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Introduction: Transcatheter mitral valve replacement (TMVR) using aortic transcatheter heart valves (THV) is developing as an alternative to surgery for patients with severe mitral valve disease due to degenerated mitral bioprostheses or failed surgical rings who are poor surgical candidates. Outcomes of off-label procedures in the United States are being collected in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry. A comprehensive analysis of mitral Valve-in-Valve (VIV) versus Valve-in-Ring (VIR) outcomes has not previously been performed. Objectives: To evaluate in-hospital and 30-day clinical outcomes of mitral VIV and VIR procedures in the United States. Methods: Retrospective analysis of data from the STS/ACC TVT Registry on patients who underwent mitral VIV or VIR procedures. Results: 587 patients underwent TMVR VIV (n=494) or VIR (n=93) procedures between January 2013 and December 2016 at 144 hospitals. Median age was 76 (VIV) and 73 (VIR) years, (p=0.024), 60.9% (VIV) and 44.1% (VIR) were female (p=0.003), median left ventricular ejection fraction was 55% in VIV and 50% in VIR (p <0.001), and median STS score was 10.5% (VIV) and 9.2% (VIR), p=0.131. Transseptal access was utilized in 35% VIV and 46.2% VIR procedures, p=0.081. Procedural success was achieved in 74.4% of VIV and 57.8%VIR (p=0.239). Left ventricular outflow tract (LVOT) obstruction was more common in VIR (5.4%) vs VIV (0.06%), p=0.003. Post-procedure median mean mitral valve gradient was 4mmHg in both groups. 95.7% of VIV and 86% of VIR patients had post-procedure mitral regurgitation ≤1(+), p<0.001. In-hospital mortality was 6.9% for VIV and 9.7% for VIR (p=0.343). 30-day mortality was 9% for VIV and 12% for VIR (p=0.387). At 30-day follow up, 85.6% of VIV and 77.7% of VIR patients were in New York Heart Association class I or II (p=0.398). Conclusions: TMVR VIV and VIR using aortic transcatheter heart valves in high surgical risk patients are associated with similar in-hospital and 30-day mortality and symptom benefit. LVOT obstruction post-TMVR and residual mitral regurgitation ≥2 (+) were more frequent in VIR procedures. The long-term effect of these procedures is not known and requires further evaluation.

AbstractBackgroundRetinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression. Previous work indicated that Rbbp4 cooperates with the Rb tumor suppressor to block cell cycle entry. Here, we use genetic analysis to examine the interactions of Rbbp4, Rb, and Tp53 in zebrafish neural progenitor cell cycle regulation and survival.ResultsRbbp4 is upregulated across the spectrum of human embryonal and glial brain cancers. Transgenic rescue of rbbp4 mutant embryos shows Rbbp4 is essential for zebrafish neurogenesis. Rbbp4 loss leads to apoptosis and γ‐H2AX in the developing brain that is suppressed by tp53 knockdown or maternal zygotic deletion. Mutant retinal neural precursors accumulate in M phase and fail to initiate G0 gene expression. rbbp4; rb1 mutants show an additive effect on the number of M phase cells. In rbbp4 mutants, Tp53 acetylation is detected; however, Rbbp4 overexpression did not rescue DNA damage‐induced apoptosis.ConclusionRbbp4 is necessary for neural progenitor cell cycle progression and initiation of G0 independent of Rb. Tp53‐dependent apoptosis in the absence of Rbpb4 correlates with Tp53 acetylation. Together these results suggest that Rbbp4 is required for cell cycle exit and contributes to neural progenitor survival through the regulation of Tp53 acetylation.

AbstractObjectivesTo assess the impact of pulmonary hypertension (PH) on outcomes of patients with severe mitral annular calcification (MAC) undergoing transcatheter mitral valve replacement (TMVR).BackgroundPH is associated with poor outcomes after mitral valve surgery. Whether the presence of PH in patients with MAC undergoing (TMVR) is associated with poor outcomes, is unknown.MethodsRetrospective evaluation of 116 patients from 51 centers in 11 countries who underwent TMVR with valve in mitral annular calcification (ViMAC) using balloon‐expandable aortic transcatheter valves (THVs) from September 2012 to March 2017. Pulmonary artery systolic blood pressure (PASP) by echocardiogram was available in 90 patients. The subjects were stratified based on PASP: No PH = PASP ≤35 mmHg (n = 11); mild to moderate PH = PASP 36–49 mmHg (n = 21) and severe PH = PASP ≥50 mmHg (n = 58). Clinical, procedural, and echocardiographic outcomes were assessed.ResultsMean age was 72.7 (±12.8) years, 59 (65.6%) were female, Society of Thoracic Surgeons score was 15.8 + 11.8% and 90.0% where in New York Heart Association (NYHA) class III–IV. There was no significant difference in all‐cause mortality at 30 days (no PH = 27.3%, mild–moderate PH = 19.0%, severe PH = 31.6%; p = 0.55) or at 1 year (no PH = 54.5%, mild–moderate PH = 38.1%, severe PH = 56.1%; p = 0.36). No difference in adverse events, NYHA class or amount of residual mitral regurgitation at 1 year were observed between the groups.ConclusionThis study suggests that the presence of PH in patients with predominantly mitral stenosis with MAC undergoing TMVR does not impact mortality or adverse events. Further studies are needed to fully understand the effect of PH in this group of patients.

Abstract Background 2-stage exchange (2SE) surgery is often used to treat chronic prosthetic joint infections (PJI). IDSA guidelines do not recommend oral antibiotic suppression after 2SE. However, a recent randomized trial suggested that oral antibiotics for 3 months after arthroplasty reimplantation may prevent recurrent PJI. Objective: To compare rates of treatment failure (i.e., recurrent PJI) and adverse reactions (ARs) among patients who received &lt; 1 month of antibiotics directly after reimplantation to those who received 1-3 months of antibiotics following reimplantation (extended antibiotics). Methods This retrospective cohort study included patients with hip, knee, or shoulder PJI who underwent 2SE at 83 VA hospitals between the years 2003-2017. PJI was defined using administrative codes and microbiology data. Patients were followed for 5 years to assess treatment failure (TF) and ARs. TF was defined as recurrent PJI, debridement, or reoperation. ARs included Clostridioides difficile infections (CDI), or antibiotic associated diarrhea (AAD) during or 72 hours after antibiotics. Chi-square tests were used to compare outcomes. Cumulative incidence function curves were created to compare TF rates between those who did and did not receive extended antibiotic treatment, incorporating the competing risks of TF and death. Results Of the 433 patients, most (97%) received &lt; 1 month of oral antibiotics and 3% received extended antibiotics. The 15 patients who received extended antibiotics had similar rates of TF and ARs compared with patients who received &lt; 1 month of oral antibiotics (Table). However, there was a trend toward higher rates of CDI (6.7% vs. 3.8%) and AAD (13.3% vs. 9.6%) among those who received extended antibiotics. There was no difference in TF comparing extended antibiotics with &lt; 1 month of antibiotics, accounting for death (Figure). Table: Treatment Failure and Adverse Reactions Among Those Who Did and Did Not Receive Extended Antibiotics Conclusion Few patients received extended oral antibiotics in the study period. There were no statistically significant differences in TF or ARs between the 2 groups. Yet, there was a trend toward higher rates of ARs among the extended antibiotic group. Future prospective studies should assess both the potential benefits and ARs associated with extended antibiotics among patients undergoing 2SE surgery. Disclosures Marin L. Schweizer, PhD, 3M (Grant/Research Support)PDI (Grant/Research Support) Bruce Alexander, PharmD, Bruce Alexander Consulting (Independent Contractor) Daniel Suh, MS MPH, General Electric (Shareholder)Merck (Shareholder)Moderna (Shareholder)Smile Direct Club (Shareholder) Aaron J. Tande, MD, UpToDate.com (Other Financial or Material Support, Honoraria for medical writing) Andrew Pugely, MD, MBA, Globus Medical (Research Grant or Support)Medtronic (Consultant)United Healthcare (Consultant)

Abstract Introduction: Despite recent treatment (tx) advances that have improved overall survival (OS), multiple myeloma (MM) remains a mostly incurable malignancy. Txs become less effective with each successive line of therapy (LOT). The rapidly evolving tx landscape has raised questions about the optimal tx sequence; recent trial data may be useful to develop and test hypotheses about tx sequencing. However, real-world (RW) data have shown that while most patients (pts) with newly diagnosed MM (NDMM) receive first-line (1L) tx, attrition rates are high in later LOT, with up to 50% of transplant ineligible (TIE) pts receiving no tx beyond 1L. As many pts will not have an opportunity to be salvaged with later LOT, achieving the longest possible progression-free survival (PFS) upfront is critical. In the MAIA trial, daratumumab (DARA), lenalidomide, and dexamethasone (D-Rd) demonstrated significant PFS (hazard ratio [HR]=0.53, P&lt;0.0001) and OS (HR=0.68, P=0.0013) benefit vs Rd. In a subgroup of pts ≥65 years old in the SWOG S0777 study, bortezomib, lenalidomide, and dexamethasone (VRd) had no significant OS benefit vs Rd. In the absence of head-to-head studies comparing different tx sequences, clinical trial data can be used to explore different scenarios. Published models suggest that delaying DARA until later LOT is a viable tx strategy. Limitations of these models include basing conclusions on tx sequences other than those recommended in clinical guidelines, not accounting for the attrition rates from 1L to subsequent LOT and relying on inappropriate clinical inputs for second-line (2L) tx and beyond. While addressing those limitations, we examined different clinical scenarios to explore the clinical value of using DARA first vs saving it until a later LOT. Methods: We examined 3 potential clinical tx sequences using a lifetime three-health state clinical simulation to estimate survival outcomes in pts with TIE NDMM. The 3 health states were: 1L (time on tx + any subsequent tx-free interval), 2L (time on 2L + any subsequent LOT), and death. Tx sequences were reflective of clinical guidelines: D-Rd in 1L followed by pomalidomide (POM)- or carfilzomib (CAR)-based regimens in 2L and VRd or Rd in 1L followed by DARA-based regimens in 2L (Figure). Pt characteristics were assumed to be similar to those of pts in MAIA. Time spent in the 1L health state with D-Rd and Rd was based on time to next tx or death (TTNT) curves derived from MAIA; TTNT curves with VRd were derived by applying PFS HRs estimated in the PEGASUS study. The attrition rate for the base case analysis (58.8%) was based on MAIA data. Although similar to published studies, it includes pts who were lost to follow-up and may be an overestimate. A sensitivity analysis evaluated a more conservative estimate (27.2%) excluding censored pts. Attrition rates were assumed to be the same across tx arms. Time spent in the 2L health state with DARA-based and POM- or CAR-based regimens was based on RW OS curves derived from the nationwide EHR-derived deidentified Flatiron Health database. RW data were used as pts in published 2L trials are younger than in MAIA and many have had prior ASCT. We evaluated median OS and 5- and 10-year survival rates. Results: Using D-Rd in 1L improved median OS by 2.5 or 3.5 years compared with delaying DARA-based regimens until 2L after VRd or Rd, respectively (Table). The probability of being alive at 5 and 10 years was higher with D-Rd than with VRd or Rd as initial therapy (Table). Changes in attrition rates impacted the expected median OS, but the absolute difference in median OS was maintained, with an incremental OS benefit consistently &gt;2 years. Conclusions: Unlike previous attempts to examine outcomes with different tx sequences, we incorporated clinically representative sequences for pts with NDMM, included attrition rates, and explored their impact on OS with different tx sequences. Our approach shows that achieving the longest possible PFS in 1L drives OS outcomes. Saving agents until later LOT does not take into account that many pts do not reach 2L, as evidenced by published data on attrition rates in MM. Our findings show that in pts with TIE NDMM, starting with D-Rd may provide up to 3.5 years of additional OS gain with the currently available 2L tx. This gain could increase with new 2L agents currently in development, reinforcing the importance of using the best agents first, to increase the probability of pts benefitting from tx currently in development. Figure 1 Figure 1. Disclosures Fonseca: Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Janssen: Consultancy; GSK: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aduro: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; AbbVie: Consultancy; Mayo Clinic in Arizona: Current Employment; BMS: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Juno: Consultancy; Takeda: Consultancy; Merck: Consultancy. Hashim: Johnson and Johnson: Current Employment. Nair: Janssen Research & Development: Current Employment. He: Janssen: Current Employment, Current equity holder in publicly-traded company. Ammann: Janssen: Current Employment, Current equity holder in publicly-traded company. Lam: Janssen: Current Employment, Current equity holder in publicly-traded company. Wildgust: Janssen: Current Employment, Current equity holder in publicly-traded company. Kumar: Beigene: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Consultancy; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Background: Women have a higher rate of adverse events after mitral valve surgery. We sought to evaluate whether outcomes after transcatheter edge-to-edge repair intervention by sex have similar trends to mitral valve surgery. Methods: The primary outcome was 1-year major adverse events defined as a composite of all-cause mortality, stroke, and any bleeding in the overall study cohort. Patients who underwent transcatheter edge-to-edge repair for mitral regurgitation with the MitraClip system in the Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapy registry were evaluated. Linked administrative claims from the Centers for Medicare and Medicaid Services were used to evaluate 1-year clinical outcomes. Associations between sex and outcomes were evaluated using a multivariable logistic regression model for in-hospital outcomes and Cox model for 1-year outcomes. Results: From November 2013 to March 2017, 5295 patients, 47.6% (n=2523) of whom were female, underwent transcatheter edge-to-edge repair. Females were less likely to have >1 clip implanted ( P <0.001) and had a lower adjusted odds ratio of device success (adjusted odds ratio, 0.78 [95% CI, 0.67–0.90]), driven by lower odds of residual mitral gradient <5 mm Hg (adjusted odds ratio, 0.54 [CI, 0.46–0.63]) when compared with males. At 1-year follow-up, the primary outcome did not differ by sex. Female sex was associated with lower adjusted 1-year risk of all-cause mortality (adjusted hazard ratio, 0.80 [CI, 0.68–0.94]), but the adjusted 1-year risk of stroke and any bleeding did not differ by sex. Conclusions: No difference in composite outcome of all-cause mortality, stroke, and any bleeding was observed between females and males. Adjusted 1-year all-cause mortality was lower in females compared with males.

Background: Several studies have evaluated preprocedural imaging predictors of left ventricular outflow tract obstruction (LVOTO) after transcatheter mitral valve replacement. The patient cohorts in these studies were heterogeneous and included patients with transcatheter mitral valve replacement in failed bioprostheses, annuloplasty rings, and severe mitral annular calcification (MAC). The goal of this study was to evaluate predictors of LVOTO specific to patients undergoing valve-in-MAC. Methods: This study included patients with severe MAC who underwent valve-in-MAC and had optimal quality preprocedural multidetector row computed tomography scans eligible for retrospective analysis. Baseline demographic, echocardiographic, and procedural data on these patients were collected. multidetector row computed tomography parameters were analyzed for association with LVOTO, defined as increase in mean LVOT gradient by ≥10 mm Hg with accompanying hemodynamic instability. Results: Seventy-one patients with optimal preprocedural computed tomography scans were included in this study (mean age, 72.5±13.5 years), 9 of which developed LVOTO (all female). Baseline mean LVOT area, neo-LVOT area (145.3 versus 270.9 mm 2 ; P =0.006), indexed neo-LVOT area (90.1 versus 157.4; P =0.05), and virtual transcatheter heart valve to septum distance (3.1 versus 6.9 mm; P =0.002) were lower in the LVOTO group. Expected % LVOT area reduction was higher in the latter group (58.3 versus 42.7%; P =0.008). In the univariable analysis, the baseline mean LVOT area, neo-LVOT area, indexed neo-LVOT area, and valve to septum distance were all significantly associated with LVOTO. Conclusions: The systolic mean LVOT area, neo-LVOT area, indexed neo-LVOT, expected percentage LVOT area reduction, and the valve to septum distance were associated with LVOTO after valve-in-MAC.

SEV may serve as new biomarkers for predicting the individual response of insulin sensitivity to exercising.

Abstract Context Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known. Objective To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences. Methods Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis. Results Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed. Conclusion Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects.

Background: Exploration of cerebrospinal fluid (CSF) amino acids and the impact of dietary intake on central levels may provide a comprehensive understanding of the metabolic component of Alzheimer’s disease. Objective: The objective of this exploratory study was to investigate the effects of two diets with varied nutrient compositions on change in CSF amino acids levels in adults with mild cognitive impairment (MCI) and normal cognition (NC). Secondary objectives were to assess the correlations between the change in CSF amino acids and change in Alzheimer’s disease biomarkers. Methods: In a randomized, parallel, controlled feeding trial, adults (NC, n = 20; MCI, n = 29) consumed a high saturated fat (SFA)/glycemic index (GI) diet [HIGH] or a low SFA/GI diet [LOW] for 4 weeks. Lumbar punctures were performed at baseline and 4 weeks. Results: CSF valine increased and arginine decreased after the HIGH compared to the LOW diet in MCI (ps = 0.03 and 0.04). This pattern was more prominent in MCI versus NC (diet by diagnosis interaction ps = 0.05 and 0.09), as was an increase in isoleucine after the HIGH diet (p = 0.05). Changes in CSF amino acids were correlated with changes in Alzheimer’s disease CSF biomarkers Aβ42, total tau, and p-Tau 181, with distinct patterns in the relationships by diet intervention and cognitive status. Conclusion: Dietary intake affects CSF amino acid levels and the response to diet is differentially affected by cognitive status.