Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study

Abstract

Objectives: This study hypothesized that there is an association between chronic stress (as indexed by resting amygdalar activity [AmygA]), hematopoietic system activity (HMPA), and subclinical cardiovascular indexes (aortic vascular inflammation [VI] and noncalcified coronary plaque burden [NCB]) in psoriasis (PSO). The study also hypothesized that treatment of PSO would improve these parameters.

Background: PSO is a stress-related chronic inflammatory condition that is associated with increased prevalence of subclinical cardiovascular disease (CVD). In individuals without PSO, stress has been linked to CVD through a serial biological pathway that involves the amygdala, hematopoietic tissues, and atherosclerotic plaques.

Methods: A total of 164 consecutive patients with PSO and 47 healthy volunteers underwent 18-fluorodeoxyglucose positron emission tomography/computed tomography scans for assessment of AmygA, HMPA, and VI, as well as coronary computed tomography angiography scans for quantifying NCB. Furthermore, a consecutive subset of 30 patients with severe PSO (Psoriasis Area Severity Index Score >10) were followed at 1 year to assess the relationship between skin disease improvement and AmygA, HMPA, VI, and NCB.

Results: The PSO cohort was middle-aged (mean age: 50 years), had low cardiovascular risk (Framingham risk score: median: 3) and had mild to moderate PSO activity (median Psoriasis Area Severity Index Score: 5.6). AmygA was higher in patients with PSO compared to volunteer participants. AmygA was associated with HMPA (bone marrow activity: β = 0.20, p = 0.01) and subclinical CVD (VI: β = 0.31, p < 0.001; NCB: β = 0.27, p < 0.001) The AmygA-CVD association was in part mediated by HMPA (VI: 20.9%, NCB: 36.7%). Following 1 year of PSO treatment in those with severe disease, improvement in skin disease was accompanied by a reduction in AmygA, bone marrow activity, and VI, with no progression of NCB.

Conclusions: In PSO, a chronic inflammatory disease state, AmygA, which is a manifestation of chronic stress, substantially contributes to the risk of subclinical CVD. Additional studies that use psychometric measures of stress are required to explore therapeutic impact.

Keywords: amygdala; atherosclerosis; inflammation; psoriasis; stress.

Figure 1. CONSORT and Flow Diagram showing recruitment scheme.

A) Recruitment scheme for patients at the National Institutes of Health. ¹⁸FDG PET/CT: ¹⁸Fluorodeoxyglucose positron emission-computed tomography. B) Study design outlining the imaging modalities used to measure outcomes of interest at cross-section and over time.

Figure 1. CONSORT and Flow Diagram showing recruitment scheme.

A) Recruitment scheme for patients at the National Institutes of Health. ¹⁸FDG PET/CT: ¹⁸Fluorodeoxyglucose positron emission-computed tomography. B) Study design outlining the imaging modalities used to measure outcomes of interest at cross-section and over time.

Figure 2. Multiplanar coronary CT angiography derived reconstructed views of left anterior descending coronary artery in a patient with severe psoriasis.

CCTA reconstruction from severe psoriasis patient showing the left anterior descending coronary artery (left), planar reconstruction (right) depicting non-calcified plaque burden of the coronary artery, and transverse section (middle) revealing low-attenuation lipid-rich high-risk plaque (green and red).

Figure 3. Mediation analysis - amygdalar, bone marrow, and vascular disease in psoriasis (N=164).

A) Mediation analyses showing the indirect effect of bone marrow activity on the relationship between resting amygdalar and aortic vascular inflammatory activity. B) Mediation analyses showing the added effect of bone marrow activity on the relationship between resting amygdalar activity and non-calcified coronary plaque burden. *TBR: Target-to-background ratio; SUV: Standardized uptake value. Blue arrow: Total effect, Yellow arrow: Direct effect, Green arrow: Indirect effect **Likelihood ratio test: A) χ²=18.33, p<0.001, B) χ²=87.50, p<0.001 ***Model adjusted for Framingham risk score, waist-to-hip ratio, lipid treatment and C-reactive protein.

Figure 4. A psoriasis model showing stress leading to subclinical cardiovascular disease.

Amygdalar activity has been linked to cardiovascular disease through sympathetic nervous system pathways. We investigated an alternative pathway in an inflammatory disease state involving hematopoietic system activation, which in part mediates aortic vascular inflammation and non-calcified coronary plaque.

Figure 5. Amygdalar ¹⁸FDG uptake at baseline and one-year.

Representative fused ¹⁸Fluorodeoxyglucose positron emission-computed tomographic images^# (axial view) from a patient who had reduction in psoriatic skin disease severity, showing ¹⁸FDG uptake in amygdala at baseline (left) and one year (right). SUV: standardized uptake value Baseline: Target-to-background ratio (1.14) = Max Amygdala SUV (9.71)/Mean Temporal SUV (8.50) One-year: Target-to-background ratio (1.05) = Max Amygdala SUV (7.52)/Mean Temporal SUV (7.18) # Blue represent mild to moderate FDG uptake, yellow and green represent moderate FDG uptake and red represents highest FDG uptake.

Figure 6. Bone marrow ¹⁸FDG uptake at baseline and one year.

Representative fused ¹⁸Fluorodeoxyglucose positron emission-computed tomographic images^# (sagittal view) from a patient who had reduction in psoriatic skin disease severity, showing ¹⁸FDG uptake in T1 to L5 vertebrae at baseline (left) and one year (right). SUV: standardized uptake value Baseline: Max Amygdala SUV = 4.02 One-year: Max Amygdala SUV = 3.55 # Blue represent mild to moderate FDG uptake, yellow and green represent moderate FDG uptake and red represents highest FDG uptake.