Evolution of definitions and understanding of vascular complications related to transcatheter aortic valve replacement.

Vascular complications have emerged as a major clinical challenge during transcatheter aortic valve replacement (TAVR). Recent reports demonstrate that major vascular complications not only predict major bleeding, transfusions, and renal failure, but are also associated with increased mortality. During the early development of TAVR, heterogeneous definitions of vascular complications were used in the literature. However, the Valve Academic Research Consortium has made significant progress in standardizing outcomes definitions in the study of this emerging technology. This has resulted in a rapidly expanding body of high-quality clinical research exploring important outcomes of TAVR, including vascular complications. This review seeks to summarize the literature and to explore the current state of knowledge with respect to the incidence, predictors, clinical impact, and management of vascular complications associated with TAVR.

Paravalvular leak after transcatheter aortic valve replacement.

Paravalvular leak (PVL) is a frequent complication of transcatheter aortic valve replacement (TAVR) that occurs at a much higher rate after TAVR than after conventional surgical aortic valve replacement. Recent reports indicating that PVL may be associated with increased late mortality have raised significant concern. However, the heterogeneity of methods for assessing and quantifying PVL, in addition to lack of consistency in the timing of this assessment, complicate the understanding of its true prevalence, severity, and clinical implications. The following review is an effort to consolidate current knowledge in this area in order to better understand the incidence, progression, and clinical impact of post-TAVR PVL, as well as to focus future research efforts on the assessment, prevention, and treatment of this important complication.

Lysine 188 substitutions convert the pattern of proteasome activation by REGgamma to that of REGs alpha and beta.

11S REGs (PA28s) are multimeric rings that bind proteasomes and stimulate peptide hydrolysis. Whereas REGalpha activates proteasomal hydrolysis of peptides with hydrophobic, acidic or basic residues in the P1 position, REGgamma only activates cleavage after basic residues. We have isolated REGgamma mutants capable of activating the hydrolysis of fluorogenic peptides diagnostic for all three active proteasome beta subunits. The most robust REGgamma specificity mutants involve substitution of Glu or Asp for Lys188. REGgamma(K188E/D) variants are virtually identical to REGalpha in proteasome activation but assemble into less stable heptamers/hexamers. Based on the REGalpha crystal structure, Lys188 of REGgamma faces the aqueous channel through the heptamer, raising the possibility that REG channels function as substrate-selective gates. However, covalent modification of proteasome chymotrypsin-like subunits by 125I-YL3-VS demonstrates that REGgamma(K188E)'s activation of all three proteasome active sites is not due to relaxed gating. We propose that decreased stability of REGgamma(K188E) heptamers allows them to change conformation upon proteasome binding, thus relieving inhibition of the CT and PGPH sites normally imposed by the wild-type REGgamma molecule.

Global analysis of proteasomal substrate specificity using positional-scanning libraries of covalent inhibitors.

The proteasome is a large protease complex consisting of multiple catalytic subunits that function simultaneously to digest protein substrates. This complexity has made deciphering the role each subunit plays in the generation of specific protein fragments difficult. Positional scanning libraries of peptide vinyl sulfones were generated in which the amino acid located directly at the site of hydrolysis (P1 residue) was held constant and sequences distal to that residue (P2, P3, and P4 positions) were varied across all natural amino acids (except cysteine and methionine). Binding information for each of the individual catalytic subunits was obtained for each library under a variety of different conditions. The resulting specificity profiles indicated that substrate positions distal to P1 are critical for directing substrates to active subunits in the complex. Furthermore, specificity profiles of IFN-gamma-regulated subunits closely matched those of their noninducible counterparts, suggesting that subunit swapping may modulate substrate processing by a mechanism that does require a change in the primary sequence specificity of individual catalytic subunits in the complex. Finally, specificity profiles were used to design specific inhibitors of a single active site in the complex. These reagents can be used to further establish the role of each subunit in substrate processing by the proteasome.