Citations

Abstract To discover lipidomic alterations during pregnancy in mothers who subsequently delivered small for gestational age (SGA) neonates and identify predictive lipid markers that can help recognize and manage these mothers, we carried out untargeted lipidomics on maternal serum samples collected between 24–28 weeks of gestation. We used a nested case-control study design and serum from mothers who delivered SGA and appropriate for gestational age babies. We applied untargeted lipidomics using mass spectrometry to characterize lipids and discover changes associated with SGA births during pregnancy. Multivariate pattern recognition software Collaborative Laboratory Integrated Reports (CLIR) was used for the post-analytical recognition of range differences in lipid ratios that could differentiate between SGA and control mothers and their integration for complete separation between the two groups. Here, we report changes in lipids from serum collected during pregnancy in mothers who delivered SGA neonates. In contrast to normal pregnancies where lysophosphatidic acid increased over the course of the pregnancy owing to increased activity of lysophospholipase D, we observed a decrease (32%; P = 0.05) of 20:4-lysophosphatidic acid in SGA mothers, which could potentially compromise fetal growth and development. Integration of lipid ratios in an interpretive tool (CLIR) could completely separate SGA mothers from controls demonstrating the power of untargeted lipidomic analyses for identifying novel predictive biomarkers. Additional studies are required for further assessment of the lipid biomarkers identified in this report.

Background: Acute cellular rejection is a major determinant of mortality and retransplantation after heart transplantation. We sought to evaluate the prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for the risk of acute cellular rejection after heart transplantation. Methods: The present study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure×hyperemic mean transit time. The primary end point was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared by using multivariable Cox proportional hazards regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of C-index, net reclassification index, and integrated discrimination index. Results: The mean age of recipients was 51.2±13.1 years (81.2% male), and the cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 versus 16.8±11.1, P =0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-U increase: adjusted hazard ratio, 1.18 [95% CI, 1.04–1.34], P =0.011) and the optimal cutoff value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% versus 3.8%; adjusted hazard ratio, 15.3 [95% CI 3.6–65.7], P <0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 versus 0.74, P <0.001; net reclassification index 1.05, P <0.001; integrated discrimination index 0.20, P <0.001). Conclusions: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02798731.

Abstract Purpose: The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors. Experimental Design: To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes. Results: We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA. Conclusions: Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.

ABSTRACT/SUMMARY Purpose Common LOXL1 protein-altering variants are significant genetic risk factors for exfoliation syndrome (XFS) and the related secondary glaucoma (XFG). A rare LOXL1 missense allele was associated with protective effects in a Japanese cohort, suggesting that other rare alleles may also exhibit protective effects. The goal of this study is to assess the contributions of rare LOXL1 variants to XFS/XFG risk in cases and controls from the United States (US). Methods LOXL1 rare variants (minor allele frequency (MAF) < 1%) were identified from Human exome BeadArray (Illumina) data for 1118 XFS/XFG cases and 3661 controls (Mass Eye and Ear (MEE) cohort) and from exome sequence data for 284 cases and 37,499 controls in All of Us (AoU) The distribution of rare variants, haplotypes, and diplotypes was examined using Fisher exact test. Results Four rare LOXL1 missense alleles, more common in controls, were identified in MEE, P= 7.6E-4), and 456 variants identified in AoU were found only in controls (P=0.045). The rare protective alleles were preferentially located (P= 5.8E-45) in a LOXL1 intrinsic disordered region (IDR) potentially involved in LOXL1 aggregation. Haplotypes that included the rare or minor variants were more common in controls compared to cases in both MEE (Odds Ratio (OR)= 0.21 (95% Confidence interval (CI): 0.19-0.24), P=1.7E-173) and AoU (OR=0.28 (95% CI: 0.23-0.34), P=4.4E-41), and heterozygous diplotypes were also significantly associated with reduced risk overall in both MEE (OR= 0.45 (95% CI: 0.52-0.39), P= 1.7E-89) and AoU (OR=0.26 (95% CI: 0.18-0.33, P=7.6E-28). Diplotypes comprised of only homozygous genotypes were associated with increased disease risk in both MEE and AoU (OR= 4.16 (95% CI: 3.60-4.76), P= 4.2E-89 and 5.26 (95% CI: 4.12-6.73), P=1.87E-42, respectively) and excess homozygosity and decreased heterozygosity was correlated with disease risk for common LOXL1 variants across multi-ethnic populations (P=1.0E-6). Conclusions Using exome array and exome sequence data from XFS/XFG cases and controls from the United States, we identified rare protective LOXL1 missense variants and show that the distribution of the corresponding haplotypes and diplotypes was associated with lower risk of XFS/XFG. Diplotype results also demonstrated that LOXL1 allelic heterozygosity was inversely associated, while homozygosity was associated with increased disease risk. These results suggest that LOXL1 MAF variation among populations, with corresponding variation in genotype heterozygosity and homozygosity, determines the XFS/XFG association.

AbstractAimsThe prognostic implication of left atrial (LA) dysfunction and left ventricular diastolic dysfunction (LVDD) in patients with coarctation of aorta (COA) is unknown. The purpose of this study was to determine whether LA dysfunction and LVDD were associated with mortality in COA patients.Methods and resultsThis is a retrospective review of adults (age ≥18 years) with repaired COA that underwent transthoracic echocardiogram (2000–18). LVDD was determined using the 2016 guidelines for LV diastolic function assessment, and LA dysfunction was assessed using LA reservoir strain. Of 721 patients, LV diastolic function could be determined in 635 (88%); and 414 (65%) had no LVDD, while 146 (23%), 53 (8%), and 22 (4%) had Grade I/II/III LVDD, respectively. The mean LA reservoir strain was 39 ± 11%, and patients were divided into quartiles: top quartile (reference group), mild LA dysfunction, moderate LA dysfunction, and severe LA dysfunction. Grade III LVDD (but not Grades I and II) was associated with death/transplant. On the other hand, there was an incremental risk of death/transplant across LA strain quartiles: mild LA dysfunction [hazard ratio (HR) 1.16, 1.04–2.06], moderate LA dysfunction (HR 1.75, 1.27–3.58), and severe LA dysfunction (HR 3.49, 1.88–7.16). Of 86 patients with indeterminate diastolic function, there was a trend towards a lower 5-year transplant-free survival in patients with LA dysfunction vs. normal LA function (83% vs. 91%, P = 0.06).ConclusionLA dysfunction (but not LVDD) was associated with incremental risk of mortality and thus can be used for prognostication in all patients including those with indeterminate diastolic function.

Objectives We investigated haemodynamics and clinical outcomes according to type of pulmonary hypertension (PH) in patients with constrictive pericarditis (CP). Background As the prevalence of CP with concomitant myocardial disease (mixed CP) grows, PH is more commonly seen in patients with CP. However, haemodynamic and outcome data according to the presence or absence of PH are limited. Methods 150 patients with surgically confirmed CP who underwent echocardiography and cardiac catheterisation within 7 days at two tertiary centres were divided into three groups: no-PH, isolated postcapillary PH (Ipc-PH) and combined postcapillary and precapillary PH (Cpc-PH). Primary outcome was all-cause mortality during follow-up. Result In this retrospective cohort study, 110 (73.3%) had PH (mean pulmonary artery pressure ≥25 mm Hg). Cpc-PH, using defined cut-offs for pulmonary vascular resistance (>3 Wood units) or diastolic pulmonary gradient (≥7 mm Hg), was seen in 18 patients (12%). The Cpc-PH group had a higher prevalence of comorbidities (diabetes and atrial fibrillation) and concomitant myocardial disease as an aetiology of CP than other groups. Pulmonary vascular resistance had a significant direct correlation with medial E/e′ by Doppler echocardiography (r=0.404, p<0.001). Survival rate was significantly lower in the Cpc-PH than the no-PH (p=0.002) and Ipc-PH (p=0.024) groups. On multivariable analysis, age, New York Heart Association functional class IV, medial e′ velocity, Cpc-PH and Ipc-PH were independently associated with long-term mortality. Conclusion Combined postcapillary and precapillary PH develops in a subset of patients with CP and is associated with long-term mortality after pericardiectomy.

Abstract Aims Spectrum bias can arise when a diagnostic test is derived from study populations with different disease spectra than the target population, resulting in poor generalizability. We used a real-world artificial intelligence (AI)-derived algorithm to detect severe aortic stenosis (AS) to experimentally assess the effect of spectrum bias on test performance. Methods and results All adult patients at the Mayo Clinic between 1 January 1989 and 30 September 2019 with transthoracic echocardiograms within 180 days after electrocardiogram (ECG) were identified. Two models were developed from two distinct patient cohorts: a whole-spectrum cohort comparing severe AS to any non-severe AS and an extreme-spectrum cohort comparing severe AS to no AS at all. Model performance was assessed. Overall, 258 607 patients had valid ECG and echocardiograms pairs. The area under the receiver operator curve was 0.87 and 0.91 for the whole-spectrum and extreme-spectrum models, respectively. Sensitivity and specificity for the whole-spectrum model was 80% and 81%, respectively, while for the extreme-spectrum model it was 84% and 84%, respectively. When applying the AI-ECG derived from the extreme-spectrum cohort to patients in the whole-spectrum cohort, the sensitivity, specificity, and area under the curve dropped to 83%, 73%, and 0.86, respectively. Conclusion While the algorithm performed robustly in identifying severe AS, this study shows that limiting datasets to clearly positive or negative labels leads to overestimation of test performance when testing an AI algorithm in the setting of classifying severe AS using ECG data. While the effect of the bias may be modest in this example, clinicians should be aware of the existence of such a bias in AI-derived algorithms.

Background: Atrial fibrillation (AF) is a low-flow state and may underestimate aortic stenosis (AS) severity. Single-high Doppler signals (HS) consistent with severe AS (peak velocity ≥4 m/s or mean gradient ≥40 mm Hg) are averaged down in current practice. The objective for the study was to determine the significance of HS in AF low-gradient AS (LGAS). Methods: One thousand five hundred forty-one patients with aortic valve area ≤1 cm 2 and left ventricular ejection fraction ≥50% were identified and classified as high-gradient AS (HGAS) (≥40 mm Hg) and LGAS (<40 mm Hg), and AF versus sinus rhythm (SR). Available computed tomography aortic valve calcium scores (AVCS) were retrieved from the medical record. Outcomes were assessed. Results: Mean age was 76±11 years, female 47%. Mean gradient was 51±12 in SR-HGAS, 48±10 in AF-HGAS, 31±5 in SR-LGAS, and 29±7 mm Hg in AF-LGAS, all P ≤0.001 versus SR-HGAS; HS were present in 33% of AF-LGAS. AVCS were available in 34%. Compared with SR-HGAS (2409 arbitrary units; interquartile range, 1581–3462) AVCS were higher in AF-HGAS (2991 arbitrary units; IQR1978–4229, P =0.001), not different in AF-LGAS (2399 arbitrary units; IQR1817–2810, P =0.47), and lower in SR-LGAS (1593 arbitrary units; IQR945–1832, P <0.001); AVCS in AF-LGAS were higher when HS were present ( P =0.048). Compared with SR-HGAS, the age-, sex-, comorbidity index-, and time-dependent aortic valve replacement-adjusted mortality risk was higher in AF-HGAS (hazard ratio=1.82 [1.40–2.36], P <0.001) and AF-LGAS with HS (hazard ratio=1.54 [1.04–2.26], P =0.03) but not different in AF-LGAS without HS or SR-LGAS (both P =not significant). Conclusions: Severe AS was common in AF-LGAS. AVCS in AF-LGAS were not different from SR-HGAS. AVCS were higher and mortality worse in AF-LGAS when HS were present.

BACKGROUND: Idiopathic recurrent pericarditis (IRP) is a debilitating condition that can be recalcitrant to conventional therapy. Some patients develop steroid dependency with the attendant risks of systemic side effects and increased future recurrence. Anakinra is a recombinant human interleukin-1 receptor antagonist that reduces systemic inflammatory responses. The aim of this study was to evaluate the therapeutic role of anakinra in IRP. Methods: We retrospectively studied consenting patients with treatment refractory IRP who received anakinra, between January 2009 and November 2013. The primary end points were symptom resolution and steroid discontinuation. Results: Nine patients were followed for a median of 16.8 (IQR 1.3-24) months. Study subjects were predominantly female (7 [78%]) with a median age of 53 (IQR 38 - 58) years. All 9 patients had failed maximum tolerated doses of NSAIDs, colchicine and prednisone (median dose 20 mg [IQR 15 - 22.5]). Primary symptom was chest pain in 9 (100%), with concurrent dyspnea in 5 (56%) patients. Symptom duration prior to anakinra initiation was 24 (IQR 13 - 71) months. Indication for anakinra was steroid sparing agent in 7 (78%) and symptom control in 2 (22%) patients. The dosage was 100 mg once daily via subcutaneous injection. Baseline LVEF was 62% (IQR 59% - 67%). Echocardiographic findings include pericardial effusion in 3 (33%), pericardial thickening in 6 (67%), and constrictive physiology in 4 (44%). Pericardial enhancement on cardiac MRI was seen in 7 (78%) patients. All 9 patients (100%) had symptom improvement with complete resolution in 8 (89%) and partial resolution in 1 (11%) patient. At last follow up, all 9 (100%) patients had discontinued NSAIDs and colchicine, 5 (56%) patients discontinued and 4 (44%) had reduced prednisone dosage. All patients remained on anakinra at the end of follow up. The only reported side effect was transient injection site reaction in 4 (44%) patients. In 2 (22%) patients, attempted anakinra weaning was unsuccessful due to symptomatic flare after 6 weeks. Conclusion: Anakinra is an effective alternative agent for the management of steroid dependent IRP. It provides remarkable symptomatic amelioration, limits steroid dependency, and is associated with minimal side effects.