Fluorescent-labeled derivatives of the Antennapedia-derived cell-penetating peptide penetratin, and of the simpler but similarly charged peptides R(6)GC-NH(2) and K(6)GC-NH(2), are shown to be able to translocate into large unilamellar lipid vesicles in the presence of a transbilayer potential (inside negative). Vesicles with diverse lipid compositions, and combining physiological proportions of neutral and anionic lipids, are able to support substantial potential-dependent uptake of all three cationic peptides. The efficiency of peptide uptake under these conditions is strongly modulated by the vesicle lipid composition, in a manner that suggests that more than one mechanism of peptide uptake may operate in different systems. Remarkably, peptide uptake is accompanied by only minor perturbations of the overall barrier function of the lipid bilayer, as assessed by assays of vesicle leakiness under the same conditions. Fluorescence microscopy of living CV-1 and HeLa cells incubated with the labeled peptides shows that the peptides accumulate in peripheral vesicular structures at early times of incubation, consistent with an initial endosomal localization as recently reported, but gradually accumulate in the cytoplasm and nucleus during more extended incubations (several hours). Our findings indicate that these relatively hydrophilic, polybasic cell-penetrating peptides can translocate through lipid bilayers by a potential- and composition-dependent pathway that causes only minimal perturbation to the overall integrity and barrier function of the bilayer.

This large survey uncovered significant gaps in the knowledge and attitudes of surgeons toward the diagnosis and management of bicuspid aortopathy, many of which were at odds with current guideline recommendations. Efforts to promote knowledge translation in this area are strongly encouraged.

Background: Despite the rapid adoption of transcatheter aortic valve replacement (TAVR) since its initial approval in 2011, the frequency and outcomes of surgical explantation of TAVR devices (TAVR-explant) is poorly understood. Methods: Patients undergoing TAVR-explant between January 2012 and June 2020 at 33 hospitals in Michigan were identified in the Society of Thoracic Surgeons Database and linked to index TAVR data from the Transcatheter Valve Therapy Registry through a statewide quality collaborative. The primary outcome was operative mortality. Indications for TAVR-explant, contraindications to redo TAVR, operative data, and outcomes were collected from Society of Thoracic Surgeons and Transcatheter Valve Therapy databases. Baseline Society of Thoracic Surgeons Predicted Risk of Mortality was compared between index TAVR and TAVR-explant. Results: Twenty-four surgeons at 12 hospitals performed TAVR-explants in 46 patients (median age, 73). The frequency of TAVR-explant was 0.4%, and the number of explants increased annually. Median time to TAVR-explant was 139 days and among known device types explanted, most were self-expanding valves (29/41, 71%). Common indications for TAVR-explant were procedure-related failure (35%), paravalvular leak (28%), and need for other cardiac surgery (26%). Contraindications to redo TAVR included need for other cardiac surgery (28%), unsuitable noncoronary anatomy (13%), coronary obstruction (11%), and endocarditis (11%). Overall, 65% (30/46) of patients underwent concomitant procedures, including aortic repair/replacement in 33% (n=15), mitral surgery in 22% (n=10), and coronary artery bypass grafting in 16% (n=7). The median Society of Thoracic Surgeons Predicted Risk of Mortality was 4.2% at index TAVR and 9.3% at TAVR-explant ( P =0.001). Operative mortality was 20% (9/46) and 76% (35/46) of patients had in-hospital complications. Of patients alive at discharge, 37% (17/37) were discharged home and overall 3-month survival was 73±14%. Conclusions: TAVR-explant is rare but increasing, and its clinical impact is substantial. As the utilization of TAVR expands into younger and lower-risk patients, providers should consider the potential for future TAVR-explant during selection of an initial valve strategy.

ImportanceIn patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited.ObjectiveTo report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial.Design, Setting, and ParticipantsSURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021.InterventionPatients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis.Main Outcomes and MeasuresThe prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years.ResultsA total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm2 vs 1.8 [0.6] cm2; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention.Conclusions and RelevanceAmong intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

BackgroundAs high-risk cardiac patients frequently remain within hospital while waiting for surgery, the aim of the present study was to determine the role of preoperative length of hospital stay on mediastinitis, and also, to assess contemporary risk factors for this complication.MethodsThe source population consisted of 6653 consecutive patients undergoing coronary bypass surgery, valve surgery, or both between September 2000 and September 2009 at a single tertiary care hospital. A retrospective cohort analysis was used to assess the effect of 18 preoperative variables, including length of stay, on mediastinitis.ResultsMediastinitis developed in 108 patients (1.6%) resulting in an in-hospital mortality rate of 13.9%. Independent predictors of mediastinitis included obesity (2.59, CI 1.58-4.23), COPD (2.44, CI 1.55-3.84), diabetes (2.16, CI 1.44-3.24), and impaired estimated glomerular filtration rate. Preoperative hospital stay was also found to be an independent risk factor leading to a 15% increased risk of mediastinitis per week of stay. The primary wound pathogen was coagulase negative staphylococcus (82%) followed by multi-flora isolates (49%), but was unrelated to hospital stay.ConclusionsIn addition to the traditional risk factors, prolonged preoperative hospital stay is also a significant and potentially modifiable predictor for the development of mediastinitis following cardiac surgery. All efforts should be made to minimize the delay in operating on hospitalized patients awaiting heart surgery.