Dissertation committee:
Κίμων Σταματελόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Αθανάσιος Πρωτογέρου, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευστάθιος Μανιός, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνος Στέλλος, Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Χαϊδελβέργης
Ιγνάτιος Οικονομίδης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Αλέξανδρος Μπριασούλης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Γεωργιόπουλος, Επίκουρος Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Πατρών
Summary:
Background and aims: Amyloid-beta (40) (Αb40), a proinflammatory and pro-atherosclerotic peptide, is associated with concurrent subclinical atherosclerotic cardiovascular disease (ASCVD) and with major adverse cardiac events in both primary and secondary prevention settings conferring additive and reclassification value over traditional risk factors and risk scores. This evidence supports the hypothesis that Αβ40 could be a biomarker of ASCVD. However, mechanistic data on the association of Αb40 with in vivo morphological characteristics of atherosclerosis related with plaque vulnerability are not available. We aimed to examine the association of Αβ40 levels with characteristics of the carotid artery wall in the general population.
Methods: We analyzed consecutively recruited individuals with clinically overt ASCVD (n=138) and without ASCVD (n=342) from the Athens Cardiometabolic cohort. Carotid atherosclerosis was assessed by high-resolution ultrasonography and the images were analyzed using a dedicated software (AMS v3.03). Grey scale median (GSM) of intima-media thickness (IMT) and plaques, reflecting plaque composition and vulnerability, was the primary end-point of the study. The total and maximal plaque areas were also assessed. In n=56 patients undergoing carotid endarterectomy, histological plaque features were analysed. Vascular markers in patient without clinically overt ASCVD were assessed at two time-points (median of 35.5 months from baseline). Plasma Αb40 levels were measured at baseline.
Results: Increased Αβ40 levels were associated with higher odds for lower IMT GSM and lower plaque GSM in all carotid sites (OR=2.54 increase for highest vs lower Αβ40 tertiles 95% CI: 1.35, 4.79, p=0.004 for IMT GSM and OR= 4.78 increase for highest vs lower Αβ40 tertiles 95% CI: 1.69, 13.52, p=0.025 for plaque GSM) after adjustment for the core model and sum of carotid wall thickness. Moreover, increased Αβ40 levels were associated with increased odds for higher total and maximal plaque area (OR= 3.81 increase for highest vs lower Αβ40 tertiles 95% CI: 1.35, 10.75, P=0.011, OR=4.68 increase for highest vs lower Αβ40 tertiles 95% CI: 1.68, 14.21, P=0.002 for maximal and total plaque area, respectively). These associations did not change after further adjustment for hs-CRP and lipid-lowering treatment. In patients with stable coronary artery disease and acute coronary syndrome, Aβ40 levels were not associated with markers of carotid plaque and IMT (p>0.05 for all). Importantly, increased Αβ40 levels were associated with decreasing or persistently low GSM levels of IMT and plaque (OR= 2.78 increase for highest vs lower Αβ40 tertiles 95% CI: 1.46, 3.68, p=0.002 for IMT GSM and OR=4.5 increase for highest vs lower Αβ40 tertiles 95% CI: 1.63, 12.44, p=0.004, for plaque GSM) at follow-up after adjustment for the core model and sum of carotid wall thickness. Moreover, increased Αβ40 levels were associated with higher odds for increased or persistently high carotid atherosclerosis burden (OR=4.49 95% increase for highest vs lower Αβ40 tertiles CI: 1.54, 13.09, p=0.006 for delta of maximum plaque area and OR=5.15 increase for highest vs lower Αβ40 tertiles increase 95% CI: 1.70, 15.58, p=0.004 for delta of total of plaque area) at follow-up after adjustment for the core model. These associations did not materially change after further adjustment for hs-CRP and lipid-lowering treatment. In the histological analysis, Ab40 levels were associated with lower incidence of calcified plaques (OR=0.222 95% CI: 0.055-0.895, p=0.034) and plaques without high-risk features (OR=0.177, 95% CI: 0.034, 0.918, p=0.039).
Conclusions: In patients without clinically overt ASCVD, high circulating Αβ40 levels are cross-sectionally and longitudinally associated with markers of carotid plaque vulnerability irrespective of traditional risk factors, systemic inflammation and the extent of atherosclerotic burden. Moreover, Aβ40 levels were associated with histological features of lower plaque calcification and lower incidence of plaques without high-risk features in severely stenotic plaques from patients undergoing endarterectomy These findings support experimental evidence linking Αβ40 with plaque vulnerability possibly mediating its established association with major adverse cardiovascular events.
Keywords:
Carotid plaque echogenicity, Subclinical atherosclerosis, Cardiovascular disease, Amyloid-beta
