Abstract
Background:A coronary artery calcium (CAC) score of zero confers a low but nonzero risk of atherosclerotic cardiovascular events (CVD) in asymptomatic patient populations, and additional risk stratification is needed to guide preventive interventions. Soluble tumor necrosis factor receptors (sTNFR-1 and sTNFR-2) are shed in the context of TNF-alpha signaling and systemic inflammation, which play a role in atherosclerosis and plaque instability. We hypothesized that serum sTNFR-1 concentrations may aid in cardiovascular risk stratification among asymptomatic patients with a CAC score of zero.Methods:We included all participants with CAC=0 and baseline sTNFR-1 measurements from the prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA). The primary outcome was a composite CVD event (myocardial infarction, stroke, coronary revascularization, cardiovascular death).Results:The study included 1471 participants (mean age 57.6 years, 64% female), with measured baseline sTNFR-1 ranging from 603 pg/mL to 5544 pg/mL (mean 1294 pg/mL ±378.8 pg/mL). Over a median follow-up of 8.5 years, 37 participants (2.5%) experienced a CVD event. In multivariable analyses adjusted for Framingham Score, doubling of sTNFR-1 was associated with a 3-fold increase in the hazards of CVD (HR 3.0, 95% CI: 1.48-6.09, P = 0.002), which remained significant after adjusting for traditional CVD risk factors individually (HR 2.29; 95% CI: 1.04-5.06, P=0.04). Doubling of sTNFR-1 was also associated with progression of CAC >100, adjusted for age (OR 2.84, 95% CI: 1.33-6.03, P=0.007).Conclusions:sTNFR-1 concentrations are associated with more CVD events in participants with a CAC score of zero. Utilizing sTNFR-1 measurements may improve cardiovascular risk stratification and guide primary prevention in otherwise low-risk individuals.
Highlights
The pathogenesis of coronary artery disease (CAD) is complex and is characterized by abnormal lipid metabolism and chronic inflammation, leading to endothelial dysfunction and subintimal deposition of low-density lipoproteins (LDL) [1]
The concept of causality between inflammation and atherosclerosis has been proposed with the CANTOS trial, which showed that anti-inflammatory therapy with canakinumab resulted in a significant reduction in adverse cardiovascular events [6]
A total of 6814 participants were included in the Multi-Ethnic Study of Atherosclerosis (MESA)
Summary
The pathogenesis of coronary artery disease (CAD) is complex and is characterized by abnormal lipid metabolism and chronic inflammation, leading to endothelial dysfunction and subintimal deposition of low-density lipoproteins (LDL) [1]. Soluble tumor necrosis factor receptors (sTNFR-1 and sTNFR-2) are shed during TNF-α cytokine signaling. Circulating levels of sTNFR-1 and sTNFR-2 have been shown to increase with TNF-α activity in response to pro-inflammatory stimuli [7]. They are useful markers of TNF-α activity due to their long half-lives in the serum. A coronary artery calcium (CAC) score of zero confers a low but nonzero risk of atherosclerotic cardiovascular events (CVD) in asymptomatic patient populations, and additional risk stratification is needed to guide preventive interventions. Soluble tumor necrosis factor receptors (sTNFR-1 and sTNFR-2) are shed in the context of TNF-alpha signaling and systemic inflammation, which play a role in atherosclerosis and plaque instability. We hypothesized that serum sTNFR-1 concentrations may aid in cardiovascular risk stratification among asymptomatic patients with a CAC score of zero
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