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Background Patients with Eisenmenger syndrome are known to have a high incidence of sudden cardiac death ( SCD ), yet the underlying causes are not well understood. We sought to define the predictors of SCD in this population. Methods and Results A retrospective analysis of all patients with Eisenmenger syndrome from 2 large tertiary referral centers was performed. ECGs, prolonged ambulatory recordings, echocardiograms, and clinical histories were reviewed; and the cause of death was identified. A total of 246 patients (85 [34.6%] men) with a mean age of 37.3 (±14.2) years were followed up for a median of 7 years. Over the study period, 136 patients died, with 40 experiencing SCD and 74 experiencing cardiac death (sudden and nonsudden). Age, atrial fibrillation, prolonged QRS duration, complete heart block, right atrial enlargement, right bundle branch block, increased right atrial pressure, impaired biventricular function, and the presence of a pacemaker were associated with increased risk of SCD , whereas advanced pulmonary hypertension therapies were protective. Atrial fibrillation (11.45‐fold increased risk; P <0.001) and QRS duration ≥120 ms (2.06‐fold increased risk; P =0.034) remained significant predictors of SCD in the multivariate analysis, whereas advanced pulmonary hypertension therapies were strongly protective against SCD ( P <0.001). Conclusions Atrial arrhythmias, impaired ventricular function, and conduction system disease were associated with increased risk of SCD in this cohort of patients with Eisenmenger syndrome, providing an opportunity for early risk stratification and potential intervention. Clinical heart failure symptoms (New York Heart Association class ≥ II ) were predictive of increased mortality but not of SCD , suggesting a potential arrhythmic cause behind SCD .

AbstractIntroductionWe created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD.MethodsThe CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants.ResultsThe CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non‐fluent/agrammatic variant primary progressive aphasia participants.DiscussionThe global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

Background: Mechanical injury in the conduction system requiring permanent pacemaker (PPM) associated with transcatheter aortic valve replacement (TAVR) procedure is a common complication. The objective of this study was to use ambulatory monitor BodyGuardian to assess late occurrence of atrioventricular block (AVB) after TAVR. Methods: This prospective study evaluated 365 patients who underwent TAVR at Mayo Clinic, Rochester, Minnesota between June 2016 and August 2017. Patients who received PPM for bradycardia after TAVR before discharge were considered as the PPM group. Those not requiring PPM received a BodyGuardian system (BodyGuardian group) for 30 days of continuous monitoring. Primary end point was Mobitz II or third-degree atrioventricular block (II/III AVB) at 30-day follow-up. Results: Of 365 patients, 74 who had a PPM or an implantable cardioverter-defibrillator before TAVR and 94 who were enrolled in other studies were excluded. Of 197 patients enrolled in the study, 70 (35.5%) received PPM and 127 had BodyGuardian before the hospital dismissal. Eleven of 127 (8.6%) BodyGuardian group required PPM within 30 days after TAVR for late occurrence of symptomatic bradycardia. In total, 33 of 197 (16.7%) patients developed II/III AVB (24 before and 9 after discharge). Thirty-four patients had preexisting right bundle branch block. Of them, 16 (47%) developed II/III AVB. Of 53 patients who developed new left bundle branch block after TAVR, 14% progressed to II/III AVB within 30 days. Conclusions: In patients without a standard post-TAVR pacing indication, yet a potential risk to develop AVB, a strategy of 30-day monitoring identifies additional patients who require permanent pacing.

AbstractIntroductionConventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z‐scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z‐scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.MethodsIn this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).ResultsCorrected Z‐scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted‐R2.DiscussionNonlinearly corrected Z‐scores with respect to age, sex, and education with age‐varying residual standard deviation allow for improved detection of non‐normative extreme cognitive scores.

Abstract Background Venous stenosis is a well-recognized complication of transvenous leads when patients require lead revisions or device upgrade. In these cases, balloon venoplasty or alternative venous access with subcutaneous tunneling can be performed. Purpose Compare the outcomes of venoplasty vs. tunneling in patients requiring additional transvenous lead implantation. Methods A single center retrospective cohort study of all patients undergoing lead implantation/revision requiring venoplasty or tunneling from 2005–2017. Chi-squared and Wilcoxon Rank-Sum tests were used to compare categorical and continuous variables. Results Ninety five patients met our inclusion criteria (60 venoplasty & 35 tunneling). There was no difference in procedure success rates (p-value=0.98). Tunneling was associated with less fluoroscopy time but higher incidence of acute complications (0% vs. 23%, p-value=0.002) most requiring invasive intervention and/or blood product transfusion. Long term outcomes were comparable and related to lead failure or infection. Outcomes for tunneling vs. venoplasty Variable Tunneling (n=35) Venoplasty (n=60) p-value Age Y 67 (23–84) 70 (29–91) 0.25 Male (%) 24 (69%) 41 (68%) 0.98 Number of existing leads 2.1 (1–4) 2.4 (0–4) 0.1 Age of oldest lead 7.0 (0–21) 7.2 (0–33) 0.73 Number of new leads 1.2 (1–3) 1.4 (1–3) 0.26 Fluoroscopy time (SD) min 29.2 (21.3) 39.7 (21.5) 0.012 Procedure success (%) 35 (100%) 55 (92%) 0.9 Acute complications (%) 8 (23%)1 0 (0%) 0.0002 Pocket hematoma/bleed 4 (11%)2 Hemothorax 2 (6%)3 Pericarditis 1 (3%) Lead compromise 1 (3%) Follow up M 18 (0–76) 28 (0–98) N/A Long term lead issues (%) 6 (17%) 10 (17%) 0.95 Long term complication requiring intervention 4 (11%) 8 (13%) N/A Procedure success: functional lead placed as a result of venoplasty or tunneling. 1Two patients required blood products. 2Two patients required invasive intervention. 3One patient required chest tube and the other ICU admission. Conclusions Balloon venoplasty is associated with similar rates of success and a less incidence of acute complications when compared subcutaneous tunneling. Acknowledgement/Funding NIH T32 Training Grant HL07111-40

Abstract Recent guideline statements approve the performance of magnetic resonance imaging (MRI) in patients with non-conditional cardiac implantable electronic devices (CIEDs) under certain closely monitored conditions. Data from current registries may have lower power to discern changes that may occur in the CIED after the MRI. Objective We aimed to systematically review the literature to identify the adverse events and significance of changes in device function associated with performing MRI in patients with CIEDs Methods A comprehensive literature search of the databases was performed between 1980- 2017. Two independent reviewers selected studies and extracted data. A random-effects model was used for meta-analysis. Results A total of 7,422 patients underwent 8,865 MRI studies. No death occurred post MRI. Clinical adverse events were extremely rare (mostly less than 1%) and are summarized in Table 1. No significant changes in the pooled mean effect size estimate was noted for the changes in the lead parameters (pacing threshold, sensing and impedance) Binary outcomes post magnetic resonance imaging in patients with non-conditional cardiac implantable electronic devices Outcome Sample size Number of patients Rate SE LL of CI UL of CI Death 7401 0 0 0 0 0 Atrial arrhythmia 7173 10 0.001 0.0004 0.0007 0.0024 Ventricular arrhythmia 7371 9 0.0012 0.0004 0.0006 0.0022 Oversensing 4981 17 0.0034 0.0008 0.0020 0.0053 Inhibition of pacing 7371 6 0.0008 0.0003 0.0003 0.0016 Lead Failure/Generator Failure 7475/7475 2/8 0.0002/0.0011 0.0001/0.0004 0.0001/0.0005 0.0009/0.002 Power on Reset 1388 105 0.0131 0.0014 0.0107 0.0161 Did not complete scan 6851 13 0.0019 0.0005 0.0011 0.0031 Chest pain 7080 11 0.0021 0.0004 0.0008 0.0027. Lead threshold rise (>0.5v/>50%-A/V) 5076/6246 12/16 0.0024/0.0026 0.0007/0.0006 0.0013/0.0015 0.0040/0.0041 Change in Battery voltage >0.04V 7132 42 0.0061 0.0009 0.0043 0.0079 Sensing decrease >50%-A/V 5087/5834 17/9 0.0033/0.0015 0.0008/0.0005 0.0020/0.0008 0.0052/0.0028 Impedance changes >50ohms/>50% 5810 22 0.0038 0.0008 0.0024 0.0057 Rise in cardiac enzymes 1703 26 0.0152 0.0030 0.0102 0.0219 A, atrial; V, ventricular; SE, standard Error; LL, lower limit; UL, upper limit; CI, Confidence intervals. Conclusions MRI in patients with non-conditional CIEDs can be performed with high degree of safety and low rate of clinical events when performed under standardized protocols Acknowledgement/Funding None

Abstract Introduction: Heparin-induced Thrombocytopenia (HIT) is a potentially life and limb threatening pro-thrombotic syndrome triggered by antibodies to platelet factor 4 (PF4)/polyanion complexes. Commonly used screening tests such as the PF4/Heparin ELISA (PF4 ELISA), while easy to perform in the near-patient setting, are highly non-specific. In contrast, more accurate tests such as the serotonin release assay (SRA) are technically complex, require radioactivity and are performed in only a handful of reference laboratories. These diagnostic challenges lead to both unnecessary anticoagulant use as well as avoidable cases of severe bleeding. Recent reports suggest that a relatively simple three-hour flow cytometry-based test that uses PF4-treated normal platelets, the PEA (PF4-dependent p-selectin Expression Assay), is at least as accurate as the SRA for identifying patients who have HIT (Thromb Haemost. 2015 Nov 25;114(6):1322-3; Chest. 2016 Sep;150(3):506-15; Chest. 2017 Oct;152(4):e77-e80). Here we describe results of a large prospective study designed to compare the accuracy of the SRA and PEA for HIT diagnosis in a clinical setting. Methods: The PEA and SRA were performed on serum samples obtained from adult patients (≥18 yrs.) from 2 large tertiary care academic hospitals from May 2016 to Sep 2017. All inpatients for whom PF4 ELISA testing was ordered were included in the study. The PEA was performed with platelets pretreated with PF4 at 3 concentrations: 30mcg/mL (PEA30), 10mcg/mL (PEA10) and 3mcg/mL (PEA3). Sera were batch-tested in both assays (SRA and PEA) using the same target platelets. The central laboratory was blinded to clinical history and to the results of the PF4 ELISA performed by participating hospitals at the time of diagnosis. Both centers performed IgG-specific PF4 ELISAs and utilized manufacturer-recommended cut-offs for positivity. Predefined "more-stringent" and "less stringent" criteria based on clinical findings (4Ts score) and results of PF4 ELISA testing were used to define the likelihood of a patient having HIT (Table 1A). Receiver Operating Curve (ROC) analysis was performed and Area Under the Curve (AUC) of each assay was calculated to assess their diagnostic accuracy. Since high test specificity was desired, positive cut-offs that maximized the sum of sensitivity and specificity in a specificity range of ≥90% and ≥95% were derived. To evaluate non-inferiority of the PEA to the SRA, we assessed whether the lower limit of the one-sided 95% confidence interval of the ΔAUC (PEA-SRA) was higher than a non-inferiority margin of 5% and 10%. Results: A total of 440 patient samples were tested with both assays. Seventeen and 28 patients were classified as having true HIT based on the use of the more- and less-stringent criteria, respectively. When classified by more-stringent criteria, the AUC was numerically greater for each of the three PEA tests than for the SRA (Table 1B). All tests had excellent accuracy (AUC>0.90, "excellent" by the Traditional academic point system). Using less-stringent criteria, the PEA30 had the highest AUC estimate followed by the SRA (Table 1C). Positive cut-offs generated at test specificities of ≥90% and ≥95% using data classified by more stringent criteria are shown in Table 1D. PEA3 was non-inferior to the SRA at a 5% non-inferiority margin, and all PEA tests were non-inferior at the 10% margin using the more stringent classification for true HIT (Fig 1A). In the less-stringently classified data set, the PEA30 was non-inferior to the SRA at a 10% margin (Fig 1B). Conclusions: The PEA, a 3-hour, non-radioactive functional HIT assay demonstrated high diagnostic accuracy and was non-inferior to the SRA using commonly accepted non-inferiority margins for diagnostic testing (5-10%). The technical advantages of the PEA over the SRA may encourage its widespread adoption as a rapid-turnaround, accurate and near-patient diagnostic for patients with suspected HIT. Disclosures Jones: BloodCenter of Wisconsin: Patents & Royalties. Curtis:Ionis Pharmaceuticals: Consultancy. Bougie:BloodCenter of Wisconsin: Patents & Royalties. Aster:BloodCenter of Wisconsin: Patents & Royalties. Garcia:Shingoi: Consultancy; Retham Technologies LLC: Consultancy; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Bristol Meyers Squibb: Consultancy; Portola: Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy. Padmanabhan:BloodCenter of Wisconsin: Patents & Royalties: Patent/royalties for HIT diagnostic testing; Veralox Therapeutics: Other: Advisory Board; Retham Technologies LLC: Equity Ownership, Other: Retham seeks to develop HITDx(TM), a new assay for HIT diagnosis; TerumoBCT: Consultancy; GE Healthcare: Other: Material support for Clinical Quality Improvement Initiative; Janssen Pharmaceuticals: Consultancy.

Abstract Abstract 2477 Background: Aurora A kinase (AAK) is a key mitotic regulator, inhibition of which results in mitotic spindle defects, mitotic delay, and apoptosis. AAK is amplified or overexpressed in a number of heme-lymphatic malignancies. This phase 1, multicenter study (NCT00697346) is the first to assess safety, tolerability, and pharmacokinetics (PK) of the investigational AAK inhibitor alisertib (MLN8237) in patients with advanced hematologic malignancies. Methods: Patients aged ≥18 years with relapsed/refractory hematologic malignancy, confirmed radiographically or clinically evaluable disease, and ECOG performance status 0–2, were eligible for inclusion. Patients with prior allogeneic transplant were excluded; there was no restriction on the number of prior therapies. Patients received escalating doses (standard 3+3 design) of alisertib as either a powder-in-capsule (PIC) or enteric coated tablet (ECT) formulation. Alisertib PIC was administered as a twice-daily (BID) loading dose on Day 1, then once daily (QD) on Days 2–14 or 2–21, followed by 14 or 7 days' rest, respectively, in 28-day cycles. Alisertib ECT administration followed the same scheme in the first dose group, and subsequent groups received divided (BID) doses for 7 days plus 14 days' rest in 21-day cycles. Endpoints included maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, PK, and response. Results: 55 patients were included (PIC n=28, ECT n=27); median age was 61 years (range 27–82), 42% had prior ASCT, and 78% had received ≥3 prior therapies. 60% of patients had non-Hodgkin's lymphoma, 35% multiple myeloma, and 5% chronic lymphocytic leukemia/small lymphocytic lymphoma. Patients received a median of 2 cycles (range 1–14); 8 patients are ongoing. The MTD on the alisertib PIC 14-day + 14 days' rest schedule was 45 mg QD, established following occurrence of DLTs in four patients at higher dose levels: Gr 4 thrombocytopenia, Gr 4 neutropenia (65 mg QD); Gr 3 febrile neutropenia, Gr 4 thrombocytopenia (90 mg QD). In patients receiving alisertib ECT, the MTD was determined as 50 mg BID on a 7-day + 14 days' rest schedule; four DLTs were observed in three patients: at 40 mg QD for 14 days, one patient had Gr 4 febrile neutropenia, and one patient had Gr 4 bullous dermatitis and Gr 4 neutropenia; at 50 mg BID for 7 days, one of nine patients had Gr 4 neutropenia. The most common drug-related adverse events (AEs) were neutropenia (PIC 46%, ECT 63%), thrombocytopenia (39%, 41%), and diarrhea (29%, 41%); most common Gr ≥3 drug-related AEs were neutropenia (PIC 36%, ECT 52%), thrombocytopenia (29%, 26%), and anemia (14%, 26%). 24 patients (PIC n=12, ECT n=12) had serious AEs; the most common was febrile neutropenia (PIC n=1, ECT n=4). Tolerability appeared generally similar between the PIC and ECT formulations. Six patients (PIC n=3, ECT n=3) died during the study (PIC: renal failure, airway obstruction, progressive large cell lymphoma; ECT: progressive myeloma [n=2], hypercalcemia); no deaths were considered to be related to alisertib. Alisertib absorption was rapid with an overall median Tmax of 2 hours. The overall mean terminal half-life following multiple dosing was 19 hours. The mean peak/trough (P/T) ratio was 5 following QD dosing as PIC. The mean accumulation ratio and P/T ratio were 2.5 and 2.1, respectively, following BID dosing as ECT. At data cut-off (29 March, 2011), 42 patients were evaluable for response. Antitumor activity was observed in five patients (PIC n=3, ECT n=2) who had partial responses; 11 patients had a best response of stable disease (PIC n=6, ECT n=5) and 26 had progressive disease (PIC n=14, ECT n=12). Seven patients received ≥5 cycles of therapy, including one patient (PIC group; post-transplant grade 3B follicular lymphoma) with resolution of B symptoms who received alisertib for >1 year. Conclusions: The MTDs of the PIC and ECT formulations of alisertib are 45 mg QD for 14 days (+14 days' rest) and 50 mg BID for 7 days (+ 14 days' rest), respectively, in patients with advanced, non-leukemic hematologic malignancies. AEs were generally manageable and were consistent with inhibition of AAK in highly proliferative tissues (gastrointestinal and hematologic AEs). Current data support further investigation and expansion at the MTDs is ongoing. Data from PK, safety, and tolerability collectively support the progression of ECT formulation at 50 mg BID for 7 days in a 21-day cycle into phase 2 development. Disclosures: Off Label Use: Investigational agent in clinical development for the treatment of advanced hematologic malignancies and solid tumors. Goy:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Reeder:Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding; Celgene: Institutional research funding. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Danaee:Millennium Pharmaceuticals, Inc.: Employment. Xiao:Millennium Pharmaceuticals, Inc.: Employment. Benaim:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Shea:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

Abstract Abstract 2799 Background: Aurora A kinase (AAK) is important in a diverse set of mitotic processes and is amplified or overexpressed in a number of heme-lymphatic malignancies. MLN8237 is an investigational, orally administered, selective AAK inhibitor in clinical development for the treatment of hematologic and solid tumors. This multicenter study (NCT00697346) is the first phase 1 program to assess safety and pharmacology of MLN8237 in patients with advanced hematologic malignancies. Methods: Eligible patients were aged ≥18 yr, had response-evaluable, relapsed or refractory hematologic malignancies, and had ECOG performance status 0–2; there was no restriction on the number of prior therapies, but prior allogeneic transplant was excluded. Patients received escalating doses of MLN8237 as powder-in-capsule formulation in a 3+3 design. Endpoints included safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and response. Results: Twenty-eight patients were included; median age was 62 yr (range 41–74), 50% were male, 86% were white, and 43% had prior transplant. Diagnoses were non-Hodgkin's lymphoma (68%), including diffuse large B-cell (DLBCL), mantle cell, follicular, and small lymphocytic lymphoma; multiple myeloma (29%); and chronic lymphocytic leukemia (4%). Seventy-nine percent of patients had received ≥3 prior therapies. Patients initially received a 21-day treatment schedule of MLN8237 25 or 35 mg (BID loading dose on Day 1, then QD on Days 2–21) followed by a 7-day rest period (28-day cycles). Based on results with the first two cohorts, subsequent cohorts received a 14-day treatment schedule of MLN8237 35, 45, 65, or 90 mg (BID loading dose on Day 1, then QD on Days 2–14) followed by a 14-day rest period (28-day cycles). Median number of cycles administered was 2 (range 1–14+). After escalation to 90 mg (maximum administered dose), two DLTs per cohort led to de-escalation to 65 mg and then 45 mg, which was the MTD on the 14-day schedule. The most common treatment-related adverse events (AEs) were neutropenia (46%), thrombocytopenia (36%), and asthenic conditions (32%); grade ≥3 treatment-related AEs were reported in 14 (50%) patients, and 13 (46%) had a serious AE. DLTs included grade 3–4 myelosuppression associated with infection or delay in treatment, which were generally manageable by reduction in dose or schedule. AEs were generally reversible and manageable, although 5 (18%) patients discontinued due to AEs. Three patients died, from causes (renal failure; airway obstruction; progressive large cell lymphoma) not considered related to MLN8237. Following multiple doses, an overall median Tmax of 2 hr, a mean t1/2 of 23 hr, and a peak/trough ratio of 5 were observed. The geometric mean of steady-state AUC increased from 19,534 to 30,811 nM*hr when the daily dose was increased from 25 to 65 mg. With the 14-day schedule, antitumor activity was observed in a patient with relapsed DLBCL treated with 65 mg and reduced to 45 mg, who enrolled after disease progression following ifosfamide-carboplatin-etoposide (ICE) salvage therapy. A durable PR coupled with resolution of B symptoms sustained for >1 yr was observed in a patient with post-transplant grade 3B follicular lymphoma treated with 35 mg, escalated per protocol to 45 mg and then 65 mg. Stable disease (SD; 5 months) was observed in a patient with myeloma treated at 90 mg. Conclusions: MLN8237 toxicities were consistent with AAK inhibition in proliferating tissue (chiefly bone marrow), and were generally manageable. The MTD was 45 mg on the 14-day schedule in these patients with advanced hematologic malignancies. Antitumor activity was observed, and repeat cycles were tolerable over 6–12 months in some patients who achieved PR or SD. The results support further investigation of MLN8237 in heme-lymphatic malignancies, and ongoing clinical development includes alternative schedules and formulations. Disclosures: Padmanabhan: Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of advanced hematologic malignancies. Shea:Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Vose:Millennium Pharmaceuticals, Inc.: Research Funding. Goy:Millennium Pharmaceuticals, Inc., Celgene, GSK, Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Fingert:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Fowler:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Research Funding; Cephalon: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria.