Inflammation and early atherosclerosis beyond traditional risk factors: an imaging study

BACKGROUND AND AIMS: Understanding how inflammation contributes to subclinical atherosclerosis (SA) plaque burden, beyond the impact of established cardiovascular risk factors, holds significant implications for the success of preventive strategies focused on the reduction of atherosclerotic cardiovascular disease. The aim of this study was to investigate the relative contribution of inflammation, low-density lipoprotein cholesterol (LDLc), and systolic blood pressure (SBP), as determinants of SA plaque burden in a cohort of middle-aged, asymptomatic individuals, using non-invasive imaging techniques. METHODS: Participants from the Progression of Early Subclinical Atherosclerosis (PESA) study (median age 45 years) underwent longitudinal screening every 3 years (baseline, 3- and 6-year visits) involving serial blood testing [including white blood cell (WBC) count, fibrinogen, oxidized LDLc, and high-sensitivity C-reactive protein], physical examinations and imaging assessments with three-dimensional vascular ultrasound of peripheral arteries, and coronary artery calcium quantification. Global plaque volume (GPV, mm3; bilateral carotid plus femoral plaque burden) at 6-year follow-up was the primary outcome. Multivariable linear regression and proportional odds models determined the link of GPV to both inflammatory markers and established cardiovascular risk factors. RESULTS: Of the 3471 participants, 58% had SA (GPV >0 mm3) at 6-year follow-up. WBC count had the strongest statistical associations with 6-year SA burden after adjusting for age, sex, baseline LDLc, and mean SBP, with an estimated 32.6% increase in GPV per one standard deviation (SD) increase in WBC (Z = 7.33, P < 1 × 10-10). GPV at 6 years increased 40.9% per one SD increase in baseline LDLc and 42.7% per one SD increase in mean SBP (Z = 8.80 and Z = 7.97, respectively, both P < 1 × 10-10; their SDs were 29.4 mg/dL and 11.5 mmHg, respectively), followed by fibrinogen (16.8% increase in GPV per one SD increase, Z = 3.91, P < .0001). High-sensitivity C-reactive protein was not predictive of greater GPV at 6 years (Z = 1.36, P = .174). For WBC, the marked trend in risk occurred only at levels above its median. Similar patterns were observed for separate analyses of carotid and femoral plaque volumes, and coronary artery calcium. Increasing levels of WBC and fibrinogen were also associated with a greater anatomical spread of disease. CONCLUSIONS: Inflammation contributes to SA burden, as assessed by direct plaque quantification, beyond the effects of LDLc and SBP. These findings indicate that inflammation, captured through the use of systemic inflammatory markers, is a risk factor relevant across the entire continuum of atherosclerosis, exerting a deleterious impact comparable to that of LDLc and SBP.