Citations

Abstract Aims Native T1 times from T1 mapping cardiac magnetic resonance (CMR) are associated with myocardial fibrosis in aortic stenosis (AS). We investigated whether changing patterns in native T1 predict clinical outcomes after aortic valve replacement (AVR) in severe AS patients. Methods and results Forty-three patients with severe AS (65.9 ± 8.1 years; 24 men) who underwent T1 mapping CMR at baseline and 1 year after AVR were prospectively enrolled. Upper limit of native T1 from healthy volunteers was used to define normal myocardium and diffuse fibrosis (native T1 < 1208.4 and ≥1208.4 ms, respectively). Participants were categorized into Group 1 (pre- and post-AVR normal myocardium; n = 11), Group 2 (pre-AVR diffuse fibrosis and post-AVR normal myocardium; n = 18), and Group 3 (post-AVR diffuse fibrosis; n = 14). Native T1 significantly decreased 1 year after AVR (pre-AVR, 1233.8 ± 49.7 ms; post-AVR, 1189.1 ± 58.4 ms; P < 0.001), which was associated with left ventricular (LV) mass regression (△native T1 vs. △LV mass index, r = 0.454, P = 0.010) and systolic function improvement (△native T1 vs. △LV ejection fraction, r = −0.379, P = 0.012). Group 2 showed greater functional improvements, whereas these benefits were blunted in Group 3. Group 3 had significantly worse outcomes than Group 1 [hazard ratio (HR), 9.479, 95% confidence interval (CI) 1.176–76.409; P = 0.035] and Group 2 (HR 3.551, 95% CI 1.178–10.704; P = 0.024). Conclusion AVR-induced changes in native T1 values are associated with LV systolic functional changes as well as prognosis in severe AS. Post-AVR T1 mapping CMR can be used as an imaging biomarker.

Background: We aim to study the incidence of major complications related to procedure defined as in-hospital death, myocardial infarction, stroke, pericardial effusion or tamponade, percutaneous coronary intervention due to iatrogenic coronary dissection, or unplanned bypass surgery within 72 hours after diagnostic left heart catheterization (LHC; primary end point). Furthermore, all causes of in-hospital death after LHC were adjudicated and reported (secondary end point). Methods and Results: Diagnostic LHC procedures (aortic angiography; coronary, including graft, angiography; and left ventricular angiography) from January 1, 2002, through December 31, 2013, were identified using the clinical scheduling system at Mayo Clinic, Rochester, and complications were identified through electronic records. International Classification of Diseases, Ninth Revision billing codes were used. Registration was queried to identify all-cause mortality. All events were reviewed and adjudicated. There were 43 786 diagnostic LHC procedures; 97.3% were coronary angiograms. The mean age of patients was 64.5 years (13.6), and the majority were male (61.5%). Primary end point was seen in 36 (0.082%) procedures or 8.2 of 10 000 LHCs. Combined right sided procedures with LHC did not increase the risk of major complications. Cardiogenic and septic shock, cardiac arrhythmia, and postsurgical complication were the most common causes of in-hospital death after LHC. Conclusions: The overall rates of major complications related to diagnostic cardiac catheterization procedures are extremely rare. The majority of the deaths occurring post-diagnostic LHC procedures were secondary to acute illness rather than directly related to diagnostic procedure.

Abstract Introduction: Cryoanalgesia has been applied to minimally invasive repair of pectus excavatum (MIRPE). After implementation of cryoanalgesia at our institution, we had several cases of delayed postoperative pneumothorax. The purpose of this study was to critically evaluate the complications and efficacy of cryoanalgesia in MIRPE. Materials and Methods: We performed a single institution retrospective review of pediatric patients undergoing MIRPE from June 2017 to July 2018. Multimodal (MM) analgesia was used in all patients. In addition, most patients received either cryoanalgesia or elastomeric pain pumps (EPPs) as adjuncts to postoperative analgesia. Primary outcome was clinically significant late pneumothorax. Secondary outcomes included length of stay, pain scores, opiate use, and bar displacement requiring reoperation. Results: A total of 101 patients undergoing MIRPE were included: 45 had cryoanalgesia + MM, 45 EPP + MM, and 11 MM alone. Postoperative tube thoracostomy was placed in 5 patients with cryoanalgesia (4 pneumothorax; 1 effusion), 1 patient with EPP (1 pneumothorax), and none in MM alone ( P = .25). Pain scores at discharge were similar in all groups. Cryoanalgesia patients received less overall inpatient opioids than other groups ( P < .05). No patient required reoperation for bar displacement. Conclusion: Cryoanalgesia is an effective therapy for pain control in MIRPE. Because thermal injury can occur on the lung and chest wall with cryoanalgesia, we implemented techniques to limit and prevent this injury. Cryoanalgesia offers a safe alternative for postoperative analgesia with significant reduction in inpatient opioid requirement. Larger prospective studies are required to assess the long-term impact and complications of cryoanalgesia.

Significance Statement Targeting plasma cells to reduce the risk of antibody-mediated rejection and decreased allograft survival due to anti-HLA donor-specific antibodies has not been explored in transplantation. After sensitizing eight rhesus macaques with two sequential mismatched skin allografts, the authors desensitized four with daratumumab (anti-CD38 mAb) and plerixafor (anti-CXCR4) before transplant. Compared with controls, the daratumumab-treated animals had significantly reduced donor-specific antibody levels and prolonged renal graft survival; however, this reduction was not maintained. Two patients treated with daratumumab—one with therapy-resistant acute kidney antibody-mediated rejection and a highly sensitized heart transplant candidate—exhibited a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and heart graft access. These findings suggest daratumumab merits investigation as a potential therapeutic strategy, although further research is needed. Background Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production. Methods To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant. Results The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P <0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P <0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell–mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access. Conclusions Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.

ObjectiveTo assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Vasculitis (RAVE) trial and identify novel potential risk factors.MethodsVTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA‐associated vasculitis (AAV).ResultsVTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0–2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247–134.842]; P = 0.006), positive proteinase 3 (PR3)–ANCA (HR 7.731 [95% CI 1.021–58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448–10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491–69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566–185.805]; P = 0.005), PR3‐ANCA (HR 9.12 [95% CI 1.158–71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453–10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607–75.075]; P < 0.001) remained.ConclusionPatients diagnosed as having AAV with pulmonary hemorrhage, positive PR3‐ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.

The possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) and inflammation has been suggested, but the molecular mechanisms underlying this link, especially during atherogenesis, remain unclear. In endothelial cells (ECs) exposed to disturbed flow (d-flow), p90 ribosomal S6 kinase (p90RSK) bound to MAGI1, causing MAGI1-S741 phosphorylation and sentrin/SUMO-specific protease 2 T368 phosphorylation-mediated MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation upregulated EC activation via activating Rap1. MAGI1-K931 deSUMOylation induced both nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, which accelerated EC activation and apoptosis, respectively. Microarray screening revealed key roles for MAGI1 in the endoplasmic reticulum (ER) stress response. In this context, MAGI1 associated with activating transcription factor 6 (ATF-6). MAGI1 expression was upregulated in ECs and macrophages found in atherosclerotic-prone regions of mouse aortas as well as in the colonic epithelia and ECs of patients with inflammatory bowel disease. Further, reduced MAGI1 expression in Magi1 –/+ mice inhibited d-flow–induced atherogenesis. In sum, EC activation and ER stress–mediated apoptosis are regulated in concert by two different types of MAGI1 posttranslational modifications, elucidating attractive drug targets for chronic inflammatory disease, particularly atherosclerosis.

Background: Hemodynamic performance of prostheses after transcatheter aortic valve replacement (TAVR) is generally better than after surgical aortic valve replacement (SAVR), especially in patients with a small native annulus size. However, it remains unclear whether differences are consistent for patients with a different propensity for developing prosthesis-patient mismatch (PPM), considering annulus size and body size of patients. Methods and Results: The SURTAVI trial (Surgical Replacement and Transcatheter Aortic Implantation) compared TAVR using a self-expandable valve with SAVR in intermediate-risk patients. Multidetector computed tomography–based aortic annulus size consisted of the perimeter-derived diameter, which was divided by body surface area to produce an indexed annulus size. Patients were categorized into a small (9–12 mm/m 2 ), medium (>12–14 mm/m 2 ), and large (>14–18 mm/m 2 ) group according to indexed annulus size. We compared TAVR and SAVR for PPM, hemodynamics, and clinical, and functional outcomes through 1-year follow-up within the size groups. Patients who underwent TAVR received a larger prosthesis with increasing indexed annulus size ( P <0.001), while there was no difference in prosthesis size in patients who underwent SAVR ( P =0.74). Patients in all size groups had significantly larger indexed effective orifice area and lower mean gradients at discharge after TAVR versus SAVR. Rates of PPM were significantly lower with TAVR versus SAVR in all groups ( P <0.001) and declined with larger indexed annulus sizes with both TAVR ( P =0.04) and SAVR ( P =0.03). Indexed annulus size was an independent predictor of PPM after TAVR and SAVR. Clinical outcomes were comparable between TAVR and SAVR across all groups, apart from a significantly higher rate of reintervention after TAVR versus SAVR in the large indexed annulus size group (2.5% versus 0%; P =0.01) but without significant interaction ( P int =0.81). Conclusions: Rates of PPM were significantly lower after TAVR than after SAVR across all groups of indexed annulus size, reflecting better hemodynamic performance of transcatheter versus surgical valves, irrespective of the propensity to develop PPM. More attention should be directed to prevention of PPM after SAVR. This information should be considered by the Heart Team to recommend a specific procedure or valve. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01586910.