ABSTRACT
Background: Different imaging techniques, such as echocardiography (ECHO) and CT, allow to assess aortic stenosis (AS) severity and could be used to study its progression. But only PET/CT open opportunities to assess activity of valvular inflammation and calcification in vivo. The aim of this study was to assess prognostic value of valvular inflammation and calcification measured by 18F-FDG and 18F-NaF PET/CT in patients with tricuspid (TAV) and bicuspid aortic valve (BAV). Methods: The study included 71 patients aged 40-70 years with mild, moderate and severe asymptomatic calcific AS. Patients were divided into two groups according to valve morphology: with BAV and TAV. All patients underwent standard ECHO, CT calcium scoring PET/CT with 18F-NaF and 18F-FDG. All patients were evaluated during a follow-up visit with evaluation of ECHO parameters. (16.8 ± 4.2 months). Results: TAV and BAV groups were comparable in AS severity by ECHO (peak aortic jet velocity (Vmax): 2.90 [2.60; 3.50] vs. 2.96 [2.55; 3.31] m/s, p = 0.83). TBR max 18F-FDG did not vary in TAV and BAV patients (1.15 [1.06; 1.23] vs. 1.11 [1.03; 1.20], p = 0.39). Both groups did not differ in valvular calcification degree (Agatston score 1,058 [440; 1798] vs. 1,128 [533; 2,360], p = 0.55) and calcification activity assessed by 18F-NaF uptake level (TBR max 1.50 [1.30; 1.78] vs. 1.48 [1.27; 1.83], p = 0.97). 18F-NaF TBR max was associated with AS severity measured by Vmax in men and women with TAV (r = 0.54; p = 0.04 vs. r = 0.53; p = 0.03). In BAV group this relationship was true only in female patients (r = 0.1; p = 0.67 vs. r = 0.7; p = 0.0004). There was no association between Vmax and TBR max 18F-FDG was revealed in TAV and BAV groups. During follow-up period, the most important positive predictors of AS progression in TAV obtained by multinomial logistic regression analysis were Vmax, and 18F-NaF TBR. Whereas in BAV the highest predictive value showed model included age and Vmax. Conclusion: 18F-NaF PET/CT may be considered as the valuable predictor for hemodynamic progression of calcific AS in case of TAV. 18F-FDG PET/CT does not play a significant role to predict the AS progression.
ABSTRACT
The study aimed to compare composition of peripheral blood T-cell subsets and assess their surface expression of CD39 and CD73 ectonucleotidases in patients with severe and moderate aortic stenosis (AS) as well as to evaluate involvement of T-cell-mediated immune processes in valve calcification. The study was performed with 38 patients suffering from severe calcified aortic stenosis (SAS), 33 patients with MAS, and 30 apparently healthy volunteers (HVs). The relative distribution and percentage of T-cell subsets expressing CD39 and CD73 were evaluated by flow cytometry. T helper (Th) and cytotoxic T-cell subsets (Tcyt) were identified by using CD3, CD4, and CD8 antibodies. Regulatory T cells (Tregs) were characterized by the expression of CD3, CD4, and high IL-2R alpha chain (CD25high) levels. CD45R0 and CD62L were used to assess differentiation stage of Th, Tcyt, and Treg subsets. It was found that MAS and SAS patients differed in terms of relative distribution of Tcyt and absolute number of Treg. Moreover, the absolute number of Tcyt and terminally differentiated CD45RA-positive effector T-cells (TEMRA) subset was significantly higher in SAS vs. MAS patients and HVs. However, the absolute and relative number of naïve Th and the absolute number of Treg were significantly higher in MAS vs. SAS patients; the relative number of naïve Tregs was significantly (p < 0.01) decreased in SAS patients. It was shown that CD73 expression was significantly higher in SAS vs. MAS patients noted in all EM, CM, TEMRA, and naïve Th cell subsets. However, only the latter were significantly increased (p = 0.003) in patients compared with HVs. SAS vs. MAS patients were noted to have significantly higher percentage of CD73+ EM Tcyt (p = 0.006) and CD73+ CM Tcyt (p = 0.002). The expression of CD73 in patients significantly differed in all three Treg populations such as EM (p = 0.049), CM (p = 0.044), and naïve (p < 0.001). No significant differences in CD39 expression level was found in MAS and SAS patients compared with the HV group. Overall, the data obtained demonstrated that purinergic signaling was involved in the pathogenesis of aortic stenosis and calcification potentially acting via various cell types, wherein among enzymes, degrading extracellular ATP CD73 rather than CD39 played a prominent role.
ABSTRACT
Background. The NOTCH pathway is known to be important in the pathogenesis of calcific aortic valve disease, possibly through regulators of osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK), and its ligand (RANKL) system. The purpose of the present study was to search for possible associations between NOTCH1 gene mutations and circulating levels of OPG and soluble RANKL (sRANKL) in patients with aortic stenosis (AS). Methods. The study was performed on 61 patients with AS including 31 with bicuspid and 30 with tricuspid aortic valves. We applied a strategy of targeted mutation screening for 10 out of 34 exons of the NOTCH1 gene by direct sequencing. Serum OPG and sRANKL levels were assessed. Results. In total, 6 genetic variants of the NOTCH1 gene including two new mutations were identified in the study group. In an age- and arterial hypertension-adjusted multivariable regression analysis, the serum OPG levels and the OPG/sRANKL ratio were correlated with NOTCH1 missense variants. All studied missense variants in NOTCH1 gene were found in Ca(2+)-binding EGF motif of the NOTCH extracellular domain bound to Delta-like 4. Conclusion. Our results suggest that the OPG/RANKL/RANK system might be directly influenced by genetic variants of NOTCH1 in aortic valve calcification.
