N. V. Hernandez1, S. Grenon1,2, J. L. Ramirez1, S. A. Khetani1,2, W. J. Gasper1,2, D. Lindqvist3,4, O. M. Wolkowitz3, N. K. Hills5, G. J. Zahner1 2Veterans Affairs Medical Center,Vascular Surgery Section,San Francisco, CA, USA 3University Of California – San Francisco,Department Of Psychiatry,San Francisco, CA, USA 4Lund University,Department Of Psychiatry,Lund, , Sweden 5University Of California – San Francisco,Department Of Epidemiology And Biostatistics,San Francisco, CA, USA 1University Of California – San Francisco,Department Of Surgery,San Francisco, CA, USA
Introduction:
Inflammation is an important factor in the pathogenesis of peripheral artery disease (PAD) and is known to play a role in depression. The present study seeks to understand the association between depressive symptoms and inflammation in patients with PAD.
Methods:
A cross-sectional sample of 117 patients with PAD (97% male and 76% Caucasian) was recruited from the San Francisco Veterans Affairs Medical Center. Inclusion criteria included claudication symptoms with an abnormal ankle-brachial index (ABI < 0.9) or a history of prior peripheral revascularization for symptomatic PAD. Patients taking immunosuppressants and those with renal, liver, or other acute disease states were excluded. Patients were categorized into three subgroups based upon worsening depressive symptoms defined by Patient Health Questionnaire (PHQ-9) scores: no symptoms (score of 0-4, n=62), mild symptoms (score of 5-9, n=33), and depression (score ≥10, n=22). Serum levels of high-sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (ICAM-1), and tumor necrosis factor-alpha (TNF-α ) were assayed and log-transformed for multivariable analysis. Additionally, inflammatory markers were standardized and summed to create a total inflammatory score.
Results:
Patients with depression exhibited a greater comorbidity with PTSD compared to patients with mild symptoms or no symptoms (57% vs 21% and 12% respectively, p≤.001) and were more likely to be Caucasian (95% vs 85% and 65% respectively, p=.02). In unadjusted analysis, inflammation levels trended upward among groups with no symptoms, mild symptoms, and depression, reported in respective order: IL-6 (medians: 1.17, 1.30, 1.65 IQRs: 0.93-1.73, 0.89-1.88, 1.20-2.41 pg/mL, p=.10), CRP (medians: 2.30, 3.65, 4.0 IQRs: 1.4-4.1, 1.75-6.0, 1.9-8.5 mg/L, p=.06), and total inflammatory score (medians: -1.1, -0.33, 1.3 IQRs: -1.88-0.77, -1.64-0.86, -1.07-3.21, p=.06). In a multivariable analysis that controlled for age, ethnicity, ABI, and atherosclerotic risk factors, mild symptoms and depression were predictive of a higher total inflammatory score (mild symptoms vs. no symptoms p=.04, and depression vs. no symptoms p=.007). IL-6 was marginally higher in the mild symptoms group (p=.06) and significantly higher in the depression group (p=.006) compared to the group with no symptoms. CRP, ICAM-1, and TNF-α levels all trended upward among groups with depressive symptoms, but did not reach statistical significance.
Conclusions:
After controlling for risk factors and PAD severity, depression severity was independently associated with greater inflammation in PAD, as demonstrated by increasing levels of the total inflammatory score and of IL-6. Future research should examine the strength and directionality of this relationship through larger prospective cohort studies as well as investigate the pathophysiological mechanism responsible.