Splenic Metabolic Activity Predicts Risk of Future Cardiovascular Events

Abstract

Objectives: In this study, we sought to determine: 1) whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte pro-inflammatory remodeling, and 2) whether splenic activity independently predicts the risk of cardiovascular disease (CVD) events. Background: Preclinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of pro-inflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether: 1) a cardiosplenic axis exists in humans, and 2) whether splenic activation relates to CVD risk. Methods: 18FDG-PET imaging was performed in 508 individuals across two studies. In the first study we performed FDG-PET imaging in 22 patients with recent ACS and 22 controls. FDG uptake was measured in spleen and arterial wall while pro-inflammatory gene expression of circulating leukocytes was assessed by qRT-PCR. In a second study, we examined the relationship between splenic tissue FDG uptake with subsequent CVD events during follow-up (median 4 years) in 464 patients who previously had undergone FDG-PET imaging. Results: Splenic activity increased after ACS and was significantly associated with multiple indices of inflammation: a) up-regulated gene expression of pro-inflammatory leukocytes, b) increased C-reactive protein, and c) increased arterial wall inflammation (FDG uptake). Moreover, in the second study, splenic activity (≥median) was associated with increased risk of CVD events (HR [95% CI] =3.3 [1.5, 7.3], p=0.003) which remained significant after adjustment for CVD risk factors (HR = 2.26 [1.01, 5.06], p=0.04) and for arterial FDG uptake (HR=2.68 [1.5–7.4], p=0.02). Conclusions: Our findings demonstrate increased splenic metabolic activity after ACS and its association with pro-inflammatory remodeling of circulating leukocytes. Moreover, we observe that metabolic activity of the spleen independently predicts risk of subsequent CVD events. Collectively, these findings provide evidence of a cardiosplenic axis in humans similar to that shown in preclinical studies.