Collagenase Total Occlusion-1 (CTO-1) trial: a phase I, dose-escalation, safety study.

BACKGROUND: Percutaneous interventions for chronic total occlusions have low success rates, primarily because of failure of guide wire crossing. Collagen-rich matrix constitutes the main barrier to chronic total occlusion crossing. In preclinical studies, local delivery of a bacterial collagenase formulation improved guide wire crossing. The Collagenase Total Occlusion-1 (CTO-1) Trial is a phase I, dose-escalation trial to assess the safety and efficacy of collagenase therapy to facilitate guide wire crossing in coronary artery chronic occlusions. METHODS AND RESULTS: Twenty subjects with ≥1 previous failure of chronic total occlusion guide wire crossing were enrolled at 2 sites. Subjects were treated in 4 distinct cohorts of 5 patients, with escalation of collagenase dose in each cohort from 300 to 1200 µg. Collagenase was locally delivered into the occlusions with either an over-the-wire balloon system (n=8) or a fine-cross microcatheter (n=12) for a period of 30 minutes. Subjects were brought back to the catheterization laboratory for guide wire crossing and angioplasty the next day. Guide wire crossing was successfully achieved in 15 subjects (75%). A soft-tip guide wire (Whisper, Pilot-50, Fielder XT) was either the sole or predominant guide wire used in 75% of successful crossings. Non-ST-segment-elevation myocardial infarctions occurred in 3 patients as a result of side-branch ischemia during stenting. Computed tomographic angiography at 3 months showed no late complications and patent stents in successfully treated chronic total occlusion. Anginal improvement occurred with a reduction in Canadian Cardiovascular Society class from baseline to 3 months (2.5±0.6 versus 0.9±0.9; P<0.001). CONCLUSION: Local delivery of collagenase into coronary chronic total occlusion is feasible and safe with encouraging guide wire crossing results in previously failed cases. Larger clinical trials are required to determine efficacy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01271335.

Angiographic and clinical outcomes after implantation of drug eluting stents in bifurcation lesions with crush or kissing stent technique.

BACKGROUND: Long-term outcome after bifurcation stenting with drug-eluting stents (DES) for obstructive coronary artery disease is poorly understood. In this study, we report 6-9-month angiographic follow-up and long-term clinical outcomes after implantation of drug-eluting stents by crush and kissing stent technique for coronary bifurcation lesions. METHODS: Consecutive patients undergoing bifurcation stenting with DES by crush or kissing stent technique were enrolled in a prospective registry. Angiographic follow-up was obtained at 6-9 months and clinical follow-up completed for a median of 38 months. RESULTS: A total of 86 patients participated in the study. Bifurcation stenting by crush technique was performed in 73 (85%) and by kissing stent in 13 (15%) patients. Stenting of left main bifurcation was applied in 24 (28%) patients. Angiographic follow-up was completed in 75 (87%) patients and showed restenosis in the main for 8 (11%) and side branch for 20 (27%) patients. Clinical follow-up was available for a median duration of 38 months. During follow-up, 2 (2%) patients died, 4 (5%) experienced myocardial infarction (MI), and 11 (13%) underwent target vessel revascularization (TVR) with an overall major adverse cardiac event (MACE) rate of 16%. In left main cohort, angiographic restenosis occurred in 9 (37%) patients, and 3 (12%) patients required TVR. There were no deaths or stent thrombosis. A comparison of crush and kissing stent technique showed significantly higher angiographic restenosis with crush (26% vs 13% in kissing stent patients, P = 0.046) and 95% of restenosis in crush group involved ostium of the side branch. There was no difference in clinical outcomes between the crush and kissing stent groups. Final kissing balloon dilatation (FKB) was successful in 65 (89%) patients in the crush group and associated with a significant reduction in MACE (8% in FKB successful vs 37% in FKB unsuccessful, P = 0.04) during follow-up. CONCLUSION: Bifurcation stenting with crush or kissing stent technique is safe and associated with a low rate of TLR and MACE on long-term follow-up. Crush stenting is associated with a significantly higher rate of side branch restenosis compared to kissing stent technique. FKB is associated with significant reduction in MACE during follow-up.

Visible angiographic complications predict short and long-term outcomes in patients with post-procedural creatine-phosphokinase elevation.

OBJECTIVES: To assess whether visible angiographic complication is related to outcome in patients with elevated creatine phosphokinase (CK-MB) following percutaneous coronary intervention (PCI). BACKGROUND: Elevated biomarkers following PCI are associated with increased incidence of adverse events but the absolute risk of such events is low. A more specific marker of risk is needed. METHODS: Consecutive patients with elevated post-PCI CK-MB were divided into two groups according to presence (n = 115, 43%) or absence (n = 150, 57%) of an angiographic complication. A control group (n = 250) was randomly chosen from 2,403 patients undergoing PCI during the same period without CK-MB elevation. Major adverse cardiac events (MACE) were assessed at 30 days and 1 year. RESULTS: Patients with an identifiable angiographic complication and elevated postprocedural CK-MB had significantly worse outcomes at 30 days and 1 year compared with biomarker positive patients without an identifiable complication and control patients (30 day MACE rate: 8% vs 0% vs 0.4%, respectively, p < 0.001; 1 year MACE rate: 26% vs 11% vs 11%, respectively, p = 0.002, all p-values for angiographic complication vs no angiographic complication and for angiographic complication vs control). Biomarker positive patients without identifiable angiographic complication had an excellent short and long term outcome, which was no different from biomarker negative patients (1 year MACE rate: 11% vs 11%, p = 0.53). CONCLUSION: Post-PCI patients without visible angiographic complications have an excellent short and long term outcome. These findings call into question the need for routine CK-MB monitoring after PCI in the absence of clinical symptoms or angiographic complication.

Intraluminal filling defects on coronary angiography: more than meets the eye.

Intraluminal filling defects are occasionally encountered on coronary angiography and often related with coronary thrombi. However, other conditions affecting the coronary arteries may present with similar angiographic findings causing diagnostic uncertainty. Accurate characterization of the angiographic filling defect is critical, particularly in patients planned for a percutaneous coronary intervention (PCI), as diagnosis of a coronary thrombus not only increases the risk of post procedural adverse events but also requires a specific therapeutic approach. In this paper, we report three patients in whom coronary angiography revealed intraluminal filling defects mimicking coronary thrombi. When further investigated with intravascular ultrasound (IVUS) as a part of the planned PCI, the thrombus was excluded and alternate etiology of the filling defect was confirmed in all patients. The angiographic "pseudothrombi" were produced by coronary dissection in one and by heavy calcification within the atherosclerotic plaque in two patients. The use of IVUS allowed accurate characterization of the angiographic filling defect and provided important information to guide management and optimize therapeutic approach.

A lightweight, inexpensive robotic system for insect vision.

Designing hardware for miniaturized robotics which mimics the capabilities of flying insects is of interest, because they share similar constraints (i.e. small size, low weight, and low energy consumption). Research in this area aims to enable robots with similarly efficient flight and cognitive abilities. Visual processing is important to flying insects' impressive flight capabilities, but currently, embodiment of insect-like visual systems is limited by the hardware systems available. Suitable hardware is either prohibitively expensive, difficult to reproduce, cannot accurately simulate insect vision characteristics, and/or is too heavy for small robotic platforms. These limitations hamper the development of platforms for embodiment which in turn hampers the progress on understanding of how biological systems fundamentally work. To address this gap, this paper proposes an inexpensive, lightweight robotic system for modelling insect vision. The system is mounted and tested on a robotic platform for mobile applications, and then the camera and insect vision models are evaluated. We analyse the potential of the system for use in embodiment of higher-level visual processes (i.e. motion detection) and also for development of navigation based on vision for robotics in general. Optic flow from sample camera data is calculated and compared to a perfect, simulated bee world showing an excellent resemblance.

Radial versus femoral access for emergent percutaneous coronary intervention with adjunct glycoprotein IIb/IIIa inhibition in acute myocardial infarction--the RADIAL-AMI pilot randomized trial.

BACKGROUND: Transradial percutaneous coronary intervention (PCI) results in fewer vascular complications, earlier ambulation, and improved patient comfort. Limited data exist for radial access in acute myocardial infarction, where reperfusion must occur quickly. METHODS: In a multicenter pilot trial, 50 patients with myocardial infarction requiring either primary or rescue PCI were randomized to radial or femoral access. All operators had previously performed at least 100 transradial cases. Procedure times were prospectively recorded. RESULTS: Thrombolysis was used in 66% of the cases and glycoprotein IIb/IIIa inhibitors in 94%. Crossover from radial to femoral access was required in one case. Percutaneous coronary intervention was performed in 47 patients, with stenting in 45. One procedural failure occurred with radial access because of inability to cross the occlusion. The time from local anesthesia to first balloon inflation was 32 (25th percentile 26, 75th percentile 38) minutes for radial access and 26 (22, 33) minutes for femoral access (P = .04). There were no significant differences in contrast use or fluoroscopy time. No patient experienced major bleeding or required transfusion. Doppler studies demonstrated 2 asymptomatic radial occlusions and 2 pseudoaneurysms (1 from each group). One patient in the femoral group died 2 days after PCI. At 30 days, there were no strokes or reinfarctions and no patient required bypass surgery or repeat PCI. CONCLUSIONS: Primary and rescue PCI can be performed with high success rates using either radial or femoral access. Although radial access was associated with a longer time to first balloon inflation, the difference was small and likely not clinically significant. In patients without shock, major bleeding and vascular complications are infrequent with either access site despite the high use of thrombolysis and glycoprotein IIb/IIIa inhibitors.

Bailout use of platelet glycoprotein IIb-IIIa inhibition during coronary stent implantation: observations from the ESPRIT trial.

Glycoprotein (GP) IIb/IIIa inhibitors are often used as a rescue or bailout therapy to manage complications arising during percutaneous coronary intervention, rather than as prophylactic treatment. We sought to identify the characteristics and outcomes of patients requiring bailout treatment. The ESPRIT trial randomized 2,064 patients to receive eptifibatide or placebo starting immediately before percutaneous coronary intervention (PCI). Bailout therapy was used in 77 patients: 43 (4.2%) randomized to placebo and 34 (3.3%) to eptifibatide (p = 0.3). Bailout therapy for thrombosis was used more often in the placebo group (2.1% versus 1.0%; p = 0.03). Multivariable predictors of bailout included a greater than or equal to 90% stenosis, or visible thrombus on the baseline angiogram, and no aspirin pre-treatment before PCI. However, overall the model predicted bailout poorly (c-index = 0.64). The need for bailout cannot be reliably predicted using baseline characteristics. Patients experiencing complications have poor clinical outcomes despite bailout use of GP IIb/IIIa inhibitors.

Process analytical technology case study part I: feasibility studies for quantitative near-infrared method development.

This article is the first of a series of articles detailing the development of near-infrared (NIR) methods for solid-dosage form analysis. Experiments were conducted at the Duquesne University Center for Pharmaceutical Technology to qualify the capabilities of instrumentation and sample handling systems, evaluate the potential effect of one source of a process signature on calibration development, and compare the utility of reflection and transmission data collection methods. A database of 572 production-scale sample spectra was used to evaluate the interbatch spectral variability of samples produced under routine manufacturing conditions. A second database of 540 spectra from samples produced under various compression conditions was analyzed to determine the feasibility of pooling spectral data acquired from samples produced at diverse scales. Instrument qualification tests were performed, and appropriate limits for instrument performance were established. To evaluate the repeatability of the sample positioning system, multiple measurements of a single tablet were collected. With the application of appropriate spectral preprocessing techniques, sample repositioning error was found to be insignificant with respect to NIR analyses of product quality attributes. Sample shielding was demonstrated to be unnecessary for transmission analyses. A process signature was identified in the reflection data. Additional tests demonstrated that the process signature was largely orthogonal to spectral variation because of hardness. Principal component analysis of the compression sample set data demonstrated the potential for quantitative model development. For the data sets studied, reflection analysis was demonstrated to be more robust than transmission analysis.

Process analytical technology case study: part II. Development and validation of quantitative near-infrared calibrations in support of a process analytical technology application for real-time release.

This article is the second of a series of articles detailing the development of near-infrared (NIR) methods for solid dosage-form analysis. Experiments were conducted at the Duquesne University Center for Pharmaceutical Technology to demonstrate a method for developing and validating NIR models for the analysis of active pharmaceutical ingredient (API) content and hardness of a solid dosage form. Robustness and cross-validation testing were used to optimize the API content and hardness models. For the API content calibration, the optimal model was determined as multiplicative scatter correction with Savitsky-Golay first-derivative preprocessing followed by partial least-squares (PLS) regression including 4 latent variables. API content calibration achieved root mean squared error (RMSE) and root mean square error of cross validation (RMSECV) of 1.48 and 1.80 mg, respectively. PLS regression and baseline-fit calibration models were compared for the prediction of tablet hardness. Based on robustness testing, PLS regression was selected for the final hardness model, with RMSE and RMSECV of 8.1 and 8.8 N, respectively. Validation testing indicated that API content and hardness of production-scale tablets is predicted with root mean square error of prediction of 1.04 mg and 8.5 N, respectively. Explicit robustness testing for high-flux noise and wavelength uncertainty demonstrated the robustness of the API concentration calibration model with respect to normal instrument operating conditions.

Thrombin-activatable fibrinolysis inhibitor (TAFI): a novel predictor of angiographic coronary restenosis.

The fibrinolytic system is closely related to several processes that are involved in restenosis. We previously showed that low PAI-1 plasma levels predicted restenosis. Recently, a different fibrinolytic inhibitor, TAFI, has been described. The aims of this study were to evaluate the relationship between pre-procedural plasma levels of TAFI and late angiographic restenosis and the interaction between TAFI and PAI-1.We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty or stenting of de novo native coronary artery lesions. TAFI and PAI-1 antigen levels were measured in plasma samples drawn before the procedure. Follow-up coronary angiography was performed in 92% of patients. There was a significant correlation between pre-procedural TAFI levels and 6-month % diameter stenosis (DS) (r = 0.21; p = 0.013). The overall angiographic restenosis rate (DS>50%) was 31%. Pre-procedural TAFI levels were significantly higher in patients with restenosis (108 +/- 33% versus 94+/-30%, p = 0.011). Restenosis rates for patients in the upper tertile of TAFI levels were 2-fold higher than for those in the lowest tertile (45% versus 22%; p = 0.016). A combination of high TAFI and low PAI-1 levels identified patients at the highest risk of restenosis (53%) compared to 14% in patients with low TAFI and high PAI-1 levels; p = 0.027. In conclusion, pre-procedural plasma TAFI antigen levels identify patients at increased risk for restenosis after PCI.

Do glycoprotein IIb/IIIa inhibitors interact with assays for myocardial necrosis?

OBJECTIVES: To determine whether glycoprotein (GP) IIB/IIIA inhibitors interact with cardiac marker assays: total creatine kinase (CK), CK-MB, and troponin-I (TnI). DESIGN AND METHODS: Two blood samples were collected during coronary angiography or angioplasty and analyzed for cardiac markers: one after arterial sheath insertion and the second 10 mins later. In the first phase (n=101), heparin and GP IIb/IIIa inhibitors were given between samples, in the second phase (n=45) only heparin was given, and in the third phase (n=54) neither drug was given. RESULTS: In each phase, there was a significant decline in total CK over the 10 min period. There were no consistent significant changes in CK-MB or TnI. CONCLUSIONS: Neither GP IIb/IIIa inhibitors nor i.v. heparin interact with cardiac marker assays. There is a small but significant decline in total CK levels within 10 mins of arterial puncture that is unrelated to administration of these drugs.

Thr325Ile polymorphism of the TAFI gene is related to TAFI antigen plasma levels and angiographic restenosis after percutaneous coronary interventions.

BACKGROUND: The fibrinolytic system is closely related to several processes that are involved in restenosis. We have previously shown that high pre-procedural plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) antigen predicted angiographic restenosis. The aims of this study were to evaluate the relationship between Thr325Ile polymorphisms, plasma levels of TAFI antigen, and late angiographic restenosis after percutaneous coronary intervention (PCI). METHODS: We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty or stenting of de novo native coronary artery lesions. Blood samples were drawn before the procedure. TAFI antigen levels were measured, as well as the presence of TAFI Ile325Thr genetic variation. Follow-up coronary angiography was performed in 90% of patients. RESULTS: The genotypes based on Ile325Thr substitution had significantly different TAFI antigen levels: genotype C/C>C/T>T/T (111+/-29%, 87+/-24%, and 59+/-22%, respectively, p<0.006). T/T genotype was associated with lower rates of restenosis compared to C/T and C/C genotypes (25% versus 37% and 33%, respectively, p<0.05). CONCLUSIONS: These data suggest that plasma TAFI antigen levels are genetically controlled. The T/T Thr325Ile polymorphism of the TAFI gene is associated with lower plasma levels of TAFI antigen and lower restenosis rates after PCI.

Is thyroid frozen section too much for too little?

BACKGROUND: The role of frozen section (FS) in thyroid disease is controversial. The goal of this study was to identify a cohort of patients who may or may not benefit from FS. METHODS: Two hundred thirty-one patients who underwent thyroidectomy were evaluated in regard to fine-needle aspiration (FNA), FS, and the extent of surgery. RESULTS: In all, 155 patients underwent FNA, 140 patients underwent FS, and 103 patients had both. A final diagnosis of malignancy was obtained in 47 of 231 patients. FNA had a sensitivity of 50% and a specificity of 99%, and FS had a sensitivity of 50% and a specificity of 100% for diagnosing malignancy. Accounting for the clinical findings and FNA results, FS results altered the extent of thyroidectomy in 1 of 103 patients. CONCLUSIONS: The increased costs for the operative time and the pathologists needed to obtain routine FS are not supported with any substantial benefit in patient outcome.

Chorea in a pregnant woman with rheumatic mitral stenosis.

Chorea gravidarum is a rare movement disorder of pregnancy with a broad differential diagnosis. Although often a benign condition, it may indicate underlying acute rheumatic fever, antiphospholipid antibody syndrome or a hypercoagulable state. However, now that rheumatic fever is rare in western countries, chorea gravidarum occurs most commonly in patients with chronic rheumatic heart disease. Heightened awareness of chorea gravidarum and the morbidity of the often associated rheumatic heart disease, particularly in immigrants from developing countries, is essential for early diagnosis and effective management. A case of chorea gravidarum in a woman with rheumatic mitral stenosis is described. The diagnostic approach, pathophysiology and management of this rare condition are discussed.

Radial versus femoral access for rescue percutaneous coronary intervention with adjuvant glycoprotein IIb/IIIa inhibitor use.

BACKGROUND: The transradial approach has not been evaluated for "rescue" percutaneous coronary intervention (PCI) with glycoprotein (GP) IIb/IIIa inhibitor following failed thrombolysis. OBJECTIVES: To compare the safety and procedural outcomes of the transradial and transfemoral approaches to rescue PCI. METHODS: Rescue PCI cases with adjuvant GP IIb/IIIa inhibitor performed at two centres were reviewed retrospectively, and the bleeding rates, equipment use and procedure times for the femoral and the radial approach were compared. RESULTS: Radial access was attempted in 47 of 111 cases (42%) and crossover to femoral access was required in two cases (4%). Major bleeding occurred in three patients in the radial group (6%) and in 12 patients in the femoral group (19%; P=0.06). Radial access was associated with less access site-related major bleeding (0% versus 9%; P=0.04) and fewer transfusions (4% versus 19%; P=0.02). After excluding patients with intra-aortic balloon pump, this difference was no longer statistically significant (4% versus 8%; P=0.7). Fluoroscopy times and contrast use were similar, and the time to first balloon inflation was slightly longer with radial access (33 min versus 30 min; P=0.07). CONCLUSIONS: In selected patients, the transradial approach for rescue PCI is safe and effective. The present findings warrant further study in a prospective, randomized trial.

Impact of new-onset persistent left bundle branch block on late clinical outcomes in patients undergoing transcatheter aortic valve implantation with a balloon-expandable valve.

OBJECTIVES: The aim of this study was to determine the impact of new-onset persistent left bundle branch block (NOP-LBBB) on late outcomes after transcatheter aortic valve implantation (TAVI). BACKGROUND: The impact of NOP-LBBB after TAVI remains controversial. METHODS: A total of 668 consecutive patients who underwent TAVI with a balloon-expandable valve without pre-existing LBBB or permanent pacemaker implantation (PPI) were included. Electrocardiograms were obtained at baseline, immediately after the procedure, and daily until hospital discharge. Patients were followed at 1, 6, and 12 months and yearly thereafter. RESULTS: New-onset LBBB occurred in 128 patients (19.2%) immediately after TAVI and persisted at hospital discharge in 79 patients (11.8%). At a median follow-up of 13 months (range 3 to 27 months), there were no differences in mortality rate between the NOP-LBBB and no NOP-LBBB groups (27.8% vs. 28.4%; adjusted-hazard ratio: 0.87 [95% confidence interval (CI): 0.55 to 1.37]; p = 0.54). There were no differences between groups regarding cardiovascular mortality (p = 0.82), sudden death (p = 0.87), rehospitalizations for all causes (p = 0.11), or heart failure (p = 0.55). NOP-LBBB was the only factor associated with an increased rate of PPI during the follow-up period (13.9% vs. 3.0%; hazard ratio: 4.29 [95% CI: 2.03 to 9.07], p < 0.001. NOP-LBBB was also associated with a lack of left ventricular ejection fraction improvement and poorer New York Heart Association functional class at follow-up (p < 0.02 for both). CONCLUSIONS: NOP-LBBB occurred in ∼1 of 10 patients who had undergone TAVI with a balloon-expandable valve. NOP-LBBB was associated with a higher rate of PPI, a lack of improvement in left ventricular ejection fraction, and a poorer functional status, but did not increase the risk of global or cardiovascular mortality or rehospitalizations at 1-year follow-up.

RNA polymerase II mutations conferring defects in poly(A) site cleavage and termination in Saccharomyces cerevisiae.

Transcription termination by RNA polymerase (Pol) II is an essential but poorly understood process. In eukaryotic nuclei, the 3' ends of mRNAs are generated by cleavage and polyadenylation, and the same sequence elements that specify that process are required for downstream release of the polymerase from the DNA. Although Pol II is known to bind proteins required for both events, few studies have focused on Pol II mutations as a means to uncover the mechanisms that couple polyadenylation and termination. We performed a genetic screen in the yeast Saccharomyces cerevisiae to isolate mutations in the N-terminal half of Rpb2, the second largest Pol II subunit, that conferred either a decreased or increased response to a well-characterized poly(A) site. Most of the mutant alleles encoded substitutions affecting either surface residues or conserved active site amino acids at positions important for termination by other RNA polymerases. Reverse transcription polymerase chain reaction experiments revealed that transcript cleavage at the poly(A) site was impaired in both classes of increased readthrough mutants. Transcription into downstream sequences beyond where termination normally occurs was also probed. Although most of the tested readthrough mutants showed a reduction in termination concomitant with the reduced poly(A) usage, these processes were uncoupled in at least one mutant strain. Several rpb2 alleles were found to be similar or identical to published mutants associated with defective TFIIF function. Tests of these and additional mutations known to impair Rpb2-TFIIF interactions revealed similar decreased readthrough phenotypes, suggesting that TFIIF may have a role in 3' end formation and termination.

Acetylation of the SUN protein Mps3 by Eco1 regulates its function in nuclear organization.

The Saccharomyces cerevisiae SUN-domain protein Mps3 is required for duplication of the yeast centrosome-equivalent organelle, the spindle pole body (SPB), and it is involved in multiple aspects of nuclear organization, including telomere tethering and gene silencing at the nuclear membrane, establishment of sister chromatid cohesion, and repair of certain types of persistent DNA double-stranded breaks. How these diverse SUN protein functions are regulated is unknown. Here we show that the Mps3 N-terminus is a substrate for the acetyltransferase Eco1/Ctf7 in vitro and in vivo and map the sites of acetylation to three lysine residues adjacent to the Mps3 transmembrane domain. Mutation of these residues shows that acetylation is not essential for growth, SPB duplication, or distribution in the nuclear membrane. However, analysis of nonacetylatable mps3 mutants shows that this modification is required for accurate sister chromatid cohesion and for chromosome recruitment to the nuclear membrane. Acetylation of Mps3 by Eco1 is one of the few regulatory mechanisms known to control nuclear organization.

Long-term outcomes after transcatheter aortic valve implantation: insights on prognostic factors and valve durability from the Canadian multicenter experience.

OBJECTIVES: This study sought to evaluate the long-term outcomes after transcatheter aortic valve implantation (TAVI) in the Multicenter Canadian Experience study, with special focus on the causes and predictors of late mortality and valve durability. BACKGROUND: Very few data exist on the long-term outcomes associated with TAVI. METHODS: This was a multicenter study including 339 patients considered to be nonoperable or at very high surgical risk (mean age: 81 ± 8 years; Society of Thoracic Surgeons score: 9.8 ± 6.4%) who underwent TAVI with a balloon-expandable Edwards valve (transfemoral: 48%, transapical: 52%). Follow-up was available in 99% of the patients, and serial echocardiographic exams were evaluated in a central echocardiography core laboratory. RESULTS: At a mean follow-up of 42 ± 15 months 188 patients (55.5%) had died. The causes of late death (152 patients) were noncardiac (59.2%), cardiac (23.0%), and unknown (17.8%). The predictors of late mortality were chronic obstructive pulmonary disease (hazard ratio [HR]: 2.18, 95% confidence interval [CI]: 1.53 to 3.11), chronic kidney disease (HR: 1.08 for each decrease of 10 ml/min in estimated glomerular filtration rate, 95% CI: 1.01 to 1.19), chronic atrial fibrillation (HR: 1.44, 95% CI: 1.02 to 2.03), and frailty (HR: 1.52, 95% CI: 1.07 to 2.17). A mild nonclinically significant decrease in valve area occurred at 2-year follow-up (p < 0.01), but no further reduction in valve area was observed up to 4-year follow-up. No changes in residual aortic regurgitation and no cases of structural valve failure were observed during the follow-up period. CONCLUSIONS: Approximately one-half of the patients who underwent TAVI because of a high or prohibitive surgical risk profile had died at a mean follow-up of 3.5 years. Late mortality was due to noncardiac comorbidities in more than one-half of patients. No clinically significant deterioration in valve function was observed throughout the follow-up period.