A score including ADAM17 substrates correlates to recurring cardiovascular event in subjects with atherosclerosis

Abstract

a b s t r a c tObjective: Atherosclerosis disease is a leading cause for mortality and morbidity. The narrowing/rupture of a vulnerable atherosclerotic plaque is accountable for acute cardiovascular events. However, despite of an intensive research, a reliable clinical method which may disclose a vulnerable patient is still unavailable.Approach and results: We tested the association of ADAM17 (A Disintegrin and Metallo Protease Domain 17) circulating substrates (sICAM-1, sVCAM-1, sIL6R and sTNFR1) with a second major cardiovascular events [MACEs] (cardiovascular death, peripheral artery surgeries, non-fatal myocardial infarction and non-fatal stroke) in 298 patients belonging to the Vascular Diabetes (AVD) study. To evaluate ADAM17 activity we create ADAM17 score through a RECPAM model. Finally we tested the discrimination ability and the reclassification of clinical models. At follow-up (mean 47 months, range 1e118 months), 55 MACEs occurred (14 nonfatal MI, 14 nonfatal strokes, 17 peripheral artery procedures and 10 cardiovascular deaths) (incidence ¼ 7.8% person-years). An increased risk for incident events was observed among the high ADAM17 score individuals both in univariable (HR 19.20, 95% CI 15.82e63.36, p < 0.001) and multivariable analysis (HR 3.42, 95% CI 1.55 e7.54, p < 0.001). Finally we found that ADAM17 score significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement ¼ 9%, p ¼ 0.012) and correctly reclassifying 10% of events and 41% of non-events resulting in a cNRI ¼ 0.51 (p ¼ 0.005). Conclusion: We demonstrated a positive role of ADAM17 activity to predicting CV events. We think that an approach that targets strategies beyond classic cardiovascular risk factors control is necessary in individuals with an established vascular atherosclerosis.

Gene silencing of TACE enhances plaque stability and improves vascular remodeling in a rabbit model of atherosclerosis

“…In this study, we found that gene silencing of TACE markedly decreased the serum levels of sTNF-α, sICAM-1, sVCAM-1 and sMCP-1 with the most significant reduction of sTNF-α, suggesting that TNF-α is likely the most important substrate of TACE. Previous studies found that the deficiency of TNF-α in ApoE −/− mice reduced the lesion size of atheroma 27 , and a recent elegant study by Federici M’s group clearly demonstrated that patients with a higher ADAM 17 score including sICAM-1 and sVCAM-1 exhibited increased cardiovascular events 28 . The present study revealed the independent role of sTNF-α and sICAM-1 in plaque vulnerability in our animal model, which lent support to Federici M’s study.…”

The predictive role of interleukin 6 trans-signalling in middle-aged men and women at low-intermediate risk of cardiovascular events

“…Research on sIL6R is inconsistent, with two case control studies displaying no difference in sIL6R levels between ischemic stroke cases and controls whereas levels of IL6 were higher in cases (160,178). Moreover, in subjects with manifest CVD, sIL6R showed no association with recurrent CVE while in post-MI patients, high circulating levels of sIL6R were associated with increased risk of recurrent CVE (151,179). Levels of sgp130 have been demonstrated to be transiently reduced after stroke and to correlate positively with blood pressure and carotid intima media thickness in stroke patients (160,180).…”

A Disintegrin and Metalloprotease 17 in the Cardiovascular and Central Nervous Systems

“…ADAM17 activity is correlated to adverse clinical outcomes in acute coronary atherosclerosis (Satoh et al, 2008 ; Gutiérrez-López et al, 2011 ; Rizza et al, 2015 ). An important group of substrates for ADAM17 includes adhesion molecules such as ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), L-selectin, and others.…”

“…Local over-activity of ADAM17 may weaken atherosclerotic plaques, causing its rupture. In this context, Rizza et al suggested that measuring ADAM17 activity may predict major cardiovascular events in subjects with established atherosclerosis (Rizza et al, 2015 ). Although ADAM17 activity was evaluated in an indirect manner through the measurement of its substrates in circulation, authors suggest that it is reasonable to assume that the increase in these molecules is related to increased ADAM17 activity in inflammatory sites.…”

“…These data confirm that ADAM17 is an important regulator of TNF-α maturation and may be a potential target for the inhibition of cellular TNF-α production in cardiovascular disorders. In addition, it was demonstrated that an imbalance between ADAM17 and TIMP3 is characteristic of unstable carotid plaques (Menghini et al, 2013 ; Rizza et al, 2015 ). On the other hand, treatment with soluble TIMP3 can impart a neuro-protective effect and enhance neurite out-growth both in vitro and in animals with brain-injury, in vivo by activating the Akt-mTORC1 signaling pathway (Gibb et al, 2015 ).…”