Defining Optimal Left Ventricular Assist Device Short-Term Outcomes May Provide Insight into Programmatic Quality Assessment.

BACKGROUND: Patients have substantial variability in perioperative outcomes after left ventricular assist device (LVAD) implant. A perioperative multidimensional tool integrating mortality, adverse events (AEs), and patient-reported outcomes to assist in quality improvement initiatives is needed. METHODS: Patients undergoing HeartMate 3 LVAD implant (1/1/2017 and 1/31/2024) in the Society of Thoracic Surgeons' Intermacs registry were studied. A Cox proportional hazard multivariable analysis incorporating AEs as time-varying covariates for mortality out to 180 days was used to generate the Intermacs Short-Term Composite Quality (INSITE) score, reflecting the adjusted hazard ratio (HR) for mortality contributed by each AE, applying global ranking methodology. In those alive and on support at 6 months, multivariable logistic regression (odds ratio, OR) was used to examine the impact of AEs on health-related quality of life (QOL) at 180 days, captured through the INSITE-QOL score. Failure to achieve ≥1 point increase in visual analog scale (VAS) from baseline was the event in the QOL analysis. RESULTS: Of 13,148 patients, 4,389 (33.4%) suffered at least one AE or death through 180 days. Stroke (survival: HR 13.1; QOL: HR 1.7), dialysis (survival: HR 31.4; QOL: HR 4.2), prolonged respiratory failure (survival: HR 5.7; QOL: HR 2.3), reoperation (Survival: HR 3.4; QOL: HR 1.6) and right heart failure (survival: 5.0; QOL: HR 1.4), contributed to both mortality and failure to improve QOL at 180 days (all p<0.05). The median INSITE and INSITE-QOL scores were 0.0 [0.0,1.6] and 0.0 [0.0,0.0], respectively. At 9.4% (n=17) of centers, a high INSITE score (≥13) was present in 15% of patients while the top 25% of centers had perfect INSITE-QOL scores in at least 75% of patients. CONCLUSIONS: AEs after LVAD confer differential impact on mortality and QOL, enabling development of global rank outcome scores. Given the high mortality hazard conferred by 180-day AEs, center-specific quality interventions aimed at reducing early complications provide the greatest opportunity to improve long-term survival and QOL.

RNAseq of INOCA patients identifies innate, invariant, and acquired immune changes: potential autoimmune microvascular dysfunction.

Background: Ischemia with non-obstructive coronary arteries (INOCA) is a major clinical entity that involves potentially 20%-30% of patients with chest pain. INOCA is typically attributed either to coronary microvascular disease and/or vasospasm, but is likely distinct from classical coronary artery disease (CAD). Objectives: To gain insights into the etiology of INOCA and CAD, RNA sequencing of whole blood from patients undergoing both stress testing and elective invasive coronary angiography (ICA) was conducted. Methods: Stress testing and ICA of 177 patients identified 40 patients (23%) with INOCA compared to 39 controls (stress-, ICA-). ICA+ patients divided into 38 stress- and 60 stress+. RNAseq was performed by Illumina with ribosomal RNA depletion. Transcriptome changes were analyzed by DeSeq2 and curated by manual and automated methods. Results: Differentially expressed genes for INOCA were associated with elevated levels of transcripts related to mucosal-associated invariant T (MAIT) cells, plasmacytoid dendritic cells (pcDC), and memory B cells, and were associated with autoimmune diseases such as rheumatoid arthritis. Decreased transcripts were associated with neutrophils, but neutrophil transcripts, per se, were not less abundant in INOCA. CAD transcripts were more related to T cell functions. Conclusions: Elevated transcripts related to pcDC, MAIT, and memory B cells suggest an autoimmune component to INOCA. Reduced neutrophil transcripts are likely attributed to chronic activation leading to increased translation and degradation. Thus, INOCA could result from stimulation of B cell, pcDC, invariant T cell, and neutrophil activation that compromises cardiac microvascular function.

Biomarker profiles associated with reverse ventricular remodelling in patients with heart failure and a reduced ejection fraction: Insights from the echocardiographic substudy of the VICTORIA trial.

AIMS: Reverse ventricular remodelling, defined as a decrease in left ventricular end-systolic volume indexed to body surface area (LVESVI) or an increase in left ventricular ejection fraction (LVEF), is associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying pathophysiological mechanisms remain unclear. METHODS AND RESULTS: We evaluated paired core-lab assessed echocardiograms and measurements of 92 biomarkers at baseline and 8 months thereafter in 419 participants with HFrEF. Reverse ventricular remodelling was defined as a >5% LVEF increase or >15% LVESVI relative decrease between baseline and 8 months. We evaluated the association between baseline biomarkers and their changes with reverse ventricular remodelling in the prospectively randomized controlled VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial. Of 419 patients (median age 66 [interquartile range 57-74] years, 27.4% women), 206 (49.2%) had reverse ventricular remodelling (either a 5% LVEF increase or a 15% LVESVI decrease). There were no differences in baseline biomarker concentrations between patients with versus those without reverse ventricular remodelling on follow-up. However, in patients with reverse ventricular remodelling there were significant decreases in biomarkers relating to inflammation and cardiac metabolism; particularly the tumour necrosis factor superfamily member 13B (ratio 0.82, 95% confidence interval [CI] 0.77-0.88), growth differentiation factor-15 (ratio 0.74, 95% CI 0.66-0.84), and insulin-like growth factor binding protein 7 (ratio 0.80, 95% CI 0.73-0.88). CONCLUSIONS: Reverse ventricular remodelling in patients with HFrEF is associated with a decrease of biomarkers related to inflammation and cardiac metabolism.

Dynamic Risk Estimation of Adverse Events in Ambulatory LVAD Patients: A MOMENTUM 3 Analysis.

BACKGROUND: Hemocompatibility-related adverse events affect patients after left ventricular assist device (LVAD) implantation but are hard to predict. OBJECTIVES: Dynamic risk modeling with a multistate model can predict risk of gastrointestinal bleeding (GIB), stroke, or death in ambulatory patients. METHODS: This was a secondary analysis of the MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial. HeartMate 3 LVAD recipients who survived to hospital discharge and were followed for up to 2 years. A total of 145 variables were included in the multistate model with multivariate logistic regression. Model performance was assessed with the area under the curve in a holdout validation cohort. A risk stratification tool was created by dividing patients into categories of predicted risk using the final model variables and associated OR. RESULTS: Among 2,056 LVAD patients, the median age was 59.4 years (20.4% women, 28.6% Black). At 2 years, the incidence of GIB, stroke, and death was 25.6%, 6.0%, and 12.3%, respectively. The multistate model included 39 total variables to predict risk of GIB (16 variables), stroke (10 variables), and death (19 variables). When ambulatory patients were classified according to their risk category, the 30-day observed event rate in the highest risk group for GIB, stroke, or death was 26.9%, 1.8%, and 4.8%, respectively. The multistate model predicted GIB, stroke, and death at any 30-day period with an area under the curve of 0.70, 0.69, and 0.86, respectively. CONCLUSIONS: The multistate model informs 30-day risk in ambulatory LVAD recipients and allows recalculation of risk as new patient-specific data become available. The model allows for accurate risk stratification that predicts impending adverse events and may guide clinical decision making. (MOMENTUM 3 IDE Clinical Study Protocol; NCT02224755).

Mechanisms of Medial Wall Thinning in Chronic Total Occlusion.

BACKGROUND: The success rate of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is lower and the risk for complications higher compared with other non-CTO PCI. Although interventionalists focus on intimal plaque characteristics, the coronary media is an important (especially for techniques involving antegrade dissection and re-entry) but poorly understood structure in CTO PCI. OBJECTIVES: The aim of the present study was to investigate coronary medial wall thinning in CTO lesions and determine how this thinning might affect CTO PCI. METHODS: A total of 2,586 sections were investigated, from arteries with evidence of CTO from 54 subjects (1,383 sections) and arteries without evidence of CTO from 54 subjects with non-coronary-related deaths (1,203 sections) after matching for age, gender, body weight, and body height. RESULTS: The medial thickness in subjects with CTO was lower than that in those with non-coronary-related death (P < 0.001). In subjects with CTO, CTO lesions had thinner medial walls compared with those with lower luminal narrowing (P < 0.001). At the CTO distal segments, the 6- to 12-mm distal segment from the distal end of the CTO had significantly less luminal narrowing (P < 0.001), and similar medial thickness, compared with the distal end of the CTO. Immunohistochemical analysis revealed that short-duration CTO had more cleaved caspase-3-positive cells in media and had significantly more CD3+, CD4+, CD8+, and CD4+CD28null T cells compared with long-duration CTO. CONCLUSIONS: CTO lesions demonstrated coronary medial thinning compared with non-CTO lesions. Further investigation of the cause-and-effect relationship among inflammation, apoptosis, and coronary medial wall thinning is warranted in future mechanistic studies.

The scaffold protein disabled 2 (DAB2) and its role in tumor development and progression.

BACKGROUND: Disabled 2 (DAB2) is a multifunctional protein that has emerged as a critical component in the regulation of tumor growth. Its dysregulation is implicated in various types of cancer, underscoring its importance in understanding the molecular mechanisms underlying tumor development and progression. This review aims to unravel the intricate molecular mechanisms by which DAB2 exerts its tumor-suppressive functions within cancer signaling pathways. METHODS AND RESULTS: We conducted a comprehensive review of the literature focusing on the structure, expression, physiological functions, and tumor-suppressive roles of DAB2. We provide an overview of the structure, expression, and physiological functions of DAB2. Evidence supporting DAB2's role as a tumor suppressor is explored, highlighting its ability to inhibit cell proliferation, induce apoptosis, and modulate key signaling pathways involved in tumor suppression. The interaction between DAB2 and key oncogenes is examined, elucidating the interplay between DAB2 and oncogenic signaling pathways. We discuss the molecular mechanisms underlying DAB2-mediated tumor suppression, including its involvement in DNA damage response and repair, regulation of cell cycle progression and senescence, and modulation of epithelial-mesenchymal transition (EMT). The review explores the regulatory networks involving DAB2, covering post-translational modifications, interactions with other tumor suppressors, and integration within complex signaling networks. We also highlight the prognostic significance of DAB2 and its role in pre-clinical studies of tumor suppression. CONCLUSION: This review provides a comprehensive understanding of the molecular mechanisms by which DAB2 exerts its tumor-suppressive functions. It emphasizes the significance of DAB2 in cancer signaling pathways and its potential as a target for future therapeutic interventions.

CD163+ Macrophages Induce Endothelial-to-Mesenchymal Transition in Atheroma.

BACKGROUND: Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163+ macrophages. Here, we explored the hypothesis that CD163+ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap. METHODS: Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone ApoE-/- and ApoE-/-/CD163-/- mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments. RESULTS: In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163+ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa ß) signaling by proinflammatory cytokines released from CD163+ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163+ macrophage-induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes. CONCLUSIONS: CD163+ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.

Evaluation of the Hemocompatibility of the Direct Oral Anticoagulant Apixaban in Left Ventricular Assist Devices: The DOAC LVAD Study.

BACKGROUND: Patients receiving left ventricular assist device (LVAD) support require long-term anticoagulation to reduce the risk of thromboembolic complications. Apixaban is a direct oral anticoagulant that has become first-line therapy; however, its safety in LVAD recipients has not been well described. OBJECTIVES: This study sought to investigate whether, in patients with a fully magnetically levitated LVAD, treatment with apixaban would be feasible and comparable with respect to safety and freedom from the primary composite outcome of death or major hemocompatibility-related adverse events (HRAEs) (stroke, device thrombosis, major bleeding, aortic root thrombus, and arterial non-central nervous system thromboembolism) as compared with treatment with warfarin. METHODS: The DOAC LVAD (Evaluation of the Hemocompatibility of the Direct Oral Anti-Coagulant Apixaban in Left Ventricular Assist Devices) trial was a phase 2, open label trial of LVAD recipients randomized 1:1 to either apixaban 5 mg twice daily or warfarin therapy. All patients were required to take low-dose aspirin. Patients were followed up for 24 weeks to evaluate the primary composite outcome. RESULTS: A total of 30 patients were randomized: 14 patients to warfarin and 16 patients to apixaban. The median patient age was 60 years (Q1-Q3: 52-71 years), and 47% were Black patients. The median time from LVAD implantation to randomization was 115 days (Q1-Q3: 56-859 days). At 24 weeks, the primary composite outcome occurred in no patients receiving apixaban and in 2 patients (14%) receiving warfarin (P = 0.12); these 2 patients experienced major bleeding from gastrointestinal sources. CONCLUSIONS: Anticoagulation with apixaban was feasible in patients with an LVAD without an excess of HRAEs or deaths. This study informs future pivotal clinical trials evaluating the safety and efficacy of apixaban in LVAD recipients. (Evaluation of the Hemocompatibility of the Direct Oral Anti-Coagulant Apixaban in Left Ventricular Assist Devices [DOAC LVAD]; NCT04865978).

Cardiac Reverse Remodeling Mediated by HeartMate 3 Left Ventricular Assist Device: Comparison to Older Generation Devices.

Currently, the fully magnetically levitated left ventricular assist device (LVAD) HeartMate 3 (HM3) is the only commercially available device for advanced heart failure (HF) patients. However, the left ventricular (LV) functional and structural changes following mechanical unloading and circulatory support (MCS) with the HM3 have not been investigated. We compared the reverse remodeling induced by the HM3 to older generation continuous-flow LVADs. Chronic HF patients (n = 405) undergoing MCS with HeartWare Ventricular Assist Device (HVAD, n = 115), HM3 (n = 186), and HeartMate II (HM2, n = 104) at four programs were included. Echocardiograms were obtained preimplant and at 1, 3, 6, and 12 months following LVAD implantation. There were no differences in the postimplant serial LV ejection fraction (LVEF) between the devices. The postimplant LV internal diastolic diameter (LVIDd) was significantly lower for HM2 at 3 and 6 months compared with HVAD and HM3. The proportion of patients achieving "cardiac reverse remodeling responder" status (defined as LVEF improvement to ≥40% and LVIDD ≤5.9 cm) was 11.9%, and was similar between devices. HeartMate 3 appears to result in similar cardiac reverse remodeling as older generation CF-LVADs, suggesting that the fully magnetically levitated device technology could provide an effective platform to further study and promote cardiac reverse remodeling.

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma.

Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRα and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

The International Society for Heart and Lung Transplantation (ISHLT): 2024 infection definitions for durable and acute mechanical circulatory support devices.

Infections remain a significant concern in patients receiving mechanical circulatory support (MCS), encompassing both durable and acute devices. This consensus manuscript provides updated definitions for infections associated with durable MCS devices and new definitions for infections in acute MCS, integrating a comprehensive review of existing literature and collaborative discussions among multidisciplinary specialists. By establishing consensus definitions, we seek to enhance clinical care, facilitate consistent reporting in research studies, and ultimately improve outcomes for patients receiving MCS.

Surveillance with dual noninvasive testing for acute cellular rejection after heart transplantation: Outcomes from the Surveillance HeartCare Outcomes Registry.

BACKGROUND: Molecular testing with gene-expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) is increasingly used in the surveillance for acute cellular rejection (ACR) after heart transplant. However, the performance of dual testing over each test individually has not been established. Further, the impact of dual noninvasive surveillance on clinical decision-making has not been widely investigated. METHODS: We evaluated 2,077 subjects from the Surveillance HeartCare Outcomes Registry registry who were enrolled between 2018 and 2021 and had verified biopsy data and were categorized as dual negative, GEP positive/dd-cfDNA negative, GEP negative/dd-cfDNA positive, or dual positive. The incidence of ACR and follow-up testing rates for each group were evaluated. Positive likelihood ratios (LRs+) were calculated, and biopsy rates over time were analyzed. RESULTS: The incidence of ACR was 1.5% for dual negative, 1.9% for GEP positive/dd-cfDNA negative, 4.3% for GEP negative/dd-cfDNA positive, and 9.2% for dual-positive groups. Follow-up biopsies were performed after 8.8% for dual negative, 14.2% for GEP positive/dd-cfDNA negative, 22.8% for GEP negative/dd-cfDNA positive, and 35.4% for dual-positive results. The LR+ for ACR was 1.37, 2.91, and 3.90 for GEP positive, dd-cfDNA positive, and dual-positive testing, respectively. From 2018 to 2021, biopsies performed between 2 and 12-months post-transplant declined from 5.9 to 5.3 biopsies/patient, and second-year biopsy rates declined from 1.5 to 0.9 biopsies/patient. At 2 years, survival was 94.9%, and only 2.7% had graft dysfunction. CONCLUSIONS: Dual molecular testing demonstrated improved performance for ACR surveillance compared to single molecular testing. The use of dual noninvasive testing was associated with lower biopsy rates over time, excellent survival, and low incidence of graft dysfunction.

Integrating molecular and clinical variables to predict myocardial recovery.

Mechanical unloading and circulatory support with left ventricular assist devices (LVADs) mediate significant myocardial improvement in a subset of advanced heart failure (HF) patients. The clinical and biological phenomena associated with cardiac recovery are under intensive investigation. Left ventricular (LV) apical tissue, alongside clinical data, were collected from HF patients at the time of LVAD implantation (n=208). RNA was isolated and mRNA transcripts were identified through RNA sequencing and confirmed with RT-qPCR. To our knowledge this is the first study to combine transcriptomic and clinical data to derive predictors of myocardial recovery. We used a bioinformatic approach to integrate 59 clinical variables and 22,373 mRNA transcripts at the time of LVAD implantation for the prediction of post-LVAD myocardial recovery defined as LV ejection fraction (LVEF) ≥40% and LV end-diastolic diameter (LVEDD) ≤5.9cm, as well as functional and structural LV improvement independently by using LVEF and LVEDD as continuous variables, respectively. To substantiate the predicted variables, we used a multi-model approach with logistic and linear regressions. Combining RNA and clinical data resulted in a gradient boosted model with 80 features achieving an AUC of 0.731±0.15 for predicting myocardial recovery. Variables associated with myocardial recovery from a clinical standpoint included HF duration, pre-LVAD LVEF, LVEDD, and HF pharmacologic therapy, and LRRN4CL (ligand binding and programmed cell death) from a biological standpoint. Our findings could have diagnostic, prognostic, and therapeutic implications for advanced HF patients, and inform the care of the broader HF population.

CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality.

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development-either alone, or in the context of other genetic alterations-and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation-akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC.

Utilization Practices of Inferior Vena Cava Filters at an Academic Medical Center.

INTRODUCTION:  Anticoagulation is the mainstay of management for patients with venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Inferior vena cava (IVC) filters are indicated in select patients who are not candidates for anticoagulation. There is a lack of quality evidence supporting other indications. In addition, long-term benefits and safety profiles of IVC filters have not been established. We investigated the utilization practice of IVC filters in a contemporary series of patients in a tertiary academic medical center. METHODOLOGY:  A retrospective review of 200 patients who received IVC filters at Virginia Commonwealth University (VCU) Medical Center in the years 2017 and 2018 was conducted. Adult patients 18 years of age or older with or without cancer were included, and patients were selected consecutively until data on 200 patients were collected. Data on patient demographics, an indication of IVC filter placement, filter retrieval rate, and re-thrombosis events over a median follow-up period of nine months were extracted from the electronic medical record and analyzed. RESULTS: A total of 200 patients (105 male and 95 female) were included with a median age of 61 years (range 17-92 years). Of the 200 patients, 97 (48.5%) had a DVT, 28 (14%) had a PE, 73 (36.5%) had both a PE and DVT, and 2 (1%) had thrombosis at other sites. A total of 130 (65%) patients had an IVC filter placed because of a contraindication to anticoagulation, while 70 (35%) had an IVC filter placed for other nonstandard indications, which included new or worsening VTE despite anticoagulation, recent VTE who must have anticoagulation held during surgery, primary prevention in high-risk patients, and extensive disease burden among other reasons. Seventy-two (36%) patients had active malignancy at the time of filter placement, and 64 (32%) were lost to follow-up. Of the 119 patients who were potentially eligible for filter retrieval, 55 (46%) patients had their IVC filters removed at a median of five months after insertion. Of the 55 patients who had IVC filters removed, 8 (14.5%) patients experienced a re-thrombosis event within a median follow-up of 39 months. Of the 145 patients who still had their filter in place at the time of death or last follow-up, 5 (3.4%) patients experienced a re-thrombosis event within a median follow-up of three months. CONCLUSIONS:  One-third of the patients in this series had an IVC filter placed without a standard indication, and less than half of them had the IVC filters removed within one year of placement. Additionally, one-third of the patients were lost to follow-up, highlighting the need for improved structured follow-up programs and education among both patients and providers regarding the indications for placement and retrieval to minimize complications.

Sex-specific patterns of donor-derived cell-free DNA in heart transplant rejection: An analysis from the Genomic Research Alliance for Transplantation (GRAfT).

BACKGROUND: Noninvasive methods for surveillance of acute rejection are increasingly used in heart transplantation (HT), including donor-derived cell-free DNA (dd-cfDNA). As other cardiac biomarkers differ by sex, we hypothesized that there may be sex-specific differences in the performance of dd-cfDNA for the detection of acute rejection. The purpose of the current study was to examine patterns of dd-cfDNA seen in quiescence and acute rejection in male and female transplant recipients. METHODS: Patients enrolled in the Genomic Research Alliance for Transplantation who were ≥18 years at the time of HT were included. Rejection was defined by endomyocardial biopsy with acute cellular rejection (ACR) grade ≥2R and/or antibody-mediated rejection ≥ pAMR 1. dd-cfDNA was quantitated using shotgun sequencing. Median dd-cfDNA levels were compared between sexes during quiescence and rejection. The performance of dd-cfDNA by sex was assessed using area under the receiver operator characteristic (AUROC) curve. Allograft injury was defined as dd-cfDNA ≥0.25%. RESULTS: One hundred fifty-one unique patients (49 female, 32%) were included in the analysis with 1,119 available dd-cfDNA measurements. Baseline characteristics including demographics and comorbidities were not significantly different between sexes. During quiescence, there were no significant sex differences in median dd-cfDNA level (0.04% [IQR 0.00, 0.16] in females vs 0.03% [IQR 0.00, 0.12] in males, p = 0.22). There were no significant sex differences in median dd-cfDNA for ACR (0.33% [0.21, 0.36] in females vs 0.32% [0.21, 1.10] in males, p = 0.57). Overall, median dd-cfDNA levels were higher in antibody-mediated rejection (AMR) than ACR but did not significantly differ by sex (0.50% [IQR 0.18, 0.82] in females vs 0.63% [IQR 0.32, 1.95] in males, p = 0.51). Elevated dd-cfDNA detected ACR/AMR with an AUROC of 0.83 in females and 0.89 in males, p-value for comparison = 0.16. CONCLUSIONS: There were no significant sex differences in dd-cfDNA levels during quiescence and rejection. Performance characteristics were similar, suggesting similar diagnostic thresholds can be used in men and women for rejection surveillance.

Contemporary approach to cardiogenic shock care: a state-of-the-art review.

Cardiogenic shock (CS) is a time-sensitive and hemodynamically complex syndrome with a broad spectrum of etiologies and clinical presentations. Despite contemporary therapies, CS continues to maintain high morbidity and mortality ranging from 35 to 50%. More recently, burgeoning observational research in this field aimed at enhancing the early recognition and characterization of the shock state through standardized team-based protocols, comprehensive hemodynamic profiling, and tailored and selective utilization of temporary mechanical circulatory support devices has been associated with improved outcomes. In this narrative review, we discuss the pathophysiology of CS, novel phenotypes, evolving definitions and staging systems, currently available pharmacologic and device-based therapies, standardized, team-based management protocols, and regionalized systems-of-care aimed at improving shock outcomes. We also explore opportunities for fertile investigation through randomized and non-randomized studies to address the prevailing knowledge gaps that will be critical to improving long-term outcomes.