some conclusions: Subclinical atherosclerosis is highly prevalent in the PESA cohort, with nearly half the participants presenting with intermediate or generalized disease. Prevalence is higher in men and in the iliofemoral arteries, highlighting the value of screening this territory. A substantial proportion of low-risk participants had subclinical atherosclerosis, imaging of early atherosclerosis may be particularly valuable in this setting. Long-term follow-up will determine whether detection of early atherosclerosis has any impact on predicting and preventing cardiovascular events.

35 Some conclusions: The PESA study is expected to identify new imaging and biological factors associated with the presence and progression of atherosclerosis in asymptomatic people and will help to establish a more personalized management of medical care.

36 PESA-CNIC-SANTANDER 2015 TEAM Informática Clinica Radiología Coordinación Citaciones Actividad Fisica Dirección Imagen avanzada Psicosociales Laboratorio Imagen basica Thank you for your attention!

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