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Objective Transcarotid access for transcatheter aortic valve replacement is emerging as an alternative to more traditional nonfemoral access options such as transapical or transaortic; however, comparative data are limited. The purpose of the study was to analyze outcomes after transcatheter aortic valve replacement using transcatheter compared with transthoracic (transapical/transaortic) access. Methods The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry was queried for patients who underwent transcarotid, transapical, or transaortic transcatheter aortic valve replacement with the SAPIEN 3 (Edwards Lifesciences, Irvine, Calif) transcatheter heart valve between June 2015 and July 2019. Thirty-day unadjusted outcomes were evaluated, and propensity score matching and logistic regression were used to compare transcatheter access with transthoracic access. Results In the propensity-matched analysis, 667 transcarotid transcatheter aortic valve replacement procedures were compared with 1334 transthoracic procedures. Transcarotid transcatheter aortic valve replacement was associated with lower mortality (4.2% vs 7.7%, P = .004), less new-onset atrial fibrillation (2.2% vs 12.1%, P Conclusions Transcatheter aortic valve replacement using transcarotid access is associated with lower 30-day mortality, less atrial fibrillation, shorter intensive care unit and overall length of stay, fewer readmissions, greater improvement in Kansas City Cardiomyopathy Questionnaire scores, and no significant difference in stroke or major vascular complications compared with transthoracic access.

With continued growth of transcatheter aortic valve replacement (TAVR), safe alternative access remains important for patients without adequate transfemoral (TF) access. Registry-based outcomes with transcarotid (TC) TAVR are favorable compared to transapical or transaxillary/subclavian, but TC vs TF comparisons have not been made. Our objective was to compare outcomes between TF and TC access routes for TAVR at a high-volume United States center. Methods: We retrospectively evaluated all TF and TC TAVR procedures from June 11, 2014 (first TC case) through December 31, 2019. The primary outcomes were 30-day stroke and 30-day mortality. Secondary outcomes were 1-year stroke, 1-year survival, and 30-day and 1-year life-threatening/major bleeding, vascular complications, and myocardial infarction. Propensity score weighted (PSW) models were used to compare risk-adjusted TF and TC outcomes. Of 1,465 TAVR procedures, 1319 (90%) were TF and 146 (10%) were TC. Procedure time and length of stay did not differ between groups. Unadjusted 30-day stroke (TF = 2.0%, TC = 2.7%, P = 0.536) and mortality (TF = 2.1%, TC = 2.7%, P = 0.629) were similar between groups. PSW 30-day stroke (odds ratio (OR) (95% confidence interval (CI)) = 0.8 (0.2-2.8)) and mortality (OR (95% CI) = 0.8 (0.2-3.0)) were similar between groups. Unadjusted and PSW 30-day major/life threatening bleeding, major vascular complications, and myocardial infarction did not differ between groups. Survival at one year was 90% (88%-92%) for TF patients and 87% (81%-93%) for TC patients (unadjusted P = 0.28, PSW hazard ratio = 1.0 (0.6-1.7)). Transcarotid TAVR is associated with similar outcomes compared to transfemoral TAVR at an experienced, high-volume center.

Truncus arteriosus (TA) is a major congenital cardiac malformation that requires surgical repair in the first few weeks of life. Interrupted aortic arch (IAA) is an associated malformation that significantly impacts the complexity of the TA operation. The aim of this study was to (1) define the comorbid conditions associated with TA and (2) determine the hospital survival and morbidity of patients with TA with and without an IAA. Data was collected from the Vizient Clinical Database/Resource Manager, formerly University HealthSystem Consortium, which encompasses more than 160 academic medical centers in the United States. The database was queried for patients admitted from 2002 to 2016 who were ≤ 4 months of age at initial admission, diagnosed with TA, and underwent complete surgical repair during that hospitalization. Of the 645 patients with TA who underwent surgery, 98 (15%) had TA with an interrupted aortic arch (TA-IAA). Both TA and TA-IAA were associated with a high prevalence of comorbidities, including DiGeorge syndrome, prematurity, and other congenital malformations. There was no difference in mortality between TA and TA-IAA (13.7–18.4%, p value = 0.227). No comorbid conditions were associated with an increased mortality in either group. However, patients with TA-IAA had a longer post-operative length of stay (LOS) compared to those without IAA (30 versus 40.3 days, p value = 0.001) and this effect was additive with each additional comorbid condition. In conclusion, the addition of IAA to TA is associated with an increased post-operative LOS, but does not increase in-hospital mortality.

We aimed to provide a perspective review of the available quantitative imaging modalities of the spine for prognostic evaluation of the adolescent idiopathic scoliosis (AIS). A technical description of the current imaging technologies for quantitative assessment of the pediatric spine with scoliosis was provided, and the pros and cons of each method were discussed. Imaging modalities that quantify the overall 3D alignment of the spine as well as the structural specification of the spinal bone, intervertebral disc, endplates, and ligaments as it pertains to development and progression of the idiopathic spinal deformities in adolescents were discussed. Low-dose and microdose stereoradiography, ultrasound, and rasterstereography provide quantitative imaging of the 3D spinal alignment with low or no radiation in standing posture which allows repetitive imaging for early detection of the curve development. Quantitative magnetic resonance imaging, including ultrashort dual-echo time and T1-rho can provide quantitative assessment of the spinal tissues relevant to development of idiopathic spinal deformity in pediatric population. New computed tomography scans that uses dual-energy can provides high-resolution measure of the current-state of the bone quality and morphology as well as the osteogenic properties of the bone by quantitative evaluation of the bone marrow. The presented imaging modalities can provide a wide spectrum of quantifiable information relevant to development and progression of the spinal deformity. Clinical application of these technologies can change the paradigm in clinical assessment of the pediatric scoliosis by improving our understanding of the pathogenesis of the idiopathic scoliosis.

Subclavian/axillary (TAx) access has become the most frequently used alternative access route for transcatheter aortic valve replacement (TAVR). Transcarotid (TC) TAVR has grown in popularity recently. Comparative data between these 2 contemporary access methods is lacking.Data were extracted from The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (TVT) Registry™ (June 2015 to October 2019) for patients undergoing TAVR by TC or TAx access with the SAPIEN 3 and SAPIEN 3 Ultra (Edwards Lifesciences, Irvine, CA) transcatheter heart valves. Procedural, index hospitalization, and 30-day outcomes were analyzed for TC vs TAx groups after 1:2 propensity matching of patient baseline characteristics.The study included 3903 cases, of which 801 TC and 3102 TAx procedures were compared. After 1:2 propensity matching, TC TAVR was associated with similar 30-day mortality (4.3% vs 5.2%, P = .34) but a significantly lower risk of stroke (4.2% vs 7.4%; hazard ratio, 0.56; 95% confidence interval, 0.38-0.83; P = .003) compared with TAx access. Other outcomes that favored TC over TAx included shorter procedure time (117.0 vs 132.4 minutes; P.001) and fluoroscopy time (16.6 vs 21.6 min; P.001), lower contrast volume (78.5 vs 96.7 mL; P.001), shorter length of stay in the intensive care unit (24.3 vs 25.0 hours; P = .02) and hospital (2.0 vs 3.0 days; P = .002), and more patients discharged to home (82.9% vs 74.6%; P.001).TC TAVR is associated with similar mortality and a significant reduction in stroke compared with the TAx approach. If femoral access is precluded, TC may be a safe, or at times, preferred avenue of transcatheter valve delivery.

Background The COVID-19 pandemic has disrupted routine cardiovascular care, with unclear impact on procedural deferrals and associated outcomes across diverse patient populations. Methods Cardiovascular procedures performed at 30 hospitals across six Western states in two large, non-profit healthcare systems (Providence St. Joseph Health and Stanford Healthcare) from December 2018-June 2020 were analyzed for changes over time. Risk-adjusted in-hospital mortality was compared across pandemic phases with multivariate logistic regression. Results Among 36,125 procedures (69% percutaneous coronary intervention, 13% coronary artery bypass graft surgery, 10% transcatheter aortic valve replacement, and 8% surgical aortic valve replacement), weekly volumes changed in two distinct phases after the initial inflection point on February 23, 2020: an initial period of significant deferral (COVID I: March 15 to April 11) followed by recovery (COVID II: April 12 onwards). Compared to pre-COVID, COVID I patients were less likely to be female (p=0.0003), older (p, Graphical Abstract Image, graphical abstract

There has been evidence that cyclical mechanical stimulation may be osteogenic, thus providing opportunities for nonpharmacological treatment of degenerative bone disease. Here, we applied this technology to a cohort of postmenopausal women with varying bone mineral density (BMD) T-scores at the total hip (-0.524 ± 0.843) and spine (-0.795 ± 1.03) to examine the response to intervention after 1 year of daily treatment with 10 minutes of vibration therapy in a randomized double-blinded trial. The device operates either in an active mode (30 Hz and 0.3 g) or placebo. Primary endpoints were changes in bone stiffness at the distal tibia and marrow adiposity of the vertebrae, based on 3 Tesla high-resolution MRI and spectroscopic imaging, respectively. Secondary outcome variables included distal tibial trabecular microstructural parameters and vertebral deformity determined by MRI, volumetric and areal bone densities derived using peripheral quantitative computed tomography (pQCT) of the tibia, and dual-energy X-ray absorptiometry (DXA)-based BMD of the hip and spine. Device adherence was 83% in the active group (n = 42) and 86% in the placebo group (n = 38) and did not differ between groups (p = .7). The mean 12-month changes in tibial stiffness in the treatment group and placebo group were +1.31 ± 6.05% and -2.55 ± 3.90%, respectively (group difference 3.86%, p = .0096). In the active group, marrow fat fraction significantly decreased after 12 months of intervention (p = .0003), whereas no significant change was observed in the placebo group (p = .7; group difference -1.59%, p = .029). Mean differences of the changes in trabecular bone volume fraction (p = .048) and erosion index (p = .044) were also significant, as was pQCT-derived trabecular volumetric BMD (vBMD; p = .016) at the tibia. The data are commensurate with the hypothesis that vibration therapy is protective against loss in mechanical strength and, further, that the intervention minimizes the shift from the osteoblastic to the adipocytic lineage of mesenchymal stem cells. © 2020 American Society for Bone and Mineral Research (ASBMR).

Stroke has long been a devastating complication of any cardiovascular procedure that unfavorably affects survival and quality of life. Over time, strategies have been developed to substantially reduce the incidence of stroke after traditional cardiovascular procedures such as coronary artery bypass grafting, isolated valve surgery, and carotid endarterectomy. Subsequently, with the advent of minimally invasive technologies including percutaneous coronary intervention, carotid artery stenting, and transcatheter valve therapies, operators were faced with a new host of procedural risk factors, and efforts again turned toward identifying novel ways to reduce the risk of stroke. Fortunately, by understanding the procedural factors unique to these new techniques and applying many of the lessons learned from prior experiences, we are seeing significant improvements in the safety of these new technologies. In this review, the authors: 1) carefully analyze data from different cardiac procedural experiences ranging from traditional open heart surgery to percutaneous coronary intervention and transcatheter valve therapies; 2) explore the unique risk factors for stroke in each of these areas; and 3) describe how these risks can be mitigated with improved patient selection, adjuvant pharmacotherapy, procedural improvements, and novel technological advancements.

Infections involving internal cardiac devices can be very challenging to treat, and almost universally require complete device extraction for successful management. Of the pathogens that cause device-related endocarditis, fungi such as Candida albicans are notoriously difficult to manage because of their propensity to produce large vegetations and the need for long-term treatment with potentially toxic medications. Furthermore, individuals who develop fungal, device-associated endocarditis are typically among the most complex patients, with significant comorbidities that place them at high risk for open heart procedures such as surgical device extraction. We present a case of one such patient in whom treatment of Candida albicans device-related endocarditis was managed using AngioVac® aspiration of a large right atrial vegetation with simultaneous laser sheath extraction of the implantable cardioverter-defibrillator lead.

Stroke is a devastating, potential complication of any cardiovascular procedure including transcatheter aortic valve implantation (TAVI). Even clinically silent lesions as detected by magnetic resonance imaging have been associated with poor long-term cognitive outcomes. As a result, extensive efforts have been focused on developing stroke preventative strategies including the development of novel embolic protection devices. These devices aim to reduce this risk by capturing or deflecting emboli away from the cerebral circulation. Areas covered: This review provides an insight into the incidence and mechanisms of neurologic events during TAVI, explores the design features and initial human experience of each of the cerebral embolic protection devices that have been used during TAVI, and carefully explains the major clinical trials of each of these devices with a focus on safety, efficacy and other reported outcomes. Expert commentary: The potential benefit of neuroprotection cannot be ignored as TAVI widens its scope to include younger and lower-risk patients wherein preventing a procedure related cerebral injury would potentially prevent long-term morbidity and mortality.

Toll-like receptor (TLR) 2/1 signalling is linked to autophagy through transcriptional actions of the 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-vitamin D receptor (VDR) complex. Population-specific effects have been reported for TLR2/1-VDR signalling. We hypothesized that population effects extend to autophagy and are influenced by vitamin D status. Serum 25(OH)D3 of healthy South Africans (Black individuals n = 10, White individuals n = 10) was quantified by LC-MS/MS. Primary monocytes-macrophages were supplemented in vitro with 1,25(OH)2D3 and stimulated with the lipoprotein Pam3CysSerLys4. TLR2, VDR, hCAP18, Beclin1, LC3-IIB, cytokines and CYP24A1 mRNA were quantified by flow cytometry and RT-qPCR, respectively. Black individuals showed significantly lower overall cumulative LC3-IIB (P

OBJECTIVES To develop a protocol for using a pre-existing, permanent pacemaker or defibrillator device for rapid ventricular pacing during transcatheter valve procedures and demonstrate feasibility. BACKGROUND Placement of a passive fixation, temporary pacemaker wire is considered routine during most transcatheter valve procedures to facilitate controlled or rapid ventricular pacing at the time of balloon expansion or valve deployment. Many patients presenting for such procedures have a pre-existing, permanent pacemaker or defibrillator device which could be used for the same function, obviating the need for temporary pacemaker wire placement. METHODS We developed a strategy for rapid pacing from the pre-existing device using a programmer during transcatheter valve procedures in consecutive patients over a 3-month period. Complications and clinical outcomes were recorded. RESULTS There were 135 transcatheter valve procedures performed during the study. Of these, 28 (20.7%) had pre-existing devices (17 transcatheter aortic valve replacement, 3 aortic valve-in-valve, 2 mitral valve-in-valve, and 6 balloon aortic valvuloplasty). All patients underwent rapid ventricular pacing using a commercially available device programmer. There were no adverse events related to device pacing and no patients required placement of a temporary pacemaker wire during the procedure. At 30-days follow-up, there were no deaths, one major vascular complication related to arterial access, and one patient with renal failure requiring dialysis. CONCLUSION Pacing from a commercially available device programmer is safe, feasible, and may reduce both procedural cost and complications such as cardiac tamponade by avoiding placement of a temporary pacemaker lead during transcatheter valve procedures.

Cardiovascular disease (CVD) has been the leading global cause of death for the last 15 years. In 2016, CVD, and resulting sudden and severe medical emergencies, accounted for 15.2 million deaths globally (1). Early CVD pathophysiology is characterized by both inflammation and microcalcification of vasculature. Currently, detection and observation of the disease at this stage are difficult. Additionally, the cause-effect relationships among symptoms remain unknown (2, 3, 4, 5). Nevertheless, inflammation and calcification have independently been connected to CVD risk (1, 6). Moreover, studies have shown that calcification specifically in the aorta is associated with an increased risk of death from CVD (7). For these reasons, this study aims to establish a method to examine and quantify the relationship between inflammation and plaque microcalcification in the descending thoracic aorta, and develop a strategy to better detect these CVD risk factors. PET/CT imaging with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and 18-Sodium Fluoride (NaF) radiotracers were used to detect plaque inflammation and vascular microcalcification, respectively. The thoracic aorta was then manually segmented on PMOD, and inflammation/microcalcification in each participant’s aorta were quantified by calculating the mean standard uptake value (SUV) for both radiotracers. The relationship between inflammation and microcalcification, as well as how both contribute to CVD, were analyzed by comparing SUVs for control participants and patients. It was found that participants with CVD have significantly more inflammation and microcalcification in this area than that among controls and that aortic inflammation and microcalcification are positively correlated with each other and with age.

PURPOSE: Fractures in vertebral bodies are among the most common complications of osteoporosis and other bone diseases. However, studies that aim to predict future fractures and assess general spine health must manually delineate vertebral bodies and intervertebral discs in imaging studies for further radiomic analysis. This study aims to develop a deep learning system that can automatically and rapidly segment (delineate) vertebrae and discs in MR, CT, and X-ray imaging studies. RESULTS: We constructed a neural network to output 2D segmentations for MR, CT, and X-ray imaging studies. We trained the network on 4490 MR, 550 CT, and 1935 X-ray imaging studies (post-data augmentation) spanning a wide variety of patient populations, bone disease statuses, and ages from 2005–2020. Evaluated using 5-fold cross validation, the network was able to produce median Dice scores > 0.95 across all modalities for vertebral bodies and intervertebral discs (on the most central slice for MR/CT and on image for X-ray). Furthermore, radiomic features (skewness, kurtosis, mean of positive value pixels, and entropy) calculated from predicted segmentation masks were highly accurate (r ≥ 0.96 across all radiomic features when compared to ground truth). Mean time to produce outputs was < 1.7 seconds across all modalities. CONCLUSIONS: Our network was able to rapidly produce segmentations for vertebral bodies and intervertebral discs for MR, CT, and X-ray imaging studies. Furthermore, radiomic quantities derived from these segmentations were highly accurate. Since this network produced outputs rapidly for these modalities which are commonly used, it can be put to immediate use for radiomic and clinical imaging studies assessing spine health.

Aortic stenosis (AS) is an increasingly common problem in developed countries. While surgical aortic valve replacement (SAVR) has long been the gold standard for managing severe, symptomatic AS, there has been a significant shift in the age and complexity of patients requiring intervention, and as a result, an increasing number of patients are not candidates for surgery. Transcatheter aortic valve replacement (TAVR) has developed into a vital alternative for inoperable patients and has shown excellent results in high- and even moderate-risk populations. As the technology has evolved over more than a decade since the first in-human TAVR, the procedure itself has become in many ways routine, has shown excellent safety, and has been adopted by hundreds of hospitals throughout the world. Despite this rapid expansion of TAVR technology, the patient population remains very complex, and individuals frequently have significant comorbid conditions that make TAVR anything but routine. Therefore, the goal of this chapter is to discuss the management of especially high-risk or atypical patients requiring TAVR, how to approach uncommon anatomy or comorbid conditions, and the management of unusual procedural complications.

DEPDC5 is a newly identified epilepsy-related gene implicated in focal epilepsy, brain malformations, and Sudden Unexplained Death in Epilepsy (SUDEP). In vitro, DEPDC5 negatively regulates amino acid sensing by the mTOR complex 1 (mTORC1) pathway, but the role of DEPDC5 in neurodevelopment and epilepsy has not been described. No animal model of DEPDC5-related epilepsy has recapitulated the neurological phenotypes seen in patients, and germline knockout rodent models are embryonic lethal. Here, we establish a neuron-specific Depdc5 conditional knockout mouse by cre-recombination under the Synapsin1 promotor. Depdc5 flox/flox -Syn1 Cre (Depdc5cc+) mice survive to adulthood with a progressive neurologic phenotype that includes motor abnormalities (i.e., hind limb clasping) and reduced survival compared to littermate control mice. Depdc5cc+ mice have larger brains with increased cortical neuron size and dysplastic neurons throughout the cortex, comparable to the abnormal neurons seen in human focal cortical dysplasia specimens. Depdc5 results in constitutive mTORC1 hyperactivation exclusively in neurons as measured by the increased phosphorylation of the downstream ribosomal protein S6. Despite a lack of increased mTORC1 signaling within astrocytes, Depdc5cc+ brains show reactive astrogliosis. We observed two Depdc5cc+ mice to have spontaneous seizures, including a terminal seizure. We demonstrate that as a group Depdc5cc+ mice have lowered seizure thresholds, as evidenced by decreased latency to seizures after chemoconvulsant injection and increased mortality from pentylenetetrazole-induced seizures. In summary, our neuron-specific Depdc5 knockout mouse model recapitulates clinical, pathological, and biochemical features of human DEPDC5-related epilepsy and brain malformations. We thereby present an important model in which to study targeted therapeutic strategies for DEPDC5-related conditions.

Transcatheter aortic valve implantation (TAVI) is now a widely adopted option for many inoperable and high risk patients with severe aortic valve stenosis, and clinical trials continue to show great benefit with regards to mortality and major cardiovascular endpoints. As the technology continues to expand and possibly grow to include intermediate and low risk populations, investigators have remained focused on efforts to reduce the risk of peri-procedural complications, of which neurologic events remain some of the most feared. Fortunately, contemporary studies have shown a significant decline in the risk of stroke with TAVI as compared to early clinical trials, and no difference when compared to surgical aortic valve replacement in the most recent trials. This review will focus on current methods for diagnosing, defining, and quantifying the effect of stroke after TAVI, explore the evidence with regards to stroke risk in various populations undergoing these procedures, discuss possible mechanisms for both early and late neurologic events after TAVI, and discuss strategies for both pharmacologic and device based embolic protection during these procedures.

Patient: Female, 60Final Diagnosis: Pulmonary vein stenosis following single lung transplantSymptoms: Dyspnea on exertion and dry coughMedication: —Clinical Procedure: Balloon angioplasty and stenting of the left common pulmonary veinSpecialty: Cardiology Objective: Unusual clinical course Background: Pulmonary vein stenosis (PVS) is a rare event following lung transplantation, but is a serious complication that requires prompt diagnosis and treatment. Case Report: We describe the case of a 60-year-old woman who underwent single-lung transplantation for idiopathic pulmonary fibrosis (IPF). One year following her single-lung transplant, she was admitted to the hospital for hypoxemic respiratory failure. The results of quantitative lung perfusion scintigraphy (LPS) raised the possibility of a diagnosis of PVS. Computed tomography angiography (CT angiography) of the chest identified more than 50% stenosis of the left common pulmonary vein at the anastomotic site with the left atrium. She was successfully treated with angioplasty and stent placement guided by intravascular ultrasonography. Post dilatation of the PVS, the pulmonary venous pressure gradient decreased from 12–16 mm Hg to 3–4 mm Hg. At three-month follow-up, the patient reported resolution of her shortness of breath. In support of this case report, we review the management of four previously reported cases from the literature of lung transplantation associated with PVS. Conclusions: PVS should be considered in the differential diagnosis of lung transplant patients who present with worsening dyspnea. Quantitative LPS and CT angiography are important in the diagnosis of PVS. Successful management of PVS, with salvage of the transplanted lung and the prevention of further surgical interventions, may be achieved with intravascular ultrasound-guided angioplasty and stent placement.

Background The impact of coronary artery disease ( CAD ) on outcomes after transcatheter aortic valve replacement ( TAVR ) is understudied. Literature on the prognostic role of CAD in the survival of patients undergoing TAVR shows conflicting results. This meta‐analysis aims to investigate how CAD impacts patient survival following TAVR . Methods and Results We completed a comprehensive literature search of Embase, MEDLINE , and the Cochrane Library, and included studies reporting outcome of TAVR based on CAD status of patients for the analysis. From the initial 1631 citations, 15 studies reporting on 8013 patients were analyzed using a random‐effects model. Of the 8013 patients undergoing TAVR , with a median age of 81.3 years (79–85.1 years), 46.6% (40–55.7) were men and 3899 (48.7%) had CAD (ranging from 30.8% to 78.2% in various studies). Overall, 3121 SAPIEN / SAPIEN XT / SAPIEN 3 (39.6%) and 4763 CoreValve (60.4%) prostheses were implanted, with transfemoral access being the most frequently used approach for the implantation (76.1%). Our analysis showed no significant difference between patients with and without CAD for all‐cause mortality at 30 days post TAVR , with a cumulative odds ratio of 1.07 (95% confidence interval, 0.82–1.40; P= 0.62). However, there was a significant increase in all‐cause mortality at 1 year in the CAD group compared with patients without CAD , with a cumulative odds ratio of 1.21 (95% confidence interval, 1.07–1.36; P =0.002). Conclusions Even though coexisting CAD does not impact 30‐day mortality, it does have an impact on 1‐year mortality in patients undergoing TAVR . Our results highlight a need to revisit the revascularization strategies for concomitant CAD in patients with TAVR.

Transcatheter aortic valve implantation (TAVI) has become a widely accepted strategy for the treatment of aortic stenosis in patients at intermediate, high, or prohibitive surgical risk. After >1 decade of innovation and clinical trial experience, the available technology for TAVI has grown enormously, and now includes a myriad of vascular access approaches and innovative valve designs. As a result, the range of patients who can benefit from these advances continues to grow rapidly. Furthermore, given the improved safety profile and clinical success of current-generation devices in randomized trials, the use of TAVI among even low-risk populations is justified in current trials. With the rapid dissemination and expansion of this technology, operators need to have a comprehensive understanding of how to select the appropriate procedural approach for each individual patient. In this Review, we detail the current evidence for TAVI among different patient populations, discuss the different vascular access approaches currently in use, and explore differences in design features among currently available and investigational valve systems. Furthermore, we provide an overview of important considerations for special patient populations, such as those with existing mitral prostheses, bicuspid aortic stenosis, isolated aortic regurgitation, or severe left ventricular outflow tract calcification.

Background Reversibility of left ventricular ( LV ) dysfunction in high‐risk aortic stenosis patient and its impact on survival after transcatheter aortic valve replacement ( TAVR ) are unclear. We aimed to evaluate longitudinal changes of LV structure and function after TAVR and their impact on survival. Methods and Results We studied 209 patients with aortic stenosis who underwent TAVR from May 2006 to December 2012. Echocardiograms were used to calculate LV end‐diastolic volume index (LV EDV i), LV ejection fraction, LV mass index ( LVM i), and global longitudinal strain before, immediately (TAVR . During a median follow‐up of 1345 days, 118 patients died, with 26 dying within 1 year. Global longitudinal strain, LVEDV i, LV ejection fraction, and LVM i improved during follow‐up. In patients who died during the first year, death was preceded by LVEDV i and LVM i increase. Multivariable longitudinal data analysis showed that aortic regurgitation at baseline, aortic regurgitation at 30 days, and initial LVEDV i were independent predictors of subsequent LVEDV i. In a joint analysis of longitudinal and survival data, baseline Society of Thoracic Surgeons score was predictive of survival, with no additive effect of longitudinal changes in LVEDV i, LVM i, global longitudinal strain, or LV ejection fraction. Presence of aortic regurgitation at 1 month after TAVR was the only predictor of 1‐year survival. Conclusions LV reverse remodeling was observed after TAVR , whereas lack of LVEDV i and LVM i improvement was observed in patients who died during the first year after TAVR . Post‐ TAVR , aortic regurgitation blocks reverse remodeling and is associated with poor 1‐year survival after TAVR .

Early trials involving transcatheter aortic valve replacement raised concerns for an elevated risk of neurologic events compared to surgical AVR. Contemporary studies suggest declining rates with better patient selection, improved operator experience, and newer generation devices. Events are usually embolic in nature, occur in the periprocedural period, and can lead to increased morbidity and mortality. Current investigations are focused on developing embolic protection devices for intraprocedural use and optimizing antiplatelet and anticoagulant regimens. These efforts aim to further reduce the incidence of stroke, which is particularly important as the technology expands to include intermediate and possibly low surgical risk populations.

Hypertrophic cardiomyopathy (HCM) is a complex and heterogeneous disease with different anatomical variants, physiologic manifestations, and genetic underpinnings. Even asymptomatic patients with HCM are at potential risk for sudden cardiac death and require risk stratification and consideration of

Amyloid is a generic term for insoluble, often intensely hydrophobic, fibrous protein aggregates that arise from inappropriately folded versions of naturally-occurring polypeptides. The abnormal generation and accumulation of amyloid, often referred to as amyloidogenesis, has been associated with the immune and pro-inflammatory pathology of several progressive age-related diseases of the human central nervous system (CNS) including Alzheimer's disease (AD) and age-related macular degeneration (AMD). This 'research perspective' paper reviews some of the research history, biophysics, molecular-genetics and environmental factors concerning the contribution of amyloid beta (Aβ) peptides, derived from beta-amyloid precursor protein (βAPP), to AD and AMD that suggests an extensive similarity in immune and inflammatory degenerative mechanisms between these two CNS diseases.

Ventricular septal rupture (VSR) after acute myocardial infarction is increasingly rare in the percutaneous coronary intervention era but mortality remains high. Prompt diagnosis is key and definitive surgery, though challenging and associated with high mortality, remains the treatment of choice. Alternatively, delaying surgery in stable patients may provide better results. Prolonged medical management is usually futile, but includes afterload reduction and intra-aortic balloon pump placement. Using full mechanical support to delay surgery is an attractive option, but data on success is limited to case reports. Finally, percutaneous VSR closure may be used as a temporizing measure to reduce shunt, or for patients in the sub-acute to chronic period whose comorbidities preclude surgical repair.

This is a case of a 61 year old woman with chest discomfort and evidence of an inferior, ST-elevation myocardial infarction, who develops persistent cardiogenic shock and respiratory failure after primary percutaneous coronary intervention. We discuss the differential diagnosis for cardiogenic shock after acute myocardial infarction (AMI) including left ventricular failure, right ventricular failure, iatrogenic causes such as over-medication or bleeding complications, and mechanical complications of AMI including ventricular septal rupture (VSR), papillary muscle rupture, and free-wall rupture with cardiac tamponade. We focus on modalities for making the diagnosis including physical exam findings, trans-thoracic echocardiography, left ventriculogram, and right-heart catheterization. Medical as well as surgical management is discussed. Finally, we explore the controversial aspects regarding the evidence for intra-aortic balloon pump use in patients with cardiogenic shock after AMI, the optimal timing of surgical repair for VSR, and percutaneous options for VSR closure.

AimTo assess plasma zinc and copper concentration in individuals with autism and correlate these levels with symptom severity.Subjects and MethodsPlasma from 102 autistic individuals, and 18 neurotypical controls, were tested for plasma zinc and copper using inductively-coupled plasma-mass spectrometry. Copper and zinc levels and Cu/Zn were analyzed for possible correlation with severity of 19 symptoms.ResultsAutistic individuals had elevated plasma levels of copper and Cu/Zn and lower, but not significantly lower, plasma Zn compared to neurotypical controls. There was a correlation between Cu/Zn and expressive language, receptive language, focus attention, hyperactivity, fine motor skills, gross motor skills and Tip Toeing. There was a negative correlation between plasma zinc concentration and hyperactivity, and fine motor skills severity.DiscussionThese results suggest an association between plasma Cu/Zn and severity of symptoms associated with autism.

4,4'-Methylenedianiline (DAPM) is an aromatic diamine used directly in the production of polyurethane foams and epoxy resins, or as a precursor to MDI in the manufacture of some polyurethanes. In our prior experiments, we showed that chronic, intermittent treatment of female rats with DAPM resulted in vascular medial hyperplasia of pulmonary arteries. In addition, treatment of vascular smooth muscle cells (VSMC) in culture with DAPM increased the rates of proliferation in a manner that was inhibited by co-treatment with N-acetylcysteine but was not associated with oxidative stress. We thus hypothesized that NAC treatment inhibited DAPM toxicity by competing for binding reactive intermediates formed through DAPM metabolism. Because the peroxidase enzyme cyclooxygenase is constitutively expressed in VSMC, and because cyclooxygenase is known to metabolize similar aromatic amines to electrophilic intermediates, we further hypothesized that DAPM-induced VSMC proliferation was dependent upon COX-1/2-mediated bioactivation. To test this hypothesis, we treated VSMC with DAPM and measured cell proliferation, COX-2 expression, COX-1/2 activity, and levels of covalent binding. DAPM treatment resulted in a dose-dependent increase in proliferation that was abolished by co-treatment with the COX-2-selective inhibitor celecoxib. In addition, DAPM exposure increased the rates of proliferation in VSMC isolated from wild-type but not COX-2 (-/-) mice. Paradoxically, treatment with DAPM reduced the cellular production of PGE(2) and PGF(2α), but dose-dependently increased the COX-2 protein levels. Covalent binding of [(14)C]-DAPM to VSMC biomolecules was greater in wild-type than in COX-2 (-/-) cells. However, covalent binding of [(14)C]-DAPM was not altered by co-treatment with a nonselective inhibitor of cytochromes P450. These studies thus suggest that DAPM-induced VSMC proliferation may be due to bioactivation of DAPM, perhaps through the action of cyclooxygenase. The data furthermore suggest that DAPM's mechanism of action may possibly involve inhibition or suicide inactivation of COX-2. In addition, because we observed an increase in DAPM-induced VSMC proliferation in cells isolated from female compared to male rats, further studies into the potential interplay between DAPM, the estrogen receptor, and COX-2 seem warranted.

The MitraClip is an US Food and Drug Administration-approved device for inoperable patients with severe degenerative mitral regurgitation (MR) and is under investigation for use in patients with severe functional MR. Simultaneously grasping both leaflets of the mitral valve can be technically challenging, however, in patients with a restricted posterior leaflet. We present one such case in which a pigtail catheter, placed retrograde into the left ventricle, was able to push the ventricular surface of the posterior leaflet into closer approximation with the anterior leaflet, and facilitate successful clip placement. We provide this report in hopes that it will provide a useful strategy for interventionalists faced with this challenging situation.

Moderate to severe aortic regurgitation after transcatheter aortic valve replacement is associated with worse outcomes. The impact of mild aortic regurgitation has been less clear, possibly because of the broad categories that have been used in clinical trials, but holds increasing importance in the study of next-generation devices in low- and intermediate-risk cohorts. A more granular scheme, which is common in clinical practice and proposed for future trials, may add prognostic value.We evaluated all patients undergoing transfemoral transcatheter aortic valve replacement at the Cleveland Clinic from 2006 to 2012. The degree of aortic regurgitation after transcatheter aortic valve replacement was reported from the echocardiography database based on a clinical, transthoracic echocardiogram performed within 30 days of the procedure. Aortic regurgitation was finely discriminated on the basis of a multiwindow, multiparametric, integrative approach using our usual clinical scale: none, trivial to 1+, 1+, 1 to 2+, 2+, 2 to 3+, 3+, 3 to 4+, or 4+.There were 237 patients included in the analysis. By controlling for age, gender, Society of Thoracic Surgeons score, baseline ejection fraction, and aortic regurgitation before transcatheter aortic valve replacement, there was a significant increase in mortality for each half grade of aortic regurgitation compared with the complete absence of aortic regurgitation after transcatheter aortic valve replacement. The unit hazard ratio for each 1+ increase in aortic regurgitation after transcatheter aortic valve replacement was 2.26 (95% confidence interval, 1.48-3.43; P .001) considering aortic regurgitation as a continuous variable. Other clinical variables did not significantly affect mortality.Even mild aortic regurgitation after transcatheter aortic valve replacement is associated with worse long-term mortality. There may be prognostic value in reporting milder categories of aortic regurgitation with more granular gradations.

Cardiac amyloidosis is an under recognized and underdiagnosed heart failure etiology characterized by protein misfolding, myocardial deposition, and restrictive cardiomyopathy. Cardiac involvement in elderly patients most commonly results from the transthyretin protein (ATTR) and carries a poor

Moderate to severe aortic regurgitation (AR) after trans-catheter aortic valve replacement (TAVR) is associated with worse outcomes. The impact of mild AR remains controversial. We evaluated all patients undergoing TF-TAVR at our institution from 2006-2012 (Edwards SAPIEN Valve System, 9000TFX).

The majority of cancer-related deaths (90%) are happened due to metastasis from the primary tumor site to distant organs. MLN8237 is a small, highly selective molecule inhibitor of Aurora A kinase (AURKA), which results in disruption of the mitotic spindle, chromosome segregation collapse, and inhibition of cell proliferation. Numerous studies have showed that levels of AURKA are elevated in many types of cancer, including breast cancer. Our previous studies indicated that MLN8237 is extremely potent against pulmonary metastasis, but not the primary tumor in orthotropic xenograft model. To further enhance MLN8237 based regiment, its combination with other therapeutic compounds can be used. As a potential partner we chose eribulin - fully synthetic macrocyclic analogue of the marine natural product halichondrin B. Eribulin belong to the class of non-taxane microtubule destabilizing molecules, currently used in clinic to treat taxol resistant metastatic breast cancer. In present study we have investigated the effect of MLN8237 and eribulin against breast cancer in vivo and in vitro. The results showed that combination of drugs possess a synergistic effect on both primary tumor and metastases, through inducing cytotoxic autophagy and apoptosis. This data clearly indicate great potential behind the MLN8237 based therapies and introduce a new hope for the eradication of metastatic breast cancer. Citation Format: Elena N. Pugacheva, Varvara Kozyreva, Anna Kiseleva, Ryan Ice, Brandon Jones, Yuriy Loskutov. Combination of eribulin and AURKA inhibitor prevents metastatic colonization and eradicates established metastases in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1084. doi:10.1158/1538-7445.AM2017-1084

Background: Computed tomography angiography (CTA) is used to predict the size and orientation of transcatheter aortic valve replacement (TAVR) devices in the annulus. We previously showed that the annular plane does not predict the orientation of the valve after deployment. We hypothesized that a

Background: The impact of Coronary artery disease (CAD) on the outcome after Transcatheter Aortic Valve Replacement (TAVR) is not understood well. Finding an optimum revascularization strategy for the TAVR patients who have concomitant CAD is also an ongoing debate. We sought to evaluate the

Background: The Medtronic CoreValve, a self-expanding (SE) valve is comprised of trileaflet porcine pericardial tissue sutured into a nitinol frame, as opposed to the balloon-expandable (BE) Edwards SAPIEN 3, a trileaflet bovine pericardial valve mounted in a cobalt chromium stent. We sought to