Reperfusion in Patients With ST-Segment-Elevation Myocardial Infarction With Cardiogenic Shock and Prolonged Interhospital Transport Times.

BACKGROUND: In patients with ST-segment-elevation myocardial infarction complicated by cardiogenic shock, primary percutaneous coronary intervention (pPCI) is the preferred revascularization option. Little is known about the efficacy and safety of a pharmacoinvasive approach for patients with cardiogenic shock presenting to a non-PCI hospital with prolonged interhospital transport times. METHODS: In a retrospective analysis of geographically extensive ST-segment-elevation myocardial infarction network (2006-2021), 426 patients with cardiogenic shock and ST-segment-elevation myocardial infarction presented to a non-PCI-capable hospital and underwent reperfusion therapy (53.8% pharmacoinvasive and 46.2% pPCI). The primary clinical outcome was a composite of in-hospital mortality, renal failure requiring dialysis, cardiac arrest, or mechanical circulatory support, and the primary safety outcome was major bleeding defined as an intracranial hemorrhage or bleeding that required transfusion was compared in an inverse probability weighted model. The electrocardiographic reperfusion outcome of interest was the worst residual ST-segment-elevation. RESULTS: Patients with pharmacoinvasive treatment had longer median interhospital transport (3 hours versus 1 hour) and shorter median symptom-onset-to-reperfusion (125 minute-to-needle versus 419 minute-to-balloon) times. ST-segment resolution ≥50% on the postfibrinolysis ECG was 56.6%. Postcatheterization, worst lead residual ST-segment-elevation <1 mm (57.3% versus 46.3%; P=0.01) was higher in the pharmacoinvasive compared with the pPCI cohort, but no differences were observed in the worst lead ST-segment-elevation resolution ≥50% (77.4% versus 81.8%; P=0.57). The primary clinical end point was lower in the pharmacoinvasive cohort (35.2% versus 57.0%; inverse probability weighted odds ratio, 0.44 [95% CI, 0.26-0.72]; P<0.01) compared with patients who received pPCI. An interaction between interhospital transfer time and reperfusion strategy with all-cause mortality was observed, favoring a pharmacoinvasive approach with transfer times >60 minutes. The incidence of the primary safety outcome was 10.1% in the pharmacoinvasive arm versus 18.7% in pPCI (adjusted odds ratio, 0.41 [95% CI, 0.14-1.09]; P=0.08). CONCLUSIONS: In patients with ST-segment-elevation myocardial infarction presenting with cardiogenic shock and prolonged interhospital transport times, a pharmacoinvasive approach was associated with improved electrocardiographic reperfusion and a lower rate of death, dialysis, or mechanical circulatory support without an increase in major bleeding.

Change Management Accompanying Implementation of Decision Support for Prevention of Acute Kidney Injury in Cardiac Catheterization Units: Program Report.

Purpose of program: Different models exist to guide successful implementation of electronic health tools into clinical practice. The Contrast Reducing Injury Sustained by Kidneys (Contrast RISK) initiative introduced an electronic decision support tool with physician audit and feedback into all of the cardiac catheterization facilities in Alberta, Canada, with the goal of preventing contrast-associated acute kidney injury (CA-AKI) following coronary angiography and intervention. This report describes the change management approaches used by the initiative and end-user's feedback on these processes. Sources of information and methods: The Canada Health Infoway Change Management model was used to address 6 activities relevant to project implementation: governance and leadership, stakeholder engagement, communications, workflow analysis and integration, training and education, and monitoring and evaluation. Health care providers and invasive cardiologists from all sites completed preimplementation, usability, and postimplementation surveys to assess integration and change success. Key findings: Prior to implementation, 67% of health providers were less than satisfied with processes to determine appropriate contrast dye volumes, 47% were less than satisfied with processes for administering adequate intravenous fluids, and 68% were less than satisfied with processes to ensure follow-up of high-risk patients. 48% of invasive cardiologists were less than satisfied with preprocedural identification of patients at risk of acute kidney injury (AKI). Following implementation, there were significant increases among health providers in the odds of satisfaction with processes for identifying those at high risk of AKI (odds ratio [OR] 3.01, 95% confidence interval [CI] 1.36-6.66, P = .007), quantifying the appropriate level of contrast dye for each patient (OR 6.98, 95% CI 3.06-15.91, P < .001), determining the optimal amount of IV fluid for each patient (OR 1.86, 95% CI 0.88-3.91, P = .102), and following up of kidney function of high risk patients (OR 5.49, 95%CI 2.45-12.30, P < .001). There were also significant increases among physicians in the odds of satisfaction with processes for identifying those at high risk of AKI (OR 19.53, 95% CI 3.21-118.76, P = .001), quantifying the appropriate level of contrast dye for each patient (OR 26.35, 95% CI 4.28-162.27, P < .001), and for following-up kidney function of high-risk patients (OR 7.72, 95% CI 1.62-36.84.30, P = .010). Eighty-nine percent of staff perceived the initiative as being successful in changing clinical practices to reduce the risk of CA-AKI. Physicians uniformly agreed that the system was well-integrated into existing workflows, while 42% of health providers also agreed. Implications: The Canada Health Infoway Change Management model was an effective framework for guiding implementation of an electronic decision support tool and audit and feedback intervention to improve processes for AKI prevention within cardiac catheterization units.

Objectif du program: Il existe différents modèles pour guider la mise en œuvre efficace d'outils électroniques dans la pratique clinique. L'initiative Contrast RISK (Contrast Reducing Injury Sustained by Kidneys) a permis d'introduire un outil électronique d'aide à la décision avec surveillance par le médecin et rétroaction dans tous les établissements de l'Alberta (Canada) pratiquant le cathétérisme cardiaque, dans le but de prévenir les insuffisances rénales aiguës associées aux produits de contraste (IRA-PC) après une coronarographie et une intervention. Le présent rapport décrit les approches de gestion du changement utilisées dans le cadre de l'initiative, ainsi que les commentaires des utilisateurs sur ces processus. Sources de l'information et méthodologie: Le modèle de gestion du changement d'Inforoute Santé du Canada a été employé pour aborder six activités pertinentes pour la mise en œuvre de projets: gouvernance et leadership, engagement des intervenants, communications, analyze du flux de travail et intégration, formation et éducation, surveillance et évaluation. Les prestataires de soins et les cardiologues spécialisés en interventions invasives de tous les sites ont répondu à un sondage avant, pendant et après la mise en œuvre afin d'évaluer le succès de l'intégration et du changement. Principaux résultats: Avant la mise en œuvre, 67% des prestataires de soins étaient insatisfaits des processus pour déterminer les volumes appropriés des produits de contraste, 47% étaient insatisfaits des processus pour administrer l'hydratation intraveineuse et 68% étaient insatisfaits des processus de surveillance des patients présentant un risque élevé. Près de la moitié (48%) des cardiologues spécialisés en interventions invasives étaient insatisfaits du processus d'identification préalable des patients présentant un risque élevé d'IRA. Après la mise en œuvre, on a observé une augmentation significative de la satisfaction des prestataires de soins à l'égard des processus pour identifier les patients présentant un risque élevé d'IRA (rapport de cote [RC]: 3,01; IC 95%: 1,36-6,66; P = .007), quantifier le niveau approprié de produit de contraste pour chaque patient (RC: 6,98; IC 95%: 3,06-15,91; P < .001), déterminer le volume optimal d'hydratation IV pour chaque patient (RC: 1,86, IC 95%: 0,88-3,91; P = .102) et surveiller la fonction rénale chez les patients présentant un risque élevé (RC: 5,49 IC 95%: 2,45-12,30; P < .001). On a également observé une augmentation significative de la satisfaction des médecins à l'égard des processus pour identifier les patients présentant un risque élevé d'IRA (RC: 19,53; IC 95%: 3,21-118,76; P = .001), quantifier le niveau approprié de produit de contraste pour chaque patient (RC: 26,35; IC 95%: 4,28-162,27; P < .001) et surveiller la fonction rénale des patients présentant un risque élevé (RC: 7,72; IC 95%: 1,62-36,84,30; P = .010). Une grande majorité du personnel (89%) était d'avis que l'initiative avait permis de changer les pratiques cliniques visant à réduire le risque d'IRA-PC. L'ensemble des médecins s'entendait pour dire que le système était bien intégré dans les flux de travail existants; 42% des prestataires de soins étaient également de cet avis. Conclusion: Le modèle de gestion du changement d'Inforoute Santé du Canada s'est avéré un cadre efficace pour guider la mise en œuvre d'un outil électronique d'aide à la décision et d'une intervention de surveillance et de rétroaction visant à améliorer les processus de prévention de l'IRA dans les unités de cathétérisme cardiaque.

Effect of Clinical Decision Support With Audit and Feedback on Prevention of Acute Kidney Injury in Patients Undergoing Coronary Angiography: A Randomized Clinical Trial.

Importance: Contrast-associated acute kidney injury (AKI) is a common complication of coronary angiography and percutaneous coronary intervention (PCI) that has been associated with high costs and adverse long-term outcomes. Objective: To determine whether a multifaceted intervention is effective for the prevention of AKI after coronary angiography or PCI. Design, Setting, and Participants: A stepped-wedge, cluster randomized clinical trial was conducted in Alberta, Canada, that included all invasive cardiologists at 3 cardiac catheterization laboratories who were randomized to various start dates for the intervention between January 2018 and September 2019. Eligible patients were aged 18 years or older who underwent nonemergency coronary angiography, PCI, or both; who were not undergoing dialysis; and who had a predicted AKI risk of greater than 5%. Thirty-four physicians performed 7820 procedures among 7106 patients who met the inclusion criteria. Participant follow-up ended in November 2020. Interventions: During the intervention period, cardiologists received educational outreach, computerized clinical decision support on contrast volume and hemodynamic-guided intravenous fluid targets, and audit and feedback. During the control (preintervention) period, cardiologists provided usual care and did not receive the intervention. Main Outcomes and Measures: The primary outcome was AKI. There were 12 secondary outcomes, including contrast volume, intravenous fluid administration, and major adverse cardiovascular and kidney events. The analyses were conducted using time-adjusted models. Results: Of the 34 participating cardiologists who were divided into 8 clusters by practice group and center, the intervention group included 31 who performed 4327 procedures among 4032 patients (mean age, 70.3 [SD, 10.7] years; 1384 were women [32.0%]) and the control group included 34 who performed 3493 procedures among 3251 patients (mean age, 70.2 [SD, 10.8] years; 1151 were women [33.0%]). The incidence of AKI was 7.2% (310 events after 4327 procedures) during the intervention period and 8.6% (299 events after 3493 procedures) during the control period (between-group difference, -2.3% [95% CI, -0.6% to -4.1%]; odds ratio [OR], 0.72 [95% CI, 0.56 to 0.93]; P = .01). Of 12 prespecified secondary outcomes, 8 showed no significant difference. The proportion of procedures in which excessive contrast volumes were used was reduced to 38.1% during the intervention period from 51.7% during the control period (between-group difference, -12.0% [95% CI, -14.4% to -9.4%]; OR, 0.77 [95% CI, 0.65 to 0.90]; P = .002). The proportion of procedures in eligible patients in whom insufficient intravenous fluid was given was reduced to 60.8% during the intervention period from 75.1% during the control period (between-group difference, -15.8% [95% CI, -19.7% to -12.0%]; OR, 0.68 [95% CI, 0.53 to 0.87]; P = .002). There were no significant between-group differences in major adverse cardiovascular events or major adverse kidney events. Conclusions and Relevance: Among cardiologists randomized to an intervention including clinical decision support with audit and feedback, patients undergoing coronary procedures during the intervention period were less likely to develop AKI compared with those treated during the control period, with a time-adjusted absolute risk reduction of 2.3%. Whether this intervention would show efficacy outside this study setting requires further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT03453996.

Transcatheter Aortic Valve Implantation in a Failed Perceval Sutureless Valve, Complicated by Aortic Annular Rupture.

As the use of surgically implanted sutureless aortic valves has increased over the past decade, we expect to encounter their failure increasingly in coming years. We describe a case of Perceval aortic valve failure with stent infolding and severe stenosis. This condition was treated with valve-in-valve transcatheter aortic valve implantation and complicated by aortic annular rupture at the site of infolding. This case is important because it outlines the limited experience with valve-in-valve transcatheter aortic valve implantation to treat failed sutureless valves and identifies sutureless valve infolding as a potential risk for annular rupture.

Puisque l'implantation valvulaire aortique sans suture s'est accrue au cours de la dernière décennie, nous nous attendons à rencontrer de plus en plus de défaillances de valves dans les années à venir. Nous décrivons un cas de défaillance de la valve aortique Perceval avec pliage de l'endoprothèse et sténose grave. Le traitement qui consistait en l'implantation valvulaire aortique de type valve-in-valve par cathéter a été compliqué par la rupture de l'anneau aortique au site du pliage. Il s'agit d'un cas important puisqu'il décrit le peu d'expérience en matière d'implantation valvulaire aortique de type valve-in-valve par cathéter dans le traitement des valves sans suture défectueuses et établit que le pliage d'une valve sans suture expose à un risque de rupture de l'anneau.

Ticagrelor or clopidogrel dual antiplatelet therapy following a pharmacoinvasive strategy in ST-segment elevation myocardial infarction.

OBJECTIVES: To describe and evaluate outcomes in STEMI patients sustained on clopidogrel compared to those switched to ticagrelor following fibrinolysis. BACKGROUND: World-wide, many STEMI patients cannot achieve timely PCI and therefore require fibrinolysis. Although comparable 30-day and 1-year safety was shown with clopidogrel or ticagrelor in the TREAT study, there is paucity of long-term outcomes in pharmacoinvasive treated STEMI. METHODS: We conducted an observational cohort study evaluating consecutive pharmacoinvasive STEMI patients treated in a network, comparing those switched to ticagrelor to those sustained on clopidogrel. The primary efficacy composite was one-year all-cause death, recurrent myocardial infarction, and stroke with major bleeding and intracranial hemorrhage (ICH) as the safety outcomes. Multivariable Cox regression model was used to examine the association between P2Y12 inhibitor and outcomes with inverse probability weighting. RESULTS: Of 1426 pharmacoinvasive STEMI patients, 28% (n = 396) were converted to ticagrelor at a mean of 9.9 h after fibrinolysis with comparable GRACE Risk Scores (median; 158 vs 157, p0.352). The primary composite occurred in 3.5% of ticagrelor and 7.0% of clopidogrel treated patients (p0.014). Following adjustment, ticagrelor was associated with a 54% lower composite outcome (adjusted HR 0.46, 95% confidence interval 0.26-0.84). Major bleeding 6.3% vs 6.1% (NS) and ICH 0.0% vs 0.2% (NS) were similar. CONCLUSIONS: In a prospective STEMI cohort, switching to ticagrelor compared with sustaining clopidogrel following fibrinolysis pharmacoinvasive reperfusion reduced recurrent ischemic events at 1-year with no differences in major bleeding or ICH. Aligned with randomized data, these findings provide support to switch pharmaco-invasively treated STEMI patients.

Effects of Transcatheter Aortic Valve Implantation on Frailty and Quality of Life.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an effective alternative to surgical valve replacement in high-risk patients with severe aortic stenosis. Although measures of frailty have been used to attempt to predict outcomes in this population, few studies have demonstrated changes in these measures. METHODS: We performed a prospective, observational study of 171 patients undergoing TAVI, of whom 44 had maximal follow-up of 1 month and 50 had maximal follow-up of 1 year. Quality of life was assessed using the Minnesota Living With Heart Failure Questionnaire, Katz Index of Independence in Activities of Daily Living questionnaire, and patient perception of overall well-being. Frailty was measured using the 10-m walk test and handgrip strength testing. RESULTS: In the overall cohort, participants demonstrated improvements in quality of life metrics, but deterioration in 10-m walk test and handgrip at 1 month. These trends continued at 1 year. However, patients in the lowest quintile of handgrip and 10-m walk test demonstrated a trend of improvements in these metrics during follow-up. CONCLUSIONS: Despite improvements in quality of life after TAVI, no improvements in frailty were observed in patients at 1 year.

CONTEXTE: Le remplacement valvulaire aortique par cathéter (TAVI) est une solution de rechange efficace à la chirurgie de remplacement valvulaire chez les patients atteints de sténose aortique grave et présentant un risque élevé. Les mesures de la fragilité sont utilisées pour tenter de prévoir les résultats au sein de cette population. Néanmoins, peu d'études ont permis d'objectiver les variations de ces mesures. MÉTHODOLOGIE: Nous avons réalisé une étude observationnelle prospective portant sur 171 patients ayant subi un TAVI, dont 44 suivis pendant un mois ou moins, et 50 durant un an ou moins. La qualité de vie a été évaluée au moyen de questionnaires ­ Minnesota Living With Heart Failure Questionnaire et Katz Index of Independence in Activities of Daily Living Questionnaire ­ et en fonction de la perception du patient relativement à son bien-être général. La fragilité a été mesurée à l'aide d'un test de marche sur dix mètres et d'un test de force de préhension. RÉSULTATS: Dans l'ensemble de la cohorte, une amélioration des mesures de la qualité de vie a été observée parallèlement à une détérioration des résultats au test de marche sur dix mètres et au test de force de préhension après un mois. Les tendances à cet égard se sont poursuivies au bout d'un an. Cependant, les résultats des patients du quintile inférieur au test de marche sur 10 m et au test de force de préhension ont eu tendance à s'améliorer au cours de la période de suivi. CONCLUSIONS: Malgré une amélioration de la qualité de vie après le TAVI, la fragilité des patients ne s'est nullement améliorée après un an.

Pharmacoinvasive Strategy Versus Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction in Clinical Practice: Insights From the Vital Heart Response Registry.

BACKGROUND: Recent clinical trial data support a pharmacoinvasive strategy as an alternative to primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction. We evaluated whether this is true in a real-world prehospital ST-segment elevation myocardial infarction network using ECG assessment of reperfusion coupled with clinical outcomes within 1 year. METHODS: Of the 5583 ST-segment elevation myocardial infarction patients in the Alberta Vital Heart Response Program (Cohort 1 [2006-2011]: n=3593; Cohort 2 [2013-2016]: n=1990), we studied 3287 patients who received a pharmacoinvasive strategy with tenecteplase (April 2013: half-dose tenecteplase was employed in prehospital patients ≥75 years) or pPCI. ECGs were analyzed within a core laboratory; sum ST-segment deviation resolution ≥50% was defined as successful reperfusion. The primary composite was all-cause death, congestive heart failure, cardiogenic shock, and recurrent myocardial infarction within 1 year. RESULTS: The pharmacoinvasive approach was administered in 1805 patients (54.9%), (493 [27.3%] underwent rescue/urgent percutaneous coronary intervention and 1312 [72.7%] had scheduled angiography); pPCI was performed in 1482 patients (45.1%). There was greater ST-segment resolution post-catheterization/percutaneous coronary intervention with a pharmacoinvasive strategy versus pPCI (75.8% versus 64.3%, IP-weighted odds ratio, 1.59; 95% CI, 1.33-1.90; P<0.001). The primary composite was significantly lower with a pharmacoinvasive approach (16.3% versus 23.1%, IP-weighted hazard ratio, 0.84; 95% CI, 0.72-0.99; P=0.033). Major bleeding and intracranial hemorrhage were similar between a pharmacoinvasive strategy and pPCI (7.6% versus 7.5%, P=0.867; 0.6% versus 0.6%; P=0.841, respectively). In the 82 patients ≥75 years with a prehospital pharmacoinvasive strategy, similar ST-segment resolution and rescue rates were observed with full-dose versus half-dose tenecteplase (75.8% versus 88.9%, P=0.259; 31.0% versus 29.2%, P=0.867) with no difference in the primary composite (31.0% versus 25.0%, P=0.585). CONCLUSIONS: In this large Canadian ST-segment elevation myocardial infarction registry, a pharmacoinvasive strategy was associated with improved ST-segment resolution and enhanced outcomes within 1 year compared with pPCI. Our findings support the application of a selective pharmacoinvasive reperfusion strategy when delay to pPCI exists.

Success Begins With Failure: An Alternative Approach in Transfemoral Transcatheter Aortic Valve Replacement Using an Antegrade Wire Crossing Technique.

Transcatheter aortic valve replacement has transitioned from an experimental procedure to an important alternative therapy for patients with symptomatic aortic stenosis and high surgical risk. We present a case outlining an approach to deal with the issue of "failure to cross" the aortic valve in transcatheter aortic valve replacement from the transfemoral retrograde approach.

Le remplacement valvulaire aortique par cathéter est passé d'une intervention expérimentale à un traitement alternatif important pour les patients atteints d'une sténose aortique symptomatique et exposés à un risque opératoire élevé. Nous présentons un cas qui décrit une approche pour remédier au problème d'« échec à traverser ¼ la valvule aortique lors du remplacement valvulaire aortique par cathéter selon une approche par voie rétrograde fémorale.

Transcatheter Mitral Valve Intervention for Chronic Mitral Regurgitation: A Plethora of Different Technologies.

Chronic mitral regurgitation (MR) remains a common cardiovascular condition resulting in significant morbidity and mortality. With an aging population, increasing trends for both primary (degenerative) and secondary (functional) MR have become apparent. Although the gold standard remains surgical intervention with mitral valve repair/replacement, comorbid conditions have steered the development of less invasive technologies to mitigate perioperative surgical risk. Transcatheter mitral valve repair using a percutaneous edge-to-edge technique is the most widely available choice at present. However, other transcatheter mitral valve repair techniques such as annuloplasty and chordal implantation are notable alternatives. Moreover, emerging technologies in transcatheter mitral valve replacement are rapidly establishing their roles in the field of chronic severe MR therapy. Hence, it is imperative to understand the indications and limitations of these various transcatheter mitral valve interventions to provide the best and most up-to-date clinical care for patients. This review will outline current evidence and patient selection criteria for such device-based therapies.

Relationships Between Baseline Q Waves, Time From Symptom Onset, and Clinical Outcomes in ST-Segment-Elevation Myocardial Infarction Patients: Insights From the Vital Heart Response Registry.

BACKGROUND: Using a comprehensive ST-segment-elevation myocardial infarction registry, we evaluated the relationships of baseline Q waves, time from symptom onset, and reperfusion strategy with in-hospital clinical outcomes. METHODS AND RESULTS: Consecutive ST-segment-elevation myocardial infarction patients from a defined health region were classified by the presence of baseline Q waves and additionally into primary percutaneous coronary intervention, fibrinolysis, or no reperfusion. ECGs were collected at baseline, after reperfusion, and analyzed for the presence of Q waves using Selvester criteria. Among 2290 ST-segment-elevation myocardial infarction patients, 36.9% had Q waves on their baseline ECG. Patients with Q waves were older (median age, 59 versus 57), were more often male (82.0% versus 75.4%), had higher heart rate (80 versus 72), had higher Global Registry of Acute Coronary Events risk score (129 versus 127), and were with longer time to reperfusion (42 minutes longer). They had higher composite end points (16.3% versus 10.0%), consistent across times from symptom onset to presentation (15.4% versus 9.9% ≤3 hours; 18.5% versus 8.9% >3 to ≤6 hours; 15.9% versus 11.3% >6 hours; Q and no Q, respectively). Baseline Q waves, but not time to reperfusion, were associated with an increased odds of the in-hospital composite end point of death, congestive heart failure, cardiogenic shock, and reinfarction (adjusted odds ratio, 1.65; 95% confidence interval, 1.18-2.30; P=0.003). Type of reperfusion did not modify the association of baseline Q waves and in-hospital outcomes (P interaction=0.918). CONCLUSIONS: The presence of baseline Q waves, rather than time to treatment, was significantly associated with adverse in-hospital events in real-world patients, regardless of reperfusion strategy used.

Coordination by Cdc42 of Actin, Contractility, and Adhesion for Melanoblast Movement in Mouse Skin.

The individual molecular pathways downstream of Cdc42, Rac, and Rho GTPases are well documented, but we know surprisingly little about how these pathways are coordinated when cells move in a complex environment in vivo. In the developing embryo, melanoblasts originating from the neural crest must traverse the dermis to reach the epidermis of the skin and hair follicles. We previously established that Rac1 signals via Scar/WAVE and Arp2/3 to effect pseudopod extension and migration of melanoblasts in skin. Here we show that RhoA is redundant in the melanocyte lineage but that Cdc42 coordinates multiple motility systems independent of Rac1. Similar to Rac1 knockouts, Cdc42 null mice displayed a severe loss of pigmentation, and melanoblasts showed cell-cycle progression, migration, and cytokinesis defects. However, unlike Rac1 knockouts, Cdc42 null melanoblasts were elongated and displayed large, bulky pseudopods with dynamic actin bursts. Despite assuming an elongated shape usually associated with fast mesenchymal motility, Cdc42 knockout melanoblasts migrated slowly and inefficiently in the epidermis, with nearly static pseudopods. Although much of the basic actin machinery was intact, Cdc42 null cells lacked the ability to polarize their Golgi and coordinate motility systems for efficient movement. Loss of Cdc42 de-coupled three main systems: actin assembly via the formin FMNL2 and Arp2/3, active myosin-II localization, and integrin-based adhesion dynamics.

Ninein is essential for apico-basal microtubule formation and CLIP-170 facilitates its redeployment to non-centrosomal microtubule organizing centres.

Differentiation of columnar epithelial cells involves a dramatic reorganization of the microtubules (MTs) and centrosomal components into an apico-basal array no longer anchored at the centrosome. Instead, the minus-ends of the MTs become anchored at apical non-centrosomal microtubule organizing centres (n-MTOCs). Formation of n-MTOCs is critical as they determine the spatial organization of MTs, which in turn influences cell shape and function. However, how they are formed is poorly understood. We have previously shown that the centrosomal anchoring protein ninein is released from the centrosome, moves in a microtubule-dependent manner and accumulates at n-MTOCs during epithelial differentiation. Here, we report using depletion and knockout (KO) approaches that ninein expression is essential for apico-basal array formation and epithelial elongation and that CLIP-170 is required for its redeployment to n-MTOCs. Functional inhibition also revealed that IQGAP1 and active Rac1 coordinate with CLIP-170 to facilitate microtubule plus-end cortical targeting and ninein redeployment. Intestinal tissue and in vitro organoids from the Clip1/Clip2 double KO mouse with deletions in the genes encoding CLIP-170 and CLIP-115, respectively, confirmed requirement of CLIP-170 for ninein recruitment to n-MTOCs, with possible compensation by other anchoring factors such as p150Glued and CAMSAP2 ensuring apico-basal microtubule formation despite loss of ninein at n-MTOCs.

Transcatheter Valve-in-Valve: A Cautionary Tale.

Transcatheter aortic valve replacement (TAVR) by valve-in-valve (VIV) implantation is an alternative treatment for high-risk patients with a degenerating aortic bioprosthesis. We present a case of transapical TAVR VIV with a 29-mm Edwards SAPIEN XT (ESV) (Edwards Lifesciences, Irvine, CA) into a 29-mm Medtronic Freestyle stentless bioprosthesis (Medtronic Inc, Minneapolis, MN) in which unanticipated dilatation of the Freestyle bioprosthesis resulted in intraprocedural embolization of the TAVR valve, necessitating urgent conversion to a conventional surgical aortic valve replacement (AVR). Our experience suggests that TAVR VIV with the 29-mm ESV in the setting of a degenerated 29-mm Freestyle stentless bioprosthesis must be undertaken with caution.

Loss of strumpellin in the melanocytic lineage impairs the WASH Complex but does not affect coat colour.

The five-subunit WASH complex generates actin networks that participate in endocytic trafficking, migration and invasion in various cell types. Loss of one of the two subunits WASH or strumpellin in mice is lethal, but little is known about their role in mammals in vivo. We explored the role of strumpellin, which has previously been linked to hereditary spastic paraplegia, in the mouse melanocytic lineage. Strumpellin knockout in melanocytes revealed abnormal endocytic vesicle morphology but no impairment of migration in vitro or in vivo and no change in coat colour. Unexpectedly, WASH and filamentous actin could still localize to vesicles in the absence of strumpellin, although the shape and size of vesicles was altered. Blue native PAGE revealed the presence of two distinct WASH complexes, even in strumpellin knockout cells, revealing that the WASH complex can assemble and localize to endocytic compartments in cells in the absence of strumpellin.

From Coronary Care Units to Cardiac Intensive Care Units: Recommendations for Organizational, Staffing, and Educational Transformation.

Medical care in Canadian cardiac units has changed considerably over the past 3 decades in response to an increasingly complex and diverse patient population admitted with acute cardiac pathology. To maintain the highest level of care for these patients, there is a pressing need to evolve traditional coronary care units into contemporary cardiac intensive care units. In this article we aim to highlight the current variations in Canadian units, develop approaches to overcome logistical and infrastructural obstacles, and propose staffing and training recommendations that would allow for the establishment of contemporary cardiac intensive care units.

Outcomes of consecutive patients referred for consideration for transcatheter aortic valve implantation from an encompassing health-care region.

Procedural outcomes for transcatheter aortic valve implantation (TAVI) are well described. However, limited information exists regarding patient screening and selection. Thus, the purpose of the study was to review consecutive patients referred for TAVI from an inclusive-defined population. The Mazankowski Alberta Heart Institute TAVI program has maintained a prospective database on all referred patients. Patients are reviewed in outpatient clinic attended by a nurse, cardiologist, cardiac surgeon, and administrative assistant. After workup is complete, a TAVI Heart Team conference occurs to accept or reject each patient. Since November 2009, 276 patients (145 men and 131 women) have been referred with a steady increase in the number of referrals annually. Mean age was 82.2 years (men 81.6 and women 82.8), with 13% aged <70 years. Mean EuroSCORE was 13.8 and mean STS score was 5.7. Of the referred patients, 34% received TAVI, 17% were rejected, 12% underwent open AVR, 10% refused TAVI, and 27% are currently being assessed or followed. There were no differences in the mean EuroSCORE (13.4 vs 14.3; p = 0.64) or STS scores (5.2 vs 6.4; p = 0.13) of those accepted for TAVI versus those who were not. In conclusion, a team-based approach to assess this complex patient population is essential to ensure efficient and comprehensive evaluation, in turn determining appropriate care allocation. With expansion of clinical experience and the evidence supporting TAVI, the Heart Teams defined to assess this patient population will be burdened with increased clinical commitment and require appropriate support.

The microtubule end-binding protein EB2 is a central regulator of microtubule reorganisation in apico-basal epithelial differentiation.

Microtubule end-binding (EB) proteins influence microtubule dynamic instability, a process that is essential for microtubule reorganisation during apico-basal epithelial differentiation. Here, we establish for the first time that expression of EB2, but not that of EB1, is crucial for initial microtubule reorganisation during apico-basal epithelial differentiation, and that EB2 downregulation promotes bundle formation. EB2 siRNA knockdown during early stages of apico-basal differentiation prevented microtubule reorganisation, whereas its downregulation at later stages promoted microtubule stability and bundle formation. Interestingly, although EB1 is not essential for microtubule reorganisation, its knockdown prevented apico-basal bundle formation and epithelial elongation. siRNA depletion of EB2 in undifferentiated epithelial cells induced the formation of straight, less dynamic microtubules with EB1 and ACF7 lattice association and co-alignment with actin filaments, a phenotype that could be rescued by inhibition with formin. Importantly, in situ inner ear and intestinal crypt epithelial tissue revealed direct correlations between a low level of EB2 expression and the presence of apico-basal microtubule bundles, which were absent where EB2 was elevated. EB2 is evidently important for initial microtubule reorganisation during epithelial polarisation, whereas its downregulation facilitates EB1 and ACF7 microtubule lattice association, microtubule-actin filament co-alignment and bundle formation. The spatiotemporal expression of EB2 thus dramatically influences microtubule organisation, EB1 and ACF7 deployment and epithelial differentiation.