Atherosclerosis and its consequences are the most common causes of death worldwide. Lipid accumulation and associated inflammatory processes are critical to atherosclerosis progression. Investigators from Projects 1 and 2 recently observed that chronic psychosocial stress accelerates hematopoiesis and promotes inflammation in atherosclerotic mice. It is currently unknown if this is relevant in humans. Post-traumatic stress disorder (PTSD), triggered by exposure to extreme traumatic events, is associated with elevated circulating markers of inflammation and higher risk for MI. PTSD patients therefore provide a unique opportunity to study the mechanisms linking chronic psychosocial stress and atherosclerosis. In Project 3 we will employ innovative PET combined with magnetic resonance imaging (PET/MRI) to simultaneously study the hematopoietic system, the artery wall, and the brain's fear system, which comprises the amygdala and anterior cingulate cortex (ACC), to elucidate the relationship between psychosocial stress and systemic inflammation/atherosclerosis in a two center clinical study looking at: I) individuals with PTSD, II) individuals without PTSD but with exposure to severe psychosocial trauma (Trauma Control), and III) matched volunteers with neither PTSD nor exposure to trauma (Healthy Control). Participants in the three study groups, recruited from urban settings in New York and Boston, will be group-matched by age, gender, and Framingham risk scores (FRS). We will recruit 80 subjects in each group and in Aim 1, investigate the relationship between PTSD and atherosclerotic inflammation and burden measured by PET/MRI.
In Aim 2, we will examine the relationships between brain's fear circuit responsiveness to threat assessed by functional MRI (fMRI) and white matter integrity assessed by diffusion tensor imaging (DTI) and relate these data to hematopoietic system activation, and vascular inflammation measured by fluorodeoxyglucose (FDG)-PET and atherosclerotic burden measured by MRI. Additionally these parameters will also be related to blood hematopoietic progenitor migration measured using multiparametric fluorescence-activated cell sorting (FACS). Together, these data will provide a very unique picture of the multi-system link between the human brain, hematopoietic organs, inflammatory cells, and the artery wall.

Public Health Relevance

Project 3 of this Program Project Grant examines the relationship between psychosocial stress and its relationship with atherosclerotic inflammation, cell proliferation and burden using novel PET/MRI. Individuals with post-traumatic stress disorder, trauma controls and healthy controls will be recruited into a two center clinical study. We will use functional MRI to examine the relationship between activation of fear circuits in the brain and relate these data to hematopoietic system activation, and vascular inflammation measured by FDG- PET, and atherosclerotic burden measured by MRI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL131478-01A1
Application #
9209356
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Danthi, Narasimhan
Project Start
Project End
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Seijkens, Tom T P; van Tiel, Claudia M; Kusters, Pascal J H et al. (2018) Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis. J Am Coll Cardiol 71:527-542
Ishai, Amorina; Osborne, Michael T; Tung, Brian et al. (2018) Amygdalar Metabolic Activity Independently Associates with Progression of Visceral Adiposity. J Clin Endocrinol Metab :
Braza, Mounia S; van Leent, Mandy M T; Lameijer, Marnix et al. (2018) Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance. Immunity 49:819-828.e6
Fayad, Zahi A; Swirski, Filip K; Calcagno, Claudia et al. (2018) Monocyte and Macrophage Dynamics in the Cardiovascular System: JACC Macrophage in CVD Series (Part 3). J Am Coll Cardiol 72:2198-2212
Braza, Mounia S; Conde, Patricia; Garcia, Mercedes et al. (2018) Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance. Am J Transplant 18:1247-1255
Duivenvoorden, Raphaël; Mulder, Willem J M (2018) Imaging Tropoelastin in Atherosclerosis. Circ Cardiovasc Imaging 11:e008147
Senders, Max L; Mulder, Willem J M (2018) Targeting myeloperoxidase in inflammatory atherosclerosis. Eur Heart J 39:3311-3313
Senders, Max L; Hernot, Sophie; Carlucci, Giuseppe et al. (2018) Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis. JACC Cardiovasc Imaging :
Senders, Max L; Que, Xuchu; Cho, Young Seok et al. (2018) PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis. J Am Coll Cardiol 71:321-335
Calcagno, Claudia; Fayad, Zahi A (2017) Intraplaque and Cellular Distribution of Dextran-Coated Iron Oxide Fluorescently Labeled Nanoparticles: Insights Into Atherothrombosis and Plaque Rupture. Circ Cardiovasc Imaging 10:

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