No abstract

IntroductIon Aortic stenosis (AS) is the most common valvular heart disease in adults, with the highest prevalence among elderly patients. Aortic valvular lesions have some similarities to atherosclerosis including chronic inflammation, the presence of lipoproteins, cholesterol, macrophages, T cells, 1 and calcification. 2 Growing evidence indicates that AS is an active, potentially modifiable inflammatory process.In contrast to multiple cytokines involved in the development of AS, adipocytokines in AS have attracted less inter est despite their role in atherosclerosis. Adiponectin, leptin, and resistin play a major role in glucose meta bolism, insulin

This study is the first to show that AVS is characterized by increased plasma Lp-PLA2 levels associated with the severity of AVS, which suggests active involvement of Lp-PLA2 in the pathogenesis of AVS.

BackgroundWe evaluated exercise-induced changes in the profile of circulating cytokines and growth factors in patients with AS.MethodsWe studied 32 consecutive asymptomatic moderate-to-severe AS patients and 32 age and sex-matched controls. Plasma levels of interleukin (IL)-6, IL-10, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-β were measured at 4 time points, i.e. at rest, at peak bicycle exercise, one hour and 24 hours after a symptom-limited exercise.ResultsExercise increased all the 5 markers in both groups (all p<0.0001). The maximum levels of all tested cytokines were higher in the AS group (all p<0.05) compared with controls. In AS patients the highest levels of VEGF, IL-6, and IL-10 were observed one hour after exercise, while in the control group at peak exercise. In both groups maximum TGF- β levels were observed one hour after exercise. HGF levels were higher at peak and one hour after test in the AS group (p = 0.0001), however the maximum value in AS was observed at peak while in controls after test. In both groups TGF-β was the only marker that remained increased 24 hours after exercise compared with the value at rest (p = 0.0001). The cytokines and growth factors showed no association with heart rate and the workload.ConclusionIn asymptomatic patients with moderate-to-severe AS, exercise produces a different pattern of changes in circulating cytokines and growth factors, and maximum levels of all tested cytokines were significantly higher in AS patients compared with the control group.

Asymptomatic moderate-to-severe AS patients respond to exercise with more pronounced and prolonged increase in thrombin generation, together with impaired fibrinolysis as compared to controls. Repeated episodes of exercise-induced prothrombotic state in AS might contribute to the progression of this disease.

Background High hemodynamic forces similar to those observed in aortic stenosis (AS) can trigger neutrophil extracellular traps (NETs) formation. Purpose An involvement of NETosis in the AS pathogenesis is unknown. Methods We enrolled 25 patients, median age 64.9 [range, 58–69] years with isolated severe AS (transvalvular pressure gradient, PGmean: 53.6±11.3 mm Hg, PGmax: 85.1±17.6 mmHg), after aortic valve replacement and 15 healthy sex/age-matched controls. Autopsy-derived aortic valves from 5 healthy donors served as negative control. Transverse valve sections were taken from the mid and commissural areas of the leaflet and cryosectioned by a Leica CM 1520 cryostat. Valvular expression of citrullinated histone H3 (citH3), together with myeloperoxidase (MPO), and neutrophil elastase (NE) as NETs biomarkers and macrophages (CD68) were evaluated by single- and double- immunostaining. Plasma concentrations of citH3 and interleukin 6 (IL-6) were also determined. Results All stenotic and healthy valves expressed citH3 in the leaflets' endothelial and sub-endothelial layers at the aortic side. The in loco expression of citH3-positive cells was higher in AS patients compared with controls (42.3±8.7% vs. 7.2±4.8%, p<0.05) and correlated with disease severity measured as aortic valve area (AVA; r=−0.84, p<0.0001), as well as PGmean (r=0.62, p<0.001), and PGmax (r=0.52, p>0.05). Double-staining revealed that within stenotic leaflets 28.3±8.4% of cells were citH3/MPO- and 25.2±7.1% citH3/NE-positive. None of control valves showed MPO or NE-positivity. Moreover, 6.6±1.9% of valvular cells (17.2±5.4% of citH3-positive cells) showed citH3/CD68 double-positivity and were identified as macrophages. Plasma levels of citH3 were 59% higher in AS patients then in controls (p<0.05), and the concentrations of citH3 correlated with IL-6 levels (r=0.44, p<0.05) and AVA (r=−0.48, p<0.05). Conclusions The presence of NETs in stenotic valves and association with AS severity might suggest novel mechanisms involved in the disease progression. This work was supported by the grant from the Polish National Science Center (DEC-2017/01/X/NZ5/02006 to R.K-T.). Acknowledgement/Funding This work was supported by the grant from the Polish National Science Center (DEC-2017/01/X/NZ5/02006 to R.K-T.).