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We previously showed that coincident exposure to heat shock (HS; 42°C for 2 h) and TNF-α synergistically induces apoptosis in mouse lung epithelium. We extended this work by analyzing HS effects on human lung epithelial responses to clinically relevant injury. Cotreatment with TNF-α and HS induced little caspase-3 and poly(ADP-ribose) polymerase cleavage in human small airway epithelial cells, A549 cells, and BEAS2B cells. Scratch wound closure rates almost doubled when A549 and BEAS2B cells and air-liquid interface cultures of human bronchial epithelial cells were heat shocked immediately after wounding. Microarray, qRT-PCR, and immunoblotting showed fibroblast growth factor 1 (FGF1) to be synergistically induced by HS and wounding. Enhanced FGF1 expression in HS/wounded A549 was blocked by inhibitors of p38 MAPK (SB203580) or HS factor (HSF)-1 (KNK-437) and in HSF1 knockout BEAS2B cells. PCR demonstrated FGF1 to be expressed from the two most distal promoters in wounded/HS cells. Wound closure in HS A549 and BEAS2B cells was reduced by FGF receptor-1/3 inhibition (SU-5402) or FGF1 depletion. Exogenous FGF1 accelerated A549 wound closure in the absence but not presence of HS. In the presence of exogenous FGF1, HS slowed wound closure, suggesting that it increases FGF1 expression but impairs FGF1-stimulated wound closure. Frozen sections from normal and idiopathic pulmonary fibrosis (IPF) lung were analyzed for FGF1 and HSP70 by immunofluorescence confocal microscopy and qRT-PCR. FGF1 and HSP70 mRNA levels were 7.5- and 5.9-fold higher in IPF than normal lung, and the proteins colocalized to fibroblastic foci in IPF lung. We conclude that HS signaling may have an important impact on gene expression contributing to lung injury, healing, and fibrosis.

Objectives: To demonstrate safety, feasibility and short-term clinical outcomes after transcatheter aortic valve-in-valve (ViV) implantation under local anesthesia without contrast aortography or echocardiographic guidance. Background: Transcatheter ViV implantation is an emerging treatment modality for patients with degenerative surgical bioprostheses. Given the radiopaque properties of the surgical aortic valve (SAV) frame, ViV procedures can often be performed with fluoroscopic guidance alone. Methods: ViV implantation was performed in 37 patients with SAV failure under local anesthesia without contrast aortography. Clinical and echocardiographic data were obtained at baseline, discharge, and 30 days. Results: Mean age was 74 ± 10 years and STS predicted risk of mortality was 5.6 ± 2.4%. Mean transaortic gradient decreased from 39.4 ± 15.5 mmHg to 13 ± 6.3 mmHg at discharge (p

Background Stent thrombosis (ST) is rare, but is associated with significant morbidity and mortality. Methods We analyzed data from the British Columbia (BC) Registry from April 2011–January 2012. Results 101 ST cases were reported and verified. Based on timing, ST was considered early (≤30days) in 35.6%, late (>30days–1year) in 17.8% and very late (>1year) in 46.5%. The majority (68.5%) presented with STEMI, and the remaining with non-STEMI (31.5%). Most vessels were functionally occluded (TIM1 flow grade ≤1 in 67.1%). Thrombus burden was high (TIMI thrombus grade ≥4 in 77.2%). Aspiration thrombectomy was performed in 41% of cases. New stents were implanted in 62.4% cases. Intra-coronary imaging was low (11%). At the original stent implantation, STEMI was the clinical presentation in 39.6%, the lesion was complex in 62.1%, and thrombus was visualized in 23.0%. Prognosis after ST was unfavorable with high mortality (11.9% at 30days and 16.8% at one year), and further revascularization (5.0% repeat PCI and 6.9% coronary artery bypass graft surgery). Early ST was associated with worse clinical outcome compared to late/very late ST: 30-day mortality at 22.2% versus 6.2% (p=0.02), and 1-year mortality at 27.8% versus 10.8% (p=0.05). Conclusions In this prospective registry from BC, all ST presented with myocardial infarction, and the majority was treated with emergency PCI. Additional stents were commonly implanted with infrequent use of intracoronary imaging. Mortality rate was higher for early ST in comparison with late/very late ST. A comprehensive approach should be developed to treat this difficult complication.

Background Isolated tricuspid valve surgery is associated with high morbidity and mortality, especially in patients with prior cardiac surgery. The transcatheter Forma Repair System (Edwards Lifesciences, Irvine, California) is designed to provide a surface for native leaflet coaptation to reduce tricuspid regurgitation (TR) by occupying the regurgitant orifice area. Objectives This study sought to evaluate the feasibility and exploratory efficacy with this transcatheter repair system for the treatment of severe TR. Methods Seven high-risk patients with severe TR and clinical signs of heart failure were declined for surgery and offered transcatheter treatment with this device. All procedures were performed within a cardiac catheterization laboratory or hybrid operating room under general anesthesia with transesophageal echocardiographic guidance. Vascular access was via the left axillary vein. Baseline characteristics, procedural and in-hospital outcomes, as well as 30-day follow-up were prospectively collected. Results All patients had severe TR and New York Heart Association (NYHA) functional class II to IV (mean age 76 ± 13 years; mean logistic EuroSCORE 25.7 ± 17.4%), and underwent device implantation to improve tricuspid leaflet coaptation, thereby reducing TR. Device implantation was successful without procedural complications in all patients, with significant reductions in TR severity (moderate in 3 patients and mild in 4 patients). Median hospital length of stay was 4 days. At 30-day follow-up, all patients but 1 demonstrated improvements in NYHA functional status (to class II) with pronounced reductions in the presence and severity of peripheral edema. TR severity was assessed as being moderate at 30-day transthoracic echocardiography follow-up in all patients. No complications related to the device or vascular access were observed during follow-up. Conclusions A transcatheter-based treatment option for severe TR appears safe and feasible with this repair system. Improvements in TR severity were documented in all patients, which were accompanied by improvements in peripheral edema and functional status.

Objectives This study sought to describe the development of a multicenter, transcatheter aortic valve replacement program and regional systems of care intended to optimize coordinated, efficient, and appropriate delivery of this new therapy. Background Transcatheter aortic valve replacement (TAVR) has become an accepted treatment option for patients with severe aortic stenosis who are at high surgical risk. Regional systems of care have led to improvements in outcomes for patients undergoing intervention for myocardial infarction, cardiac arrest, and stroke. We implemented a regional system of care for patients undergoing TAVR in British Columbia, Canada. Methods We describe a prospective observational cohort of 583 patients who underwent TAVR in British Columbia between 2012 and 2014. Regionalization of TAVR care in British Columbia refers to a centrally coordinated, funded, and evaluated program led by a medical director and a multidisciplinary advisory group that oversees planning, access to care, and quality of outcomes at the 4 provincial sites. Risk-stratified case selection for transfemoral TAVR is performed by heart teams at each site on the basis of consensus provincial indications. Referrals for lower volume and more complicated TAVR, including nontransfemoral access and valve-in-valve procedures, are concentrated at a single site. In-hospital and 30-day outcomes are reported. Results The median age was 83 years (interquartile range [IQR]: 78 to 87 years) and median STS score was 6% (IQR: 4% to 8%). Transfemoral access was performed in 499 (85.6%) cases and nontransfemoral in 84 (14.4%). Transcatheter valve-in-valve procedures in for failed bioprosthetic valves were performed in 43 patients (7.4%). A balloon-expandable valve was inserted in 386 (66.2%) and a self-expanding valve in 189 (32.4%). All-cause 30-day mortality was 3.5%. All-cause in-hospital mortality and disabling stroke occurred in 3.1% and 1.9%, respectively. Median length of stay was 3 days (IQR: 3 to 6 days), with 92.8% of patients discharged directly home. Conclusions This experience demonstrates the potential benefits of a regional system of care for TAVR. Excellent outcomes were demonstrated: most patients had short in-hospital stays and were discharged directly home.

There is little data on right ventricular (RV) remodeling patterns in complex congenital heart disease (CHD) patients with right ventricle to pulmonary artery (PA) conduits, and novel RV imaging modalities have not been explored in this population. Knowledge of the RV remodeling process is an important first step to future understanding and tracking of the RV response to pressure and volume overload in this diverse population. Three-dimensional knowledge-based reconstruction (3DKBR) derived from two-dimensional transthoracic echocardiography (TTE-3DKBR) is a novel approach to RV assessment. The aims of this study were twofold: (1) to assess the feasibility and accuracy of 3DKBR in patients with CHD with RV to PA conduits and (2) to characterize the three-dimensional shape of the RV across the spectrum of CHD with RV to PA conduits.Seventeen patients with tetralogy of Fallot, pulmonary atresia with ventricular septal defect, or truncus arteriosus (mean age, 29 ± 8 years; 24% women) and a conduit referred for cardiac magnetic resonance imaging (CMR) were prospectively recruited and underwent TTE-3DKBR. TTE-3DKBR echocardiographic image acquisition was performed using a standard ultrasound scanner linked to a Ventripoint Medical Systems unit. The surface RV volumetric reconstruction was performed by transmitting two-dimensional data points to an online database and comparing these with a lesion-specific catalog to derive the RV reconstruction. Parameters analyzed were end-diastolic volume (EDV), end-systolic volume, and ejection fraction. Intertechnique agreement was assessed using Pearson's correlation analysis, coefficients of variation, and Bland-Altman analysis. Three-dimensional shape comparisons of RV surface reconstructions were performed via automated validation testing of CMRs from 43 patients (mean age, 30 ± 8 years; 32% women) with RV to PA conduits (tetralogy of Fallot, n = 15; pulmonary atresia, n = 19; and truncus arteriosus, n = 9) distinct from patients in the 3DKBR comparison.There was good correlation and agreement between the two modalities: EDV, R = 0.77, P = .0004; end-systolic volume, R = 0.93, P .0001; ejection fraction, R = 0.75, P .0005. On Bland-Altman analyses, CMR EDV was slightly larger TTE-3DKBR, while EF was slightly higher by 3DKBR. Qualitative and quantitative assessment both demonstrated RV shape diversity based on surface reconstructions.This study demonstrates that TTE-3DKBR is an alternative technology that can be used to assess the RV in patients with complex CHD with a conduit. A novel method was used to compare RV shapes in this important population, and our results draw specific attention to the fact that the RV both within and outside diagnostic groups has very different unpredictable shapes and should not be treated equally. Our findings should set into motion future work focused on indices of RV shape and their impact on overall RV function and clinical outcomes, hence defining optimal timing of conduit revision, which at the current time is very unclear.

With the advent of transcatheter mitral valve replacement (TMVR) [(1)][1], the assessment of mitral annular dimensions by computed tomography (CT) is of increasing relevance. The nonplanar, saddle-shaped, 3-dimensional structure of the mitral annulus has been well established [(2)][2] with the

The nonplanar, saddle-shaped structure of the mitral annulus has been well established through decades of anatomic and echocardiographic study. Its relevance for mitral annular assessment for transcatheter mitral valve implantation is uncertain.Our objectives are to define the methodology for CT-based simplified "D-shaped" mitral annular assessment for transcatheter mitral valve implantation and compare these measurements to traditional "saddle-shaped" mitral annular assessment.The annular contour was manually segmented, and fibrous trigones were identified using electrocardiogram-gated diastolic CT data sets of 28 patients with severe functional mitral regurgitation, yielding annular perimeter, projected area, trigone-to-trigone (TT) distance, and septal-lateral distance. In contrast to the traditional saddle-shaped annulus, the D-shaped annulus was defined as being limited anteriorly by the TT distance, excluding the aortomitral continuity. Hypothetical left ventricular outflow tract (LVOT) clearance was assessed.Projected area, perimeter, and septal-lateral distance were found to be significantly smaller for the D-shaped annulus (11.2 ± 2.7 vs 13.0 ± 3.0 cm(2); 124.1 ± 15.1 vs 136.0 ± 15.5 mm; and 32.1 ± 4.0 vs 40.1 ± 4.9 mm, respectively; P.001). TT distances were identical (32.7 ± 4.1 mm). Hypothetical LVOT clearance was significantly lower for the saddle-shaped annulus than for the D-shaped annulus (10.7 ± 2.2 vs 17.5 ± 3.0 mm; P.001).By truncating the anterior horn of the saddle-shaped annular contour at the TT distance, the resulting more planar and smaller D-shaped annulus projects less onto the LVOT, yielding a significantly larger hypothetical LVOT clearance than the saddle-shaped approach. CT-based mitral annular assessment may aid preprocedural sizing, ensuring appropriate patient and device selection.

Aims The aim of this study was to examine the short- and medium-term outcomes of transcatheter aortic valve replacement (TAVR) with the self-expanding and repositionable Portico valve (St. Jude Medical, St. Paul, MN, USA). Methods and results A total of 57 patients underwent TAVR with the Portico valve between March 2012 and August 2014, representing the first-in-human experience and the entire early experience in Canada. Patients were followed up at 30 days and one year with repeat echocardiography and clinical review. Patients were 80.8±7.3 years of age, and the Society of Thoracic Surgeons predicted risk of mortality was 7.7±5.7%. All patients had a valve implanted and four patients (7%) required a second valve. At 30 days, there were two deaths (3.5%), three disabling strokes (5.3%), and new pacemakers in five (8.8%) patients. Echocardiography revealed moderate/severe aortic regurgitation in two patients (3.6%). At one year, survival was 84.2% and echocardiographic findings were unchanged. Conclusions Transcatheter aortic valve replacement with the repositionable Portico valve provides satisfactory short- and medium-term haemodynamic and clinical results.

Recent research has identified younger women as an "at-risk" population with rising prevalence of cardiac risk factors and excess mortality risk following acute myocardial infarction (AMI). However, population-based data on trends in AMI hospitalization and early mortality post AMI among younger adults is scarce. We, therefore, aimed to provide a 10-year, descriptive analysis of these trends in a Canadian setting.We assessed trends and sex differences in AMI hospitalization and 30-day mortality rates using negative binomial and logistic regression, respectively. From 2000 to 2009, there were 70,628 AMI hospitalizations in adults aged ≥20 years, in British Columbia, Canada, with 17.1% of cohort being younger adults ≤55 years. Overall, age-standardized AMI rates (per 100,000 population) declined similarly in men (295.8 to 247.7) and women (152.1 to 128.8) [sex-year interaction p=0.81]. However, these trends differed according to age (age-sex-year interaction p=0.02) with increased rates observed only in younger women (+1.7% per year; p=0.04). The 30-day mortality rates declined similarly for women (19.4% to 13.9%) and men (13.0% to 9.3%) (sex-year interaction p=0.33). Yet, younger women continued to have excess mortality risk, compared with younger men, even in the most recent period [odds ratio: (2008-09)=1.61 (95% onfidence interval: 1.25, 2.08)].While the overall AMI hospitalization and 30-day mortality rates significantly declined in women and men, hospitalization rates in women ≤55 years increased and their excess risk of 30-day mortality persisted. These findings highlight the need to intensify strategies to reduce the incidence of AMI and improve outcomes after AMI in younger women.

Background— The effect of preoperative mitral regurgitation (MR) on clinical outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) is controversial. This study sought to examine the impact of moderate and severe MR on outcomes after TAVR and surgical aortic valve replacement (SAVR). Methods and Results— Data were drawn from the randomized Placement of Aortic Transcatheter Valve (PARTNER) Trial cohort A patients with severe, symptomatic aortic stenosis undergoing either TAVR (n=331) or SAVR (n=299). Both TAVR and SAVR patients were dichotomized according to the degree of preoperative MR (moderate/severe versus none/mild). At baseline, moderate or severe MR was reported in 65 TAVR patients (19.6%) and 63 SAVR patients (21.2%). At 30 days, among survivors who had isolated SAVR/TAVR, moderate/severe MR had improved in 25 SAVR patients (69.4%) and 30 TAVR patients (57.7%), was unchanged in 10 SAVR patients (27.8%) and 19 TAVR patients (36.5%), and worsened in 1 SAVR patient (2.8%) and 4 TAVR patients (5.8%; all P =NS). Mortality at 2 years was higher in SAVR patients with moderate or severe MR than in those with mild or less MR (49.8% versus 28.1%; adjusted hazard ratio, 1.73; 95% confidence interval, 1.01–2.96; P =0.04). In contrast, MR severity at baseline did not affect mortality in TAVR patients (37.0% versus 32.7%, moderate/severe versus none/mild; hazard ratio, 1.14; 95% confidence interval, 0.72–1.78; P =0.58; P for interaction=0.05). Conclusions— Both TAVR and SAVR were associated with a significant early improvement in MR in survivors. However, moderate or severe MR at baseline was associated with increased 2-year mortality after SAVR but not after TAVR. TAVR may be a reasonable option in selected patients with combined aortic and mitral valve disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00530894.

ObjectivesThe study sought to describe the authors' experience with mitral transapical transcatheter valve-in-valve implantation (TVIV).BackgroundIncreasing numbers of mitral biological prostheses are being implanted in clinical practice. Transcatheter valve-in-valve implantation may be a lower risk alternative treatment for high-risk patients with mitral valve degeneration.MethodsTwenty-three consecutive patients with severe mitral bioprosthetic valve dysfunction underwent transapical mitral TVIV between July 2007 and September 2012. Bioprosthetic failure was secondary to stenosis in 6 (26.1%), regurgitation in 9 (39.1%), and combined in 8 (34.8%) patients.ResultsAll patients were elderly (mean age 81 ± 6 years) and at high-risk for conventional redo surgery (Society of Thoracic Surgeons score 12.1 ± 6.8%). Successful transapical mitral TVIV was accomplished in all patients using balloon expandable valves (Edwards Lifesciences, Irvine, California) with no intraoperative major complications. One (4.4%) major stroke and 6 (26.1%) major bleeds were reported during hospitalization. Mitral transvalvular gradient significantly decreased from 11.1 ± 4.6 mm Hg to 6.9 ± 2.2 mm Hg following the procedure (p < 0.01). Intervalvular mitral regurgitation was absent (47.8%) or mild (52.2%) in all cases after mitral TVIV. No cases of transvalvular regurgitation were seen. All patients were alive on 30-day follow-up. At a median follow-up of 753 days (interquartile range: 376 to 1,119 days) survival was 90.4%. One patient underwent successful mitral TVIV reintervention at 2 months due to atrial migration of the transcatheter valve. All patients alive were in New York Heart Association functional class I/II with good prosthetic valve performance.ConclusionsTranscatheter transapical mitral valve-in-valve implantation for dysfunctional biological mitral prosthesis can be performed with minimal operative morbidity and mortality and favorable midterm clinical and hemodynamic outcomes.

This article describes school's obligations related to bullying behavior, the assessment of bullying students and their victims, the evaluation of claimed damages due to bullying, and potential interventions for both individuals and school systems to reduce the frequency of bullying behavior. This article assists evaluators when assessing youth who are involved in bullying behavior, either as victims or perpetrators. Key areas highlighted include an overview of bullying behaviors, legal issues related to a school's responsibility in preventing or curtailing bullying behaviors, important components of a bullying assessment, and proposed interventions to minimize bullying.

How similar are the brains of listeners who hear the same content expressed in different languages? We directly compared the functional magnetic resonance (fMRI) brain responses of English speakers and Russian speakers who listened to a real-life Russian narrative and its English translation. During the translation we tried to preserve the content of the narrative while reducing the structural similarities across languages. The story evoked similar brain responses across languages, which were invariant to the structural changes, beginning just outside early auditory areas and extending through temporal, parietal and frontal cerebral cortices. Surprisingly, the inter-language similarity in these areas is nearly as strong as the similarity of the brain responses within each language group. The present results demonstrate that the human brain processes real-life information in a manner that is largely insensitive to the language in which that information is conveyed. The methods introduced here can potentially be used to quantify the transmission of meaning across cultural and linguistic boundaries.

OBJECTIVES This study sought to evaluate outcomes after implantation of a second transcatheter heart valve (THV in THV) for acute THV failure. BACKGROUND Aortic regurgitation after transcatheter aortic valve replacement (TAVR) may be valvular due to prosthetic leaflet dysfunction or paravalvular due to poor annular sealing. METHODS Patients undergoing aortic balloon expandable TAVR at 3 centers were prospectively evaluated at baseline intraprocedurally at hospital discharge and annually. RESULTS Of 760 patients undergoing TAVR 21 (2.8) received a THV in THV implant due to acute severe regurgitation. Aortic regurgitation was paravalvular in 18 patients and transvalvular in the remaining 3 patients. THV in THV implantation was technically successful in 19 patients (90) and unsuccessful in 2 patients (10) who subsequently underwent open heart surgery. Mortality at 30 days and 1 year was 14.3 and 24 respectively. After successful THV in THV mean aortic valve gradient fell from 37 ± 12 mm Hg to 13 ± 5 mm Hg (p < 0.01); aortic valve area increased from 0.64 ± 0.14 cm(2) to 1.55 ± 0.27 cm(2) (p < 0.01); and paravalvular aortic regurgitation was none in 4 patients mild in 13 patients and moderate in 2 patients. At 1 year follow up 1 patient had moderate and the others had mild or no paravalvular leaks. The mean transvalvular gradient was 15 ± 4 mm Hg which was higher than in patients undergoing conventional TAVR (11 ± 4 mm Hg p = 0.02). CONCLUSIONS THV in THV implantation is feasible and results in satisfactory short and mid term outcomes.

The BioHealth Capital Region (Maryland, Virginia, and Washington, DC; BHCR) is flush with colleges and universities training students in science, technology, engineering, and mathematics disciplines and has one of the most highly educated workforces in the United States. However, current educational approaches and business recruitment tactics are not drawing sufficient talent to sustain the bioscience workforce pipeline. Surveys conducted by the Mid-Atlantic Biology Research and Career Network identified a disconnect between stakeholders who are key to educating, training, and hiring college and university graduates, resulting in several impediments to workforce development in the BHCR: 1) students are underinformed or unaware of bioscience opportunities before entering college and remain so at graduation; 2) students are not job ready at the time of graduation; 3) students are mentored to pursue education beyond what is needed and are therefore overqualified (by degree) for most of the available jobs in the region; 4) undergraduate programs generally lack any focus on workforce development; and 5) few industry–academic partnerships with undergraduate institutions exist in the region. The reality is that these issues are neither surprising nor restricted to the BHCR. Recommendations are presented to facilitate improvement in the preparation of graduates for today’s bioscience industries throughout the United States.

ObjectivesThis study was undertaken to compare the hemodynamic performance of a percutaneous bioprosthesis to that of surgically implanted (stented and stentless) bioprostheses for the treatment of severe aortic stenosis.MethodsFifty patients who underwent percutaneous aortic valve implantation (PAVI) with the Cribier-Edwards or Edwards SAPIEN bioprosthetic valve (Edwards Lifesciences, Inc., Irvine, California) were matched 1:1 for sex, aortic annulus diameter, left ventricular ejection fraction, body surface area, and body mass index, with 2 groups of 50 patients who underwent surgical aortic valve replacement (SAVR) with a stented valve (Edwards Perimount Magna [SAVR-ST group]), or a stentless valve (Medtronic Freestyle, Medtronic, Minneapolis, Minnesota [SAVR-SL group]). Doppler echocardiographic data were prospectively obtained before the intervention, at discharge, and at 6- to 12-month follow-up.ResultsMean transprosthetic gradient at discharge was lower (p < 0.001) in the PAVI group (10 ± 4 mm Hg) compared with the SAVR-ST (13 ± 5 mm Hg) and SAVR-SL (14 ± 6 mm Hg) groups. Aortic regurgitation (AR) occurred more frequently in the PAVI group (mild: 42%, moderate: 8%) compared with the SAVR-ST (mild: 10%, moderate: 0%) and SAVR-SL (mild: 12%, moderate: 0%) groups (p < 0.0001). At follow-up, the mean gradient in the PAVI group remained lower (p < 0.001) than that of the SAVR-ST group, but was similar to that of the SAVR-SL group. The incidence of severe prosthesis-patient mismatch was significantly lower (p = 0.007) in the PAVI group (6%) compared with the SAVR-ST (28%) and SAVR-SL (20%) groups. However, the incidence of AR remained higher (p < 0.0001) in the PAVI group compared with the 2 other groups.ConclusionsPAVI provided superior hemodynamic performance compared with the surgical bioprostheses in terms of transprosthetic gradient and prevention of severe prosthesis-patient mismatch, but was associated with a higher incidence of AR.

Transcatheter aortic valve replacement (TAVR) required precise knowledge of the anatomic dimensions and physical characteristics of the aortic valve, annulus, and aortic root. Most groups currently use angiography, transthoracic echocardiography (TTE), or transesophageal echocardiography (TEE) to assess aortic annulus dimensions and anatomy. However, multislice computed tomography (MSCT) may allow more detailed 3-dimensional assessment of the aortic root. Twenty-six patients referred for TAVR underwent MSCT. Scans were also obtained for 18 patients after TAVR. All patients underwent pre- and postprocedural aortic root angiography, TTE, and TEE. Mean differences in measured aortic annular diameters were 1.1 mm (95% confidence interval 0.5, 1.8) for calibrated angiography and TTE, -0.9 mm (95% confidence interval -1.7, -0.1 mm) for TTE and TEE, -0.3 mm (95% confidence interval -1.1, 0.6 mm) for MSCT (sagittal) and TTE, and -1.2 mm (95% confidence interval -2.2, -0.2 mm) for MSCT (sagittal) and TEE. Coronal systolic measurements using MSCT, which corresponded to angiographic orientation, were 3.2 mm (1st and 3rd quartiles 2.6, 3.9) larger than sagittal systolic measurements, which were in the same anatomic plane as standard TTE and TEE views. There was no significant association between either shape of the aortic annulus or amount of aortic valve calcium and development of perivalvular aortic regurgitation. After TAVR, the prosthesis extended to or beyond the inferior border of the left main ostium in 9 of 18 patients (50%), and in 11 patients (61%), valvular calcium was

Background We reported the first case of successful transapical transcatheter aortic valve implantation in a human subject in 2005 and have now completed a 12-month follow-up on our first 26 patients. This is, to date, the longest follow-up of patients undergoing transapical aortic valve implantation. Methods Between October 2005 and January 2007, 26 patients (13 female) underwent transcatheter transapical aortic valve implantation with either 23- or 26-mm Edwards Lifesciences transcatheter bioprostheses. All patients with symptomatic aortic stenosis were declined for conventional aortic valve replacement because of unacceptable operative risks and were not candidates for transfemoral aortic valve implantation because of poor arterial access. Clinical and echocardiographic follow-up was performed before discharge and at 1, 6, and 12 months. Data from the 17 patients who survived over 12 months were used for comparisons of the baseline and follow-up results. Results The mean age was 80 ± 9 years, and the predicted operative mortality was 37% ± 20% by using logistic EuroSCORE and 11% ± 6% by using the Society of Thoracic Surgeons Risk Calculator. Valves were successfully implanted in all patients. Six patients died within 30 days (30-day mortality, 23%), and 3 patients died from noncardiovascular causes after 30 days (late mortality, 12%). Among patients who survived at least 30 days, 12-month survival was 85%. There were no late valve-related complications. New York Heart Association functional class improved significantly. The aortic valve area and mean gradient remained stable at 12 months (1.6 ± 0.3 cm 2 and 9.6 ± 4.8 mm Hg, respectively). Conclusion Our 1-year clinical and echocardiographic outcomes suggest that transapical transcatheter aortic valve implantation is a viable alternative to conventional aortic valve replacement in selected high-risk patients.

Objectives: Early clinical outcomes in selected high-risk patients undergoing catheter-based aortic valve replacement (AVR) compare favorably with conventional surgical AVR. Improved understanding of the mechanisms of success and failure of transcatheter AVR will likely improve outcomes further. To this end, we examined our experience during the developmental phases of transcatheter AVR and describe the causes and management of prosthetic valve malposition. Methods: Transcatheter balloon-expandable AVR was performed in 170 patients at two centers. Malposition was defined as prosthetic valve implantation in a location other than within the native valve. Patients were prospectively identified and followed as part of an ongoing database. Results: Valve malposition occurred in 9 of 170 patients (5.3%). Final position was supravalvular in eight of nine cases. In all cases, embolization to the ascending aorta occurred within a few cardiac cycles following deployment. Importantly, late embolization was not observed. In most cases, the prosthesis was uneventfully repositioned in the more distal aorta. Positioning was subvalvular in one patient (0.6%), resulting in a severe regurgitation with residual native valve stenosis. Implantation of a second transcatheter valve was attempted in six patients and was successful in all. Conventional AVR was performed in two patients, with early mortality in one. At late follow-up (mean 412 days), seven of nine patients remain alive (78%) with a functioning prosthesis and relief of aortic stenosis. Conclusions: Malposition of current balloon-expandable aortic valves is a largely preventable complication. An improved understanding of the procedure will likely minimize this possibility and mitigate the consequences should malposition occur. © 2008 Wiley-Liss, Inc.

Background— Percutaneous aortic valve replacement represents an endovascular alternative to conventional open heart surgery without the need for sternotomy, aortotomy, or cardiopulmonary bypass. Methods and Results— Transcatheter implantation of a balloon-expandable stent valve using a femoral arterial approach was attempted in 50 symptomatic patients with severe aortic stenosis in whom there was a consensus that the risks of conventional open heart surgery were very high. Valve implantation was successful in 86% of patients. Intraprocedural mortality was 2%. Discharge home occurred at a median of 5 days (interquartile range, 4 to 13). Mortality at 30 days was 12% in patients in whom the logistic European System for Cardiac Operative Risk Evaluation risk score was 28%. With experience, procedural success increased from 76% in the first 25 patients to 96% in the second 25 ( P =0.10), and 30-day mortality fell from 16% to 8% ( P =0.67). Successful valve replacement was associated with an increase in echocardiographic valve area from 0.6±0.2 to 1.7±0.4 cm 2 . Mild paravalvular regurgitation was common but was well tolerated. After valve insertion, there was a significant improvement in left ventricular ejection fraction ( P P =0.01), and functional class ( P Conclusion— Percutaneous valve replacement may be an alternative to conventional open heart surgery in selected high-risk patients with severe symptomatic aortic stenosis.

The physiologic and pathologic functions of sphingosine kinase (SK) require translocation to specific membrane compartments. We tested the hypothesis that interactions with actin filaments regulate the localization of SK1 to membrane surfaces, including the plasma membrane and phagosome. Macrophage activation is accompanied by a marked increase in association of SK1 with actin filaments. Catalytically-inactive (CI)- and phosphorylation-defective (PD)-SK1 mutants exhibited reductions in plasma membrane translocation, colocalization with cortical actin filaments, membrane ruffling, and lamellipodia formation, compared with wild-type (WT)-SK1. However, translocation of CI- and PD-SK1 to phagosomes were equivalent to WT-SK1. SK1 exhibited constitutive- and stimulus-enhanced association with actin filaments and F-actin-enriched membrane fractions in both intact macrophages and a novel in vitro assay. In contrast, SK1 bound G-actin only under stimulated conditions. Actin inhibitors disrupted SK1 localization and modulated its activity. Conversely, reduction of SK1 levels or activity via RNA interference or specific chemical inhibition resulted in dysregulation of actin filaments. Thus, the localization and activity of SK1 are coordinately regulated with actin dynamics during macrophage activation.

Introduction and objectives The self-expanding Portico valve is a new transcatheter aortic valve system yielding promising preliminary results, yet there are no comparative data against earlier generation transcatheter aortic valve systems. The aim of this study was to compare the hemodynamic performance of the Portico and balloon-expandable SAPIEN XT valves in a case-matched study with echocardiographic core laboratory analysis. Methods Twenty-two patients underwent transcatheter aortic valve implantation with the Portico 23-mm valve and were matched for aortic annulus area and mean diameter measured by multidetector computed tomography, left ventricular ejection fraction, body surface area, and body mass index with 40 patients treated with the 23-mm SAPIEN XT. Mean aortic annulus diameters were 19.6 ± 1.3 mm by transthoracic echocardiography and 21.4 ± 1.2 mm by computed tomography, with no significant between-group differences. Doppler echocardiographic images were collected at baseline and at 1-month of follow-up and were analyzed in a central echocardiography core laboratory. Results There were no significant between-group differences in residual mean transaortic gradients (SAPIEN XT: 10.4 ± 3.7 mmHg; Portico: 9.8 ± 1.1 mmHg; P = .49) and effective orifice areas (SAPIEN XT: 1.36 ± 0.27 cm 2 ; Portico, 1.37 ± .29 cm 2 ; P = .54). Rates of severe prosthesis-patient mismatch (effective orifice area 2 /m 2 ) were similar (SAPIEN XT: 13.5%; Portico: 10.0%; P = .56). No between-group differences were found in the occurrence of moderate-severe paravalvular leaks (5.0% vs 4.8% of SAPIEN XT and Portico respectively; P = .90). Conclusions Transcatheter aortic valve implantation with the self-expanding Portico system yielded similar short-term hemodynamic performance compared with the balloon-expandable SAPIEN XT system for treating patients with severe aortic stenosis and small annuli. Further prospective studies with longer-term follow-up and in patients with larger aortic annuli are required.

We report our 8-year experience in transcatheter aortic and mitral valve-in-valve (VinV) implantation.Feasibility and good early outcomes associated with transcatheter aortic and mitral VinV implantation into failed surgical bioprostheses have been confirmed, but the mid-term and long-term outcomes of transcatheter aortic and mitral VinV is unknown.A total of 73 patients with aortic (n = 42) and mitral (n = 31) bioprosthetic valve dysfunction underwent transcatheter VinV implantation between April 2007 and December 2013. Edwards balloon-expandable transcatheter valves (Edwards Lifesciences Inc., Irvine, California) were used. Median follow-up was 2.52 years with a maximum of 8 years.Seventy-two patients (mean age 79.7 ± 9.4 years, 32 women) underwent successful VinV implantation (success rate 98.6%). At 30 days, all-cause mortality was 1.4%, disabling stroke 1.4%, life-threatening bleeding 4.1%, acute kidney injury requiring hemodialysis 2.7%, and coronary artery obstruction requiring intervention 1.4%. No patient had greater than mild paravalvular leak. Estimated survival rates were 88.9%, 79.5%, 69.8%, 61.9%, and 40.5% at 1, 2, 3, 4, and 5 years, respectively. The small surgical valve size (19 and 21 mm) was an independent risk factor for reduced survival in aortic VinV patients. At 2-year follow-up, 82.8% of aortic and 100% of mitral VinV patients were in New York Heart Association functional class I or II.Transcatheter VinV for failed surgical bioprostheses can be performed safely with a high success rate and minimal early mortality and morbidity. Transcatheter VinV provides encouraging mid-term clinical outcomes in this high-risk elderly cohort of patients. Transcatheter VinV is an acceptable alternative therapy for failed aortic or mitral bioprostheses in selected high-risk patients.

The aim of this study was to evaluate a strategy of intentional underexpansion of excessively oversized balloon-expandable transcatheter heart valves (THVs) in terms of clinical outcomes, valve function, and frame durability at 1 year.Transcatheter aortic valve replacement requires the selection of an optimally sized THV to ensure paravalvular sealing and fixation without risking annular injury. However, some patients have "borderline" annular dimensions that require choosing between a THV that may be too small or another that may be too large.We evaluated 47 patients at risk of annular injury who underwent transcatheter aortic valve replacement (TAVR) with an oversized, but deliberately underexpanded, THV followed by post-dilation if required. Clinical evaluation, echocardiography, and cardiac computed tomography were performed pre-TAVR, post-TAVR, and at 1 year.Deployment of oversized THVs with modest underfilling of the deployment balloon (10% by volume) was not associated with significant annular injury. Paravalvular regurgitation was mild or less in 95.7% of patients, with post-dilation required in 10.7%. THV hemodynamic function was excellent and remained stable at 1 year. Computed tomography documented stent frame circularity in 87.5%. Underexpansion was greatest within the intra-annular THV inflow (stent frame area 85.8% of nominal). There was no evidence of stent frame recoil, deformation, or fracture at 1 year.In carefully selected patients with borderline annulus dimensions and in whom excessive oversizing of a balloon-expandable SAPIEN XT valve (Edwards Lifesciences, Inc., Irvine, California) is a concern, a strategy of deliberate underexpansion, with ad hoc post-dilation, if necessary, may reduce the risk of annular injury without compromising valve performance.

Background— Mitral annuloplasty is the most common surgical procedure performed for ischemic mitral regurgitation (MR). Surgical mitral annuloplasty is limited by morbidity, mortality, and MR recurrence. We evaluated the safety and feasibility of a transvenous catheter-delivered implantable device to provide a percutaneous alternative to surgical mitral annuloplasty. Methods and Results— Five patients with chronic ischemic MR underwent percutaneous transvenous implantation of an annuloplasty device in the coronary sinus. Implantation was successful in 4 patients. Baseline MR in the entire group was grade 3.0±0.7 and was reduced to grade 1.6±1.1 at the last postimplantation visit when the device was intact or the last postprocedural visit in the patient in whom the device was not successfully implanted. Separation of the bridge section of the device occurred in 3 of 4 implanted devices and was detected at 28 to 81 days after implantation. There were no postprocedural device-related complications. Conclusions— Percutaneous implantation of a device intended to remodel the mitral annulus is feasible. Initial experience suggests a possible favorable effect on MR. Percutaneous transvenous mitral annuloplasty warrants further evaluation as a less invasive alternative to surgical annuloplasty.

Objectives: We describe the technique of, and our experience with, rapid ventricular burst pacing to facilitate transcatheter heart valve implantation. Background: Endovascular therapeutic procedures frequently require the precise placement of implantable devices. The precision of transcatheter device deployment may be hampered by cardiac motion or the effects of intravascular flow. Burst pacing is associated with a reduction in stroke volume, cardiac output, transvalvular flow, and cardiac motion. Methods: Rapid pacing was used in 40 consecutive patients with severe aortic stenosis undergoing implantation of catheter-delivered prosthetic valves. Clinical, procedural, and hemodynamic records were reviewed. Results: A mean of 5 ± 2 burst pacing sequences at rates of 150–220 min−1 were used during balloon valvuloplasty and valve deployment. The duration of pacing required during valve deployment was 12 ± 3 sec. Pacing was relatively well tolerated when cautiously used with judicious recovery intervals and pressor support. Rapid pacing was associated with a rapid and effective reduction in systemic blood pressure, pulse pressure, transvalvular flow as well as cardiac and catheter motion. Conclusions: Rapid pacing is a relatively reliable technique to facilitate precise transcatheter deployment of prosthetic heart valves and other endovascular therapeutic devices. © 2006 Wiley-Liss, Inc.

Background: Paravalvular leaks (PVLs) are a well-recognized complication of prosthetic valve replacement. Most are asymptomatic and benign, but some may cause symptoms due to a large regurgitant volume or hemolysis. Medical therapy is palliative, while reoperation carries significant morbidity and mortality. Percutaneous transcatheter closure techniques, now routinely applied in the management of pathological cardiac and vascular communications, may be adaptable to PVL closure, potentially offer symptomatic relief. Methods: We reviewed our experience with attempted percutaneous closure of PVLs, using data from medical and procedural records. Results: Between 2001 and 2004, 14 procedures were performed in 10 patients, all under general anesthesia, with transesophageal and radiographic guidance. Mitral (9) and aortic (1) valve replacements were involved, both mechanical and bioprosthetic. A variety of devices were used, including atrial septal occluders, patent ductus arteriosus occluders, and coils (all of label use). Six had a single procedure, which was technically successful in four: in two, the PVL could not be crossed. Four underwent a second procedure, which was technically successful in three; in one the previously deployed device was dislodged necessitating urgent, but ultimately uneventful, surgical removal and leak repair. One patient had transient severe hemolysis, which resolved after 1 week. At 1-year follow-up (9/10 pts) three had died, five had sustained symptomatic improvement while 1 patient with a residual leak still required regular blood transfusions. Conclusions: Percutaneous closure of PVLs is time-consuming but feasible in selected patients, with a reasonable degree of technical and clinical success. A second procedure may be necessary and a variety of complications can occur. © 2006 Wiley-Liss, Inc.

Study objective Current risk stratification tools do not identify very-low-risk patients who can be safely discharged without prolonged emergency department (ED) observation, expensive rule-out protocols, or provocative testing. We seek to develop a clinical prediction rule applicable within 2 hours of ED arrival that would miss fewer than 2% of acute coronary syndrome patients and allow discharge within 2 to 3 hours for at least 30% of patients without acute coronary syndrome. Methods This prospective, cohort study enrolled consenting eligible subjects at least 25 years old at a single site. At 30 days, investigators assigned a diagnosis of acute coronary syndrome or no acute coronary syndrome according to predefined explicit definitions. A recursive partitioning model included risk factors, pain characteristics, physical and ECG findings, and cardiac marker results. Results Of 769 patients studied, 77 (10.0%) had acute myocardial infarction and 88 (11.4%) definite unstable angina. We derived a clinical prediction rule that was 98.8% sensitive and 32.5% specific. Patients have very low risk of acute coronary syndrome if they have a normal initial ECG, no previous ischemic chest pain, and age younger than 40 years. In addition, patients at least 40 years old and with a normal ECG result, no previous ischemic chest pain, and low-risk pain characteristics have very low risk if they have an initial creatine kinase-MB (CK-MB) less than 3.0 μg/L or an initial CK-MB greater than or equal to 3.0 μg/L but no ECG or serum-marker increase at 2 hours. Conclusion The Vancouver Chest Pain Rule for early discharge defines a group of patients who can be safely discharged after a brief evaluation in the ED. Prospective validation is needed.

Objective To determine the characteristics and prognostic importance of right ventricular (RV) dilatation and dysfunction in patients with cardiogenic shock secondary to left ventricular (LV) dysfunction enrolled in the Should we emergently revascularize occluded coronaries for cardiogenic shock (SHOCK) trial. Methods LV and RV size and function were quantified by echocardiography in 99 patients with cardiogenic shock secondary to predominant LV dysfunction. Results For all patients, RV dysfunction was not associated with a poor 1-year survival. When the 59 patients with RV dysfunction were stratified into two morphologic groups based upon LV-to-RV end-diastolic area ratio (LV/RV) < or ≥ 2, the presence of disproportionate RV enlargement (LV/ RV

Mycobacterium tuberculosis (M.tb) is a leading cause of global infectious mortality. The pathogenesis of tuberculosis involves inhibition of phagosome maturation, leading to survival of M.tb within human macrophages. A key determinant is M.tb-induced inhibition of macrophage sphingosine kinase (SK) activity, which normally induces Ca2+ signaling and phagosome maturation. Our objective was to determine the spatial localization of SK during phagocytosis and its inhibition by M.tb. Stimulation of SK activity by killed M.tb, live Staphylococcus aureus, or latex beads was associated with translocation of cytosolic SK1 to the phagosome membrane. In contrast, SK1 did not associate with phagosomes containing live M.tb. To characterize the mechanism of phagosomal translocation, live cell confocal microscopy was used to compare the localization of wild-type SK1, catalytically inactive SK1G82D, and a phosphorylation-defective mutant that does not undergo plasma membrane translocation (SK1S225A). The magnitude and kinetics of translocation of SK1G82D and SK1S225A to latex bead phagosomes were indistinguishable from those of wild-type SK1, indicating that novel determinants regulate the association of SK1 with nascent phagosomes. These data are consistent with a model in which M.tb inhibits both the activation and phagosomal translocation of SK1 to block the localized Ca2+ transients required for phagosome maturation.

One-third of the world’s population is infected with Mycobacterium tuberculosis (Mtb), and three million people die of tuberculosis each year. Following its ingestion by macrophages (MPs), Mtb inhibits the maturation of its phagosome, preventing progression to a bactericidal phagolysosome. Phagocytosis of Mtb is uncoupled from the elevation in MP cytosolic Ca2+ that normally accompanies microbial ingestion, resulting in inhibition of phagosome-lysosome fusion and increased intracellular viability. This study demonstrates that the mechanism responsible for this failure of Ca2+-dependent phagosome maturation involves mycobacterial inhibition of MP sphingosine kinase. Thus, inhibition of sphingosine kinase directly contributes to survival of Mtb within human MPs and represents a novel molecular mechanism of pathogenesis.

Inoperable aortic stenosis may be treated with either transcatheter aortic valve replacement (TAVR) or medical management (MM) with or without balloon aortic valvuloplasty (BAV). The aim of this study was to compare the long-term echocardiographic findings among TAVR, MM, and BAV in patients with severe, inoperable aortic stenosis.A total of 358 inoperable patients in the Placement of Aortic Transcatheter Valves trial were randomized to MM or TAVR. Echocardiograms obtained at baseline, 30 days, and 1, 2, and 3 years were analyzed by a central core laboratory.At baseline, TAVR and MM were similar, with more frequent Society of Thoracic Surgeons score10 (51.7% vs 65.0%, P = .03) and larger end-systolic volumes (54.5 ± 29.3 vs 69.1 ± 48.0 mL, P = .03) in MM. By 30 days after TAVR, mean aortic valve gradient had decreased (from 43.8 ± 14.7 to 10.0 ± 4.3 mm Hg, P.001), ejection fraction had increased (from 53.2 ± 12.4% to 56.7 ± 10.0%, P.001), and left ventricular (LV) mass index had decreased (from 144.7 ± 36.1 to 140.0 ± 37.9 gm/m(2), P.05). After 1 year, aortic valve gradients and area were unchanged, while LV mass index had decreased by another 16 gm/m(2) (to 124 gm/m(2)). By 30 days after BAV, mean aortic valve gradient had decreased from 43.4 ± 15.0 to 31.9 ± 11.1 mm Hg, while ejection fraction and LV mass index were unchanged; gradient reverted to baseline at 1 year. No changes in gradients or mass were seen in MM patients.TAVR results in immediate and sustained relief in pressure overload and improved LV systolic function, with continued regression of hypertrophy over 3 years. Poor clinical results with BAV are explained by the modest and transient reductions in pressure overload with BAV, which were not accompanied by improved LV function or remodeling. TAVR is the preferred treatment in eligible inoperable patients (ClinicalTrials.gov identifier NCT00530894).

The appropriate management of patients with mitral regurgitation (MR) and left ventricular dysfunction (LVD) is controversial. The study aim was to determine whether the presence of contractile reserve (CR) assessed by dobutamine stress echocardiography (DSE) was associated with improved outcomes.Death and heart transplantation were analyzed as the primary outcomes associated with the presence of CR. A total of 125 consecutive patients (96 males, 29 females; mean age 60 +/- 12 years) with left ventricular ejection fraction (LVEF)or = 35% and hemodynamically significant MR underwent DSE between 1999 and 2005. CR was defined as an increase in LVEF ofor = 10% during dobutamine infusion.Among 125 patients, 55 (43.0%) showed evidence of CR. Within five years after DSE, 24 patients (34.3%) in the CR- group and seven (12.7%) in the CR+ group had died or required heart transplantation (p0.01, log rank). After adjusting for age, baseline LVEF, NYHA class and moderate/severe tricuspid regurgitation (TR), CR remained an independent predictor of time to death or heart transplantation (HR 0.34; 95% CI: 0.15-0.76, p0.01). Improvement in the degree of MR was present at one year in 85.0% of CR+ patients, and in 62.5% of CR- patients (p = 0.03). An improvement of 5% in LVEF was noted in the CR+ group, compared to 0% in the CR- group (p = 0.04).In patients with advanced LVD and severe MR, CR detected by DSE was associated with significant reductions in the risk of death and heart transplantation.

The SAPIEN 3 valve (S3V) is a new-generation transcatheter valve with enhanced anti-paravalvular leak properties, but no data comparing with earlier transcatheter valve systems are available. We aimed to compare the hemodynamic performance of the S3V and the SAPIEN XT valve (SXTV) in a case-matched study with echo core laboratory analysis. A total of 27 patients who underwent transcatheter aortic valve replacement (TAVR) with the S3V were matched for prosthesis size (26 mm), aortic annulus area, and mean diameter measured by computed tomography, left ventricular ejection fraction, body surface area, and body mass index with 50 patients treated with the SXTV. The prosthesis size was determined by oversizing of 1% to 15% of annulus area. Doppler echocardiographic images collected at baseline and 1-month follow-up were analyzed in a central echocardiography core laboratory. The need for postdilation was higher in the SXTV group (20% vs 4%, p = 0.047), and mean residual gradient and effective orifice area were similar in both groups (p >0.05). The incidence of paravalvular aortic regurgitation was greater with the SXTV (≥mild: 42%, moderate: 8%) than with the S3V (≥mild: 7%, moderate: 0%; p = 0.002 for ≥mild vs SXTV). The implantation of an S3V was the only factor associated with trace or no paravalvular leak after TAVR (p = 0.007). In conclusion, TAVR with the S3V was associated with a very low rate of paravalvular leaks and need for balloon postdilation, much lower than that observed with the earlier generation of balloon-expandable valve (SXTV). The confirmation of these results in a larger cohort of patients will represent a major step forward in using transcatheter valves for the treatment of aortic stenosis.

The heat shock response (HSR) is an ancient and highly conserved process that is essential for coping with environmental stresses, including extremes of temperature. Fever is a more recently evolved response, during which organisms temporarily subject themselves to thermal stress in the face of infections. We review the phylogenetically conserved mechanisms that regulate fever and discuss the effects that febrile-range temperatures have on multiple biological processes involved in host defense and cell death and survival, including the HSR and its implications for patients with severe sepsis, trauma, and other acute systemic inflammatory states. Heat shock factor-1, a heat-induced transcriptional enhancer is not only the central regulator of the HSR but also regulates expression of pivotal cytokines and early response genes. Febrile-range temperatures exert additional immunomodulatory effects by activating mitogen-activated protein kinase cascades and accelerating apoptosis in some cell types. This results in accelerated pathogen clearance, but increased collateral tissue injury, thus the net effect of exposure to febrile range temperature depends in part on the site and nature of the pathologic process and the specific treatment provided.

Significant tricuspid regurgitation (TR) is a marker for late-stage myocardial and valvular heart disease. Whether preoperative TR affects clinical outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) has never been investigated. This study sought to identify the impact of moderate and severe TR on outcomes after TAVR.All patients undergoing TAVR from January 2007 to August 2012 at St. Paul's Hospital, Vancouver, Canada, (n = 518) were dichotomized according to the severity of preoperative TR (moderate/severe vs. none/mild). All clinical outcomes were defined according to the valve academic research consortium-2 definitions.At baseline, moderate or severe TR was reported in 79 patients (15.2%). At 30 days, moderate/severe TR had improved in 12 patients (15.2%), was unchanged in 46 patients (58.3%), and worsened in 7 patients (8.9%). Of those with none/mild TR at baseline, 35 (7.9%) patients had moderate TR at 30-day follow-up. Two-year all-cause (38.4% vs. 20.0%, Log-rank test, P = 0.001) and cardiac mortality (12.9% vs. 4.6%, Log-rank test, P = 0.004) as estimated by Kaplan-Meier analysis were considerably higher in patients with significant TR. However, significant TR did not emerge as independent risk factor for 2-year all-cause mortality (adjusted OR: 1.55, 95% confidence interval (CI): 0.91-2.64, P = 0.105). Pre-specified subgroups showed an interaction between TR and left ventricular systolic function (Pinteraction = 0.047). Indeed, moderate/severe TR was significantly related to mortality only in patients with left ventricular ejection fraction (LVEF) 40% (adjusted OR: 2.01, CI: 1.05-3.84, P = 0.036). In patients with LVEF ≤ 40%, TR had no significant impact on all-cause mortality (adjusted OR: 1.04, CI: 0.34-3.16, P = 0.946). No significant interactions were identified regarding patients with perioperative moderate/severe mitral regurgitation (Pinteraction = 0.829) and patients with baseline systolic pulmonary artery pressure ≥ 60 mm Hg (Pinteraction = 0.669).In patients undergoing TAVR, significant preoperative TR was present in 15% of patients and associated with more comorbidities. Despite being associated with a doubling of mortality rate, after a robust adjustment, significant TR was not an independent predictor of 2-year mortality. However, a significant interaction between TR and left ventricular systolic function was found. The response of TR to TAVR was extremely variable.

Off-pump transcatheter, transapical valve-in-valve aortic valve implantation into a failed surgically implanted aortic valve was successfully performed in an 85-year-old man. He was discharged on postoperative day 5, and remained well at his 16-month follow-up. Echocardiography at 12 months showed normal prosthetic valve function without displacement, recoil, or regurgitation. Transcatheter transapical valve-in-valve aortic valve implantation is feasible and could be a viable approach for selected patients.

OBJECTIVESThe purpose of this study was to determine the origin of the pulmonary venous systolic flow pulse using wave-intensity analysis to separate forward- and backward-going waves.BACKGROUNDThe mechanism of the pulmonary venous systolic flow pulse is unclear and could be a “suction effect” due to a fall in atrial pressure (backward-going wave) or a “pushing effect” due to forward-propagation of right ventricular (RV) pressure (forward-going wave).METHODSIn eight patients during coronary surgery, pulmonary venous flow (flow probe), velocity (microsensor) and pressure (micromanometer) were recorded. We calculated wave intensity (dP × dU) as change in pulmonary venous pressure (dP) times change in velocity (dU) at 5 ms intervals. When dP × dU > 0 there is a net forward-going wave and when dP × dU < 0 there is a net backward-going wave.RESULTSSystolic pulmonary venous flow was biphasic. When flow accelerated in early systole (S1), pulmonary venous pressure was falling, and, therefore, dP × dU was negative, −0.6 ± 0.2 (x ± SE) W/m2, indicating a net backward-going wave. When flow accelerated in late systole (S2), pressure was rising, and, therefore, dP × dU was positive, 0.3 ± 0.1 W/m2, indicating a net forward-going wave.CONCLUSIONSPulmonary venous flow acceleration in S1 was attributed to a net backward-going wave secondary to a fall in atrial pressure. However, flow acceleration in S2 was attributed to a net forward-going wave, consistent with propagation of the RV systolic pressure pulse across the lungs. Pulmonary vein systolic flow pattern, therefore, appears to be determined by right- as well as left-sided cardiac events.

The present case demonstrates the percutaneous implantation of a bioprosthetic valve in a patient with severe aortic stenosis. An 85-year-old man with significant comorbidities was determined to be at unacceptable risk with traditional surgical valve replacement. Percutaneous aortic valve implantation was performed, was successful and uncomplicated, with significant clinical and hemodynamic improvement. Currently, this procedure is an option only for symptomatic patients who are not appropriate candidates for surgical valve replacement.

Calcific aortic stenosis is the most common valvular disease affecting the elderly. Surgical aortic valve replacement improves symptoms and prognosis, but mortalities may be as high as 20% in elderly patients with left ventricular dysfunction. Catheter-based aortic valve implantation was recently achieved through antegrade venous and retrograde arterial routes. We report on the deployment of an aortic valve prosthesis for severe aortic stenosis through the apex of the left ventricle in a 75-year-old patient without cardiopulmonary bypass or sternotomy.

Background Marked variation exists concerning the utilization of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). The objective of this study was to examine differences in predictors of mode of revascularization across 3 provincial jurisdictions. Methods All patients who underwent PCI and isolated CABG in British Columbia, Alberta, and Nova Scotia between 1996 and 2007 were considered. Age- and sex-standardized rates of PCI and CABG per 100,000 population and PCI to CABG ratios were calculated by year and province. Logistic regression models were constructed to identify independent predictors of mode of revascularization in each province. Results A total of 32,190 and 69,409 patients underwent CABG and PCI, respectively, during the study period. Significant increases in the age- and sex-adjusted PCI to CABG ratios were observed in all 3 provinces, but these ratios differed between provinces. Across all 3 jurisdictions, female sex and diagnosis of acute coronary syndrome favoured increased PCI vs CABG, and increased age, left main, or 3-vessel disease occurring before myocardial infarction, and diabetes favoured lower PCI vs CABG. After adjusting for clinical and angiographic factors, there remained a significant variation in choice of PCI vs CABG between the 3 provinces over time. Conclusions Significant interprovincial variability in PCI to CABG ratios was observed. Though certain patient-related factors predictive of either PCI or CABG were identified, factors beyond clinical presentation played a role in the choice of revascularization approach.

Background Prosthesis–patient mismatch (PPM) is a predictor of mortality after aortic valve replacement (AVR). Objective We examined whether accurate 3-dimensional annular sizing with multidetector CT (MDCT) is predictive of PPM after transcatheter AVR (TAVR). Methods One hundred twenty-eight patients underwent MDCT then TAVR. Moderate PPM was defined as an indexed effective orifice area ≤0.85 cm 2 /m 2 and severe ≤0.65 cm 2 /m 2 . MDCT annular measurements (area, short and long axis) were compared with the size of the selected transcatheter heart valve (THV) to obtain (1) the difference between prosthesis size and CT-measured mean annular diameter and (2) the percentage of undersizing or oversizing (calculated as 100 × [MDCT annular area – THV nominal area]/THV nominal area). In addition, the MDCT annular area was indexed to body surface area. These measures were evaluated as potential PPM predictors. Results We found that 42.2% of patients had moderate PPM and 9.4% had severe PPM. Procedural characteristics and in-hospital outcomes were similar between patients with or without PPM. THV undersizing of the mean aortic annulus diameter was not predictive of PPM (odds ratio [OR], 0.84; 95% CI, 0.65–1.07; P = .16; area under the receiver-operating characteristic curve [AUC], 0.58). THV undersizing of annular area was not predictive of PPM (OR, 0.96; 95% CI, 0.80–1.16; P = .69; AUC, 0.52). Indexed MDCT annular area was, however, predictive of PPM (OR, 0.24; 95% CI, 0.10–0.59; P Conclusions PPM is frequent after TAVR. Appropriate annular oversizing does not reduce the rate or severity of PPM. Patient annulus size mismatch, identified by indexed MDCT annular area, is a significant predictor of PPM.

Left ventricular hypertrophy is very prevalent among patients with renal insufficiency. Known hypertrophic factors, such as systemic hypertension, do not adequately account for the prevalence of left ventricular hypertrophy in these patients. Circulating growth factors may stimulate cardiomyocyte growth and contribute to the development of left ventricular hypertrophy. The effects of sera from patients with (n = 30) and without (n = 5) chronic renal insufficiency on the growth of cultured adult cardiomyocytes were compared. An adult rat cardiomyocyte primary culture system was established with a high purity of cardiomyocyte population as confirmed by immunocytochemical staining of cardiac contractile proteins. Myocytes responded with increased [3H]thymidine incorporation when treated with angiotensin II, epidermal growth factor, hydrocortisone and insulin, and with increased [3H]phenylalanine incorporation when treated with parathormone, isoproterenol, phenylephrine and insulin. Renal insufficiency serum stimulated [3H]thymidine incorporation was 1.5 times that of the control (P0.02) and also tended to increase incorporation of [3H]phenylalanine compared to the control (P = N.S.). Increased [3H]thymidine incorporation by renal insufficiency serum did not correlate with serum insulin, parathormone or glucose in the renal insufficiency patients. A quantitative reverse transcriptase polymerase chain reaction (RT-PCR) method was used to measure renal insufficiency serum-induced atrial natriuretic peptide mRNA expression in cultured cardiomyocytes. Atrial natriuretic peptide (ANP) mRNA was increased 1-3-fold in cardiomyocytes treated with renal insufficiency sera in comparison to control sera. These data suggest that circulating growth factor(s) may contribute to the development of cardiac hypertrophy in patients with renal insufficiency.

Recent observations have highlighted errors in the thermodilution technique of measuring cardiac output. Thus, cardiac output measurements using transesophageal echocardiography and the Fick method were compared with simultaneous thermodilution measurements.In 13 mechanically ventilated critically ill patients, cardiac output was determined simultaneously using (1) transesophageal echocardiography (COTEE, (2) the Fick method (COFICK, and (3) thermodilution (COTD immediately before and after a rapid infusion of 500 mL of saline. Left ventricular end-diastolic and end-systolic areas were measured using the transesophageal echocardiographic transgastric short axis view, and COTEE was calculated from the corresponding volumes. Absolute cardiac output values and the changes from before to after saline infusion (delta CO) were compared using analysis of variance, linear regression, and the Bland and Altman method.There were no significant differences between COTEE (8.0 +/- 3.4), COFICK (8.4 +/- 3.3), and COTD (8.3 +/- 3.0) or between delta COTEE, delta COFICK, and delta COTD using analysis of variance. However, correlations between COTEE and COTD (r2 = 0.46; P.00001), COFICK and COTD (r2 = 0.46; P.0001), and COTEE and COFICK (r2 = 0.42; P.0001) were only moderately good. Using the method of Bland and Altman, the mean difference (+/-2 standard deviations) between COTEE and COTD was 0.3 +/- 4.3 L/min, between COFICK and COTD was -1.0 +/- 3.8 L/min, and between COTEE and COFICK was 0.6 +/- 5.6 L/min, whereas the difference between delta COTEE and delta COTD was 0% +/- 26%, between delta COFICK and delta COTD was 9% +/- 46%, and between delta COTEE and delta COFICK was 8% +/- 39%.There are substantial differences in cardiac output as measured by these three methods, best demonstrated using the method of Bland and Altman. The variability of cardiac output and its derivatives (eg, oxygen delivery) should be borne in mind when making clinical decisions on individual patients.

Left ventricular hypertrophy (LVH) is present in over 70% of patients commencing dialysis. It is an independent risk factor for cardiac death, which is the cause of death in approximately 45% of patients in dialysis. The prevalence of LVH in patients earlier in the course of renal insufficiency is unknown. As part of a prospective longitudinal study evaluating the progression of comorbid diseases in patients with progressive renal disease, we evaluated LVH. In 175 consecutive patients attending a renal insufficiency clinic we obtained technically adequate echocardiograms and estimated left ventricular mass index (LVMI) using two-dimensional targeted M-mode echocardiography. We calculated LVMI using the American Society of Echocardiography cube formula method regressed to anatomic validation. The population consisted of 115 men and 60 women ranging in age from 20 to 82 years (mean age, 51.5 years). The mean creatinine was 403 +/- 207 micro mol/L (+/-SD), representing a creatinine clearance (Ccr) of 25.5 +/- 17 mL/min. Left ventricular hypertrophy was defined as LVMI greater than 131 g/m(2) in men and greater than 100 g/m(2) in women, and was present in 38.9% of the population studied. We demonstrate that the prevalence of LVH increased with progressive renal decline: 26.7% of patients with Ccr greater than 50 mL/min had LVH, 30.8% of those with Ccr between 25 and 49 mL/min had LVH, and 45.2% of patients with severe renal impairment (Ccr

Objectives.This study sought to investigate whether right atrial pressure could be used to estimate pericardial pressure during positive end-expiratory pressure (PEEP).Background.Because of elevated intrathoracic pressure during PEEP, pulmonary capillary wedge pressure may not accurately reflect left ventricular preload. An estimate of pericardial pressure during PEEP would allow assessment of transmural filling pressure.Methods.In eight patients, at the start of cardiac surgery, pericardial and pleural pressures were recorded by balloon transducers placed over the anterolateral left ventricular wall. We also recorded intravascular pressures and left ventricular short-axis area by transesophageal echocardiography.Results.A stepwise increase in PEEP from 0 to 15 cm H2O caused a linear increase in pleural pressure from 0.3 ± 0.6 (mean ± SEM) to 6.1 ± 0.8 mm Hg (p < 0.01). Pericardial pressure increased from 2.3 ± 0.5 to 5.9 ± 0.6 mm Hg (p < 0.01). The correlation between right atrial (Pra) and pericardial pressure (Pperic) was good: Pra= 0.85 × Pperic+ 1.8, r = 0.77. The correlation between changes in right atrial pressure and in pericardial pressure was better: ΔPra= 0.96 × ΔPperic− 0.2, r = 0.97. Pulmonary capillary wedge pressure increased with PEEP (p < 0.05), whereas left ventricular area decreased (p < 0.05). However, there was a progressive reduction in transmural pressure, calculated as wedge pressure minus pericardial pressure (p < 0.05), and in transmural pressure, estimated as wedge pressure minus right atrial pressure (p < 0.05). The estimated transmural filling pressure correlated (r = 0.86) with enddiastolic area.Conclusions.The present observations suggest that right atrial pressure may be used to estimate changes in pericardial pressure with PEEP and that pulmonary capillary wedge pressure minus right atrial pressure is a potentially clinically useful approximation of transmural filling pressure.

Transcatheter aortic valve implantation with the self-expandable CoreValve (CV) and the balloon-expandable Edwards SAPIEN (ES) bioprostheses has been widely used for the treatment of severe aortic stenosis. However, a direct comparison of the hemodynamic results associated with these 2 prostheses is lacking. The aim of the present study was to compare the hemodynamic performance of both bioprostheses. A total of 41 patients who underwent transcatheter aortic valve implantation with the CV prosthesis were matched 1:1 for prosthesis size (26 mm), aortic annulus size, left ventricular ejection fraction, body surface area, and body mass index with patients who underwent transcatheter aortic valve implantation with the ES prosthesis. Doppler-echocardiographic data were prospectively collected before the intervention and at hospital discharge, and all examinations were sent to, and analyzed in, a central echocardiography core laboratory. The mean transprosthetic residual gradient was lower (p = 0.024) in the CV group (7.9 ± 3.1 mm Hg) than in the ES group (9.7 ± 3.8 mm Hg). The effective orifice area tended to be greater in the CV group (1.58 ± 0.31 cm(2) vs 1.49 ± 0.24 cm(2), p = 0.10). The incidence of severe prosthesis-patient mismatch was, however, similar between the 2 groups (effective orifice area indexed to the body surface area ≤0.65 cm(2)/m(2); CV 9.8%, ES 9.8%, p = 1.0). The incidence of paravalvular aortic regurgitation was greater with the CV (grade 1 or more in 85.4%, grade 2 or more in 39%) than with the ES (grade 1 or more in 58.5%, grade 2 or more in 22%; p = 0.001). The number and extent of paravalvular leaks were greater in the CV group (p0.01 for both comparisons). In conclusion, transcatheter aortic valve implantation with the CV prosthesis was associated with a lower residual gradient but a greater rate of paravalvular aortic regurgitation compared to the ES prosthesis. The potential clinical consequences of the differences in hemodynamic performance between these transcatheter heart valves needs to be addressed in future studies.

BACKGROUND: Computed tomography (CT) annular measurements are predictive of paravalvular regurgitation after transcatheter aortic valve replacement (TAVR) which is a predictor of mortality and morbidity. OBJECTIVES: To demonstrate the rationale and potential implications of new CT sizing recommendations for TAVR. METHODS: The CT sizing recommendations aim to ensure routine transcatheter heart valve (THV) oversizing of the aortic annular area [(THV external area/systolic annular area 1) × 100; range 1 20; target 10 15]. Consecutive patients (n = 120) underwent CT before TAVR with balloon expandable valves sized by transesophageal echocardiography (TEE). Retrospectively the CT recommended THV size was compared with the actual size implanted. RESULTS: Compared with TEE application of the newly developed CT based sizing recommendations would have led to implantation of a larger valve in 33.3 (40/120) no change in valve size in 55.8 (67/120) and a smaller valve in 10.8 (13/120). In patients when CT recommended a larger valve the incidence of at least moderate paravalvular regurgitation was 25 (10/40) compared with 4.5 (3/67; P < 0.01) when both TEE and CT recommendations were in agreement. Using diastolic versus systolic CT measurements results in 20 of patients receiving smaller THVs. TEE sizing resulted in 33.3 (40/120) of valves being undersized (THV area < CT systolic annular area) with a mean annular oversizing of 9.4 ± 17.4 (range: 21.5 to 65.9) without annular rupture. In contrast the CT sizing recommendations results in mean annular oversizing of 13.9 ± 8.0 (range 1.3 29.8). CONCLUSION: These CT sizing recommendations enable standardized moderate overexpansion of the aortic annulus. Clinical outcomes from these recommendations are being prospectively assessed in a multicenter trial.