Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

BACKGROUND: The phytosterol guggulsterone is a potent anti-inflammatory mediator with less side effects than classic steroids. This study assesses the impact of guggulsterone on tissue factor (TF) expression and thrombus formation. METHODS AND RESULTS: Guggulsterone inhibited TNF-alpha-induced endothelial TF protein expression and surface activity in a concentration-dependent manner; in contrast, dexamethasone did not affect TNF-alpha-induced TF expression. Guggulsterone enhanced endothelial tissue factor pathway inhibitor and impaired plasminogen activator inhibitor-1 as well as vascular cell adhesion molecule-1 protein. Real-time polymerase chain reaction revealed that guggulsterone inhibited TNF-alpha-induced TF mRNA expression; moreover, it impaired activation of the MAP kinases JNK and p38, while that of ERK remained unaffected. In vivo, guggulsterone inhibited TF activity and photochemical injury induced thrombotic occlusion of mouse carotid artery. Guggulsterone also inhibited TF expression, proliferation, and migration of vascular smooth muscle cells in a concentration-dependent manner. CONCLUSIONS: Guggulsterone inhibits TF expression in vascular cells as well as thrombus formation in vivo; moreover, it impairs vascular smooth muscle cell activation. Hence, this phytosterol offers novel therapeutic options, in particular in inflammatory diseases associated with an increased risk of thrombosis

Midregional Proadrenomedullin Improves Risk Stratification beyond Surgical Risk Scores in Patients Undergoing Transcatheter Aortic Valve Replacement

BACKGROUND: Conventional surgical risk scores lack accuracy in risk stratification of patients undergoing transcatheter aortic valve replacement (TAVR). Elevated levels of midregional proadrenomedullin (MR-proADM) levels are associated with adverse outcome not only in patients with manifest chronic disease states, but also in the general population. OBJECTIVES: We investigated the predictive value of MR-proADM for mortality in an unselected contemporary TAVR population. METHODS: We prospectively included 153 patients suffering from severe aortic stenosis who underwent TAVR from September 2013 to August 2014. This population was compared to an external validation cohort of 205 patients with severe aortic stenosis undergoing TAVR. The primary endpoint was all cause mortality. RESULTS: During a median follow-up of 258 days, 17 out of 153 patients who underwent TAVR died (11%). Patients with MR-proADM levels above the 75th percentile (0.01) and improved the model's net reclassification index (0.89, 95% CI (0.28-1.59). These results were confirmed in the independent validation cohort. CONCLUSIONS: Our study identified MR-proADM as a novel predictor of mortality in patients undergoing TAVR. In the future, MR-proADM should be added to the commonly used EuroSCORE II for better risk stratification of patients suffering from severe aortic stenosis

Evaluation of calcium loss after transcatheter aortic valve implantation

OBJECTIVES: Aortic valve calcification and changes after transcatheter aortic valve implantation (TAVI) were specifically assessed by computed tomography (CT). The main difference between TAVI and the conventional technique is the compression of the cusps of the calcified native valve against the aortic wall before implantation. The objective of this study was to quantify the segmented calcification in the area of the basal annular plane before and after TAVI. METHODS: The CT scans of 20 patients (13 male and 7 female; mean age: 82.9 ± 8.1 years) were assessed. The aortic valve calcification was segmented; derived from this segmentation volume, mass and Hounsfield units (HU)/density of the calcifications on the annulus and cusps before and after TAVI were evaluated. Pre- and postoperative data were compared regarding potential calcification loss and calcification distances to the left and right coronary ostia. RESULTS: Significantly lower postprocedural mean volumes and masses for all cusps (P < 0.001) were found. The mean differences in the volume for the non-coronary, right-coronary and left-coronary cusp were -156.8 ± 53.73, -155.5 ± 62.54 and -115 ± 57.53 mm(3), respectively, and differences in mass were -88.78 ± 29.48, -95.2 ± 39.27 and -71.56 ± 35.62 mg, respectively. Over all cusps, mean HU increased after intervention [784.41 ± 92.5 HU (pre) and 818.63 ± 78.71 HU (post); P < 0.004]. In 80.03% of all cusps, calcification loss was found; all patients were affected. Significantly lower (P < 0.047) postprocedural mean distances were found from the left and right coronary ostia to the next calcification point. CONCLUSIONS: Our results show a significant loss of calcification in all patients after TAVI, with a reduction in the calcification distances to the coronary ostia and the compression of calcification in the area of the device landing zone. The clinical implications of this finding need to be investigated further