No abstract

TAVR was a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. (Funded by Medtronic; SURTAVI ClinicalTrials.gov number, NCT01586910 .).

Cross-talk between calpain and caspase proteolytic systems has complicated efforts to determine their distinct roles in apoptotic cell death. This study examined the effect of overexpressing calpastatin, the specific endogenous calpain inhibitor, on the activity of the two proteolytic systems following an apoptotic stimulus. Human SH-SY5Y neuroblastoma cells were stably transfected with full-length human calpastatin cDNA resulting in 20-fold overexpression based on Western blot and 5-fold greater calpain inhibitory activity in cell extracts. Wild type and calpastatin overexpressing (CST1) cells were neuronally differentiated and apoptosis-induced with staurosporine (0.1-1.0 M). Calpastatin overexpression decreased calpain activation, increased caspase-3-like activity, and accelerated the appearance of apoptotic nuclear morphology. Following 0.1-0.2 M staurosporine, plasma membrane integrity based on calcein-acetoxymethyl fluorescence was significantly greater at 24 h in differentiated CST1 compared with differentiated wild type cells. However, this protective effect was lost at higher staurosporine doses (0.5-1.0 M), which resulted in pronounced caspase-mediated degradation of the overexpressed calpastatin. These results suggest a dual role for calpains during neuronal apoptosis. In the early execution phase, calpain downregulates caspase-3-like activity and slows progression of apoptotic nuclear morphology. Subsequent calpain activity, facilitated by caspase-mediated degradation of calpastatin, contributes to plasma membrane disruption and secondary necrosis.Although the role of caspases in the apoptotic cascade has been extensively characterized, the role of calpains is less clear. Ubiquitously expressed calpains I and II are reversibly activated by calcium and regulated by the specific endogenous inhibitor, calpastatin (1). Calpain activation during apoptosis has been observed in a number of cell culture and in vivo models of apoptosis (2-18). The role of calpain appears to depend on the cell type being studied. Calpain inhibitors reduce apoptotic cell death in CHO 1 cells, PC12 cells, U937 cells thymocytes, metamyelocytes, lymphocytes, auditory sensory cells, human lung carcinoma cells, cardiac myocytes, and neurons (2, 5, 11-13, 16, 17, 19 -27). In contrast, calpain inhibitors have been reported to induce apoptosis in Molt 4, HL-30 cells, human acute and chronic lymphocytic leukemia cells, and human prostate carcinoma cells (18, 28 -30). Even within the same cell line, the role of calpain can vary depending on type and severity of apoptotic stimulus (4,14,15,17). Determining the relative roles of calpains and caspases in apoptotic cell death is further complicated by the growing body of evidence for cross-talk between the two proteolytic systems. Calpain-mediated cleavage of caspases-3, -7, -8, -9, and -12 has been reported with varying functional consequences (5,8,12,(31)(32)(33). Calpain-mediated N-terminal truncation of caspase-3 to a p30 polypeptide enhanced activation in one study and inhibited activat...

Quantity and asymmetry of AVC in all regions of the aortic valve complex predict greater than or equal to mild PVR and performance of PD, with the exception of Leaflet asymmetry. Quantity of AnnulusLVOT and Leaflet calcification independently predict PVR and PD when taking into account multidetector row computed tomography area cover index.