Strategies for Facilitating Totally Percutaneous Transfemoral TAVR Procedures

Transcatheter aortic valve replacement (TAVR) has transformed the treatment of aortic stenosis and should ideally be performed as a totally percutaneous procedure via the transfemoral (TF) approach. Peripheral vascular disease may impede valve delivery, and vascular access site complications are associated with adverse clinical outcome and increased mortality. We review strategies aimed to facilitate TF valve delivery in patients with hostile vascular anatomy and achieve percutaneous management of vascular complications

Treatment and Imaging Modalities of Giant Coronary Aneurysms Resulting from Kawasaki Disease and Presenting as Acute Inferior Wall Myocardial Infarction

Giant coronary aneurysms are late sequelae of Kawasaki disease (KD). We describe a 53-year-old patient who presented with acute myocardial infarction and proximal aneurysms of all three coronary arteries. Coronary angiography demonstrated the aneurysms, but CT angiography allowed accurate assessment of the real dimensions of the aneurysms and making the decision on the preferred method of revascularization. The patient underwent coronary bypass surgery and is asymptomatic at follow-up

Improved Sugar Puckering Profiles for Nicotinamide Ribonucleoside for Hybrid QM/MM Simulations

The coenzyme nicotinamide adenine dinucleotide (NAD⁺) and its reduced form (NADH) play ubiquitous roles as oxidizing and reducing agents in nature. The binding, and possibly the chemical redox step, of NAD⁺/NADH may be influenced by the cofactor conformational distribution and, in particular, by the ribose puckering of its nicotinamide–ribonucleoside (NR) moiety. In many hybrid quantum mechanics–molecular mechanics (QM/MM) studies of NAD⁺/NADH dependent enzymes, the QM region is treated by semiempirical (SE) methods. Recent work suggests that SE methods do not adequately describe the ring puckering in sugar molecules. In the present work we adopt an efficient and practical strategy to correct for this deficiency for NAD⁺/NADH. We have implemented a cost-effective correction to a SE Hamiltonian by adding a correction potential, which is defined as the difference between an accurate benchmark density functional theory (DFT) potential energy surface (PES) and the SE PES. In practice, this is implemented via a B-spline interpolation scheme for the grid-based potential energy difference surface. We find that the puckering population distributions obtained from free energy QM­(SE)/MM simulations are in good agreement with DFT and in fair accord with experimental results. The corrected PES should facilitate a more accurate description of the ribose puckering in the NAD⁺/NADH cofactor in simulations of biological systems

Effect of Asp122 Mutation on the Hydride Transfer in <i>E. coli</i> DHFR Demonstrates the Goldilocks of Enzyme Flexibility

Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) in the presence of NADPH. The key hydride transfer step in the reaction is facilitated by a combination of enzyme active site preorganization and correlated protein motions in the Michaelis–Menten (E:NADPH:DHF) complex. The present theoretical study employs mutagenesis to examine the relation between structural and functional properties of the enzyme. We mutate Asp122 in Escherichia coli DHFR, which is a conserved amino acid in the DHFR family. The consequent effect of the mutation on enzyme catalysis is examined from an energetic, structural and short-time dynamic perspective. Our investigations suggest that the structural and short-time dynamic perturbations caused by Asp122X mutations (X = Asn, Ser, Ala) are along the reaction coordinate and lower the rate of hydride transfer. Importantly, analysis of the correlated and principle component motions in the enzyme suggest that the mutation alters the coupled motions that are present in the wild-type enzyme. In the case of D122N and D122S, the mutations inhibit coupled motion, whereas in the case of D122A, the mutation enhances coupled motion, although all mutations result in similar rate reduction. These results emphasize a Goldilocks principle of enzyme flexibility, that is, enzymes should neither be too rigid nor too flexible

Effect of Asp122 Mutation on the Hydride Transfer in <i>E. coli</i> DHFR Demonstrates the Goldilocks of Enzyme Flexibility

Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) in the presence of NADPH. The key hydride transfer step in the reaction is facilitated by a combination of enzyme active site preorganization and correlated protein motions in the Michaelis–Menten (E:NADPH:DHF) complex. The present theoretical study employs mutagenesis to examine the relation between structural and functional properties of the enzyme. We mutate Asp122 in Escherichia coli DHFR, which is a conserved amino acid in the DHFR family. The consequent effect of the mutation on enzyme catalysis is examined from an energetic, structural and short-time dynamic perspective. Our investigations suggest that the structural and short-time dynamic perturbations caused by Asp122X mutations (X = Asn, Ser, Ala) are along the reaction coordinate and lower the rate of hydride transfer. Importantly, analysis of the correlated and principle component motions in the enzyme suggest that the mutation alters the coupled motions that are present in the wild-type enzyme. In the case of D122N and D122S, the mutations inhibit coupled motion, whereas in the case of D122A, the mutation enhances coupled motion, although all mutations result in similar rate reduction. These results emphasize a Goldilocks principle of enzyme flexibility, that is, enzymes should neither be too rigid nor too flexible

Incidence, Causes, and Outcomes Associated With Urgent Implantation of a Supplementary Valve During Transcatheter Aortic Valve Replacement.

Importance Transcatheter aortic valve replacement (TAVR) failure is often managed by an urgent implantation of a supplementary valve during the procedure (2-valve TAVR [2V-TAVR]). Little is known about the factors associated with or sequelae of 2V-TAVR. Objective To examine the incidence, causes, and outcomes of 2V-TAVR. Design, Setting, and Participants A retrospective cohort study was performed using data from an international registry of 21 298 TAVR procedures performed from January 1, 2014, through February 28, 2019. Among the 21 298 patients undergoing TAVR, 223 patients (1.0%) undergoing 2V-TAVR were identified. Patient-level data were available for all the patients undergoing 2V-TAVR and for 12 052 patients (56.6%) undergoing 1V-TAVR. After excluding patients with missing 30-day follow-up or data inconsistencies, 213 2V-TAVR and 10 010 1V-TAVR patients were studied. The 2V-TAVR patients were compared against control TAVR patients undergoing a 1-valve TAVR (1V-TAVR) using 1:4 17 propensity score matching. Final analysis included 1065 (213:852) patients. Exposures Urgent implantation of a supplementary valve during TAVR. Main Outcomes and Measures Mortality at 30 days and 1 year. Results The 213 patients undergoing 2V-TAVR had similar age (mean [SD], 81.3 [0.5] years) and sex (110 [51.6%] female) as the 10 010 patients undergoing 1V-TAVR (mean [SD] age, 81.2 [0.5] years; 110 [51.6%] female). The 2V-TAVR incidence decreased from 2.9% in 2014 to 1.0% in 2018 and was similar between repositionable and nonrepositionable valves. Bicuspid aortic valve (odds ratio [OR], 2.20; 95% CI, 1.17-4.15; P = .02), aortic regurgitation of moderate or greater severity (OR, 2.02; 95% CI, 1.49-2.73; P < .001), atrial fibrillation (OR, 1.43; 95% CI, 1.07-1.93; P = .02), alternative access (OR, 2.59; 95% CI, 1.72-3.89; P < .001), early-generation valve (OR, 2.32; 95% CI, 1.69-3.19; P < .001), and self-expandable valve (OR, 1.69; 95% CI, 1.17-2.43; P = .004) were associated with higher 2V-TAVR risk. In 165 patients (80%), the supplementary valve was implanted because of residual aortic regurgitation after primary valve malposition (94 [46.4%] too high and 71 [34.2%] too low). In the matched 2V-TAVR vs 1V-TAVR cohorts, the rate of device success was 147 (70.4%) vs 783 (92.2%) (P < .001), the rate of coronary obstruction was 5 (2.3%) vs 3 (0.4%) (P = .10), stroke rate was 9 (4.6%) vs 13 (1.6%) (P = .09), major bleeding rates were 25 (11.8%) vs 46 (5.5%) (P = .03) and annular rupture rate was 7 (3.3%) vs 3 (0.4%) (P = .03). The hazard ratios for mortality were 2.58 (95% CI, 1.04-6.45; P = .04) at 30 days, 1.45 (95% CI, 0.84-2.51; P = .18) at 1 year, and 1.20 (95% CI, 0.77-1.88; P = .42) at 2 years. Nontransfemoral access and certain periprocedural complications were independently associated with higher risk of death 1 year after 2V-TAVR. Conclusions and Relevance In this cohort study, valve malposition was the most common indication for 2V-TAVR. Incidence decreased over time and was low overall, although patients with a bicuspid or regurgitant aortic valve, nontransfemoral access, and early-generation or self-expandable valve were at higher risk. These findings suggest that compared with 1V-TAVR, 2V-TAVR is associated with high burden of complications and mortality at 30 days but not at 1 year

Impact of Predilatation Prior to Transcatheter Aortic Valve Implantation With the Self-Expanding Acurate neo Device (from the Multicenter NEOPRO Registry).

Safety and feasibility of transfemoral Acurate neo implantation without systematic predilatation are not fully investigated. Our aim was to evaluate the use and impact of pre-implantation balloon aortic valvuloplasty (pre-BAV) before transcatheter aortic valve implantation (TAVI) with Acurate neo. The NEOPRO Registry retrospectively included 1,263 patients who underwent transfemoral TAVI with Acurate neo at 18 centers between January 2012 and March 2018. Information on pre-BAV was available for 1,262 patients (99.9%). Primary end points were pre-discharge moderate-to-severe paravalvular aortic regurgitation (PAR II+), 30-day new permanent pacemaker implantation, and 30-day all-cause mortality or stroke. A total of 1,262 patients who underwent TAVI with (n = 1,051) or without predilatation (n = 211) were included. A reduction in the pre-BAV rate was observed during the study period (from 95.7% in the first date quintile to 78.4% in the last date quintile). Patients who underwent pre-BAV had higher degrees of aortic valve (AV) and left ventricular outflow tract (LVOT) calcification. Primary endpoints were similar between pre-BAV and no pre-BAV groups (PAR II+ 5.5% vs 3.4%, p = 0.214; 30-day permanent pacemaker implantation 9.0% vs 8.0%, p = 0.660; 30-day death or stroke 4.9% vs 4.4%, p = 0.743). The need for postdilatation and other procedural outcomes were comparable between groups. Predilatation did not have a significant impact on primary endpoints across AV and LVOT calcification subgroups (subgroup analyses) and was not independently associated with primary endpoints (multivariate analyses). In conclusion, transfemoral Acurate neo implantation without predilatation appears to be feasible and safe, especially in patients with milder degrees of AV and LVOT calcification